Beruflich Dokumente
Kultur Dokumente
Second Edition
Surgical Management of
Edited by
Michael DAngelica MD
Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center New York, New York, USA and
First published in 2003 by M. Dunitz Ltd, United Kingdom This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK. Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017, USA. 2011 Informa UK Ltd, except as otherwise indicated. No claim to original U.S. Government works. Reprinted material is quoted with permission. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, unless with the prior written permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK, or the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (http://www.copyright.com/ or telephone 978750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. This book contains information from reputable sources and although reasonable efforts have been made to publish accurate information, the publisher makes no warranties (either express or implied) as to the accuracy or fitness for a particular purpose of the information or advice contained herein. The publisher wishes to make it clear that any views or opinions expressed in this book by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the publisher. Any information or guidance contained in this book is intended for use solely by medical professionals strictly as a supplement to the medical professionals own judgement, knowledge of the patients medical history, relevant manufacturers instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures, or diagnoses should be independently verified. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as appropriately to advise and treat patients. Save for death or personal injury caused by the publishers negligence and to the fullest extent otherwise permitted by law, neither the publisher nor any person engaged or employed by the publisher shall be responsible or liable for any loss, injury or damage caused to any person or property arising in any way from the use of this book. A CIP record for this book is available from the British Library. ISBN-13: 978-1-84184-693-4 Orders may be sent to: Informa Healthcare, Sheepen Place, Colchester, Essex CO3 3LP, UK Telephone: +44 (0)20 7017 5540 Email: CSDhealthcarebooks@informa.com Website: http://informahealthcarebooks.com/ For corporate sales please contact: CorporateBooksIHC@informa.com For foreign rights please contact: RightsIHC@informa.com For reprint permissions please contact: PermissionsIHC@informa.com
Typeset by Exeter Premedia Services Printed and bound in the United Kingdom
Contents
List of contributors Foreword Preface I ANATOMY/IMAGING/SURGICAL TECHNIQUE 1 Surgical anatomy of the liver and bile ducts
Robert Jones and Graeme J. Poston
vii x xi
1 17 24 36 46 53 63 73 81 89
18 Chemotherapy-associated hepatotoxicity
Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey
180
3 Hepatic resection
Ajay V. Maker and Michael DAngelica
192
197 208
8 Pancreatic resection
Thilo Hackert, Moritz Wente, and Markus W. Bchler
233
148
30 Liver trauma
Timothy G. John, Myrddin Rees, and Fenella K. Welsh
CONTENTS
31 Portal hypertension
Michael D. Johnson and J. Michael Henderson
280
IV PANCREAS A. Malignant
III BILE DUCTS AND GALLBLADDER A. Malignant 36 Management of advanced gallbladder cancer
Hiromichi Ito and William R. Jarnagin
439 451
37 Extrahepatic cholangiocarcinoma
Yuji Nimura
48 Chronic pancreatitis
Jakob R. Izbicki, Oliver Mann, Asad Kutup, and Kai A. Bachmann
343
49 Pancreatic injury
Demetrios Demetriades, Beat Schnriger, and Galinos Barmparas
463
470
373
Index
vi
List of contributors
Ghassan K. Abou-Alfa MD Assistant Attending, Memorial Sloan-Kettering Cancer Center, and Assistant Professor, Weill Medical College at Cornell University, New York, New York, USA Hamid Abdollahi MD Senior Resident (General Surgery), Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Ren Adam MD, PhD AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Inserm, Unit 785, and Universit Paris-Sud, UMR-S 785, Villejuif, France Steven A. Ahrendt MD Associate Professor of Surgery, University of Pittsburgh Medical Center, UPMC Passavant Cancer Center, Pittsburgh, Pennsylvania, USA Peter J. Allen MD Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Bilal Al-Sarireh MBBCh, FRS, PhD Consultant Hepatopancreatobiliary and Laparoscopic Surgeon, Swansea University, and Department of Surgery, Morristown Hospital, Swansea, UK Junichi Arita MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Kai A. Bachmann Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Galinos Barmparas Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA David L. Bartlett Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, and National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA Eliano Bonaccorsi-Riani Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Universit catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium Jason A. Breaux MD Surgical Oncology Fellow, University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, Pennsylvania, USA Murray F. Brennan Benno C. Schmidt Clinical Chair in Oncology, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Karen T. Brown MD Attending Radiologist, Memorial Sloan-Kettering Cancer Center, and Professor of Clinical Radiology, Weill Medical College at Cornell University, New York, New York, USA Richard Bryant MBBS, FRACS Royal Brisbane Hospital, Brisbane, Queensland, Australia Markus W. Bchler Department of General Surgery, University of Heidelberg, Heidelberg, Germany C. Ross Carter West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK Jooyeun Chung MD Department of Surgery, The Methodist Hospital, Houston, Texas, USA Kevin Conlon Professor of Surgery, University of Dublin, Trinity College Dublin, and Professorial Surgical Unit, Education Centre, AMNCH, Dublin, Ireland Michael DAngelica MD Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, New York, USA Dowmitra Dasgupta MD, FRCS Consultant Hepato-Pancreatico-Biliary Surgeon, Department of Upper GI Surgery, Castle Hill Hospital, Cottingham, UK Matthew P. Dearing Department of Surgery, Norfolk & Norwich University Hospital, Norwich, UK R. DeMatteo Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Demetrios Demetriades Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA Mark Duxbury Clinical Surgery, University of Edinburgh Royal Infirmary, Edinburgh, UK Stephen W. Fenwick MD, FRCS Consultant Hepatobiliary Surgeon, North Western Hepatobiliary Unit, University Hospital Aintree, Lower Lane, Liverpool, UK Yuman Fong MD Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Helmut Friess Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universitt Mnchen, Munich, Germany O. James Garden Regius Professor of Clinical Surgery, Clinical and Surgical Sciences (Surgery), University of Edinburgh, Royal Infirmary, Edinburgh, UK Thilo Hackert Department of Surgery, University of Heidelberg, Heidelberg, Germany Lisa J. Harris MD Senior Resident (General Surgery), Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA J. Michael Henderson Chief Quality Officer, Cleveland Clinic, Cleveland, Ohio, USA Stephen N. Hochwald MD Chief, Division of Surgical Oncology, University of Florida, Gainesville, Florida, USA Michael G. House MD Assistant Professor, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
vii
LIST OF CONTRIBUTORS
Lucy Hann MD Professor of Radiology, Weill Cornell Medical Center, and Director of Ultrasound Memorial Sloan-Kettering Cancer Center, New York, New York, USA Julie K. Heimbach Mayo Clinic, Rochester, Minnesota, USA Steven N. Hochwald University of Florida Medical School, Box 100286, Gainesville, FL 326100286, USA E. Hoti AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Villejuif, France, and Liver Transplant Unit, Saint Vincents University Hospital, Dublin, Ireland Shin Hwang Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea Hiromichi Ito MD Department of Surgery, Michigan State University, Lansing, Michigan, USA Kaori Ito MD Department of Surgery, Michigan State University, Lansing, Michigan, USA Jakob R. Izbicki FACS Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany William R. Jarnagin MD Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Timothy G. John MD, FRCSEd (Gen) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Michael D. Johnson MD Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA Robert Jones MB, ChB, MRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK C. Kahlert Department of Surgery, University of Heidelberg, Heidelberg, Germany Vincent Karam Centre Hpatobiliaire, Hpital Paul Brousse, Villejuif, France Steven C. Katz MD Director of Surgical Immunotherapy, Roger Williams Medical Center, Providence, Rhode Island, USA Khalid Khwaja MD Director of Kidney and Pancreas Transplantation, Senior Staff Surgeon, Lahey Clinic, Burlington, Massachusetts, USA Nancy E. Kemeny MD Memorial Sloan-Kettering Cancer Center, New York, New York, USA Jrg Kleeff Department of Surgery, Klinikum rechts der Isar, Technische Universitt Mnchen, Munich, Germany Norihiro Kokudo MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Asad Kutup Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany W. Y. Lau Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, SAR C. K. Leow Mount Elizabeth Medical Centre, Singapore, Singapore Keith D. Lillemoe MD Jay L. Grosfeld Professor and Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA Sung-Gyu Lee Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea Michael P. La Quaglia MD Department of Surgery, Pediatric Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Jan P. Lerut MD, PhD, FACS Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Universit catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium Duan Li MD Assistant Attending Radiologist, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Chung Mao Lo Professor, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China J. Peter A. Lodge MD, FRCS Professor and Clinical Director, HPB & Transplant Unit, St. James University Hospital, Leeds, UK Ajay V. Maker MD Director of Surgical Oncology, Creticos Cancer CenterAdvocate Illinois Masonic Medical Center; Departments of Surgery and Microbiology/Immunology, University of Illinois at Chicago, Chicago, Illinois, USA Masatoshi Makuuchi MD, PhD Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan Hassan Malik MD, FRCS Hepatobiliary Unit, Department of Surgery, University Hospital Aintree, Liverpool, UK Oliver Mann Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Maureen McEvoy MD Department of Surgery, Pediatric Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Colin J. McKay West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK Andr L. Mihaljevic Department of Surgery, Klinikum rechts der Isar, Technische Universitt Mnchen, Munich, Germany David M. Nagorney Mayo Clinic, Rochester, Minnesota, USA Yuji Nimura MD President, Aichi Cancer Center, Chikusaku, Nagoya, Japan Giuseppe Orlando Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St Luc Universit catholique de Louvain, Department of Abdominal and Transplantation Surgery, Brussels, Belgium
viii
LIST OF CONTRIBUTORS
Nicholas ORourke MBBS, FRACS Royal Brisbane Hospital, Brisbane, Queensland, Australia Martin Palavecino MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Purvi Y. Parikh MD Department of Surgery, Albany Medical College, Albany, New York, USA Samir Pathak MD, ChB, MSC, MRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK Henry A. Pitt MD Indiana University, Indianapolis, Indiana, USA Graeme J. Poston MS, FRCS (Eng), FRCS (Ed) Centre for Digestive Diseases, University Hospital Aintree, and Department of Surgery, The Royal Liverpool University Hospitals, Liverpool, UK Derek G. Power MD Memorial Sloan-Kettering Cancer Center, New York, New York, USA Myrddin Rees MS, FRCS, FRCS (Ed) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Michael Rhodes Department of Surgery, Norfolk & Norwich University Hospital, Norwich, UK Charles B. Rosen Mayo Clinic, Rochester, Minnesota, USA Gerardo Sarno MD Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK Rajesh Satchidanand MD, FRCS Clinical Fellow, North Western Hepatobiliary Centre, Aintree University Hospital, Liverpool, UK Beat Schnriger Division of Trauma and Surgical Critical Care, University of Southern California, Los Angeles, California, USA Lawrence H. Schwartz Department of Radiology, Columbia University College of Physicians and Surgeons, and Radiologist-in-Chief, New YorkPresbyterian Hospital/ Columbia University Medical Center, New York, New York, USA Margo Shoup MD, FACS Chief, Division of Surgical Oncology, Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA Jason K. Sicklick Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Steven M. Strasberg MD, FRCS(C), FACS, FRCS (Ed) Pruett Professor of Surgery and Head Hepato-Pancreato-Biliary and Gastrointestinal Surgery, Washington University in Saint Louis and Barnes-Jewish Hospital, Saint Louis, Missouri, USA Jason W. Smith MD Chief Resident, Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA Nick Stern Consultant Gastroenterologist, Digestive Diseases Department, University Hospital Aintree, Liverpool, UK Richard Sturgess Consultant Gastroenterologist and Clinical Director, Digestive Diseases Department, University Hospital Aintree, Liverpool, UK Adriano Tocchi Head of 1st Department of Surgery and Chief of the Gastro-intestinal and Hepato-biliary Surgical Service, University of Rome Sapienza Medical School, Rome, Italy Ludovic Trinquart Department of Radiology, Assistance-Publique Hpitaux de Paris, Hpital Beaujon, Clichy, France Bernard Van Beers Department of Radiology, Assistance-Publique Hpitaux de Paris, Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche biomdicale Bichat-Beaujon, Paris, France Jean-Nicolas Vauthey MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Valrie Vilgrain Department of Radiology, Assistance-Publique Hpitaux de Paris, Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche biomdicale Bichat-Beaujon, Paris, France Vanessa de Villa Assistant Professor, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China J. Weitz MD Department of Surgery, University of Heidelberg, Heidelberg, Germany Fenella K. S. Welsh MA, MD, FRCS (Gen Surg) Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK Moritz Wente Department of Surgery, University of Heidelberg, Heidelberg, Germany Vincent Kah Hume Wong MBCB, MRCS Research Fellow in Hepatopancreatobiliary & Transplant Surgery, HPB & Transplant Unit, St. James University Hospital, Leeds, UK A. Peter Wysocki Department of Surgery, Logan Hospital, Meadowbrook, Queensland, Australia Charles J. Yeo MD The Samuel D. Gross Professor and Chair, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Daria Zorzi MD Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
ix
Foreword
As recent progress in hepato-pancreato-biliary (HPB) surgery has been evident since the first edition of this book was published eight years ago, Dr. Graeme Poston, Dr. Mike DAngelica, and Dr. Ren Adam, internationally recognized authorities in HPB surgery, have attempted to rewrite the second edition, joined by selected numerous worldwide specialists renowned as expert authors in each field to present a current view of the surgical and non-surgical management of benign and malignant HPB disorders. This book demonstrates the wisdom of the new knowledge and technical skills of these diverse disciplines where cooperative efforts contribute toward the benefit of the patients with HPB disorders. The general surgeon will find this volume to be a useful source of current thoughts on how to manage the diverse HPB diseases. Yuji Nimura MD President, Aichi Cancer Center Professor Emeritus, Nagoya University Graduate School of Medicine Past President, International Hepato-Pancreato-Biliary Association (IHPBA)
Preface
Hepato-pancreato-biliary (HPB) surgery is now firmly established within the repertoire of modern general surgery. Indeed, in many major tertiary centers there are now specific teams for both pancreatic and liver surgery. However, in most hospitals outside these major centers the day-to-day management and decision-making for patients with these disorders remains the remit of the general surgeon. Following the launch of the highly successful first edition of this book eight years ago there have been considerable advances in the surgical management of HPB disorders. Many of these relate to related specialties (radiology, oncology, gastroenterology, and anesthesia) and also directly to surgery (liver transplantation, caval bypass and replacement, laparoscopic surgery to name but a few). As such the second edition has been completely rewritten from scratch. As with the first edition, the purpose of this edition is twofold. First, it is intended to cover the spectrum of common HPB diseases that will confront the general surgeon in his or her regular practice. Second, we hope that this work will be sufficiently comprehensive to cover the broad spectrum of HPB surgery for candidates coming to examinations at the completion of surgical training. We are indebted to the many international contributors for their perseverance and patience over the gestation of this project, which is greatly appreciated. Lastly, we are grateful to our publishers, Informa Healthcare, for their help during the preparation of this project. Graeme J. Poston Michael DAngelica Ren Adam September 2010
xi
Surgical anatomy of the liver and bile ducts Robert Jones and Graeme J. Poston
lobar anatomy (2). The first successful elective liver resection was performed two years later by von Langenbuch, who excised a portion of the left lobe of the liver containing an adenoma in 1888 (9). He had to reopen the abdomen several hours after the operation because of reactionary hemorrhage, but was able to ligate the bleeding vessels and return the oversewn liver to the abdomen. Two years later in 1890, the Baltimore surgeon McLane Tiffany reported the successful removal of a benign liver tumor (10), and the following year Lucke described the successful resection of a cancerous growth of the liver (11). Surgery was now becoming a recognized treatment for liver pathology. Advances in surgery closely mirrored increased understanding of the functional anatomy of the liver (1214). The first attempt to define the functional anatomy of the liver, which could possibly guide current surgical practice, was made by Cantlie in 1898, while working in Hong Kong. He dissected the livers of executed prisoners (15) and making vascular casts, he demonstrated that the main division between the right and left lobe in fact extended from approximately the gallbladder fossa, to the right side of the IVC, posterosuperiorly. Cantlies line, therefore, follow a line drawn from the gallbladder fossa, along the middle hepatic vein, to the IVC (Figs. 1.2 and 1.3) (3). In 1911, Wendel reported the first case of right lobectomy for a primary tumor (16), however this procedure did not follow the precise anatomical plane described by Cantlie. In 1939, while working in Paris, the Vietnamese surgeon Ton That Tung described the venous drainage of the liver in relation to the true lobar anatomy (Fig. 1.4) (17). The first anatomically correct description of a left lateral segmentectomy was made by Raven in 1948 while resecting metastatic colon cancer (18). Four years later, Lortat-Jacob and Robert finally described a similar approach to the true right hepatic lobectomy, based on the anatomical principles described by Cantlie (Fig. 1.6) (19). Healey and Schroy were the first to demonstrate in 1953 that the right lobe was further divided into an anterior and a posterior sector (20). They also showed that the left lobe was divided into a medial and lateral sector by the line of the falciform ligament and umbilical vein (Fig. 1.5). Understanding of the functional anatomy of the liver continued to develop, and in 1957, Goldsmith and Woodburne described a number of anatomical planes through the liver parenchyma that followed this functional anatomy. Their paper finally defined true right lobectomy (right hepatectomy), left lobectomy (left hepatectomy), and left lateral segmentectomy (Fig. 1.6) (21).
The success of any surgical intervention on the liver and bile ducts is totally dependent on a thorough working knowledge of their anatomy. As the number of patients undergoing hepatobiliary surgery is increasing, good understanding of the anatomy of this area is increasingly important for any surgeon with an interest in the gastrointestinal tract. Command of this anatomy is also essential for the successful interpretation of functional imaging of hepatobiliary anatomy. When operating on the liver and biliary tree, the surgeon has to obey three basic tenets.
Remove all pathologically involved tissue. Preserve the maximal amount of functioning nonpathological liver tissue. Perform safe resection, while ensuring adequate blood supply to the remaining hepatic parenchyma.
Historically, the liver was described according to its morphological appearance (1,2). However, these three tenets have altered the approach to surgery, and the liver is now considered from a functional and therefore surgical perspective.
morphological anatomy
Historically, when viewed at laparotomy, the liver appears divided into a larger right lobe, and a smaller left lobe by the umbilical fissure and falciform ligament (Figs. 1.1 and 1.2) (3). Situated on the inferior surface of the right lobe is the transverse hilar fissure, which constitutes the posterior limit of the right lobe. The quadrate lobe was defined as the portion of the right lobe lying anterior to this transverse hilar fissure and to the right of the umbilical fissure, its other margin being defined by the gallbladder fossa. The caudate lobe, which is anatomically and functionally separate from the rest of the liver, lies posterior to the hilum, between the portal vein and the inferior vena cava (IVC) (4). This historical anatomical approach does not consider the vasculature or biliary drainage of the liver and is of only limited use when planning surgical resection.
IVC Right free border of lesser omentum Figure 1.1 Morphological anatomy.
Umbilical ssure
Quadrate lobe
supply (inflow and outflow), and therefore viability, to the remaining hepatic parenchyma. The description of Couinaud is the most complete and exact, and also the most useful for the operating surgeon, and therefore it is this description that will be used throughout this book.
Couinaud, who in 1957 produced a huge number of vasculobiliary casts of the liver (23,24). Couinaud was able to demonstrate that the liver appeared to consist of eight anatomical segments, each of which could potentially be separately resected without affecting the physiological viability of the other segments. Couinaud redefined the caudate lobe as segment 1 and Goldsmith and Woodburnes left lobe as segments 2 and 3. The quadrate lobe was termed segment 4, and more recently has been subdivided by further studies of its portal blood supply into 4A (superiorly) and 4B (inferiorly). The right liver consists of segments 5 (anteroinferiorly), 6 (posteroinferiorly), 7 (posterosuperiorly), and 8 (anterosuperiorly) (Fig. 1.7). Couinaud later suggested a further clarification, in which the caudate lobe to the left of the IVC remained segment 1, with that to the right being redefined as segment 9 (25). Resections based on these anatomical segments enable the surgeon to safely operate following the three central tenets described above; remove all pathologically involved tissue, preserve the maximal amount of nonpathological liver tissue, and perform safe resection, while ensuring an adequate blood
These anatomical studies of the functional anatomy of the liver allow us to define hepatic segments based upon both the distribution of the portal pedicles and the drainage of the hepatic veins (Fig. 1.5). The three main hepatic veins (right, middle, and left) divide the liver into four sectors, each of which receives a portal pedicle containing branches of the hepatic artery, hepatic duct, and portal vein; thus producing an alternation between hepatic veins and portal pedicles. These four sectors, demarcated by the hepatic veins, are the portal sectors, each sector therefore receiving an independent portal supply. For the same reason, the scissurae containing the hepatic veins are termed the portal scissurae while the scissurae containing portal pedicles are the hepatic scissurae (Fig. 1.5). Thus, the liver is divided by the main portal scissura along the line of the middle hepatic vein into two discrete hemilivers, along the line previously described by Cantlie (15). We therefore refer to these hemilivers as right and left livers, rather than right and left lobes, to avoid confusion with the anatomical lobes, particularly since there is no visible surface marking that permits individualization of the true lobes. As described by Cantlie, the main portal scissura runs posteriorly from the middle of the gallbladder fossa to the right side of the IVC (Fig. 1.5). Therefore, the right and left livers, demarcated by the main portal scissura, are independent in terms of their portal and arterial vascularization and their biliary drainage. These right and left livers are both further divided into two by the other two portal scissurae, delineated by the right and left hepatic veins. Goldsmith and Woodburne refer to these further divisions as segments (21), but for the rest of this book, we will use the more generally accepted nomenclature of Couinaud, which refers to these divisions as sectors (23). The
Right inferior hepatic vein (variable) IVC Gallbladder, note that the middle vein may lie supercially in the gallbladder fossa Figure 1.4 Venous drainage of the liver.
IVC
Middle hepatic vein in main portal scissura following Cantlie's line Left hepatic vein in left portal scissura Lateral segment of left lobe
2 8 1 4
Falciform ligament 6 5 Medial segment of left lobe Right anterior sector Right liver Portal vein Left liver
right liver is divided by the right portal scissura (right portal vein) into an anteromedial (or anterior) sector containing segments 5 inferiorly and 8 superiorly, and a posterolateral (or posterior) sector containing segments 6 inferiorly and 7 superiorly (Fig. 1.5). When the liver lies in its normal position within the upper abdominal cavity, the right posterolateral sector lies directly behind the right anteromedial sector, and this scissura is therefore almost in the coronal plane. Therefore in the clinical setting (particularly when imaging the liver), it is better to speak of these anterior and posterior sectors (Fig. 1.5). The exact location of the right portal scissura is imprecise, because it has no external landmarks. According to Couinaud (23), it extends from the edge of the liver at the middle point between the back of the liver and the right side of the
gallbladder bed along the right hepatic vein posteriorly to the confluence of the right hepatic vein and the IVC (2628). The venous drainage of the right liver is variable in that, in addition to the right and middle hepatic veins, there are often a number of smaller hepatic veins draining directly into the IVC from segments 6 and 7. Not infrequently (6368%) segment 6 drains directly into the IVC through a distinct inferior right hepatic vein, larger than these other venous tributaries to the IVC, which can be a significant bonus in the preservation of residual hepatic function when undertaking extended left hepatectomies (Fig. 1.4) (29,30). The left portal scissura, along the left hepatic vein, divides the left liver into two sectors: an anterior sector containing segments 3 and 4 and a posterior sector containing segment 2
(A)
(B)
(C)
(D)
(E) Figure 1.6 Formal hepatectomies: (A) right hepatectomy; (B) left hepatectomy; (C) left lateral segmentectomy; (D) extended left hepatectomy; (E) extended right hepatectomy.
8 8 7 2 1 5 6 6 4 3 5 4 7 1
(A)
(B)
Figure 1.7 Functional division of the liver and of the liver segments according to Couinauds nomenclature (A) as seen in the patient and (B) in the ex vivo position.
(A)
(B)
(C)
(D)
(E) Figure 1.8 Other hepatic sectorectomies: (A) right posterior sectorectomy; (B) right anterior sectorectomy; (C) left medial sectorectomy (segments 4A and 4B); (D) right inferior hepatectomy; (E) right superior hepatectomy.
of the main portal branch to segment 2. At this point, the left branch of the portal vein turns forward and caudally in the recessus of Rex (23) (Figs. 1.12 and 1.13). As the duct draining segment 3 begins its posterior course it lies superficially in the umbilical fissure, often immediately under Glissons capsule. As such it is usually easily accessible at surgery to allow a biliary enteric (segment 3 hepaticojejunostomy) anastomosis for biliary drainage if such access is not possible at the porta hepatis. The left hepatic duct then passes beneath the left liver at the posterior base of segment 4, lying just above and behind the left branch of the portal vein. After the left duct crosses the anterior edge of that vein it joins the right hepatic duct to form the common duct at the hepatic ductal confluence. In this transverse portion, where it lies below the liver parenchyma, it receives one to three small branches from segment 4 (23). The right hepatic duct (Fig. 1.14) drains segments 5 to 8 and arises from the convergence of the two main sectoral (anterior 5 and 8, and posterior 6 and 7) tributaries. The right posterior sectoral duct runs almost horizontally (26) and comprises the confluence of the ducts from segments 6 and 7 (Fig. 1.15). The right posterior duct joins the right anterior sectoral duct (formed by the confluence of the ducts from segments 5 and 8)
Figure 1.9 Completion of segment 4 resection with portal bifurcation lying inferiorly in front of the inferior vena cava.
Figure 1.11 Exposing the hilar plate by raising the inferior surface of segment 4B, thus demonstrating the condensation of Glissons capsule, which will cover the extra hepatic confluence of the right and left hepatic ducts.
Figure 1.10 Left lateral segmentectomy immediately prior to division of the portal structure lying inferiorly and the left hepatic vein lying superiorly.
Figure 1.12 Exposing the recessus of Rex by distraction of the falciform ligament to demonstrate the bifurcation of segment 3 and segment 4 bile ducts.
RHD RHA
4 (ant.) CHD 3
PV
HA
Recessus of Rex
Figure 1.13 Biliary and vascular anatomy of the left liver. Note the position of segment 3 duct above the corresponding vein and its relationship to the recessus of Rex.
as it descends vertically (26). This right anterior sectoral duct lies to the left of the right anterior sectoral branch of the intrahepatic portal vein as it ascends within the parenchyma (Fig. 1.15). The junction of the two main right biliary ducts usually occurs immediately above the right branch of the portal vein (23). The right hepatic duct is considerably shorter than its counterpart on the left, which it joins to form the common hepatic duct in front of the right portal vein (Fig. 1.15). The caudate lobe (segments 1 and 9) has its own separate biliary drainage. This segment comprises two anatomically and functionally distinct portions, a caudate lobe proper (which consists of a right and left part) located at the posterior aspect of the liver, and a caudate process passing behind the portal structures to fuse with segment 6 of the right liver. In nearly half of individuals, three separate bile ducts drain these distinct parts, while in a quarter of individuals, there is a common biliary duct between the right portion of the caudate lobe proper and the caudate process, while the left part of the caudate lobe is drained by an independent duct. However, the site of drainage of these ducts is variable. Most authors advocate en bloc resection of the caudate lobe during resection of hilar cholangiocarcinoma (31), since the tumor usually infiltrates these ducts draining the caudate lobe. Certainly these authors have demonstrated that in 88% of cases of hilar cholangiocarcinoma coming to resection there is histological evidence of tumor infiltration of the caudate lobe along these ducts.
Figure 1.14 Demonstration of the right hepatic duct lying within the gallbladder fossa.
HA
Figure 1.15 Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectoral duct and the vertical course of the anterior sectoral duct.
Segment 4 Glisson's capsule Lig.teres RHD RHA RPV Cystic artery Cystic duct Gallbladder CHD Umbilical ssure Line of incision of hilar plate to expose left hepatic duct CBD HA Retroduodenal artery Gastroduodenal artery Splenic vein LPV LHD LHA
Cystic plate
Hilar plate Superior mesenteric artery and vein Figure 1.17 Anterior aspect of biliary anatomy. Note the hepatic duct confluence anterior to the right hepatic artery and origin of the right portal vein. Note also the course of the cystic artery, arising from the right hepatic artery and passing posteriorly to the common hepatic duct.
Figure 1.16 Demonstration of the relationship between the posterior aspect of the base of segment 4 and the biliary confluence. Note the extension of Glissons capsule to invest the portal structures at the hilum (hilar plate) and extending over the hepatic surface of the gallbladder (cystic plate). Exposure of the extrahepatic left hepatic duct is achieved by incising the hilar plate at the base of segment 4 medially as far as the umbilical fissure.
(A)
(B)
(C)
biliary anomalies
The biliary anatomy described above, comprising a right and left hepatic duct joining to form a common hepatic duct occurs in between 57% (23) and 72% (8) of cases. This variance may be explained by Couinauds (23) description of a triple confluence of right posterior sectoral duct, right anterior sectoral duct, and left hepatic duct in 12% of cases, which Healey and Schroy do not describe. There are many other abnormalities in biliary anatomy. Couinaud described a right sectoral duct joining the main bile duct in 20% of individuals (right anterior sectoral in 16%, right posterior sectoral in 4%). In addition, a right sectoral duct (posterior in 5%, anterior in 1%) may join the left hepatic duct in 6% of cases. In 3% of cases, there is an absence of a defined hepatic duct confluence with all the sectoral ducts joining separately and in 2% the right posterior sectoral duct may join the neck of the gallbladder or be entered by the cystic duct (23) (Fig. 1.20). Similarly, there are common variations of the intrahepatic biliary anatomy. Healey and Schroy (20) describe the classical intrahepatic biliary arrangement outlined above in 67% of
(D)
(E)
(F)
(G)
(H)
Figure 1.18 The eight most common variations in the anatomy of the arterial supply (cystic artery) to the gallbladder.
(A)
(B) Figure 1.19 (A) Venous drainage of the gallbladder. (B) The lymphatic drainage of the gallbladder towards the coeliac axis.
10
ra rp Ih rp
ra Ih
57% (A) ra rp Ih
12% (B) ra Ih
6% D1 (D) ra rp
5% D2
1% 4 4 3 ra rp 1 1% E2 ra rp Ih 2
2 1 3% E1 (E) 2%
11
86% 7
7 3
3 f 1% 2
Contraindications to this approach include patients with a very deep hilum, which is displaced upward and rotated laterally (36), and those patients who have undergone removal or atrophy of either the right or left livers resulting in hilar rotation. In this situation, the bile duct may come to lie behind the portal vein. When approaching the segment 3 duct (segment 3 hepaticojejunostomy), follow the round ligament (in which runs the remnant of the obliterated umbilical veins) through the umbilical fissure to the point where it connects with the left branch of the portal vein within the recessus of Rex. This junction may sometimes be deeply embedded within the parenchyma of the fissure. The bile ducts of the left liver are located above the left branch of the portal vein, whereas the corresponding arteries lie below the portal vein. Dissection of the round ligament on its left side allows exposure of either
12
(A)
(B)
(C)
(D)
Figure 1.22 Main variations in gallbladder and cystic duct anatomy: (A) bilobed gallbladder; (B) septum of gallbladder; (C) diverticulum of gallbladder; (D) variations in cystic duct anatomy.
(A) 75%
(B) 20%
(C) 5%
Figure 1.23 Different types of union of the cystic duct and common hepatic duct: (A) angular (75%); (B) parallel (20%); (C) spiral (5%).
the pedicle or anterior branch of the duct from segment 3. This dissection is achieved by mobilizing the round ligament and pulling it downwards, thereby freeing it from the depths of the umbilical fissure. This procedure usually requires the preliminary division of the bridge of liver tissue that runs between the inferior parts of segments 3 and 4. The umbilical fissure is then opened and with downward traction of the ligamentum teres an anterior branch of the segment 3 duct is exposed on its left side. Sometimes it may be necessary to perform a superficial liver split to gain access to this duct. In the usual situation of chronic biliary obstruction with dilatation of the intrahepatic bile ducts, the segment 3 duct is generally easily located above the left branch of the portal vein. However, in the situation of left liver hypertrophy, it may be necessary to perform a more extensive
hepatic veins
In an oblique ultrasonic view, the three hepatic veins join the IVC to form a characteristic W, with its base on the IVC. A similar view can be seen on CT scan. These veins are usually easily seen: the left hepatic vein separating segment 2 from segments 3 and 4, the middle hepatic vein separating segment 4 from 5 and 8, and the right hepatic vein separating 5 and 8 from 6 and 7.
portal system
The portal supply to the left lobe, when viewed obliquely, can be seen as a side-on H, with the left portal vein giving its
13
Left branch of the hepatic artery Right branch of the hepatic artery Hepatic artery
Gastroduodenal artery
(A)
M.H. artery L.H. artery R.H. artery Cystic Proper hepatic Right gastric Supraduodenal
Splenic
Gastroduodenal (B)
Common hepatic
Figure 1.24 (A) The biliary duct blood supply; (B) conventional arterial anatomy of the liver (50%).
branch to segment 2, before dividing into the terminal branches to 3 and 4. The portal supply to the right lobe also demonstrates a sideon H in the oblique view. The right branch of the portal vein forms the cross bar of the H, with the branches to segment 5 to 8 forming the arms.
identified using the landmarks outlined above. The scans were then reviewed, with the lesion being attributed to the nearest portal branch. Sixteen percent of lesions had a different segmental location if the portal branch was used instead of the conventional technique (Fig. 1.29) (54).
key points
A full understanding of the lobar, sectoral, and segmental anatomy of the liver and biliary system is an essential prerequisite for successful liver surgery. The surgeon must appreciate the wide variation in extrahepatic biliary anatomy.
14
4a
8 (A) (B)
IVC
(C)
(D)
Figure 1.27 CT scan of upper liver in venous phase showing the left, middle and right hepatic veins draining into the inferior vena cava (IVC).
(E)
(F)
Figure 1.28 CT scan of the liver in portal phase showing the left portal vein passing anteriorly between segments 3 and 4 within the recessus of Rex.
RAPV LPV
RPPV
MPV
Figure 1.26 Portal phase CT scan through porta hepatis showing the left portal vein (L) lying centrally and the anterior (RA) and posterior (RP) divisions of the right portal vein (R).
Figure 1.29 Percutaneous direct portogram showing the relationships of the anterior (RAPV) and posterior (RPPV) to the main (MPV) and left (LPV) portal veins.
15
references
1. Glisson F. Anatomia Hepatis. London: Typ. Du-Gardianis, 1654. 2. Rex 1888. Cited in Hobsley M. The anatomical basis of partial hepatectomy. Proc R Soc Med Engl 1964; 57: 5504. 3. Schwartz SI. Historical Background. In: McDermott WV Jr, ed. Surgery of the liver. Boston, MA: Blackwell Scientific, 1989: 312. 4. McIndoe AH, Counsellor VX. A report on the bilaterality of the liver. Arch Surg 1927; 15: 589. 5. Lau WY. The history of liver surgery. J R Coll Surg Edin 1997; 42: 3039. 6. Mikesky WE, Howard JM, DeBakey ME. Injuries of the liver in three hundred consecutive cases. Int Abstr Surg 1956; 103: 3234. 7. Dalton HC. Gunshot wound of the stomach and liver treated by laparotomy and suture of the visceral wounds. Ann Surg 1888; 8: 81100. 8. Luis A. Di un adenoma del fegato. Centralblatt fur chirg 1887; 5: 99. Abstract from Ganzy, delle cliniche 1886, 23, No 15. 9. Langenbuch C. Ein Fall von Resektion eines linksseitigen Schnurlappens der Leber. Berl Klin Wosch 1888; 25: 378. 10. Tiffany L. The removal of a solid tumor from the liver by laparotomy. Maryland Med J 1890; 23: 531. 11. Lucke F. Entfernung der linken Krebsiten Leber Lappens. Cantrallbl Chir 1891: 6: 115. 12. Cattell RB. Successful removal of liver metastasis from carcinoma of the rectum. Lehey Clin Bull 1940; 2: 711. 13. Wangensteen OH. The surgical resection of gastric cancer with special reference to: (1) the closed method of gastric resection; (2) coincidental hepatic resection; and (3) preoperative and postoperative management. Arch Surg 1943; 46: 879906. 14. Keen WW. Report of a case of resection of the liver for the removal of a neoplasm with a table of seventy six cases of resection of the liver for hepatic tumor. Ann Surg 1899; 30: 26783. 15. Cantlie J. On a new arrangement of the right and left lobes of the liver. J Anat Physiol (Lond) 1898; 32:49. 16. Wendel W. Beitrage zur Chirurgie der Leber. Arch Klin Chir Berlin 1911; 95: 88794. 17. Ton That Tung. La vascularisation veineuse du foie et ses applications aux resections hepatiques. These, Hanoi, 1939. 18. Raven RW. Partial hepatectomy. Br J Surg 1948; 36: 397401. 19. Lortat-Jacob JL, Robert HG. Hepatectomie droite regle. Presse Med 1952; 60: 54950. 20. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human liver. Arch Surg 1953; 66: 599616. 21. Goldsmith NA, Woodburne RT. Surgical anatomy pertaining to liver resection. Surg Gynaecol Obstet 1957; 195: 31018. 22. Hjortsjo CH. The topography of the intrahepatic duct systems. Acta Anat 1951; 11: 599615. 23. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson, 1957. 24. Couinaud C. Lobes et segments hepatiques. Note sur larchitecture anatomiques et chirurgicales du foie. Presse Med 1952; 62: 70912. 25. Couinaud C. Anatomy of the dorsal sector of the liver. In: Couinaud C, ed. New Considerations on Liver Anatomy. Paris: Couinaud, 1998: 3961. 26. Ton That Tung. Les Resections Majeures et Mineures Du Foie. Paris: Masson, 1979. 27. Caprio G. Un caso de extirpacion die lobulo izquierdo die hegado. Bull Soc Cir Urag Montevideo 1931; 2: 159. 28. Bismuth H, Houssin D, Castaing D. Major and minor segmentectomies reglees in liver surgery. World J Surg 1982; 6: 1024. 29. Mancuso M, Nataline E, Del Grande G. Contributo alla conoscenza della struttura segmentaria del fegato in rapportto al problema della resezione epatica. Policlinico, Sez Chir 1955; 62: 25993.
30. Couinaud C. Surgical anatomy of the liver revisited. C Couinaud, 15 rue Spontini, Paris, 1989. 31. Mizumoto R, Kawarada Y, Suzuki H. Surgical treatment of hilar carcinoma of the bile duct. Surg Gynecol Obstet 1986; 162: 1538. 32. Rocko JM, Swan KG, Di Gioia JM. Calots triangle revisited. Surg Gynecol Obstet 1981; 153: 41014. 33. Wood D. Eponyms in biliary tract surgery. Am J Surg 1979; 138: 74654. 34. Byden EA. The anatomy of the choledochaoduodenal junction in man. Surg Gynecol Obstet 1957; 104: 64152. 35. Delmont J. Le sphincter dOddi: anatomie traditionelle et fonctionelle. Gastroenterol Clin Biol 1979; 3: 15765. 36. Bismuth H, Lazorthes F. Les Traumatismes Operatoires de la Voie Biliaire Principale. Paris: Masson, Vol 1, 1981. 37. Champetier J, Davin JL, Yver R, Vigneau B, Letoublon C. Aberrant biliary ducts (vasa aberrantia): surgical implications. Anat Clin 1982; 4: 13745. 38. Gross RE. Congenital anomalies of the gallbladder. A review of a hundred and forty-eight cases with report of a double gallbladder. Arch Surg 1936; 32: 13162. 39. Hobby JAE. Bilobed gallbladder. Br J Surg 1979; 57: 8702. 40. Rachad-Mohassel MA, Baghieri F, Maghsoudi H, Nik Akhtar B. Duplication de la vesicule biliaire. Arch Francais des Maladies de lAppareil Digestif 1973; 62: 67983. 41. Perelman H. Cystic duct duplication. J Am Med Assoc 1961; 175: 71011. 42. Boyden EA. The accessory gallbladder. An embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat 1926; 38: 177231. 43. Rogers HI, Crews RD, Kalser MH. Congenital absence of the gallbladder with choledocholithiasis. Literature review and discussion of mechanisms. Gastroenterology 1975; 48: 5249. 44. Newcombe JF, Henley FA. Left sided gallbladder. A review of the literature and a report of a case associated with hepatic duct carcinoma. Arch Surg 1964; 88: 4947. 45. Kune GA. The influence of structure and function in the surgery of the biliary tract. Ann R Coll Surg Engl 1970; 47: 7891. 46. Northover JMA, Terblanche J. A new look at the arterial blood supply of the bile duct in man and its surgical implications. Br J Surg 1979; 66: 37984. 47. Northover JMA, Terblanche J. Applied surgical anatomy of the biliary tree. In: Blumgart LH, ed. Biliary Tract, Vol 5. Edinburgh: Churchill Livingstone, 1982. 48. Bismuth H, Franco D, Corlette NB, Hepp J. Long term results of Roux-enY hepaticojejunostomy. Surg Gynecol Obstet 1978; 146: 1617. 49. Voyles CR, Blumgart LH. A technique for construction of high biliary enteric anastomoses. Surg Gynecol Obstet 1982; 154: 8857. 50. Blumgart LH, Kelley CJ. Hepaticojejunostomy in benign and malignant bile duct stricture: approaches to the left hepatic ducts. Br J Surg 1984; 71: 25761. 51. Hepp J, Couinaud C, Labord et Lutilisation du canal hepatique gauche dans le reparations de la voie biliaire principale. Presse Med 1956; 64: 9478. 52. Smadja C, Blumgart LH. The biliary tract and the anatomy of biliary exposure. In: Blumgart LH, ed. Surgery of the Liver and Biliary Tract, 2nd edn. Edinburgh: Churchill Livingstone, 1994: 1124. 53. Strunck H, Stuckmann G, Textor J et al. Limitations and pitfalls of Couinauds segmentation of the liver in transaxial imaging. Eur Radiol 2003; 13: 247282. 54. Rieker O, Mildenberger P, Hintze C et al. Segmentanatomie der Leber in der Computertomographie: Lokalisieren wir die Lasionen richtig. Rofo 2000; 171: 14752.
16
17
Figure 2.1 Overview of the relationship of the pancreas to other important structures in the upper abdomen. Plate 1098, From Anatomy of the Human Body, Henry Gray 1918.
(A)
(B)
(C)
Figure 2.2 (A) Duct of Santorini is patent all the way to the duodenum. (B) Duct of Santorini is the main drainage. (C) The two ducts are not in communication with each other.
ramifications with the dorsal pancreatic, pancreatica magna, and splenic arteries. The SMA gives rise to the more variable inferior pancreaticoduodenal (IPD) artery, which divides into branches to form both an anterior and posterior anastomotic arcade with branches from the superior pancreaticoduodenal artery (8). Superior Pancreaticoduodenal Artery The superior pancreaticoduodenal is a short branch of the GDA that arises after the takeoff of the right gastroepiploic artery (Fig. 2.4). It is angiographically identifiable in about 10% of specimens and is generally about 8 mm in length (9). Although rare, it is reported to occasionally arise from the left hepatic artery. When present, the superior pancreaticoduodenal artery divides into anterior and posterior branches, which anastomose with the inferior branches from the SMA. In the remaining cases, the posterior superior pancreaticoduodenal
(PSPD) artery is seen arising from the GDA prior to the right gastroepiploic takeoff. The anterior superior pancreaticoduodenal (ASPD) artery has a caliber between 1 and 3 mm and is considered the most important blood supply to the head of the pancreas. In the majority of cases, it is a terminal branch of the GDA after it has given off the PSPD and the right gastroepiploic arteries. The ASPD can be duplicated in up to 7% of cases and rarely is absent. Case reports of extremely rare anomalies exist, reporting the origin of this artery from almost all of the major branches of the celiac and SMAs (9). Posterior Superior Pancreaticoduodenal Artery This artery forms the superior portion of the posterior arcade that forms anastomoses with the posterior branch of the IPD artery. The PSPD artery is most commonly found as a branch of the GDA 1 to 2 cm after the takeoff of the hepatic artery (10). Up to 10% of cases may see the PSPD arise from the superior
18
Cystic artery
Figure 2.3 Arterial anatomy of the pancreas, the celiac axis and its major branches. Plate 532, From Anatomy of the Human Body, Henry Gray 1918.
pancreaticoduodenal and in rare instances may arise from any of the hepatic arteries. The most common course of the PSPD after it leaves the GDA posteriorly is it runs over the portal vein (PV) and the anterior edge of the top of the pancreas where it enters the gland and finds the common bile duct and makes a right-handed spiral around the duct passing posterior to it just above the ampulla. It then runs deep in the parenchyma of the pancreas to find its connection with the posterior inferior artery. The PSPD gives off collateral branches to form the blood supply to the intrapancreatic portion of the common bile duct, it generally gives off the supraduodenal artery and occasionally the retroduodenal artery, rarely it may give a branch to the gallbladder or an accessory right hepatic artery (10). Inferior Pancreaticoduodenal Artery The IPD artery is present in about 70% of cases and is the common trunk that gives rise to the anterior and posterior inferior pancreaticoduodenal (AIPD and PIPD) arteries that form the anastomotic arcades supplying the head of the pancreas (11). In the remaining 30% of cases, the AIPD and PIPD arise directly from the SMA. The IPD may arise directly from the SMA as the first collateral branch from 2 to 5 cm distal to the origin and take a short course from its posterior takeoff into the inferior edge of the pancreatic parenchyma, or alternatively, it may arise as a common trunk with the first jejunal
a S t o m
C r e a t o r
O x e n t e
branch, the pancreaticoduodenaljejunal (PDJ) trunk in which case it takes a longer course to the pancreas. The IPD crosses posterior to the SMV and the posterior surface of the pancreas and does not give off any branches prior to dividing into its anterior and posterior termini (11). Anterior and Posterior Inferior Pancreaticoduodenal Arteries These arteries supply the inferior part of the anastomotic arches that supply the head of the pancreas. They arise most often from a common IPD artery. They may also originate directly from the SMA or less commonly directly from the first jejunal artery or from a replaced hepatic artery. The main course of the AIPD is to follow the inferior curve of the pancreas and find its partner the ASPD (12). It may give off a branch to the duodenaljejunal flexure or to form a transverse pancreatic artery. The PIPD runs more posterior and cephalad than the AIPD and ultimately finds the PSPD or alternatively terminates as small end arteries. It may supply a collateral branch to the transverse pancreatic artery when present (12). Dorsal Pancreatic Artery The main blood supply to the neck and body of the pancreas is the dorsal pancreatic (DP) artery. It most commonly arises from the splenic artery near its origin at the celiac axis (13). It may also take its origin from the celiac trunk itself, the
19
S t o m a c h
Figure 2.4 Arterial anatomy of the pancreas, demonstrating the gastroduodenal and its branches of the anterior and posterior pancreaticoduodenal arteries forming the anastomotic arcades with the branches from the superior mesenteric artery. Plate 533, From Anatomy of the Human Body, Henry Gray 1918.
common hepatic or the GDA. Alternatively, the DP may arise from the SMA. The course of the DP artery is usually in the form of an inverted T with a right and left branch that form after a short 1 to 3 cm course. When the artery arises from the splenic artery, it tends to angle back to the right, if it takes off from the celiac, hepatic, or GDA, then it transverses the neck in a leftward direction. When coming from the SMA it comes up from the bottom of the pancreas. The right branch of the DP forms an anastomosis with left anastomotic pancreatic artery from the ASPD. The left branch becomes the transverse pancreatic artery (13). Caudal and Great Pancreatic Arteries The great pancreatic artery is often present and is given off from the splenic artery at the junction of the body and tail. It collateralizes with the transverse pancreatic artery. The caudal pancreatic artery takes its origin from the left gastroepiploic, the distal splenic artery or a branch from the splenic hilum and forms anastomotic connections with the great pancreatic and transverse pancreatic arteries (3). The arterial blood supply to the pancreas is rich and complex. Most of the primary arterial conduits form some
anastomotic connection and this shared blood supply is one of the challenges of pancreatic surgery. When operating in the deepest recesses of the abdomen, having an intimate knowledge of the standard arterial anatomy as well as the most common alternatives will allow the pancreatic surgeon to maximize patient safety. That same surgeon must keep in mind that the arterial anatomy in this area is subject to wide variation and that one must always be prepared to address the aberrant anatomy. To that end, having good preoperative imaging to establish before the operation what the arterial anatomy is can be a valuable aid whether by angiography or by computed tomography (CT) angiography. Venous Drainage of the Pancreas The veins of the pancreas follow the course of the corresponding arteries in most cases. They are generally more superficially located than the arteries and depending on the location in the pancreas drain into the PV, SMV, the inferior mesenteric vein, or the splenic vein. In the head of the pancreas, there is a venous arcade that mirrors the arterial anastomoses and of the four main veins all, but the PSPD vein, which empties directly into the PV, find their way to the SMV. In addition, there are
20
12 12b1 1 12a2 3 5
8a 16 8p 10
14a
14d
18
13b
15
14d
numerous small bridging veins between the head of the pancreas and the SMV and PV as they course behind the pancreas, which must be carefully ligated during a resection. The fact that there are rarely venous branches that enter the SMV or PV on their anterior surfaces makes the dissection along the plane anterior to these vessels possible during pancreaticduodenectomy. Two large veins drain the body and tail of the pancreas, the splenic vein, which courses along the superior edge of the pancreas and the transverse pancreatic vein along the inferior margin. The portal vein is formed on the posterior surface of the neck of the pancreas by the confluence of the splenic vein and the SMV. The inferior mesenteric vein may join at this point as well, but more commonly joins the splenic vein or SMV proximal to the confluence (Fig. 2.4).
while the right side drains the lower portion of the head, which developed from the ventral bud and constitutes the retroportal lymphatics (15,16). The superior pancreatic nodes drain the upper half of the neck, body and tail of the pancreas, and a portion of the head. They primarily lie along the superior border of the gland or in the gastropancreatic fold and gastrohepatic ligament (17). The inferior pancreatic nodes similarly drain the inferior half of the gland and lie along the inferior border as well as draining into the superior mesenteric nodes or the periaortic nodes. The anterior nodes are located along the surface of the pancreas that lies adjacent to the duodenum and are called the infrapyloric lymph nodes and the pancreaticoduodenal nodes. These anterior nodes may also drain into nodes along the root of the transverse colonic mesentery that is adjacent to the head of the pancreas. The posterior nodes run along the posterior pancreaticoduodenal border and include the nodes along the lower portion of the common bile duct, portal vein and nodes at the origin of the SMA. The tail of the pancreas forms several lymphatic trunks that reach out into the hilum of the spleen and form the superior and inferior lymph nodes (3,16). This simplified lymphatic mapping system is that adapted by the International Union against Cancer (UICC). A more comprehensive and clinically useful system was developed by the Japanese Research System, which divides lymph node stations into 18 different designations and rates them according to the likelihood of metastatic spread. Nodal stations 13 and 17 are the most likely to harbor disease with
21
Superior mesenteric vein AIPD-V PIPD-V ASPD-V Figure 2.6 Major venous drainage for the pancreas. First jejunal tributary
The pancreas lies in the recesses of the upper abdomen and remains one of the most challenging organs to manage from a clinical or operative standpoint. Its rich blood supply, close associations with major vascular structures, intimate relation to the common bile duct, and the attachments to the duodenum and spleen all contribute to the complexity of surgical intervention in both malignant and benign disease (7). A thorough understanding of the three dimensional relationship of the arterial blood supply and major veins in proximity to the pancreas make approaching pancreatic resection possible. As we move into an era of minimally invasive surgery, being able to recognize the anatomy and its variations with minimal cues from adjacent structures will become increasingly important and continued study of these complex relationships allows the mind to know, so that the eye may see.
references
1. Opie EL. Anatomy of the Pancreas and its Variations. Disease of the Pancreas: Its Cause and Nature, 1st edn. Philadelphia, PA: J.B. Lippincott Company, 1903: 359. 2. Saisho Y, Butler AE, Meier JJ, et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin Anat 2007; 20: 93342. 3. Skandalakis LJ, Colborn GL, Skandalakis JE. Surgical anatomy of the pancreas. In: Baker RJ, Fischer JE, eds. Mastery of Surgery, Vol. 2, 4th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2001: 2448. 4. Kuroda A, Nagai H. Surgical anatomy of the pancreas. In: Howard J, Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas, 3rd edn. Baltimore, MD: Lippincott Williams & Wilkins, 1998: 869. 5. Cattell RB, Warren KW. The anatomy and physiology of the pancreas. In: Cattell RB, Warren KW, eds. Surgery of the Pancreas. Philadelphia, PA: Saunders, 1953. 6. Hollinshead WH. The thorax, abdomen and pelvis. In: Hollinshead WH, ed. Anatomy for Surgeons. Vol. 2. New York: Medical Department, Harper and Row Publishers, 1971: 430. 7. Anson BJ, McVay CB, Callander CL. The Abdomen. Surgical Anatomy. Philadelphia, PA: Saunders, 1971. 8. Woodburne RT, Olsen LL. The arteries of the pancreas. Anat Rec 1951; 111: 25570. 9. Bertelli E, Di Gregorio F, Bertelli L, Mosca S. The arterial blood supply of the pancreas: A review. I. The superior pancreaticoduodenal and the anterior superior pancreaticoduodenal arteries. An anatomical and radiological study. Surg Radiol Anat 1995; 17: 97106, 1013. 10. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. II. The posterior superior pancreaticoduodenal artery. An anatomical and radiological study. Surg Radiol Anat 1996; 18: 19. 11. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. III. The inferior pancreaticoduodenal artery. An anatomical review and a radiological study. Surg Radiol Anat 1996; 18: 6774. 12. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A. The arterial blood supply of the pancreas: A review. IV. The anterior inferior and posterior pancreaticoduodenal aa., and minor sources of blood supply for the head of the pancreas. An anatomical review and radiologic study. Surg Radiol Anat 1997; 19: 20312. 13. Bertelli E, Di Gregorio F, Mosca S, Bastianini A. The arterial blood supply of the pancreas: A review. V. The dorsal pancreatic artery. An anatomic review and a radiologic study. Surg Radiol Anat 1998; 20: 44552. 14. Navas V, OMorchoe PJ, OMorchoe CC. Lymphatic system of the rat pancreas. Lymphology 1995; 28: 420. 15. Pissas A. Anatomoclinical and anatomosurgical essay on the lymphatic circulation of the pancreas. Anat Clin 1984; 6: 25580. 16. Donatini B, Hidden G. Routes of lymphatic drainage from the pancreas: A suggested segmentation. Surg Radiol Anat. 1992; 14: 3542.
47% and 29%, respectively (18,19) (Fig. 2.6). Classification of lymphatic involvement will become increasingly important as increasing numbers of targeted therapies become available in pancreatic cancer.
22
23
introduction
Though liver anatomy and physiology have been studied for centuries, liver surgery still is a relatively young field. Just 30 years ago, the mortality of major hepatic resection neared 25%. This high mortality limited its utility and deterred patients and referring physicians from considering surgery. The current generation of hepatobiliary surgeons has an increased understanding of the segmental anatomy of the organ and has seen a dramatic decrease in the mortality of liver surgery to nearly 1% largely due to a dramatic decrease in blood loss (1). This chapter will address the basic principles and techniques to safely approach liver resection.
basic principles
Surgical Indications: Benign vs. Malignant Disease Though this chapter focuses on the technical aspects of hepatic resection, an understanding of when liver resection is indicated is of paramount importance. Due to advances in modern imaging techniques and an increased knowledge of the natural history of liver lesions, tumors that may have been resected in the past for diagnostic uncertainty are now often observed. Similarly, malignant lesions that were not resected in the past but referred for nonsurgical therapy are now being treated with resection. Indications for specific benign and malignant processes are outlined in other chapters; however, the general principles are mentioned here. Benign Disease Partial hepatectomy for benign conditions should be parenchymal preserving and reserved for lesions that are symptomatic, have premalignant potential, or carry an unclear diagnosis. Wide margins are not necessary, therefore in some cases, for example, focal nodular hyperplasia (FNH) or hemangiomas, enucleation may be safely performed, although in some instances an anatomic segmental resection may be the safest approach (24). This is addressed at the end of the chapter and detailed in other chapters. Malignant Disease Partial hepatectomy for malignant conditions must obtain a clear surgical margin, and is suitable for well-selected patients with both primary and metastatic cancer. We have found increased patient survival with margins of at least 1 cm in patients undergoing resection for metastatic colorectal cancer (513), though other series suggest that a negative margin, regardless of the distance, is sufficient (14,15). The exception may be in slow-growing tumors with multiple liver metastases, such as neuroendocrine tumors, where tumor debulking may be of value. As long as the functional remnant liver is adequate, usually about 25% liver volume in otherwise
24
HEPATIC RESECTION
hilar cholangiocarcinomas are also at increased risk of liver failure postoperatively. The functional residual liver volume should be calculated to insure adequate liver function postresection. A healthy, noncirrhotic individual requires a functional hepatic reserve of at least 20% of the original nontumoral liver volume. The regenerative capacity of the liver should enable full functional compensation within weeks of resection; once greater than 70% of liver volume is resected, however, there is a risk of clinically significant liver insufficiency. This risk is minimal if specimen volume has been replaced with tumor, in which case compensatory hypertrophy will have already occurred. Preoperative Imaging (See Also Chapters 3, 4, and 11) Fine-cut triphasic helical computed tomography (CT) with CT angiogram is the single most useful study in preoperative evaluation of liver tumors. When the study includes the chest, abdomen, and pelvis, preoperative staging is reliable and can identify areas outside of the liver that may need further evaluation or confirm nonoperative candidates. CT can define the vascular anatomy, identify anatomical variants, determine resectability, estimate the functional liver residual volume, and identify preoperative biliary drainage strategies, thereby obviating the need for further radiographic studies. CT angiography in particular has almost prevented the need for traditional angiography. 3-D reconstruction of the vasculature is particularly helpful in identifying vascular anomalies quickly and temporally. Furthermore, 3-D reconstruction of the vascular anatomy may lead to more accurate visualization of tumor vessel relationships and may be a more accurate study to predetermine the operative line of transection (25). Magnetic resonance imaging can also provide high-quality vascular and volumetric assessments of the liver but its principal role is in characterizing liver tumors of unclear etiology. In experienced hands, ultrasound is a fast, inexpensive, and noninvasive modality that can quickly obtain information regarding tumor size and the amount of liver involvement, particularly in gallbladder and biliary tumors. It is especially helpful in distinguishing cysts from solid tumors and should be used in addition to CT to evaluate cysts for the presence of septations or mural thickening, which would suggest cystadenoma or a cystadenocarcinoma. Duplex ultrasound is also particularly helpful as a dynamic study to identify vasculature in relation to tumor masses. Anesthetic Techniques Operative and perioperative morbidity and mortality have been decreased in part due to changes in anesthetic practices over the evolution of hepatic resection. A focus on maintaining low central venous pressure (CVP) can greatly reduce blood loss and keep the operative field clean for proper visualization of the biliary and vascular anatomy during parenchymal transaction. This is accomplished by positioning the patient in mild Trendelenberg and minimizing intravenous fluid to maintain systolic blood pressures above 90 mmHg and urine output to about 25 mL/h. If the IVC is still distended after mobilization of the liver, parenchymal transection can wait until central venous pressure is decreased through use of narcotics, vasodilatory inhalation agents, or direct vasodilators. A central venous pressure of less than 5 mmHg can be maintained during the periods of liver mobilization and parenchymal transection. Though a cental venous catheter is a useful tool to follow the CVP, the surgeon can also look for a nondistended IVC and for blood coursing through flat intrahepatic veins. If transection is performed under Pringle control, bleeding is generally from hepatic veins, therefore, with a low hepatic venous pressure, even large tears in hepatic veins can be visualized to allow ligation or repair without massive hemorrhage. By Poiseuilles law, blood flow is exponentially proportional to the radius of the vessel; therefore, even minor decreases in venous distention can decrease blood loss exponentially. With these techniques, the risk of postoperative renal failure has not been shown to be significant, nor has the risk of air embolism, which can be minimized, regardless, by keeping the patient in about 15 of Trendelenberg (26,27). Normal resuscitation is performed after the resection is completed and hemostasis has been achieved.
basic techniques
Positioning, Skin Incision, and Exposure The patient should be positioned supine with the arms extended at right angles to the body. Any self-retaining retractor can be utilized, however, we prefer the Goligher retractor to elevate the costal margin, and this crossbar can be fitted to the table to form a 45 angle from top of the crossbar to the xyphoid. The patient should be prepped from the mid-chest to below the umbilicus, and draped to expose the right chest in the event a right thoracotomy is necessary to gain additional exposure. Though some groups routinely make a J-shaped thoracoabdominal incision, in our experience a thoracoabdominal incision was rarely necessary in over 1800 cases (2). We employ selective use of diagnostic laparoscopy based on the risk of unresectable disease (28), and conform the type of incision to the expected resection. For access to both lobes of the liver, a bilateral subcostal incision can be used with or without vertical midline extension. For the great majority of liver resections, we employ a hockey stick incision, which includes a right subcostal incision with vertical midline extension to the xyphoid. These incisions, when combined with the Goligher retractor, provide good exposure of the suprahepatic IVC, even with large right-sided tumors. We have found a higher rate of incisional hernia with a Mercedes incision compared to a hockey stick incision (29). For left-sided resections, a midline incision may suffice. Occasionally, when there is severe right-sided hepatic atrophy or exposure to the suprahepatic IVC is necessary for safety, extension into the right chest can be helpful (Fig. 3.1). Mobilization The ligamentum teres is divided between clamps and ligated, leaving a long secure ligature that is used as a handle to further expose the porta hepatis. The thin veil of the falciform ligament is incised along its length to free it from the anterior abdominal wall and expose the ligamentum teres. In obese individuals, the area where the falciform is fused to the anterior abdominal wall may be invested within a large fat pad. This fat pad can be removed with diathermy from beneath
25
A D
Figure 3.1 Incisions for liver resection. B-D, initial upper midline exploration. A-B-C, ideal for exposure of the whole liver (hockey stick). C-D-E, the classic chevron incision with A-D (Mercedes) extension. C-D, right subcostal incision. F, thoracoabdominal extension. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Figure 3.2 Mobilization of the liver begins with downward traction on the liver and division of the falciform ligament to the inferior vena cava. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
26
HEPATIC RESECTION
vascular load endo-GIA staple fire. Once this is divided, the right liver is mobile and the lateral aspect of the right hepatic vein is exposed. The left liver is mobilized similarly, however since it does not lie on the vena cava, an extensive caval dissection is not necessary. Sharp and blunt dissection over the suprahepatic IVC will expose the groove between the right vein and the common trunk of the middle and left and middle hepatic veins. Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. The groove between the left and middle hepatic veins can be exposed with sharp dissection if there is no long intrahepatic common channel (Fig. 3.4). Care must be taken here to identify the phrenic vein as it courses on the underside of the diaphragm to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to the liver surface (Fig. 3.5). As the left lateral segment is released from its peritoneal attachments, it is also useful to place a hand or laparotomy pad under the left lateral segment and anterior to the caudate to provide traction and to protect the stomach, bowel, and spleen from diathermic injury. Further mobilization of the left liver can be accomplished by dividing the lesser omentum as well as the ligamentum venosum either at the left portal vein or left hepatic vein insertions to expose these vessels and the underlying caudate lobe.
vascular isolation
Once the liver is mobilized, there are essentially three steps to safely perform a hepatectomy. These involve vascular inflow control, vascular outflow control, and parenchymal transection. Inflow Control All major hepatic resections require control of the vascular inflow to be accomplished safely. Furthermore, adequate
Figure 3.3 Multiple small venous branches from the IVC to the posterior liver must be individually dissected and divided. When all of these branches are controlled, all that is left to expose the right hepatic vein will be a fibrous band of tissue, the caval ligament. A tunnel can be safely created behind this ligament and above the right hepatic vein with a Kelly clamp. Once this is divided, the entire right liver is mobile and the venous outflow can be encircled and controlled. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
27
Figure 3.4 Sharp and blunt dissection over the suprahepatic IVC exposes the right, middle and left hepatic veins. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Diaphragm
Diathermy
Figure 3.5 Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. Care must be taken here to identify the phrenic vein as it courses on the underside of the diaphragm to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to the liver surface. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
28
HEPATIC RESECTION
major hepatectomy, extrahepatic control of these vessels is preferred. Standard anatomy consists of a single right hepatic vein entering the vena cava, and a left and middle hepatic vein that is joined and entering the cava as a single trunk. Autopsy studies of the left and middle hepatic venous trunk have elucidated at least five types of hepatic vein trunk variants (39). The right hepatic vein is typically encircled after the dissection of the vena cava and caval ligament has been carried out as described earlier. The base of the right hepatic vein should be dissected sharply and once exposed, a clamp can be passed between the right and middle hepatic veins. Exposure of the left and middle hepatic vein extraheaptically can be challenging. The groove between the right and middle hepatic veins is initially developed from above the liver. The left liver is mobilized and the ligamentum venosum is divided just before its insertion into the left hepatic vein. Here a tunnel is carefully developed underneath the middle and left hepatic vein and they are encircled (Fig. 3.6). It is often difficult to individually encircle the left or middle hepatic vein extrahepatically but this depends on the anatomy of the common trunk. It is important to identify the hepatic venous anatomy on preoperative imaging and recognize variations in the branching patterns, since bleeding in this area can be difficult to control. Ligation of the hepatic venous outflow of the liver can also be accomplished during parenchymal transection with careful exposure of the cava and the origin of these veins once the liver has been transected to expose them. The exposures for specific resections are discussed later in the chapter. Parenchymal Transection Once vascular inflow and outflow to the lobe or segment has been controlled, all that remains is division of the liver parenchyma. There are many techniques to accomplish this. The instruments used are left to the surgeons preference, but it is imperative that the vessels and ducts divided be identified and dissected before division. Transection of the liver should be a deliberate dissection of intrahepatic structures rather than simply coagulation of liver tissue. In addition to the ability to confidently ligate each branch on the transection line, it allows one to identify the venous drainage and pedicle inflow to the remnant liver. Moreover, in cases where the tumor margin is adjacent to major hepatic veins and portal pedicles, it allows precise extirpation of the tumor. For these reasons, we prefer a simple crushing technique. Glissons capsule is scored with diathermy along the transection line and a Kelly clamp is used to crush the liver tissue and expose the vessels and ducts for clipping, ligation, or bipolar energy sealing. Larger pedicles are suture ligated or stapled (40). The operative surgeon crushes the tissue in small linear planes, the assistant clips or seals the vessels, and the surgeon divides the structures. In this fashion, the transection line is quickly and efficiently completed. Though not always necessary, inflow occlusion with a Pringle maneuver may be used to decrease blood loss, and an entire lobe can often be transected with three to four sessions of 1015 minutes on Pringle with 5 minutes off. After removal of the specimen, the raw surface is carefully inspected for bile leaks, which are suture ligated or clipped. Some groups advocate injection of dye or intralipid via the cystic duct to identify open biliary tributaries for ligation. Since drainage is associated with prolonged hospital stay, increased infection, and no change in a need for interventional radiology directed drainage, we do not routinely place drains after hepatic resection in the absence of biliary reconstruction (41).
(A)
(B)
Figure 3.6 (A) Medial retraction of the left lateral segment exposes the ligamentum venosum. (B) The ligamentum venosum is divided sharply where it is tethered to the left hepatic vein, releasing the vein and enabling a tunnel to be dissected under the middle and left hepatic veins and anterior to the IVC. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
29
Goldsmith and Woodburne Right hepatic lobectomy Extended right hepatic lobectomy Left hepatic lobectomy Extended left lobectomy Left lateral segmentectomy
Brisbane Right hemihepatectomy Right trisectionectomy Left hemihepatectomy Left trisectionectomy Left lateral sectionectomy
Segments resected V, VI, VII, VIII IV,V,VI, VII, VIIIb II, III, IV II, III, IV, V, VIIIb II, III
30
HEPATIC RESECTION
is divided, parenchymal transection is completed to the IVC, the lateral venous attachments to the IVC are ligated and divided, the right hepatic vein is stapled, the coronary and triangular ligaments are divided, and the specimen is removed. Right Trisectionectomy (Right Lobectomy, Extended Right Lobectomy, Right Trisegmentectomy) A right trisectionectomy is a right hemihepatectomy extended to include segment IV. The liver is mobilized as described for a right hepatectomy. To approach the inflow and outflow of segment IV, the ligamentum teres is elevated to expose the umbilical fissure. If a bridge of tissue between segments III and IV is present concealing the fissure, this should be divided with diathermy. Here, the ligamentum teres can be traced to its embryologic origin at the left portal vein. Incising the fibrous tissue that tethers the left main pedicle to the base of the umbilical fissure releases the left-sided structures from the undersurface of segment IV, and it opens up the fissure. To safely perform a right trisectionectomy, the left hepatic duct should be freed clear of the proposed plane of transection. This is accomplished by lowering the hilar plate as previously described. The inflow and outflow to the right liver are controlled and divided as previously described. Once the right hepatic vein has been divided, the middle vein can usually be encircled. The liver tissue is divided to the right of the falciform ligament and the pedicles feeding segments IVa and IVb are ligated and divided as they come off the main left pedicle (Fig. 3.9). Unless tumor mandates, a deliberate dissection within the umbilical fissure is usually not necessary. As the plane of transection is deepened toward the IVC superiorly, the middle hepatic vein is encountered, dissected, and divided with a stapler. It is absolutely critical to protect the left hepatic vein as narrowing or transection of this vein will likely result in liver failure or massive hemorrhage secondary to a lack of other venous return from the liver.
(A)
(B)
(C)
(D)
(E) Figure 3.7 The anatomy and classification of major hepatic resections. (A) right hepatectomy, (B) left hepatectomy, (C) left lobectomy, (D) extended left hepatectomy, (E) right lobectomy.
31
Figure 3.9 To expose and control the portal pedicles to segment IV, the liver tissue is divided to the right of the falciform ligament and the pedicles feeding segments IVA and IVB are ligated and divided as they come off the main left pedicle. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Figure 3.8 During right hepatectomy, the right hepatic artery usually passes posterior to the common bile duct and is sharply dissected, ligated, and divided to the right of the duct. After cholecystectomy, retraction of the cystic duct will expose the underlying artery. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
Left Hemihepatectomy (Left Hepatectomy, Left Hepatic Lobectomy) A left hemihepatectomy involves excision of segments II IV. The left lobe of the liver is mobilized, the umbilical fissure is exposed, and the hilar plate is lowered as previously described. The gastrohepatic ligament is entirely divided, with care taken to identify any accessory or replaced left hepatic arteries not identified on preoperative imaging. The left hepatic artery is dissected at the base of the umbilical fissure and divided. The caudate branch of the portal vein is identified before the left main portal vein enters the umbilical fissure. If the caudate lobe is to be spared, the portal vein is ligated and divided distal to this vein. A line of demarcation marking the right-sided border of segment IV corresponds with a plane that usually extends from the IVC to the base of the gallbladder fossa (Cantlies line). This principle plane is the same as that seen in a right hemihepatectomy. Segments II and III are reflected medially and the middle and left hepatic veins are identified, encircled and divided extrahepatically as described earlier. The left hepatic vein is often not amenable to circumferential extrahepatic exposure initially but can be exposed after splitting the liver back to its origin. Parenchymal transection completes the excision. Left Trisectionectomy (Extended Left Hepatectomy, Extended Left Lobectomy, Left Trisegmentectomy) A left trisectionectomy involves removal of segments II, III, IV, V, and VIII. The entire liver is mobilized. The inflow and outflow to the left lobe are controlled as previously
described for a left hemihepatectomy. The inflow to segments V and VII can be addressed in a few ways. The anterior sectoral pedicle can be encircled intrahepatically either through hepatotomies or after transection in the right scissura to the left of the right hepatic vein. The pedicle can be encircled and clamped confirming flow the posterior sector. Alternatively, an extensive hilar dissection can be carried out to identify and divide the arterial and portal branches to the right anterior sector. It is critical that preoperative imaging is reviewed for anatomic variations in the inflow and outflow to the right liver. Once the anterior sectoral inflow is divided, a near horizontal line of demarcation becomes evident anterior to the right hepatic vein and dividing the right anterior and posterior sectors. Parenchymal transection continues anterior to the right hepatic vein and the specimen is removed. The middle hepatic vein is necessarily taken as part of this resection and is addressed as described earlier. A left trisectionectomy is a challenging operation that requires significant experience with major hepatic resections. Left Lateral Sectionectomy (Left Lobectomy, Left Lateral Segmentectomy) A left lateral sectionectomy involves removal of segments II and III. The left lobe of the liver is mobilized and the hilar plate is lowered as previously described. Just to the left of the umbilical fissure, the portal pedicles to segments II and III are identified and divided. These can be identified and controlled through multiple hepatotomies or during parenchymal transaction in a plane just to the left of the falciform ligament. A deliberate dissection in the umbilical fissure is usually not necessary. The left hepatic vein is usually divided after parenchymal resection back to its origin but can also be controlled extrahepatically as described in the outflow control section of the chapter.
32
HEPATIC RESECTION
care must be taken to avoid injury to the middle and left hepatic veins. Segments II or III The approach to excising either segment II or III is the same as that for a left lateral segmentectomy, except the plane between the segments needs to be defined. This plane is identified by the course of the left hepatic vein, segment 3 being anterior and segment 2 being posterior. Inflow control to either segment is achieved in the umbilical fissure. Ligation of the portal pedicle will guide resection along the plane of demarcation. Care must be taken to divide the branches of the left hepatic vein draining the excised segment, but to leave the main left hepatic vein intact to drain the remnant liver. Segment IV As described in a right trisectionectomy, the inflow to segment IV is found to the right of the umbilical fissure. The hilar plate is lowered to protect the left bile duct and to provide access to the multiple pedicles to segment IV. Ligation of these pedicles will provide a line of demarcation along Cantlies line. During parenchymal transection, the venous drainage of segments IVa and IVb are divided sequentially to the left of the middle vein on the lateral border of the segment, and along the umbilical fissure on the medial border of the segment, where the umbilical vein often courses. The middle hepatic vein can be sacrificed in this operation if necessary with adequate drainage of the right liver and segments 2 and 3. Segments V and VIII (Anterior Sector) The inflow to segments V and VIII are from the right anterior sectoral pedicle. This can be approached and controlled extrahepatically or intrahepatically as described for a left trisectionectomy. If the anterior and posterior sectoral pedicles branch within the liver parenchyma, a hepatotomy over the anterior pedicle is necessary. Alternatively, the liver can be transected in the principal plane down to the base of the anterior sector where its origin can be controlled, typically posterior to terminal middle hepatic vein branches. The anterior sector lies between the right and middle hepatic veins, i.e., between Cantlies line and a transverse plane anterior to segments VI and VII. This horizontal plane of transection can be better defined by clamping the anterior pedicle to demarcate the right, left, and posterior borders. The transection line between V and VIII is demarcated and defined intrahepatically when control of the isolated segmental inflow is obtained. The middle hepatic vein can usually be safely divided in this operation if necessary, but in the absence of a large accessory right hepatic vein, the right hepatic vein must be preserved for adequate drainage of the posterior sector. Segments VI and VII (Posterior Sector) The inflow to segments VI and VII are from the posterior sectoral pedicle. This can often be approached and controlled in the fissure of Ganz, though the anatomy of anterior and posterior pedicles can be highly variable. If the anterior and posterior sectoral pedicles branch within the liver parenchyma,
33
conclusion
Major hepatic resections for benign and malignant tumors can be accomplished safely and efficaciously. Proper patient selection, precise preoperative imaging, specific anesthetic techniques, and knowledge of the principal complications are essential. Study of each patients segmental anatomy will allow inflow and outflow control and the ability to tailor the resection needed for each individual.
references
1. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: Analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236(4):397407.
34
HEPATIC RESECTION
26. Cunningham JD, Fong Y, Shriver C, et al. One hundred consecutive hepatic resections: Blood loss, transfusion, and operative technique. Arch Surg 1994;129(10):10506. 27. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: Blood loss, blood transfusion, and the risk of postoperative renal dysfunction. J Am Coll Surg 1998;187(6):6205. 28. DAngelica M, Fong Y, Weber S, et al. The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases. Ann Surg Oncol 2003 Mar;10(2):1839. 29. DAngelica M, Maddineni S, Fong Y, et al. Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedes-type incisions compared to extended right subcostal incisions. World J Surg 2006;30(3):4108. 30. Blumgart L. Hepatic resection. In: Dudley HAF, Rob C, Smith of Marlow RS, Pories WJ, eds. Rob & Smiths operative surgery, 4th edn. London, Boston: Butterworth Scientific, 1982:v. 31. Tung TT. Les Re?sections Majeures et Mineures du Foie. 1979. 32. Launois B, Jamieson GG. The posterior intrahepatic approach for hepatectomy or removal of segments of the liver. Surg Gynecol Obstetrics 1992;174(2):1558. 33. Launois B, Jamieson GG. The importance of Glissons capsule and its sheaths in the intrahepatic approach to resection of the liver. Surg Gynecol Obstetrics 1992;174(1):710. 34. Hepp J, Couinaud C. [Approach to and use of the left hepatic duct in reparation of the common bile duct.]. Presse Med. 1956;64(41):9478. 35. Delva E, Camus Y, Nordlinger B, et al. Vascular occlusions for liver resections. Operative management and tolerance to hepatic ischemia: 142 cases. Ann Surg 1989;209(2):2118. 36. Emond J, Wachs ME, Renz JF, et al. Total vascular exclusion for major hepatectomy in patients with abnormal liver parenchyma. Arch Surg 1995;130(8):82430; discussion 301. 37. Emre S, Schwartz ME, Katz E, Miller CM. Liver resection under total vascular isolation. Variations on a theme. Ann Surg 1993;217(1):1519. 38. Hannoun L, Borie D, Delva E, et al. Liver resection with normothermic ischaemia exceeding 1 h. Br J Surg. 1993;80(9):11615. 39. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the inferior vena cava. Surgery Gynecol Obstetrics 1981;152(1):4350. 40. Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am Coll Surgeons 1997;185(1):93100. 41. Fong Y, Brennan MF, Brown K, Heffernan N, Blumgart LH. Drainage is unnecessary after elective liver resection. Am J Surg 1996;171(1):15862. 42. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Le Foie: Etudes Anatomiques et Chirurgicales. 1957. 43. Goldsmith NA, Woodburne RT. The surgical anatomy pertaining to liver resection. Surg Gynecol Obstet 1957;105:3108. 44. Starzl TE, Iwatsuki S, Shaw BW, Jr, et al. Left hepatic trisegmentectomy. Surg Gynecol Obstet 1982;155(1):217. 45. Starzl TE, Koep LJ, Weil R, 3rd, et al. Right trisegmentectomy for hepatic neoplasms. Surg Gynecol Obstet 1980;150(2):20814. 46. Chik BH, Liu CL, Fan ST, et al. Tumor size and operative risks of extended right-sided hepatic resection for hepatocellular carcinoma: implication for preoperative portal vein embolization. Arch Surg 2007;142(1):639; discussion 9. 47. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL. Anterior approach for difficult major right hepatectomy. World J Surg 1996;20(3):3147; discussion 8. 48. Lai ECS, Fan ST, Lo CM, et al. Hepatic resection for hepatocellular carcinoma: An audit of 343 patients. Ann Surg 1995;221(3):2918. 49. Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001;193(1):10911. 50. Couinaud C. Bases anatomiques des hepatectomies gauche et droite reglees. J Chir 1954;70:93366. 51. Zorzi D, Mullen JT, Abdalla EK, et al. Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases. J Gastrointest Surg 2006;10(1):8694. 52. DeMatteo RP, Palese C, Jarnagin WR, et al. Anatomic segmental hepatic resection is superior to wedge resection as an oncologic operation for colorectal liver metastases. J Gastrointest Surg 2000;4(2):17884. 53. Polk W, Fong Y, Karpeh M, Blumgart LH. A technique for the use of cryosurgery to assist hepatic resection. J Am Coll Surg 1995;180(2):1716. 54. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with special reference to the caudate lobe. World J Surg 1988;12(1):210. 55. Heloury Y, Leborgne J, Rogez JM, et al. The caudate lobe of the liver. Surg Radiol Anat 1988;10(1):8391. 56. Takayama T, Makuuchi M. Intraoperative ultrasonography and other techniques for segmental resections. Surg Oncol Clin N Am 1996;5(2):2619. 57. Lerut J, Gruwez JA, Blumgart LH. Resection of the caudate lobe of the liver. Surgery Gynecol Obstetrics 1990;171(2):1602. 58. Hata F, Hirata K, Murakami G, Mukaiya M. Identification of segments VI and VII of the liver based on the ramification patterns of the intrahepatic portal and hepatic veins. Clin Anat 1999;12(4):22944.
35
introduction
Ultrasound is the initial study of choice in most clinical situations due to the lack of ionizing radiation, relatively low cost, and accessibility in varied settings such as at the bedside or in the operating suite. Ultrasound differs from other crosssectional imaging techniques in that it uses sound propagation and reflection from interfaces within tissue for imaging. Images are generated by piezoelectric material within the transducer that transmits and receives the sound signal. Higher frequency transducers provide the best resolution, but high frequencies are attenuated more rapidly in tissue. For that reason, transducer frequency is selected for the application. Superficial structures are evaluated at frequencies in the range of 6 to 18 MHz and transabdominal ultrasound, which requires better penetration, typically uses frequencies ranging from 3 to 6 MHz. Doppler is a unique feature of ultrasound for imaging vessels and blood flow. When moving blood is insonated, the frequency of the returning signal is proportional to blood velocity. A cursor is placed over a specific blood vessel and images are obtained in both gray scale and Doppler (termed Duplex scanning). The Doppler information can then be displayed in three different formats: (1) spectral Doppler, (2) color Doppler, and (3) power Doppler. Spectral Doppler shows a waveform with velocity changes and flow direction over time. Color Doppler displays mean velocities and direction of flow within vessels. The color codes assigned for velocities are usually displayed in the upper left aspect of the image. Power Doppler gives the amplitude of the Doppler signal without direction or frequency information; since it is not angledependent, it is very useful for imaging low flow and tortuous vessels. Ultrasound contrast agents further improve applications for vascular imaging. Current contrast agents use microbubbles encapsulated within thin lipid spheres. After intravenous injection, the microbubbles remain intravascular and do not diffuse into the interstitium as do MRI and CT contrast agents. After a low-power ultrasound signal is applied, the microbubbles oscillate (expand and contract) at harmonic frequencies that are detected by the transducer (1,2). With these ultrasound contrast agents, it is now possible to image tumor vasculature in exquisite detail (37) (Fig. 4.1). Despite the versatility of ultrasound, there are limitations. Sound is reflected at bone and air interfaces so scans are obtained from different positions to avoid intestinal air or rib artifact. This lack of standardized perspective compared to axial imaging format of CT and MRI may present difficulty for referring clinicians who are unfamiliar with the technique. To lessen bowel gas interference, 6-hour fast is recommended to improve visualization of the pancreas and liver and to provide sufficient gallbladder distension. Another significant limitation
liver
Anatomically the liver is divided into sectors that are defined by the scissurae that contain the hepatic veins; these sectors are then subdivided into individual hepatic segments that each contain intact portal and arterial inflow and hepatic venous outflow and draining bile ducts (8,9). Ultrasound hepatic anatomy is shown in Fig. 4.2. Diffuse Liver Disease Diffuse liver abnormalities include fatty infiltration, hepatitis, and cirrhosis. Hepatic steatosis is present in 17% to 33% of the general population and in 70% of overweight individuals (10). On ultrasound, the liver has diffusely increased echogenicity and in advanced cases significant sound beam attenuation obscures the deep liver. Areas of focal sparring may be seen anterior to the portal confluence and adjacent to the gallbladder. Hepatic steatosis impacts perioperative outcome and accurate preoperative diagnosis would be useful (11). Fatty infiltration increases liver stiffness, which can be measured by tissue displacement in response to the transmitted ultrasound wave. These elastography techniques hold promise for diagnosis of diffuse infiltrative liver diseases such as hepatic steatosis and early-stage hepatic fibrosis (1214). Focal Hepatic Lesions Cystic lesions Ultrasound is the best modality to differentiate cystic from solid liver masses and to determine the internal architecture of cystic lesions. Simple cysts, found in 2% to 3% of patients (15), have thin wall, no internal echoes, and bright posterior enhancement. Even if the cyst is lobulated or has thin septation, benign diagnosis can be made (16). Symptomatic large simple cysts may be treated with ultrasound-guided aspiration and sclerosis (15,17), but it is extremely important to assess the cyst wall. Mural nodularity, thick tumor rim, and internal vascularity may indicate neoplasm such as biliary cystadenoma and these lesions should not be unroofed or aspirated since complete surgical resection is required. Cystic liver metastases present as complex cysts often with solid or
36
(A)
(B)
Figure 4.1 Microbubble contrast enhanced ultrasound image of a hypervascular liver mass. (A) Contrast enhanced image shows the intense hypervascularity of this liver lesion (arrow) that proved to be focal nodular hyperplasia. (B) The lesion (arrows) is subtle on the corresponding grayscale image. (Complements of Siemens Medical Solutions, Ultrasound Division. Malvern, PA.)
irregular rim. These are typically from sarcoma, cystadenocarcinomas of the ovary and pancreas, and mucinous colon carcinoma primaries (16,18). Ovarian metastases are characteristically peripheral implants. Squamous cell tumors with necrosis appear as cystic masses and other metastases may cavitate in response to chemotherapy. The appearance of cyst contents on ultrasound can be used for differential diagnosis. Pyogenic abscess initially may be echogenic and later liquified with debris, fluid-fluid levels, and irregular wall (Fig. 4.3). Echogenic reflections with reverberations, seen in 20% to 30% of cases, suggest air within the abscess (18). The classic echinococcal cyst is a complex cyst with well-defined wall, containing double echogenic lines. Multiple, internal echogenic foci, snowstorm signs settle in the dependent portions of the cyst. Localized splits in the cyst wall, with floating, undulating membranes, are also characteristic and the cyst wall may calcify (19,20). Hematomas in the acute stage may be echogenic and then they have layering lowlevel echoes from blood, and later become honeycombed with septation. When a preexisting cyst becomes hemorrhagic, internal septation may be thick and irregular, but they float freely in real-time and are not rigid. Solid Liver Lesions Solid liver lesions are further characterized by lesion echogenicity, vascularity, and peripheral halo. Definitive diagnosis of benignity can be made for hemangiomas, focal fatty infiltration, and focal fatty sparing because of their classic ultrasound features. Benign focal nodular hyperplasia can also be identified when the characteristic spokewheel vascular pattern, tortuous feeding artery, and marked hypervascularity are seen on contrast-enhanced ultrasound or Doppler images (Fig. 4.1). Hypoechoic liver masses and lesions with a peripheral halo are suspicious for malignancy. Although CT and MRI are used for tumor staging, there can be added benefit from ultrasound to
(1) assess lesions that are too small to characterize by CT, (2) define the relationship of tumor to bile ducts, and (3) evaluate vascular encasement and tumor margin (Fig. 4.4). Typical hemangioma, seen in 70% to 80% of cases, is a uniformly echogenic mass with sharp margin (21) (Fig. 4.5A). The multiple vascular interfaces within the hemangioma cause the increased echogenicity and margin is well-demarcated since histopathologically hemangiomas lack a capsule. Hemangiomas have absent or minimal flow on Doppler imaging; they are never hypervascular. Another common appearance of hemangioma is a mass with thin peripheral echogenic rim with mixed central echogenicity (Fig. 4.5B). Giant hemangiomas > 5 cm often lack these characteristic ultrasound features because of central fibrosis, necrosis, and myxomatous degeneration. A study of 213 patients with typical hemangioma appearance and without risk for hepatic malignancy found only one patient with malignancy on long term follow-up and concluded that typical hemangiomas in low-risk patients do not require follow-up (22). This rule does not apply to patients with cirrhosis, hepatitis, or chronic liver disease that places them at increased risk for hepatocellular carcinoma, nor does it apply to patients who already have malignancies, and particularly not to those with primary tumors that exhibit echogenic metastases. Caturelli et al. (23) studied 2,000 patients with cirrhosis. Of these, 44 had hemangioma-like lesions. On follow-up, half proved to be hepatocellular carcinomas and half hemangiomas. Thus, in patients at risk for hepatocellular carcinoma, any echogenic lesion merits further evaluation or follow-up. Other benign conditions such as focal fatty infiltration and focal sparing are diagnosed by geographic margins and typical location in segment 4 anterior to the portal vein bifurcation or less commonly, adjacent to the gallbladder. Focal fat appears echogenic relative to normal liver and areas of focal sparing are less echogenic than fatty infiltrated liver. A useful finding on Doppler evaluation is that vessels cross undisturbed
37
(A)
(B)
(C)
(D)
(E) Figure 4.2 Normal liver anatomy. (A) Transverse view of the right lobe. The middle hepatic vein separates the right from left hepatic lobes. The right hepatic vein divides the right anterior sector (segments 8 and 5) and the right posterior sector (segments 7 and 6). R = right hepatic vein, M = middle hepatic vein, IVC = inferior vena cava. (B) Longitudinal view of the right lobe reveals the right hepatic vein RHV and the hepatic segments. RK = right kidney. (C) Transverse view of the portal vein bifurcation. Segments are numbered. R = right portal vein, L = left portal vein, RK = right kidney, IVC = inferior vena cava, A = aorta. (D) Longitudinal view of the left lobe. The left hepatic vein separates the posterior left sector segment 2 from the anterior sector (segments 3 and 4). The caudate, segment 1, is demarcated anteriorly by the fissure for the ligamentum venosum (arrowhead) and the inferior vena cava posteriorly. IVC = inferior vena cava. RPV = right portal vein. (E) Color Doppler sagittal image of the portal vein reveals hepatopetal flow.
38
Figure 4.3 A 50-year-old woman several years postpancreaticoduodenectomy for duodenal carcinoid developed fever after hepatic artery embolization for control of hepatic metastases. Right hepatic liquified abscess (asterisk) with posterior acoustic enhancement (arrowhead). Small posterior solid metastases (small arrows) are also seen.
(A)
(B)
Figure 4.4 Colorectal metastasis to left hepatic lobe was evident on ultrasound but not by CT done the same day. (A) The lateral left lobe was considered negative on CT. (B) Longitudinal ultrasound revealed a segment II metastases with peripheral halo (calipers) consistent with malignant lesion.
(A)
(B)
Figure 4.5 Hemangioma. (A) Typical hemangioma (arrow) is uniformly echogenic with no surrounding halo. (B) An atypical hemangioma with a thin bright rim (arrow) is shown in this longitudinal view of the right hepatic lobe. Another hemangioma (arrowhead) is noted peripherally.
39
(A)
(B)
(C) Figure 4.6 Acute cholecystitis in a 56-year-old woman with abdominal pain. (A) Longitudinal view reveals a laminated appearance to the anterior gallbladder wall (arrowheads) and gallstone (arrow) with posterior acoustic shadow. (B) Transverse view shows thickened wall at 6 mm (calipers). (C) Longitudinal color Doppler image reveals vascular flow within the gallbladder wall.
(A)
(B)
Figure 4.7 Gallbladder carcinoma. (A) Longitudinal and (B) transverse sonogram of the gallbladder reveals a stone (arrowhead) with acoustic shadowing. The anterior fundus is narrowed and surrounded by hypoechoic soft tissue that infiltrates the adjacent liver (arrows).
40
pancreas
The echotexture of the normal pancreas is uniform and slightly higher echogenicity than liver. With aging and obesity, fatty infiltration of the pancreas may further increase echogenicity. The pancreatic duct is best seen transversely and is normally less than 2 mm in the body and 3 mm in the head (39). Diffuse Pancreatic Diseases In acute pancreatitis, the pancreas may become enlarged and hypoechoic with indistinct margins from edema. The edema may involve the entire gland or only a portion, usually the head. Peripancreatic fluid is a useful diagnostic feature; fluid and vascular mural thickening may also be observed (40) (Fig. 4.8). Pancreatic duct may be dilated. In the most acute stage, ileus limits ultrasound visualization and CT is more useful, but ultrasound has a role to exclude biliary calculi as an etiology for the pancreatitis (4144). Severe inflammation progresses to inflammatory pancreatic mass or phlegmon with fluid collection, hemorrhage, and necrosis. Fluid is commonly seen within the lesser sac, anterior pararenal spaces, transverse mesocolon, small bowel mesentery, and parapancreatic spaces (45). Pseudocysts may persist for a minimum of 4 weeks after
Figure 4.8 Acute pancreatitis in a patient with AIDS. Transverse sonogram of the pancreas reveals heterogeneous pancreatic parenchyma and edema of the splenic vein (arrow). The vein has a layered appearance with a ring of hypoechoic fluid within the wall of the vessel. Fluid also is seen in the peripancreatic space (arrowheads).
41
(A)
(B)
(C) Figure 4.9 Unresectable pancreatic adenocarcinoma. (A) Longitudinal ultrasound image of the pancreas shows an enlarged pancreatic head (m) and dilated common bile duct (arrow), PV = portal vein, IVC = inferior vena cava. (B) Transverse sonogram reveals the pancreatic head mass (m) and dilated pancreatic duct (arrows) anterior to the splenic vein (SV). IVC = inferior vena cava, a = aorta. (C) Transverse sonogram reveals a left hepatic metastasis (arrows). R = right hepatic vein, M = middle hepatic vein, IVC = inferior vena cava.
significant solid component are more likely to be malignant (47,55,58). Aspirates of cystic lesions are relatively acellular but fluid analysis for tumor markers is useful. Brugge et al. (59) reported that elevated cyst fluid CEA level had 79% accuracy for diagnosis of mucinous tumors.
intraoperative ultrasound
Intraoperative ultrasound (IOUS) is an important tool for (1) assessment of tumors at the time of resection, (2) vascular mapping during hepatic resection or live split liver donor transplantation, and (3) guidance during intraoperative tumor ablation or biopsy (6064) (Fig. 4.10). During hepatic resection, IOUS is used to characterize liver lesions that are indeterminate or occult on preoperative imaging. IOUS can accurately assess tumor extent relative to vascular structures and bile ducts (6568); this is important since approximately 1 to 2 cm margin should be available between the tumor and vessels for optimal surgical outcome and vessel encasement or thrombosis may alter surgical approach (6972). A prospective study by Cerwenka et al. (73) evaluated the role of IOUS in patients who had partial hepatectomy after standardized hepatic protocol preoperative MRI. Small additional lesions with mean size of 1.5 cm were found by IOUS in 7% of patients and in 5% of patients IOUS findings altered surgical strategy (73,74). IOUS altered management in 20% of patients who had resection for primary or secondary hepatic malignancies. Even with recent improvements in crosssectional imaging, there was no significant difference in resection
rate (72%), detection of unrecognized additional tumors (20% vs. 14% p=0.70), or detection of vascular involvement when groups in the years1999 to 2003 and 2003 to 2005 were compared (68,7476). Special dedicated high-frequency (510 MHz) transducers are required for IOUS; these transducers can be applied directly on the area of interest to improve resolution compared to transabdominal ultrasound, which is limited by distance and abdominal wall artifact. Typically IOUS probes are small T-shaped linear and hockey-stick-shaped probes, which are easy to manipulate within restricted operative fields. Transducer specifications should include good near field resolution and Doppler capabilities. It is preferable to have the scanner connected to the hospital network to provide (1) access for consultation at remote sites during real-time scanning and (2) permanent image archiving in the electronic record. Review of preoperative imaging is essential before IOUS since preoperative planning increases the efficiency of the procedure. While performing IOUS, the surgeon should avoid applying excessive pressure. If vessels become compressed, it is difficult to assess patency or encasement. Light touch with the transducer can be used as a palpation method to differentiate between soft benign lesions such as hemangiomas, focal fat, and fat sparing versus malignant lesions, which are usually firm (77,78). IOUS may be limited for lesions in the high right lobe or in the posterior subdiaphragmatic location where access is
42
(A)
(B)
(C) Figure 4.10 Intraoperative ultrasound reveals additional hepatic lesions. (A) A 2 cm segment 7 liver lesion (arrows) with peripheral halo and (B) an 8 mm segment 6 lesion (arrow) were seen on preoperative imaging. (C) A nonpalpable 6 mm lesion (arrow) in segment 4A was not evident on preoperative imaging. Lesions were resected with diagnosis of metastatic neuroendocrine carcinoma; primary site later identified in the pancreas. (Complements of Robert A. Kane, M.D., Professor of Radiology, Harvard Medical School, Chief, Body and Abdominal Ultrasound Imaging, Beth Israel Deaconess Medical Center, Boston, MA.)
difficult. In that situation, scanning from the opposite surface of the liver may improve visualization. Artifacts in the near field of the image may also obscure lesions near the hepatic surface. If this occurs, the surgeon can immerse the liver in a sterile saline bath, thereby changing the focus zone to better visualize the superficial anatomy. Another difficulty may be encountered when attempting to visualize lesions near a surgical margin. Echogenic foci from air bubbles in the parenchyma after cauterization or radiofrequency ablation may mimic echogenic mucin-containing colorectal metastases. This pitfall can be mitigated by imaging before intervention to accurately determine number, size, and location of lesions (7981). New advances in intraoperative and interventional ultrasound techniques now allow fusion of ultrasound, CT, and MRI images and electromagnetic tracking to more precisely localize lesions for biopsy and thermal ablation procedures. For example, after initial CT data is entered, information from electromagnetic sensors is applied onto the needle device and the patient can guide the needle track in real time even when the needle is out of the ultrasound imaging plane. This process brings two data sets into spatial alignment. Such techniques have shown improved needle tracking for
interventional procedures and better three-dimensional visualization of tumor and treatment zone during radiofrequency ablation (63,8284).
references
1. Cosgrove D. Ultrasound contrast agents: an overview. Eur J Radiol 2006; 60(): 32430. 2. Wilson SR, Burns PN, Muradali D,et al. Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma, and metastasis. Radiology 2000;215(1):15361. 3. Albrecht T, Blomley MJ, Burns PN, et al. Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study. Radiology. 2003; 227(2): 36170. 4. Ascenti G, Mazziotti S, Zimbaro G, et al. Complex cystic renal masses: characterization with contrast-enhanced US. Radiology 2007; 243(1): 15865. 5. Burns PN, Wilson SR. Focal liver masses: enhancement patterns on contrast-enhanced images--concordance of US scans with CT scans and MR images. Radiology 2007; 242(1): 16274. 6. Correas JM, Claudon M, Tranquart, et al. The kidney: imaging with microbubble contrast agents. Ultrasound Q 2006; 22(1): 5366. 7. Kabakci N, Igci E, Secil M, et al. Echo contrast-enhanced power Doppler ultrasonography for assessment of angiogenesis in renal cell carcinoma. J Ultrasound Med 2005; 24(6): 74753.
43
44
45
introduction
The recent increase in the geriatric population in society and increased life span have raised the expectation from surgeons to expand their operative indications to include geriatric patients. In liver surgery, the indications for hepatectomy have been expanded to include patients aged 70 and older, and several studies have demonstrated acceptable long-term survival of elderly patients after such surgery (1,2). In 1937, Brooks reported the results of surgery for 287 patients aged 70 and older. The operative mortality rate was high (19%), and onethird of patients who had abdominal operations died in hospital. Nevertheless, the author emphasized that with the rapid growth of the elderly population, and prolonged life expectancy, surgeons will increasingly be confronted with surgical problems among the elderly and must therefore strive to improve their results by studying physiologic processes in the aged (2,3). In the seven decades since Brooks paper, advancements in anesthesiology and intensive care, an increased knowledge of liver physiology, surgical hepatic anatomy, and resection techniques have encouraged hepatic resection in elderly patients, achieving improved surgical outcomes. Because of the high prevalence of liver cancers and aging of the world population, the elderly population considered for liver resection has increased (4,5). Also an effective multidisciplinary approach and better selection of elderly patients leads to reduced age-related perioperative morbidity and mortality (6). Moreover, the definition of elderly patients has been better defined so avoiding unnecessary confusion that has generated over the past years. Although advances in minimally invasive ablative techniques have increased the treatment options for patients with malignant hepatobiliary disease, liver resection remains the only treatment demonstrated to offer long-term survival (79). Also the past three decades have seen a dramatic decline in the mortality rate after liver resection in selected elderly patients, which is less than 5% in tertiary cancer care referral centers (2,6,10). Colorectal cancer has become a major public health problem that increasingly affects older people (11), and because the liver is the most common site of metastases, the number of elderly so affected is increasing (12). Liver resection is also successfully performed in aged patient suffering primary malignancies such as hepatocellular carcinoma (HCC) with results comparable to those seen in younger people. In this chapter, we highlight the main advances performed in liver surgery, taking into account all the issues that are still a matter of debate for elderly patients with primary or metastatic liver disease.
definition of elderly patients The age at which persons become elderly depends on social, environmental, and individual factors. Nowadays, after years 46
47
hepatocellular carcinoma
Primary tumors of the liver are among the most common solid tumours worldwide (4).
48
49
financial cost
In the current climate of scarce health care resources, treatment for elderly patients has been under close scrutiny. Several studies have shown that elderly patients have benefited from liver resection for malignancy with results comparable to those younger than 70 years of age. The use of health care resources in terms of intensive care unit and in-hospital stays is no different than in the younger population, and some of this costsaving can be attributed to better support in terms of anesthesia and community nursing (32). Therefore careful selection of patients using the ASA grade and meticulous surgical technique are essential to achieve better outcomes after hepatic resection in patients over the age of 70 years.
conclusions
Age alone should not be considered a contraindication for liver resection: hepatectomy is safe, effective, and a curative therapy in the elderly. Major hepatectomies are the feasible procedure in patients older than 70 years who have preserved liver function and controllable medical conditions, yielding close to 0% operative mortality and low morbidity rates in specialized tertiary centers.
references
1. Takenaka K, Shimada M, Higashi H, et al. Liver resection for hepatocellular carcinoma in the elderly. Arch Surg. 1994; 129(8): 84650. 2. Fong Y, Blumgart LH, Fortner JG, Brennan MF. Pancreatic or liver resection for malignancy is safe and effective for the elderly. Ann Surg 1995; 222(4): 42634; discussion 347. 3. Brooks B. Surgery in patients of advanced age. Ann Surg 1937; 105(4): 48195. 4. Fong Y, Brennan MF, Cohen AM, et al. Liver resection in the elderly. Br J Surg 1997; 84(10): 138690. 5. WHO. AgeingExploding the Myths. Ageing and Health Program (AHE). WHO. 1999. 6. Adam R, Frilling A, Elias D, et al. Liver resection of colorectal metastases in elderly patients. Br J Surg 2010; 97(3): 36676. 7. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995; 19(1): 5971. 8. Jaeck D, Bachellier P, Guiguet M, et al. Long-term survival following resection of colorectal hepatic metastases. Association Francaise de Chirurgie. Br J Surg 1997; 84(7): 97780. 9. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230(3): 30918; discussion 1821. 10. Poon RT, Fan ST, Lo CM, et al. Hepatocellular carcinoma in the elderly: results of surgical and nonsurgical management. Am J Gastroenterol 1999; 94(9): 24606. 11. Cooper GS, Yuan Z, Landefeld CS, Johanson JF, Rimm AA. A national population-based study of incidence of colorectal cancer and age. Implications for screening in older Americans. Cancer 1995; 75(3): 77581. 12. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989; 210(2): 12738. 13. de Liguori Carino N, van Leeuwen BL, Ghaneh P, et al. Liver resection for colorectal liver metastases in older patients. Crit Rev Oncol Hematol 2008; 67(3): 2738. 14. Cescon M, Grazi GL, Del Gaudio M, et al. Outcome of right hepatectomies in patients older than 70 years. Arch Surg 2003; 138(5): 54752.
50
51
52
Small solitary hepatic metastases: when and how? David L. Bartlett and Yuman Fong
survival results for hepatic metastasectomy
While the purpose of this chapter is not to provide an in-depth review of the results of hepatic metastasectomy, a general sense of expected cure rate and prolongation of survival after hepatic metastasectomy for various histologies is required in order to make an informed decision regarding resection of small hepatic metastases. Colorectal Metastases Colorectal cancer, compared to other histologies, is more likely to present as disease isolated to the liver. The natural history of unresected solitary hepatic metastases from colorectal cancer was described by Wagner et al. where 39 patients with solitary metastases did not undergo therapy and the median survival was 24 months (3). Wood et al. described 15 patients with solitary hepatic metastases left untreated with a mean survival of 17 months (4). There is a considerable body of literature on the results of hepatic metastasectomy for colorectal cancer. The overall 5-year survival ranges from 22% to 39% (5). In many studies, low number and small size are associated with improved prognosis such that a small solitary metastasis from colorectal cancer has a greater than 50% of 5-year survival. Nuzzo et al. report 56% actuarial 5-year survival in patients with solitary metachronous hepatic metastases from colorectal cancer less than 4 cm in size (1). Table 6.1 reviews the results of the largest series for solitary metastasectomy. After resection of solitary metastases from colorectal cancer, 5-year survival ranges from 30% to 47% (610). These reports do not consider the small solitary metastases separately from the entire group of solitary metastases. The size of the lesion is expected to affect prognosis and, therefore, the actual results for small solitary hepatic metastases may be even better than the numbers reported in Table 6.1. Liver resection for hepatic colorectal metastases is, therefore, safe and effective, and may be curative. Neuroendocrine Metastases For cancers of other than colorectal origin, patients with hepatic metastases from neuroendocrine tumors have been thought to be the most likely to benefit from surgical resection. Certainly, if the tumor were symptomatic for either hormonal or physical reasons, resection should be considered even though cure is unlikely. Because of the indolent nature of these tumors, durable palliation can be achieved with cytoreduction. Fiveyear survival rates for untreated hepatic metastases from neuroendocrine tumors have ranged from 13% to 54% (1115). In patients with no symptoms, the case for surgical resection, or any treatment for that matter, is less clear. We and others (16) have adopted a very aggressive approach even for asymptomatic tumors based only on retrospective data.
introduction
The management of patients with small hepatic metastases from colorectal cancer and other histologies requires the consideration of many diverse patient- and tumor-related factors. These factors include the natural history of the tumor type, the expected cure rate after surgical treatment, effectiveness of alternative treatments, and the morbidity of surgical resection. In general, the indications for any major surgical procedure include the potential for cure, prolongation of survival, and palliation of symptoms. For metastatic tumors to the liver in selected cases, the cure rate may be over 50% for colorectal cancer (1), but will be exceedingly rare for other histologies such as gastric cases, and melanoma and sarcoma. Small metastases to the liver generally do not cause symptoms (except for hormone secreting neuroendocrine tumors) and, therefore, palliation of symptoms is not a common indication for management of these lesions. Nevertheless, many issues remain unresolved. Does resection of a small solitary hepatic metastasis prolong survival in cases where the patient is likely to develop widespread metastases in the future? Is there any harm in allowing a tumor to go untreated for a period of time, knowing that with close follow-up the resection option may still be possible in the future? Do metastases metastasize such that a delay in management may obviate the curative option? Unfortunately, all of these difficult issues are only addressed by sparse data in the literature. The risk and extent of the surgical procedure plays a significant role in the decision making for management of small hepatic metastases. It is more reasonable to excise an enlarged subcutaneous lymph node for metastatic cancer than it is to perform a hepatic lobectomy when the chance of benefit is low in both cases. As other less invasive ablative options become routine therapy, it may be reasonable to consider these options in cases where surgical resection is unreasonable. These alternative options include percutaneous approaches at ablation such as radiofrequency ablation and percutaneous alcohol injection (2). Laparoscopic procedures may also be an alternative for the management of small hepatic metastases, including laparoscopic resection of tumors and laparoscopically directed ablation such as cryotherapy. If the risks, discomfort, and hospital stay are truly minimal, then it becomes reasonable to consider local treatment of these lesions, even with a small chance of overall benefit to the patient. This chapter will provide an overview of the data on survival benefit after resection of hepatic metastases and the techniques of surgical management. A brief discussion of minimally invasive and percutaneous procedures for management of small solitary hepatic metastases will follow. In addition, a discussion of the role for adjuvant therapy after resection or ablation of the hepatic metastases will be included.
53
Table 6.1 Survival After Hepatic Resection for a Solitary Colorectal Metastasis
Actuarial 5-year survival (%) 37 30 36a 47 47 Median survival (months) 45 54
Author Hughes et al. (6) Rosen et al. (7) Scheele et al. (8) Taylor et al. (9) Fong et al. (10)
a
Histology Neuroendocrine Neuroendocrine Genitourinaryb Sarcoma Breast/melanoma/sarcoma Breast Breast Gastric Gastric Gastrointestinale
N 15 74 34 14 41 21 34 21 A07 A07
Actuarial 5-year survival (%) 73 73a 60 A00 26 A09 18 19c 14d A00
4-year survival. Includes renal (5), testicular (9), adrenal (7), ovary (7), uterine (4), cervix (2). 4 of 21 actual 5-year survivors. d 1 of 7 actual 5-year survivors. e Includes gastric (5), pancreatic (2). NR: not reached.
54
patient selection
Colorectal Metastases In order to decide when surgical resection is reasonable for small solitary hepatic metastases, it is important to review prognostic factors that are independent of size and number, which may influence the decision regarding management of these tumors. Many studies have examined data on prognostic factors for outcome after hepatic resection for colorectal metastases. The time to development of liver tumor after resection of the primary, pathologic margin, stage of the primary tumor, tumor number, carcinoembryonic antigen levels, satellitosis, extrahepatic disease, and positive surgical margin have all been shown to predict survival after hepatic resection for colorectal metastases independent of size (7,8,10,32). Extrahepatic disease is considered a contraindication to hepatic resection. Even the presence of perihepatic lymph nodes portends a poor prognosis and generally is felt to be a contraindication to resection. Particularly in the cases of small solitary hepatic metastases with extrahepatic disease, there would be no advantage to resection or ablation of the liver tumor because systemic disease will likely be the ultimate cause of death regardless of what is done with the liver metastases. Of the other various factors that are prognostic for outcome, surgical margin, and satellitosis are the least useful in patient selection. No one would subject a patient to surgical resection expecting a positive margin. Satellitosis cannot be easily assessed preoperatively and therefore is a poor selection criterion for surgery.
do metastases metastasize?
For small solitary hepatic metastases, where many months of growth would still not preclude resection, the question is whether a waiting period would allow for further spread of the tumor from the metastatic deposit itself. If metastatic tumors were unable to further metastasize, waiting for the first sign of progression prior to initiating treatment and allowing other metastatic disease to declare itself would seem a reasonable approach. If, however, metastases are able to spread during that waiting period, then the chance of potential cure may be adversely affected by the delay in
55
Neuroendocrine Tumors Patients with symptomatic neuroendocrine tumors should be considered for resection or ablation. For the small tumor, symptoms are most likely derived from hormonal secretion by the tumors, and such hormone levels will also provide a marker for effectiveness of the ablation or resection. For asymptomatic tumors, a period of observation to allow assessment of the pace and aggressiveness of the tumors is reasonable when the tumors are small. At the first signs of progression, resection or ablation should be considered. Noncolorectal, Nonneuroendocrine Tumors Harrison et al. defined prognostic factors involved in the resection of noncolorectal, nonneuroendocrine hepatic metastases (26). In this study, 96 patients underwent liver resection. The prognostic factors of significance on multivariate analysis included the disease-free interval (>36 months), curative resection (versus palliative incomplete resection), and primary tumor type. Their conclusions would suggest that regardless of histology, with a long disease-free interval patients may benefit from surgical resection.
resection techniques
For small solitary metastases to the liver, the goal of resection is to completely excise the tumor while preserving the maximum normal hepatic parenchyma. Preserving parenchyma facilitates postoperative recovery and also provides flexibility for further resections should intrahepatic recurrences occur (35). Small surface-oriented metastases can be excised using a nonanatomic wedge resection, whereas deeper lesions require formal segmentectomies or sectorectomies. A goal of at least a 1 cm margin is reasonable (36). The use of intraoperative ultrasound is important to rule out other small hepatic metastases, which may not be evident on preoperative scans and in defining the intersegmental planes for designing the approach to segmentectomy. Even for wedge resections, ultrasound is beneficial in defining the vascular anatomy around the lesion, which may help minimize blood loss. Wedge Resections Wedge resections must be performed meticulously to avoid inadvertently leaving a positive margin. Large chromic liver sutures can be placed and used for retraction during dissection. The parenchymal dissection should be performed along the lines used for other forms of liver resection. We prefer the Kelly clamp technique where the clamp is used to crush the normal parenchyma, exposing vessels that are then clipped, tied, suture ligated, or stapled using a vascular stapling device (37). The Pringle maneuver is used intermittently for 5 minutes at a time followed by reperfusion of the parenchyma, during which time the argon beam coagulator is used to coagulate small bleeding vessels on the surface. This technique is superior to the simple use of electrocautery for the dissection, which is often attempted for what seems to be routine wedge resections. The char effect of the electrocautery prevents adequate visualization of the anatomy, making it quite easy to stray into large vessels or into the tumor.
0.8
Survival
0.6
0.4
0.2
0.0 0 12 24 Months Figure 6.1 Prediction of long-term outcome for small (<3 cm) (N = 293) metastatic deposits based on clinical risk score (CRS). CRS is based on the following five criteria: (1) node positive primary cancer, (2) disease-free interval <12 months, (3) number of liver tumors >1, (4) size of liver tumor >5 cm and (5) CEA > 200 ng/dl. For score = 02 (N = 236) (open box), the median survival was 56 months and the 5-year survival 47%. For score = 34 (N = 57) (filled triangles), the median survival was 32 months and the 5-year survival 24%. 36 48 60
56
57
(A)
(B)
(C)
(D)
Figure 6.2 An example of a small, solitary colorectal metastasis to segment VI. (A) MRI reveals subtle abnormality not seen on CT scan. (B) Intraoperative ultrasound reveals the tumor and adjacent segment VI portal vein. (C) Intersegmental planes have been marked on the liver capsule with electrocautery and parenchymal dissection begun. (D) Resected segment with tumor (microscopic negative margins). (Special thanks to Dr Peter Choyke for MRI scan.)
radiofrequency ablation (45). These techniques will be discussed further in chapter 8. They provide ideal alternatives to laparotomy and major liver resection for the treatment of small solitary hepatic metastases, since the small tumor is the most likely to be completely treated by ablation techniques. Furthermore, treatment by ablative techniques does not preclude future resection. Percutaneous approaches to tumor ablation are even more attractive than laparoscopic procedures. Local injection of toxic agents such as ethanol has been shown to be effective for hepatocellular cancers, however these agents have not been proven for other histologies and are known to be poorly effective for colorectal cancer (2). Radiofrequency ablation can be performed percutaneously under ultrasound guidance with local anesthesia. Figure 6.3 demonstrates a case of a metastatic pancreatic cancer 2 years after a dramatic primary response to gemcitabine and radiation therapy. Because the patient will likely begin to fail in multiple sites in the near future with limited survival potential, a laparotomy and hepatic resection was not considered reasonable. She was treated with percutaneous radiofrequency ablation, achieving a good zone of necrosis encompassing the mass, and she spent only one day in the hospital with very minimal discomfort. How such procedures, which have low morbidity and which maintain quality of life, will factor
in the treatment of patients with small hepatic metastases must be addressed by studies with sufficient follow-up to define the local recurrence rate.
adjuvant chemotherapy
The role for adjuvant systemic chemotherapy after the removal of small solitary hepatic metastases is not well defined. Even for hepatic colorectal metastases, which are commonly treated with surgery, data on adjuvant chemotherapy after liver resection is sparse. Two retrospective studies have suggested a benefit of adjuvant systemic chemotherapy after metastasectomy, but others have not supported this (6,4648). Use of systemic chemotherapy after resection of hepatic colorectal metastases is based mainly on data demonstrating adjuvant 5-fluorouracil (5-FU) and levamisol or 5-FU and leucovorin to decrease recurrence rate and improve survival when used after resection of the primary tumor (49). It is hoped that a similar benefit will be seen when 5-FUbased chemotherapy is used after metastasectomy. Current practice is to offer adjuvant 5-FU-based chemotherapy after hepatic resection to patients who have had no previous chemotherapy. There are currently no data to support the use of irinotecan and oxaliplatin in an adjuvant setting, although studies are in progress.
58
(A)
(B)
(C) Figure 6.3 An example of a small, solitary pancreatic cancer metastasis treated with percutaneous radiofrequency ablation. (A) Pretreatment CT scan reveals hypodense 3 cm right lobe liver metastasis. (B) Ultrasound hoto with radiofrequency probe inserted into tumor. (C) Post-treatment scan (3 weeks) reveals large zone of necrosis replacing prior tumor. (Special thanks to Dr Thomas Shawker for ultrasound photo.)
For patients with hepatic colorectal metastases, the most common site of tumor recurrence after liver resection is the remnant liver (50). In the treatment of patients with small hepatic metastases, there is particular concern that even smaller undetected metastases may subsequently present as a liver tumor recurrence. Regional chemotherapy to treat the liver site is therefore a theoretically attractive option for adjuvant care. Data addressing the utility for such hepatic arterial infusional (HAI) chemotherapy had been sparse, consisting only of four small single-arm studies (5153) and a single, small, randomized trial consisting of 36 patients (54). These preliminary studies demonstrated safety of such an approach, but efficacy data were insufficient to support the routine use of adjuvant intraarterial chemotherapy. Two large randomized trials examining adjuvant HAI have been completed. In the first trial (55), 224 patients from 25 centers were randomized to either no adjuvant therapy or adjuvant HAI 5-FU + systemic folinic acid. Although no difference was found between the groups, technical factors compromised this study such that only 34 of the 114 patients randomized to chemotherapy completed the adjuvant treatments. In another study, Kemeny et al. randomized 156 patients to either systemic 5-FU + leucovorin or HAI floxuridine (FUDR) + systemic 5-FU after complete resection of tumor (56). There was a significant survival advantage to HAI that is most likely related to local liver tumor control. We believe HAI chemotherapy is effective and
should be considered as an adjuvant to resection of hepatic colorectal metastases. For noncolorectal, nonneuroendocrine histologies metastatic to the liver, the most likely cause of death will be related to the disease outside the liver, regardless of how the liver is managed. For patients who are likely to develop systemic metastases in the near future, it may be reasonable to offer chemotherapy prior to resection. If the tumor responds, then a resection will be performed with confidence that other micrometastatic disease may be effectively treated with chemotherapy. If the tumor does not respond and the liver remains the only site of metastatic disease, resection is performed with increased confidence conferred by the longer period of observation. If the patient advances systemically during chemotherapy, then it is very unlikely that a resection would have been of benefit and the patient will have avoided the potential morbidity, pain, discomfort, and recovery time of an hepatic resection. That patient can go on to obtain second-line chemotherapy, investigational chemotherapy, or have no additional treatment.
conclusions
Algorithms for the management of small solitary hepatic metastases are shown in Figure 6.4. Both patient and tumor characteristics must be considered in making management decisions. The most important tumor-related characteristic is
59
Resection
Observation or chemotherapy
Ablation
Resection
No extrahepatic progression
Extrahepatic progression
Chemotherapy
Symptomatic
Resection
Ablation
Observation Resection Progression No progression Effective chemotherapy (>20% response) No effective chemotherapy
Observation (C)
Trial of chemotherapy
Ablation vs observation
Figure 6.4 Algorithms for the management of small hepatic metastases. (A) Algorithm for colorectal metastases (CRS, clinical risk score). (B) Algorithm for neuroendocrine metastases. (C) Algorithm for non-colorectal, non-neuroendocrine metastases.
histology. For patients with colorectal cancer (Fig. 6.4A), the prognostic factors for tumor recurrence after resection are well defined. Using the clinical risk score (CRS) as selection criterion, patients with CRS = 02 are ideal candidates for resection. Those with CRS = 34 should consider observation or chemotherapy prior to a definitive hepatic procedure. Immediate ablation or resection should be performed in the setting of a clinical trial, and most appropriately a trial examining adjuvant therapy. For neuroendocrine cancers (Fig. 6.4B), symptomatic tumors should be treated with resection and/or ablation when possible. When the cancer is found in an asymptomatic patient, a period of observation is not unreasonable because of the often indolent nature of these tumors. At resection, the principle should be to leave as much normal liver behind in order to minimize the risk of liver failure and in order to allow for
repeat anatomic liver resections in the future for recurrent disease. Enucleation with positive margins is acceptable for treatment of this histology because resection is almost never curative, and such cytoreduction can provide significant and durable palliation with minimum risk. For patients with small, solitary, noncolorectal nonneuroendocrine tumors, the most significant factor in terms of prognosis seems to be the disease-free interval (Fig. 6.4C). For patients with a long disease-free interval from primary resection a curative surgical resection is indicated as the most effective means of therapy. While it may be still unlikely that these patients can be cured, they must be given the benefit of the doubt and the most optimal procedure performed. The definition of long has been arbitrarily set at 36 months by Harrison et al. (26), but in reality it must vary according to histology. For gastric cancer, 1224 months would be
60
references
1. Nuzzo G, Giuliante F, Giovannini I, Tebala GD, Clemente G, Vellone M. Resection of hepatic metastases from colorectal cancer. Hepato-gastroenterology 1997; 44: 7519. 2. Alexander HR, Bartlett DL, Fraker DL, Libutti SK. Regional treatment strategies for unresectable primary or metastatic cancer confined to the liver. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: JB Lippincott, 1996: 119. 3. Wagner JS, Adson MA, van Heerden JA, Adson MD, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199: 5028. 4. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin Oncol 1976; 2: 2858. 5. Fong Y, Blumgart LH, Cohen AM. Surgical treatment of colorectal metastases to the liver. CA Cancer J Clin 1995; 45: 5062. 6. Hughes KS, Simon R, Songhorabodi S. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Surgery 1988; 103: 27888. 7. Rosen CB, Nagorney DM, Taswell HF et al. Perioperative blood transfusion and determinants of survival after liver resection for metastatic colorectal carcinoma. Ann Surg 1992; 216: 493505. 8. Scheele J, Stang R, Altendort-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995; 19: 5971. 9. Taylor M, Forster J, Langer B, Taylor BR, Greig PD, Mahut C. A study of prognostic factors for hepatic resection for colorectal metastases. Am J Surg 1997; 173: 46771. 10. Fong Y, Cohen AM, Fortner JG et al. Liver resection for colorectal metastases. J Clin Oncol 1997; 15: 93846. 11. Moertel CG. An odyssey in the land of small tumors. J Clin Oncol 1987; 5: 150322. 12. Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988; 104: 10117. 13. Declore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am Coll Surg 1994; 178: 188211. 14. Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975; 36: 5609. 15. Sjoblom SM. Clinical presentation and prognosis of gastrointestinal carcinoid tumours. Scand J Gastroenterol 1988; 23: 77987. 16. McEntee GP, Nagourney DMN, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990; 108: 1091. 17. Chen H, Hardacre JM, Uzra A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg 1998; 187: 8892. 18. Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World J Surg 1995; 19: 7682. 19. Raab R, Nussbaum KT, Behrend M, Weimann A. Liver metastases of breast cancer: results of liver resection. Anticancer Res 1998; 18: 22313. 20. Elias D, Lasser PH, Montrucolli D, Bonvallot S, Spielmann M. Hepatectomy for liver metastases from breast cancer. Eur J Surg Oncol 1995; 21: 5103. 21. Jaques DP, Coit DG, Casper ES, Brennan MF. Hepatic metastases from soft-tissue sarcoma. Ann Surg 1995; 221: 3927. 22. Schwartz SI. Hepatic resection for noncolorectal nonneuroendocrine metastases. World J Surg 1995; 19: 725. 23. Salmon RJ, Levy C, Plancer C, et al. Treatment of liver metastases from uveal melanoma by combined surgery-chemotherapy. Eur J Surg Oncol 1998; 24: 12730. 24. Ochiai T, Sasako M, Mizuno S. Hepatic resection for metastatic tumours from gastric cancer: analysis of prognostic factors. Br J Surg 1994; 81: 11758. 25. Bines SD, England G, Deziel DJ, Witt TR, Doolas A, Roseman DL. Synchronous, metachronous and multiple hepatic resections of liver tumors originating from primary gastric tumors. Surgery 1993; 114: 799805. 26. Harrison LE, Brennan MF, Newman E et al. Hepatic resection for noncolorectal, nonneuroendocrine metastases: a fifteen-year experience with ninety-six patients. Surgery 1997; 121: 62532.
key points
Factors that determine management
Natural history of tumor type Expected cure rate after surgical treatment Effectiveness of alternative treatment strategies Morbidity of surgical resection
Good evidence for long-term survival Colorectal metastases Neuroendocrine metastases Survival possible in highly selected cases Breast cancer Sarcoma (especially gastrointestinal stromal tumors) Melanoma
Contraindications Extrahepatic disease (except solitary pulmonary metastases) Positive hilar lymph nodes Relative contraindications Presentation within 12 months of resection of primary tumor CEA >200 ng/dl >1 liver tumor Tumor >5 cm in size Positive resection margin
61
62
Managing complications of hepatectomy Fenella K. S.Welsh, Timothy G. John, and Myrddin Rees
postoperative morbidity and mortality on an initial univariate analysis, it failed to independently predict outcome on subsequent multivariate analysis. Similarly, Belghitis group found that the in-hospital mortality rate was significantly higher in those patients with cirrhosis (8.7%) compared to those without underlying liver disease (1%, p < 0.001), but this was not subjected to multivariate analysis (7). Thus while liver resection in cirrhotic patients is technically more challenging than resecting normal liver, with a higher incidence of bleeding, septic complications, and postoperative liver failure (14), these two studies would suggest that in experienced high-volume centers, liver resection can be safely performed in patients with early cirrhosis. The common complications of hepatectomy may be classified as specific to the procedure or of a more general nature (Table 7.3). This chapter will deal with these complications in turn, focusing on their definition, incidence, predisposing factors, prevention, presentation, investigation, and treatment.
introduction
The safety of elective liver surgery has improved dramatically in the past 30 years. A multicenter American series comprising 621 liver resections published in the late 1970s reported a 13% mortality (1). By contrast, recent large published series describe posthepatectomy mortality rates of 0% to 4.4%, with 19.6% to 45% morbidity (28) (Table 7.1). Furthermore, individual units have demonstrated a significant reduction in morbidity and mortality over time, despite ever-widening the indications for hepatectomy (6,8). This dramatic improvement in immediate postoperative outcome can be explained by increased specialization of liver surgery in high-volume centers (9), better selection of patients in terms of hepatic functional reserve and comorbid conditions, advances in surgical technique, including greater understanding of hepatic segmental anatomy and improved instrumentation for the parenchymal transection. Furthermore, anesthesia and critical care has improved enormously, the routine use of low central venous pressure (CVP) anesthesia being a particular advance. However, even a 20% complication rate remains significant, particularly if the indication for hepatectomy is for livingdonor transplantation. Furthermore, postoperative morbidity can also adversely affect disease-specific and disease-free survival (1012). Thus the short- and long-term consequences of postoperative morbidity, coupled with increasing litigation, and limited health care resources, has renewed the drive to further improve the immediate outcome from liver resection, with emphasis on prevention of and improved management of complications, when they occur. The precise definitions of the specific complications such as bleeding, bile leak, and hepatic insufficiency are still without consensus. Moreover, the stratification of the severity of each complication is still unclear. Standardized definitions, grading, and reporting of the complications of hepatectomy are needed to allow an objective, quality assessment of outcome data from different units and further improve results. The system proposed and validated by Clavien, focusing on the therapeutic consequences of complications in order to rank their severity, is currently the best available (13). However, it is still not universally adopted within the surgical community. A number of studies have attempted to identify the risk factors associated with complications and death from hepatectomy, three of which are detailed in Table 7.2. From these studies, there is consensus that the estimated blood loss or blood transfusion rate, the extent of hepatic resection, and an additional extrahepatic procedure are all independent predictors of morbidity and mortality. In addition, medical comorbidity, an elevated preoperative creatinine, preoperative thrombocytopenia, or hypoalbuminemia also appear to increase the operative risk. However, in the Hong Kong study (8), while cirrhosis per se was associated with increased
bleeding
Incidence Bleeding is the most feared complication of hepatectomy, both on the operating table and in the immediate aftermath of surgery. In the 1960s and 1970s, it was the cause of major morbidity and mortality. The 1974 Liver Tumor Survey was a multicenter series of 621 hepatic resections performed in 98 U.S. centers, published in 1977. It reported a 13% mortality, with 15 of the 82 deaths (18%) due to exsanguinating hemorrhage in the operating room and bleeding being the documented primary cause of death in 26 of the 76 patients (34%), where the cause of death could be determined (1). However, bleeding is now relatively rare, with the median estimated blood loss for an elective hepatectomy being 345 to 600 ml (3,6) and the need for perioperative blood transfusion now being the exception rather than the rule. Indeed, the incidence of major hemorrhagic complications is rare, 0.7% (7/1005) in our own series (3). Of these seven cases, there were no on-table deaths, five patients were treated nonoperatively and two underwent reexploration for bleeding from a hepaticojejunal anastomosis and a left caudate branch of the portal vein respectively. In the Sloan-Kettering series of 1803 patients, the incidence is similar (1%) (6). Prevention Prevention remains the key to the management of bleeding. In the preoperative assessment, a careful drug history should be taken. If the patient is on drugs such as aspirin, clopidogrel, or warfarin, the indication for the treatment should be reviewed, and the drugs stopped where possible. Patients on warfarin as prophylaxis for thromboembolic events can be managed with an inferior vena cava (IVC) filter, placed preoperatively. It is
63
Poon et al.
19892003
1222
32.4%
Table 7.2 Three Studies Reporting the Independent Predictors of Morbidity and Mortality after Hepatic Resection
Reference Jarnagin et al. Years of study 19912001 No of resections 1803 Predictors of morbidity Estimated blood loss Extent of resection + EH procedure preoperative creatinine Hypoalbuminemia Medical comorbidity Male gender ASA score Extent of resection Steatosis Blood transfusion + EH procedure Thrombocytopenia Blood transfusion + EH procedure Predictors of mortality Estimated blood loss Extent of resection + EH procedure preoperative bilirubin Thrombocyt openia Age + EH procedure (in patients with malignancy)
Belghiti et al.
19901997
Poon et al.
19892003
1222
important to identify patients with tricuspid regurgitation or right heart disease, where the anesthetist may encounter difficulties in lowering the CVP, as this may influence the extent of resection. Careful evaluation and correction of coagulation abnormalities should be performed pre- and perioperatively, particularly in the cirrhotic patient. Two key maneuvers are used to prevent bleeding during hepatic transection: portal triad clamping and low CVP anesthesia. Portal triad clamping, first described by Pringle in 1908, reduces hepatic arterial and portal venous bleeding (15,16). Although a European survey demonstrated that the use of inflow occlusion is not universal, it did confirm that most hepatic surgeons resort to it in difficult cases and that experienced surgeons are more likely to use it routinely (17). However, a recent systematic review and meta-analysis of the effect of inflow occlusion on postoperative morbidity and mortality failed to demonstrate any significant outcome
benefit (18). This is confirmed by another systematic review published in 2009, which compared 166 patients with vascular occlusion to 165 patients with no vascular occlusion (19). However, despite the small numbers involved, this later study showed that blood loss was significantly lower in those patients who had vascular occlusion. A low CVP reduces back bleeding from hepatic veins during the transection (2022) and is now accepted practice during liver resection worldwide. Indeed, following the introduction of low CVP anesthesia in our own unit, the mean blood loss was significantly reduced from 2116 to 426 ml (3). However, these techniques can test the patients cardiovascular reserve. Obstructing the portal blood flow causes venous congestion of bowel and in combination with warm ischemic liver injury, releasing a flush of anerobic metabolites and cytokines back into the circulation on release of the clamp (23). Low CVP anesthesia relies on patients being maintained in a
64
Investigation and Treatment The hemoglobin concentration and clotting screen should be performed urgently, ensuring that the patient has an up-todate cross match. Any coagulopathy should be corrected. If the patient remains shocked, appropriate investigations may include endoscopy and mesenteric arteriography. Ultimately, as in our own series, small number of patients may need to return to the operating theatre for surgical control of hemorrhage.
biliary complications
Biliary stricture
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolus; MI, myocardial infarction; CVA, cerebrovascular accident.
hypovolemic state until liver resection has been completed (20,21). This is in contrast to most other major surgical procedures, where patients have large volumes of crystalloid and colloid perioperatively. While a recent meta-analysis has confirmed that the use of the antifibrinolytic agent aprotinin can significantly reduce transfusion requirements during liver transplantation (24), there is no evidence for its routine use during liver resection (25). In contrast, a prospective double-blind randomized trial of tranexamic acid, another antifibrinolytic agent, has shown that its use perioperatively significantly reduced the blood loss and transfusion requirements in elective liver resection (26). Two prospective randomized controlled trials have failed to show any benefit of using recombinant factor VIIa in either noncirrhotic (27) or cirrhotic (28) patients undergoing hepatectomy. Since the early 1990s, the use of fibrin sealants has become a popular aid hemostasis at the hepatic parenchymal transection site. Two early randomized trials suggested some benefit in achieving hemostasis (29) and reducing postoperative blood loss (30), although the numbers involved were small. A more recent trial of a carrier-bound fibrin sealant (TachoSil) suggested it was quicker and more effective hemostasis compared to argon beam coagulation (31). However, the numbers involved were again small (<65 patients in each group). A larger prospective randomized trial of fibrin glue versus control involving 300 patients undergoing hepatic resection was published in 2007 (32). This showed no difference in blood loss, blood transfusion, or overall morbidity between those who received the fibrin glue and those who did not. This study provides the best evidence to date that the routine use of such topical hemostats is not justified, although it is our own personal bias that fibrin glue needs to be combined with a collagen matrix to be effective. Presentation Postoperatively, patients who are bleeding may present with classical signs of shock, persistent blood loss in an abdominal drain, a drop in hemoglobin, or gastrointestinal bleeding.
Incidence and Definition of a Bile Leak Bile leak remains a persistent problem after hepatectomy, with a reported incidence of 1% to 12% (3,33). In addition, it appears to be the most common complication after living donor hepatectomy, with an incidence of 7.5% in the 731 donors in one Japanese series (34) and 9% in 381 donors in an American series (35). The variable incidence may be explained by the different patient populations analyzed and the lack of consensus regarding the definition. The Amsterdam group has defined bile leakage as one or more of the following criteria: the presence of persisting bile-stained effluent from an abdominal drain, leakage detected on radiological imaging, and occurrence of a bile collection drained percutaneously or found during relaparotomy (36). This definition of a bile leak, used in conjunction with Claviens severity grading (13), could be widely applied in clinical practice. Prevention Meticulous technique during the parenchymal transection, ensuring that both small and large bile ducts are adequately secured with clips, ties, or sutures, is vital for the prevention of bile leakage. Inspection of the cut surface and application of a clean white-gauze swab is usually enough to reveal a bile leak, which must then be sutured. Methods for testing for bile leakage have previously been advocated and include injection of the biliary system (usually via the cystic duct stump) with saline solution or methylene blue, or formal direct cholangiography after the transection has been completed. However, the only prospective randomized study has shown no evidence that such maneuvers reduce the bile-leak rate (37) and thus this technique cannot be recommended as a routine. While one study has show that topical fibrin glue significantly reduces the bile-leak rate following hepatectomy (38), other studies have failed to show any benefit (29,39). Thus there is no clear evidence that topical hemostatic agents used after the liver resection on the parenchymal surface reduce the bile-leak rate (33). Risk Factors for a Bile Leak There is consensus in the literature that extended hepatic resections are associated with an increased risk of bile leak (36). An Italian series of 610 liver resections without a concurrent hepaticojejunostomy reported a 3.6% incidence of postoperative bile leakage (38). On multivariate analysis, they found that resection of a peripheral cholangiocarcinoma (relative risk 5.5) and hepatectomies including segment 4 (relative risk 3.1) were the only independent risk factors for a bile leak.
65
hepatic insufficiency
Definition and Incidence There is currently no internationally accepted definition of postoperative liver failure or hepatic insufficiency. Belghitis group have proposed the 50-50 criteria, which are a prothrombin index <50% of normal (corresponding to an International Normalized Ratio (INR) of 1.7 or more) and a serum bilirubin > 50 mol/L on postoperative day 5, as a simple, accurate predictor of liver failure and death (47). On the fifth postoperative day, both prothrombin time and bilirubin should have returned to normal values. They found that the persistence of the 50-50 criteria at this time indicated a significant impairment of liver function and was associated with a 59% risk of early postoperative mortality, compared with a 1.2% risk if the criteria were not met. They recently prospectively evaluated these criteria in a cohort of 436 elective hepatectomies and found that the 50-50 criteria on postoperative days 3 and 5 were accurate predictors of death on multivariate analysis (48). The MD Anderson group reviewed data from 1059 noncirrhotic patients who underwent a major hepatectomy and found that a peak bilirubin of more than 120 mol/L (7.0 mg/d/L), accurately predicted liver-related death and suggested that this be used as a definition (49). By this definition, the incidence of postoperative liver failure with or without multiorgan failure resulting in death in their series was 2.8%. In the French multicenter series of 1568 hepatectomies, the incidence of liver failure was 43/1568 (2.7%), however this was responsible for death in 7/43 (16%) of those patients (50). In the Hong Kong series (8), postoperative liver failure occurred in 47 out of the 1222 hepatic resections (3.8%), but again, it is not defined. This series had a higher incidence of patients (59.2%) with cirrhosis or chronic hepatitis compared to most Western case series. Overall, the reported incidence in the literature ranges from 0.7% to 9.1% (51).
66
67
intra-abdominal infection
Importance and Incidence Posthepatectomy infections are important as they can precipitate liver failure and death, as discussed earlier. The incidence of infected perihepatic collections ranges from 2.7% to 6.1% in modern case series (6,8), but is higher (12.8%) in older series (74). The incidence of infected ascites is less than 1% (8). Factors Affecting the Incidence of Intra-abdominal Infection The decreasing incidence of intra-abdominal infections over time is a reflection of the evolution of liver surgery in the past 30 years. In Yanagas series of 149 liver resections performed between 1973 and 1984, 19 patients (12.8%) developed intraperitoneal septic complications, of whom 13 patients died of liver failure (74). They identified five risk factors for this, which were: (1) right or extended right hepatectomy, (2) age > 65 years, (3) operation time > 5 hours, (4) blood loss > 3L, and (5) postoperative bleeding, which required a laparotomy to achieve hemostasis. A further Japanese case series of 535 hepatectomies performed between 1992 and 2005 reported that advanced age, diabetes mellitus, the use of silk sutures, and bile
68
renal failure
Definition and Incidence Renal failure is defined as the need for renal replacement therapy. Studies have shown that 3% to 7% of patients require renal replacement therapy after liver resection (21,87). In our own case series, the incidence is 0.9% (unpublished data). Etiology of Renal Failure After Hepatic Resection There are three main factors which may contribute to the development of renal failure following liver resection. Elderly patients and those with conditions such as hypertension, atherosclerosis, or chronic kidney disease are at risk (88). These patients have a reduced capacity for neurohumoral autoregulation of glomerular blood flow during surgery and thus an increased risk of acute tubular necrosis (ATN) (88). Perioperative use of NSAIDs may also impair normal autoregulation of glomerular perfusion through inhibition of arteriolar dilatory prostaglandins (88) and should be avoided in patients with preoperative renal impairment. The second factor relates to the hit of surgery. Two key factors in the pathogenesis of ATN are hypovolemia and renal damage by inflammatory mediators (87). Both these events are predictable in every hepatic resection that employs low CVP anesthesia and portal inflow occlusion. Obstruction of the portal blood flow with the Pringle maneuver causes splanchnic venous congestion and, in combination with warm ischemic liver injury, results in a flush of anerobic metabolites and cytokines into the systemic circulation on release of the hepatic inflow clamp (23). Low CVP anesthesia relies on patients being maintained in a hypovolemic state until liver resection has been completed (20,21). This is in contrast to most other major surgical procedures, where patients are given significant volumes of crystalloid and colloid in the perioperative period. Moreover, vasodilators are often used to further reduce the CVP, leading to distributive changes in blood flow (20). Certainly, low CVP anesthesia with or without hepatic inflow occlusion can produce major circulatory changes, potentially resulting in ATN and subsequent renal impairment or failure (87). Another factor, which contributes to the etiology of renal failure following liver resection is a low perfusion state either secondary to cardiac dysfunction or distributive circulatory changes, such as sepsis or hepatorenal failure (87,88). Postoperative renal dysfunction is often multifactorial. Consequences of Postoperative Renal Failure The potential consequences of acute kidney injury include increased risk of mortality and may contribute to the development of chronic kidney disease (89).
cardiac complications
In our own series, the Sloan-Kettering and the Hong-Kong series, the most common cardiac complication of hepatectomy is arrhythmia, with an incidence of 2% to 5% (6,8). Myocardial infarction and heart failure will also occur in about 1% of patients. At-risk patients should be identified preoperatively and undergo a cardiac assessment with exercise or pharmacological stress echocardiography and coronary angiography. Cardiac function should be optimized preoperatively with medical therapy, coronary stenting, and coronary artery bypass grafting as required. We have also used a perioperative intra-aortic balloon pump (86).
69
wound complications
The incidence of wound infection was 5.2% in the SloanKettering series, with a further 10 patients (0.5%) having a wound dehiscence (6). The Hong Kong series of 1222 liver resections reports double these complication rateswith 115 patients (9.4%) developing a wound infection and 16 patients (1.3%) suffering wound dehiscence (8). An explanation of the higher incidence of wound complications in the Hong Kong series may be their higher percentage of cirrhotic patients (33% vs. 9%). A study from Japan of 626 liver resections, with a 7.7% incidence of incisional hernias, examined the risk factors for this (90). Risk factors included the type of incision, with a reversed T incision having a significantly higher incidence of an incisional hernia (21.7%) compared to midline (6.3%), J-shaped (4.7%), or a right transverse incision with long midline extension (5.4%). Furthermore, postoperative ascites, body mass index, repeat hepatectomy, and steroid use were also significant risk factors. The incidence of reported incisional hernia was 0.2% in our own series, with the two known patients who developed incisional hernias undergoing repair of these at the time of repeat liver resection. We believe this low incidence is related to the method of closure of the J-shaped wound, with a tension-free, 2-layer closure, using a 6:1 suture (looped 0-nylon) to woundlength ratio, as opposed to the traditional 4:1 ratio (85).
conclusions
The safety of elective liver surgery has improved dramatically in the past 30 years, despite ever-widening indications for hepatectomy. However, complications still happen and prevention is the key to minimizing their incidence. When complications do occur, they should be aggressively managed, in a high-dependency environment, by a multidisciplinary team. International consensus regarding definitions of complications and a severity classification is still required.
references
1. Foster JH and Berman MM. Solid liver tumours. Major Problems in Clinical Surgery, Vol. 22. Philadelphia, PA: WB Saunders, 1977: 1342. 2. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 2003; 138:1198206. 3. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a Multifactorial model of 929 patients. Ann Surg 2008; 247: 12535. 4. Wei AC, Greig PD, Grant D, et al. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006; 13: 66876. 5. Malik HZ, Prasad KR, Halazun KJ, et al. Preoperative prognostic scoring for predicting survival after hepatic resection for colorectal liver metastases. Ann Surg 2007; 246: 80614.
70
71
72
background
Pancreatic cancer remainswith an overall long-term survival rate of less than 1%one of the most difficult cancers to treat. It is the fourth leading cause of cancer-related mortality in the Western world and is responsible for around 30,000 deaths per year in the United States and 65,000 per year in Europe (1,2). In only 10% to 20% of pancreatic cancer patients potentially curative surgery is possible, and even in these patients, the median survival is only 10 to 18 months with 5-year survival rates of approximately 20% to 25% (3,4). Nonetheless, surgery remains the only treatment option with the chance of cure. Pancreatic surgery has significantly changed during the past few years. Irrespectively, pancreas resections remain an intervention of particular significance, often technically challenging and with high logistic demands for preoperative diagnostics and perioperative management. Recently, the value of centralization of pancreatic surgery in high volume institutions has been demonstrated. The current mortality rates following pancreatic resections are well below 5% in specialized surgical centers (5,6).
standard resections
Whipple Resection Partial Pancreaticoduodenectomy (Whipple resection) with or without distal stomach resection is the surgical option for tumors of the pancreatic head, which account for the majority of pancreatic cancers (Fig. 8.1). Pylorus-preserving pancreaticoduodenectomy has been proven to be equal to the classical pancreaticoduodenectomy in terms of tumor recurrence or long-term survival, and should therefore be considered the standard procedure for tumors of the pancreatic head (7). Key steps of the surgical procedure are the postpyloric division of the duodenum, which is usually carried out by use of a stapling device andmeanwhile common in many centersthe supracolic division of the ascending duodenum as soon as this portion is reached during resection. This modification facilitates the resection procedure and allows manual control of the pancreatic head without switching positions between the supra- and infracolic department. Division of the pancreas is done sharply above the superior mesenteric vein after this has been tunneled to make sure that the vein is not injured during resection and that the dissection can be done without vein replacement (see below). After removing the specimen, tumor-free resection margins should be confirmed intraoperatively by frozen sections of the cut end of the bile duct and the cut end of the pancreatic remnant. Bleeding control along the pancreatic dissection margin is achieves by carefully stitching single bleeding sites with monofilament and nonabsorbable sutures. The pancreatic duct must be seen and protected during this procedure. During pancreaticoduodenectomy, a standardized lymphadenectomy needs to be carried out. This includes the complete
73
Figure 8.1 Partial pancreaticoduodenectomy. Classical Whipple resection (left) and pylorus-preserving modification (right).
Figure 8.2 Intraoperative situs after partial pancreaticoduodenectomy. Pancreatic remnant with probe introduced, dissected portal vein and hepatic artery. A jejunal loop is prepared for the pancreaticojejunostomy.
mesenteric vein are suitably located for this procedure. Dissection of the pancreas is performed above the vein after tunneling and lifting up the body of the gland. The dissection itself can be done sharply or by using a stapling device, preferably with a thickness-adopted adjustment of the stapler. To date, there are no high-power studies to support either procedure. In case of sharp dissection, we prefer a V-shaped transection line. As in other resections, tumor-free resection margins should be examined by intraoperative frozen section. The pancreatic duct is separately closed by a monofilament Z-shaped nonabsorbable suture and the transection line can afterward be closed by single stitches covering the complete margin by pancreatic capsular tissue. There is no need or evidence for any further covering of the resection margin by sealants or patches (18). This procedure implies a certain limitation concerning the extent of distal resection toward the head of the
pancreas. The larger the tissue area of the transected parenchyma gets, the more difficult it gets to close the parenchyma, which is associated with increased fistula rates. Therefore, the right margin of the superior mesenteric vein represents the limit to which a safe surgical closure of the pancreatic remnant can be performed. In case of transection by a stapling device, this limitation is technically implied by the length of the stapler line. No additional sutures are necessary after stapler dissection. Despite all approaches, fistula development after distal pancreatectomy remains an unsolved problem. Fistula rates range from 12% to 40% (8,19). To address this clinical problem, remnant closure by sutures after sharp dissection is currently compared to stapler dissection in a randomized controlled study (DISPACT trial) in a multicenter approach including 21 European centers and 360 patients by February 2009 (20). A spleen-preserving distal pancreatectomy can be performed in benign lesions or intraductal papillary mucinous neoplasias (IPMNs), if the splenic vessels are not involved in the tumor or cystic process. However, there are no clear advantages in preserving the spleen in adult patients (21). Possible advantages could be infection prophylaxis, less operative blood loss, fistula rates as well as fewer thromboembolic complications (22,23). By contrast, the risk of splenic infarction and portal hypertension has to be regarded whenever the spleen is preserved. From the currently available literature mainly retrospective studiesnone of these parameters is clearly proven, further studies have to address this topic in the future. By contrast, there is growing evidence that distal pancreatectomy can be performed with good results laparoscopically. This approach is usually performed using 5 trocars and stapler dissection of the pancreas. It is routinely performed in several centers with results comparable to the open approach in terms of operative morbidity and outcome (23). The possible advantages of laparoscopic operations, with faster patient recovery, less pain medication, and better cosmetic results are currently evaluated in larger series. Total Pancreatectomy The concept of total pancreatectomy has to be divided into the rescue procedure in not conservatively managed postoperative
74
PANCREATIC RESECTION
Figure 8.3 Pancreatico-jejunostomy. Preparation of duct sutures (upper left), position of the jejunal loop (upper right), anterior wall sutures (lower left), and completed anastomosis (lower right).
complications caused by the pancreatic remnant after head resections and the primarily performed total removal of the gland with or without the spleen (24). Completion pancreatectomy may be necessary in case of severe complication like insufficiency of the pancreaticojejunostomy with septic or bleeding complications. In this situation, an early completion operation can be life-saving for the patient and is technically similar to a distal pancreatectomy after disconnection of the pancreas anastomosis (25,26). Primary total pancreatectomy can be required in patients with a nonaltered pancreatic remnant due to the soft tissue texture, e.g., in distal bile dust cancer or duodenal tumors without congestion of the pancreatic duct, which can make the pancreatic anastomosis a dangerous reconstruction. The surgeon has to evaluate the costbenefit relation carefully; in doubtful situations a risky anastomosis should rather be avoided. From the oncological point of view, extensive main-duct IPMNs, IPMNs with progression to carcinoma, familial or multifocal pancreatic cancer are indications for a primary total pancreatectomy. Furthermore, this procedure may be necessary if a tumor-free resection margin and R0 situation cannot be achieved otherwise (2429). The resection can be performed as a two-part procedure with an
initial head resection similar to a Whipple procedure followed by the distal resection, which facilitates the surgical preparation, or with a removal of the gland as a complete specimen, if a pancreatic transection implies the risk of tumor cell spilling. Whenever possible, a pylorus-preserving reconstruction should be preferred. Duodenum-Preserving Pancreatic Head Resection The best technique for the surgical treatment of pancreatic head lesions in chronic pancreatitis is still under debate. Partial pancreatoduodenectomy with or without preservation of the pylorus have served for many years as the primary surgical procedure. However, these resections are unsatisfactory in terms of late morbidity with an incidence of up to 48% of postoperative diabetes mellitus (30). Today, duodenumpreserving pancreatic head resection duodenum-preserving pancreatic head resection (DPPHR), which was introduced by Beger in 1972 (31), has undergone several modifications and is considered the standard procedure for nonmalignant head lesions in chronic calcified pancreatitis (32). Whenever possible, depending on the extent of the calcified and fibrotic lesions, the Berne modification as the most tissue-sparing
75
Figure 8.4 Pylorus-preserving pancreatic head resection (Berne modification). Note the incision and fixation of the bile duct in the resection cavity.
Figure 8.5 Pylorus-preserving pancreatic head resection (Berne modification). Resection cavity with first layer of the posterior wall of the pancreaticojejunostomy (left), completed anastomosis (right).
76
PANCREATIC RESECTION
achieve surgical cure. Limited resections represent a tissuesparing treatment option to minimize the risk of exocrine or endocrine pancreatic insufficiency postoperatively (42) and to reduce surgical morbidity and mortality by reduced operative trauma. One of the most important aspects to perform an enucleation successfully is the accurate localization of the tumor or cystic lesion. Besides preoperative localization by CT or MRI scan, the most important tool for tumor location is the experience of the surgeon performing the exploration (4346). Mobilization of the pancreas is essential when tumors or cystic lesions have to be located to enable a careful digital examination of the suspected lesion. This should be supplemented by intraoperative ultrasound to exclude multifocal tumorous lesions especially in endocrine tumors or IPMNs. In addition, a possible relation to the pancreatic duct can only be clarified by ultrasound examination, if there is any doubt about it intraoperatively (47). A tumor size of 2.5 cm in diameter can be regarded as the limit for a safely performed enucleation. Tumors measuring more than 2.5 cm in size show malignant histological changes significantly more frequently, making a local surgical approach impossible. Besides, tissue trauma and wound surface following an enucleation reach a critical size for development of fistulas or other complications including bleeding or postoperative pancreatitis (47). Enucleation itself is performed by careful dissection along the tumor under clip ligation or stitching of vessels supplying the lesion (Fig. 8.6). There is no evidence for any sealant or glue application after completing of the enucleation. Drain placement is essential as currently fistula rates of approximately 20% are reported (48), most of them, however, clinically uncomplicated.
exceptional indications
Vessel Resections A common problem in pancreatic head resections is tumor adherence to the superior mesenteric or portal vein. Today, portal vein resection has become an established procedure and can be carried out with morbidity rates of that are comparable to standard Whipple procedures (4956). Portal vein resection can be performed as a tangential resection with a direct suture or a patch reconstruction. In cases where a segmental resection is required due to a more extensive tumor adherence, either a direct anastomosis or the interposition of an autologous venous graft such as the saphenous vein or an allograft, e.g., a gore-tex tube. In case of a primary anastomosis, it is essential to mobilize the mesenteric root completely, which implies the complete mobilization of the right hemicolon. After this preparation, a tension-free reconstruction of defects up to 3 cm length is usually possible. The anastomosis is performed as a running suture of the posterior and anterior vessel wall with two 5-0 or 6-0 nonabsorbable sutures. When defects cannot be reconstructed by the patients vein alone, a size-adopted graft should be inserted in a similar end-to-end manner (52). Kinking of any venous anastomosis must be avoided to prevent intra- and postoperative vein or graft thrombosis with consecutive failure of the bowel circulation. In certain situations, it may be helpful not only to minimize the time of intraoperative occlusion of the mesenteric/portal vein but also to clamp the superior mesenteric artery for this period to avoid venous congestion and swelling of the small bowel and the right hemicolon (Fig. 8.7). Arterial resection is a rather uncommon surgical procedure during pancreatic cancer resection. If the superior mesenteric artery is involved in the tumor process, this is a general exclusion criterion for resection and has only been reported in few patients (56). By contrast, tumor adherence or infiltration along the celiac axis must not be considered as generally irresectable (43,53). In selected patients, the celiac trunk might be resected down to its aortic orifice in Whipple as well as in left resection or total pancreatectomies (5456). As long as the proper hepatic artery can be preserved, a reconstruction is possible. The left gastric and splenic artery can usually be cut without reconstruction, a consecutive
Figure 8.7 Examples of portal vein resections. Direct end-to-end anastomosis (left) and graft implantation (right).
77
Figure 8.8 Pancreatic cancer recurrence resection. Intraoperative finding of the recurrence located in the interaortocaval space (left), situs after resection (right) prior to intraoperative radiation.
78
PANCREATIC RESECTION
localized metastastic disease, indicating favorable tumor biology and justifying the aggressive operative approach. This has to be embedded in a global oncological concept, must be decided highly individually and cannot be regarded as a standard procedure (65).
13. Pedrazzoli S, Liessi G, Pasquali C, et al. Postoperative pancreatic fistulas: Preventing severe complications and reducing reoperation and mortality rate. Ann Surg 2009; 249(1): 97104. 14. Veillette G, Dominguez I, Ferrone C, et al. Implications and management of pancreatic fistulas following pancreaticoduodenectomy: The Massachusetts General Hospital experience. Arch Surg 2008; 143(5): 47681. 15. Reid-Lombardo KM, Farnell MB, Crippa S, et al. Pancreatic anastomotic leakage after pancreaticoduodenectomy in 1,507 patients: A report from the Pancreatic Anastomotic Leak Study Group. J Gastrointest Surg 2007; 11(11): 14518; discussion 1459. Epub 2007 Aug 21. 16. Molinari E, Bassi C, Salvia R, et al. Amylase value in drains after pancreatic resection as predictive factor of postoperative pancreatic fistula: Results of a prospective study in 137 patients. Ann Surg 2007; 246(2): 2817. 17. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: An international study group (ISGPF) definition. Surgery 2005; 138(1): 813. 18. Knaebel HP, Diener MK, Wente MN, et al. Systematic review and metaanalysis of technique for closure of the pancreatic remnant after distal pancreatectomy. Br J Surg 2005; 92(5): 53946. 19. Andrn-Sandberg A, Wagner M, Tihanyi T, et al. Technical aspects of leftsided pancreatic resection for cancer. Dig Surg 1999; 16(4): 30512. 20. Diener MK, Knaebel HP, Witte ST, et al. DISPACT trial: A randomized controlled trial to compare two different surgical techniques of DIStal PAnCreaTectomystudy rationale and design. Clin Trials 2008; 5(5): 53445. 21. Fernndez-Cruz L, Ordua D, Cesar-Borges G, Angel Lpez-Boado M. Distal pancreatectomy: En-bloc splenectomy vs spleen-preserving pancreatectomy. HPB (Oxford) 2005; 7(2): 938. 22. Kimura W, Moriya T, Ma J, et al. Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein. World J Gastroenterol 2007; 13(10): 14939. 23. Distal pancreatectomy: radical or spleen-preserving? Chromik AM, Janot M, Slberg D, Seelig MH, Uhl W. Chirurg 2008; 79(12): 112333. 24. Keck T, Hopt UT. Total pancreatectomy: Renaissance of a surgical procedure. Chirurg 2008; 79(12): 113440. 25. Wente MN, Shrikhande SV, Kleeff J, et al. Management of early hemorrhage from pancreatic anastomoses after pancreaticoduodenectomy. Dig Surg 2006; 23(4): 2038. Epub 2006 Jul 26. 26. Bchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003; 138(12): 13104; discussion 1315. 27. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004; 239(6): 78897; discussion 7979. 28. Inagaki M, Obara M, Kino S, et al. Pylorus-preserving total pancreatectomy for an intraductal papillary-mucinous neoplasm of the pancreas. J Hepatobiliary Pancreat Surg 2007; 14(3): 2649. Epub 2007 May 29. 29. Mller MW, Friess H, Kleeff J, Dahmen R, Wagner M, Hinz U, BreischGirbig D, Ceyhan GO, Bchler MW. Is there still a role for total pancreatectomy? Ann Surg 2007; 246(6): 96674; discussion 9745. 30. Sakorafas GH, Farnell MB, Nagorney DM, et al. Pancreatoduodenectomy for chronic pancreatitis: long-term results in 105 patients. Arch Surg 2000; 135: 51723. 31. Beger HG, Buchler M, Bittner RR, et al. Duodenum-preserving resection of the head of the pancreas in severe chronic pancreatitis. Early and late results. Ann Surg 1989; 209: 27378. 32. Diener MK, Rahbari NN, Fischer L, et al. Duodenum-preserving pancreatic head resection versus pancreatoduodenectomy for surgical treatment of chronic pancreatitis: A systematic review and meta-analysis. Ann Surg 2008; 247(6): 95061. 33. Cataldegirmen G, Bogoevski D, Mann O, et al. Late morbidity after duodenum-preserving pancreatic head resection with bile duct reinsertion into the resection cavity. Br J Surg 2008; 95(4): 44752. 34. Bchler MW, Friess H, Muller MW, et al. Randomized trial of duodenumpreserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995; 169: 659. 35. Farkas G, Leindler L, Daroczi M, et al. Prospective randomised comparison of organ-preserving pancreatic head resection with pylorus-preserving pancreaticoduodenectomy. Langenbecks Arch Surg 2006; 391: 33842.
conclusion
Pancreatic surgery has undergone a remarkable development during the last decades. Appropriate surgical approaches have been established and can be used in differential indications today. In pancreatic cancer, standard resections include the classical Whipple operation and the pylorus-preserving modification, which should be preferred whenever possible as well as a distal or total pancreatectomy in extended tumors of the gland. All of these procedures can be carried out safely with surgical mortality rates well below 5% in specialized centers due to a high grade of standardization and experience. Modern tissue-sparing procedures such as the duodenum-preserving pancreatic head resection in chronic pancreatitis or tumor enucleations offer limited approaches for circumscribed nonmalignant pancreatic pathologies. Furthermore, extended resections for the treatment of pancreatic malignancies including multivisceral and recurrence resectionsare technically feasible although the oncological outcome of these procedures has to be further evaluated and pancreatic cancer treatment must always be embedded in an interdisciplinary concept of surgery and adjuvant therapy to ensure best possible outcome.
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 2007; 57(1): 4366. 2. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford) 2008; 10(1): 5862. 3. Wagner M, Redaelli C, Lietz M, et al. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 2005; 91: 58694. 4. Schnelldorfer T, Ware AL, Sarr MG, et al. Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: Is cure possible? Ann Surg 2008; 247(3): 45662. 5. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346(15): 112837. 6. McPhee JT, Hill JS, Whalen GF, et al. Perioperative mortality for pancreatectomy: A national perspective. Ann Surg 2007; 246(2): 24653. 7. Diener MK, Knaebel HP, Heukaufer C, et al. A systematic review and meta-analysis of pylorus-preserving versus classical pancreaticoduodenectomy for surgical treatment of periampullary and pancreatic carcinoma. Ann Surg 2007; 245(2): 187200. 8. Michalski CW, Kleeff J, Wente MN, et al. Systematic review and metaanalysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg 2007; 94(3): 26573. 9. Bchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after pancreatic resection: Toward the end of completion pancreatectomy. Arch Surg 2003; 138(12): 13104; discussion 1315. 10. Wente MN, Shrikhande SV, Kleeff J, et al. Management of early hemorrhage from pancreatic anastomoses after pancreaticoduodenectomy. Dig Surg 2006; 23(4): 2038. Epub 2006 Jul 26. 11. Hartel M, Wente MN, Hinz U, et al. Effect of antecolic reconstruction on delayed gastric emptying after the pylorus-preserving Whipple procedure. Arch Surg 2005; 140(11): 10949. 12. Tani M, Terasawa H, Kawai M, et al. Improvement of delayed gastric emptying in pylorus-preserving pancreaticoduodenectomy: Results of a prospective, randomized, controlled trial. Ann Surg 2006; 243(3): 31620.
79
80
Pancreatic resection and the associated complications remain challenging problems for patients and surgeons. Since the earliest reports describing the technique of pancreaticoduodenectomy (PD) by Kausch and Whipple, significant reductions in operative mortality and morbidity have been achieved (1,2). Postoperative mortality rates have been reduced from greater than 25% in the 1960s to less than 5% in specialized centers (3). The lower risk of death following pancreatic resection is due to advances in operative technique, improvements in perioperative care, percutaneous and endoscopic management of complications, and refinements in patient selection (4). Unfortunately, morbidity rates for PD continue to exceed 30% to 40% in large series (59). We discuss the prevalence, nature, predisposing factors, and management for major surgical complications that occur following pancreatic resection. While there are many nonsurgical complications that occur following pancreatic resection, these are not addressed. Right, left, central, and total pancreatectomies are discussed separately where appropriate. The most common individual complications are considered, followed by factors affecting morbidity rates. Throughout, we outline operative strategies and postoperative interventions that impact the risk and severity of surgical complications following pancreatectomy.
specific complications
Pancreatic Anastomotic Leak and Pancreatic Fistula Pancreatic leak occurs in 7% to 29% of patients following pancreatic resection (Tables 9.1 and 9.2) (5,7,1014). The wide range in incidence is due in part to variability in defining the manifestations of pancreatic leaks and several classification systems have been proposed (9,15,16). Given similarity in management and clinical manifestations, pancreatic leak, fistula, fluid collection, and abscess will be considered together (12). Parenchymal consistency and the extent of operation are associated with pancreatic leak following right or left pancreatectomy (Table 9.3) (17). Small pancreatic duct diameter is a predictor of leak following PD (7,18). Management of fluid collections resulting from a pancreatic leak may involve operative drains, placement of postoperative drains, or reoperation (Fig. 9.1). Vin et al. reported that prolonged drainage was predicted by volume collected during the first 48 hours, fluid amylase >1000, or distal pancreatectomy (12). The magnitude of the pancreatic leak may also depend on whether the source is the main duct or parenchyma (19). Those patients who do develop pancreatic leaks are more likely to suffer from other complications or death, and this risk is exacerbated by superimposed infection (12). Numerous strategies have been attempted to minimize the chances of pancreatic leakage and these are discussed below.
81
depend on its location. Extraluminal PPH may arise from the gastroduodenal artery (GDA), splenic artery, or tributaries of the superior mesenteric vessels. Intraperitoneal hemorrhage is often associated with a pancreatic leak and options include reoperation or angioembolization. When reoperation is selected, completion pancreatectomy and suture ligation of the bleeding vessel have been advocated (45). Operative intervention more than 1 week following pancreatic resection may be particularly challenging due to adhesions and tissue friability (46). Arterial embolization is valuable under these circumstances, with a success rate of approximately 80% (Fig. 9.2) (41). We advocate distal ligation of the GDA to
ensure the technical feasibility of angioembolization as it may not be possible when the bleeding point is in close proximity to the common hepatic or superior mesenteric artery. Intraluminal PPH should be initially addressed endoscopically and may originate from anastomoses, mucosal ulceration, or the cut pancreatic surface. When bleeding is found to originate from the cut pancreatic surface, hemostasis may be achieved during reoperation through a jejunotomy or gastrotomy (32). In summary, PPH may occur in up to 9% of patients. The timing and location of the bleeding in patients suffering from PPH are important factors in predicting outcome and determining appropriate management. The overall mortality of PPH is as high as 16% and delayed PPH is associated with a 47% chance of death (41,43). Appreciation of the clinical factors associated with PPH, including sentinel bleeding, sepsis, and pancreatic leak, facilitates prompt recognition. Bile Leak The incidence of choledochoenteric leak following PD is notably lower than pancreatic leak or fistula (Table 9.1). The larger size of the bile duct and more reliable tissue integrity may account for the relative infrequency of biliary leak when compared to pancreatic leak. Similar to pancreatic leak, bile leak is associated with both sterile and infected intraabdominal fluid collections (47). The vast majority of biliary leaks or fistulae can be managed by percutaneous, transhepatic, or transabdominal drainage (48).
82
*p < 0.05, DGE = delayed gastric emptying, PD = standard pancreaticoduodenectomy, PPPD = pylorus-preserving pancreaticoduodenectomy, LOS = length of stay, EBL = estimated blood loss.
Figure 9.1 The patient presented with fever and abdominal pain 2 weeks after a pancreaticoduodenectomy. A CT scan revealed a fluid collection in the RUQ (long arrow), which was managed with CT-guided percutaneous drainage (catheter indicated by short arrow). The amylase level in the aspirated fluid was consistent with a pancreatic leak (11,320 U/L).
Death Long-term survival following pancreatic resection is a function of the underlying disease, while perioperative mortality is related to the occurrence of complications, in addition to patient, institutional, and technical factors. Fortunately, the perioperative mortality rate following pancreatic resection has been reported to be less than 2% in the most recent large series (1214,47,49,50). Pancreatic leak (11) and PPH (40,51,52) are the complications most frequently associated with perioperative mortality. As noted above, the improved mortality rates following pancreatic resection are due in large part to better management of complications. The vast majority of complications can be managed percutaneously, thereby reducing their severity and the risk of death (47).
Investigators at Johns Hopkins compared PG and PJ in 145 patients who underwent PD and found that the two methods were associated with similar leak rates (53). Several
83
*p < 0.05 versus the control group, ^statistical significance not indicated.
84
85
Ib Ib Ib III Ib Ia
A A A C A A
Recommended grading of categories of evidence: Ia, evidence from meta-analysis of randomised controlled trials; Ib, evidence from at least one randomised controlled trial; IIa, evidence from at least one controlled study without randomisation; IIb, evidence from at least one other type of quasi-experimental study; III, evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case-control studies; IV, evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Recommended strengths of management recommendation: A, directly based on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence; C, directly based on category III evidence or extrapolated recommendation from category I or II evidence; D, directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence.
summary
While the mortality rates following pancreatic resection have improved dramatically, the incidence of complications remains high. Based upon the available literature, several recommendations have been proposed ( Table 9.6). Refinements in our abilities to detect and manage complications following pancreatectomy account, in large part, for improved perioperative mortality statistics. Further progress in enhancing the safety of pancreatic resection will depend upon the development of more effective measures to prevent and treat postpancreatectomy complications. Better understanding of the biology of the diseases we subject to pancreatic resection will allow for more precise patient selection and improve both perioperative and long-term outcomes.
references
1. Kausch W. Das carcinoma der papilla duodeni und seine radikale entfernung. Beitr Klin Chir 1912; 78: 43951. 2. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of vater. Ann Surg 1935; 102(4): 76379. 3. Stojadinovic A, Brooks A, Hoos A, et al. An evidence-based approach to the surgical management of resectable pancreatic adenocarcinoma. J Am Coll Surg 2003; 196(6): 95464. 4. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery 2007;142(1): 205. 5. Balcom JH, Rattner DW, Warshaw AL, et al. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136(4): 3918. 6. Buchler MW, Wagner M, Schmied BM, et al. Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003; 138(12): 13104; discussion 1315.
7. Muscari F, Suc B, Kirzin S, et al. Risk factors for mortality and intraabdominal complications after pancreatoduodenectomy: multivariate analysis in 300 patients. Surgery 2006; 139(5): 5918. 8. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997; 226(3): 24857; discussion 257. 9. Grobmyer SR, Pieracci FM, Allen PJ, et al. Defining morbidity after pancreaticoduodenectomy: use of a prospective complication grading system. J Am Coll Surg 2007; 204(3): 35664. 10. Bottger TC, Engelmann R, Junginger T. Is age a risk factor for major pancreatic surgery? An analysis of 300 resections. Hepatogastroenterology 1999; 46(28): 258998. 11. Gouma DJ, van Geenen RC, van Gulik TM, et al. Rates of complications and death after pancreaticoduodenectomy: risk factors and the impact of hospital volume. Ann Surg 2000; 232(6): 78695. 12. Vin Y, Sima CS, Gertrajdmen GI, et al. Management and outcomes of postpancreatectomy fistula, leak, and abscess: results of 908 patients resected at a single institution between 2000 and 2005. J Am Coll Surg 2008; 207(4): 490. 13. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 2006; 10(9): 1199210; discussion 12101. 14. Ferrone CR, Warshaw AL, Rattner DW, et al. Pancreatic fistula rates after 462 distal pancreatectomies: staplers do not decrease fistula rates. J Gastrointest Surg 2008; 12(10): 16917; discussion 16978. 15. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111(5): 51826. 16. DeOliveira ML, Winter JM, Schafer M, et al. Assessment of complications after pancreatic surgery: A novel grading system applied to 633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006; 244(6): 9317; discussion 9379. 17. Bartoli FG, Arnone GB, Ravera G, Bachi V. Pancreatic fistula and relative mortality in malignant disease after pancreaticoduodenectomy. Review and statistical meta-analysis regarding 15 years of literature. Anticancer Res 1991; 11(5): 183148.
86
87
88
10
introduction
Laparoscopy offers great advantages to the patient with HPB disease. Although described in the early part of the 20th century, crude instrumentation limited its use. Progress seemed slow until the 1960s saw widespread uptake in the gynecologic community, with the Hopkins rod lens system greatly improving the optics. Sporadic reports of laparoscopic staging for HPB cancer soon followed, but it was not until the handheld camera development in the 1980s that the minimal access explosion began. Now surgeons could view the image on a monitor, and use two hands to operate instruments, while an assistant held the camera. Even the gall bladder could be removed using tiny incisions. The next 10 years saw almost every abdominal operation attempted, such that the interest now is not in what can be done, but in what should be done, and how best to do it.
laparoscopic cholecystectomy
Cholecystectomy was the first general surgical procedure to be widely performed laparoscopically. Following the first reports in 1985 and 1988 (1), the technique was rapidly popularized (25). Despite a possible increase in the incidence of severe bile duct injuries, the benefits of the laparoscopic approach have subsequently been confirmed by meta-analysis (6), demonstrating shorter hospital stay and faster convalescence with no difference in operating time or complications. There are various techniques in common usage, with the surgeon standing either on the patients right or left or between the legs, with the choice of technique depending on local teaching and personal preference. There are, however, fundamental principles to safely performing a laparoscopic cholecystectomy. Correct identification of the anatomy is fundamental. Most bile duct injuries are due to misperception rather than technical errors (7). It is important to understand the normal variations in biliary anatomy and how pathological changes may alter the relationships between the structures. The 30 telescope permits better visualization of Calots triangle. Hartmanns pouch is retracted laterally and inferiorly so that the angle between the cystic and common hepatic ducts is increased rather than closed. Calots triangle is dissected high, just beneath the edge of the gall bladder, on both its anterior and posterior surfaces, to clearly identify the cystic duct and cystic artery as the only structures passing to the gall bladder (the critical view (8)). Dissection is never carried below the plane of Rouvires sulcus (9). Routine intraoperative cholangiography is recommended. This has been shown to decrease the risk and severity of biliary injury (10). It is essential that the full complement of upper duct anatomy is visualized to be certain that the common bile duct or an aberrant right hepatic duct is not being excised. It
Flushing Small filling defects in the bile duct may be air bubbles, and only the dynamic image of fluoroscopy may allow visible distortion or coalescence of these bubbles. Small stones low in the bile duct may be flushed or pushed into the duodenum using the cholangiogram catheter, with intravenous glucagon occasionally helping by relaxing the sphincter. Transcystic Stone Extraction Formal duct exploration is performed, where possible (in about two-thirds of cases), via a transcystic approach. We prefer to use a purpose-built Nathanson CBD exploration catheter (Cook). This allows manipulation of a basket under contrast-assisted fluoroscopy. The cystic duct is dissected lower, close to the common bile duct. Balloon dilatation of the
89
Figure 10.1 Laparoscopic transcystic cholangiography demonstrating calculus in the distal common bile duct.
Figure 10.2 The calculus from Figure 10.1 after transcystic extraction utilizing the Nathanson basket. Inset: completion cholangiography.
90
pancreatic pseudocyst
Pancreatic pseudocysts can be managed endoscopically with gastrotomy and stenting (perhaps the only current valid indication for NOTES [Natural Orifice Transabdominal Endoscopic Surgery]). Pancreatic pseudocysts can also be drained internally via a laparoscopic approach (3846). Most commonly the pseudocyst is located in the lesser sac and the appropriate procedure is a cyst-gastrostomy. An anterior gastrotomy is made. The cyst can be seen bulging forward, adherent to the posterior stomach wall, which is incised with diathermy or the harmonic scalpel to enter the cyst. Cyst fluid will come flowing out under pressure at this point, and is important to have an instrument ready to pass into the cyst so that the point of communication is not lost. The cyst fluid is aspirated with the sucker and the cyst emptied. A linear stapler is then introduced into the small cyst-gastrotomy to create a wide cystgastrostomy, and the residual unstapled edges are sutured together. The pseudocyst can be entered with the laparoscope and inspected, and any debris removed. The anterior gastrotomy is then closed with sutures or a stapling device. In some cases, the position of the pseudocyst will require a side-to-side cyst-gastrostomy or Roux-en-Y cyst-enterostomy. Published reports suggest that laparoscopic cyst-gastrostomy has a higher initial success rate and lower recurrence rate than endoscopic cyst-gastrostomy (42,47). As the cyst-gastrostomy created via the endoscopic approach is only small, any large debris is unable to exit the cyst. However, endoscopic approaches can be improved with using balloon dilatation and multiple stents to maintain better drainage, endoscopic ultrasound to guide the procedure and avoid vessels (48,49), and with the development of stapling instrumentation for natural orifice surgery (50).
laparoscopic staging
A proportion of patients with hepatobiliary and pancreatic malignancies will appear to be resectable on noninvasive
Figure 10.3 Peritoneal metastases at staging laparoscopy and carcinoma of the head of the pancreas.
91
laparoscopic pancreatectomy
Distal pancreatectomy is well suited to a laparoscopic approach. The usual indication is a solid or cystic tumor of the tail of the pancreas that is not clearly benign on preoperative imaging. The procedure may involve en-bloc resection of the spleen and splenic vessels; preservation of the spleen with preservation of the splenic vessels; or preservation of the spleen without preservation of the splenic vessels with the spleen supplied from the short gastric and gastroepiploic vessels (the Warshaw technique (118)). For lesions close to the spleen, when splenectomy is necessary, the approach can be similar to laparoscopic splenectomy, with the patient left side up, and the spleen and distal pancreas mobilized from lateral to medial. After division of the short gastric vessels and the gastrocolic omentum, the pancreas can be divided en bloc with the splenic vessels using a linear stapler. For a medial to lateral approach, the pancreatic neck is divided, either with a stapling device or with the harmonic scalpel with subsequent suture closure of the pancreatic stump. Where the splenic vessels are being resected, the splenic vein is divided with a stapling device and the splenic artery divided with a stapling device or locking clips. If the splenic vessels are to be preserved, then the tail of the pancreas is dissected carefully from them with control of the small vessels with clips and/or the harmonic scalpel or
92
Pure laparoscopic: where the liver resection is completed laparoscopically and the specimen removed via a remote incision; Hand assisted: where the surgeon operates with his nondominant hand inside the abdomen, placed via an airtight device, through which the specimen is removed; Hybrid liver resection (145): where the liver is mobilized laparoscopically and most of the resection is done through a smaller than usual right upper quadrant incision; Conversion: where the surgeon changes to an open operation from one of the above. One can also convert from pure laparoscopic to hand assist or hybrid.
The most suitable cases for a laparoscopic approach are solitary small (<5 cm) lesions located in the peripheral segments (26) of the liver. Larger lesions are acceptable if they are pedunculated or located in the left lateral section. Multiple lesions may be suitable if they can be resected with a single anatomic hepatectomy with a clear margin, but not where multiple complicated or bilobar procedures are required. Hemihepatectomies can be considered for a laparoscopic approach where the plane of transection and major structures (pedicles, hepatic veins and inferior vena cava) are well clear of any lesions. Lesions located in segments 7 and 8 are difficult to approach laparoscopically for a tumorectomy as the costal margin limits the approach angles of the instruments, and there is a real risk of compromising the deep margin for fear of causing difficultto-control bleedingthey should only be considered for a laparoscopic tumorectomy if they are particularly small and superficial, otherwise they need to be considered for an open procedure or a laparoscopic right hemihepatectomy. The procedures are usually performed in the supine position, often with the surgeon standing between the legs. The left lateral decubitus position is useful for lesions in segments 6 and 7, which enables better exposure of the right posterior section of the liver. Hand ports may be used. These are most useful in right sided resections where mobilization is difficult, either in nonanatomical resections with a posterior tumor in the right lobe, or right hemihepatectomies with a bulky right lobe. Good quality laparoscopic equipment is vital. A good 10-mm laparoscopic right angle is also a very important tool. An initial laparoscopy is performed, and laparoscopic ultrasound is used to identify the lesions and their relationships to the appropriate anatomy (Fig. 10.4). A tape can be placed around the hepatic pedicle in readiness for a Pringle maneuver if required; this is usually reserved for situations where bleeding is encountered rather than used routinely, and uses an intermittent protocol (as the time of transection tends to be longer than in open surgery). The gall bladder is resected where indicated, but after division of the cystic duct and artery, it may be left attached to the liver until later in the procedure to help maneuver the liver, such that the gall bladder and round ligament become the two handles of the liver. It is a
93
Figure 10.4 Laparoscopic ultrasound used to mark out resection line for a tumor in segment 6.
useful point to divide the round ligament flush with the anterior abdominal wall such that there is not dangling tissue irritatingly obstructing the view and dirtying the camera through the whole procedure. There are many methods of parenchymal transection: harmonic scalpel (Ethicon), Ligasure device (Covidien), Gyrus (Gyrus ACMI), CUSA (Integra), TissueLink (Salient Surgical Technologies), stapling devices, water jet, and metal clips. Each have their advantages and disadvantages, and used appropriately each can have their place. Personal preference and experience as well as local teaching and availability determine the choice. The various energy-delivery devices will not control the large venous structures; these must be identified intraparenchymally and controlled with clips or stapling devices. It is also prudent to individually control the large pedicular branches. Stapling devices can be used en-masse across portions of the parenchyma to control the larger structures within, but a degree of finesse is lost and unexpected bleeding can be encountered. The combination of the harmonic scalpel for the superficial 2 cm of dissection with the CUSA for the deeper dissection is a good technique (147). A good alternative is the Ligasure device, which when used with a modified technique (closing while activating, using the cutting blade sparingly, with gentle saline irrigation to prevent charring) can be used to dissect out the larger intraparenchymal structures (148). Left lateral sectionectomy begins with mobilization of the falciform ligament, left coronary ligament, and lesser omentum to mobilize the left lobe. The parenchyma is divided so as to expose the upper surface of the segments 2 and 3 pedicles intrahepatically. The pedicles are then divided with a stapler. The parenchymal transection is then completed to expose the left hepatic vein intrahepatically, which is divided with a stapler. An alternative to this technique is mass stapling of the left lateral section (149,150). Left lateral sectionectomy is particularly suitable to a laparoscopic approach and arguments have been made that the laparoscopic approach should be used routinely for this resection (149,151).
Figure 10.5 Laparoscopic dissection of the right portal vein. The right hepatic artery has been divided. The cystic duct has been divided and is used to retract the bile duct. The right portal vein has been looped. The left portal vein is clearly demonstrated and the right portal vein can be seen dividing into its anterior and posterior branches.
For a left hepatectomy, the left liver is mobilized as above. The left hepatic artery and left portal vein are dissected extrahepatically, demonstrating the line of demarcation. The parenchymal transection is then begun, opening the liver to allow a good exposure of the left pedicle and sufficient space to introduce a stapling device to divide the left bile duct. The parenchymal transection is then continued, exposing the left hepatic vein intrahepatically, which is divided with a stapling device to complete the transection. A right hepatectomy can be performed either with an anterior or a traditional approach. An anterior approach begins with an extrahepatic dissection and division of the right hepatic artery and right portal vein (Fig. 10.5). The parenchymal transection is then begun, opening the liver to allow an intrahepatic division of the right bile duct. The parenchymal transection is then completed down to the anterior surface of the inferior vena cava. The minor hepatic veins are then divided between clips, followed by the right hepatic vein and hepatocaval ligament with stapling devices. The final step is mobilization of the liver and division of the right coronary ligament. In the traditional approach, there is the same extrahepatic division of the right hepatic artery and right portal vein, with full mobilization of the liver and division of the hepatocaval ligament and right hepatic vein before transection of the parenchyma (Fig. 10.6). Laparoscopic right hepatectomy is a difficult procedure that requires expertise in both laparoscopic and hepatic surgery. The specimen is removed intact in a bag, either through the hand port incision, a previous appendicectomy scar, or a Pfannenstiel incision. After this period of desufflation, the extraction incision is closed to allow re-establishment of the pneumoperitoneum to confirm hemostasis, as bleeding may have been tamponaded by the pressure of the pneumoperitoneum. In any type of laparoscopic liver resection, significant
94
references
1. Reynolds W. The first laparoscopic cholecystectomy. J Soc Laparoendosc Surgeons 2001; 5(1): 8994. 2. Dubois F, Berthelot G, Levard H. Laparoscopic cholecystectomy: historic perspective and personal experience. Surgical Laparosc Endosc 1991; 1(1): 527. 3. Schirmer BD, Edge SB, Dix J, et al. Laparoscopic cholecystectomy. Treatment of choice for symptomatic cholelithiasis. Ann Surg 1991; 213(6): 66576; discussion 677. 4. Bailey RW, Zucker KA, Flowers JL, et al. Laparoscopic cholecystectomy. Experience with 375 consecutive patients. Ann Surg 1991; 214(4): 531 40; discussion 5401. 5. Fielding GA. Laparoscopic cholecystectomy. Aust NZ J Surg 1992; 62(3): 1817. 6. Keus F, de Jong JAF, Gooszen HG, van Laarhoven CJHM. Laparoscopic versus open cholecystectomy for patients with symptomatic cholecystolithiasis. Cochrane Database of Systematic Reviews (Online). 2006; (4): CD006231. 7. Way LW, Stewart L, Gantert W, et al. Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and cognitive psychology perspective. Ann Surg 2003; 237(4): 4609. 8. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic cholecystectomy. J Am Coll Surg 1995; 180(1): 10125. 9. Hugh TB, Kelly MD, Mekisic A. Rouvires sulcus: a useful landmark in laparoscopic cholecystectomy. Br J Surg 1997; 84(9): 12534. 10. Fletcher DR, Hobbs MS, Tan P, et al. Complications of cholecystectomy: risks of the laparoscopic approach and protective effects of operative cholangiography: a population-based study. Ann Surg 1999; 229(4): 44957. 11. Rhodes M, Nathanson L, ORourke N, Fielding G. Laparoscopic exploration of the common bile duct: lessons learned from 129 consecutive cases. Br J Surg 1995; 82(5): 6668. 12. ORourke NA, Fielding GA. Laparoscopic cholecystectomy for acute cholecystitis. Aust NZ J Surg 1992; 62(12): 9446. 13. Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database of Systematic Reviews (Online). 2006; (4): CD005440. 14. UK guidelines for the management of acute pancreatitis. Gut 2005; 54 Suppl 3: iii19. 15. Cameron DR, Goodman AJ. Delayed cholecystectomy for gallstone pancreatitis: re-admissions and outcomes. Ann Royal Coll Surgeons Engl 2004; 86(5): 35862. 16. Cheruvu CVN, Eyre-Brook IA. Consequences of prolonged wait before gallbladder surgery. Ann Royal Coll Surgeons Engl 2002; 84(1): 202. 17. DeIorio AV, Vitale GC, Reynolds M, Larson GM. Acute biliary pancreatitis. The roles of laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography. Surg Endosc 1995; 9(4): 3926. 18. Frei GJ, Frei VT, Thirlby RC, McClelland RN. Biliary pancreatitis: clinical presentation and surgical management. Am J Surg 1986; 151(1): 1705. 19. Ong S, Christie PM, Windsor JA. Management of gallstone pancreatitis in Auckland: progress and compliance. ANZ J Surg 2003; 73(4): 1949. 20. Ranson JH. The timing of biliary surgery in acute pancreatitis. Ann Surg 1979; 189(5): 65463. 21. Sargen K, Kingsnorth AN. Management of gallstone pancreatitis: effects of deviation from clinical guidelines. J Pancreas 2001; 2(5): 31722. 22. Gurusamy K, Junnarkar S, Farouk M, Davidson BR. Meta-analysis of randomized controlled trials on the safety and effectiveness of day-case laparoscopic cholecystectomy. Br J Surg 2008; 95(2): 1618. 23. Campbell-Lloyd AJM, Martin DJ, Martin IJ. Long-term outcomes after laparoscopic bile duct exploration: a 5-year follow up of 150 consecutive patients. ANZ J Surg 2008; 78(6): 4924. 24. Fielding GA, ORourke NA. Laparoscopic common bile duct exploration. Aust NZ J Surg 1993; 63(2): 1135. 25. Martin IJ, Bailey IS, Rhodes M, et al. Towards T-tube free laparoscopic bile duct exploration: a methodologic evolution during 300 consecutive procedures. Ann Surg 1998; 228(1): 2934.
Figure 10.6 Mobilization of the right liver from the inferior vena cava.
bleeding can be encountered, and the surgeon must have the requisite laparoscopic skills to be able to control this situation. Good skills in laparoscopic suturing are essential. Conversion to laparotomy may certainly be required, but immediate conversion is not always the best response. Venous bleeding is often partly tamponaded by the pneumoperitoneum. The bleeding source is identified and controlled with a grasper, and hemostasis is achieved with suturing or a clip as appropriate. If initial maneuvers are not successful then conversion is required without persisting for too long or worsening the bleeding. These are potentially dangerous situations that require both skill and judgment. Assessment of laparoscopic liver resection has been based on series (144,147149,151173) and retrospective comparative studies (145,174185). These reports from expert centers demonstrate that laparoscopic liver resection can be performed safely, and that despite a longer operating time there is the potential for reduced hospital stay and reduced bleeding. Despite initial concerns, CO2 embolus occurs uncommonly. The oncologic results in nonrandomized studies have been good (145,158,174177,180), but care must be taken in interpreting these series, as those patients undergoing laparoscopic resection have been selected with smaller and fewer tumors that would normally also infer a better prognosis. There is a potential benefit in cirrhotic patients, with a lower incidence of ascites postoperatively (147,176), as well as fewer adhesions that facilitate subsequent transplantation (186).
conclusion
Laparoscopic approaches for the simplest of HPB procedures, cholecystectomy, have literally exploded around the world. More complex operations have been reported in small series, but have not been taken up with the same enthusiasm. As technology improves, and the skill set of surgeons increases, it seems inevitable to us that more and more will be done. As long as basic oncologic principles are adhered to, and the surgical maxim of conversion if concerned is followed, patients will continue to benefit from this exciting surgery.
95
96
97
98
99
11
Cross-sectional imaging for HPB disorders (MRI and CT) Lawrence H. Schwartz
In contrast to hepatic veins, which course between liver segments, portal veins and their accompanying artery and bileduct branches define the center of each segment. The main portal vein (PV) typically branches extrahepatically into the left and right portal veins (LPV and RPV, respectively); the RPV divides into the anterior and posterior sectoral branches, while the LPV enters the umbilical fissure and provides branches to the left lobe. While this describes standard anatomy, approximately one-third of patients have variant portal venous anatomy (Table 11.1) (4). In standard arterial anatomy the common hepatic artery arises from the celiac axis and divides into the gastroduodenal artery and the proper hepatic artery. The proper hepatic artery then gives rise to the right and left hepatic arteries. However, nearly one-half of patients have variations in their hepatic arterial system. A list of arterial variants demonstrated in a recent study is shown in Table 11.2 (1). Pancreas The pancreas is divided into the head, uncinate process, neck, body, and tail. These divisions are based upon external landmarks such as the superior mesenteric vein (SMV), which lies under the neck of the gland and defines the separation between the head and the body. The pancreas has a long course through the retroperitoneum and is intimately associated with multiple organs including the transverse colon, stomach, duodenum, and spleen. Additionally, it has a close relationship with the portal venous system that, in part, defines the resectability of pancreatic masses. The pancreas has a rich arterial supply that comes from multiple branches of the celiac and superior mesenteric arteries. As in hepatic surgery, preoperative determination of variations in peripancreatic vascular anatomy can greatly aid in operative planning.
overview
The maturation of surgery of the liver, biliary tract, and pancreas as field unto itself has happened concomitantly with, and partly as a result of, advances in cross-sectional imaging. Rather than relying on expected anatomy based on textbooks, surgeons can now plan operations based on the precise anatomical details of each individual patient. The ability to predict anatomical variations, which are present in nearly one-half of the patients, has taken the element of surprise out of the operating room and can help reduce operative morbidity (1). In this chapter, we briefly discuss the application of computed tomography (CT) and magnetic resonance imaging (MRI) to the surgical management of disease of the liver, biliary tract, and pancreas. We begin by reviewing the relevant cross-sectional anatomy of the organs being studied. Next, we discuss the various techniques used to obtain high-quality CT and MRI images of the liver, biliary tract, and pancreas. Finally, we review the cross-sectional imaging characteristics of important pathological entities commonly encountered by surgeons caring for patients with diseases of the liver, biliary tract, and pancreas.
cross-sectional anatomy
The effective use of cross-sectional imaging in the diagnosis and treatment of disorders of the liver, biliary tract, and pancreas mandates a strong understanding of anatomy. Developing this understanding of the complex three-dimensional structures and being able to extrapolate from two-dimensional representations requires a structured approach. A more detailed description of relevant anatomy can be reviewed in the previous chapters and elsewhere, therefore we will here focus on the interpretation of cross-sectional anatomy and its relation to in situ anatomy (2). Liver and Biliary Tract Segmental liver anatomy is the basis for modern liver surgery; therefore, we provide a framework with which to define this anatomy for each patient based upon cross-sectional imaging. Cantlies plane, also known as the main portal fissure, is an imaginary plane drawn from the gallbladder fossa toward the inferior vena cava (IVC) that divides the anatomical right and left lobes of the liver. The course of the middle hepatic vein (MHV) is fairly constant and lies in this otherwise potentially avascular plane; therefore, it can be used to delineate the two lobes on cross-sectional imaging (3). The right hepatic vein (RHV) defines the plane separating the anterior (segments 5 and 8) and posterior sectors (segments 6 and 7) of the right lobe. While the plane of the left hepatic vein (LHV) separates the anterior and posterior sectors of the left lobe, its anatomy is highly variable, making it a less useful landmark.
technique
Liver and Biliary Tract CT is commonly used as the primary modality to detect, characterize, and follow hepatic or biliary pathology. Modern multislice helical CT scanners allow for the rapid acquisition of large volumes of data in a single patient breath-hold, thereby allowing for the construction of high-resolution axial, coronal, sagittal, and three-dimensional images. Noncontrast CT allows us to make determinations about the character of the liver parenchyma based on changes in density. This is useful for detecting global hepatic abnormalities; however, it does not allow for the precise delineation of hepatic vascular structures nor the detection and characterization of subtle hepatic masses. CT examination of the liver, therefore, relies on iodinated contrast enhancement. Accurate CT imaging requires achieving maximal differences in attenuation between tissues, therefore understanding the contrast enhancement
100
Table 11.2 Frequency of Different Arterial Variants Seen at CT Angiography in 371 Patients
Type of finding Classic celiac arterial anatomy Replaced RHA off SMA Replaced LHA off LGA Artery to segments 2 and 3 off LGA Artery to segments 4A and 4B off RHA Trifurcation of CHA into GDA, RHA, and LHA RHA off celiac axis Accessory LHA off LGA LGA directly oft abdominal aorta CHA off SMA CHA directly off the aorta RHA off GDA Accessory RHA Common trunk of celiac axis and SMA Medial and lateral branches separate off CHA LHA off CHA GDA off RHA SMA gives rise to GDA LHA off celiac axis RHA off aorta Segment 4 branch off GDA Extrahepatic branching of RHA into anterior and posterior with artery to segment 4 off anterior division of RHA No. of findings (o = 394|) 188 54 30 19 17 15 13 13 11 6 6 5 3 2 2 2 2 2 1 1 1 1 % of patients (n = 371) 51 15 8 5 5 4 4 4 3 2 2 1 1 <1 <1 <1 <1 <1 <1 <1 <1 <1
Note: Twenty patients had two variants seen at CT and one patient had four variants. Abbreviations: LHA, left hepatic artery; RHA, right hepatic artery; LGA, left gastric artery; SMA, superior mesenteric artery; CHA, common hepatic artery; GDA, gastroduodenal artery. Source: Reprinted with permission from Ref. 4.
101
(A)
(B)
Figure 11.1 Biliary cystadenoma. (A) T2- and (B) postcontrast T1-weighted images of a biliary cystadenoma hanging off the inferior portion of the right lobe of the liver. Arrows indicate solid enhancing component of mass distinguishing this from a simple cyst.
102
(A)
(B)
Figure 11.2 Hemangioma. (A) T1-weighted postcontrast imaging reveals a nodular peripheral enhancement (black arrow) pattern in the early arterial phase that is characteristic of hemangiomas. (B) T2-weighted imaging reveals a hyperintense, lobulated lesion.
(A)
(B)
(C)
(D)
Figure 11.3 Focal Nodular Hyperplasia (A) T1-weighted precontrast image is isointense to hepatic parenchyma (B) T2-weighted image is also isointense to hepatic parenchyma except the central scar (arrow), which is bright (C) T1-weighted postcontrast image in the arterial phase demonstrates homogenous, hyperintense enhancement with the central scar enhancing on (D) delayed postcontrast images.
103
104
(A)
(B)
Figure 11.4 Hepatocellular carcinoma. (A) Arterial phase CT image demonstrating a dominate right-lobe mass. (B) Note the change in enhancement on the portal venous phase of imaging.
(A)
(B)
Figure 11.5 Gallbladder carcinoma. T2-weighted MRI (A) axial and (B) coronal images demonstrate a solid mass in the gallbladder with hyperintense surrounding liver parenchyma consistent with local extension of the tumor into the liver parenchyma.
differentiation is necessary. The presence on MRI of dependent debris within a cystic pancreatic lesion has been found to be highly suggestive of the diagnosis of pseudocyst (20). Serous cystadenoma (SCA) are the most common benign neoplasm of the pancreas and are typically asymptomatic findings, however a proportion of patients do present with symptoms due to mass effect (21). SCA are comprised of multiple smaller cysts and may have a variable appearance based on the size of the cysts that comprise them. In fact, microcystic tumors may have an appearance on CT more consistent with that of a solid tumor. MRI and ultrasound may be helpful in defining the cystic nature of such tumors. Since asymptomatic SCA do not require treatment, differentiating them from other malignant or premalignant lesions is critical. In the event that imaging characteristics are nondiagnostic, biopsy or resection may be indicated. Intraductal papillary mucinous neoplasms (IPMN) are premalignant tumors arising from the main pancreatic duct or its
Figure 11.6 Colorectal cancer metastasis. Irregular hypodense central lesion on contrast-enhanced CT represents a colorectal liver metastasis.
105
(A)
(B)
Figure 11.7 Neuroendocrine metastases. (A) Innumerable hypodense neuroendocrine metastatic nodules with variable levels of rim-enhancement on portal venous phase contrast-enhanced CT. (B) Coronal slice demonstrates direct extension of tumor into the portal vein (arrow).
(A)
(B)
Figure 11.8 Intraductal papillary mucinous neoplasm (IPMN). (A) T1-weighted postcontrast imaging reveals a low-intensity multilocular lesion in the head and uncinate process of the pancreas suspicious for a side-branch IPMN. (B) T2-weighted images demonstrate high signal intensity.
branches. IPMN contain epithelium ranging from benign adenoma to invasive adenocarcinoma. IPMN are differentiated based on whether they arise from side-branches or from the main pancreatic duct, with the latter having a higher potential for progressing to invasive malignancy. Cross-sectional imaging reveals a cystic region within or adjacent to the pancreatic parenchyma that may demonstrate continuity with the pancreatic ductal system. Factors that influence the decision to perform pancreatectomy for IPMN include size, growth, and the presence of fibrous septations or solid components. Mucinous cystic neoplasms (MCN) are less common lesions, typically seen in women, which are characterized by ovarian-type stroma. MCN are also felt to be premalignant lesions, therefore their resection is recommended. MCN have imaging characteristics similar to those of IPMN, with the absence of a definable connection to the main pancreatic ductal system (Fig. 11.8). Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PNET), also known as islet cell tumors, are rare malignant neoplasms that have a relatively slow growth rate. While most PNET are nonfunctional, they
may secrete hormones that lead to clinical symptoms, especially in the setting of metastatic disease to the pancreas. PNET are typically hypervascular lesions that show early arterial phase enhancement on CT, but may be isodense on portal venous phase. Small functional tumors may prove difficult to identify on cross-sectional imaging studies, therefore accurate timing of imaging to the arterial phase of enhancement is important. Similarly, MRI imaging of PNET usually demonstrate high signal intensity on T2-weighted images and low intensity on T1-weighted images with significant contrast enhancement (22) (Fig. 11.9). Solid Pseudopapillary Tumor Solid pseudopapillary tumor (SPT) of the pancreas is a rare, indolent tumor that most commonly affects women in the first three decades of life. Although it has metastatic potential, malignant behavior is uncommon, therefore resection is considered curative. CT imaging is varied and may demonstrate a large lesion with internal hemorrhage or cystic degeneration. While vascular encasement, pancreatic ductal dilatation, and hepatic metastases are seen only in the carcinomatous variant
106
Figure 11.9 Neuroendocrine pancreatic tumor. A well-preserved fat plane is seen separating this large hypervascular neuroendocrine tumor in the head of the pancreas from the superior mesenteric/portal vein. Areas of hypoattenuation towards the middle of the tumor are suggestive of central ischemia.
of this tumor, more typical findings based on size, capsule thickness, internal composition, and calcification pattern do not help to differentiate benign and malignant lesions (23). Acinar Cell Carcinoma Although acinar cells comprise the bulk of pancreatic tissue, acinar cell carcinomas (ACC) are very uncommon. ACC are typically well-circumscribed tumors that may be lobulated and may be heterogeneous or homogeneous in appearance on cross-sectional imaging (24). ACC range from being completely solid to mostly cystic with at least some solid components and central necrotic areas may be seen. Biliary or pancreatic ductal dilatation is occasionally seen. Contrast-enhanced CT shows homogeneous enhancement of solid components, but less than that of the surrounding pancreas. T2-weighted MRI images may show hyperintense signal in relation to pancreatic parenchyma. Pancreatic Adenocarcinoma Pancreatic adenocarcinoma, commonly referred to as pancreatic cancer, is the most common malignant neoplasm of the pancreas. It is a highly aggressive malignancy that carries with it an extremely high mortality rate, having an incidence that nearly equals its mortality rate. Because of the biologically aggressive nature of pancreatic cancer, the majority of patients present with metastatic or unresectable disease. Contrast-enhanced CT usually shows a hypoattenuating poorly defined mass with dilatation of the pancreatic duct distally and, in the case of tumors of the pancreatic head, biliary ductal dilatation as well. Biliary and/or pancreatic ductal dilatation may also be seen in the absence of an identifiable mass, and dilatation of both of these ductal systemsthe double duct signis a classic sign of adenocarcinoma of the head of the pancreas. The double duct sign is not, however, pathognomonic for pancreatic cancer and may be associated with benign processes (25). MRI has the advantage of being usable in patients with diminished renal function and can be combined with MRCP to provide detail about the biliary and pancreatic ductal systems in a noninvasive fashion (Fig. 11.10). The primary determinants of the resectability of pancreatic lesions inevitably relate to vascular involvement, since the
Figure 11.10 Pancreatic adenocarcinoma. Contrast-enhanced CT reveals a hypointense solid-appearing mass in the tail of the pancreas. This appearance on cross-sectional imaging is characteristic of pancreatic adenocarcinoma.
pancreas is intimately associated with the portal venous system and in close proximity to the celiac artery and superior mesenteric artery (SMA). High-quality cross-sectional imaging clearly defines these relationships and predicts the likelihood of successful resection. Metastatic Cancer to the Pancreas In contrast to the liver, the pancreas is a rare site of metastatic disease. Although multiple types of cancer have been reported to metastasize to the pancreas, renal cell carcinoma, nonsmall cell lung carcinoma, and lymphoma are the most common sources of isolated pancreatic metastases. Renal cell carcinoma metastases to the pancreas are typically well-circumscribed, arterial-enhancing lesions, while other histologies tend to be more diffuse and variable in enhancement patterns.
conclusions
CT and MRI have become essential components in the diagnosis, perioperative management, and follow-up of hepatic, biliary, and pancreatic pathology. Therefore, the ability to appropriately order and interpret these studies, in consultation with radiologists, is a prerequisite to the surgical management of patients with such diseases.
references
1. Winston CB, Lee NA, Jarnagin WR, et al. CT angiography for delineation of celiac and superior mesenteric artery variants in patients undergoing hepatobiliary and pancreatic surgery. AJR Am J Roentgenol 2007; 189(1): W1319. 2. Blumgart LH. Surgery of the Liver, Biliary Tract, and Pancreas, 4th edn. Philadelphia, PA: Saunders Elsevier, 2007. 3. Kamel IR, Lawler LP, Fishman EK. Variations in anatomy of the middle hepatic vein and their impact on formal right hepatectomy. Abdom Imaging 2003; 28(5): 66874. 4. Covey AM, Brody LA, Getrajdman GI, Sofocleous CT, Brown KT. Incidence, patterns, and clinical relevance of variant portal vein anatomy. AJR Am J Roentgenol Oct 2004; 183(4): 105564.
107
108
12
Liver metastases: detection and imaging Valrie Vilgrain, Ludovic Trinquart, and Bernard Van Beers
The role of Doppler techniques is often limited because flow signals in liver metastases are usually too low to be detected except in markedly hypervascular liver metastases. Because there are no specific features of metastases at conventional US, the differentiation of a single metastasis from other lesions is usually not possible but on the other hand, US is helpful to characterize benign lesions such as hepatic cysts and hemangiomas in oncological patients. While in many European countries, US was the recommended imaging follow-up method, CT or MRI is nowadays preferred in oncological patients.
The liver is the second most frequent site of metastases, after lymph nodes, providing a very suitable environment for the growth of metastases because of its rich blood supply from the systemic and splanchnic system. The overall extent of liver involvement in cancer patients is unknown but liver metastases have been found in 30% to 70% of patients who die because of cancer, depending on their primary tumor (1). Liver metastases frequently arise from colorectal cancer (CRC), with 15% to 20% of patients presenting with synchronous liver metastases and another 15% developing metachronous metastases to the liver within five years (2,3). But unlike many other types of cancers, the presence of distant metastases from CRC does not necessarily preclude curative treatment. In fact, CRC metastases are confined to the liver in 25% of patients (4). This confinement of metastatic disease to the liver has allowed progress in the treatment of these patientsvia hepatic resection, regional chemotherapy, and thermoablative treatments, and the benefits of such approaches are demonstrated by the fact that survival of up to 25% of patients 10 year after resection of these metastases is possible. Isolated liver metastases also often arise from gastric and pancreatic cancersbecause of the portal venous drainage to the liverand less frequently from breast or lung cancers. But most non-CRC liver metastases are associated with distant metastatic spread to other organs and so require a more systemic therapeutic approach. However, metastases confined to the liver may also be seen in ocular melanoma, breast cancer, neuroendocrine tumors, renal cell cancers, and some sarcomas (57). In this context, the goal of imaging for liver metastases is twofold: first to establish an early and accurate diagnosis of liver metastases, second to stage preoperatively those patients with liver metastases confined to the liver, especially when the primary tumor is CRC. The diagnostic value of ultrasound (US), contrast-enhanced US, multidetector computed tomography (CT), and magnetic resonance (MR) imaging with nonspecific gadolinium chelates and liver-specific contrast agent is discussed. Pitfalls and limitations of imaging are shown. Lastly, the role of imaging in assessing number, localization, and size of metastases to determine resectability is emphasized.
contrast-enhanced ultrasound
The principle of this technique is to increase the lesion-to-liver contrast, using intravascular microbubble contrast agents, which allows enhanced detection of smaller liver metastases not seen on conventional US. Most contrast agents used nowadays provide strong and persistent signal enhancement due to harmonic resonance at low mechanical index, where minimal or no bubble destruction occurs. Examination includes a continuous evaluation of the lesion enhancement during the arterial (1530 seconds delay), portal venous (3060 seconds delay), and delayed (23 minutes delay) phases. Most liver metastases are hypovascular and exhibit no or minimal enhancement on the arterial phase. Interestingly, whatever the lesion enhancement is on the arterial phase, metastases show nonenhancing defects on the delayed phase, which seem to be the most useful determinant for both lesion detection and characterization (Fig. 12.1). This strong washout sign is caused by the biokinetics of the US contrast agents that are purely vascular effects; conversely to nonspecific CT and MR contrast agents that spread into the interstitium. Indeed, the use of contrast agents improves the sensitivity of US in detecting individual lesions by about 20% in comparison to baseline, independent of the type of contrast agent used (9). Contrast-enhanced US imaging is technically successful in most patients except those with severe obesity and marked steatosis in whom penetration of contrast-specific imaging is limited.
imaging techniques
Ultrasound Liver metastases are generally multiple, spherical, and have well-defined margins. Most lesions are hypoechoic. The most common hyperechoic metastases are observed in patients with CRC or neuroendocrine tumors. Large lesions often have more central hypoechogenicity related to areas of necrosis. A hypoechoic halo is seen surrounding the lesions in 40% of cases (8). More rarely, liver metastases may appear as diffuse infiltration.
computed tomography
Computed tomography (CT) is the most commonly used imaging modality for both detection and characterization of liver metastases. Multidetector helical CT is now the standard technique. It reduces the scan time, with high coverage and high-quality 3D reconstructions. The examination comprises of an unenhanced scan and, after intravenous administration of nonionic iodine contrast medium, two acquisitions at the late arterial phase and the portal venous phase. During the latter, the liver parenchyma enhances
109
(A)
(B)
(C) Figure 12.1 (AC) Portal-phase CT shows a small liver tumor that is not characteristic of liver metastasis. This lesion is homogeneous and hyperechoic on ultrasound (B). Portal-phase contrast-enhanced ultrasound demonstrates washout, which is highly suggestive of liver malignancy (C).
the arterial phase. A key finding is the presence of a halo (11), which has been shown as a quite sensitive and specific finding for liver metastases. However, unenhanced, arterial-phase and delayed-phase imaging (which is optional) are helpful for differentiating benign lesions such as cyst, hemangioma, or hepatocellular tumors from metastases.
Figure 12.2 Portal-phase CT demonstrating multiple heterogeneous lesions suggestive of liver metastases.
and it increases the lesion conspicuity of hypovascular tumors (10) (Fig. 12.2). Most liver metastases are hypoattenuating and hypovascular on unenhanced scans, meaning that they are better seen on the portal venous phase than on
110
(A)
(B)
(C)
(D)
Figure 12.3 (AD) MR imaging of a colorectal metastasis. The tumor is hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the peripheral halo on portal-phase T1-weighted imaging and the delayed enhancement due to fibrous stroma (C and D).
reticuloendothelial system (ferumoxides) or hepatobiliary captation (Mn-DPDP or specific hepatobiliary gadolinium chelates). Briefly, the nonspecific gadolinium chelates are used for lesion characterization, while the others have been proposed for preoperative staging. The principle of the latter is to increase the lesion-to-liver contrast by decreasing markedly the signal of the liver on T2 sequences (ferumoxides) or increasing it on T1-weighted sequences (13). Some authors have also proposed double-contrast MR combining specific and nonspecific contrast agents. Similarly to CT, nonspecific gadolinium MR imaging should include baseline precontrast images and sequential acquisitions at arterial, portal, and equilibrium phases. In a large series of 516 liver metastases from various tumors in 165 consecutive patients, most liver metastases were hypovascular (64% of all patients and 91% of patients with colon cancer) ( 12 ). A hypervascular pattern of enhancement was identified in 36% of patients. During the arterial phase, peripheral ring enhancement was seen in 72% of patients. On the portal venous and delayed phase, incomplete central progression of lesion enhancement was found in two-thirds of patients ( 12 ) ( Fig. 12.3 ). Peripheral washout in metastases on delayed-phase images was identified in one-third
of patients with hypervascular metastases and almost never in hypovascular metastases ( 12 ) ( Fig. 12.4 ). After administration of liver-specific contrast agents, liver metastases that lack functioning hepatocytes or Kupffer cells do not enhance postcontrast, resulting in improved lesion conspicuity ( 14 ). Diffusion-weighted MR imaging is quite interesting in liver metastases. Nasu et al. (15) have shown increased detection of metastatic lesions with a combination of diffusion-weighted imaging and precontrast T1- and T2-weighted imaging when compared with liver-specific contrast MR imaging. Parikh et al. have shown that diffusion-weighted sequences were as accurate as T2-sequences for characterization of focal liver lesions including metastases (16) (Fig. 12.5).
111
(A)
(B)
(C)
(D)
Figure 12.4 (AD) MR imaging of endocrine metastases. The tumors are strongly hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the strong hypervascularity on arterial-phase T1-weighted imaging and the washout on portal-phase imaging (C and D).
(A)
(B)
Figure 12.5 MR imaging of liver metastases. Multiple tumors are seen on T2-weighted imaging (A). Conspicuity of small tumors is more evident on diffusionweighted imaging (B).
112
perfusion imaging
Liver metastases induce changes in liver perfusion and have been shown to increase arterial blood flow and the arterial portal flow ratio (hepatic perfusion index) compared to normal liver. Interestingly, animal studies have demonstrated that those changes may be detected at an early stage when liver metastases are occult on other imaging modalities (18). Hepatic perfusion index can be obtained using various techniques: nuclear medicine, US, CT, or MR imaging. Early results in patients were promising but lack of standardization in utilization, lack of consensus regarding the imaging modality, and the presence of multiple mathematical models have meant that perfusion has not been adopted in routine practice.
calcification during response to chemotherapy (19) (Fig. 12.6). Whether liver metastatic calcification carries a prognostic significance in CRC is still questionable. Intrabiliary Metastases Intrinsic bile duct involvement by metastases may occur either by growing from within or invading the lumen of the bile ducts. The most common intrabiliary metastases arise from colorectal carcinoma. Most patients present with various degree of biliary obstruction including jaundice (20). The presence of macroscopic intrabiliary extension seems to be a good indicator in patients with CRC showing less aggressive features (21). Pitfalls and Limitations The two most difficult situations in oncological patients are the changes in the liver such as steatosis that can create pseudolesions or hide true metastases, and the characterization of small lesions. Steatosis is not always homogeneous and may have either focal fatty sparing, or more rarely focal fatty deposit. Furthermore, fatty livers are often observed in cancer patients who have received chemotherapy. Clearly, in this context, MR is superior to CT by combining fat-suppressed T1 sequences and in- and opposed-phase T1-weighted imaging that can diagnose both focal and diffuse changes, and help to differentiate focal fat from metastases (Fig. 12.7). Another issue is the characterization of small liver lesions in cancer patients. Those lesions (smaller than 1 or 2 cm) are often deemed too small to characterize, and due to the high prevalence of benign lesions in the liver, are more frequently benign than malignant. Schwartz et al. reported in a series of 2978 cancer patients that metastases represented only 11.6% of patients with small liver lesions (22). Other authors have shown that the positive predictive value for malignancy increased notably using a cut-off of 20 mm compared to 10 mm (23). Yet, for an individual patient, we cannot rely only on lesion size for characterization. While CT is an excellent imaging modality for detection, it is not as good as US, contrast-enhanced US, and MR imaging when characterizing small liver lesions (24,25).
(A)
(B)
Figure 12.6 (A and B) Liver metastases before and after chemotherapy. Note the significant decrease in size of the tumors. Furthermore, the tumors present diffuse calcifications after chemotherapy.
113
(A)
(B)
(C)
Figure 12.7 (AC) Liver metastases developed on a fatty liver. The tumor located in the posterior part of the segment 4 is barely visible on portal-phase CT (A) and is better seen on pre- and postcontrast T1-weighted imaging (B and C).
CI 0.610.80). Moreover, in the 35 studies with specificity higher than 85%, [18F]FDG PET was still the most sensitive technique, the combined sensitivity being 55% for US, 72% for CT, 76% for MR imaging, and 90% for FDG PET. The second systematic review was published by Bipat et al. in 2005 and aimed at evaluating CT, MR imaging, and [18F]
114
Multidetector-row CT scanning is often the first choice for a screening liver examination at many institutions. This technique also enables rapid scanning of the chest and abdomen and allows evaluation of extrahepatic disease. MRI enhanced with SPIO is probably a more sensitive method than multidetector-row CT for detecting liver metastases (35,36), but to our knowledge, no study has evaluated the added value of MR imaging after multidetector-row CT examination and the consequences in treatment planning.
Based on the existing evidence, it is difficult to provide highstrength management recommendations. Our policy at our institution is to perform systematically a multidetector CT in patients with liver metastases. PET/CT is indicated for the detection of extrahepatic tumor before liver surgery. MR imaging is not routinely performed and is reserved for characterization of small liver lesions, in fatty livers, and in difficult cases after multidetector CT. For lesion characterization, we use nonspecific contrast MR agents, while for tumor detection and preoperative staging, we use liver-specific contrast agents. In both cases, our protocol includes diffusion-weighted MR sequences. Intraoperative US is routinely performed in our institution and intraoperative contrast-enhanced US is under investigation.
preoperative staging
Due to their biological properties, most liver metastases that are resected are secondary to CRC. Selected isolated liver metastases from breast cancer, sarcoma, renal cell cancer
115
Does the future liver remnant have sufficient volume for the perioperative and postoperative course? This question is easily addressed by CT or MR volumetric measurement. Does the future liver remnant have satisfactory vascular inflow, venous outflow, and biliary drainage? Again CT or MR imaging is adequate to answer this question. Is there any contraindication to performing an R0 resection? This point is more difficult as classical contraindications such as bilobar metastases are overcome in most specialized centers either by twostep resection with preoperative portal embolization to increase the remaining normal liver parenchyma or downsizing with chemotherapy, or combination of resection and thermal ablation (37). However, it is crucial to evaluate the relationship between the liver tumors and important anatomical landmarks such as the inferior vena cava (IVC), hepatic venous confluence, and the main portal pedicles. Did the liver metastases respond to preoperative chemotherapy? Preoperative chemotherapy is currently performed in resectable patients as it has been shown to reduce the risk of events of progression-free survival in eligible and resected patients (38). In these patients, the role of imaging is to evaluate the tumor response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Association with targeted therapy may render more complex this assessment.
references
1. Pickren J, Tsukada Y, Lane W. Analysis of autopsy data. In: Weiss L, Gilbert H, eds. Liver Metastasis. Boston, MA: Hall, 1982: 218. 2. Kune GA, Kune S, Field B, et al. Survival in patients with large-bowel cancer. A population-based investigation from the Melbourne Colorectal Cancer Study. Dis Colon Rectum 1990; 33: 93846. 3. Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006; 244: 2549. 4. Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993; 71: 425266. 5. Elias D, Lasser P, Ducreux M, et al. Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study. Surgery 2003; 133: 37582. 6. Hughes K, Sugarbaker P. Resection of the liver for metastatic solid tumors. In: SA R, ed. Surgical Treatment of Metastatic Cancer. Philadelphia, PA: Lippincott, 1987; 12564. 7. Leyvraz S, Spataro V, Bauer J, et al. Treatment of ocular melanoma metastatic to the liver by hepatic arterial chemotherapy. J Clin Oncol 1997; 15: 258995. 8. Albrecht T. Detection and characterisation of liver metastases. In: Lencioni R, ed. Enhancing the Role of Ultrasound with Contrast Agents. Milan: Springer, 2006; 5367.
9. Albrecht T, Hoffmann CW, Schmitz SA, et al. Phase-inversion sonography during the liver-specific late phase of contrast enhancement: improved detection of liver metastases. AJR Am J Roentgenol 2001; 176: 11918. 10. van Leeuwen MS, Noordzij J, Feldberg MA, Hennipman AH, Doornewaard H. Focal liver lesions: characterization with triphasic spiral CT. Radiology 1996; 201: 32736. 11. Nino-Murcia M, Olcott EW, Jeffrey RB, Jr., et al. Focal liver lesions: pattern-based classification scheme for enhancement at arterial phase CT. Radiology 2000; 215: 74651. 12. Danet IM, Semelka RC, Leonardou P, et al. Spectrum of MRI appearances of untreated metastases of the liver. AJR Am J Roentgenol 2003; 181: 80917. 13. Kim KW, Kim AY, Kim TK, et al. Small (< or = 2 cm) hepatic lesions in colorectal cancer patients: detection and characterization on mangafodipir trisodium-enhanced MRI. AJR Am J Roentgenol 2004; 182: 123340. 14. Schima W, Kulinna C, Langenberger H, Ba-Ssalamah A. Liver metastases of colorectal cancer: US, CT or MR? Cancer Imaging 2005; 5 Spec No A: S14956. 15. Nasu K, Kuroki Y, Nawano S, et al. Hepatic metastases: diffusion-weighted sensitivity-encoding versus SPIO-enhanced MR imaging. Radiology 2006; 239: 12230. 16. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging. Radiology 2008; 246: 81222. 17. Badiee S, Franc BL, Webb EM, et al. Role of IV iodinated contrast material in 18F-FDG PET/CT of liver metastases. AJR Am J Roentgenol 2008; 191: 14369. 18. Cuenod C, Leconte I, Siauve N, et al. Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT. Radiology 2001; 218: 55661. 19. Hale HL, Husband JE, Gossios K, Norman AR, Cunningham D. CT of calcified liver metastases in colorectal carcinoma. Clin Radiol 1998; 53: 73541. 20. Povoski SP, Klimstra DS, Brown KT, et al. Recognition of intrabiliary hepatic metastases from colorectal adenocarcinoma. HPB Surg 2000; 11: 38390, discussion 3901. 21. Kubo M, Sakamoto M, Fukushima N, et al. Less aggressive features of colorectal cancer with liver metastases showing macroscopic intrabiliary extension. Pathol Int 2002; 52: 51418. 22. Schwartz LH, Gandras EJ, Colangelo SM, Ercolani MC, Panicek DM. Prevalence and importance of small hepatic lesions found at CT in patients with cancer. Radiology 1999; 210: 714. 23. van Erkel AR, Pijl ME, van den Berg-Huysmans AA, et al. Hepatic metastases in patients with colorectal cancer: relationship between size of metastases, standard of reference, and detection rates. Radiology 2002; 224: 4049. 24. Eberhardt SC, Choi PH, Bach AM, et al. Utility of sonography for small hepatic lesions found on computed tomography in patients with cancer. J Ultrasound Med 2003; 22: 33543; quiz 34546. 25. Mueller GC, Hussain HK, Carlos RC, Nghiem HV, Francis IR. Effectiveness of MR imaging in characterizing small hepatic lesions: routine versus expert interpretation. AJR Am J Roentgenol 2003; 180: 67380. 26. Bipat S, van Leeuwen MS, Ijzermans JN, et al. Imaging and treatment of patients with colorectal liver metastases in the Netherlands: a survey. Neth J Med 2006; 64: 14751. 27. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT, MR imaging, and PET for diagnosis: meta-analysis. Radiology 2005; 237: 12331. 28. Kinkel K, Lu Y, Both M, Warren RS, Thoeni RF. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology 2002; 224: 74856. 29. Rappeport ED, Loft A. Liver metastases from colorectal cancer: imaging with superparamagnetic iron oxide (SPIO)-enhanced MR imaging, computed tomography and positron emission tomography. Abdom Imaging 2007; 32: 62434.
116
35.
36. 37.
38.
117
13
introduction
Colorectal cancer (CRC) is a common malignancy with a very high incidence in Western countries. Approximately 150,000 new cases of CRC occur each year in the United States, accounting for more than 55,000 cancer-related deaths (1). Over half the patients diagnosed with CRC will develop liver metastases (CRLM) during the course of their disease (2), of which 15% to 25% will have liver metastases at the time of the diagnosis (3,4). In the absence of surgical treatment, 5-year survival is exceptional (5) and even with the best chemo- and bio-therapies, to date, median survival of unresected disease does not exceed two years (6,7). On the other hand, long-term survival and potential cure after surgical resection for CRLM has been demonstrated by numerous studies. Surgery is therefore considered as the treatment of choice for patients with resectable CRLM, yielding a 5-year survival between 35% and 52% (8,9). As a result, hepatic resection has evolved from a rare procedure associated with considerable mortality to a routine surgery with an operative mortality risk of around 2% (10,11). At present, the low operative mortality along with survival improvement has led to an expansion of more extensive liver surgery and to a clear change in surgical indications to a point where virtually no tumor should be considered unresectable provided that resection can be complete. These advances combined with novel systemic and regional ablative therapies have modified the course of the disease, transforming it from a uniformly fatal to increasingly curable for a majority of patients.
patient evaluation
Patient Selection for Surgery In deciding which patient will tolerate liver resection, a number of factors will need to be considered, including patient comorbidities. Age per se is not an independent factor for increased operative risk (15). This is a very important fact, considering that an increasing proportion of patients being evaluated for surgery for malignant disease, are elderly. On the other hand, scores like the American Society of Anaesthesiology (ASA) (16) or the preoperative Acute Physiology and Chronic Health Evaluation score do significantly influence the incidence of postoperative complications. Patients with an ASA score > 1 have been shown to have more than three times the mortality and twice the morbidity compared to those patients with an ASA of 1 (16). Therefore, a major goal of the preoperative evaluation is to identify patients who are at high operative risk so those who have a prohibitive risk can be excluded from surgery whereas those with manageable comorbidities can have these conditions addressed preoperatively in an attempt to reduce their operative risk. Definition of Tumor Resectability The earlier definition of the resectability (based on factors such as number of lesions, size, distribution, etc.) has been progressively challenged resulting on a concept shift, which now focuses on whether a macroscopic and microscopic complete (R0) resection of the liver lesion as well as complete resection of any extrahepatic diseases can be performed. At present, CRLM are defined as resectable if two aspects are fulfilled: (1) oncological anticipation that the disease can be completely resected without any residual hepatic or extrahepatic disease; (2) maintenance of an adequate volume of the future remnant liver with preserved vascular inflow, outflow, and biliary drainage. In general, at least 25% of the total liver is the minimum safe volume that can be left after liver resection in patients with normal liver parenchyma (17). Preoperative Imaging The complex decision to determine resectability requires detailed anatomic imaging to determine tumor location, exclude unresectable extrahepatic metastases, and assess the adequacy of the liver parenchyma after surgery. There are a
118
Therefore, the absence of safe margins of resection should not be considered as an absolute contraindication to surgery provided that all tumors can be macroscopically resected. However, at the present surgeons should continue to plan hepatic resection with a preserved safety zone and avoid routine use of minimum margin surgery.
The number of metastases (4) is no longer considered a contraindication (28) to liver resection (based on the fact that long-term survival can be obtained for patients with four or more metastases treated with
The presence of extrahepatic disease reduces the hope of long-term survival and it has been considered as a contraindication to liver resection. Lately, however, resection in patients with extrahepatic disease with curative intent has been advocated by some groups. In a French series (40) of 84 patients who underwent complete resection of extrahepatic disease concurrently with hepatic resection, the
119
Whereas preoperative factors may be generally instructive, these should not be used to exclude patients from surgical consideration. Patients with one or multiple negative prognostic factors can still derive a significant survival advantage from hepatic resection of their CRLM. To conclude, it is important to mention that at the present time the only unchallenged contraindication to liver resection Table 13.1B Survival Rates for Each Score Grade
Survival (%) Fongs score Score 0 1 2 3 4 5 1 year 93 91 89 86 70 71 3 years 72 66 60 42 38 27 5 years 60 44 40 20 25 14 Median (mo) 74 51 47 33 20 22 Risk groups Low risk Intermediate risk High risk Nordlingers score Risk factors 02 34 57 2 years 79 60 43
120
121
Figure 13.1 Picture showing multiple metastasectomies with maximal preservation of the liver parenchyma.
liver may be treated with an anatomical, segment-oriented resection. The extent of liver resection (major vs. minor or anatomic vs. nonanatomic resection) is not by itself a prognostic factor. Therefore, independently of being anatomic or nonanatomic, resection should spare as much as possible the nontumoral parenchyma, bearing in mind that new recurrences could eventually develop for which surgery could possibly be indicated again (see Fig. 13.1).
postoperative management
Adjuvant Systemic Chemotherapy At present, despite several chemotherapy regimens, data would support the use of 5-FU and leucovorin as adjuvant chemotherapy after liver resection if patients have not previously failed this regimen. Portier et al., in a multicenter trial that randomized 173 patients after hepatectomy for CRLM to surgery alone or to surgery followed by chemotherapy (5-FU/ Leucovorin), demonstrated that patients who received adjuvant chemotherapy had a significantly better disease-free survival compared to that of patients treated with surgery alone (34% vs. 27%; p = 0.03) (71). A year later, Park et al., in a large two-center study comparing 518 patients treated with no chemotherapy (379 American, 139 European) to 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy, demonstrated that systemic adjuvant chemotherapy prolongs survival after hepatic resection for colorectal metastases (72). Patients subjected to adjuvant chemotherapy had improved survival (p = 0.007) even after stratification by clinical risk score (p = 0.001). In every clinical risk score category, patients subjected to adjuvant chemotherapy had a higher chance of survival (range 1.32.0 times). Meanwhile, for those who have previously failed this regimen, an oxaliplatin- or irinotecan-based regimen should be considered. Despite that there has not been a clear demonstration of efficacy of any regimen, the higher response rate observed in patients treated with FOLFOX or FOLFIRI over the 5-FU/leucovorin has resulted in many groups to preferentially use these regimens in adjuvant settings.
122
Author Nordlinger et al. Fong et al. Minagawa et al. Suzuki et al. Choti et al. Adam et al. Kato et al. Abdalla et al. Tanaka et al. Fernandez et al. Pawlik et al. Wei et al.
Year 1995 1999 2000 2001 2002 2003 2003 2004 2004 2005 2005 2006
Adjuvant Intra-arterial Chemotherapy A number of studies have reported the safety, efficacy, and feasibility of adjuvant regional hepatic chemotherapy. Kusunoki et al. conducted a nonrandomized trial of HAI versus systemic chemotherapy after radical liver surgery. He showed that the 5-year survival was significantly better for the HAI group compared to the 5-year survival of the systemic group (59% vs. 27%, p < 0.001) (73). Kemeny et al., in an intergroup study of 109 patients randomized to surgery alone or surgery and HAI-FUDR, demonstrated that the 4-year disease-free survival was significantly better in the HAI group (67% vs. 43%) (74). In another larger study, 156 patients were randomized to resection and systemic 5-FU or resection and combined systemic 5-FU and HAIFUDR. The patients who were treated with regional therapy had a significantly better 2-year survival (86% vs. 72%) and markedly improved liver disease control (75). In conclusion, convincing evidence currently exist to support the use of adjuvant chemotherapy, either systemic or regional, to prevent to some extent the risk of recurrence following liver resection. Outcomes of Resection for Colorectal Liver Metastases Morbidity and Mortality Overall, the perioperative mortality of liver resection for CRLM does not exceed 2%, ranging between 0% and 5% in most published series (10,11,76) and is strongly influenced by perioperative blood loss, liver function, and extent of liver resection. In experienced units, even major hepatic resections, constituting around 50% of cases have perioperative mortality not exceeding 2% (76). The principal causes of death are liver failure and sepsis. It has been observed that the mortality has changed little over the last two decades, however, this does not mean that there has not been progress made. With improved safety, surgeons are increasingly performing more extensive resections,
which explain the fact why the operative mortality and longterm survival have plateaued. In contrast, the perioperative morbidity rate is reported to be greater than 20% (28,77). The major morbidity associated with liver resection includes hemorrhage (13%), bile leak and/or fistula (4%), pleural effusion/pneumonia (510%/520%), and hepatic failure (38%). Of the nonliver-related complications, intra-abdominal sepsis is found to be the most frequent major complication, and pulmonary infection is the most frequent minor complication. Among liver-related complications, liver failure is the most serious and occurs in 3% to 8% of all major liver resections often being lethal. Similarly, intraoperative hemorrhage, although rare, is another major complication with a mortality as high as 17% (78). Long-term Survival Results Large series have reported a 5-year survival after hepatectomy for CRLM of 35% to 52% with a 33- to 46-month median survival (8,9,46,79) (see Table 13.2). However, recent data have shown an improved 5-year survival rate of 58% after complete resection of CRLM (35). Also, a number of series with sufficiently long-term follow-up indicate that the 10-year survival after resection can be expected in 20% to 30% of patients (12,46,80) (see Table 13.2 and Fig. 13.1). Similarly the International Registry of Hepatic Metastases of Colorectal Cancer (LiverMetSurvey), which to date includes more than 8000 patients, has demonstrated a 5- and 10-year survival of 41% and 26%, respectively. An important oncologic question is whether the recently improved systemic therapies can achieve the same results as resection for CRLM? This seems unlikely considering that longterm survival beyond 5-years is rare without liver resection (5) (Fig. 13.2). Indeed, the survival results can be questioned if considering that the patients who undergo resection are selected and may have better outcomes due to less aggressive disease.
123
100 90 80 70 60 50 40 30 20 10 0 0
Patient survival after a 1st liver operation for colorectal metastases: 8179 patients Log rank p = <0.0001
7% 1 2 Resected 3 4 5 Resected 6
Nonresected
Figure 13.2 Five- and ten-year survival following hepatectomy for colorectal liver metastases. Source: www.livermetsurvey.org.
124
Paul Brousse Hospital 473 patients (Apr. 88Jul. 99) 100 80 66% Survival (%) 60 40 20 0 0 1 2 3 4 5 6 Years 52% 33% 23% No surgery 7 8 9 10 p = 0.01 48% 30% 91% Resectable: 335 Initially non-resectable: 138 No surgery
Figure 13.3 Curves demonstrating 5- and 10-year survival for initially resectable patients and for patients who underwent rescue surgery. Source : From Ref. (82).
(A)
(B)
(C)
125
found that the rate increases when treating multiple lesions (>8), large lesions (>3 cm), or tumors located to major blood vessels (blood warmth may impair the freezing process).
RFA is currently the most commonly applied ablation method. RFA involves localized application of conductive thermal energy to destroy tumor cells. Specifically alternating electric current in the range of radiofrequency waves (460 kHz) is applied from a generator through a needle electrode placed directly into the tumor.
Limitations of RFA are related to the lesion size (suitable for lesions 3 cm) or when a maximum of three tumors are present as well as the anatomical location of the tumor. In the vicinity of large hepatic vessels, the heat sink effect significantly increases the risk of incomplete ablation. Also, the risk of thermal injury is increased when nodules are close to main biliary structures or to extrahepatic organs. RFA procedure, when performed in combination with surgery, increases the resectability and curability for patients in whom hepatic resection alone is not curative. Adding RFA to hepatic resection has been reported to be well tolerated with a perioperative morbidity and mortality comparable to those seen after resection alone (94). For metastases considered as unresectable, RFA combined with hepatic resection can achieve a median survival as high 37 months (95).
Cryotherapy involves freezing and thawing of liver tumors by means of a cryoprobe. Tumor necrosis occurs by direct cellular freezing and indirectly through vascular thrombosis and tissue anoxia. Results of such treatment combined with hepatic resection for patients not eligible for hepatic resection alone have shown a 5-year survival rate of 24%, better than those obtained by palliative chemotherapy (96,97). Local recurrence at the site of cryotherapy occurs in 5% to 44% of patients and it has been
Portal Vein Embolization Portal vein embolization (PVE), which was first described by Makuuchi (98), is used to trigger a compensatory hypertrophy of the future remnant liver. In patients with an otherwise normal liver, current guidelines recommend preoperative PVE when the ratio of the remnant liver volume is <30%. Patients submitted to prolonged chemotherapy with a high risk of induced hepatic lesions should benefit from this method when this ratio is less than 40%. PVE can be performed percutaneously or using the ilocolic vein approach via a limited laparotomy. After PVE, hepatic volume is routinely evaluated using CT scanner volumetry, which gives information about the degree of the compensatory hypertrophy as well as the status of the metastatic disease. The optimal time interval necessary to induce maximum hypertrophy after PVE has not been established yet, although some Japanese teams use to perform resection as early as 2 weeks after the PVE. The majority of groups, however, would usually use a 4 to 6 weeks of interval between PVE and surgery. PVE is safe and does not add significant morbidity. In our series, a significant increase of liver volume following preoperative PVE was observed in 43% of patients, allowing 63% of originally unresectable liver metastases to be subsequently operated (99). The feasibility and the influence on the outcome in patients requiring an extended hepatectomy has been reported by other investigators also. Farges et al. (100) published the results of a prospective study of PVE performed in patients undergoing right hepatectomy for either primary liver cancer or metastatic liver disease. They demonstrated significantly fewer postoperative complications when PVE was used to increase the FLR volume in patients with chronic liver disease whose anticipated FLR was <40%. In contrast, patients with normal liver function who underwent a right hepatectomy did not benefit from PVE, as it was expected, since the remaining liver usually represents more than 30% of the functional liver volume. In summary, the PVE needs to be performed only in patients who are being considered for an extended right hepatic resection. PVE is rarely necessary prior to extended left hepatectomy because the right posterior sector typically constitutes about 30% of the total liver volume (101,102). On the other hand, in patients who have been treated with heavy neoadjuvant chemotherapies with a high risk of induced parenchymal liver lesions the PVE should be performed when the ratio of the remnant liver volume to the total estimated liver volume is less than 40%. The selective use of PVE may enable safe and potentially curative hepatic resection in a subset of patients with advanced colorectal metastases who would otherwise have been marginal candidates for resection because of an inadequate FLR or significant underlying liver disease.
126
(A)
(B)
(C)
(D)
Figure 13.5 Radiological follow-up of a patient treated with combination of neoadjuvant chemotherapy and two-stage hepatectomy. 1A, hepatic metastases before chemotherapy treatment. 1B, planning of surgery after tumor downstaging (before the first hepatectomy). 1C, first hepatectomy. 1D, liver remnant following the second hepatectomy (segments IV and I).
Table 13.3 Reported Survival Outcomes after Two-Stage Hepatectomy for Colorectal Liver Metastases
Patient survival (%) Author/Institution Adam et al. (2000) Jaeck et al. (2004) Shimada et al. (2004) Togo et al. (2005) Adam et al. (2007) No of patients 16 33 12 11 45 Success rate (%) 81 76 100 100 69 Mortality rate (%) 15 0 0 0 6.5 Morbidity rate (%) 45 56 NA 18 48 Median (months) 31 18 35 3 years 35 54 45 47 5 years 28
NA, not available. The mortality rates concern the second operation.
127
Patients with bilobar multinodular metastases for which a planned resection would leave more than three nodules or any nodule larger than 3 cm in the remnant liver could be candidates for two-stage hepatectomy (Fig. 13.6C).
No residual tumor should be left in the future remnant liver at the first intervention. If the resection alone cannot remove all lesions, one of the ablative methods (RFA, cryotherapy) has to be used for local tumor destruction in order to prevent tumor progression during the regeneration of the remnant liver. At the first intervention, portal dissection and mobilization of the lobe that is to be resected during the second intervention should be avoided.
In summary, based on the nature of the metastatic disease (number, size, and distribution), the treatment strategies, which can be applied with the aim of achieving a complete treatment of CRC liver metastases include the following:
Patients with unilobar multinodular metastases requiring resection of more than 60% to 70% of the functional liver parenchyma should undergo preoperative portal vein embolization. Following PVE, the induced hypertrophy of the future remnant liver allows for a curative resection while minimizing the risk of postoperative hepatic insufficiency (Fig. 13.6A). Patients with bilobar multinodular metastases for which a planned resection would leave no more than three nodules and none larger than 3 cm in the remnant liver are preferentially treated with a multimodal approach consisting of hepatic resection combined with RFA or cryotherapy of the unresectable nodules (Fig. 13.6B).
Extended Liver Surgery (Total Vascular Exclusion and Cooling) Involvement of the IVC and/or the confluence of hepatic veins by liver metastases is another situation that can be considered as a contraindication to liver resection. Currently, employing total vascular exclusion (TVE) of the liver and vascular reconstruction techniques can make surgery possible without taking further risks for this specific group of patients. As the experience has grown with TVE, an increasing number of patients are being operated with acceptable morbidity and mortality. Conventional TVE consists of clamping of the liver inflow (Pringle maneuver) as well as clamping of the supra and infrahepatic vena cava. Alternatively, in cases with no caval involvement by the tumor, selective control of the hepatic veins can be achieved allowing preservation of the caval flow. In cases whereby the caval clamping is associated with hemodynamic disturbances (hypotension), a venovenous bypass is necessary through which venous blood from femoral and portal vein is diverted to axillary or internal jugular vein. A drawback of these techniques, however, is that almost inevitably would induce warm ischemia for which the maximal duration of tolerance is assumed to be around 60 to 90 minutes. For cases which require interruption of hepatic blood flow for more than 60 minutes, hypothermic perfusion of the liver should be instituted to prevent the consequences of a long warm ischemic time. Such combination was evaluated in a study conducted in our center, which demonstrated that TVE combined with hypothermic perfusion was associated with a better ischemic tolerance and liver function as well as significantly lower complication rates compared to TVE 60 min. Combined liver and vena cava resection is another procedure facilitated by combined TVE and hypothermic perfusion. In
Figure 13.6 Diagrammatic illustration of the surgical strategies used when treating patients with nonresectable multimodal metastatic disease. (A) Multifocal unilobar metastases. (B) Multifocal bilobar metastatases. (C) Multifocal bilobar metastases. RFA, radio frequency ablation; Cryo, cryotherapy.
128
Table 13.4 Reported Survival Outcomes after Repeat Liver Resection for Recurrent Colorectal Metastases
Patient survival (%) Author/Institution Fernandez et al. Adam et al. Yamamoto Muratore et al. Suzuke et al. Petrowsky et al. Adam et al. Shaw et al. Year 1995 1997 1999 2001 2001 2002 2003 2006 No of patients 170 64 75 29 26 126 199 66 1 years 87 48 86 89 3 years 45 60 31 35 62 51 46 5 years 32 41 32 34 32 44
(%) 100 89% 88% 82% 54% 60 46% 40 42% 36% 32% 28% First hepatectomy Second hepatectomy Third hepatectomy
80
20
0 0 1 No 416 139 6 2 1 yr 267 80 49 3 2 yrs 169 37 31 3 yrs 120 27 15 4 4 yrs 83 19 10 5 yrs 60 13 6 5 Year
Figure 13.7 Survival after 1st, 2nd, and 3rd hepatectomy from the time of the index operation. Source: From Ref. (112).
129
In patients who are chemonave with four or more synchronous CRLM and a nonocclusive primary, neodjuvant chemotherapy can be appropriate followed by repeated MRI and PET CT. Neoadjuvant chemotherapy can also be administered in patients with two to three bilobar CRLM. By contrast, if a patient belonging to this group has comorbidities or there is a concern about chemotherapy-related hepatotoxicity at a time when an extended resection is required, initial surgery would be indicated. Instead for patients with one to two unilobar metastatic diseases, upfront surgery should be considered first. Single or staged intervention? The optimal timing for resection of synchronous CRLM and the primary tumor remains a matter of controversy. Most surgeons
130
conclusions
The surgical treatment of colorectal hepatic metastases represents the only potentially curative therapeutic option able to achieve long-term survival and a hope for cure. Newer treatment strategies have shifted from the traditional concept of successive lines of medical therapy to that of a continuum of care in which medical and surgical treatment combinations are tailored to the clinical settings. To optimize the treatment of CRLM, management by a multidisciplinary team consisting of oncologists, surgeons, and radiologists is of the utmost importance. Advances in body and hepatic imaging has allowed for more accurate selection of patients with colorectal liver metastases. Imaging modalities are now able to detect minimal metastatic, which not very long ago would have been very difficult to do so. The significance of the prognostic factors has changed, although helpful in stratifying patients with regards to prognosis, should not be used to exclude otherwise resectable patients from surgery. Data on the use of neoadjuvant and adjuvant therapy to decrease recurrence risk and improve survival in patients with initially resectable metastases are encouraging, while further evidence and assessment is needed. With newer chemotherapy regimens, a significant proportion of unresectable patients are currently switched to resectable, opening the way to a survival benefit, which is not very different to that of initially resectable patients. The use of modern surgical techniques has resulted in a reduction of perioperative mortality and morbidity, whereas tumor ablation techniques, PVE, and radical liver
131
references
1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 1030. 2. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989; 210: 12738. 3. Blumgart LH, Allison DJ. Resection and embolization in the management of secondary hepatic tumors. World J Surg 1982; 6: 3245. 4. Jatzko G, Wette V, Muller M, et al. Simultaneous resection of colorectal carcinoma and synchronous liver metastases in a district hospital. Int J Colorct Dis 1991; 6: 11114. 5. Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer a comparison with respective treatment. Ann Surg 1984; 199: 5028. 6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leukovorin for metastatic colorectal cancer. N Eng J Med 2004; 350: 233542. 7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan refractory metastatic colorectal cancer. N Eng J Med 2004; 351: 33745. 8. Ambiru S, Miyazaki M, Isono T, et al. Hepatic resection for colorectal metastasesanalysis of prognostic factors. Dis Colon Rectum 1999; 42: 6329. 9. Yazaki M, Ito H, Nakagava K, et al. Aggressive surgical resection for hepatic metastases involving the inferior vena cava. Am J Surg 1999; 177: 2948. 10. Kato K, Yasui K, Hirai T, et al. Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded in 18 institutions. Dis Colon Rectum 2003; 46: S2231. 11. Mutsaerts EL, van RS, Zoetmulder FA, et al. Prognostic factors and evaluation of surgical management of hepatic metastases from colorectal origin: a 10 year single institute experience. J Gastrointest Surg 2005; 9: 17886. 12. Wood CB, Gillis CR, Blumgart LH. A retrospective study of the natural history of patients with liver metastases from colorectal cancer. Clin Oncol 1976; 2: 2858. 13. Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancer. Arch Surg 1976; 111: 3304. 14. Scheele J, Strangl R, Altendorf-Hofmann A, Gall FP. Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 1991; 110: 1329. 15. Mentha G, Huber O, Robert J, et al. Elective hepatic resection in the elderly. Br J Surg 1992; 79: 5579. 16. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred forty seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Col Surg 2000; 191: 3846. 17. Vauthey JN, Pawlik TM, Abdalla EK, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 2004; 239: 72230. 18. Sica GT, Ji H, Ross PR. CT and MR imaging of hepatic metastases. AJR Am J Roentgenol 2000; 174: 6918. 19. Scott DJ, Guthrie JA, Arnold P, et al. Dual phase helical CT versus portal venous phase CT for detection of colorectal liver metastases: correlation with intraoperative sonography, surgical and pathological findings. Clin Radiol 2001; 56: 23542.
132
133
134
14
Chemotherapy for metastatic colorectal cancer Derek G. Power and Nancy E. Kemeny
schedule as randomized data has shown the superiority of this regimen compared with other 5-FU/LV schedules (16). Over the last few years, three new chemotherapeutic agentsirinotecan, oxaliplatin, and capecitabine (an oral version of 5-FU)have been approved for the treatment of metastatic CRC. Irinotecan is a topoisomerase inhibitor and activity in the metastatic setting was established in randomized studies comparing irinotecan with best supportive care. In patients who progressed on fluorouracil therapy, one-year survival rates were increased from 14% to 36% with the use of single agent irinotecan (17). Combinations of irinotecan and 5-FU/ LV were then studied in the first-line setting. A randomized trial of irinotecan added to infusional 5-FU/LV compared to 5-FU/LV alone demonstrated an increased response rate (35% vs. 22%, respectively, p = 0.005) and a survival benefit of 3 months (17 vs. 14 months, respectively, p = 0.031). Grades 3 to 4 toxicities were more common in the irinotecan group, e.g. diarrhea (44% vs. 26%) and neutropenia (29% vs. 2%) (18). A phase III study of 683 patients compared weekly irinotecan and bolus 5-FU/LV (IFL) to 5-FU/LV alone. The IFL regimen increased response rate (39% vs. 21%, p < 0.001) and survival (14.8 vs. 12.6 months, respectively, p = 0.04) (19). The FOLFIRI regimen, that is, irinotecan combined with the deGramont 5-FU/LV combination, has been shown to be safe and efficacious in the first-line setting and is now accepted as the optimal way to combine irinotecan and FU/ LV. Response rates approaching 40% and median overall survival of 17 to 23 months have been reported (20,21). The randomized BICC-C trial (before the addition of bevacizumab) reported a median OS of 23.1 months for FOLFIRI vs. 17.9 months for mIFL and 18.9 months for CapIRI (capecitabine and irinotecan) with response rates of 47%, 42%, and 39%, respectively (21). Oxaliplatin is a platinum derivative and works by alkylating DNA. As a single agent, oxaliplatin is not superior to LV5FU-2 and has limited activity in advanced CRC (22,23). In the firstline setting, the FOLFOX regimen, that is, combination oxaliplatin and LV5FU-2 given as the deGramont schedule, was shown to be safe, efficacious, and superior to LV5FU-2 with response rates of 50% and median overall survival of 16 months (24). FOLFIRI compared with FOLFOX showed response rates of 56% and 54%, respectively, and no difference in median overall survival 20.6 versus 21.5 months (p = NS) (25). A phase III trial by Colucci and colleagues comparing FOLFIRI and FOLFOX4 also showed essentially equal efficacy in terms of response rate, time to progression, and overall survival (26). The intergroup trial showed that patients receiving FOLFOX had a median survival of 19.5 months compared to 17.4 months for irinotecan plus oxaliplatin (IROX) or 15 months for IFL (p = 0.001) (27,28). Efficacy of the FOLFOX
introduction
Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide and in Western countries, and it is the second most frequent cause of cancer-related death (1). The United States has the highest annual incidence of invasive CRC, and in 2008 an estimated 148,810 cases of CRC were diagnosed and 49,960 people died from the disease (2). At diagnosis, 20% to 25% of all patients will have synchronous liver metastases and at least another 60% of patients who develop metastatic disease will have metachronous liver metastases (3,4). The liver is the only metastatic site in about onethird of patients and this can be explained by the portal venous drainage of the colon and rectum to liver (5). Overall liver metastases are seen in approximately 20% to 70% of patients with CRC and lung metastases are seen in 10% to 20%. (6) For many years, the approach to patients with metastatic CRC was minimalist with fluorouracil-based chemotherapy being the only palliative option and median survival rarely exceeding one year (7). Surgical developments over the last 10 years in resection of liver metastases have resulted in improved long-term survival. Several large surgical series have shown 5-year survival rates averaging 30% to 40%, and in some patients a chance of cure, with 20% survival at 10 years after hepatic resection (810). Developments in chemotherapy, both systemic and regional, have resulted in a radically changed landscape for patients with metastatic CRC. Those patients who present with initially unresectable liver metastases, 80% to 85% of cases, may now have the chance of hepatic resection after chemotherapy downstaging. Even if liver resection is not possible, median survival has increased with modern chemotherapies (3,11). This review will focus on developments in chemotherapy and biologic therapy for the treatment of metastatic CRC and highlight how a true multidisciplinary approach has resulted in improved survival for this common disease.
systemic chemotherapy for unresectable liver disease (first and second line)
The fluorinated pyrimidine antimetabolites have been the cornerstone of systemic treatment for CRC for over 50 years. Fluorouracil (5-FU) was the only chemotherapeutic agent available for nearly 35 years. Response rates with bolus 5-FU were 10% to 20% with median survival around 10 to 12 months (12). Modifications of the 5-FU dosing schedule were studied and it was found that a protracted infusion of the drug increased response rates to 20% to 30% and median survival to 12 to 14 months (13,14). The addition of the biomodulator folinic acid [leucovorin (LV)] to 5-FU similarly increased response rates and median overall survival (14,15), and it has now become standard to combine 5-FU bolus plus 48-hour infusion with bolus LV (deGramont LV5FU-2) in a bimonthly
135
RR, response rate; mTTP, median time to progression (in months). mOS, median overall survival (in months).
regimen was also shown in the randomized TREE1 study, which compared mFOLFOX6 to bolus FU/LV/oxaliplatin and to capecitabine/oxaliplatin. Response rates were 41%, 20%, and 27%, respectively, and median OS was 19.2, 17.9, and 17.2 months, respectively (29). Overall, the FOLFOX and FOLFIRI regimens have improved response rate, time to progression, and overall survival compared to 5-FU/LV (30). Replacing 5FU/LV with capecitabine and combining with oxaliplatin (XELOX) has been shown to be noninterior to FOLFOX and thus is a third alternative for first-line treatment (31). The combination of capecitabine and irinotecan, however, is not well tolerated and is associated with high rates of severe vomiting and diarrhea. Therefore the bolus/infusional schedule of FU, LV5FU-2 is the preferred mode of administration in combination with irinotecan (21). In the second-line setting, after treatment failure with oxaliplatin or irinotecan-based regimens, results are less impressive (Table 14.1). Response rates of up to 18% and median overall survival of 6 to 14 months have been reported (32,33). It is noteworthy that in those patients who are 5-FU refractory, there is no difference in outcome if second-line therapy begins with either FOLFOX or irinotecan. In a phase III study of 491 5-FU-resistant patients with mCRC, median overall survival with second line FOLFOX was 13.8 versus 14.3 months for irinotecan alone (p = 0.38) (34).
Catheter in artery
the study, initial extrahepatic disease in some studies, and the fact that HAI was not used in all cases though the patients are included in the survival data. The CALGB 9481 study compared HAI FUDR + Dexamethasone (Dex) with systemic intravenous (IV) FU/LV and did not have a crossover (39). Dexamethasone was added to the FUDR in the pump as it had previously been shown to decrease FUDR toxicity and increase efficacy (40). There was a significant increase in overall survival in the HAI FUDR Dex arm versus the systemic FU/LV arm (24.4 vs. 20 months, respectively, p = 0.0034). Quality of life assessment showed that the HAI arm experienced significantly better physical functioning compared with the systemic arm. The 51% 2-year survival compared favorably with systemic combinations of Oxaliplatin/5FU/LV (25), or irinotecan/5FU/LV (41). The use of HAI alone, however, in a new meta-analysis using the old flawed studies did not show an increased survival (38). With new systemic therapies, it is more appropriate to think of a combination of these regimens with HAI FUDR/Dex.
136
137
138
16 32.5 33.3 26
(oxaliplatin, irinotecan and bolus/infusional 5FU/LV) in patients with initially unresectable (or not optimally resectable) disease and report increasing rates of R0 hepatic resections and overall survival (Table 14.2). In a phase III study of 244 patients, conducted by the Gruppo Onclogico Nord-Ovest (GONO) group, FOLFOXIRI was compared with FOLFIRI. The rate of R0 hepatic resections was 36% for the triplet compared with 12% for the doublet (p = 0.017) (86). This group recently updated the long-term outcome of 196 patients with initially unresectable mCRC treated with FOLFOXIRI in two phase II and one phase I trials. The overall R0 resection rate was 19% and at 5 years, 29% of patients are free of disease (87). Another phase III study of 283 patients showed that the addition of oxaliplatin to FOLFIRI increased the resection rate of lung and liver metastases from 4% to 10%. Of those who underwent surgery after FOLFOXIRI, 86% had an R0 resection (88). Subset analysis of the oxaliplatin stop-go OPTIMOX-1 study showed that FOLFOX4 was superior to FOLFOX7 in terms of overall survival after an R0/R1 resection (51 vs. 38 months, respectively) (89). HAI combined with systemic therapy in nonrandomized studies has demonstrated high response and resection rates. In a retrospective series examining HAI FUDR Dex in patients who had all received prior oxaliplatin/5FU/LV and some had prior irinotecan as well, the response rate for 39 patients was 44%, and median OS from the time of initiation of HAI was 20.1 months, while it was 32 months from the initiation of treatment of their metastatic disease. Eighteen percent of patients proceeded to surgical resection or ablation (90). HAI FUDR/Dex combined with oxaliplatin and irinotecan based regimens produced resectability rates of up to 47% in patients who were definitely unresectable at presentation and 53% had received prior systemic therapy. The median survival for all patients was 41 months. Survival for the chemotherapy naive group was 50 months while it was 38 months for those previously treated (43). The benefit of HAI therapy given in a neoadjuvant setting has also been highlighted by Auer and colleagues. Radiologic complete response of liver metastases in patients treated with HAI FUDR was more likely to represent a true CR when
compared to systemic neoadjuvant chemotherapy (68% vs. 29%), and the liver recurrence rate was 14% in the HAI group versus 42% in the preoperative systemic chemotherapy group (p < 0.001) (91,92). The benefit of HAI in the neoadjuvant setting has also been reported with the use of other drugs besides FUDR. In a phase II study, Ducreux and colleagues reported the efficacy and relative safety of HAI Oxaliplatin plus 5FU/LV in 26 patients with initially unresectable liver metastases. Median overall survival and median disease free survival was 27 months and 27 months, respectively (93). The intention to treat response rate was 64% and 5 patients proceeded to R0 liver resection. Recent work by Boige and colleagues used HAI Oxaliplatin combined with systemic FU/LV after systemic failure with either FOLFOX or FOLFIRI or both (94). Median PFS and overall survival were 7 months and 16 months, respectively, and 7 out of 39 patients previously deemed unresectable were able to undergo an R0 liver resection. The use of preoperative HAI Oxaliplatin has also been reported by Elias and colleagues to be significantly associated with a true pathologic complete response even when missing metastases are left in place at hepatectomy (95). These studies suggest that regional therapy may produce a higher rate of true cured lesions than systemic therapy as described in the Benoist study where persistent macroscopic or microscopic residual disease or early recurrence in situ was observed in 83% of liver metastases having a complete response on imaging (96). The toxicity profile of HAI Oxaliplatin is abdominal pain (grades 34, 14%) and neutropenia (grades 34, 43%) (97). Irinotecan is not more useful via HAI route as the systemic levels of the active metabolite SN-38 are similar to that seen when irinotecan is given systemically (9799). Biologic agents are also being used in combination with systemic chemotherapy in patients with initially unresectable liver disease. Recent data has shown that bevacizumab in combination with chemotherapy may increase hepatic resection rates and does not appear to impact adversely on surgical outcome or liver regeneration. In a nonrandomized phase II trial by Gruenberger and colleagues, the addition of bevacizumab to XELOX in patients with potentially resectable liver metastases resulted in an objective response rate of 73%, a resection rate of 93%, and no intraoperative or wound healing complications (100,101). To evaluate whether preoperative bevacizumab affects patients going for liver resection, the Bevacizumab Expanded Access Trial (BEAT) was designed and has thus far concluded that metastatectomy is feasible after bevacizumab treatment (102). Combination of EGFR antibodies with systemic chemotherapy may also have the potential to increase resection rates of unresectable or possibly resectable liver metastases. Adam and colleagues reported that combining Cmab with oxaliplatin- or irinotecan-based chemotherapy in chemorefractory patients with unresectable liver metastases can result in salvage liver resection rates of 17%. With a median follow-up of 16 months, 92% of resected patients (23/25) were alive and 10 patients (40%) were disease-free. There was no significant increase in operative mortality or liver injury. Median overall (OS) and progression-free survival (PFS) from initiation of cetuximab therapy was 20 and 13 months, respectively
139
140
141
PFS, hepatic progression-free survival; OS, overall survival; MS, median survival. ** Interleukin, carboplatin, mitomycin, epirubicin, LV, urographin. ! Mean survival. ^ 3-year overall survival.
FUDR dose >50 U/L 0 to <2 X ref 2 to <3 X ref 3 to <4 X ref 4 X ref <3 X ref >90 U/L 0 to <1.2 X ref 1.2 to 1.5 X ref 1.5 X ref <1.2 X ref >1.2 md/dl 0 to <1.2 X ref 1.2 to <1.5 X ref 1.5 X ref <1.2 X ref 100% 80% 50% HOLD 50% off last dose FUDR 100% 80% HOLD 25% off last dose FUDR 100% 50% HOLD 25% off last dose
50 U/L 0 to <3 X ref 3 to <4 X ref 4 to <5 X ref 5 X ref <4 X ref Alk Phos 90 U/L 0 to <1.5 X ref 1.5 to >2 X ref 2 X ref <1.5 X ref Total Bilirubin 1.2 mg/dl 0 to <1.5 X ref 1.5 to <2 X ref 2 X ref <1.5 X ref
Reference value is the value obtained on the day patient received the last FUDR dose. Current value is that obtained at pump emptying or on the day of planned treatment (whichever is higher).
142
references
1. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 58192. 2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 7196. 3. Kemeny N. Presurgical chemotherapy in patients being considered for liver resection. Oncologist 2007; 12: 82539. 4. Rees M, Tekkis PP, Welsh FK, et al: Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008; 247: 12535. 5. Kemeny N. Management of liver metastases from colorectal cancer. Oncology (Williston Park). Oncology (Williston Park) 2006; 20: 116176. 6. Penna C, Nordlinger B. Colorectal metastasis (liver and lung). Surg Clin North Am 2002; 82: 107590, xxi. 7. Meyerhardt JA, Mayer RJ. Drug therapy: Systemic therapy for colorectal cancer. N Engl J Med 2005; 352: 47687. 8. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239: 81827. 9. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004; 240: 43850. 10. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25: 457580. 11. Alberts SR, Wagman LD: Chemotherapy for colorectal cancer liver metastases. Oncologist 2008; 13: 106373. 12. Hoff PM, Cassidy J, Schmoll HJ. The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist 2001; 6 Suppl 4: 311. 13. Meta-Analysis Group in Cancer. Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 1998; 16: 353741. 14. Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 3018. 15. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004; 22: 376675. 16. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15: 80815. 17. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 14138. 18. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 10417. 19. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 90514. 20. Maiello E, Gebbia V, Giuliani F, et al. FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dellItalia Meridionale (GOIM). Ann Oncol 2005; 16 Suppl 4: iv5660. 21. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25: 477986.
conclusions
Liver resection should now be considered in all patients with liverconfined metastatic disease from CRC. Modern systemic chemotherapy with irinotecan- and oxaliplatin-based regimens can increase resection rates is a significant number of patients. The addition of biologic agents in patients with the appropriate molecular signature may increase repose rates and resectability rates even further. Long-term cures are possible in patients who undergo liver resection and series with 10-year survivors have been reported (10). In those patients in whom resection is not possible, overall survival has increased from less than 1 year with fluorouracil regimens to over 2 years with chemobiologic regimens (74). Hepatic arterial infusion with FUDR has consistently demonstrated increased response rates and hepatic progression-free survival compared to systemic chemotherapy. The combination of HAI FUDR with modern chemotherapy and perhaps chemobiologic therapy can result in increased resection rates of initially unresectable liver disease and also has a role to play after liver resection.
143
42.
43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
55. 56.
57.
58.
59.
60.
144
145
146
147
15
Multimodal approaches to the management of colorectal liver metastases Gerardo Sarno and Graeme J. Poston
purpose, and then the role(s) of each of the possible treatment modalities (surgery, ablation, systemic chemotherapy, regional chemotherapy/radiotherapy, and biological therapies) as well as the strategy of which treatment to use in which sequence.
This chapter focuses on the recent development of multimodal strategies intended to increase the pool of patients with colorectal liver metastases (CRLMs) for whom curative treatment may be possible. These strategies include improved preoperative staging, new standards for surgical resection, novel surgical strategies, the application of modern systemic chemotherapy in the neoadjuvant setting, an emerging role for ablative therapies, greater emphasis on the collaborative, multidisciplinary management of this disease, and most recently, the question of whether to resect the liver disease before the primary bowel tumor. It is now clear that an aggressive multidisciplinary approach to the management of this problem can result in one-third of these patients now being considered for treatment that even if not achieving complete cure, offers significant long-term survival. Colorectal cancer is globally a growing cause of public health concern (1,2). The prevalence is increasing at 5% per year among the burgeoning middle classes in both China and India, and in western society is expected to increase in incidence by over 30% over the next 20 years because of evergrowing elderly (>70 years of age) population (1,2).The liver is frequently the only site in 30% to 40% of patients with advanced disease (3). By the time of initial diagnosis of colorectal cancer, nearly a quarter of patients will have clinically detectable CRLMs, despite increasing patient and clinician awareness of the disease (1,4,5). Historically, these patients have a poorer prognosis when compared to those who subsequently develop metachronous diseases (1,5). Of those who undergo apparently successful resection of the primary tumor, nearly half will develop liver metastases, usually within the first 3 years after colectomy (1,4,5). Until recently, surgery was the only treatment that offered the chance of cure for CRLM, and until recently, only far less than 20% of these patients were considered suitable for attempted curative resection; historically, the remaining patients being offered palliative and symptomatic treatment (6). Recent data suggest that ablation therapy (radiofrequency or RFA, microwave) might achieve long-term survival, but with poorer overall results compared to surgical resection (7). The other major advance in recent years has been the availability of medical oncology strategies using chemotherapeutic and biologic agents not only to significantly prolong survival in incurable disease, but also to bring initially inoperable patients to surgical resection with curative intent (8). Recently, it has become a legal requirement in a number of European countries (UK, France, Belgium, and Spain) for all cancer patients to be discussed within the setting of a multidisciplinary team (MDT) before any treatment intervention commences. In order for such an MDT to be effective in the management of colorectal cancer liver metastases, the team must undertake a number of specific steps in determining the extent of spread of the cancer, and the best modalities for this
computeed tomography
Recent advances in computed tomography (CT) technology (helical CT and multidetector row helical CT) have improved performance in speed of acquisition, resolution, and ability to image the liver during various phases of contrast enhancement with greater precision (9,12). Using intravenous iodinated contrast media these techniques characterize liver lesions based on their enhancement patterns during the various phases of contrast circulation in the liver (12). CT has limitations, including
148
resection margins
Historically, resection was only considered if the hepatobiliary surgeon believed that the metastasis could be resected with a margin of healthy surrounding liver that was >1 cm. The new standards challenge the 1 cm rule. More recent studies show that size of the resection margin has no effect on survival, as long as the margin is microscopically clear of disease (20,21).
surgery
There are many substantial prospective and retrospective series of surgical resection of CRLM consistently show 5-year survival rates following liver resection of 30% to 50%, depending on selection criteria (15). The problem encountered when attempting to interpret these reports is that although there are more than 600 in the literature, barely 30 series are prospective studies, reporting more than 100 patients from reliable high-volume centers, and with median follow-up of >24 months (15). However, from these reports nearly all patients who survive for more than 5 years can usually be considered cured of the disease.
149
Figure 15.1 Three-year progression-free survival comparing surgery alone to surgery with perioperative chemotherapy in the EORTC 40983 (EPOC) trial (30).
secondary CRLM resection rates) when compared to conventional chemotherapy alone. Therefore, even more patients with initially unresectable CRLM may respond to treatment with combinations of systemic treatments in the future (2729). Recent data from the German Phase II CELIM study have suggested that as many as 40% of patients with unresectable kras wild type colorectal cancer metastases confined to the liver may now be brought to liver resection with curative intent using combinations of cetuximab with either oxaliplatin-based or irinotecan-based chemotherapy regimens (30). Recent data have suggested that the addition of perioperative (both neoadjuvant with adjuvant) chemotherapy using FOLFOX to surgical resection confers improved disease-free survival when compared to surgery alone (31). These data need to be interpreted with caution since the study did not demonstrate its primary endpoint (3-year disease-free survival on intention to treat at the point of initial randomization), and only achieved significance on the analysis of operated patients, when ineligible patients were excluded (Fig. 15.1).
are often too close to major vascular structures to be considered resectable with a clear margin. Just as a surgical margin would be likely to be compromised, high blood flow immediately adjacent to the tumor will conduct away heat, leading to incomplete ablation and tumor recurrence (2). The efficacy of RFA in unresectable CRLM has been established by several large cohort studies with median survivals of 28.9 to 36 months being achieved (32,33). Presently the dearth of prospective randomized controlled trials comparing RFA with chemotherapy over chemotherapy alone in unresectable CRLM is being addressed by the EORTC CLOCC trial (EORTC 40004). Early progression-free survival data from this study have suggested that the addition of RFA to FOLFOX-based chemotherapy confers a statistically significant improved progression-free survival of 17 months compared to 10 months for FOLFOX alone (T Ruers, personal communication). Microwave ablation therapy is now becoming commercially available. The major advantage of microwave ablation over RFA is speed. Whereas it may take 20 to 30 minutes to achieve an adequate ablation of a 3-cm metastasis using RFA, microwave can achieve the same degree of tumor destruction in only 3 to 4 minutes.
150
Determine if patient is candidate for hepatic resection or HR and RFA or RFA alone
Extrahepatic disease
Consider chemotherapy
Not candidate for HR or RFA Response Consider chemotherapy Hepatic resection Response
All tumor(s) resectable
No response
HR and RFA
Some tumor(s) resectable and some ablatable
(Laparotomy HR and RFA)
RFA alone
All tumor(s) ablatable but not resectable
Lapartomy, Laparoscopic or Percutaneous)
Figure 15.2 The possible treatment strategy algorithm for patients with colorectal liver metastases (40).
synchronous CRLM should have immediate definitive lifesaving treatment (endoscopic stenting, resection with either a stoma or immediate reconstruction). Most surgical oncologists would recommend that in situations where resection of the primary tumor may be more demanding (T2T3 rectal carcinoma), or when the management strategy for the primary tumor requires neoadjuvant treatment (chemoradiotherapy for T3T4 rectal carcinoma), or the liver disease (albeit technically resectable) is of such an extent that it requires at least a hemi-hepatectomy or more, then planned sequential staged procedures carry lower perioperative risk (36,37). However, when considering staged sequential treatment strategies, concerned must remain about the risk of tumor progression at both sites during treatment (31,3840). For
patients presenting with asymptomatic primary tumors in the presence of unresectable liver metastases, it would be reasonable to propose a course of systemic chemotherapy and base subsequent treatment strategies on the degree of response (38). Those patients whose chemotherapy response is sufficient that their liver disease is now amenable to potential hepatectomy can now be considered for surgery with curative intent (31,3840). For the 6% to 10% of patients with present with inoperable disease and continue to progress while on chemotherapy (23,31), consideration can be given to further lines of chemotherapy, but overall the outlook is poor and futile surgery can be avoided. For patients with primary colon cancer (as opposed to primary rectal tumors) with initially unresectable liver whose disease responds so well that an R0 resection of all tumor sites
151
should the liver resection take precedence over the bowel surgery?
The fundamental question is now whether or not, having achieved a window of therapeutic opportunity to deal with the liver disease, does the liver disease takes precedence over the primary tumor (39,40)? It has been proposed that the liver disease should be resected first, and then following eradication of the liver disease, subsequently deal with the primary bowel tumor. Using this strategy, potentially curative surgery for both primary and secondary disease has been achieved in 16 of 20 (80%) such patients in small singlecenter series (38).
conclusions
If feasible, surgical resection remains the gold standard of treatment for CRLM. Unfortunately, patients still present with advanced colorectal cancer. Modern chemotherapy regimens offer increasing numbers of patients with initially unresectable CRLM the chance of being brought to potentially curative liver surgery (Fig. 15.2) (41). The remaining controversies in this field are the timing of such surgery and the strategic decisions of which operation (bowel first, liver first, or synchronous combined surgery) is now the first procedure of choice? The role of the MDT in the management of colorectal cancer liver metastases is to collate all the available data that can lead to an accurate assessment of disease spread and stage, then using these data, to plan an effective treatment strategy that ideally is focused on possible cure, but in any event is aimed at gaining maximal survival advantage for our patients.
references
1. Poston GJ. Surgical strategies for colorectal liver metastases. Surg Oncol 2004; 13: 12536. 2. Primrose JN. Treatment of colorectal metastases: Surgery, cryotherapy or radiofrequency ablation. Gut 2002; 50: 15. 3. Weiss L, Grundmann E, Torhorst J, et al. Hematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 1986; 150: 195203. 4. Sugarbaker PH. Surgical decision making for large bowel cancer metastatic to the liver. Radiol 1990; 174: 6216. 5. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994; 343: 140510. 6. Geoghegan JG, Scheele J. Treatment of colorectal liver metastases. Br J Surg 1994; 86: 15869. 7. Abdalla E, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239: 81825. 8. Bismuth H, Adam R, Levy F, et al. Resection of nonresectable metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224: 50920. 9. Sahani DV, Kalva SP. Imaging the liver. Oncologist 2004; 9: 38597. 10. McLoughlin JM, Jensen EH, Malafa M. Resection of colorectal liver metastases. Cancer Control 2006; 13: 3241. 11. Vauthey JN. Patients with hepatic colorectal metastases. Program of the AHPBA 2006 consensus conference; January 25, 2006; San Francisco, CA.
152
153
16
introduction
Neuroendocrine tumors (NET), including both carcinoid tumors and islet tumors, are derived from primitive neuroectodermal cells that are distributed throughout the body during embryonic development (14). Therefore, NETs originate from various organs but most commonly involve the lungs, bronchi, and gastrointestinal tract (2,5). NETs were traditionally classified into foregut, midgut, and hindgut derivatives based on their presumed origin of gut. Currently, it is replaced by the WHO classification system of 2000 according to the histological differentiation (6). Clinical presentations widely differ depending on both their organ and excess hormone production (e.g., serotonin, histamine, tachykinins, and prostaglandins) (3,5). The overall incidence of NET has been reported to be 1 to 2 cases per 100,000 people (5) (Tables 16.1 and 16.2). Hepatic metastasis is the second common metastasis following lymph node metastasis in NETs (3) (Fig. 16.1). Up to 45% of patients with abdominal carcinoid will present with bowel obstruction and more than half of patients who were explored for bowel obstruction due to NETs are found to have hepatic metastases. Despite of the fact that liver is the common metastatic site of NETs, primary hepatic NET is extremely rare (0.6% of all NETs) (2). In this chapter, we describe specifically about the management of hepatic metastases of NETs.
diagnosis
Clinical Features Hepatic metastases of NET could be diagnosed preoperatively following investigation of a specific hormonal syndrome or following the incidental finding of hepatomegaly or an abdominal mass. Or it could be discovered at the abdominal exploration for primary gastrointestinal NETs. Besides hormonal symptoms, patients will complain local symptoms due to tumor bulk (pain, early satiety, or palpable mass). Subclinical hepatic metastasis does not require treatments, however, lifestyle-altering symptoms or biologically aggressive tumors require treatment (7). Demographics, presentation, symptoms, tumor histology, and primary tumor location of patients with NET-hepatic metastasis are summarized in Table 16.3 (8). The most representative symptom of patients with NETs is carcinoid syndrome. It is caused by systemic circulation of hormonal products from bulky metastatic NETs. This syndrome is a manifestation of late stage of NET and 5% to 10% of all NET patients present with this syndrome (1,5,9,10). In patients with NET-hepatic metastasis, carcinoid syndrome is frequently evident, at least biochemically (1). Common symptoms and signs include cutaneous flushing (7180%), diarrhea (7680%), hepatomegaly (71%), carcinoid heart disease (4170%), asthma (925%), pellagra (2%) (3,1115).
154
Table 16.2 Anatomical Location of NETs (Carcinoid Only, Except for Islet Cell Tumors) from SEER 19731999
% Lung, bronchi, and trachea Stomach Duodenum Jejunum Ileum Appendix Cecum Colon Rectum Other
Source: Adapted from Ref. (2).
28 5 3 2 15 5 4 5 14 6
the primary site. Sensitivity of CT/MRI is reported to be about 80%. The detection rates are 76% to 100% for CT alone and 67% to 81% for MRI alone (31). Triple phase spiral CT is the most informative to evaluate NET-hepatic metastasis. NEThepatic metastasis-associated findings are defined as mass lesions with calcification and radiating strands of fibrosis (36) (Fig. 16.3) (Grade III. Recommendation C). Positron Emission Tomography (PET) [18F]Fluoro-2-deoxy-d-glucose (FDG)-PET scan became an essential tool for many cancers to detect cancer cells, which were not seen in other imaging, or to quantify metastatic sites by the whole body image. The utility of 18F-PET scan for NETs is not well supported. Because typically NETs are slow growing with a low metabolic rate, the uptake of 18F by NETs cannot be visualized (37,38). The detection rates are reported as 25% to 73% (1,39). Instead, PET scan with the radioactive serotonin precursor 11C-5 HT, and 68Ga/64Cu coupled to octreotide revealed an excellent detection rate (40). Since there were no large studies to assess the efficacy of PET scan compared to other diagnostic imaging (41), the role of PET scan for NETs is still unclear (Grade III. Recommendation C).
Radiolabeled Metaiodobenzylguanidine (MIBG) Because NETs concentrate MIBG, the administration of 123 I-MIBG is another option to detect metastatic NETs. Sensitivity and specificity were reported as 55% to 70% and 95%, respectively (42,43). Although the accuracy of this test is inferior to that of SSTR scintigraphy, MIBG is a useful alternative of SSTR scintigraphy in patients on long-acting SST analog in whom SSTRs may have been occupied by SST analogue already (42,43) (Grade III. Recommendation C).
Diagnostic Imaging Somatostatin Receptor (SSTR) Scintigraphy Given the clinical presentation and biochemical confirmation of NETs, topographical localization of primary tumor and metastases should be pursued. SSTR scintigraphy utilizing 111 In-labelled SST analog (octreotide) can detect NETs that express SSTRs. Sensitivity of this test is reported as 84% (57 93%) (1,34,35) (Fig. 16.2). The simultaneous use of single positron emission computed tomography (SPECT) can enhance the sensitivity. This is the first choice of diagnostic imaging test to find the primary site of carcinoid tumors (Grade III. Recommendation C). Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) CT and MRI are utilized to obtain more precise image of local extent of tumor if surgery is contemplated, but not to look for
155
Figure 16.1 Macroscopic (A) and microscopic (B) views of large resected hepatic neuroendocrine liver metastasis (stained for chromogranin-A). Note the hypervascularity of the metastasis compared to the background liver and comparable colorectal liver metastases.
% 40 60 52 years % 74 26 % 55 55 36 15 5 4 1 % 48 31 21 % 49 25 9 16
Hepatic Resection Surgical resection of NET-hepatic metastasis is categorized into curative intent resection or palliation intent resection (debulking/cytoreductive surgery). Both of approaches contribute to the improvement of symptoms and the prolonged survival. Curative intent resection is indicated for patients with solitary or localized hepatic metastasis. Only 10% to 25% of NET-hepatic metastasis is found in this category. Palliation intent resection is applied to patients with considerable symptom due to multiple, bulky extended tumor. The removal of more than 90% of the tumor bulk allows a significant palliation. Concurrent resection of extrahepatic tumors is often performed. Regional lymphadenectomy should be done because lymph node metastasis is common in NETs. Administration of SST analogs will be required for patients with residual tumors. Curative resection is associated with longer survival than noncurative resection (91% vs. 76% at 5 years; median 3050 vs. 1632 months, respectively). Summary of literature review regarding postoperative outcomes is shown in Table 16.5 (8,4758). Postoperative morbidity and mortality rates are 22% (3-26%) and 3% (06%). Although perioperative carcinoid crisis is not very frequent (03%), precaution should be always taken. Relief of symptom was achieved in 92% (46100) of patients. Disease-free survival is 17 to 60 months (median 41 months) and 36% (1642%) at 5 years. Hepatic recurrence is reported in 82% of patients (52). Survivals have an estimated median of 67 (5281) months. Five-year survival rate extends up to 73% (3185%). Ten-year survival is reported as 35% (Grade III. Recommendation C).
treatment
Treatment of NET-hepatic metastasis is required for patients with lifestyle-altering symptoms, or biologically aggressive tumors. The principal requirements are to remove the primary and metastatic sites in order to reduce levels of bioactive agents (27,4446). Therefore, surgical resection is the first choice as long as patients fit to surgery. Treatment options include hepatic resection, hepatic artery occlusion, radiofrequency ablation, cryoablation, liver transplantation, and medical therapy. Indications and timing of therapy are still controversial.
Hepatic Artery Embolization Hepatic artery embolization (HAE) is a rational approach against liver malignancies by using the discrepancy of blood supply between liver tumor and normal liver. The selective occlusion of hepatic artery causes hypoxic damage of tumor. Patients with NET-hepatic metastasis who dont fit for surgery will benefit from this therapy. Indications include (i) rapid enlargement of tumor mass, (ii) increasing symptoms, and (iii) patient preference for the procedure in lieu of other treatment (46). Occlusive and/or chemotherapeutic agents are infused into the hepatic artery through an angiography catheter (5).
156
Mild symptoms
Disabling symptoms
Figure 16.3 Computed tomography scan of multiple neuroendocrine hepatic metastases from a primary small bowel carcinoid. Figure 16.2 Indium-111 Octreotide scan demonstrating octreotide avid liver metastases.
A diagnostic angiography should be obtained from a femoral approach to confirm the anatomy of artery and the patency of portal vein before the administration of the therapeutic agents (Fig. 16.4). Patients should receive SST analogs before the procedure to prevent hormonal adverse events (59). There are no definitive data to support the agents for embolization such as Gelfoam, Ivalon, starch particles, lipidol, or radio isotope-loaded spheres. Selection of chemotherapeutic agents is also still inconclusive. Cisplatin, doxorubicin, and mitomycin are most commonly utilized. Almost all of patients experience postprocedural abdominal pain, nausea, vomiting, and fever. Transaminase levels will shoot up dramatically, and then followed by the elevation of
alkaline phosphatase and or serum bilirubin. Tumor-related hormone level will increase temporarily, however, it can be obviated with SST analogs administration (59). Major complications include gastrointestinal bleeding, gastric and duodenal ulceration, hepatic abscess, ischemic necrosis of gallbladder or small intestine, pancreatitis, sepsis, renal failure, hepatorenal syndrome, portal vein thrombosis, sclerosing cholangitis, arterial thrombosis, and arrythmias (60). Since these complications are common and even can be fatal, patient selection should be strict and postprocedural hospital stay with careful monitoring is warranted. Overall, morbidity rate ranges from 3% to 20%, mortality rate ranges from 0% to 7% (Table 16.6). Successful symptomatic relief and the reduction of tumor size can be achieved; however, the duration of palliation may
157
No. of patients 17
Chen (MD, USA) (48) Chamberlain (NY, USA) (8) Jaeck (Strasbourg, France) (49) Yao (IL, USA) (50) Chung (CA, USA) (51) Sarmiento (MN, USA) (52) Knox (TN, USA) (53) Mazzaferro (Milan, Italy) (54) Osborne (FL, USA) (55) Musunuru (WI, USA) (56) Landry (KT, USA) (112) Eriksson (Uppsala, Sweden) (58) Median
1998 2000 2001 2001 2001 2003 2004 2007 2006 2006 2008 2008
15 34 13 16 31 170 17 36 61 13 23 42
27 27 42 30 26 NA NA NA NA 20 NA 18 27
NA NA NA 12 26 14 24 NA 3 NA 26 20 22
0 6 0 0 3 1 0 0 2 NA 0 0 3
NA NA 69% at 3 years 42% at 5 years NA 16% at 5 years NA 19% at 10 years NA NA NA NA 36% at 5 years
21 NA NA
60 46 9104 NA 35 50 NA NA 41
73% at 5 years 76% at 5 years 68% at 6 years 73% at 5 years 31% at 5 years 61% at 5 years 85% at 5 years 59% at 10 years NA 83% at 3 years 75% at 5 years NA 73% at 5 years
be limited due to recurrence or rearterization of tumors. The occlusive agent alone is associated with a relief of symptom rate 49% (33100%), median disease-free survival at 15 (837) months, and median disease-specific survival at 24 (24120) months (55,56,6168). Whereas the embolization with chemotherapeutic agents results in a relief of symptom rate 75% (6192%), median disease-free survival is 14 (1019) months, and median disease-specific survival 33 (2549) months. The summary of recent literature review is shown in Table 16.7 (Grade III. Recommendation C). Hepatic Radiofrequency Ablation Radiofrequency ablation (RFA) can be performed percutaneously or laparoscopically for patients who are unfit for hepatic resection or intraoperative RFA in addition to hepatic resection is also advantageous. High-frequency alternating current causes ionic agitation that is converted into heat, and leads coagulation necrosis of tumor. The probes can deploy 4 to 5 cm in a single session with up to 200 W of power (Fig. 16.5).
Figure 16.4 Typical angiogram of multiple neuroendocrine hepatic metastases prior to embolization.
158
Year 1989 1998 1999 2002 2006 2007 3 0 49 38% at 1 year NA NA NA 15 55 35 24 59 15 Gelfoam Polyvinyl alcohol particles Lipiodol/Gelfoam Polyvinyl alcohol particles Trisacryl gelatin microsphere (embosphere) NA 17 0 5 0 0 6 0 0 0 3852 89100 64 59 33 8 15 NA 37 NA 8 Gelfoam NA 0 38 NA
Morbidity (%)
Mortality (%)
Relief of symptoms (%) Disease free survival (%) Disease specific survival (%)
Occlusive agent alone (HAE) Nobin (Lund, Sweden) (63) 38% at 1 year NA NA NA NA NA 72
Eriksson (Uppsala, Sweden) (64) Brown (NY, USA) (113) Schell (FL, USA) (17) Osborne (FL, USA) (55) Granberg (Uppsala, Sweden) (65)
Median
24
HAE with systemic chemotherapy Moertel (MN, USA) (68) Loewe (Vienna, Austria) (67) 1994 2003 12 7 98 111 23 NA, including surgical ligation N-Butyl-2-cyanoacrylate, Lipiodol 12 NA 5 9 98.0 NA
NA NA NA
49 39 44
Median Combination with chemotherapeutic agents (HACE) Ruszniewski (Paris, France) (114) 1993 Drougas (TN, USA) (60) 1998 24 15 14 46 122 23 14 20 0 4 5 8 60 0 0 NA 75 64 78 92 2003 2007 2007
NA NA NA NA 5% at 5 years
13 NA 17 14 10
NA 25 48 33 33
2008
59
Doxorubicin, Lipiodol Doxorubicin, cisplatin, mitomycin C +5FU Doxorubicin, Lipiodol Cisplatin, doxorubicin, mitomycin, Lipiodol Cisplatin, doxorubicin, mitomycin, ioxaglate sodium, Lipiodol Cisplatin, doxorubicin, mitomycin NA 20 7 5 9 0
61 75 NA
NA 5% at 5 years NA
19 14 23
39 33 34
Median HAE and HACE Gupta (TX, USA) (66) 2005 123
2006
18
HAE, polyvinyl alcohol particle or gelfoam powder. HACE, for carcinoid tumor: cisplatin+doxorubicin. For islet cell tumor: 5FU+streptozocin NA
NA 9
NA 0
83 83
25 24
NA NA
NA 34
Median
159
study by Mazzaglia et al. (69) detailed the outcomes of 80 laparoscopic RFA sessions in 63 patients who underwent RFA alone for NET-hepatic metastasis (54). Relief of symptoms was achieved more than 90% of the patients. Median diseasefree survival was 11 months. Median disease-specific survival was close to 4 years. Five-year survival rate was 48% (Grade III. Recommendation C). Hepatic Cryoablation Cryoablation can be applied for patients with unresectable refractory NETs. Intraoperative approach combined with hepatic resection is common rather than cryoablation alone. The cryoprobe is inserted into tumor under ultrasound guidance. The freezing temperature of cryoprobe is maintained liquid nitrogen perfusing in the uninsulated tip. Tumor is monitored until the ice ball enveloped the tumor with a 1-cm margin of normal tissue. Multiple freezingthaw cycles lead to tumor destruction (73). Indications for this procedure are still unclear. Complications include coagulopathy, bleeding, acute renal failure, and pulmonary embolism. Morbidity rate is reported variously but at a minimum of 23%. Mortality rate is 0% to 2% (7476). Of note, this procedure is usually combined with hepatic resection; therefore, the outcomes of reported studies are not specific for cryoablation. Almost all patients experienced the relief of symptoms and biochemical response. Local recurrence at the ablated site is reported as 17% in a study from Seifert et al. (75). Median recurrence-free survival is 10 months. Median disease-specific survival is 20 to 49 months. Three-year survival rate is up to 91% (7476) (Grade III. Recommendation C). Liver Transplantation Liver transplantation is a therapeutic alternative of hepatic resection for unresectable NET-HM patients. Whereas the results of liver transplantation for other metastatic tumors are poor (77), patients with NET-hepatic metastasis have been more likely benefit from liver transplantation (57,7885). Although this approach is still controversial, Milan criteria for indication to liver transplantation in patients with NEThepatic metastasis are widely referred (Table 16.7) (54). Patients will receive a full graft, a split graft or a domino graft from deceased or living donor (78). The general principle of complete resection of both primary and metastatic tumor has to be pursued in the setting of this treatment. Therefore, transplantation could be performed with concurrent resection of extrahepatic tumor including lymphadenectomy of hepatic pedicle and hepato-duodenal ligament (54,78,86). Standard immunosuppression should be administered postoperatively. Adjuvant chemotherapy or long-acting SST analogs will be applied as appropriately (54). Table 16.8 shows the summary of literature review. Postoperative morbidity includes acute rejection episodes, acute cholangitis, and bacteremia. Overall morbidity rate are reported as 56% (3275%). Mortality rate is 10% (544%). Recent studies report that 5-year survival of 21% (3690%), with symptomatic relief occurring in all of the patients.
Figure 16.5 CT guided radiofrequency ablation of single small liver metastasis 1 day after arterial embolization.
This treatment is suitable for relatively small tumors. Indications for RFA include (i) fewer than 4 in number, (ii) smaller than 5 cm, (iii) accessible location in liver, and (iv) not in contiguity to vascular structures, bowel, or the gall bladder (46). Complications include bleeding, sepsis, and intrahepatic biliary duct damage. Morbidity rate is around 5%. No RFArelated mortality has been reported (58,69). RFA is associated with the high incidence of the recurrence at previously ablated sites (58,70,71). Local recurrence rate is reported to be 5 to 6% (69,70,72). The assessment of outcome of this procedure is somewhat difficult to be specific because many of RFA are combined with surgical resection. A large
160
Dousset (Paris, France) (47) Lang (Gottingen, Germany) (57) Lehnert(Heidelberg, Germany) (87) Rosenau (Hannover, Germany) (88) Florman (NY, USA) (89) V.Vilsteren (MN, USA) (86) Mazzaferro (Milan, Italy) (54) Olausson (Goteborg, Sweden) (90) Marin (Murcia, Spain) (91) Le Treut (Marseille, France) (78) Median
Year 1996 1997 1998 2002 2004 2006 2007 2007 2007 2008
Disease-free survival is 21% (977%) at 5 years. Median time to recurrence is 25 (1.558) months (47,54,57,78,8691) (Grade III. Recommendation C). Medical Treatment SSTR-targeted Therapy SST analogs are effective in improving hormonal symptoms due to NETs. SST inhibits the release of serotonin and other hormones from NETs (92). Because SST has a short half-life (about 2 minutes), it is not suitable for clinical use (92). Longacting SST analogues (octreotide and lanreotide) are widely applied. The response rate ranges 70% to 80% when administered subcutaneously every 6 to 12 hours (93,94). Dosage should be adjusted with clinical use from 50 to 500 g 3 times a day. Adverse effects include gallstones, steatorrhea, sinus bradycardia, cardiac conduction abnormalities, arrhythmias, hypothyroidism, hypoglycemia, and hyperglycemia (92,95). SSTR analogs are utilized for preoperative symptomatic control, preprocedural medication to prevent carcinoid crisis, and postoperative supportive therapy if residual tumors were evident (1) (Grade III. Recommendation C). Chemotherapy Chemotherapeutic agents for NETs include streptozotocin, 5-FU, doxorubicin, cyclophosphamide, etoposide, cisplatin, temozolomide, thalidomide, paclitaxel, and docetaxel (1,4). Overall response rate of chemotherapeutic alone is reported to be only 20% to 40%. At least there is one randomized trial comparing streptozocin +5FU and doxorubicin +5FU (96). The patients were enrolled this study were 249. Response rate
in two groups were similar (16% vs. 15.9%). Streptozocin + 5 FU was associated a subtle increase of survival (24.3 vs. 15.7 months), however, renal toxicity was significantly frequent in that group. Unfortunately, there are no data existing to reveal the benefit of each chemotherapeutic agent, or the combination of agents (92,9799) (Grade Ib. Recommendation B). Interferon Interferon inhibits tumor growth by directly blocking the G0/G1 phase of cell cycle. Applications of interferon to NETs have been investigated since 1982 (100103). Interferon alpha alone resulted in biochemical response rate of 7% to 66%, and tumor response rate 0% to 25%. The combination of interferon alpha and SST analogs failed to be effective (104) (Grade III. Recommendation C). Radionuclide Therapy Receptor targeted therapy with radionuclides is an emerging treatment for patients with disseminated NET metastases. 131 I-MIBG, [111In-DTPA-D-Phe] octreotide, 90yttrium, and 177 lutetium-labeled SST analogs are utilized (35,105111). Agents will be selected by uptake at diagnostic imaging. This treatment is specific and tolerated. Fair levels of biochemical response and volume reduction are reported. Symptomatic relief can be achieved. Reported adverse effect is renal damage. Adequate renal protection should be added before treatment (Grade III. Recommendation C).
summary
Summary of treatment for NET-hepatic metastasis is shown in Table 16.9.
161
Indication Hepatic resection (8,4756,58,112) Hepatic artery occlusion HAE (17,55, 6365,113) HACE (60,114118) Tumor restricted to one lobe (1) Rapid enlargement of tumor mass, (2) Increasing symptoms, (3) Patient preference for the procedure in lieu of other treatment, (4) Patients with adequate liver function and patent portal vein (1) Fewer than 4 in number, (2) Smaller than 5cm, (3) Accessible location in liver, and (4) Not in contiguity to vascular structures, bowel, or the gall bladder Small lesions. Usually combined with hepatic resection Milan criteria. See Table 16.7.
Morbidity (%) 22
Mortality (%) 3
3 20
0 5
49 75
15 14
24 33
82
NA
11
NA
48
23
95
10
45
56
10
100
25
55
key points
Diagnosis:
Hormonal symptoms (carcinoid syndrome) and/or symptoms due to hepatic mass Laboratory investigations: CgA (blood) and 5-HIAA (urine) Identify the primary and metastatic sites by SSTR scintigraphy Assess the resectability of hepatic metastasis by CT or MRI
Treatment:
Surgical resection (curative or palliative) Other liver targeted therapy (HAE/HACE, RFA, and cryotherapy) Liver transplantation for selected unresectable patients SST analogues for symptomatic control Radionuclide therapy is emerging for the disseminated disease No proven survival benefit in chemotherapy
references
1. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128(6): 171751. 2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97(4): 93459. 3. Moertel CG. Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 1987; 5(10): 150222. 4. Kvols LK. Revisiting C.G. Moertels land of small tumors. J Clin Oncol 2008; 26(31): 50057.
5. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340(11): 85868. 6. Solcia E, Capella C, Kloppel G, Heitz PU, Sobin LH, Rosai J. Endocrine tumours of the gastrointestinal tract. In: Solcia E, Kloppel G, Sobin LH, eds. Histologic typing of endocrine tumours. WHO international histological typing of endocrine tumours. Heidelberg, New York: Springer Verlag, 2000: 5767. 7. DeMatteo RP, Fong Y, Blumgart LH. Surgical treatment of malignant liver tumours. Baillieres Best Pract Res Clin Gastroenterol 1999; 13(4): 55774. 8. Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 2000; 190(4): 43245. 9. Moertel CG, Sauer WG, Dockerty MB, et al. Life history of the carcinoid tumor of the small intestine. Cancer 1961; 14: 90112. 10. Burke AP, Thomas RM, Elsayed AM, et al. Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 1997; 79(6): 108693. 11. Grahame-Smith DG. The carcinoid syndrome. Am J Cardiol 1968; 21(3): 37687. 12. Feldman JM. Carcinoid tumors and the carcinoid syndrome. Curr Probl Surg 1989; 26(12): 83585. 13. Tilson MD. Carcinoid syndrome. Surg Clin North Am 1974; 54(2): 40923. 14. Lundin L. Carcinoid heart disease. A cardiologists viewpoint. Acta Oncol 1991; 30(4): 499502. 15. Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand [A] 1976; 84(4): 32230. 16. Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory carcinoid hepatic metastases. J Surg Res 2001; 95(1): 812. 17. Schell SR, Camp ER, Caridi JG, et al. Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg 2002; 6(5): 66470. 18. Debas HT, Mulvihill SJ. Neuroendocrine gut neoplasms. Important lessons from uncommon tumors. Arch Surg 1994; 129(9): 96571; discussion 9712. 19. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and outcomes of abdominal surgery for metastatic carcinoid tumours. Br J Anaesth 2001; 87(3): 44752.
162
163
164
165
17
introduction
Approximately 90% of malignant hepatic lesions are metastases of extrahepatic primary tumors. Despite enormous progress of multimodal therapeutical options, surgical resection remains the only option for curative treatment in most of these cases. However, in contrast to colorectal or neuroendocrine hepatic metastases, the surgical approach for noncolorectal and nonneuroendocrine hepatic metastases is highly controversial. From a critical point of view, it is argued that noncolorectal, nonneuroendocrine liver metastases often belong to very aggressive types of cancer. In addition, they partly derive from extraabdominal primary tumors. In contrast to intraabdominal tumors metastasizing through the portal vein with the liver theoretically being the first filter organ, liver metastases of extraabdominal primary tumors imply a simultaneous systemic spread of tumor cells. However, resection of hepatic tumors can be accomplished safely with an appropriate risk of perioperative mortality and morbidity, and patients with favorable tumor biology might benefit from a surgical approach. Therefore, proper selected patients should be offered resection of noncolorectal, nonneuroendocrine liver metastases. Since noncolorectal, nonneuroendocrine hepatic metastases encompass a heterogeneous group of primary tumors, the management of these metastases needs to be discussed individually for each primary tumor type.
breast cancer
Breast cancer is the most frequent malignant tumor and the second most common cause of cancer death in women (1). Patients with breast cancer rarely present with isolated liver metastases, in only 10% to 20% of metastatic breast cancer, metastases are restricted solely to the liver (2,3) (Fig. 17.1). Therefore, the risk of systemic tumor relapse after removal of liver metastases is high and ought to be accounted before a surgical liver resection is contemplated. Retrospective studies report a median survival between 36 and 63 months (46) ( Table 17.1) when patients underwent surgical treatment in addition to systemic chemotherapy. In contrast, in patients treated with chemotherapy alone, the median overall survival will rarely exceed two years (7). Predictive risk factors, which should be considered for selecting appropriate patients, are lymph node status, extensive hepatic lesions requiring a major resection (8), recurrence of liver metastases within one year after resection of the primary tumor (9), R2 resection, and failure to respond to preoperative chemotherapy (4). Applying these criteria on patients with breast cancer and isolated hepatic metastases enables to select a subset of patients where liver resection may improve progression-free and overall survival compared to systemic treatment alone.
166
Table 17.1 Selected Retrospective Studies Reporting Clinical Outcome in Patients after Resection of Liver Metastases from Breast Cancer
Number of patients included 12 454 31 Median overall survival (months) 35.9 45 63
pancreatic cancer
Pancreatic cancer is one of the most aggressive tumors. It is the fourth leading cause of cancer death in females and the fifth leading cause in males worldwide (1). When pancreatic cancer is first diagnosed, the majority of patients are not amenable to surgical treatment according to the established standard criteria. Approximately only 15% to 25% of patients are eligible to curative operation procedures. One of the most frequent exclusion criteria for a curative surgical intervention is the presence of distant metastases, namely, liver metastases. In metastasized pancreatic cancer, palliative systemic chemotherapy is considered to provide the best therapeutical option. Yet, in many cases, R0 resection of liver metastases in addition to resection of the primary tumor would be technically feasible. By palliative systemic chemotherapy, median overall survival reaches approximately 6 months (2527). The impact of a curative-intent surgical intervention is still unanswered. In several retrospective studies of resection of liver metastases of pancreatic cancer, the median overall survival ranges from 6 months to 20 months (4,19,2837) (Table 17.2). In single cases, single patients have even survived longer than 5 years (30). Though, despite some encouraging results, the decision for the resection of pancreatic cancer liver metastases should be made on an individual basis where the patient is aware of a nonstandard treatment approach. Currently, resection of liver metastases is highly controversial and certainly far from being accepted by the medical community.
Author Caralt et al. (5) Adam et al. (4) Vlastos et al. (6)
gastric cancer
Table 17.2 Selected Retrospective Studies Reporting About Clinical Outcome in Patients after Resection of Liver Metastases from Pancreatic Cancer
Number of patients included 17 10 40 Median overall survival 5.9 11.4 20 5-year survival Not published Not published 25%
Author
Year
Gleisner et al. (29) 2007 Shrikande et al. (28) 2006 Adam et al. (4) 2006
The incidence of gastric cancer has steadily decreased in Europe and the United States, however, it still remains the second most common cancer worldwide. For locally advanced gastric cancer, the overall survival has been improved by treating patients with perioperative chemotherapy (38). However, for gastric adenocarcinoma with distant metastases, overall survival is still not favorable. The presence of liver metastases (Fig. 17.3) is generally considered to define a noncurative state of the disease. Patients treated by palliative chemotherapy survive approximately 9 to 10 months on average
167
sarcoma
For surgical evaluation, liver metastases originating from sarcomas can be divided into two subtypes: gastrointestinal stromal tumors and non-GIST sarcomas. Gastrointestinal stromal tumors emerge most often in the stomach, second most in the small bowl and in the colon and most rarely in the duodenum, the esophagus or nonintestinal organs (50). Almost half of the patients suffer from distant metastases and in more than 50%, the metastatic disease is isolated to the liver (51). One decade ago, a large retrospective study regarding hepatic resection for GIST metastatic to the liver reported about a median overall survival of 39 months and 5-year survival of 30% (52). Since the introduction of imatinib mesylate in the therapy of GIST (53), the oncological management has changed in favor of a multimodal treatment, improving the patient outcomes significantly. In recent retrospective studies including patients treated with imatinib mesylate, the 5-year survival was 70% (4) and median overall survival was not reached despite long periods of followup (54) (Table 17.4). However, DeMatteo et al. and Gronchi et al. observed in two retrospective studies that mainly patients with metastatic GIST responding to a preoperative tyrosine kinase inhibitor therapy profit by a surgical approach whereas nonresponder do not seem to benefit by tumor resection (55,56). These data should be taken into account when selecting appropriate patients for surgery with liver metastases of gastrointestinal stromal tumors. In summary, gastrointestinal stromal tumors metastatic to the liver require interdisciplinary therapy regimens. Besides to surgical resection, this should involve application of new medical agents such as imatinib or radiofrequency ablation for small lesions not accessible to surgical resection (54,57). Non-GIST sarcomas have a worse prognosis than gastrointestinal stromal tumors. While extremity and trunk soft tissue sarcomas most frequently metastasize to the lung, primary visceral and retroperitoneal sarcomas often disseminate to the liver (51) (Fig. 17.4). After surgical resection of liver metastases, patients have a median overall survival of 32 to 37 months and 5-year survival probability of 27% to 32% (4,54) (Table 17.4). These data demonstrate that most patients with hepatic metastases of sarcomas will succumb to their disease. Patients with a disease-free interval exceeding two years, however, seem to have a better prognosis after hepatic resection (52). These data again point to the fact that selected patients should be offered
Table 17.3 Selected Retrospective Studies Reporting about Clinical Outcome in Patients after Resection of Liver Metastases from Gastric Cancer
Number Median of patients overall included survival 42 64 40 34 15 12 5-year survival Not published 27% 18%
Author Koga et al. (41) Adam et al. (4) Ambiru et al. (46)
(39,40). Retrospective studies, reporting outcome after hepatic resection as treatment for liver metastases of gastric adenocarcinoma, estimate the overall survival between 19 and 34 months (4145) (Table 17.3). These numbers exceed the outcome of patients having merely received systemic chemotherapy. As each of these studies have included only a small number of patients probably affected by a selection bias, the data are still insufficient. To select patients with liver metastases of gastric cancer who might benefit from a surgical approach, different strategies have been implemented. Summarizing the available literature, resection of hepatic metastases seems to be associated with a better survival if solitary or metachronous lesions are being resected. As in many other tumor types, patient selection therefore seems to be the most important factor ensuring a benefit for the patients undergoing liver resection for liver metastases of gastric cancer.
168
resection of liver metastases, as they most likely will benefit from this treatment.
melanoma
Melanomas belong to the most frequent types of tumors with an increasing incidence over the last 30 years. Of the melanomas, 90% derive from the skin, 5% have an ocular origin, and 5% develop at other sites (58). Noteworthy, depending on the primary site, melanomas display a different metastasizing pattern. Cutaneous melanomas disseminate to the liver only in 15% to 20% of patients with metastatic disease (Fig. 17.5). This often happens with simultaneous metastatic decay of other organs (59). By contrast, in 40% of patients with liver metastases from uveal melanoma, the liver is the only site of the disease (60). Therefore, the number of liver metastases resected from uveal melanoma is nearly equivalent to that of cutaneous melanoma. While excision of early stage melanoma results in an excellent prognosis, chemotherapy achieves barely a median overall survival of 12 months in disseminated tumor stage (60,61). Hence, surgical resection of metastases offers the only chance for cure. However, patients amenable to a surgical intervention at the liver account for approximately only 2% to 3% of all patients representing with liver metastases of melanoma (62,63). In these cases, the median overall survival is estimated to be between 19 and 28 months and the median 5-year survival reaches 20% (4,49,62) (Table 17.5). This may justify the
169
*Including patients with both cutaneous and ocular melanoma. Within a mean follow-up of 25.4 months.
0.0!
0.02
Primary tumor
Reproductive tract Nonreproductive tract Yes No Yes No 5 cm >5 cm I >l Unilobar Bi lobar RO Rl R2 Minor major* Yes No Yes No
115 17 48 32 11 115 36
48 40 42 46 42 37 49 34 46 40 49 17 10 40 52 52 37 40 49
NS NS NS
Source: From Ref. (19). *Major liver resection: resection of 3 or more liver segments. Prior extrahepatic metastases. Presentation of the liver metastases: the same time as the primary tumor. CSS indicates cancer-specific survival; CI, confidence interval; NS, not significant.
170
summary
Resection of noncolorectal, nonneuroendocrine liver metastases is associated with an improved progression-free and overall survival in a selected subgroup of patients. However, until now, these data have been mainly obtained by retrospective studies and probably are affected by selection bias, as patients with lower performance status and poorer prognosis are less likely to have undergone surgery. Due to these limitations, a conclusion regarding a direct comparison to nonsurgical approaches cannot be drawn. Each individual case needs to be carefully assessed prior to a decision regarding a surgical approach. Furthermore, to reduce the risks of postoperative morbidity and mortality, it is recommendable to perform the surgical intervention on the liver at high-volume centers (64).
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 7196. 2. Atalay G, Biganzoli L, Renard F, et al. Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: a retrospective analysis of two prospective, randomised metastatic breast cancer trials. Eur J Cancer 2003; 39: 243949. 3. Er O, Frye K, Kau Sd CW, et al. Clinical course of breast cancer patients with metastases limited to the liver treated with chemotherapy. Cancer J 2008; 14: 6268. 4. Adam R, Chiche L, Aloia T, et al. Hepatic resection for noncolorectal nonendocrine liver metastases: analysis of 1,452 patients and development of a prognostic model. Ann Surg 2006; 244: 52435. 5. Caralt M, Bilbao I, Cortes J, et al. Hepatic resection for liver metastases as part of the oncosurgical treatment of metastatic breast cancer. Ann Surg Oncol 2008; 15: 280410. 6. Vlastos G, Smith D L, Singletary S E, et al. Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases. Ann Surg Oncol 2004; 11: 86974. 7. Alba E, Martin M, Ramos M, et al. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin Oncol 2004; 22: 258793. 8. Pocard M, Pouillart P, Asselain B, et al. [Hepatic resection for breast cancer metastases: results and prognosis (65 cases)]. Ann Chir 2001; 126: 41320. 9. Selzner M, Morse M A, Vredenburgh J J, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000; 127: 3839. 10. Rose PG, Piver MS, Tsukada Y. Metastatic patterns in histologic variants of ovarian cancer. An autopsy study. Cancer 1989; 64: 150813.
171
172
18
introduction
Hepatic resection is the only therapy that offers a chance for cure in patients with colorectal liver metastases, but only 20% of the patients are candidates for resection at the time of diagnosis (13). For those patients who are resected, the 5-year survival has been reported up to 58% (48). After hepatic resection, the majority of patients will develop recurrence within the liver with or without extrahepatic metastases. Systemic chemotherapy has been used preoperatively (9) or as an adjuvant therapy after surgery to decrease the risk of disease recurrence (10). During the last decade, an increasing number of new therapeutic agents has been developed to improve the response rates of the existing drugs (Fig. 18.1). Initially, 5-fluorouracil (5-FU)-based chemotherapy had a 20% response rate with a modest improvement in survival (11). Capecitabine was introduced as an oral alternative to intravenous 5-FU. The addition of oxaliplatin and irinotecan in combination with 5-FU increased the response rate to 50% and the conversion of unresectable metastases to resectable was subsequently reported in up to 38% of patients (12,13). Most recently, bevacizumab and cetuximab, antibodies vascular endothelial growth factor and an antiepidermal growth factor receptor, respectively, have been associated with response rates of up to 70%, when combined with standard chemotherapy (14). The rationale for preoperative chemotherapy includes (i) the downsizing of metastases, thus decreasing the amount of resected parenchyma and increasing the rate of curative resection; (ii) the identification of patients who will not benefit from surgical resection due to disease progression during chemotherapy; (iii) the early treatment of micrometastases (810). Nordlinger et al. (15) reported the results of a multicentric randomized controlled trial (EORTC Intergroup trial 40983), evaluating the outcome of patients with resectable colorectal liver metastases (no more than four metastases, no extrahepatic disease) with two arms: surgery alone versus six cycles of FOLFOX4 before and after surgery. The trial showed an increased progression-free survival at 3 years of 8.1% (from 28.1% to 36.2%, p = 0.041) in all eligible patients; and 9.2% (from 33.2% to 42.4%, p = 0.025) in all patients undergoing resection (15). Clinical and pathological studies have established associations between specific chemotherapeutic agents and histologic changes in the liver. Current evidence suggests there are two broad categories of chemotherapy-induced liver injury: nonalcoholic fatty liver disease (NAFLD), including steatosis and steatohepatitis, and sinusoidal obstruction syndrome (9) (Figs. 18.2 and 18.3). The use of sequential or combined treatments may result in mixed patterns of injuries. The objective of the present chapter is to summarize the changes induced in the liver parenchyma by chemotherapy and its effects on surgical outcomes.
173
1980
1985
1990
1995
2000
2005
Figure 18.1 During the last 10 years, several new drugs were incorporated to the armamentarium for the treatment of colorectal liver metastases. 5-FU, 5-fluorouracil; RR, response rate. Source: Modified from Ref. (33).
(A)
(B)
(C)
(D)
Figure 18.2 Nonalcoholic fatty liver disease (NAFLD). (A) Macroscopic view of a fatty liver (yellow liver). (B) Pathology specimen showing the aspect of a fatty liver. (C) Microscopic view of a simple steatosis: accumulation of large globules of fat in the cells. (D) Microscopic view of steatohepatitis: different degrees of inflammation in the field (ballooned and apoptotic cells). Source: Modified from Ref. (8).
174
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
(A)
(B)
(C)
Figure 18.3 Sinusoidal obstruction syndrome. (A) Macroscopic view of a liver with oxaliplatin-related sinusoidal injury (blue liver). (B) Pathology specimen showing the aspect of a liver with sinusoidal injury. (C) Microscopic view of sinusoidal injury: centrilobular sinusoidal dilatation with scattered macrovesicular steatosis. Source: Modified from Ref. (8).
Table 18.1 Published Data on Chemotherapy-Associated Hepatotoxicity and Its Effect on Postoperative Outcomes
Author, year Behrns, 1998 (24) Kooby, 2003 (25) Parikh, 2003 (26) Fernandez, 2005(28) Karoui, 2006(39) Vauthey, 2006 (9) Nordlinger, 2008(15) Nakano, 2008(40) Reddy, 2008 (44) Number of patients 135 325 chemo, 160 controls 61 chemo, 47 controls 37 45 chemo, 22 controls 248 chemo, 158 controls 151 chemo, 152 controls 36 chemo 39 chemo, 57 controls Major hepatectomy 100% 69% chemo, 63% controls 100% 49% 100% 68% N/A 100% 69% Drugs 5-FU irinotecan 5-FU irinotecan 5-FU irinotecan/ oxaliplatin 5-FU irinotecan/ oxaliplatin 5-FU irinotecan 5-FU oxaliplatin 5-FU oxaliplatin 5-FU oxaliplatin Bevacizumab + oxaliplatin Type of liver injury Steatosis Steatosis Steatosis Steatohepatitis Sinusoidal injury Steatohepatitis Sinusoidal injury N/A Sinusoidal injury N/A Morbidity NS Higher NS N/A Higher NS NS Higher Higher NS Mortality NS NS NS N/A NS NS+ NS NS N/A NS
Source: Modified from Ref. (45). NS, not significant; chemo, chemotherapy; 5-FU, 5-fluorouracil; N/A, not available. + Subset of patients with steatohepatitis had increase 90-day mortality.
175
Unresectable
Resectable
Second-line chemotherapy
Third-line chemotherapy
Figure 18.4 Treatment recommendation for liver metastases of colorectal cancer. Source: Adapted from Ref. (32).
surgery. More recently, a study by Gruenberger et al. provided evidence to suggest that this interval may be shortened to 5 weeks without increase in perioperative complications (35). Ribero et al. (36) analyzed the effect of bevacizumab in patients receiving oxaliplatin-based chemotherapy. The response to therapy was measured with the percentage of viable cells in the surgical specimen. Patients who received preoperative bevacizumab had a significant lower rate of viable cells compared to those patients who did not receive preoperative bevacizumab (33% vs. 45%, p = 0.02). The incidence and severity of sinusoidal injury were lower in patients receiving preoperative bevacizumab (27% vs. 54%, p = 0.006). The antiangiogenic effects of bevacizumab have raised concerns regarding potential effects on bleeding, wound healing, and liver regeneration. A study from the MDACC reported that the addition of bevacizumab to chemotherapy before portal vein embolization did not impair liver regeneration (37). Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR). No specific liver injury has been so far identified and related to the preoperative administration of cetuximab. Preclinical data in animal models investigated the effects of anti-EGFR antibodies after partial hepatectomy in mice and found that their blockade does not impair liver regeneration (38). Future investigations are needed to further study possible specific histologic changes in the liver in patients treated with biologic agents.
diagnosis
Liver function tests cannot be used to assess chemotherapyassociated liver injury, since many patients have normal laboratory values despite significant hepatic injury. A heightened index of suspicion for chemotherapy-associated hepatic injury is necessary in patients at risk for NAFLD due to obesity, diabetes, or hyperlipidemia, as well as patients who have received prolonged courses of chemotherapy. Computed tomography can identify patients with fatty infiltration by determining the density of the liver compared to the spleen (at least 10 Hounsfield units lower than the spleen). Magnetic resonance
176
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
imaging (MRI) accurately predicts steatosis on the basis of signal differences between fat and water. However, modern imaging methods cannot differentiate between steatosis and steatohepatitis. For these reasons, liver biopsy is the gold standard diagnostic procedure to confirm liver injury. Percutaneous liver biopsy may be associated with false-negative results, due to the patchy distribution of the injuries. To overcome this issue, laparoscopy with direct inspection and core biopsy may be an alternative to image-guided percutaneous biopsy in patients suspected of chemotherapy-associated liver injury, especially in those patients who are candidates for major hepatic resection. Grossly, sinusoidal injury results in the so-called blue liver syndrome, characterized by a bluish, edematous, spongiform appearance and consistency (Fig. 18.3), while steatosis results in a yellow liver (Fig. 18.2). tomography. Briefly, the contours of the FLR are delineated on the screen, and volume is calculated by adding each slices volume, determined by the surface area, slice thickness, and space between slices (42). To calculate the total liver volume, Vauthey et al. (42) determine a formula based on body surface area. The estimated liver volume is calculated using the following formula: total liver volume = 794.41 + 1267.28 body surface area. The ratio of the FLR to total estimated liver volume is defined as the standardized FLR (sFLR), which has been shown to reflect the function of the remnant liver and correlate with surgical outcome. When the sFLR is predicted to be insufficient for safe hepatic resection, portal vein embolization (PVE) is a strategy to induce hypertrophy of the FLR (42). In normal livers, if the standardized future liver remnant is 20% of total liver volume, portal vein embolization (PVE) should be considered. In patients who received extensive chemotherapy, preoperative PVE should be considered when the standardized future liver remnant is 30% of total liver volume (13). In this context, PVE is used as a procedure to test the capacity of the injured liver to regenerate. In a study by Ribero et al. (36), a degree of hypertrophy (DH = sFLR post-PVE sFLR pre-PVE) 5% predicted the occurrence of postoperative complications, either overall, liver-related complications, or liver dysfunction. Patients with significant chemotherapyassociated liver injury who have inadequate liver hypertrophy after a technically successful PVE are not candidates for a major liver resection. Another strategy for patients with chemotherapy-associated hepatotoxicity to undergo complete resection of metastases is two-stage liver resection. This approach allows resection in patients with extensive bilateral liver metastases that have responded or remain stable on chemotherapy. In the first stage, metastases in the FLR are removed with a minor resection. After the first surgery, the hepatic regenerative capacity is assessed and PVE should be performed, if the sFLR is insufficient. After adequate regeneration, a second-stage major resection is performed up to 8 weeks after PVE. In a study from MDACC, using this approach, in patients with a median of seven liver metastases, the 3-year overall and disease-free survival rates were 86% and 51%, respectively, after perioperative chemotherapy and two-stage hepatectomy (43).
prevention
Several issues should be taken into account to prevent chemotherapy-associated liver injuries. First of all, prolonged unnecessary courses of preoperative chemotherapy should be avoided. Different studies demonstrated that hepatotoxicity is strongly related to chemotherapy duration. Karoui et al. (39) analyzed two groups of patients who underwent liver resection with or without chemotherapy (5-FU irinotecan/oxaliplatin). In the chemotherapy group, five patients developed liver insufficiency versus none in the control group. Morbidity was higher in patients who received at least six cycles of chemotherapy compared to those who received five cycles or less (54% vs. 19%, p = 0.047). In another study, Aloia et al. (30) concluded that patients who received more than 12 cycles of oxaliplatin-based chemotherapy had a higher rate of reoperations and a longer length of stay compared to patients who received 12 or fewer cycles. The optimal duration of preoperative chemotherapy to maximize therapeutic benefit, while avoiding hepatotoxicity, is likely up to 4 months (i.e., 8 cycles). In the study from MDACC, patients received relatively short-course oxaliplatin for 3 to 4 months, which was not associated with increased morbidity or mortality after hepatic resection (9). Another issue to be considered is the duration of the interval between chemotherapy and liver resection. Several studies show that a longer interval between chemotherapy and hepatic resection for CLM reduces hepatotoxicity and surgical complications. However, this interval should be balanced with the risk of tumor progression during the treatment-free interval. In the European trial, Nordlinger et al. (15) reported an interval between the last dose of chemotherapy and liver resection (in the chemotherapy arm) of 2 to 5 weeks. Nakano et al. (40) observed a mean interval between the last chemotherapy and surgery of 6.5 months in patients without sinusoidal injury compared to 3.6 months in patients with sinusoidal injury. Welsh et al. (41) observed a morbidity rate of 2.6%, 5.5%, and 11% when the intervals between the last chemotherapy and surgery was 9 to 12 weeks, 5 to 8 weeks, and 5 weeks, respectively (p = 0.009). In patients with suspected chemotherapy-associated liver injury, the functional future liver remnant should be assessed prior to major liver resection to minimize postoperative complications. The future liver remnant (FLR) can be assessed using three-dimensional contrast-enhanced computed
summary
During the last decade, several new chemotherapeutics agents were introduced in the armamentarium for the treatment of colorectal liver metastases. These new drugs were used as adjuvant treatment as well as preoperative treatment before liver resection. The rationale for preoperative chemotherapy is as follows:
To increase resectability in patients initially deemed unresectable, by downsizing the metastases To improve progression-free survival in patients with resectable metastases, when compared to surgery alone To select patients who may not benefit from surgery due to tumor progression while on chemotherapy.
177
references
1. Steele G, Jr., Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989; 210: 12738. 2. Scheele J. Hepatectomy for liver metastases. Br J Surg 1993; 80: 2746. 3. Bismuth H, Adam R, Levi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224: 50920. 4. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239: 81825. 5. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235: 75966. 6. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDGPET). Ann Surg 2004; 240: 43847; discussion 44750. 7. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241: 71522. 8. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007; 94: 27486. 9. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24: 206572. 10. Chun YS, Vauthey JN. Risks of neoadjuvant chemotherapy for resectable colorectal carcinoma hepatic metastases. Curr Colorectal Cancer Rep 2008; 4: 8792. 11. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 90514. 12. Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001; 8: 34753. 13. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict longterm survival. Ann Surg 2004; 240: 64457.
178
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007; 110: 27617. Zorzi D, Chun YS, Madoff DC, Abdalla EK, Vauthey JN. Chemotherapy with bevacizumab does not affect liver regeneration after portal vein embolization in the treatment of colorectal liver metastases. Ann Surg Oncol 2008; 15: 276572. Van Buren G, 2nd, Yang AD, Dallas NA, et al. Effect of molecular therapeutics on liver regeneration in a murine model. J Clin Oncol 2008; 26: 183642. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243: 17. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg 2008; 247: 11824. 41. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection following chemotherapy for colorectal metastases is a matter of timing. Br J Cancer 2007; 96: 103742. 42. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002; 8: 23340. 43. Chun YS, Vauthey JN, Ribero D, et al. Systemic chemotherapy and twostage hepatectomy for extensive bilateral colorectal liver metastases: perioperative safety and survival. J Gastrointest Surg 2007; 11: 14981504. 44. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2008; 206: 96106. 45. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapyassociated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009; 27886.
37.
38.
39.
40.
179
19
introduction
Colorectal cancer is a common malignancy and as many as 25% of patients will have liver metastasis (CRLM) at presentation and a further 20% to 30% will develop metachronous disease following colorectal surgery (1). The vast majority of disease-related deaths are due to metastatic disease. In metastatic disease the median length of survival without treatment is approximately between 5 and 12 months (2). Currently hepatic resection is established as the treatment modality of choice for colorectal liver metastases (CRLM) with 5-year survival rates of up to 60% being reported by some groups (36). Unfortunately at the time of presentation only 20% to 30% are deemed suitable to resection because of tumor location, number of metastases, other comorbidities, and lack of hepatic reserve (7). Consequently, in recent times there has been considerable interest in the use of oxaliplatin-based neoadjuvant therapy to reduce tumor burden, so increasing the probability of achieving a curative resection and hence improve overall disease-free survival. Even patients who initially had unresectable hepatic disease may respond to chemotherapy and become resectable (8). However, despite a more aggressive approach to surgical resection and the use of combination regimens of highly active chemotherapy drugs, a significant proportion of patients are still not eligible for resection. Additionally, the high rate of recurrence seen in the liver, affecting 53% to 68% of patients requiring repeat resections can only be tolerated by a subset of patients (9). Hence, recently there has been considerable interest in thermoablative techniques and their potential role in the management of CRLM. Ablative technologies involve the delivery of localized treatment via open, laparoscopic, or percutaneous route. Theoretical advantages include less physiological stress, making treatments suitable for patients who may not otherwise be appropriate for formal resection. The potential for either percutaneous or laparoscopic approach offers an alternative for patients unfit or unwilling to undergo major abdominal surgery and general anaesthesia (913). Formal resection is guided by vasculobiliary anatomy, with significant amounts of healthy parenchyma being removed along with disease. Targeted ablations minimize the removal of healthy parenchyma, making it useful in patients with borderline parenchymal volume and function. Anatomically difficult lesions may not be amenable to formal resection, but accessible by probe ablation. Ablation can also be performed as an adjunct to surgical resection in patients with bilobar disease, where patients have the majority of their tumor burden formally resected with remnant disease burden being ablated. However, there remains a need for more long-term survival data regarding ablative therapies. There have been no randomized control trials comparing any ablative therapy to resections in patients who would be candidates for either therapy or
cryotherapy
Cryoablation of hepatic metastases using insulated probes containing liquid nitrogen/argon have been used for the destruction of CLRM (15). They are placed into each metastasis, whereupon
180
radiofrequency ablation
Radiofrequency ablation (RFA) uses radiofrequency radiation to produce heat locally within the hepatic parenchyma. The radiofrequency current generates ionic agitation, which in turn is translated into heat, resulting in the subsequent breakdown of proteins and cell membranes (43). The main advantage when compared to cryotherapy is that the probes can be placed percutaneously. However, as with all locally ablative techniques, the efficacy of the treatment diminishes with increasing size of the lesion. Hence, manufacturers have designed a variety of electrodes that can be deployed in situ to produce a number of tips. RFA refers to coagulation from all electromagnetic resources with a frequency less than 900 kHz, with the majority functioning within the parameters of 300 to 500 kHz. Initially, problems existed with early radiofrequency designs due to the effects of high temperatures in the tissue surrounding the probe. This is due to tissue impedance secondary to tissue charring. Subsequently, this impedance results in reduced dissipation of current (44,45). This problem has been the major drawback of RFA, though it has been countered somewhat by the use of cooled electrode tips. However, the principle limiting factor of RF ablation remains the size of the achievable ablated tissue. This is because only the tissue immediately adjacent to the tip is heated by ionic agitation. The remainder of the tissue is ablated via heat produced via thermal conduction. This effect is magnified in the presence of large blood vessels, which further reduce heat via a phenomenon known as the heat sink effect (19). Both normal liver parenchyma and metastatic liver are water-rich and also have an extensive blood supply (via angiogenesis in the case of metastases). Hence, thermal conduction is facilitated, but as mentioned previously, this is a less efficient means of ablation than ionic agitation. Therefore, current opinion suggests that RFA is more susceptible to the heat sink effect than microwave ablation. Various measures have been used previously to reduce the heat sink effect, such as occlusion of the portal vein and hepatic artery at the time of ablation. Although the ablative area is increased, the risk of bile duct damage and portal vein thrombosis is increased. Because of the relative simplicity of the technique, the fact that it can be performed percutaneously and the comparatively cheap devices employed, RFA is a technique that remains widely practised (32).
edge cryotherapy
Edge cryotherapy employs the application of cryotherapy to the resection margins posthepatectomy in order to extend the margins of resectability. Several studies describe the use of cryotherapy when a histopathologically positive margin is expected. During this procedure, flat cryoprobes are placed against the resection edge of the remnant liver, whereupon remnant liver tissue is frozen to a depth of at least 1 cm (34). Reported 3- and 5-year survival for these patients was 43% to 60% and 26% to 44%, respectively,
181
182
N 44 116 55 172 56 86 30 61 20 49 15 1 3.9 4.2 4 3 3.38 1.7 5.1 1.4 5 4.4 3.6 2 4 2 9.5 18 16 0 16 0 0 82 89 85 76 87 56 65 67 61 54 32.3 44 41 43 43 36 30.9 24 13 26 19 22 19 33 26 29 28 30 33 26 22.9 94.2 Metastases (n) Size (cm) EHD 1 year 2 years 3 years 4 years 5 years 22% 31% 28% 30% 30% 26% 70% Median survival (months) Major Minor 20% 55% 53%
Author
Year
Seifert (20) Seifert (21) Seifert (22) Yan (23) Kerkar (24) Brooks (25) Joosten (26) Chen (27) Kornprat (28) Paganini (open) (29) Paganini (29) (lap)
1998 1998 2003 2003 2004 2005 2005 2006 2007 2007 2007
Table 19.2 Summary of Studies Looking at Edge Cryotherapy (Survival and Complications)
Year
Extrahepatic disease %
1 year survival %
4 years survival % 37 28
5 years survival % 44 26 24
Minor 34%
Korpan (35) Dwerryhouse (37) Seifert (38) Finlay (39) Gruenberger (40) Rivoire (36) Seifert (41) Niu (42)
microwave ablation
Microwave coagulation (MCT) was initially developed in the early 1980s by Tabuse et al. in order to optimize haemostasis along the plane of dissection during hepatic resection. The microwave
183
Ultrasound probe
Ultrasound beam Iceball surrounding and encompassing tumor Cryoprobe Probe within liver
Ultrasound
(A)
(B)
Figure 19.1 Cryoablation (surgical view A) under intra-operative ultrasound control (B).
randomized Phase II, with an actual accrual of 119 patients. However, it remains a unique landmark study, probably never to be repeated, and the only prospective study to address the question of the real survival benefit of thermal ablation therapy for metastatic liver disease. Although there was a significant improvement in 3-year progression free-survival (PFS) of 27.6% for RFA + chemotherapy compared to 10.7% for chemotherapy alone (p = 0.025) (Fig. 19.3), a secondary end point, overall survival (OS) at 30 months (the primary study end point) was no different for RFA + chemotherapy (63.8%) over chemotherapy alone (58.6%) (p = 0.218) (Fig 19.4). It must be remembered that when designed, the study was never powered to demonstrate a significant result for its primary end point with such low numbers, and it is extremely unlikely that any investigators will ever be bold enough to try to repeat such a study. Therefore in the pragmatic real world, we must accept the evidence that we have, which in our opinion suggests a survival benefit for thermal ablation therapies in the treatment of relatively low-volume unresectable liver metastases.
184
Chemo (years)
4 8
2 3
1 0
Figure 19.3 Three year PFS in the CLOCC study comparing RFA + chemotherapy (27.6%) to chemotherapy alone (10.7%) (p = 0.025).
Overall survival
RF + Chemo
15 19
5 7
1 1
Figure 19.4 Thirty month OS comparing RFA+chemotherapy (63.8%) to chemotherapy alone (58.6%) (p = 0.218).
185
186
Number 54 14 30 36 102 37 25 14 122 30 25 30 66 56 68 235 73 135 52 109 16 47 23 1.8 6.2 1.2 3.25 2 1.63 1.9 2.8 3.5 1 2.8 4.1 3.2 2.7 1.6 1.75 3.12 5.57 1.3 1.4 2 2.1 2.2 2.25 2.5 2.7 2.9 3 3 3.1 3.2 3.5 3.7 3.9 3.9 4.1 5.2 No No No No 20.5 28 15 38 23 No 30 8.7 81 87 90 79 75 92 91 87 84 88 95 62 54 45 67 77 67 68 80 26 46 60 54 38 57 52.6 7 42 20.6 20.2 28 50 33 57 26 3 34 46.5 25.5 22 27 21 30 18.4 25 Metastases (n) Size (cm) EHD 1 year 2 years 3 years 4 years 5 years Median survival (months) 36 39 32 40 31.5 37 23.2 27 28 20.5 24 overall 38 28.9 30 39 18 Major 33.3 11 6.9 0 11.5 1.1 4 10 3.4 4 7.1 0.9 2.9 13 7 Minor 4 0 7 5 49.1 2.9 6 6.4 2.9
Author
Year
Ablative type
De Baere (56) Elias (57) Park (58) Knudsen (59) Sorensen (60) Lee (61) Hur (62) Lermite (51) Veltri (63) Aloia (64) Oshowo (65) Suppiah (66) Reuter (67) Hildebrand (68) Berber (69) Siperstein (70) Gilliams (53) Berber (71) Iannitti (72) Solbiati (73) Terraz (74) Abitabile (52) Stippel (75)
2000 2000 2008 2009 2007 2008 2009 2006 2008 2006 2003 2007 2009 2006 2008 2007 2005 2005 2002 2001 2007 2007 2002
RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA RFA
Table 19.4 Summary of Studies looking at RFA Resection (Survival and Complications)
Author
Year
Ablative type
Number
Metastases (n) size (cm) EHD 1 year 2 years 3 years 4 years 5 years
Major
Minor 20 22 27 11 13 11
Pawlik (76) Scaife (77) Abdalla (3) Elias (78) Joosten (26) Amersi (49) Kornprat (28) Gleisner (79) Nikfarjam (80)
RFA resection RFA resection RFA resection RFA resection RFA resection RFA resection RFA resection RFA resection RFA resection
124 50 158 63 28 74 19 66 23
3 2 2.4 3 3.3 5 2
No No No No No
92 93 92
66 67 75
43/37 47 51.2
36/22
28 68
Author Seki (85) Shibata (86) Liang (11) Yokoyama (87) Tanaka (88) Iannitti (89) Kuang (90) Ogata (91) Zhang (92) Bhardwaj (93)
Year 1999 2000 2003 2003 2005 2007 2007 2008 2008 2009
Ablative type MCT MCT MCT MCT/RFA MCT MCT MCT MCT/RFA MCT MCT N 15 14 28 12 16 33 11 32 34 24 Size (cm) 2.1 2.7 3.12 2.4 4.8 3.6 2.75 2.8 2 EHD (%) 0 0 5 5 0 22 0
Major (%) 14.0 0.0 19.0 16.1 4.0 3.4 0.0 2.6
187
Median
5 Year
4 Year
3 Year
2 Year
1 Year 0 10 20 30 40 50 60 70 80 90 100
Figure 19.5 Survival figures for studies reviewed (ablation as adjunct to surgery).
conclusions
The ideal ablative therapy should cause complete tumor ablation, yet be parenchyma sparing, reproducible, safe, and be minimally invasive. Current advancements, particularly in RFA and MCT, are promising but the perfect ablative model is still elusive. The literature cannot support the use of percutaneous ethanol injection for the treatment of colorectal metastases, though we accept that it has a role in the management of hepatocellular carcinoma. Similarly, the literature demonstrates that although cryoablation has acceptable survival figures, its ongoing use cannot be advocated given the high rate of local complications (Table 19.7). Ablative therapies offer great potential for lesions that cannot be formally resected. The increasing burden of metastatic colorectal disease means that a growing number of patients will have unresectable metastases and hence will be candidates for ablation. It is important that the ablation causes complete tumor destruction within the treatment zone. Heat sink effect may
result in tumor viability even within a seemingly completed ablation. The ability to accurately place the probe is also vital to ensure that the treatment zone encompasses the focus of disease. Currently, most centers use RFA or microwave ablation as treatment of choice. Microwave offers the theoretical advantage of larger ablation volumes, shorter ablation duration, and the ability to perform multiple simultaneous ablations to increase ablation volume as well as more predictable ablation zones around vessels. The lower local recurrence rate found in this review probably reflects the more predictable ablation characteristics on MCT. Conversely the larger body of evidence surrounding RFA is probably a manifestation of its maturity as a technology, rather than an implicit endorsement of its superiority over other technologies. The role of ablative technology in a palliative setting is unclear. However, 3-year survival of between 30% and 37% compares favorably with best supportive chemotherapy (Figs. 19.5 and 19.6). The underlying mechanism behind this remains unclear, though it may be related to decreasing the tumor burden.
188
4 Year
3 Year
2 Year
1 Year 0 10 20 30 40 50 60 70 80 90
Survival (%) Figure 19.6 Survival figures for ablative studies reviewed.
Ethanol ablation Radiofrequency ablation Microwave ablation Cryotherapy RFA+resection Edge cryotherapy
10
15 20 25 Complication rates(%)
30
35
40
The safety profiles of RFA and MCT appear similar and in the current climate, both are safe and effective therapies, which should be deployed (Fig 19.7). Further studies are needed to demonstrate long-term outcomes and ongoing research will ensure that ablative technologies continue to evolve rapidly.
references
1. (2003)CRUIC. CancerStats. Cancer Research UK Information Centre (2003)]. Available from: http://www.info.cancerresearch.org/cancerstats. 2. Hugh TJ, Kinsella AR, Poston GJ. Management strategies for colorectal liver metastasesPart I. Surg Oncol 1997; 6(1): 1930. 3. Abdalla EK, Vauthey JN, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004; 239(6): 81825; discussion 257. 4. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004; 240(3): 43847; discussion 4750.
5. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235(6): 75966. 6. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241(5): 71522, discussion 224. 7. Adam R, Huguet E, Azoulay D, et al. Hepatic resection after down-staging of unresectable hepatic colorectal metastases. Surg Oncol Clin N Am 2003; 12(1): 21120, xii. 8. Nordlinger B, Van Cutsem E, Rougier P, et al. Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer 2007; 43(14): 203745. 9. Goldberg SN, Solbiati L, Hahn PF, et al. Large-volume tissue ablation with radio frequency by using a clustered, internally cooled electrode technique: laboratory and clinical experience in liver metastases. Radiology 1998; 209(2): 3719. 10. Jiao LR, Habib NA. Experimental study of large-volume microwave ablation in the liver (Br J Surg 2002; 89: 10037). Br J Surg 2003; 90(1): 122.
189
190
191
treatment
A number of treatment options are available for patients with HCC. These include 1. Liver resection (LR) 2. Orthotopic liver transplant (OLT) including deceased/ cadaveric donor liver transplant (DDLT/CLT) and living donor liver transplant (LDLT) 3. Treatment prior to OLT: bridging the gap 4. Less invasive procedure involving chemical or thermal destruction of liver parenchyma 5. Regional or systemic chemotherapy 6. Radiotherapy including external beam irradiation or embolization with radioactive particles Before selecting a treatment option, careful consideration should be given to preoperative staging, underlying condition of the liver and the general fitness of the patient. Staging laparoscopy is a mandatory prior to LR or OLT to rule out extrahepatic disease. Assessing the residual liver function in chronic liver disease is very important before LR, as any major resection in a cirrhotic patient may result in fatal liver failure in the immediate post-operative period. Traditionally, the Child A/B/C scoring system has been used to assess the residual liver function. However, the Model for End-stage Liver Disease (MELD) scoring is used as an alternative in United States. Ascites on CECT, bilirubin of >2 mg/dL, and iodocyanine green retention test (used extensively in the East) (8) at 15 minutes of <30% bodes ill for residual liver function. Clinically relevant portal hypertension with hepatic vein gradient of >10 mm of mercury, esophageal varices, splenomegaly, and a platelet count of <100 109/L are accurate predictors of post-operative liver decompensation (12). Patients with Child
diagnosis
Asymptomatic HCC is diagnosed either as an incidental finding or on routine surveillance of at-risk population. Ultrasound scan (with or without contrast enhancement) with measurement of serum alfa-feto protein (AFP) is routinely used for screening (5,6). Once a suspicion of a focal lesion is raised, further assessment with contrast-enhanced computerized tomography (CECT) and/or magnetic resonance imaging (MRI) with contrast enhancement is needed to confirm the diagnosis of HCC. Tumor biopsy is rarely needed and in fact should be avoided in potentially resectable lesion due to the risk of tumor seeding along the needle track and intra-celomic spread. Furthermore, CECT is a good modality to look for the presence of cirrhosis, ascites, and metastases. A typical HCC shows hyper vascular enhancement with characteristic feature of early uptake of contrast and portal venous washout, an enhanced pseudocapsule, vascular invasion on CECT which gives more than 80% accuracy in diagnosing these lesions (7). MRI is more sensitive in detecting lesions 1 to 2 cm in size. A quarter of intra-hepatic lesions smaller than 10 mm is miss-diagnosed on pre-operative investigations. Diagnosing any lesion 2 cm with characteristics CECT/MRI findings is possible with a high degree of accuracy. In lesions 1 to 2 cm without concordance with two radiological investigations, a raised AFP of 400 /L and one radiological modality with positive features, diagnosis is possible (8). In lesions <10 mm, expectant follow-up with repeat imaging at 3 to 6 months is an appropriate management algorithm (Fig. 20.1).
192
Child-Pugh A
Child-Pugh BC
Solitary < 3 cm
Solitary 35 cm
23 nodules < 3 cm
Deep location
Peripheral location
No
Yes
RF ablation
Laparoscopic resection
Open resection
Transplantation
Figure 20.1 Algorithm for management of transplantable hepatocellular carcinoma used at Henri-Mondor Hospital. Source: From Ref. (29).
A can withstand up to 50% liver resection, but in those with Child B, a future remnant liver value of less than 75% is associated with major complications. LR remains the treatment of choice in early cases of noncirrhotic HCC, in tumors of <5 cm size, or up to three tumor nodules each <3 cm in size. Even though early experience with OLT yielded good results, it was fraught with recurrence (13). Increasing incidence of HCC with scarcity of donor livers available for transplant meant stringent criteria for patient selection. Hence, with the adoption of the more restrictive Conventional Milan Criteria (CMC: 1 lesion <5 cm, 23 lesions <3 cm), OLT has resulted in better long-term results (14). With increasing experience, some groups have suggested expanding the boundaries of CMC. One such recommendation is University of California, San Francisco (UCSF), criteria for patients with one lesion 6.5 cm or two to three lesions 4.5 cm with a total tumor diameter of <8 cm (15).
Liver Resection Liver resection in early HCC can be used in three different settings: (a) primary therapy, (b) to obtain material for morphological assessment of the tumor and to select patients who would benefit OLT, and (c) as a bridge therapy for those who are enlisted for OLT.
193
HCC
Stage 0
PST 0, child-pugh A, okuda 1
Stage AC
Okuda 12, PST 02, Child-Pugh AB
Stage D
Okuda 3, PST > 2, Child-Pugh C
3 nodules 3 cm
Associated diseases
Yes
No
Resection
PEI/RF
Chemoembolization
Curative treatments
Figure 20.2 Barcelona Clinic Liver Cancer staging classification and treatment schedule. Stage 0: Patients who have very early HCC are optimal candidates for resection. Stage A: Patients who have early HCC are candidates for radical therapies (resection and ablation, liver transplantation, or percutaneous treatments). Stage B: Patients who have intermediate HCC may benefit from chemoembolization. Stage C: Patients who have advanced HCC may receive new agents in the setting of a randomized, controlled trial. Stage D: Patients who have end stage disease receive symptomatic treatment. Abbreviations: LDLT, living-related donor liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency. Source: From Ref. (30).
Primary Resection Therapy LR for HCC has come a long way from early attempts with more than 50% mortality and no 5-year survival. With better understanding of tumor morphology, availability of advanced imaging modalities, patient selection, greater understanding of liver anatomy, improvement in surgical techniques, intraoperative ultrasound scan, and well-trained dedicated liver surgeons has resulted in up to 70% 5-year survival rates comparable to OLT, but a recurrence of 40% to 70% still represents a major cause of death (8,16). LR can be performed as a wedge resection, segmentectomy, or major resection. The extent of the liver resection is dependent on the size of the tumor, whether it is unifocal or multifocal and the presence or absence of cirrhosis in the residual liver. A peripherally located small lesion especially in segment 2 or 3 of liver can be safely resected either laparoscopically or by open resection. But in the presence of cirrhosis, wedge resection or non-anatomical resection in a rigid liver can be difficult and associated with significant blood loss. A hemi hepatectomy can achieve a good tumor clearance with least postoperative complications in lesions measuring 2 to 3 cm. This could be managed either laparoscopically or by handport assisted laparoscopic surgery (17). Deeply seated lesions or large single lesions measuring 3 to 5 cm with no evidence of portal hypertension need major
hepatectomy. Preoperative portal vein embolization (PVE) can be used to increase the functional residual volume of liver. Though theoretically this could overcome the problems of postoperative hepatic decompensation, barring few smaller studies, randomized controlled trials have not shown benefit from PVE (18). The ratio of functional residual volume to total liver volume should be more than 25% in non-cirrhotic livers and >40% in cirrhotic livers. In high-volume centers and in the Far East, major hepatectomies are undertaken with minimal postoperative complication rates. Tumor recurrence following primary resection has an incidence of 70%. Recurrence is more common after resection in the cirrhotic liver due to the ongoing process of carcinogenesis. It is more common in multifocal lesions, vascular invasion, and positive resection margin. Salvage OLT can be used for those with recurrence following resection, although patients will still have to fulfil the criteria for transplant. Resection Prior to OLT LR can be used to help select patients for OLT (19). This gives an opportunity to examine not only the surrounding liver but also the specimen for histo-pathological examination. A tumor with adverse morphological features (such as satellite nodules, vascular invasion) could preclude a patient for OLT even though it meets the CMC. Conversely, a large tumor which
194
references
1. Okuda K, Fujimoto I, Hanai A, et al. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 1987; 47: 496772. 2. Ross, RK, Yuan JM, Yu MC, et al. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 1992; 339: 9436
195
4. 5. 6. 7. 8. 9. 10.
11. 12.
13.
14.
15.
16.
17.
196
21
Treatment of laparoscopically discovered gallbladder cancer Jason K. Sicklick, David L. Bartlett, and Yuman Fong
diagnoses each year (13). It has an annual incidence of 1.3 per 100,000 in females and 0.8 per 100,000 in males, with an average incidence of 1.2 cases per 100,000 population per year (14). This cancer is responsible for approximately 2,800 deaths per year. The most obvious associated conditions for gallbladder cancer are gallstone disease and chronic cholecystitis. Between 75% and 98% of all patients with carcinoma of the gallbladder have cholelithiasis (15). Most importantly, gallbladder cancer will be found once in every 100 cases of presumed gallstone disease. The natural history of gallbladder cancer has been defined through many retrospective reviews and large surveillance programs. The overall 5-year survival is consistently less than 5%, with a median survival of 5 to 8 months. Piehler et al. (5) reviewed 5,836 cases in the worlds literature from 1960 to 1978. They reported an overall 5-year survival of 4.1% and a 1-year survival of 11.8%. Only about 25% were resectable for cure, and of those resected for cure, 16.5% survived 5 years. Perpetuo et al. (4) reviewed the M.D. Anderson Cancer Center experience with gallbladder cancer over 36 years and reported a 5-year survival rate of less than 5% and median survival of 5.2 months. Cubertafond et al. (16) reported the results of a French Surgical Association Survey of 724 carcinomas of the gallbladder. They reported a median survival of 3 months, a 5-year survival rate of 5%, and a 1-year survival rate of 14%. They observed no differences among the different surgical procedures adopted, and concluded that no progress had been made in the treatment of gallbladder cancer. A survey of gallbladder cancer in Wessex, United Kingdom, revealed only four patients out of 95 surviving from 8 to 72 months after the time of diagnosis (17). A review of gallbladder cancer from Australia revealed a 12% 5-year survival rate, with all survivors having stage I or II disease. The median survival for patients with stage III or IV disease was only 46 days (18). SEER data from the United States demonstrated similarly unsatisfying results, with only marginal improvement over earlier studies with median overall survival time being 10 months (95% CI 9 to 11 months), as well as 1-year, 2-year, 3-year, and 5-year overall survival rates of 46%, 30%, 23%, and 17%, respectively, in 4,180 patients (19). A multi-institutional review from Japan, on the other hand, reported a 50.7% 5-year survival for 984 patients undergoing radical resection versus 6.2% for 702 patients undergoing more conservative management (20). These results suggest that it may be possible for surgery to have a role in changing the natural history of this tumor. Therefore, it is clear that radical liver resection, or extended liver resection, in gallbladder cancer does have survival benefit in selected cases (7,21,22). Despite this data, it is important to emphasize that there has been only one small randomized, prospective trial on the treatment of gallbladder cancer. Moreover, there are no
introduction
Traditionally a great deal of pessimism has been associated with the treatment of gallbladder cancer (1). There are many reasons for the skepticism associated with this disease entity since its first description in 1778 (2). Foremost is the aggressive nature of this cancer for dissemination. Gallbladder cancer spreads early by direct invasion into the liver, as well as through lymphatics to regional nodes, by peritoneal dissemination to produce carcinomatosis, and by hematogenous means to produce synchronous liver and other distant metastases. As a result, gallbladder cancer often presents at a time when surgical excision is either no longer possible or is technically difficult while alternative therapies including chemotherapy and radiation are generally ineffective. Therefore, it is not surprising that in 1924 Blalock recommended that surgery be avoided for gallbladder cancer if the diagnosis could be made preoperatively (3). In fact, until recently, the 5-year survival in most large series was less than 5%, and the median survival was less than 6 months (4,5). In the modern era, liver resection has become increasingly safe. More recent experience has demonstrated that radical surgery may be a sensible and potentially curative option in the treatment of this disease (6,7). The data have demonstrated that surgical excision is the treatment option of choice for those patients whose gallbladder cancers are confined to the local region of the liver and porta hepatis (810). Beginning in late 1980s, when the techniques for laparoscopic cholecystectomy were introduced, a new presentation for gallbladder cancer was conceived. With the advent and popularization of laparoscopic cholecystectomy, increasing number of cases of gallbladder cancer were being discovered laparoscopically. Currently, approximately 750,000 cholecystectomies are performed in the United States annually for presumed calculous biliary disease (11). Since gallbladder cancer is encountered in 1% of cholecystectomies for cholelithiasis (7), a significant number of patients will present with this clinical scenario. Therefore, meticulous inspection of the gallbladder should be mandatory (12). The current chapter will review data addressing the utility of subsequent radical resection for laparoscopically discovered gallbladder cancer. We will begin with a brief general review of gallbladder cancer, which focuses on the natural history and results of surgical treatment. Summarized data on presentation and results of treatment for laparoscopically discovered disease will be discussed, including the differences of discovery by an open rather than laparoscopic operation.
epidemiology
Gallbladder cancer is the most common biliary tract malignancy and the fifth most common gastrointestinal malignancy in the United States. In fact, there are approximately 5,000 new
197
pathology
At early stages, gallbladder carcinomas are difficult to grossly differentiate from chronic cholecystitis. As a result, they are often found incidentally upon pathologic section. Even at late stages, when the tumor can obstruct the common bile duct and produce jaundice, gallbladder cancer is often mistaken for benign disease since associated gallstones and Mirizzis syndrome are common (23). Therefore, a long-term obstruction of the mid-common bile duct should be considered a gallbladder cancer until proven otherwise. Tumors that arise in the neck and within Hartmanns pouch may also infiltrate the common hepatic duct, making them clinically and radiographically indistinguishable from hilar cholangiocarcinomas. Approximately 60% of tumors originate in the fundus of the gallbladder, 30% in the body, and 10% in the neck (24). These tumors grow most commonly in a diffusely infiltrative form (25), with a tendency to involve the entire gallbladder, and spread in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. If such a tumor is unrecognized at the time of surgery, a simple cholecystectomy will not completely excise the disease and may lead to dissemination of tumor. Although the nodular type of tumor may show early invasion through the gallbladder wall into the liver or adjacent structures, it may be easier to control surgically than the infiltrative type because the margins are better defined. The papillary growth pattern has the best prognosis because even large tumors have only minimal invasion of the gallbladder wall (14). The most common histologic cell type of gallbladder cancers is adenocarcinoma (26). Other rare subtypes of gallbladder cancer include papillary carcinoma, mucinous carcinoma, clear cell carcinoma, signet ring carcinoma, squamous cell carcinoma, small cell (oat cell) carcinomas (27), adenosquamous tumors (28), sarcomas, carcinosarcoma, carcinoid, lymphoma, melanoma, and gastrointestinal stroma tumors (GIST) (29,30).
staging
The multitude of staging systems (Table 21.1) used for this disease has made it difficult to compare treatment results. Nevin et al. (34) originally classified patients into five stages based primarily on the thickness of invasion, and combined patients with direct liver extension or distant metastases into stage V. Donahue et al. (35) modified the Nevin system to include tumors with contiguous liver invasion as stage III and noncontiguous liver involvement as stage V. Stage IV continued to include lymph node metastases. The Japanese Biliary Surgical Society staging system separated tumors into four stages according to the degree of lymph node metastasis, serosal invasion, peritoneal dissemination, hepatic invasion, and bile duct infiltration. The main weakness of this staging system is that lymph node metastases are considered in the same stage as microinvasion of the liver. Despite these various systems, the most common system for evaluating gallbladder cancer worldwide has been the American Joint Committee on Cancer (AJCC) TNM staging system for gallbladder cancer (26). Unfortunately, the 6th edition of the AJCC staging system underwent radical changes due to a desire to match the staging of other biliary cancers. The staging system was therefore not consistent with data. A recent paper documented the deficiencies of the 6th edition staging system using 10,705 cases of this disease from the National Cancer Database (36). Thus, the new 7th edition staging will revert to a system much more in line with past staging (Table 21.1). According to this system, tumors without perimuscular invasion are considered stage I. Tumors with invasion into the perimuscular connective tissue but without extension beyond the serosa or into the liver are considered stage II. Tumors that perforate the serosa and/or directly invade the liver and/or adjacent structures, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic biliary tree are stage IIIA if
patterns of spread
Gallbladder carcinoma commonly disseminates by four modes: 1. Direct extension and invasion of the liver and adjacent organs 2. Lymphatic spread 3. Shedding and peritoneal dissemination, and 4. Hematogenous spread to distant sites. The gallbladder lies on segments IVb and V of the liver and these segments are involved early in tumors of the fundus and body. Direct extension into the portal structures (i.e., portal vein, hepatic artery, and bile duct) commonly occurs and is a major cause of symptoms. Lymphatic spread is also common and most often involves cystic and pericholedochal nodes.
198
II
III
IV
(1) Liver invasion >2 cm (T4N0M0, TxN1M0 (2) Distant metastases (TxN2M0, TxNxM1) N2 lymphadenopathy [peripancreatic (head only), periduodenal, perioportal, celiac, superior mesenteric, or paraaortic nodes] []
Transmural (T3N0M0), or T-3 with nodal involvement Metastatic disease, or vascular involvement with nodal metastases (T4N1M0)
[]
Distant metastases
[]
there is no regional lymph node metastasis. Stage IIIB tumors have nodal metastases but no vascular invasion. Stage IVA includes those patients with vascular invasion, and stage IVB includes patients with distant metastases or those with vascular invasion and nodal metastases.
clinical presentation
The clinical presentation of gallbladder cancer is often identical to biliary colic and/or chronic cholecystitis, making it difficult to diagnose preoperatively. It is also difficult to easily distinguish gallbladder cancer from benign gallstone disease from blood tests. Elevated alkaline phosphatase and/or bilirubin levels are found in cases of advanced tumors, but may also be found for patients with gallstones. A CEA greater than 4 ng/ml is 93% specific for the diagnosis of gallbladder cancer, but is only 50% sensitive (37). A serum Ca 199 level (38) greater than 20 units/ml has 79.4% sensitivity and 79.2% specificity, but neither test is routine in patients suspected of having benign disease. Vigilance for cancer in examination of preoperative sonograms or CT scans is essential. Any mass or polyp associated with the gallbladder (Fig. 21.1) or the presence of a porcelain gallbladder should raise concerns of a gallbladder cancer.Figure 21.1 It is often difficult to make the diagnosis of gallbladder cancer based upon clinical history as it often presents similarly to
Figure 21.1 CT scan demonstrating a papillary carcinoma of the gallbladder. This patient was subjected to a laparoscopic cholecystectomy in spite of this scan and required a subsequent reoperation for a potentially curative radical resection.
benign calculous disease. In a report of 42 laparoscopically discovered gallbladder cancers, in only two of the cases did the laparoscopic surgeon suspect a cancer prior to the surgical procedure (39). The laparoscopic procedure consisted of 19
199
surgical management
A wide range of operations has been advocated for gallbladder cancer from simple cholecystectomy to combined extended hepatectomy, common bile duct resection, and pancreaticoduodenectomy (50). Debate still exists as to the extent of surgery (51). A survey of prominent gastrointestinal surgeons in the United States indicated that 49% recommended lymph node dissection and 64% recommended some form of liver resection for stage T24 disease. The cynical attitude toward this disease is reflected by the recommendation of 21% of surgeons to perform only a simple cholecystectomy for nodepositive disease (52). Studying the earliest stages of the disease, incidental Tis or T1A gallbladder cancer discovered in specimens following
radiologic workup
Most patients with laparoscopically discovered gallbladder cancer will have had an ultrasound performed for suspected cholelithiasis. Review of this ultrasound may provide information concerning liver involvement by tumor, biliary extension of tumor, and/or vascular involvement. However, it is most often that another cross-sectional imaging test is indicated for further assessment of these sites for disease, as well as to assess for presence of nodal disease. The combination of CT scanning and ultrasonography (44) is the most common combination for initial assessment, although MRI scanning can be substituted for CT (45). If the initial assessment suggests evidence of laboratory or radiologic signs of biliary obstruction, assessment of the extent of biliary involvement by another imaging technique may be necessary. Gallbladder cancer can cause obstructive jaundice by direct invasion of the common hepatic duct, or by compression and involvement of the common hepatic duct by pericholedochal lymph nodes. A high correlation between Mirizzis syndrome and gallbladder cancer exists (23). Endoscopic or percutaneous cholangiograms (PTC) are the
Figure 21.2 Magnetic resonance cholangiopancreatography demonstrating extent of gallbladder cancer. Extension of tumor within and obstructing the common bile duct is shown with isolation of the left and right hepatic duct. The portal vein (white arrow) is patient and not involved by tumor.
200
local disease defined pathologically. Knowing the likelihood of further local, nodal, peritoneal disease will allow for rational therapeutic choices. Tumors Confined to the Muscular Propria (T1 Tumors) There are abundant data to indicate that early gallbladder cancer, which has not penetrated through the muscular layer of the gallbladder, is adequately treated by simple cholecystectomy. Tsukada et al. (55) demonstrated that in 15 cases with T1 lesions, there were no cases with lymph node metastasis. Table 21.3 (6,20,21,28,35,5661) summarizes results of resection for stage I disease. After simple cholecystectomy alone, the 5-year survival was 78% to 100% (59,62). In a report of 56 patients treated with simple cholecystectomy alone, only two patients recurred and subsequently died of their disease. Both had submucosal spread of the tumor to involve the cystic duct margin (21). When patients present after laparoscopic cholecystectomy with a pathologic diagnosis of T1 gallbladder cancer, a careful review of the pathology is imperative. Care must be taken to verify both negative margins including the cystic duct stump and that there are no areas of deeper invasion. If the gallbladder margin is involved by tumor, a liver resection is required. If the cystic duct stump is involved, an excision of the common bile duct, including the junction with the cystic duct, is indicated. No nodal dissection is necessary. Tumor Invading into the Subserosal Layer (Stage II) By definition, T2 tumors do not transgress the serosal plane. However, the recommended management for T2 disease is an extended or radical cholecystectomy to include a liver resection and regional lymph node dissection including periportal, peripancreatic, and celiac nodes. This recommendation is based on the pattern of spread of disease. In the most common infiltrative form of gallbladder cancer (25), the cancer often spreads in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. This results in a higher likelihood of positive margins after simple cholecystectomy. In the review by Yamaguchi and Tsuneyoshi (59), patients had tumor extending into the subserosal layer and 11 of these had positive microscopic margins after simple cholecystectomy. Furthermore, the likelihood of metastatic disease to regional
T2, submucosal invasion; T3, full thickness invasion through gallbladder wall with <2 cm extension into liver; T4, > 2 cm extension into liver. Source: From Ref. (39).
Table 21.3 Actuarial Survival Results Reported In Retrospective Reviews after Resection of Stage I Gallbladder Cancers
Author Ouchi et al. (56) Yamaguchi and Enjoji (28) Donohue et al. (35) Gall et al. (57) Ogura et al. (20) Shirai et al. (58) Yamaguchi and Tsuneyashi (59) Shirai et al. (21) Matsumoto et al. (6) Oertli et al. (60) de Aretxabala et al. (61) Year 1987 1988 1990 1991 1991 1992 1992 1992 1992 1993 1992 N 14 11 6 7 366 39 6 56 38 4 6 32 Procedure Not specified Not specified Simple cholecystectomy: 83% Simple cholecystectomy Not specified Simple cholecystectomy Simple cholecystectomy Simple cholecystectomy Extended cholecystectomy Extended cholecystectomy Simple cholecystectomy Simple cholecystectomy: 69% 3-Year survival (%) 78 100 100 86 87 100 100 100 100 100 100 94 5-Year survival (%) 71.4 Not reported 100 86 78 100 100 100 100 100 100 94
201
Table 21.4 Actuarial Survival Results Reported in Retrospective Reviews after Resection of Stage II Gallbladder Cancers
Author Yamaguchi and Enjoji (28) Donohue et al. (35) Ogura et al. (20) Gall et al. (57) Shirai et al. (58) Yamaguchi and Tsuneyashi (59) Matsumoto et al. (6) Oertli et al. (60) Cubertafond et al.a (16) Bartlett et al. (7) Paquet (107) Shih (63) Kai (64) Jensen (65) DAngelica (66)
Multi-institutional survey. Chole, cholecystectomy.
a
Year 1988 1990 1991 1991 1992 1992 1992 1993 1994 1996 1998 2007 2007 2008 2008
Procedure Not specified 67% Extended chole Not specified 86% Simple chole Simple chole Extended chole Simple chole Extended chole Simple chole 88% Simple chole Extended chole Extended chole Extended chole Simple chole Extended chole Simple chole Extended chole Extended chole
202
Table 21.5 Actuarial Survival Results reported in Retrospective Reviews after Resection of Stage III and IV Gallbladder Cancers
Author Matsumoto et al. (6) Chijiiwa and Tanaka (102) Onoyama et al. (67) Bartlett et al. (7) Ouchi et al. (56) Nakamura et al. (103) Donohue et al. (35) Gall et al. (57) Shirai et al. (58) Ogura et al. (20) Todoroki et al. (92) Nimura et al. (50) Matsumoto et al. (6) Chijiiwa and Tanaka (102) Onoyama et al. (67) Bartlett et al. (7) Kai (64) DAngelica (66) Jensen (65) Year 1992 1994 1995 1996 1987 1989 1990 1991 1992 1991 1991 1991 1992 1994 1995 1996 2007 2008 2008 N 8 12 12 8 12 13 17 8 20 453 27 14 27 11 14 7 16 63 119 Stage III III III III III/IV III/IV III/IV III/IV III/IV IV IV IV IV IV IV IV III/IV III/IV III 3-Year survival (%) 38 80 44 63 17 16 50 50 18 7 10 25 11 8 25 40 45 18 5-Year survival (%) 44 63 16 29 45 8 8 25 36 28 9 Comments Majority with common bile duct resection Extended resections only Extended resections only Extended resections only Extended resections only Includes 5 HPD, 10 extended hepatectomy Extended resections only Includes only curative resection at initial surgery All patients have lymph node metastases Multi-institutional series with 25% simple cholecystectomy All patients had IORT All patients underwent HPD Includes 3 HPD, 6 extended hepatectomy, 11 CBD resection Extended resections only Japanese staging Long-term survivors with no lymph node metastases
CBD, common bile duct; HPD, hepatopancreatoduodenectomy; IORT, intraoperative radiation therapy.
203
that operation, care must be taken to perform a full abdominal inspection to rule out peritoneal disease (85). Whether such excision of port sites is useful requires further investigation, since port recurrence may be just a marker for diffuse peritoneal dissemination of disease. Complications The operations described above are extensive procedures with substantial risks. In particular, the majority of patients undergoing treatment for gallbladder cancer are in their seventh or eighth decade of life and may be at increased risk as a consequence of concomitant medical comorbidites. In a multi-institutional review of 1686 gallbladder cancer resections from Japan, a comparison of morbidity by procedure was made (20). A morbidity of 12.8% was reported for cholecystectomy, 21.9% for extended cholecystectomy, and 48.3% for hepatic lobectomy. The mortality rates were 2.9%, 2.3%, and 17.9%, respectively. There were 150 hepatopancreatoduodenectomies for gallbladder cancer, with a 54% morbidity rate and a 15.3% mortality rate. The morbidity and mortality rates of major liver resections have decreased in later reports, even in the aged population (86). In our report of re-resection for laparoscopically discovered gallbladder cancer, all resected patients were subjected to some form of liver resection and the operative mortality was 5% (39). The most common complications are bile collections, liver failure, intra-abdominal abscess, and respiratory failure. The risk of resection for each patient and for each type of resection needs to be weighed against the chance of benefiting from the procedure based on the stage of disease.
adjuvant therapy
Because of the rarity of gallbladder cancer in general, as well as the rarity of completely resected disease, there is only one prospective, randomized trial examining the utility of adjuvant therapy for gallbladder cancer. This trial assessed 5-year overall survival in patients following noncurative resection who received postoperative adjuvant chemotheraoy using mitomycin C and 5-FU. Survival was improved with adjuvant therapy (26% vs. 1%, P = 0.03). (87) However, most data available is derived from retrospective series. Conclusive data do not support the routine use of chemotherapy (8890).
204
key points
Gallbladder cancer will be found in 1 per 100 cholecystectomy specimens (incidence 1.2 cases per 100,000 population per year).
palliative management
Palliative therapy should be considered in the context that the median survival for patients presenting with unresectable gallbladder cancer is 2 to 4 months (60,97). The goal of palliation should be relief of pain, jaundice, and bowel obstruction, as well as prolongation of life. These should be done as simply as possible given the aggressive nature of this disease. Biliary bypass for obstruction can be difficult because of advanced disease in the porta hepatis. A segment III bypass is usually necessary if surgical bypass is chosen to relieve jaundice (98,99). However, such bypasses have a 12% 30-day mortality rate (99) In the event of a preoperative diagnosis of advanced, unresectable gallbladder cancer in the jaundiced patient, therefore, a noninvasive radiologic approach to biliary drainage is justified. Systemic chemotherapy (100) and radiation therapy (101) have little effect on these tumors. Patients with unresectable disease and good functional status who desire therapy should be directed to investigational studies to determine whether any novel therapies may be of benefit.
75% to 98% association with cholelithiasis. A long obstruction of the mid-common bile duct is gallbladder cancer until proven otherwise. Radiologic investigation of gallbladder cancer: Ultrasound MRCP CT ERCP/PTC if jaundiced Surgical management: Stage I (T1N0M0): Simple cholecystectomy alone Stage II (T2N0M0): Radical cholecystectomy Stage III (T3N0M0) hepatic invasion <2 cm: Radical cholecystectomy Stage IV (T4N0M0) liver invasion >2 cm No dissemination: extended hepatectomy Widespread dissemination: no surgical option
references
1. Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg 2008;196(2):25264. 2. Kato S, Nakagawa T, Kobayashi H, Arai E, Isetani K. Septum formation of the common hepatic duct associated with an anomalous junction of the pancreaticobiliary ductal system and gallbladder cancer: report of a case. Surgery Today 1994;24(6):5347. 3. Blalock AA. A statistical study of 888 cases of biliary tract disease. Johns Hopkins Hosp Bull 1924;35:391409. 4. Perpetuo MD, Valdivieso M, Heilbrun LK, et al. Natural history study of gallbladder cancer: a review of 36 years experience at M. D. Anderson Hospital and Tumor Institute. Cancer 1978;42(1):3305. 5. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstetr 1978;147(6):92942. 6. Matsumoto Y, Fujii H, Aoyama H, et al. Surgical treatment of primary carcinoma of the gallbladder based on the histologic analysis of 48 surgical specimens. Am J Surg 1992;163(2):23945.
summary
Gallbladder cancer is an aggressive disease with a dismal prognosis. It should not, however, be approached with a fatalistic attitude. Appropriate workup and extended resection can result in a cure. Gallbladder cancer will be encountered approximately once every 100 times that a gallbladder is removed for presumed benign gallstone disease. For those patients discovered to have a T1 cancer during pathologic analysis, no further therapy is indicated as long as all the margins, including the cystic duct margin, are negative (56,58). However, T2, T3, or T4 tumors deserve consideration for reexploration (54,61,102106). Selection for re-resection relies
205
206
207
22
Liver transplantation for HCC: Asian perspectives Shin Hwang, Sung-Gyu Lee, Vanessa de Villa, and Chung Mao Lo
zation, local ablation, and injection therapy. Surgical resection has been regarded as the treatment of choice for HCC, but it has definite limitations in both tumor resectability and patient safety when hepatic functional reserve is markedly reduced. Although it has been shown that liver resection can be achieved safely in selected patients with cirrhosis (11,12), it is widely accepted that it carries a significant risk of postoperative morbidity, even in patients with ChildPugh grade A cirrhosis. With reasonable patient selection, liver resection is associated with relatively low operative mortality rates, ranging in recent studies from 0% to 4% (1113). Long-term survival results after surgical resection, however, are affected by tumor recurrence and progressive deterioration of liver function (14,15). Non-surgical treatments often result in incomplete tumor control and also reveal high recurrence rates when used for advanced HCC lesions. The natural history of untreated and non-surgically treated HCC in Asia is worse than that of similar cases in Western countries. A study from Hong Kong (16) showed that the 1-year and 2-year survival rates of patients with untreated HCC were 7.8% and 0.9%, respectively, whereas a comparable study from Spain (17) showed 54% and 40%, respectively (3).
introduction
Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly cancer worldwide (1). HCC is closely associated with chronic liver disease and more than 80% of cases occur in cirrhotic livers (2). Since functional reserve of the liver is often significantly impaired, application of treatment modalities such as liver resection, transarterial chemoembolization, or local ablation therapy is limited. Not only HCC recurrence, but also progressive deterioration of liver function decrease patient survival. Liver transplantation (LT) is the only treatment that offers a chance of cure for the tumor and the underlying liver cirrhosis at the same time, although there is an additional risk of accelerated tumor recurrence from immunosuppression. The outcome of LT for HCC in Western countries is encouraging, but availability of liver grafts still remains the main limitation for LT. Since the incidence of HCC combined with chronic liver diseases is much higher, and organ donation from deceased donors is much fewer in Asian countries compared to Western countries, it is difficult to use Deceased Donor LT (DDLT) as one of the main treatment modalities for HCC in Asia. In fact, organ donation from deceased donors remains below five per million per year in most Asian countries because of various social and cultural reasons (Fig. 22.1) (3). Because of these constraints, Living Donor LT (LDLT) is now the main method of LT in a number of Asian countries, and is an alternative to DDLT in every indication for LT. Numerous technical innovations have been achieved to secure donor safety as well as ensure patient survival. The outcomes of LT for HCC in major Asian LT centers are acceptably favorable and also comparable to those seen in Western countries (3). Patient selection criteria for HCC have also been proposed by several major Asian LT centers based on their own data (47).
history of lt in asia
LT in Asia started early and yet progressed slowly when compared with Western countries (3). The first liver transplant in Asia was performed in 1964 by Nakayama with a graft from a non-heart beating donor in Chiba, Japan (18). This was only 1 year after Starzls first attempt in the world for human LT in Denver, USA (19). It was a highly controversial exploit because organ donation from a deceased person was not accepted in Japanese culture at that time. The second transplant in Asia was performed in 1978 in Shanghai, P.R. China (3,20). In 1984, Chen, in Taiwan, performed the first liver transplant with long-term survival in Asia at a time when there was still no brain death law in that country (21). Legislation regarding brain death was passed in Singapore (22) and Taiwan in 1987, and subsequently in Japan and Korea (23). In Asia, the serious scarcity of deceased donor organ donation and strong demand for LT provided a powerful driving force for the development of LDLT as a practical alternative in replacing DDLT. The first LDLT in Asia was performed by Nagasue of Shimane University, Japan, in 1989 (24), only 1 year after the first attempt of LDLT by Raia in Brazil in 1988 (25). Subsequently Hong Kong, Korea, and Taiwan rapidly initiated pediatric LDLT programs transplanting a left lateral section or a left lobe graft from a parent donor to a child. However, the ultimate need for LDLT was in adult patients. Transplant centers in Asia have repeatedly advanced the frontier of adult-to-adult LDLT. In 1993, Makuuchi in Japan performed the first successful adult LDLT using a left lobe
208
Figure 22.1 Comparison of organ donation rates from deceased donors in different countries in the East and West in 2005 (3).
graft (26). The left lobe graft, which usually comprises less than 40% of the whole liver volume, is often too small for an adult recipient. For successful LDLT for adult patients, graft size is the most important factor in determining the outcome of LDLT and is still a controversial concern for selection of the ideal donor. The Kyoto group first reported the use of a right lobe graft for a pediatric recipient as a result of a variance in the donors arterial anatomy in 1994 (27). The first case report (28), and subsequently the first series (29) of successful adult LDLT, using a right lobe graft was reported from Hong Kong in 1997. Further technical advances in adult LDLT, including the addition of the caudate lobe to a left lobe graft (30) and the use of right lateral section grafts (31), were reported from Japan. In 1999, authors proposed conservation of the middle hepatic vein trunk to the donor, and the reconstruction of hepatic venous drainage of the right anterior section of the liver graft to avoid congestion injury of both the right lobe liver graft and the donors remnant left lobe (32). Middle hepatic vein reconstruction has apparently increased the success rate of the right lobe LDLT in adult patients and widened the safety margin and the pool of living donors. As an attempt to provide adequate graft volume for an adult recipient and minimize the risk of an individual donor, authors also performed implantation of dual grafts from two donors for one recipient in 2000 (33,34). In Asia, where the supply of deceased donor organs remains seriously limited and the demand for LT is persistently increasing, the applicability of LDLT will continue. For successful LDLT, the risk to the donor should be balanced by the greater benefit to the recipient. Every effort must be taken to minimize donor morbidities, making this procedure beneficial to the donor and the recipient (3538).
modality cannot achieve such a favorable result comparable to that of LT. However, it should be emphasized that HCC recurrence is the most common cause of late patient death after LT (4,3941). The clinical sequence of post-transplant HCC recurrence is usually much worse than in non-transplant patients since the response to treatment for HCC recurrence after LT is disappointing. To date, the most effective measure to prevent post-transplant HCC recurrence is strict selection of transplant candidates after exclusion of patients with known risk factors for HCC recurrence. Eligibility guidelines for transplantation, such as the Milan and University of California at San Francisco (UCSF) criteria, have been adopted to reduce the post-transplant HCC recurrence and the wasting of donor organs (42,43). The Milan criteria were originally established on the basis of pre-transplant imaging findings but were re-evaluated on the basis of explant liver pathology, whereas the UCSF criteria were based on explant pathology but validated by pre-transplant imaging findings. Each of these two sets of criteria is derived from the experience with DDLT (Table 22.1). Application of these criteria to LDLT has resulted in patient survival outcome, very similar to that following DDLT, as shown in high-volume multi-center cohorts from Japan and Korea (40,41). Moreover, the prognostic powers of the Milan and UCSF criteria were reported to be the same in both DDLT and LDLT (41). When selecting transplant candidates, there is a real risk of discrepancies between the pre-transplant radiological and explant pathologic staging (4,40,41). Candidates for DDLT should be selected after consideration of the extent of HCC at the time of listing, and any further progression of HCC during the waiting period. LDLT, because of its shorter waiting time, is less affected by tumor progression, permitting more flexible selection of transplant candidates than DDLT. A substantial proportion of adult LDLT patients not fulfilling the Milan or UCSF criteria has been found to survive longer than expected after LT (4,40,41,44,45). Therefore, it seems reasonable to attempt further reduction of unnecessary dropouts arising from the strict application of narrow selection criteria.
209
Tumor criteria Diameter 5 cm; Number of lesions 6; No gross vascular invasion Diameter 5 cm; Number of lesions 10; PIVKA-II 400 mAU/mL Diameter 5 cm; Number of lesion 5 Total diameter 8 cm; or total diameter >8 cm and histopathologic grades I and II, and AFP 400 ng/mL Diameter 5 cm if single lesion; or Diameter 3 cm if multiple lesions and number of lesions 3 Diameter 6.5 cm if single lesion; or Diameter 4.5 cm if 2 lesions with total diameter 8 cm
Viral hepatitis HBV: 93%, HCV: 7% HBV: 34%, HCV: 53% HCV: 62% HBV: 100%
LDLT: 100%
125
78 195
DDLT: 100%
48
4-years: 85%
4-years: 50%
168
Abbreviations: AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; PIVKA-II, prothrombin induced by vitamin K absence II; UCSF, University of California at San Francisco.
The golden standard to date for selection of HCC patients for DDLT and LDLT are the Milan criteria, while the UCSF criteria are regarded as acceptable alternative guidelines. The UCSF criteria, which expand the maximal tumor size to 6.5 cm for a single HCC lesion, produce survival rates comparable to those of the Milan criteria. However, the study populations in the original studies evaluating these two criteria do not seem to be large enough, introducing the possibility of bias from small numbers of patients with recurrent tumors (42,46). The prognostic power of these criteria appears sufficient, but their discriminatory power for those HCC patients who do not meet these criteria is not sufficiently high (4). Many highvolume LT center series or multi-center studies revealed that long-term patient survival rates look uniformly favorable when extent of HCC met the indication criteria, but the recurrence rates showed great differences among indication criteria (Fig. 22.2). Currently proposed criteria for indication of LT are summarized in Table 22.1 (47,42,47). Considering that these proposed expanded criteria also showed favorable outcomes in recent studies (47), it is probable that the Milan criteria are becoming outdated. However, the question is which criteria should be the new golden standard instead of the Milan criteria (48). It is reported that hepatitis C is a significant predictor of tumor recurrence and impaired survival after LT in patients with HCC (49), implicating that there may be a benefit in the expansion of the Milan criteria for HCC in the non-hepatitis C population. The clinical sequence of HCC in patients with HBV infection has been reported to be favorable compared to
that in patients with hepatitis C virus infection because HBV infection is more effectively controllable than hepatitis C infection after LT (50,51). Uniquely, some major LT centers in Korea and Japan challenged the Milan criteria, accepting a much higher number of nodules (five or more) (46,52). On the other hand, a number of major LT centers in the United States and Europe have mainly focused on enhanced criteria regarding the tumor diameter (more than 5 cm) (47,5355). LT is also indicated for small HCC in ChildTurcottePugh (CTP) class B or C cirrhosis, or CTP class A with portal hypertension (42,5659). However, the optimal treatment strategy for patients with small single HCC, cirrhosis with preserved liver function, and absence of portal hypertension is not yet established. No prospective randomized study has been reported which compares liver resection and LT for small HCC in cirrhotic patients who could be eligible for both treatment modalities. Authors have reported the results of liver resection in 100 cirrhotic patients with single, less than 3 cm-sized HCC who would have been eligible for primary LT, comparing with a group of 17 patients who underwent LT for HCC with similar tumor stage during diagnosis and preserved liver function (60). These results showed that 37 of 39 HCC recurrences initially occurred in the liver after resection, but only one recurrence occurred in lung after LT. Overall patient survival was not proven to be statistically different, but diseasefree survival was significantly different between the two groups (Fig. 22.3). The influence of these encouraging results of LT for HCC may be reflected on the proportion of liver recipients
210
0.6
Beyond UCSF
0.4 Beyond Milan, within UCSF 0.2 Within Milan 0.0 0 12 24 36 48 Posttransplant months 60
0.4
0.2
0.0
12
24 36 48 Posttransplant months
60
(A)
(B)
Figure 22.2 Comparison of the hepatocellular carcinoma recurrence curves between the Milan and UCSF criteria (A) and between the Milan and Asan criteria (B) (4). 1.0 0.9 0.8 Proportion of survival Proportion of survival 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 (A) 20 40 60 80 100 120 140 (B) Postoperative months P = 0.27 Hepatectomy LT 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 20 40 60 80 100 120 140 Postoperative months P = 0.047 Hepatectomy LT
Figure 22.3 Comparison of the overall patient survival (A) and recurrence-free survival (B) between the patients who undergone hepatic resection and liver transplantation for hepatocellular carcinoma (HCC) <3 cm-sized, single nodule with ChildTurcottePugh class A cirrhosis (60).
undergoing LT per year in Asia (Fig. 22.4). Hepatic resection is still a good treatment modality for selected patients because of lower cost and no requirement for donor organs. However, if a donor is available, primary LT can be considered as a preferred treatment modality for single small HCC of CTP class A cirrhosis in the presence of portal hypertension, because LT may provide excellent disease-free survival and maintenance of normal quality of life (60).
response to neoadjuvant therapy may be potentially influenced by the selection effect for tumors with better biological behavior. Such a selection bias also influences post-transplant outcome (6870). Salvage LT has been performed for recurrent HCC or deterioration of liver function after primary liver resection. From the viewpoint of pre-transplant treatment, prior liver resection has two roles: primary treatment and bridging to LT. Considering the incidence of deceased donors and high proportion of LDLT, many of prior liver resection may be intended for primary curative treatment rather than bridge treatment. There are two important points to be taken into account before performing salvage LT (71). The first is the technical feasibility of LT, especially for LDLT. The surgical condition of patients with recurrent HCC after prior liver resection is not very different to that of patients who underwent non-surgical treatment, except that adhesion and anatomical distortion exist within the abdomen, which could be overcome by technical skill (71). Some authors claim that every combination of prior hepatectomy and living donor graft is feasible for patients
211
Figure 22.4 Annual proportions of liver transplants for hepatocellular carcinoma (HCC) in Asia (excluding mainland China) (3).
undergoing salvage LDLT. The second is the main indication for salvage LT, in which there is still no consensus on eligibility criteria. Authors also suggest that the survival outcome of salvage LDLT, based on explant tumor staging, was equivalent to that of primary LDLT, and it may be reasonable that primary and salvage LDLT share the same indication criteria for HCC. For salvage LDLT, determination of the timing of LT is of practical importance. There are proposals to perform LDLT as early as the situation permits in order to avoid tumor progression, but it is unclear whether patients who had early HCC recurrence after liver resection are adequate candidates for salvage LT. If early recurrence is associated with a well-advanced tumor or unfavorable pathology, the patient may not benefit from salvage LT because there is a very high probability of post-transplant HCC recurrence. In contrast, if early recurrence is related to incomplete local control of small HCC lesions, the patient may be a candidate for salvage LT. Patients with a longer interval between prior liver resection and salvage LDLT show more favorable survival than those with a shorter interval. A thorough pre-transplant HCC workup should be performed because extra-hepatic recurrence was not uncommon in patients with recurrent HCC after resection (37,72,73). For salvage DDLT, there are two important reports revealing contradictory results. Belghiti and colleagues (74) compared 18 patients who underwent secondary LT following liver resection with 70 undergoing primary LT and assessed postoperative outcomes and long-term survival. They concluded that in selected patients, liver resection prior to LT does not increase morbidity or impair long-term survival following primary LT, and, accordingly, liver resection prior to LT can be integrated into the treatment strategy for HCC. On the other hand, Adam and colleagues (75) compared the results of secondary LT for tumor recurrence following resection of initially transplantable HCC in 17 patients with cirrhosis with those of primary LT in 195 patients. They reported that LT after liver resection was associated with a higher operative mortality, an increased risk of recurrence, and a poorer outcome compared with primary LT.
212
Proportion of survival
0.8
0.6 DDLT
0.4
0.2 LDLT 0.0 0 12 Months Figure 22.5 Cumulative survival curves after the first detection of hepatocellular carcinoma recurrence in DDLT and LDLT groups. There is no statistically significant difference between these two groups (41). 24 36
contrast to previous cytotoxic agents, most targeted agents do not induce regression of tumors but stabilize disease progression. Sorafenib is the first drug proven to prolong survival in advanced stage patients, but the survival benefit is still relatively short. Therefore, future trials should be conducted regarding the combination of sorafenib with other pre-existing treatment modalities or new targeted agents, especially in the potential role of assisting in a bridge to LT (35,87).
conclusion
The high prevalence of HCC and subsequent high incidence of HCC in the situation of very low organ donation rate in Asia lead to making a unique pattern of indication and strategy in the application of LT. HCC has begun to be a main indication of LT, especially in the form of LDLT. Effective promotion of deceased organ donation is essential in every Asian country. Although LDLT has become the main form of LT in Asia, donor safety should always be emphasized. The selection indication of LT for HCC is likely to be expanded further, but it should be prudently adopted after qualified riskbenefit analyses. Application for small HCC in patients with preserved liver function has also been an expanded indication after gradual improvements in peri-operative mortality. As before, new innovative surgical techniques will emerge to solve currently intractable technical problems. Emergence of new effective treatment modalities for HCC recurrence will expand the selection criteria further without compromising disease recurrence rate. The practice of LT in Asia will continue to evolve further, giving more benefits to patients with HCC.
references
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74108. 2. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19: 323. 3. de Villa V, Lo CM. Liver transplantation for hepatocellular carcinoma in Asia. Oncologist 2007; 12: 132131. 4. Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one largevolume center. Liver Transpl 2008; 14: 93545.
213
214
215
23
introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide (1). Added to its worldwide prevalence, there is a continued rising incidence of HCC in the western hemisphere (2). More than 80% of patients present with advanced or unresectable disease, and the recurrence rates after surgical resection is as high as 50% (3). Effective therapies for advanced HCC remain an immediate need. In the field of local therapies for locally advanced disease, extensive work has been done in regard to the feasibility and effectiveness of different ablative modalities, with several issues still in debate. In the more advanced and metastatic disease settings, recent data showed an improvement in survival in advanced HCC with sorafenib. This landmark study not only helped in defining a standard of care for advanced HCC, but also generated several clinical questions among whom to treat, and how to account for the cirrhosis and underlying liver dysfunction. Second line therapies and future clinical trials are prime time discussions.
216
(A)
(B)
(C)
Figure 23.1 (A) Pre-treatment CT (arterial phase) in patient with multi-focal HCC. (B) Non-treatment CT performed 12 hours after left hepatic and phrenic artery particle (bland) embolization. Note retained contrast material and small gas bubbles in treated tumor. (C) Post-treatment CT (arterial phase) demonstrating imaging findings consistent with necrosis of treated tumor corresponding to treated tumor that had retained contrast and gas bubbles on immediate postembolization CT scan.
(A)
(B)
Figure 23.2 (A) Pre-treatment CT in patient with large HCC in right liver with tumor thrombus extending into portal vein (B) post-treatment CT 6 weeks after bland embolization demonstrating imaging findings of necrosis of tumor within liver and portal vein.
217
218
systemic therapies
Historical Background Chemotherapy has been studied extensively in HCC. Despite reported responses ranging between 10% and 20%, no study has shown an impact on survival. Doxorubicin has been studied extensively and there is still no agreement about its use in advanced HCC, with response rates ranging between 0% (39) and 79% (40). Despite the poor or debatable outcome of most of these trials, doxorubicin became the default standard for
219
Figure 23.3 Baseline and serial follow-up scans demonstrate tumor necrosis in a hepatocellular carcinoma patient.
sorafenib group versus 7.9 months in the placebo group (p < 0.001, HR = 0.69). The study led to the approval of sorafenib by the FDA for the treatment of unresectable HCC (49) and thus sorafenib became the standard of care in this setting (Level of evidence Ib, category A). The drug-related grade 34 toxicity profile included diarrhea (8%) and hand foot syndrome (8%). Despite the infrequency of bleeding events (<1%), one should still use caution in this regard considering the anti-angiogenic nature of sorafenib. Treating Patients with Advanced Cirrhosis The exciting results of the phase III study apply mainly to patients with ChildPugh A score, similar to the population evaluated in the study. The safety and efficacy of sorafenib in patients with ChildPugh B or C cirrhosis is still however being evaluated. In the phase II study evaluating sorafenib in HCC (50), 28% of patients had ChildPugh B cirrhosis. In 28 patients from which pharmacokinetic samples were obtained, AUC (08) (mg h/L) was comparable between the ChildPugh A (25.4) and ChildPugh B (30.3) patients. Cmax (mg/L) were 4.9 and 6 for ChildPugh A and B patients, respectively, with similar drug-related side effects profiles. However, ChildPugh B patients had worsening of their liver function at a more frequent rate. A transient increase of serum bilirubin was reported in 40% of the patients with ChildPugh B compared to 18% of ChildPugh A patients. It is unclear and tough if this elevation in bilirubin is drug related or disease progression. Sorafenib acts as a substrate for UGT1A1, and the study did not collect direct bilirubin measurements, so it remains unclear if this total bilirubin may also be due to an inhibitory effect of UGT1A1 and decreased bilirubin glucuronidation. Another study evaluating sorafenib in patients with liver dysfunction may help in giving certain guidance on the use of sorafenib in patients with liver cirrhosis (51). The most commonly reported Drug-Limiting Toxicity (DLT) among patients with elevated bilirubin at baseline was further elevation of bilirubin. In the lack of any further data, one may consider the recommended doses of sorafenib reported in this study: 400 mg PO twice per day for bilirubin up to 1.5 x upper limit
of normal (ULN); 200 mg PO twice per day (or 400 mg PO daily) for bilirubin 1.5 to 3 ULN; and to avoid sorafenib for bilirubin above 3 ULN (Level of evidence IIa, category C). Nonetheless the safety of sorafenib in patients with HCC and advanced cirrhosis needs to be further studied. Future Developments In the advanced disease setting, the next step will be to evaluate other novel therapies or combinations of different agents looking for further improvement in survival. Bevacizumab, another potent anti-angiogenic agent, has been studied extensively in patients with advanced HCC (52,53). In one of the two studies of 28 patients, 4 had to discontinue therapy because of serious adverse events, including 1 transient ischemic attack and 3 serious esophageal bleeding events, which led to a modification of the study to identify and manage esophageal varices prior to enrollment (54). Bevacizumab has also been studied in combination with chemotherapy (5557) and other biologic agents. The most promising bevacizumab doublet data are in combination with erlotinib (58). Patients with HCC and CLIP 3 were treated with bevacizumab and erlotinib. Based on the intent-to-treat analysis, 7 of 34 patients had radiographic responses and 27 (79.4%) had stability of disease for as long as 8 weeks. Median progression-free survival (PFS) was 9 months and median overall survival (OS) 19 months. Grade 3 and 4 fatigue and hypertension were each reported in 15% of the cases and similar grade gastrointestinal bleeds were reported in 9% of the cases. The positive outcome of this study supports the biologic relevance of this combination of anti-angiogenic therapy and tyrosine kinase inhibitor in HCC and should be explored further. Sunitinib, another multi-targeted tyrosine kinase inhibitor, has also been tested in HCC (59). Of 26 patients treated with sunitinib at 37.5 mg daily dose, 10 (38.5%) showed stability of disease, with a median PFS of 4.1 months. Another study showed similarly promising results at the dose of 50 mg, with median TTP of 21 weeks and median OS of 45 weeks (60). Sorafenib has been evaluated in combination with doxorubicin as part of a randomized double-blinded phase II
220
references
1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001; 94: 1536. 2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999 Mar 11; 340(10): 74550. 3. Thomas MB, OBeirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P. Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy. Ann Surg Oncol 2008 Apr; 15(4): 100814. 4. Poon R T-P, Fan S-T, lo C-M, et al. Intrahepatic recurrence after curative resection of Hepatocellular carcinoma: long-Term results of treatment & prognostic factors. Ann Surg 1999; 229(2): 21622. 5. Breedis C, Young G. Blood supply of neoplasms of the liver. Am J Pathol 1954; 30: 96985. 6. Konno T. Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium. Cancer 1990; 66: 1897903. 7. Egawa H, Maki A, Mori K, et al. Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, Estradiol-Chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumors in rats. J Surg Oncol 1990; 44: 10914. 8. Raoul JL, Heresbach D, Bretagne JF, et al. Chemoembolization of hepatocellular carcinomas. A study of biodistribution and pharmacokinetics of doxorubicin. Cancer 1992; 70(3): 58590 9. Carr BI, Iwatsuki S, Baron R, et al. Intrahepatic arterial cisplatinum and doxorubicin with or without lipiodol for advanced hepatocellular carcinoma (HCC): a prospective randomized study. Proc Annu Meet Am Soc Clin Oncol 1993; 12: A668. 10. Johnson PJ, Kalayci C, Dobbs N, et al. Pharmacokinetics and toxicity of intraarterial Adriamycin for hepatocellular carcinoma: effect of coadministration of lipiodol. Hepatology 1991; 13: 1207. 11. Nakao N, Kamino K, Miura K, et al. Recurrent hepatocellular carcinoma after partial hepatectomy: value of treatment with transcatheter chemoembolization. AJR 1991; 156: 11779. 12. Ngan H, Lai C, Fan S, et al. Transcatheter arterial chemoembolization in inoperable hepatocellular carcinoma: four year follow-up. J Vasc Interv Radiol 1996; 7: 4195. 13. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002; 359: 17349. 14. Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35(5): 116471. 15. Michels NA. Collateral arterial pathways to the liver after ligation of the hepatic artery and removal of the coeliac axis. Cancer 1953; 6: 708. 16. Maluccio MA, Covey AC, Ben Porat L, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2008; 19: 8629. 17. Takayasu K, Arii S, Ikai I, et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology 2006; 131: 4619. 18. Buijs M, Vossen JA, Frangakis C, et al. Nonresectable hepatocellular carcinoma: Long-term toxicity in patients treated with transarterial chemoembolization single-center experience. Radiology 2008; 249(1): 34654. 19. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46: 47481. 20. Poon RTP, Tso WK, Pang RWC, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol 2007; 5: 11008. 21. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol 2008; 31: 26980. 22. Atassi B, Lewandowski RJ, Kulik L, et al. Treatment of unresectable hepatocellular carcinoma using intra-arterial Y90 (TheraSphere): long-term follow-up. Presented at the Society of Interventional Radiology Annual Meeting 2006, Toronto, ON, Canada.
conclusion
HCC remains prevalent worldwide and is showing a steady rise in incidence in the western hemisphere. A high number of patients are in need for either local or systemic therapies. When disease is limited to the liver, a local-regional method of treatment such as embolization or ablation should be the initial treatment. In some cases, combining these methods of treatment or using them sequentially is appropriate. Sorafenib is the first systemic treatment to demonstrate a survival advantage in a large, randomized, controlled phase III study and is now approved by the FDA for patients with unresectable HCC. Future studies are to look into improving the outcome with sorafenib further by combining with other systemic therapies or local therapies. Other uses of systemic therapies, that is, adjuvant therapy, are also under investigation.
221
222
pre-operative diagnosis
Because previous surveys of ICC have failed to define highrisk groups (37), unlike the case for hepatocellular carcinoma, early detection of ICC patients remains difficult. Moreover, absence of early symptoms in most patients with ICC leads to delays in diagnosis. Some of the possible symptoms associated with ICC include abdominal pain, anemia, and weight loss (38). In contrast to patients with extrahepatic bile duct carcinoma, only 0% to 28% of patients with ICC present with obstructive jaundice (5,6,38). There are no definite tumor markers for ICC, although carcinoembryonic antigen (CEA) and carbohydrate antigen
223
(A)
(B)
(C) Figure 24.1 Morphologic classification of intrahepatic cholangiocarcinoma according to Liver Cancer Study Group of Japan. (A) Mass-forming type. (B) Periductalinfiltrating type. (C) Intraductal-growth type. Source : From Ref. 11.
199 (CA199) are frequently elevated and so used for both helping to confirm the diagnosis and post-operative monitoring for tumor recurrence. The sensitivity and specificity of CA199 for the diagnosis of ICC have been reported to be in the range of 70% to over 90% in patients with primary sclerosing cholangitis, using various cut-off points (3942), although a much lower sensitivity (53%) was reported in a population without primary sclerosing cholangitis (43). Low sensitivities for the diagnosis of ICC have also been reported for other serum markers that are sometimes used to identify extrahepatic bile duct carcinoma, for example, the serum levels of liver transaminases, alkaline phosphatase, and total bilirubin (5). Because ICCs are essentially adenocarcinomas, they often exhibit imaging findings similar to those of metastatic liver tumors from carcinomas of the gastrointestinal tract. Typically, the tumors are partially spherical in shape, with an irregular surface, and are almost hypovascular, with peripheral enhancement on contrast-enhanced CT, MRI, and ultrasound (4446). Gastroscopy, colonoscopy, CT with optional positron emission tomography (PET) of the thorax and abdomen should be done to differentiate ICCs from metastatic tumors originating from the gastrointestinal tract. Percutaneous tumor biopsy is not recommended if surgery is considered, because it may cause tumor seeding and complicate the surgical procedure (47). The diagnostic ability of newer imaging modalities, including FDG-PET, for ICC still remains under debate. One study reported high SUV values in all of the 10 cases examined (48), and another reported that the diagnostic accuracy of PET for lymph node metastasis from this type of tumor was 86%; figures that were higher than those reported for CT or MRI; also, higher SUV values were reported to be correlated with a poorer prognosis (49).
surgical strategy
As with hepatocellular carcinoma, the counterpart of ICC as a primary liver cancer, the only treatment that may offer a
chance of long survival in patients with ICC is surgery. In the natural history of unresected ICC, the median survival after diagnosis is less than 1 year (50,51) and most patients present at an advanced stage when they are no longer suitable candidates for curative resection. A study from the United States reported that complete tumor resection was possible in only 29 of 44 patients who were considered for curative resection (5). The prognosis after palliative resection is poor, with median reported survivals of between 2 and 3 months (50,51). No consensus has been established with regard to the criteria for surgery, because of the small number of patients in each reported series. However, based on the literature, it would seem that surgery should be offered to all patients with potentially resectable ICC, regardless of tumor stage. Some have claimed that positive lymph node metastasis detected on examination of frozen sections at laparotomy is a contraindication for tumor resection (3), whereas two reports have recommended surgery for patients with lymph node metastasis, given a solitary hepatic lesion (52) or less than two lymph node metastases (53). Surgery affords no survival benefit in patients with ICC with any extent of distant metastasis (15). Although multiple hepatic lesions have been shown to be correlated with a poor prognosis (6,5456), the indication for surgery in relation to the number of tumors remains unclear at present. There is also no established consensus with regard to the optimal surgical procedure for patients with ICC. A positive surgical margin has been shown to be associated with a poor prognosis (3,5,6,54,55) and tumor invasion along Glissons sheath is often observed (57,58), therefore extended anatomical hepatic resections would seem to be a more rational surgical procedure as compared with non-anatomical limited hepatic resections. However, the superiority of such a procedure has not yet been demonstrated. A recent study reported that under certain conditions, tumor resection with a minimal surgical margin may be reasonable (59). In patients with ICC
224
Figure 24.2 Impact of lymph node metastasis on the overall survival rate of patients with ICC who underwent tumor resection. N0 indicates patients without lymph node metastasis and N1 indicates those with lymph node metastasis. Source : From Ref. 11.
Table 24.1 Outcome After Liver Resection for Intrahepatic Cholangiocarcinoma in Literature
First author Kawarada (68) Cherqui (47) Schlinkert (66) Yamamoto (31) Pichlmayr (63) Nakeeb (9) Jan (67) Casavilla (54) Madariaga (55) Chen (38) Valverde (65) Inoue (3) Okabayashi (4) Weber (56) DeOliveira (5) Shimada (59) Paik (6) Year 1990 1995 1992 1992 1995 1996 1996 1997 1998 1999 1999 2000 2001 2001 2001 2007 2008 Country Japan France USA Japan Germany USA China USA USA Taiwan France Japan Japan USA USA Japan Korea n 11 14 6 10 32 9 41 34 34 138 30 52 60 33 44 47 97 1-year survival, % 59.3 53.7 64 67 33 86 63 68 74.9 3-year survival, % 34 44.4 36.6 34 40 17 22 36 35 45 51.8 5-year survival, % 34 33 44.4 44 26.8 26 35 14 36 29 40 40 31.1 Median survival, mo 14 12.8 22 12 19 28 37.4 23
with apparent invasion of the major portal pedicles or major hepatic veins, major hepatic resection should be considered. The decision on the appropriate surgical procedure must be made with reference to the functional liver reserve; an algorithm suggested by Makuuchi and colleagues (60) has been widely adopted for this purpose. Pre-operative portal vein embolization should be considered when the optimal surgical procedure is impossible based on the functional liver reserve (61). Some reports have recommended extrahepatic bile duct resection for MF-ICC, because the majority of this type of ICC shows biliary invasion (14,57,62). The reported incidence, from studies including at least 30 patients, of lymph node metastasis in surgically treated patients with ICC is as high as 18% to 40% (3,54,55,6365). Patients with lymph node metastasis have a poor prognosis; a
nation-wide surveillance conducted in Japan (n = 495) revealed 1-, 3-, and 5-year survival rates of 52.4%, 23.1%, and 15.6%, respectively (Fig. 24.2) (23). The prognostic benefit of lymph node dissection remains controversial. Some authors have demonstrated its usefulness in cases where the tumor is solitary (52,53) and when a limited number of lymph nodes are metastatic (53). On the other hand, Shimada and colleagues (16) contradicted the survival benefit of lymph node dissection, because it was often seen in patients treated without lymph node dissection that recurrent lymph node metastasis occurred not at the hilar site but at distant sites.
225
Figure 24.3 Overall survival rates of all patients with ICC who underwent tumor resection. Source : From Ref. 11.
U, significant by univariate analysis for overall survival; M, significant by multivariate analysis for overall survival.
According to a nation-wide survey conducted in Japan, the 1-, 3-, and 5-year survival rates in 1626 patients who underwent tumor resection for ICC were 70.5%, 43.8%, and 32.7%, respectively (Fig. 24.3) (23). The results of surgical treatment for ICC, most cases of which are accounted for by MF-ICC, are summarized in (Table 24.1 (36,9,31,38,47,5456,59,63,65 68). Median survival time ranged from 12 to 37 months, and the 5-year survival rate ranged from 14% to 44%; the wide range was probably caused by the small number of patients included in the studies. According to some studies, the pre-operative mortality rates ranged between 2% and 5%. The most common site of recurrence was the liver, followed in frequency by lungs, bones, peritoneum, adrenal glands, and kidneys (54,56). The prognostic factors in patients undergoing surgery for ICC proposed in the literature are listed in (Table 24.2 (3,5,6,9,54 56,65,67,69). The indicators of poorer prognosis proposed in these multiple reports include positive lymph node metastasis, positive surgical margin, multiple hepatic lesions, presence of vascular invasion, and a large tumor size. While a large tumor size and bilobar tumor location were identified as prognostic factors by univariate analysis in a number of studies, these could
not be confirmed as prognostic factors by multivariate analysis. Despite these suggested prognostic factors, the contraindications to surgery have not yet been fully elucidated.
adjuvant therapy
Because the prognosis after tumor resection alone is far from satisfaction, adjuvant therapy may be considered in some patients. There have been only a few reports of long-term survival with such therapy among patients with ICC (70,71). Moreover, there have been no reported randomized prospective trials of adjuvant therapy in these patients, although the CRUK BILCAP study of surgery versus surgery plus adjuvant gemcitabine continues to recruit in the United Kingdom. There have also been only a few anecdotal reports of chemotherapy for patients with recurrent or unresectable ICC, using 5-FU, cisplatin, epirubicin, gemcitabine, capecitabine, and cetuximab (7276). Further therapeutic trials are therefore warranted using recently developed treatment modalities or those that are developed in the future, including radiotherapy, immunotherapy, and chemotherapy with or without molecule-targeted drugs.
226
references
1. SEER Cancer Statistics Review 19732005 [database on the Internet]. U.S. National Institute of Health. [cited 2009/02/08]. Available from: http:// www.seer.cancer.gov/ 2. Cancer Information Service [database on the Internet]. National Cancer Center. [cited 2009/02/08]. Available from: http://ganjoho.jp/ 3. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000; 127: 498505. 4. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001; 92: 237483. 5. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245: 75562. 6. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008; 23: 76670. 7. Hammill CW, Wong LL. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance. J Am Coll Surg 2008; 207: 594603. 8. Kokudo N, Makuuchi M. Extent of resection and outcome after curative resection for intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am 2002; 11: 96983. 9. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 46373; discussion 735. 10. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999; 341: 136878. 11. Liver Cancer Study Group of Japan. The General Rules for the Clinical and Pathological Study of Primary Liver Cancer, 5th ed. Tokyo: Kanehara, 2008. 12. Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatol 2006; 45: 85667. 13. Sano T, Kamiya J, Nagino M, et al. Macroscopic classification and preoperative diagnosis of intrahepatic cholangiocarcinoma in Japan. J Hepatobiliary Pancreat Surg 1999; 6: 1017. 14. Yamanaka N, Okamoto E, Ando T, et al. Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 1995; 76: 244956. 15. Isaji S, Kawarada Y, Taoka H, et al. Clinicopathological features and outcome of hepatic resection for intrahepatic cholangiocarcinoma in Japan. J Hepatobiliary Pancreat Surg 1999; 6: 10816. 16. Shimada M, Yamashita Y, Aishima S, et al. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg 2001; 88: 14636. 17. Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg 2002; 89:152531. 18. Suh KS, Chang SH, Lee HJ, et al. Clinical outcomes and apomucin expression of intrahepatic cholangiocarcinoma according to gross morphology. J Am Coll Surg 2002; 195: 7829. 19. Tajima Y, Kuroki T, Fukuda K, et al. An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg 2004; 91: 99104. 20. Yeh CN, Jan YY, Yeh TS, et al. Hepatic resection of the intraductal papillary type of peripheral cholangiocarcinoma. Ann Surg Oncol 2004; 11: 60611. 21. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74108. 22. Martin R, Jarnagin W. Intrahepatic cholangiocarcinoma. Current management. Minerva Chir 2003; 58: 46978. 23. Liver Cancer Study Group of Japan. National Surveillance of Primary Liver Cancer in Japan, 17th Report. Kyoto: Media Planning, 2006. 24. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002; 2: 10. 25. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004; 40: 4727. 26. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999; 10 (Suppl 4): 30811.
27. Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 1991; 48: 3238. 28. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002; 89: 96270. 29. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002; 51 Suppl 6: VI1-9. 30. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001; 12: 95964. 31. Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004; 95: 5925. 32. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol 2007; 102: 101621. 33. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a populationbased case-control study. Clin Gastroenterol Hepatol 2007; 5: 12218. 34. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36: 3217. 35. Dayton MT, Longmire WP, Jr., Tompkins RK. Carolis disease: a premalignant condition? Am J Surg 1983; 145: 418. 36. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007; 120: 63841. 37. Yamanaka N, Takaya Y, Oriyama T, et al. Hepatoprotective effect of a nonselective endothelin receptor antagonist (TAK-044) in the transplanted liver. J Surg Res 1997; 70: 15660. 38. Chen MF, Jan YY, Jeng LB, et al. Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 1999; 6: 13641. 39. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 199 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 1993; 68: 8749. 40. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000; 31: 711. 41. Levy C, Lymp J, Angulo P, et al. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50: 173440. 42. Charatcharoenwitthaya P, Enders FB, Halling KC, et al. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48: 110617. 43. Patel AH, Harnois DM, Klee GG, et al. The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 2000; 95: 2047. 44. Miura F, Okazumi S, Takayama W, et al. Hemodynamics of intrahepatic cholangiocarcinoma: evaluation with single-level dynamic CT during hepatic arteriography. Abdom Imaging 2004; 29: 46771. 45. Kim SJ, Lee JM, Han JK, et al. Peripheral mass-forming cholangiocarcinoma in cirrhotic liver. AJR 2007; 189: 142834. 46. Chen LD, Xu HX, Xie XY, et al. Enhancement patterns of intrahepatic cholangiocarcinoma: comparison between contrast-enhanced ultrasound and contrast-enhanced CT. Br J Radiol 2008; 81: 8819. 47. Cherqui D, Tantawi B, Alon R, et al. Intrahepatic cholangiocarcinoma. Results of aggressive surgical management. Arch Surg 1995; 130: 10738. 48. Kim YJ, Yun M, Lee WJ, et al. Usefulness of 18F-FDG PET in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging 2003; 30: 146772. 49. Seo S, Hatano E, Higashi T, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography predicts lymph node metastasis, P-glycoprotein expression, and recurrence after resection in mass-forming intrahepatic cholangiocarcinoma. Surgery 2008; 143: 76977. 50. Chu KM, Fan ST. Intrahepatic cholangiocarcinoma in Hong Kong. J Hepatobiliary Pancreat Surg 1999; 6: 14953. 51. Kim HJ, Yun SS, Jung KH, et al. Intrahepatic cholangiocarcinoma in Korea. J Hepatobiliary Pancreat Surg 1999; 6: 1428. 52. Uenishi T, Kubo S, Yamazaki O, et al. Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases. J Hepatobiliary Pancreat Surg 2008; 15: 41722.
227
228
25
Transplantation for hilar cholangiocarcinoma Julie K. Heimbach, Charles B. Rosen, and David M. Nagorney
desmoplastic tumor which leads to the inability to obtain an adequate number of cells to make a definitive diagnosis. Fluorescent in situ hybridization (FISH) is a cytologic technique which allows for the detection of aneuploidy in epithelial cells. In particular, FISH polysomy (two or more chromosomes duplicated) identifies another 20% of patients with CCA missed by conventional cytology while maintaining a specificity of 100% (13). Despite the use of advances cytologic techniques, the ability to make a timely and accurate diagnosis remains sub-optimal. The primary therapy for hilar CCA is surgical resection. There is no effective systemic therapy, though radiation may provide palliation and in exceptional cases, prolonged survival. Outcomes for resection of CCA are limited by the inability to obtain an accurate early diagnosis as many patients present with unresectable lesions. An R0 resection is possible in 70% to 80% of attempted resections and in most series, 5-year survival is approximately 25% to 30% (1419). Recent resectional approaches for CCA have included techniques such as pre-operative portal vein embolization to induce hypertrophy in the anticipated-remaining hepatic remnant for prevention of liver failure and techniques of vascular reconstruction to expand the potential for R0 resectability. Yokoyama et al. have described an extensive experience with pre-operative portal vein embolization (PVE) in 240 patients, in which selective arterial embolization has been used to improve response to PVE (20). Though the authors report a decrease in operative mortality from 21.9% to most recently (after 2001) 1.6% following PVE, they do not describe the impact of PVE on long-term survival following resection for CCA. A large series from Johns Hopkins also published in 2008 review the outcomes of 564 patients with CCA (50% hilar CCA) and reports on predictors of improved outcome following resection (21). Favorable prognostic factors included patients resected in a more recent time period (after 1995), negative margins, well-differentiated tumors, and negative lymph nodes. For patients with hilar CCA, the median survival was 30 months with 30% 5-year survival. Three other recent single-center series have been reported in the last year and all report similar survival outcomes of 30% to 40% at 5 years and included the use of extended hepatic resection with portal vein reconstruction (2224). When analysis is restricted to only to those patients with negative resection margins with or without portal vein reconstruction, a 5-year survival of 45% was reported by Hemming et al. (24). Similar improved outcomes with advanced techniques have also been reported by Neuhas et al. (25). All of these data are single-center non-randomized reports with outcomes compared to historical controls.
background
Cholangiocarcinoma (CCA) is a malignancy arising from the bile duct epithelium which has a very poor prognosis. The incidence in the United States is approximately 1.2 in 100,000, though it is far higher in Eastern Europe and Asia, and it appears to be increasing worldwide (13). Although CCA can occur anywhere along the intra- or extra-hepatic bile ducts, the most common location is at the hilar region, involving the confluence of the right and left ducts (60%) (4,5). While most patients develop CCA de novo, risk factors for the development of CCA relate to chronic inflammation of the biliary tree. In Western countries CCA is most often associated with Primary Sclerosing Cholangitis (PSC), though other risk factors include choledochal cysts, hepaticolithiasis, and parasitic infections including Clonorchis sinensis and Opisthorchis viverrini. The prevalence of CCA in patients with PSC is 5% to 15% (6). Establishing a timely diagnosis of hilar CCA is challenging. The tumor is a desmoplastic lesion which typically grows along the bile duct rather than in a radial diameter which limits early detection by cross-sectional imaging. Endoscopic brushing and biopsy are often negative even in of the presence well-established disease, and the tropism for bile producing growth in a longitudinal fashion often leads to the lack of a mass lesion, even in the face of biliary obstruction (7). Eventually, tumor growth becomes independent of bile and mass lesions develop, which are demonstrable by cross sectional imaging. Direct cholangiography (endoscopic retrograde cholangiography and percutaneous transhepatic cholangiogram) best characterizes the site, extent, and configuration of ductal CCA. However, the use of imaging modalities, including high-resolution CT and MRI, are also important for the diagnosis of CCA by providing additional information regarding adjacent structures which differentiate CCA from benign counterparts. While contrast-enhanced MRI and magnetic resonance cholangio-pancreatography have improved the diagnostic sensitivity and specificity of imaging, due to the biologic principles of the tumor, early diagnosis remains a significant problem (810). A promising technique in obtaining a tissue diagnosis may be the use of Spyglass cholangioscopy, which allows biopsy if bile duct lesions under direct endoscopic visualization. Although this technique may prove to be useful for diagnostic purposes, it will not enhance accuracy of pre-operative tumor staging (11). Thus far, no molecular markers in bile have proven reliable in establishing a more timely diagnosis. The serum marker CA 199 has not been shown to be accurate enough for screening. However, for patients with PSC and a malignant appearing stricture, serum CA 199 >130 U/mL has a sensitivity of 79% and a specificity of 98% (12). Conventional cytology has a sensitivity of only 20% to 40%, though the specificity is 100% (13). The limitation of conventional cytology is the paucicellular nature of a
229
Hilar cholangiocarcinoma Mayo clinic protocol Selected patients with unresectable hilar cholangiocarcinoma (began in 1993) Neoadjuvant radiation and chemotherapy External beam radiotherapy with bolus 5-FU Brachytherapy with protracted capcitabine
167 patients
Irradiation + 5-FU 12 deaths/disease progression 2 transplanted elsewhere 10 receiving neoadjuvant therapy 27 (19%) staged positive 2 awaiting transplantation 2 transplanted elsewhere 1 death 75 decease donor 35 living donor 1 domino donor
Staging operation to rule-out metastases or local extension of tumor precluding complete resection of tumor
Orthotopic liver transplantation Figure 25.1 Combined chemoradiotherapy followed by liver transplantation protocol for patients with unresectable hilar CCA.
Figure 25.2 Results of a combined chemoradiotherapy followed by liver transplantation protocol for hilar CCA.
230
separating hilar structures. Late effects of tissue injury from radiation therapy, which may be broadly considered a result of fibrosis and chronic ischemic injury, are also of concern. A recent retrospective analysis of 68 patients who underwent neoadjuvant chemoradiotherapy followed by OLT showed increased incidence of late vascular strictures (arterial and portal vein) when compared to controls undergoing OLT for other indications (40). The late vascular complication rate was 40%, though patient and graft survival did not differ between the groups. In most patients, these complications were manageable with a percutaneous endovascular approach. The key findings from this analysis are that arterial interposition grafts should be used to replace the irradiated native artery in all cases of deceased donor transplantation. Additionally, late strictures of the portal vein (and non-replaced arteries as in the case of a living donor transplant) should be anticipated and may be amenable to endovascular interventions.
organ allocation
The findings from the Mayo Clinic and Nebraska protocols as well as the historical data for OLT without adjuvant therapy were carefully considered by the Model for End Stage Liver Disease (MELD) Exception Study Group, which was assembled to consider standardization of diagnoses which commonly led to MELD exception scores (41). The conclusion of this group was to recommend national standardization of MELD score exceptions for patients with early stage, unresectable hilar CCA provided they are enrolled in an approved protocol which includes neoadjuvant therapy, and standard inclusion (i.e., diagnostic), and exclusion criteria. The group proposed an allocation policy applied nationally similar to that currently granted for HCC, which is based on a 10% risk of mortality subject to readjustment every three months. Currently, organ allocation in the United States for hilar CCA, as well as other diagnoses which require MELD exception, varies considerably by each region. It is possible that a national policy for MELD exceptions for common diagnoses may be considered in the future.
conclusions
Excellent outcomes can be achieved with neoadjuvant chemoradiotherapy followed by OLT for selected patients with early stage hilar CCA. Obtaining a timely diagnosis remains a key challenge regardless of whether resection or transplantation is being considered. As with hepatocellular carcinoma, it is necessary to determine the risk for disease progression following neoadjuvant therapy for patients awaiting transplantation. Given the severe donor organ shortage, continued analysis of outcomes in order to identify patients not likely to gain benefit from this aggressive protocol is necessary. In light of the results achievable with the combined neoadjuvant chemoradiotherapy protocol, however, a standardized approach to organ allocation which is applied nationally, as for HCC, is necessary and will hopefully be forthcoming. Finally, with application of the protocol across multiple centers, the key principles, such as multi-disciplinary approach, pre-transplant staging to ensure inclusion of only those without metastasis, replacement of irradiated vessels when possible as well as monitoring for postoperative vascular complications, must be highlighted.
100 90 80 70 60 50 40 30 20 10 0 0
Figure 25.3 KaplanMeier analysis of survival for patients undergoing transplantation after completion of neoadjuvant therapy at Mayo Clinic.
231
key points
1. The diagnosis of hilar CCA remains a challenge (level II evidence). 2. Based on non-randomized analysis (level II evidence), neoadjuvant chemoradiotherapy followed by liver transplantation for patients with early stage unresectable hilar CCA offers excellent survival. 3. Percutaneous, open, or transgastric biopsy of the primary tumor should not be performed due to the risk of tumor seeding into the peritoneal cavity (level II). 4. Radiation injury may lead to hepatic artery thrombosis and late vascular strictures. Native hepatic arteries should be replaced by arterial conduits in deceased donor transplantation to reduce early thrombosis. Late strictures may be amenable to endovascular treatment (level III). 5. Toxicity of the neoadjuvant therapy is signicant, and a multi-disciplinary approach including commitment from radiology, radiation oncology, medical oncology, hepatology, and hepatobiliary/ transplantation surgery is necessary.
references
1. Shaib Y, el-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004; 24: 11525. 2. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastro 2008; 24: 34956. 3. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis. Curr Opin Gastro 2008, 24: 37783. 4. Bismuth H, Castaing D. Hepatobiliary malignancy. London: Edward Arnold, 1994. 5. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999; 341: 136879. 6. Knan Sa, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002; 51 (Suppl 6): VI 19. 7. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol 2007; 47: 45475. 8. Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of cholangiocarcinoma. Semin Liv Dis 2004; 24(2): 15564. 9. Braga HJ, Imam K, Bluemke DA. MR imaging of intrahepatic cholangiocarcinoma: use of ferumoxides for lesion localization and extension. AJR 2001; 177: 11114. 10. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreaticographic findings. Am J Gastro 2000; 95: 43240. 11. Chen YK, Pleaskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorder: a clinical feasibility study. Gastrointest Endosc 2007; 65(6): 83241. 12. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19-9 in predicting cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50: 173440. 13. Moreno Luna LE, Kipp B, Halling et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 2006; 131: 106472. 14. Rea D, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 3: 45161. 15. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 46373; discussion 4735.
16. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 1996; 224: 62838. 17. Kosuge T, Yamamoto J, Shimada K, et al. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 1999; 230: 66371. 18. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg 2001; 234: 2706. 19. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001; 234: 50717; discussion 5179. 20. Yokoyama Y, Nagina M, Nishio H, et al. Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization. J Hepatobiliary Pancreat Surg 2007; 14: 44754. 21. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 5: 75562. 22. Miyazaki M, Kato A, Ito H, et al. Combined vascular resection in operative resection for hilar cholangiocarcinoma: does it work or not? Surgery 2007: 5: 5818. 23. Hasegawa S, Ikai I, Fujii H, et al. Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications. World J Surg 2007; 31: 125663. 24. Hemming AW, Kim RD, Mekeel KL, et al. Portal vein resection for hilar cholangiocarcinoma. Am Surg 2006; 72: 599605. 25. Neuhaus P, Joans S. Surgery for hilar cholangiocarcinomathe German experience. J Hepatobiliary Pancreat Surg 2000; 7(2):1427. 26. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 1993; 166: 76871; discussion 7712. 27. Jonas S, Kling N, Guckelberger O, et al. Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma. First long-terms results. Transpl Int 1998; 11 (Suppl 1): S2068. 28. Loinaz C, Abradelo M, Gomez R, et al. Liver transplantation and incidental primary liver tumors. Transplant Proc 1998; 30: 33012. 29. Iwatsuki S, Todo S, Marsh JW, et al. Treatment of hilar cholangiocarcinoma (Klatskin Tumors) with hepatic resection or transplantation. J Am Coll Surg 1998;187: 35864. 30. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69: 16337. 31. Shimoda M, Farmer DG, Colquhoun SD, et al. Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 2001; 12: 102333. 32. Robles R, Figueras J, Turrion VA, et al. Liver transplantation for hilar cholangiocarcinoma: Spanish experience. Transpl Proceedings 2003; 35: 18212. 33. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transpl 2005; 11: 14126. 34. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000; 6: 30916. 35. Sudan D, DeRoover A, Chinnakotia S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transpl 2002; 2: 7749. 36. Hasson Z, Gores GJ, Rosen CB, et al. Preliminary experience with liver transplantation in selected patients with unresectable hilar cholangiocarcinoma. Surg Oncol Clin N Am 2002; 11: 90921. 37. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 2017. 38. Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006; 12: 17037. 39. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008; 12(1): 11722. 40. Mantel HTJ, Rosen CB, Heimbach JK, et al. Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl 2007; 12: 137281. 41. Gores GJ, Gish RG, Sudan D, et al. MELD Exception Study Group. Model for end-stage liver disease (MELD) exception for cholangiocarcinoma or biliary dysplasia. Liver Transpl 2006; 12: S957.
232
Jan P. Lerut, Eliano Bonaccorsi-Riani, Giuseppe Orlando, Vincent Karam, Ren Adam, and the ELITAELTR Registry a
with intracellular vascular lumens containing red blood cells (Fig. 26.2A and B). In contrast to HAS, the hepatic acinar landmarks are better preserved. HEHE originates from endothelial cells which explains positive immunohistochemistry (IHC) for factor VIII-related antigen and for the endothelial markers CD31 and CD34. Ultrastructural examination also shows characteristic features of endothelial cells, such as a basal lamina, pinocytic vesicles, and WeibelPalade bodies (24). The clinical manifestations of HEHE are unspecific, varying from totally asymptomatic to hepatic failure (Table 26.1). The malignant potential of HEHE often remains unclear in each individual patient. Based on the analysis of the ELITAELTR study, the most frequent symptoms are non-specific upper abdominal or epigastric discomfort or pain, weakness, general malaise, and jaundice. About 20% of patients are asymptomatic and 10% present with pulmonary symptoms (Table 26.1). Hepato-splenomegaly (50%) and weight loss (20%) are the most frequent clinical signs; portal hypertension may be caused by tumor compression or venous infiltration (36). Anicteric cholestasis and cytolytic activity are frequently present (60% and 40%, respectively). Serum tumor markers are normal in the absence of accompanying liver disease. Radiological investigation identifies two different patterns of HEHE: the early peripheral and nodular, usually bilobar type (peripheral pattern), and the later confluent type (diffuse pattern) with eventual invasion of the greater vessels (Fig. 26.3A). Focal calcifications are present in 20% of tumors. Angiography reveals only moderate vascularization with displacement of marginal vessels (Fig. 26.3B and C). Scintigraphic and FDGPET imaging plays an important role in the staging of the disease, especially in view of later LT and also in view of the early detection of recurrent disease (78). Complete assessment of these patients is mandatory to exclude other, especially thoracic, disease localization. In doubtful cases thorascopic lung and/or pleural biopsy should be performed in order to exclude the often frequent thoracic involvement. Definitive diagnosis, frequently based on a high degree of suspicion, can be made by associating radiological and clinical features, such as occurrence in a young adult (usually female), the contrast between numerous intrahepatic (often calcified) tumors, the overall condition of the patient, and finally the longstanding clinical history. The diagnosis can only be confirmed by pathological examination of appropriate, surgically obtained biopsy material. The treatment algorithm of HEHE was till recently far from standardization. The literature review, including 13 very small
Vascular hepatic tumors form a continuum going from the completely benign hemangioma (HA) to the very aggressive hemangiosarcoma (HAS). Sometimes due to their difficult differential diagnosis and the rarity of the more malignant varieties, and also to the limited worldwide experience with liver resection and transplantation (LT) for these tumors, these vascular lesions are often neglected or misdiagnosed and their therapeutic management algorithm is unclear. The rarity of malignant vascular liver lesions is well demonstrated by the data of the European Liver Transplant Registry (ELTR). During the period January 1988 to June 2007, 12% (8278) of all European LT were performed because of hepatobiliary tumors, but of these, only 125 (0.1%) were done because of malignant vascular diseases. In this chapter hepatic epithelioid hemangioendothelioma (HEHE), infantile hemangioendothelioma (HIHE), and hemangiosarcoma (HAS) will be discussed, based on a recent literature review and of the experience gathered by the audited ELITAELTR during the period 1988 to 2004 (1). The information obtained from both sources allows a more clear insight into diagnosis and treatment of these rare liver diseases. For the sake of completeness, benign Nodular Regenerative Hyperplasia (NRH) is also included in this chapter because of its vascular etiopathogenesis. Hemangioma and lymphangioma are discussed in a separate chapter dealing with benign liver tumors.
The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA); see www.eltr.org.
233
(A)
(B)
Figure 26.1 Intraoperative view of 7.6 kg heavy HEHE responsible for IVC syndrome and supine dyspnea (A). Characteristic gross appearance of a HEHE hepatectomy specimen showing multiple fibrous masses with zoning phenomenon (B).
(A)
(B)
Figure 26.2 Histological features of HEHE at the periphery (A) and in the center (B) of the lesion. Source: C. Sempoux, Dept. of Pathology.
(5 pts) series and three reviews, lacks detailed data analysis, and most importantly, long-term follow-up. The published experience does not allow comparison of results of untreated and of surgically and medically treated patients. The place of LT has especially been questioned in view of well-documented spontaneous resolution, long-term survival, the high incidence of extra-hepatic disease (up to 45%) (Table 26.2), the lack of predictive clinical or histological criteria, and finally the high incidence (up to 33%) of, sometimes even very late, recurrent allograft disease (6). The largest institutional series, coming from Pittsburgh and containing 16 patients, showed that LT offers 5-year overall and disease-free survival rates of 71% and 60%, respectively (9). The Mehrabi review indicates that the treatment of choice of HEHE is total hepatic resection (3). In this literature review, the 5-year survival rates of LT, partial liver resection (reported in only very few patients), local or systemic chemo- and radiotherapy (CHTH) and treatment abstention were 55%, 75%, 30%, and 0%, respectively. Partial liver resection is not a logical treatment because HEHE is nearly always a multinodular and bilobar disease. Indeed the examination of the total hepatectomy specimens analyzed in the ELITAELTR study showed
234
(A)
(B)
(C)
Figure 26.3 CT-scan of HEHE showing the initial peripheral nodular (A) and the later confluent patterns of the disease (B). Angiography confirming the avascular nature and vascular displacement (C).
Extrahepatic localization Lung Mediastinum Peritoneum Spleen Femoral vein Brain and bone Omentum
bilobar disease in 96% of cases; 86% of the specimen contained more than 15 tumor nodules (Table 26.2). Moreover, several reports documented disease recurrence, or LT because of recurrent HEHE after partial resection; fortunately, pre-transplant liver surgery doesnt seem to impair survival after LT (6). The assessment of non-surgical treatments, such as radiotherapy, local tumor destruction, hormonotherapy, systemic or locoregional CHTH, trans-arterial embolization, and chemoembolization, is even more difficult because of the lack of uniform treatment modalities and of long-term follow-up (3). The ELITAELTR study is the largest worldwide, detailed long-term study in relation to HEHE (1). This study collected 59 European patients from 32 centers. The follow-up from diagnosis is 104 72 months (median of 93 months) and from LT 83 55 months (median of 79 months). The study validated the place of LT in the treatment of this disease and 5 and 10 years post-transplant survival rates are 83% and 74%, respectively, with 5 and 10 years recurrence-free survival rates of 82% and 64%, respectively (Fig. 26.4A and B). This study confirms that medical and/or surgical pre-LT treatment (present in 30% of pts), invasion of regional lymph node (present in 33% of pts) and of (limited) extrahepatic disease (present in 17% of pts) are not formal contraindications to LT. Combined micro- and macrovascular invasion (present in
49% of pts) is the only parameter which significantly influences outcome after LT. Mitotic index and cellular pleiomorphism are other major histological prognostic criteria reflecting more aggressive tumor behavior (10). Their influence on patient survival could not be analyzed in the ELITA ELTR study due to the impossibility of obtaining central pathology recording. The recently published UNOS data reporting 128 patients with a median follow-up of 24 months go in the same direction; 1- and 5-year patient survival rates were 80% and 64%, respectively (11). Recurrent disease after (partial and total) hepatectomy should be treated aggressively as prolonged, sometimes even disease-free, survival can be achieved (1,3). The role of re-LT in the treatment of recurrent allograft disease is unclear as only one single case has been reported (5). It is conceivable that in view of the high incidences of extrahepatic disease localization, and of recurrence in- and outside the allograft (22% in the ELITAELTR study) (Table 26.3), a more radical approach combining total hepatectomy and antiangiogenic therapy, such as use of VEGF-antibodies, -interferon and rapamycin could be of value in the treatment of HEHE (1,12). Rapamycin is of particular interest in this context as this drug is nowadays frequently used not only as a renal sparing but also as an anti-tumoral immunosuppressive drug in liver transplant recipients. Such an approach, combined with a better study of the molecular and genetic markers based on tumor biology, will be of great assistance in further improving outcome, monitoring efficacy of emerging neo- and adjuvant treatments and in recognizing the aggressive subtypes of HEHE (3,5,1315).
235
Patient survival after liver transplantation for epithelioid hemangioendothelioma: 59 patients 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 yrs 85% 3 4 yrs 83% 4 5 yrs 83% 5 6 yrs 80% 7 yrs 75% 6 8 yrs 72% 7 9 yrs 72% 8 10 yrs 72% 9 10 Survival % 2 yrs 1 yr 86% 93%
4 yrs 41
5 yrs 36
6 yrs 31
7 yrs 26
8 yrs 18
9 yrs 14
10 yrs 13
Disease free survival after liver transplantation for epithelioid hemangioendothelioma: 52 patients 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 yrs 85% 3 4 yrs 85% 4 5 yrs 82% 4 yrs 36 5 6 yrs 79% 5 yrs 31 7 yrs 76% 6 yrs 27 6 8 yrs 68% 7 yrs 23 7 9 yrs 64% 8 yrs 16 8 10 yrs 64% 9 yrs 11 10 yrs 11 9 10 Survival % 1 yr 2 yrs 90% 87%
Figure 26.4 Overall patient survival of HEHE after liver transplantation in the ELITA-ELTR study (A). Recurrent-free survival in the same patient cohort of 59 patients (B).
236
Table 26.3 Recurrence of HEHE after liver transplantation in the ELITAELTR series
Tumor recurrence in 14 (23.7%) patients: 5 patients still alive Delay posttransplantation Lung 45 35 mo 5 49 mo (range 698) AWD 59 (ChTh), 84 (Res) mo DWD 23,41,73 mo AWD 112 mo (Res, RF, ChTh) 211 and 212 mo DWD 15,73 (Res, ChTh), 79 mo (Burkitt) DWD 9 mo DWD 4 mo (ChTh) DWD 19, 20 mo
Liver
1 1 2
(A)
(B)
(C)
(D)
Figure 26.5 Macro- and microscopic features of HIHE. The lesion can be either solitary (A) or multiple (B). Type 1 HIHE is made of multiple vascular channels with a single layer of regular endothelial cells (C) whereas in type 2 HIHE more atypia are observed (D). Source: S. Gosseye, Dept. of Pathology.
237
35.3 22.6 years Children 4.4 years (112) 14 males and 8 females Six children <15 years 15 5 1 1 1 1 1 1 3 2 1 1
Figure 26.6 CT-scan of HAS showing a diffuse nodular infiltration of the liver.
(A)
(B)
(C)
Figure 26.7 HAS. Macroscopy showing a diffuse spongy tumoral mass (A); microscopy showing the development of cavitary space (B) because of the sinusoidal progressive growing of tumoral cells destroying the liver cell plates (C). Source: J. Rahier, Dept. of Pathology.
238
Survival function 1.0 0.8 Cum survival 0.6 0.4 0.2 0.0 0 5 10 15 Postoperative months 20 25
investigation shows pre-sinusoidal portal hypertension in association with a patent portal vein. Various systemic diseases are known to occur in association with NRH, such as primary biliary cirrhosis, BuddChiari syndrome, hemorraghic hereditary teleangiectasia or Rendu OslerWeber disease, lympho- and myeloproliferative disorders, collagen-vascular diseases, congenital and acquired hepatic macrovascular abnormalities, as well as exposure to toxins, such as azathioprine and some chemotherapeutic agents. Familial cases of NRH occurring without underlying or associated systemic disease have been described (26). These forms have a poor clinical course and are often associated with progressive renal failure. In relation to LT, it should be noted that recurrent allograft NRH has been reported, that NRH has been reported as a complication of chronic immunosuppression using azathioprine, leading even to re-LT, and NRH has been described in the context of living donor liver transplantation using smallfor-size grafts. Also, NRH and obliterative portal venopathy have been documented in recipients transplanted for biliary tract disease complicated with severe non-cirrhotic portal hypertension (2729). Six patients with NRH have been reported to the ELTR. Four had favorable outcomes; two died in 20 and 42 months, respectively, post-transplantation due to cardiac failure. Three patients had to be treated prior to transplantation because of bleeding esophageal varices; three presented with cholestatic cirrhosis. One patient had a previous kidney transplant. Four larger series and some case reports describing successful LT for this condition have been reported in literature (26,30).
conclusion
Due to their scarcity, difficulties in diagnosis, as well as lack of consensus around treatment of vascular tumors of the liver, there is no universally accepted standard of care for these patients. The recent review of the literature and of the audited European Liver Transplant Registry data have permitted some clarification of the therapeutic algorithms for these lesions. One should always have a high degree of suspicion in relation to these lesions which may have an extremely divergent clinical
Figure 26.8 Overall patient survival of HAS after liver transplantation in the ELITAELTR study.
(A)
(B)
Figure 26.9 Microscopic features of NRH on a HE section (A) and reticulin stain (B). Source: C. Sempoux, Dept. of Pathology.
239
references
1. Lerut JP, Orlando G, Adam R, et al. The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: report of the European liver transplant registry. Ann Surg 2007; 246: 94957. 2. Ishak K, Goodman Z, Stocker J. Tumors of the liver and intrahepatic bile ducts. Atlas of Tumor Pathology. Third series, fascicle 31 edn. Washington: Armed Forces Institute of Pathology, 1999: 282307. 3. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 2006; 107: 210821. 4. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 56282. 5. Demetris AJ, Minervini M, Raikow RB, et al. Hepatic epithelioid haemangioendothelioma biological questions based on pattern of recurrence in an allograft and tumor immunophenotype. Am J Surg Pathol 1997; 21: 26370. 6. Lerut JP, Orlando G, Sempoux C, et al. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation. Transpl Int 2004; 17: 20207. 7. Nguyen BD. Epithelioid haemangioendothelioma of the liver with F-18 FDG PET imaging. Clin Nucl Med 2004; 29: 82830. 8. Lin E, Agoff N. Recurrent hepatic epithelioid hemangioendothelioma: detection by FDG PET/CT. Clin Nucl Med. 2007; 32: 94951. 9. Madariaga JR, Marino IR, Karavia DD, et al. Long-term results after liver transplantation for primary hepatic epithelioid haemangioendothelioma. Ann Surg Oncol 1995; 2: 48387. 10. Kelleher MB, Iwatsuki S, Sheahan Dg. Epitheloid haemangioendothelioma of the liver. Clinicopathological correlation of 10 cases treated by orthotopic liver transplantation. Am J Surg Pathol 1988; 89: 9991008. 11. Rodriguez JA, Becker NS, OMahony CA, Goss JA, Aloia TA. Long-term outcomes following liver transplantation for hepatic hemangioendothelioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg 2008; 12: 1106. 12. Kayler LK, Merion RM, Arenas JD, et al. Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B. Transplantation 2002; 74: 12830. 13. Theurillat JP, Vavricka SR, Went P, et al. Morphologic changes and altered gene expression in an epithelioid hemangioendothelioma during a tenyear course of disease. Pathol Res Pract 2003; 199: 16570. 14. Calabr L, Di Giacomo AM, Altomonte M, et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferonalpha: is there room for novel anti-angiogenetic treatments? J Exp Clin Cancer Res 2007; 26: 14550. 15. Miller MA, Sandler AD. Elevated plasma vascular endothelial growth factor levels in 2 patients with hemangioendothelioma. J Pediatr Surg 2005; 40: 179. 16. Lopez-Terrada DL, Finegold MJ. Liver tumors. In: Walker AW, Durie PR, Hamilton JR, Walker-Smith JA, Watkins J, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, 5th edn. St. Louis: CV Mosby, 2008: 91126. 17. Selby DM, Stocker J Th, Waclawiw MA, et al. Infantile hemangioendothelioma of the liver. Hepatology 1994; 20: 3945. 18. Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 1999; 34: 98106. 19. Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol 2004; 35: 2009. 20. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 2007; 42: 628. 21. Maluf D, Cotterell A, Clark B, et al. Hepatic angiosarcoma and liver transplantation: case report and literature review. Transplant Proc 2005; 37: 219599. 22. Saleh HA, Tao LC. Hepatic angiosarcoma:aspiration biopsy cytology and immunocytochemical contribution. Diagn Cytopathol 1998; 18: 20811. 23. Husted TL, Neff G, Thomas MJ, Gross TG, et al. Liver transplantation for primary or metastatic sarcoma to the liver. Am J Transplant 2006; 6: 3927. 24. Weitz J, Klimstra DS, Cymes K, et al. Management of primary liver sarcomas. Cancer 2007; 109: 13916.
appendix
Recommended grading of categories of evidence Ia: Ib: IIa: IIb: III: evidence from meta-analysis of randomized controlled trials evidence from at least one randomized controlled trial evidence from at least one controlled study without randomization evidence from at least one other type of quasiexperimental study evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and casecontrol studies evidence from expert committee reports or opinions and/or clinical experience of respected authorities
IV:
Recommended strengths of management recommendation A. directly based on category I evidence B. directly based on category II evidence or extrapolated recommendation from category I evidence C. directly based on category III evidence or extrapolated recommendation from category I or II evidence D. directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence
240
241
27
introduction
While practicing in Hong Kong in 1930, Digby drew attention to a condition which was subsequently known as recurrent pyogenic cholangitis by reporting on eight cases of common duct stones of liver origin (1). The term Recurrent Pyogenic Cholangitis (RPC) was used by Cook et al. in 1954 when they reported their experience with the condition in a series of 90 patients (2). The synonyms associated with this condition include Asiatic cholangiohepatitis, oriental cholangiohepatitis, Hong Kong Disease (3), Chinese biliary obstruction syndrome (4), and primary cholangitis (5). This condition is commonly seen in Chinese living in Canton and Hong Kong but is not restricted to the Chinese in the Orient since it also occurs in Chinese immigrants in Malaysia, Singapore, North America, and Australia (68). RPC is also common in Japanese in Japan and Taiwanese in Taiwan. Although rare, RPC has also been reported to afflict occidentals (9,10).
pathogenesis
In RPC the gallstones found within the biliary system are calcium bilirubinate stones or pigmented calcium stones. Calcium bilirubinate stones are prevalent in Asia and are very rare in Europe and the United States. In addition to the presence of these friable concretions of various shapes and sizes within the biliary tree, the bile is often muddy in consistency and contains numerous fine particles of calcium bilirubinate. Biochemical analysis of these stones revealed a bilirubin content of 40.2% to 57.1% and a cholesterol content of 2.9% to 25.6%. This differs greatly from cholesterol stones, which are common in Europe and the United States, which contain >96% of cholesterol in pure cholesterol stone, and >71.3% in mixed cholesterol stone but the bilirubin content is only 0.02% to 5.0% (11). The peculiarity of the formation of calcium bilirubinate stones in RPC has been ascribed to the high incidence of bile being infected with Escherichia coli (E. coli). In man, the major portion of bilirubin is excreted in bile as bilirubin glucuronide. In the presence of -glucuronidase, bilirubin glucuronide is hydrolyzed into free bilirubin and glucuronic acid. Normally, calcium is secreted into bile and when it combines with the carboxyl radical of free bilirubin, insoluble calcium bilirubinate is formed. Normal bile is free of -glucuronidase activity, whereas bile infected with E. coli has intense -glucuronidase activity. Bile calcium content increases in the presence of biliary tract inflammation and this coupled with the increased hydrolysis of bilirubin glucuronide by the -glucuronidase from E. coli gives rise to the multiple stones formation classically seen in RPC (11). There are two types of pigmented stones, black, and brown. The infected type seen in RPC is the brown pigment stone. The postulated port of entry for the micro-organisms of bowel origin is via the portal vein from an attack of enteric
242
(A)
(B)
Figure 27.1 (A) Magnified view of Clonorchis sinensis (12.5). (B) Numerous Clonorchis removed from the CBD of one patient.
of bilirubin glucuronide to free bilirubin and glucuronic acid by the bacterial -glucuronidase present in infected bile. The free bilirubin then conjugates with calcium in the bile to form the typical calcium bilirubinate stones of RPC. In Hong Kong, RPC is no longer seen in the younger generation born and bred in modern-day Hong Kong. Young patients, in their 30s, who present to our institution with RPC are invariably immigrants from China. We suspect that the much better social and economic conditions of modern-day Hong Kong have played a role in eradicating the condition (15). The reduced incidence of gastroenteritis, the inabilility of the enteric organism, which gained entry via the portal blood, to establish itself within the liver parenchyma due to better host defense from an improved high protein, low carbohydrate diet and possibly the fact that less Chinese herbal medicine is being consumed by the modern generation of youngsters may all have contributed to the demise of this condition.
pathology
Macroscopically, due to the repeated attacks of biliary sepsis, it is common to find adhesions between the liver surface and the surrounding parietal peritoneum, especially the diaphragmatic surface, at operation. The liver surface is scarred and prominent dilated ducts may be obvious. The affected lobe of the liver, usually the left, is normally atrophic with compensatory hypertrophy of the remaining lobe. On palpation, the stones within the dilated biliary ducts are easily palpable. Occasionally, the underlying lobe can be so destroyed by the repeated attacks of cholangiohepatitis that what remains is a cavernous biliary sac with minimal surrounding liver parenchyma (Fig. 27.2). Within the sac is a soup of biliary mud and
stones. The brown pigment stones are soft stones which crumble when squeezed between fingers or forceps. The size variation goes from fine grains to stones of 4 to 5cm in diameter. The stones are irregular, can take up the shape of the biliary duct or become faceted when the stones are packed (Fig. 27.3). Apart from the stones, the bile duct is filled with biliary mud. This is a broth of mucus, altered bile products, microcalculi, desquamated epithelium, parasites, and pus. The pathological hallmark of RPC is the steadily progressive, recurrent cholangiohepatitis with periportal fibrosis. Histologically, in the early acute stage of an attack of cholangiohepatitis, it is similar to that of bacterial cholangitis associated with cholecystitis and calculus obstruction seen in the Western world (16), while the histological picture of the acute, chronic, and advanced stage of the disease is not dissimilar to that seen in sclerosing cholangitis (17). In the early lesions the lumen of the small biliary ducts is filled with pus, with rapid extension into the surrounding tissue. There is marked dissociation of the liver cells by polymorphonuclear infiltration of the sinusoids together with Kupffer cell hyperplasia. In the lobules around the affected duct there is a varying degree of cellular necrosis. Resolution of the underlying inflammation leads to dense round-cell infiltration, which is then replaced by fibrous tissue. In the larger intrahepatic ducts, the duct wall becomes inflamed, ulcerated, and destroyed together with the formation of cholangitic abscesses. Resolution results in intense fibrosis which accounts for the undue prominence of the duct wall seen on sectioning a liver affected by RPC. During the acute episode, these larger ducts can become irregular in caliber and short segments of relative stricture can occur at intervals along the duct. The duct proximal to the stenosis dilates.
243
Figure 27.2 A totally destroyed left liver lobe consisting of a cavernous biliary sac with negligible liver parenchymal tissue (f = falciform ligament).
Figure 27.3 Large number of pigment stones removed from one patient with RPC.
Recurrent attacks of infection and resolution lead to permanent damage of the duct wall and the ducts remain dilated. The relative stricture then becomes a true localized stricture. These strictures are most frequently encountered at the site of ductal confluence. One of the main concerns of these inflammatory strictures is malignant transformation into cholangiocarcinoma. Ohta et al., from their autopsy studies, suggested that repeated inflammatory damage to the ductal epithelium from the attacks of cholangitis can lead to atypical epithelial hyperplasia, dysplasia, and eventually cholangiocarcinoma (18). The left lobe of the liver is preferentially affected. The exact reason for this is unknown. One possible explanation may be the selective distribution of portal blood within the liver. Two studies suggested that the left lobe of the liver receives blood from the colon and the left lobe will be the first port of call for enteric organisms such as E. coli which have entered the portal venous system (19,20). Colonization of the bile with E. coli will lead to the production of -glucuronidase in the biliary system. Another explanation is that the more oblique course of the left hepatic duct results in poorer drainage of the left ductal system as compared to the right hepatic duct, thus leading to increased incidence of stone formation. If stones are found in the right hepatic duct, almost invariably stones are found in the left duct. In one study of 115 patients with hepatolithiasis, the ratio of stones found in the left and right hepatic ducts was 6:1 (5). The stones form in the dilated ducts proximal to the stricture site. These strictures can be multiple and bilobar in distribution and commonly occur at the origin of the right and left hepatic ducts. Stones within the common bile duct are usually lodged at the supraduodenal portion of the duct or at the ampulla. At ERCP, a patulous ampulla of Vater (probably a result of repeated passage of stones) is not an uncommon finding in patients with RPC. The bile in patients with hepatolithiasis is usually infected with enteric organisms. The two most common organisms isolated are E. coli and Klebsiella species. The overall positive bile culture rate has been reported to be as high as 87% and the incidence of positive culture in patients requiring surgical
intervention and those which settled on conservative measures is similar (90% vs. 85%) (21). The gallbladders in these patients are usually thin-walled, large, and distended. The majority of them do not contain gallstones. While the incidence of CBD stones and biliary mud varied from 60% to 90%, the incidence of associated gallstones in the gallbladder was only 15% to 40% (4,7). Macroscopically, the gallbladder looks normal but histological examination invariably shows features compatible with low-grade chronic cholecystitis. Along the gastrohepatic omentum gross lymphadenitis with enlarged lymph nodes is commonly encountered.
clinical presentation
Patients with RPC tend to be younger (third and fourth decade) than those affected by cholesterol stone disease, which is much more prevalent in older women, in the Western world. Although the condition does not have particular sex prevalence, those afflicted are almost invariably from the lower socio-economic classes. The usual presentation consists of the classical Charcots triad of abdominal pain, fever (with or without chills and rigors), and jaundice which signifies an attack of cholangitis. The patient may not notice the jaundice but a history of tea-colored urine is usual. The jaundice is usually not severe since cholangitis secondary to a completely obstructed biliary system will rapidly progress to acute suppurative obstructive cholangitis with septicemia. In addition to the triad of symptoms, these patients also develop mental confusion and shock, which is referred to as Reynauds pentad. The epigastric or right upper quadrant pain is usually described as a constant and gnawing or cutting (12) pain, which may radiate to the back. Vomiting is not a constant feature. Patients have spiking fever, not unlike that seen with an underlying abscess or collection, which normally resolves rapidly when the conservative treatment has been effective. On examination, the patient looks unwell and restless with a tinge of jaundice. The associated jaundice is typically mild and clinically can be just discernible. Abdominal examination may reveal the telltale signs of surgical scars from previous
244
investigations
Both the hematological and biochemical tests do not differentiate patients with RPC from those with other causes of biliary obstruction and infection. Full blood count will reveal an underlying leucocytosis with neutrophilia and mild thrombocytopenia in some patients. A number of patients will also have a concomitant mild derangement of the clotting profile with a prolonged prothrombin time. The deranged liver function test is compatible with an obstructive picture with a moderately raised level of bilirubin and a high serum alkaline phosphatase level. The level of -glutamyltranspeptidase is elevated. The slightly elevated alanine transaminase level in some patients is a reflection of the parenchymal damage secondary to the underlying infection within the biliary system. Other than showing the presence of pneumobilia, in some cases a plain abdominal radiograph is not helpful. The calcium bilirubinate stones are radiolucent because of the low calcium and high bilirubin content. The least expensive and most helpful investigation is ultrasonography (USG). It can demonstrate the presence of stones within the dilated intrahepatic and common bile ducts, the presence or absence of an underlying liver abscess and occasionally the presence of a solid liver mass secondary to malignancy complicating a benign stricture. Also it can reveal the presence or absence of gallstone(s) within the gallbladder. Intra- and extrahepatic ductal stones are present in the majority of patients, but cholelithiasis is much less common and is seen in the minority cases. Although intrahepatic stones normally cast sonic shadows on USG, the presence of air within the bile ducts (either spontaneously or secondary to previous biliary drainage procedures) can give rise to highly reflective echoes with posterior shadows, thus confusing and misleading the radiologist in diagnosing the presence of stones within the bile ducts. In about 3% of RPC, pneumobilia is present (22). In some cases the amorphous and small stones can form a cast of the biliary tree and, under such circumstances, highly reflective echoes and posterior acoustic shadowing on USG may be absent. It may then be difficult to identify dilated bile ducts and the ducts can appear as soft tissue masses on USG (7). USG images and its interpretations are operator dependent. Computed tomography (CT) removes this bias and can provide images of the dilated intra- and extrahepatic ducts, even if they are filled with sludge or pus. On CT scanning these
245
acute management
RPC patients have repeated attacks of acute cholangitis which would settle on conservative measures in the majority of cases. The need for urgent therapeutic interventional procedures only applies to a minority of cases, such as those with signs of peritonitis secondary to perforated gangrenous gallbladder, ruptured liver abscess, or those with septicemic shock despite conservative measures. The role of definitive procedures for most patients who settled on conservative measures depends on the frequency and severity of each attack, presence of biliary strictures (which may be malignant) and the presence of any existing co-morbid medical conditions. The initial approach to any acute attack is to control the underlying infection with the commencement of intravenous fluid infusion, antibiotic treatment after blood culture, prescription of adequate analgesia and keeping the patient nil per oral. Our standard first line antibiotic regimen is cefuroxime. Metronidazole is sometimes prescribed to cover the anaerobe Bacteroides fragilis, which is present in a minor proportion of patients who have had previous biliary tract surgery and/or complicated anatomy due to stones and strictures. An urgent ultrasound scan of the liver is performed to identify the extent of lithiasis within the biliary tree, the presence of a liver mass which can be an abscess or an underlying cholangiocarcinoma. Those patients who fail to respond or have evidence of a severe attack of cholangitis with or without shock undergo an urgent ERCP. The smallest amount of contrast feasible is used during ERCP as increased biliary pressure from excessive contrast injection will result in cholangio-venous reflux, which can lead to septicemia. No attempt is made to perform a full cholangiogram or to remove all calculi from the biliary system. In the procedure, the system is decompressed with a nasobiliary drain. Only when the patients condition has improved and stabilized would a check cholangiogram with endoscopic removal of stones be performed. If part of the biliary tree cannot be decompressed adequately because of an obstructing distal stone or stricture, then endoscopic drainage alone may not be adequate and successful. As such, percutaneous transhepatic biliary drainage of the obstructed biliary ducts will be of use. However, these drainage tubes are small and can be easily blocked by the tenacious biliary mud. If a liver abscess is present, the abscess is drained percutaneously under ultrasound guidance. The patient is monitored closely after admission for signs of deterioration. Those responding to the conservative treatment will have a reduction in abdominal pain, a fall in temperature toward normal and the disappearance of tachycardia over the first 24 to 48 hours. If there is no obvious improvement after 48 hours, the possibility of undrained biliary system or individual liver segments due to impacted stones or underlying strictures must be considered and the need for urgent surgical intervention entertained. At any time during conservative management, the presence of increasing abdominal pain coupled with shock and peritoneal signs mandate urgent surgical treatment.
Figure 27.4 Typical truncated biliary tree appearance together with the arrow or spear head sign (arrow) on ERCP. A large stone(s) in the left duct.
Figure 27.5 MR Cholangiogram demonstrating a stricture (arrow) at the confluence of the right and left hepatic ducts.
to normal or slightly dilated proximal ducts (26). Patients with Caroli disease (cavernous ectasia of the biliary tract) have dilated intrahepatic ducts and calculi but the extrahepatic ducts are disproportionately small (27). The condition is often associated with renal cystic disease (28) which, on CT, helps to distinguish it from RPC. In almost all cases, given the clinical and investigation findings, the diagnosis of RPC is seldom in doubt. The investigations
246
definitive management
The definitive management of RPC is to use a multidisciplinary approach (31), aiming to remove all biliary stones, to
247
(A)
(B)
(C) Figure 27.6 (A) ERCP demonstrating the presence of stones proximal to a relative stricture (arrow) in the left hepatic duct, (B) the stricture is dilated with a balloon prior to stone retrieval, and (C) the dilated left duct is cleared of stones.
electrohydraulic lithotripter and the fragments removed with a basket. Intrahepatic strictures can be dilated or stented. Instillation of stone dissolving agents directly into the affected biliary duct has been advocated by some, but we do not practise this approach as it is often painful, time-consuming, ineffective, and can lead to ascending cholangitis and sepsis. In patients where the initial endoscopic approach has failed, the established percutaneous route can be combined with endoscopy subsequently to achieve stone clearance or stricture dilatation. In those patients who received acute surgical intervention and T-tube decompression of the biliary system, the tract is allowed to mature. After 6 weeks, any stones present can be removed through the tract with a choledochoscope or under radiological control.
definitive surgery
Since RPC can and does affect the biliary tract at different sites with varying degrees of severity, the aim of the surgery is to provide adequate biliary drainage for bile and debris. This encompasses stone extraction, stricturoplasty or excision of
stricture, resecting non-functioning liver segments and creating a bilioenteric bypass with a permanent percutaneous access loop to the biliary tract to allow subsequent access to the biliary system for stone extraction and dilatation of stricture(s). Before embarking on definitive surgery, it is mandatory to have a complete knowledge of the location of calculi and stricture(s), and the uni- or bilobar extent of disease with or without concomitant liver atrophy. In the presence of predominantly extrahepatic disease, simple exploration of the common bile duct with intraoperative choledochoscopy will suffice. In the absence of extrahepatic ductal stricture, the incisions used for the exploration of the CBD and hepatic ducts will depend on the location of the stones (Fig. 27.7AD). We routinely remove the gallbladder in these patients since, histologically, it shows underlying evidence of low grade inflammation. Furthermore, if the sphincter of Oddi has been previously destroyed, the gallbladder will permanently be in a collapsed state. The placement of a large T-tube following the exploration will allow post-operative imaging of the biliary tracts and any residual stones found can
248
(A)
(B)
(C)
(D)
Figure 27.7 (A) Longitudinal incision for the exploration of CBD only, (B) separate incisions for exploration of the CBD and the hepatic ducts, (C) incision for the combined exploration of the CBD and one of the hepatic ducts (left side is shown), (D) horizontal incision over the hepaticojejunostomy (---- = incision).
be easily removed under radiological control or with a flexible choledochoscope. When there is stenosis of the ampulla of Vater or distal CBD, or impacted stone(s) in the lower CBD, a transduodenal sphincteroplasty is performed. In patients who have had multiple operations on the CBD, the standard approach can be difficult. Under such circumstances, Ong et al. have described an extraperitoneal approach to the duodenum, which is located by its anterior position to the right kidney. A transduodenal sphincteroplasty is performed and the CBD is explored from below (34,35). However, this approach is seldom necessary as the result of endoscopic sphincterotomy has been shown to be comparable (8). In the presence of extra- and intrahepatic calculi, stone extraction can be difficult if they are impacted, situated behind relative or true ductal strictures or, present within angulated ducts, such as the right posterior or left medial segmental ducts. Although direct hepatotomy can be performed to remove the stones, it can be very bloody if the stones are deepseated. Following the removal of all the stones within the CBD and CHD, after a choledochoscopic examination to rule out any strictures in the right and left hepatic ducts, the right and left ducts are flushed with saline. The right and left lobes of the liver are gently massaged in-between the flushing. This maneuvre normally helps to discharge more biliary mud and small
249
complications
In RPC the biliary mud and stones within the common bile duct can lead to acute pancreatitis. In 1971, Ong et al. reported that approximately half of all patients with acute pancreatitis, in Hong Kong, were associated with RPC (41). Another report claims that about 20% of RPC patients had high serum amylase levels but were clinically asymptomatic (42). In some patients, the big common bile duct stones can lead to the formation of a choledochoduodenal fistula. Liver abscesses complicating RPC can present with rupture into the peritoneal cavity or adjacent viscera. A left lobe liver abscess can rupture into the pericardial cavity and cause cardiac tamponade (43), while a right lobe abscess can lead to the formation of a pleurobiliary or bronchobiliary fistula (44). A chronic abscess can, on clinical and radiological grounds, be indistinguishable from an underlying cholangiocarcinoma. The final diagnosis can only be certain after histological examination of the resected specimen. Cholangiocarcinoma complicating RPC has been reported. The higher incidence of cholangiocarcinoma in areas where RPC is also prevalent has been attributed to the presence of Clonorchis sinensis infestation (45). In a necropsy study of 50 cases of cholangiocarcinoma, 92% of the cases were associated with clonorchiasis and intrahepatic stones were found in 20% of the cases (45). In a huge series of 1105 cases of hepatolithiasis studied over the period 1978 to 1990, Chen et al. (46) reported that the incidence of cholangiocarcinoma in these patients increased from 2.4% (between 1978 and 1987) to 13.7% (between 1988 and 1990), despite a decreasing incidence of clonorchiasis in the population. Thrombophlebitis of the branches of the portal vein due to the underlying periductal inflammation can lead to portal venous thrombosis with an enlarged spleen (6). Occasionally, septic emboli to the pulmonary tree can lead to the development of lung abscesses and significant pulmonary hypertension (6,47). Despite multiple operations, RPC patients with long-standing severe disease can develop secondary biliary cirrhosis and liver failure (48). When cirrhosis sets in, portal hypertension and bleeding esophageal varices ensue, thus making further corrective surgery for the underlying stricture(s) more hazardous. In these patients the only available option is liver transplantation.
250
conclusions
As the name implies, RPC runs a recurrent and unrelenting course with variable frequencies of attacks of cholangitis. Medical therapy is ineffective and surgical treatment is not entirely satisfactory. Despite surgery, stones and strictures can return. In Hong Kong and Taiwan, the peak age incidence of RPC has changed over the years from the third to the fifth decade in the 1950s and 1970s to the seventh decade in the early 1990s (49). This is due to an increasing proportion of patients who have survived previous surgery, only to have RPC recur again in later life. In Hong Kong, young patients in their third and fourth decade of life who present to us with RPC are invariably immigrants from mainland China. RPC is a dying disease in Hong Kong, but is still common in China. Although there are various theories on the pathogenesis of RPC, we believe the condition is closely linked to the level of social and economic conditions of a community. Surgery merely deals with the consequences of the condition, but does not address its roots. With better living conditions and public hygiene, perhaps RPC can be eradicated in this millennium. Until then, a judicious choice of a mixture of treatment, both medical and surgical, is necessary to achieve a satisfactory and long-lasting solution to a recurrent inflammatory condition.
key points
Calculi are predominantly calcium bilirubinate. Probably secondary to E. coli infection of bile. Presentation: Third and fourth decade Recurrent attacks of cholangitis Obstructive jaundice Preferentially affects left lobe. Investigations: Plain abdominal radiography (AXR) CT ERCP B1 PTC. Complications: Acute pancreatitis Liver abscess Cholangiocarcinoma Portal thrombophlebitis Secondary biliary cirrhosis.
references
1. Digby KH. Common-duct stones of liver origin. Br J Surg 1930; 17: 57891. 2. Cook J, Hou PC, Ho HC, et al. Recurrent pyogenic cholangitis. Br J Surg 1954; 42: 188203. 3. Mage S, Morel AS. Surgical experience with cholangiohepatitis (Hong Kong Disease) in Canton Chinese. Ann Surg 1965; 162: 18790. 4. Harrison-Levy A. The biliary obstruction syndrome of the Chinese. Br J Surg 1962; 49: 67485. 5. Choi TK, Wong J, Ong GB. The surgical management of primary intrahepatic stones. Br J Surg 1982; 69: 8690. 6. Chou ST, Chan CW. Recurrent pyogenic cholangitis: a necropsy study. Pathology 1980; 12: 41528. 7. Federle MP, Cello JP, Laing FC, et al. Recurrent pyogenic cholangitis in Asian immigrants. Use of ultrasonography, computed tomography, and cholangiography. Radiology 1982; 143: 1516. 8. Lam SK. A study of endoscopic sphincterotomy in recurrent pyogenic cholangitis. Br J Surg 1984; 71: 2626.
9. Wilson MK, Stephen MS, Mathur M, et al. Recurrent pyogenic cholangitis or oriental cholangiohepatitis in occidentals: case reports of four patients. Aust N Z J Surg 1996; 66: 64952. 10. Menu Y, Lorphelin JM, Scherrer A, et al. Sonographic and computed tomographic evaluation of intrahepatic calculi. AJR 1985; 145: 57983. 11. Maki T. Pathogenesis of calcium bilirubinate gallstone: role of E. coli, -glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg 1966; 164: 90100. 12. Ong GB. A study of recurrent pyogenic cholangitis. Arch Surg 1962; 84: 6389. 13. Maki T. Cholelithiasis in the Japanese. Arch Surg 1961; 82: 599612. 14. Matsushiro T, Suzuki N, Sato T, et al. Effects of diet on glucaric acid concentration in bile and the formation of calcium bilirubinate gallstones. Gastroenterology 1977; 72: 6303. 15. Leow CK, Lau WY. Biliary access procedure in the management of oriental cholangiohepatitis. Am Surg 1998; 64: 99. 16. Flinn WR, Olson DF, Oyasu R, et al. Biliary bacteria and hepatic histologic changes in gallstone disease. Ann Surg 1977; 185: 5937. 17. Thorpe MEC, Scheuer PJ, Sherlock S. Primary sclerosing cholangitis, the biliary tree and ulcerative cholangitis. Gut 1967; 8: 43548. 18. Ohta G, Nakanuma Y, Terada T. Pathology of hepatolithiasis: cholangitis and cholangiocarcinoma. Prog Clin Biol Res 1984; 152: 91113. 19. Copher GH, Dick BM. Streamline phenomena in portal vein and selective distribution of portal blood in liver. Arch Surg 1928; 17: 40819. 20. Hahn PF, Donald WD, Grier RC Jr. Physiological bilaterality of the portal circulation; streamline flow of blood into liver as shown by radioactive phosphorus. Am J Physiol 1945; 143: 1057. 21. Fan ST, Lai ECS, Mok FPT, et al. Acute cholangitis secondary to hepatolithiasis. Arch Surg 1991; 126: 102731. 22. Wastie ML, Cunningham IGE. Roentgenologic findings in recurrent pyogenic cholangitis. AJR 1973; 119: 717. 23. Itai Y, Araki T, Furui S, et al. Computed tomography and ultrasound in the diagnosis of intrahepatic calculi. Radiology 1980; 136: 399405. 24. Chan YL, Chan ACW, Lam WWM, et al. Choledocholithiasis: comparison of MR cholangiography and endoscopic retrograde cholangiography. Radiology 1996; 200: 859. 25. Park MS, Yu JS, Kim KW, et al. Recurrent pyogenic cholangitis: comparison between MR cholangiography and direct cholangiography. Radiology 2001; 220: 67782. 26. Araki T, Itai Y, Tasaka A. CT of choledochal cyst. AJR 1980; 135: 72934. 27. Kaiser JA, Mall JC, Salmen BJ, et al. Diagnosis of Caroli disease by computed tomography: report of two cases. Radiology 1979; 132: 6614. 28. Mujahed Z, Glenn F, Evans JA. Communicating cavernous ectasia of the intrahepatic ducts (Carolis disease). AJR 1971; 113: 216. 29. A0Lillemoe KD. Surgical treatment of biliary tract infection. Am Surg 2000; 66: 13844. 30. Fan ST. Transduodenal sphincteroplasty for impacted stone made unnecessary by electrohydraulic lithotripsy. Surg Gynecol Obstet 1989; 169: 3634. 31. A0Cosenza CA, Durazo F, Stain SC, et al. Current management of recurrent pyogenic cholangitis. Am Surg 1999; 68: 93943. 32. Choi TK, Wong J, Lam KH et al. Late result of sphincteroplasty in the treatment of primary cholangitis. Arch Surg 1981; 116: 11735. 33. Jeng KS, Yang FS, Ohta I, et al. Dilatation of intrahepatic biliary strictures in patients with hepatolithiasis. World J Surg 1990; 14: 58793. 34. Ong GB, Kwong KH, Cheng FCY. Extraperitoneal transduodenal choledocho-duodenostomy for removal of overlooked common bile duct stones. Aust N Z J Surg 1970; 40: 16670. 35. Choi TK, Lee NW, Wong J, et al. Extraperitoneal sphincteroplasty for residual stones: an update. Ann Surg 1982; 196: 269. 36. Fan ST, Mok F, Zheng SS, et al. Appraisal of hepaticocutaneous jejunostomy in the management of hepatolithiasis. Am J Surg 1993; 165: 3325. 37. Lau WY, Chan KL, Li AKC. Surgical treatment of inflammatory strictures of the major bile ducts. Asian J Surg 1990; 13: 514. 38. Lau WY, Fan ST, Yip WC, et al. Surgical management of strictures of the major bile ducts in recurrent pyogenic cholangitis. Br J Surg 1987; 74: 11002. 39. Hepp J, Couinaud C. Labord et lutilisation du canal hepatique gauche dans les reparations de la voie biliaire principale. Presse Med 1956; 64: 9478.
251
252
28
Liver abscess: amebic, pyogenic, and fungal Purvi Y. Parikh and Henry A. Pitt
Pathogenesis Infection occurs after fecaloral transmission of E. histolytica, which exists in either an immobile cyst form or the invasive trophozoite form. The main sources of infection are from asymptomatic carriers who transmit the cysts from water to vegetables contaminated with feces, food contaminated by fertilizers, or the hands of infected food handlers (9). The cystic form is swallowed and passes unaffected through the stomach into the intestine where the outer cyst wall is then digested by pancreatic enzymes. The trophozoite form is released into the intestine where it lives and multiplies. In most patients, the trophozoite asymptomatically colonizes the intestine, but some patients may develop amebic dysentery. The trophozoite invades through the intestinal mucosa, enters the mesenteric venules and lymphatics, travels to hepatic venules by the portal vein, and aggregates in the liver parenchyma (7). Accumulation of enough trophozoites leads to thrombosis, and necrosis and formation of an abscess. The outer rim of the abscess wall is infested by E. histolytica. The liquefied hepatic parenchyma has the appearance of anchovy paste (10). More than 80% of patients with amebic liver abscess have excess alcohol intake and thus a vulnerable liver to Entamoeba (11). Higher rates of tissue invasion are found in patients with Human Immunodeficiency Virus (HIV), splenectomy, and corticosteroid administration. Diagnosis The clinical presentation of amebic liver abscess is significantly different from pyogenic (Table 28.1). More than 90% of cases occur in men who usually live in or have a travel history to an endemic area in the last 2 to 5 months (5). Typical symptoms include fever, chills, anorexia, right upper quadrant pain, abdominal tenderness, and hepatomegaly with point tenderness over the liver or subcostal region. Diaphragmatic involvement causes right-sided pleural pain or pain referred to the shoulder (12). Patients with amebic liver abscess rarely have concurrent amebic dysentery, but 10% to 35% of patients have gastrointestinal symptoms that include nausea, vomiting, abdominal cramping, or distention (12). Jaundice, septic shock or a palpable mass may rarely be seen. Patients with an amebic liver abscess usually have a mild leukocytosis without eosinophilia (8). Mild anemia with moderate elevation of alkaline phosphatase and other liver function tests also may be present. The most common abnormality is an increased prothrombin time (12,13). Young males who are alcoholics may have normal or increased hemoglobin. If concurrent colitis is present, the wet mount prep will contain trophozoites 70% of the time if three separate stool samples are examined (11). If the patient has no colitis and a solitary liver abscess, stool samples are positive in 40% to 50% of cases (6). The definitive diagnosis of amebic liver abscess is by the detection of E. histolytica trophozoites in the abscess and by
introduction
Hepatic abscess is an uncommon disorder that continues to be a challenge to identify and treat. The three major types of hepatic abscesses are (i) pyogenic, most often polymicrobial, due to aerobic and anaerobic bacteria, (ii) amebic, due to Entamoeba histolytica, and (iii) fungal, principally due to Candida species. Pyogenic hepatic abscesses are seen most commonly in temperate climates, and in the United States they account for approximately 80% of the cases. Amebic abscesses account for about 10% of U.S. patients but are relatively more common in semitropical and tropical climates (1). Fungal abscesses are seen in 10% of U.S. cases and are increasing in frequency secondary to more immunocompromised patients as well as those having invasive hepatic procedures with prolonged antibiotic exposure (2,3). This chapter focuses on the pathogens, diagnosis, and current management of liver abscesses.
amebic abscess
Amebic liver abscess was not recognized as a separate entity until the nineteenth century. Several European investigators had suggested a relationship between dysentery and liver abscess; however, in 1875 Feder Losch discovered that Entamoeba histolytica was the causal agent. In 1890, Sir William Osler described the first North American case of amebic liver abscess when he found amoeba in a patients liver and stool sample (4). Open surgical drainage was the treatment of choice of amebic abscess until the 1930s, when aspiration and emetine became the standard of therapy. During this time, mortality decreased remarkedly from 57% to 14% by using therapeutic aspiration combined with amebicidal therapy (5). Further advancement in management happened with the introduction of serologic tests, improved radiologic imaging, and new amebicidal agents. Epidemiology Amebiasis is a widespread parasitic disease that affects people in developed and underdeveloped countries in tropical climates. Mexico, India, East and South Africa as well as Central and South America have the highest epidemic activity of E. histolytica (6). Worldwide, an estimated 500 million people are carriers of E. histolytica, and 50 million people worldwide develop amebic colitis or amebic liver abscesses resulting in 50,000 to 100,000 deaths each year (7). High-risk groups in the United States include immigrants, tourists who travel to endemic areas, institutionalized people, and the homosexual population. Amebic liver abscess is much more common in men, with a male to female ratio of 10:1. Low socio-economic status and unsanitary conditions are significant risk factors. Other associated risk factors include patients with heavy alcohol consumption, impaired immunity, malnutrition, and chronic infections (8).
253
A 4
B 9
Yes No
Figure 28.1 Paths of extension of amebic liver abscesses located within (A) the right hepatic (labels 17) and (B) the left hepatic lobe (8,9).
254
255
256
(A)
(B)
(C)
(D)
Figure 28.2 (A) CT demonstrating pyogenic abscess with air/fluid level in segment VI of the liver. (B) CT scan showing residual abscess after initial percutaneous drainage. (C) Further percutaneous drainage catheters. (D) CT demonstrating resolution of abscess.
257
Pyogenic
Fungal
with metronidazole may be administered if the bowel is thought to be the source. Parenteral administration of antibiotics for the first 10 to 14 days followed by oral agents for a total of 4 to 6 weeks is the classic recommendation. However, recent studies suggest that only 2 weeks of antibiotic therapy may be required (40). A combination of an aminoglycoside with either an extended spectrum beta-lactam, such as piperacillin, or a third generation cephalosporin is preferred for patients with K. pneumoniae liver abscesses (41). Multiple abscesses <1.5 cm in size and no other surgical disease may be treated with antibiotics alone. However, patients with multiple small abscesses usually have biliary tract disease and require biliary drainage. Matoba and coworkes recently reported that when percutaneous drainage cannot be performed and intravenous administration of antibiotics are ineffective, intermittent hepatic artery infusion therapy may be a useful alternative (42). Clinicians have questioned when the primary treatment for pyogenic liver abscesses should be aspiration alone or placement of a percutaneous catheter for drainage. Giorgio and associates treated 115 patients with percutaneous needle aspiration with a 98% success rate (43). Half the patients required only one aspiration whereas the remainder needed two to three aspirations. In 2004, C.H. Yu and associates also found that aspiration and catheter drainage had a similar mortality, success rate, and hospital stay (44). On the other hand, Rajak and associates performed a prospective randomized controlled trial comparing aspiration and catheter drainage showing a 100% success rate for catheter drainage compared to only 60% for aspiration (45). In summary, needle aspiration is less invasive and avoids all of the complications associated with catheter care. However, recurrence rates and the requirement for surgical intervention may be increased for patients who undergo aspiration alone. Although highly successful, percutaneous catheter drainage fails in approximately 10% of patients. Incomplete or unsuccessful drainage may result from the catheter being too small, highly viscous material, malposition of the catheter, or premature removal of the catheter. Furthermore, contradictions of percutaneous drainage requiring surgical drainage include patients with (i) large
or multiple abscess, (ii) abscesses of unknown etiology, (iii) ascites, (iv) a known intra-abdominal source that requires surgery, and (v) abscesses that require transpleural drainage (1). Operative intervention is recommended when complications occur following percutaneous catheter drainage or failure of non-operative treatment. Open abdominal surgical exploration involves localization of the abscess, identification of additional lesions via ultrasound, evacuation of the abscess, insertion a large-bore drainage tube, and treatment of the inciting pathology (Fig. 28.3). Post-operative lavage of the cavity through the drainage tube has been shown to be advantageous. The role of hepatic resection for the treatment of pyogenic liver abscesses remains controversial. Chou and associates published a series of 483 patients with pyogenic liver abscesses where 27 patients had a liver resection with 1 death (3.7%) (46). They concluded that when single or multiple liver abscesses have caused severe hepatic destruction, resection should be considered. Patients with significant liver atrophy and multiple pyogenic liver abscesses secondary to a long term biliary obstruction from hepatolithiasis or intrahepatic biliary stricture may also be best treated by hepatic resection (46). Outcomes Pyogenic liver abscess may be fatal if left untreated. Forty percent of patients with pyogenic liver abscesses develop complications that include pleural effusions, empyema, pneumonia, and generalized sepsis. Pyogenic liver abscesses may also cause hemobilia and hepatic vein thrombosis. Deaths in patients with pyogenic liver abscesses have been attributed to the intra-peritoneal rupture of the abscess. In one analysis, the causative bacteria in 72% of the cases of failed medical treatment were S. milleri and K. pneumoniae (47). Bacteremia, disseminated intravascular coagulopathy (DIC), septic pulmonary emboli, and acute renal failure are common complications of liver abscesses. Since the introduction of broad-spectrum antibiotics and the advancements in image-guided drainage, the mortality from pyogenic liver abscess has drastically decreased. However, the mortality in patients with multiple abscesses remains higher than in those with a solitary abscess. Liver abscesses are now diagnosed earlier and may be treated non-operatively thus reducing the mortality to less than 20% (46). Seeto and Rockey showed in their series a mortality of only 2% (27). Risk factors for mortality include septic shock, jaundice, hypoalbuminemia, malignancy, disseminated intravascular coagulopathy, APACHE II score >10, multiple abscesses, and intra-peritoneal rupture (48).
258
Site of unilocular abscess Deep multiloculated abscess Gallbladder Liver Loculations within abscess
T-extension
Liver
(A)
(B)
Figure 28.3 (A) Intra-operative ultrasound, aspiration, and anaerobic culture of abscess, and liver incision for pyogenic abscess. (B) Aerobic culture, manual disruption of loculations, and irrigation of the pyogenic abscess. Source: Reproduced from Ref. (51).
Treatment Fungal liver abscesses are treated with intravenous antifungal therapy as well as drainage of the abscess by simple aspiration, percutaneous drainage or open surgical drainage (Table 28.4). Caspofungin is the agent of choice for these patients (49,50). Patients with mixed bacterial and fungal abscesses should also be treated with appropriate systemic antibiotics for the isolated bacteria. An adequate course of caspofungin should be employed as an earlier analysis suggested that inadequate treatment with amphoteracin B was associated with a high mortality. Outcomes Very few patients develop pure fungal abscesses. Most patients have polymicrobial fungal and bacterial abscesses. The overall mortality rate is 50% because patients who do not receive antifungal therapy in early stage develop systemic fungemia (12). In addition, the underlying disease in the majority of these patients is associated with a high mortality. Moreover, the majority of these abscesses are multiple. As a result, patient survival is not influenced by different drainage procedures.
references
1. Pitt HA. Surgical management of hepatic abscess. World J Surg 1990; 14:498504. 2. Simpfendorfer CH, Henderson JM. Hepatic abscess. In: Cameron J, ed. Current Surgical Therapy, 9th edn. Philadelphia, PA: Elsevier-Mosby, 2008: 31721. 3. Lipsett PA, Huang CJ, Lillemoe KD, et al. Fungal hepatic abscess: characterization and management. J Gastrointestinal Surg 1997; 1:7884. 4. Martinez BM. Historical introduction. In: Martinez-Palomo A, ed. Amebiasis. Human Parasitic Diseases, Vol. 2. Amsterdam, Holland: Elsevier; 1986: 19. 5. Hughes MA, Petri WA Jr. Amebic liver abscess. Infect Dis Clin N Am 2000; 14: 56582.
6. Wells CD, Aruqedas M. Amebic liver abscess. S Med J 2004; 97: 67382. 7. Santi-Rocca J, Rigothier MC, Guillen N. Host-microbe interactions and defense mechanisms in the development of amoebic liver abscesses. Clin Microbiol Rev 2009; 22: 6575. 8. Tanyuksel M, Petri WA. Laboratory diagnosis of amebiasis. Clin Microbiol Rev 2003; 16:71329. 9. Salles JM, Moraes LM, Salles MC. Hepatic amebiasis. Braz J Infect Dis 2003; 7:96110. 10. Leslie DB, Dunn DL. Hepatic abscess. In: Cameron J, ed. Current Surgical Therapy, 8th edn. Philadelphia, PA: Elsevier Mosby; 2004: 298303. 11. Petri WA Jr, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis 1999; 29: 111725. 12. Haque R, Huston CD, Hughes M, et al. Current concepts: amebiasis. N Engl J Med. 2003; 48: 156573. 13. Barnes S, Lillemoe K. Liver abscess and hydatid cyst disease. In: Zinner M, Schwartz S, Ellis H, Ashley S, McFadden D, ed. Maingots Abdominal Operations, 10th edn. Stamford, CT: Appleton & Lange; 1997: 151345. 14. Haque R, Mollah NU, Ali IKM, et al. Diagnosis of amebic liver abscess and intestinal infection with the techLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol 2000; 38: 32359. 15. Sepulveda B, Manzo NTG. Clinical manifestations and diagnosis of amebiasis. In: Martinez-Palomeo A, ed. Amebiasis: Human Parasitic Diseases, No. 2 Amsterdam: Elsevier, 1986; 16987. 16. Stanley SL Jr. Amebiasis. Lancet 2003; 361: 102534. 17. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguishing amoebic from pyogenic liver abscess: a review of 577 adult cases. Trop Med Int Health 2004; 9: 71823. 18. Thomas PG, Ravindra KV. Amebiasis and biliary infection. In: Blumgart LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, 3rd edn. London: WB Saunders; 2001: 114765. 19. Blessmann J, Binh HD, Hung DM, et al. Treatment of amebic liver abscess with metronidazole alone or in combination with ultrasound-guided needle aspiration: a comparative, prospective and randomized study. Trop Med Int Health 2003; 8: 10304. 20. Chavez-Tapia NC, Hernandez-Calleros J, Tellez-Avia FI, et al. Imageguided percutaneous procedure plus metronidazole versus metronidazole alone for uncomplicated amoebic liver abscess (Review). The Cochrane Library 2009 Issue 2.
259
260
Establishing the diagnosis of a radiologically detected solid liver lesion with a satisfactory degree of certainty, a persisting problem being the differentiation of FNH from adenoma and confirming the nature of focal lesions in the cirrhotic liver. Managing patients with lesions identified incidentally at operation Managing patients following complete or partial resection of a lesion Managing patients with an incidental histological diagnosis following resection or biopsy Determining optimal follow-up of these patients based on the natural history of these lesions
In a recent clinical database review, surgery for benign disease accounted for 5% of patients undergoing resectional liver surgery (4). Advances in preoperative assessment, perioperative care, anesthesia, and surgical technique, including the increasing application of minimally invasive laparoscopic approaches, have the potential to decrease the morbidity and mortality rates associated with resectional liver surgery (5,6). A recent European study reported 87 patients treated laparoscopically with zero mortality and a low-postoperative complication rate (5%) (7). These improvements have altered the analysis of clinical risk versus benefit required when managing a patient with a diagnosis of a solid benign liver lesion but should not increase the prevalence of unnecessary liver resection.
imaging
Ultrasound (US) is often helpful in confirming an intrahepatic mass and will differentiate most cystic from solid parenchymal lesions. However, axial imaging in the form of contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) is usually required for adequate lesion characterization. Recently developed MRI contrast agents (superparamagnetic iron oxide, SPIO; gadobenate dimeglumine, Gd-BOPTA) have improved the ability to differentiate between solid benign lesions on MRI. Improvements in these modalities mean that angiography is
261
form of hemangioendothelioma with intermediate malignant potential has been reported (9). Hemangiomata are of mesenchymal origin and probably represent a congenital, hamartomatous proliferation of vascular endothelial cells. Approximately 90% are solitary and structurally, 80% are cavernous hemangiomata, the reminder being capillary hemangiomata (10). Over 90% of hemangiomata are less than 5 cm in diameter, which can occasionally make radiological characterization difficult. Current evidence indicates that hemangiomata have no malignant potential.
capillary hemangioma
In comparison to the more common cavernous form, capillary hemangiomata are generally smaller in size and are more frequently multiple. These smaller lesions are a common incidental finding in an asymptomatic patient. Once the diagnosis is established, no further treatment is required (recommendation strength: D).
cavernous hemangioma
Pathology Cavernous hemangiomata occur in up to 8% of autopsy studies. These lesions are the second most common solid hepatic tumor (10). Cavernous hemangiomata occur principally in women (F:M = 5:1) and are more common in the right liver. Large peripheral lesions may become pedunculated. The mean age at diagnosis is 50 years with most being detected between the third and fifth decade. Their prevalence is greatest in those with higher parity (11,12). Although there is no proven association with oral contraceptive use, the relationship remains controversial. Hemangiomata are generally asymptomatic until they reach diameters of over 10 cm. Symptoms include non-specific abdominal pain, pressure symptoms, and fever. Pain may be due to capsular stretching by larger lesions. Jaundice and rupture are rare. Cavernous hemangiomata may reach massive proportions, with reported lesions reaching several kilograms in weight. Giant hemangiomata are defined as those measuring 5 cm and above in diameter (13) and are multiple in 10% of cases (10). Hepatic cavernous hemangiomata may be associated with similar lesions in other organs (14). Other associated conditions, for example, liver cysts, gallbladder disease, gastroduodenal ulcers, or hiatus hernia are reported in 42% (15). In the rare KasabachMeritt syndrome intravascular coagulopathy may progress to systemic fibrinolysis and thrombocytopenia. The condition has a reported mortality rate of 20% to 30% (16). Macroscopically, cavernous hemangiomata appear purplish in color and may collapse on sectioning. A plane can generally be identified between the hemangioma and surrounding liver parenchyma. Thrombosis, fibrosis, and calcification are common features (Fig. 29.1). Cavernous hemangiomata may undergo complete fibrous transformation. Hemorrhage is remarkably rare and rupture exceptional. This lesion probably represents a congenital hamartoma with endothelium-lined spaces and fibrous septa being typical microscopic features. Lesions enlarge through ectasia rather than hypertrophy or hyperplasia.
now less commonly a part of initial patient assessment. Positron emission tomography (PET) is undergoing further evaluation as a diagnostic adjunct and laparoscopy is used increasingly to allow direct visualization of liver lesions and can be enhanced by intraoperative US. Nuclear medicine techniques such as single positron emission computerized tomography (SPECT) and tagged RBC scans, although less commonly applied, may facilitate differentiation of hemangioma from hepatocellular carcinoma. 99mTc-sulfur colloid scanning may help differentiate focal nodular hyperplasia from hepatocellular adenoma.
hemangioma adult
Hemangiomata are the most common benign solid tumor of the liver. In terms of focal liver lesions they are second only to simple cysts in frequency. Autopsy studies have shown a prevalence of up to 20% (8). Adult hemangioma differs in both presentation and histology from infantile hemangioendothelioma, which is considered elsewhere. An extremely rare adult
262
Imaging Features Hemangiomata are usually hyperechoic on US, although US is often inadequate for differentiating between solid liver lesions. Color-flow Doppler shows peripheral vessel filling. Axial imaging with CT or MRI is usually sufficient to confirm the diagnosis. The principle challenge in managing small (<3 cm) hemangiomata is differentiating them from other lesions, particularly in cases with atypical enhancement and significant arterio-venous shunting. Lesions tend to be hypodense on non-contrast CT and show peripheral followed by central enhancement. Isoenhancement with the arteries is typical. Delayed scans show persisting contrast enhancement and features such as corkscrewing and cotton wool appearance reflect the abnormal vessels within the lesion. Globular enhancement isodense with the aorta has been shown to be 67% sensitive and 100% specific in differentiating hemangiomata from metastases (17). Hemangiomata are hypointense on T1-weighted sequences. They appear very bright on T2-weighted sequences (the light bulb sign). Peripheral nodular enhancement on dynamic gadolinium-enhanced images and a non-intact ring appearance immediately after contrast with centripetal enhancement (maximal at 90s) are typical. Hemangiomata do not take up SPIO or manganese dipyridoxyl ethylenediamine diacetate (bis)phosphate (Mn-DPDP) as they do not contain Kupffer cells or hepatocytes. 99mTc-SPECT is effective in assessing hemangiomata but appears inferior to MRI (18). Management Biopsy of hemangiomata is generally contraindicated given the risk of hemorrhage and samples obtained from hemangiomata may resemble fibrosis. Resection may be justified rarely for symptomatic lesions and in cases where the diagnosis cannot be established despite investigation. Surgical resection or enucleation remains the principal effective therapies (19). Use of liver transplantation has been reported for unresectable disease in association with KasabachMerritt (20). The use of arterial ligation and embolization has not been widely
263
FNH-Like lesions FNH-like lesions have close histological similarity to FNH. Although due to a variety of processes, the common etiological factor appears to be abnormal liver vascularity, specifically increased arterial flow and decreased venous flow. Investigators have noted that FNH and hepatic adenomata occur more often in patients who have coexisting vascular tumors, portal venous thrombosis or occlusion, and those with significant portohepatic venous shunts (33,34). Other conditions associated with FNH-like lesions include BuddChiari syndrome, hereditary hemorrhagic telangectasia, and congenital hepatic fibrosis. FNH-like lesions have a tendency to increase in number or size, unlike classical FNH. Imaging Features Radiological diagnosis of FNH can be challenging and a multimodality approach is often required. CT has a reported 82% sensitivity and 97% specificity (35). A well-defined hypervascular lesion with a single central artery and spoke wheel centrifugal vessel filling is typical. FNH and FNH-like lesions are hyperintense T1-weighted MRI and hypointense on T2-weighted series. Strong arterial enhancement is often observed. MRI has a reported sensitivity of 70% and a specificity of 98% (36). In a recent study, differentiation between HA and FNH was not possible on the basis of precontrast or dynamic phase images alone. However, images acquired 1 to 3 hours after gadobenate dimeglumine enhancement, allowed differentiation between FNH and HA/adenomatosis with a specificity, PPV, NPV, and overall accuracy of 96.9%, 100%, 100%, 96.4%, and 98.3%, respectively (37). Management Management of patients with FNH and FNH-like lesions depends on the level of certainty of diagnosis. Once the diagnosis of FNH is established with confidence, no further intervention is required. In cases of diagnostic uncertainty, laparoscopic or open biopsy may be helpful and may be preferable to percutaneous needle biopsy. Although observation may be more appropriate for some patients, resection or
enucleation is preferred in most cases if surgery can be achieved safely (recommendation strength: D).
hepatocellular adenoma
Pathology Hepatocellular adenoma is usually identified as a solitary lesion in an otherwise normal liver. Adenomata are well defined but lack a capsule. Approximately 90% occur in women, most being diagnosed in the third to fifth decade. The lesions occur more commonly in the right liver. Adenomata are significantly less common than both hemangiomata and FNH. Ninety percent of patients report oral contraceptive use. The incidence is 34/100,000/year if oral contraceptive use has exceeded 2 years and their diagnosis has increased following the introduction of the oral contraceptive (38). Higher dose and longer duration of oral contraceptive use appear to promote adenoma development. Anabolic steroid use is also a risk factor for the development of a hepatocellular adenoma. Patients may present with pain due to hemorrhage into or rupture of an adenoma. The risk of bleeding is increased in larger and rapidly growing adenomata, and in patients using OCP, particularly when use is prolonged (39). Hepatocellular adenomata are associated with abnormalities of carbohydrate metabolism. Adenomata are observed more frequently in glycogen storage disease type 1 (glucose-6phosphatase deficiency), type 3 (glycogen debrancher deficiency), galactosemia, and iron overload. In these patients, adenomata develop at an earlier age and tend to show a male preponderance (2:1) (40,41). Sectioning reveals a yellow or pale brown tumor with surrounding normal tissue and a variable degree of encapsulation (Fig. 29.4). There may be evidence of hemorrhage (Fig. 29.5). Adenomata are generally uniform masses consisting of benignappearing hepatocytes without ducts or portal triads. Hepatocytes are pale due to increased levels of glycogen or fat. Venous lakes (peliosis hepatis, vide infra) may be present. Initially, Kupffer cells were thought to be absent from adenomata but molecular techniques have confirmed their presence in these lesions. However, adenomata generally do not sequester 99m Tc-sulfur colloid which is taken up preferentially by Kupffer
264
(A)
(B)
Figure 29.4 (A) Intraoperative image of pedunculated peripheral hepatocellular adenoma. (B) Section through resected hepatocellular adenoma.
PET appears to be useful in differentiating benign from malignant liver lesions (43) and 11C-acetate PET may have additional benefit in detecting HCC. In a study by Ho et al., benign tumors, such as adenomata and hemangiomata, were not 11C-acetate-avid. FNH showed only mild 11C-acetate uptake (44). Management In cases of acute hemorrhage, resuscitation may be combined with hepatic arterial embolization or laparotomy and packing to facilitate transfer to a specialist center. Formal hepatic resection represents optimal treatment for this group of acute patients, although this may be deferred in a stable patient with confined hemorrhage (recommendation strength: D). Discontinuing oral contraceptive use is probably advisable since there have been reports of lesion regression on their cessation, although there is little compelling evidence to support this position for all patients (recommendation strength: D). Although adenomata may regress following discontinuation of the oral contraceptive (45,46), malignant transformation has also been reported despite its discontinuation and in contraceptive-naive patients (47). Adenomata are currently thought to be premalignant with an approximate transformation rate of 10% (48). Transformation should be suspected in adenomata that increase in size, particularly in conjunction with increasing alpha-fetoprotein levels. The risk of malignant transformation is higher in males and in patients with large lesions. Difficulties in differentiating adenomata from FNH or HCC are commonly encountered in young female patients. Because of the abnormal vasculature typical of these lesions, biopsy is associated with a significant risk of hemorrhage and is generally contraindicated. In summary, if a focal liver lesion is suspected to be an adenoma, surgical resection should be considered, especially for symptomatic or large (5 cm or more in diameter) adenomata, provided resection can be accomplished safely (49) (recommendation strength: C).
cells. Adenomata fall into three molecular pathological subgroups: (1) those with inactivated hepatocyte nuclear factor 1-alpha (HNF-1alpha, chromosome 12q)-, (2) those with betacatenin activation, and (3) those with inflammatory changes. These subtypes reportedly display differing characteristics on MRI (42). Imaging Features Hepatocellular adenomata are usually heterogeneous in appearance on US. CT appearances are iso/hypodense precontrast with variable enhancement. There may be evidence of recent hemorrhage or infarction. MRI demonstrates a well-defined fatty lesion which is iso/ hyperintense on T1 sequences and mildly hyperintense on T2 MRI. Gadolinium-enhanced studies show hypervascularity in the arterial phase. Enhancement is often heterogeneous. Angiography demonstrates a peripherally supplied hypervascular lesion with areas of hypovascularity due to hemorrhage or infarction. Isotope scanning may help differentiate hepatocellular adenoma from FNH, an adenoma appearing as a filling defect (black hole sign).
hepatocellular adenomatosis
Pathology Hepatocellular adenomatosis is a rare condition, first recognized by Flejou et al. in 1985 (40). The condition is defined
265
266
pseudolipoma
These unusual lesions consist of well-differentiated subcapsular adipose tissue and may occur if an adherent fatty structure becomes detached and incorporated into the liver parenchyma. Pseudolipomata may require differentiation form metastasis, although they require no specific treatment. Peliosis Hepatis Peliosis hepatis refers to the development of multiple abnormal vascular channels with secondary fibrosis. This condition is associated with anabolic steroid use as well as with tuberculosis and, in some cases, other tumors.
267
key points
Benign liver tumors are increasingly detected due to greater use of improved diagnostic imaging There may be an increasing trend to resect benign lesions with the introduction of laparoscopic surgery Successful management of patients with benign liver lesions requires accurate diagnosis and an understanding of the natural history Most patients with benign liver tumors do not have associated liver disease Benign liver tumors rarely require surgery although, when necessary, centralized expert management minimizes associated morbidity and mortality Inappropriate investigation can lead to morbidity and compromises definitive treatment Hemangioma is the most common solid benign liver tumor Hepatocellular adenomata are rare but are associated with significant complications, are viewed as premalignant and generally warrant resection Hepatocellular adenomata are associated with oral contraceptive use. While controversial, no established links exist for hemangiomata or focal nodular hyperplasia A focal lesion in a cirrhotic liver should be regarded as malignant until proven otherwise Progressive symptoms, an enlarging tumor, complications or raising tumor markers are relative indications for resection
appendix
Recommended Grading of Categories of Evidence Ia: Ib: IIa: IIb: III: evidence from meta-analysis of randomized controlled trials evidence from at least one randomized controlled trial evidence from at least one controlled study without randomization evidence from at least one other type of quasiexperimental study evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and casecontrol studies evidence from expert committee reports or opinions and/or clinical experience of respected authorities
IV:
268
C:
D:
references
1. Morino M, Morra I, Rosso E, Miglietta C, Garrone C. Laparoscopic vs open hepatic resection: a comparative study. Surg Endosc 2003; 17(12): 19148. 2. Koffron AJ, Auffenberg G, Kung R, Abecassis M. Evaluation of 300 minimally invasive liver resections at a single institution: less is more. Ann Surg 2007; 246(3): 38592. 3. Koffron A, Geller D, Gamblin TC, Abecassis M. Laparoscopic liver surgery: Shifting the management of liver tumors. Hepatology 2006; 44(6): 16941700. 4. Dimick JB, Cowan JA Jr., Knol JA, Upchurch GR Jr. Hepatic resection in the United States: indications, outcomes, and hospital procedural volumes from a nationally representative database. Arch Surg 2003; 138(2): 18591. 5. Buell JF, Thomas MT, Rudich S, et al. Experience with more than 500 minimally invasive hepatic procedures. Ann Surg 2008; 248(3): 47586. 6. Polignano FM, Quyn AJ, de Figueiredo RS, et al. Laparoscopic versus open liver segmentectomy: prospective, case-matched, intention-to-treat analysis of clinical outcomes and cost effectiveness. Surg Endosc 2008; 22(12): 256470. 7. Descottes B, Glineur D, Lachachi F, et al. Laparoscopic liver resection of benign liver tumors. Surg Endosc 2003; 17(1): 2330. 8. Karhunen PJ. Benign hepatic tumours and tumour like conditions in men. J Clin Pathol 1986; 39(2): 1838. 9. Frider B, Bruno A, Selser J, et al. Kasabach-Merrit syndrome and adult hepatic epithelioid hemangioendothelioma an unusual association. J Hepatol 2005; 42(2): 2823. 10. Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am 1975; 59(4): 9951013. 11. Sewell JH, Weiss K. Spontaneous rupture of hemangioma of the liver. A review of the literature and presentation of illustrative case. Arch Surg 1961; 83: 72933. 12. Schwartz SI, Husser WC. Cavernous hemangioma of the liver. A single institution report of 16 resections. Ann Surg 1987; 205(5): 456465. 13. Adam YG, Huvos AG, Fortner JG. Giant hemangiomas of the liver. Ann Surg 1970; 172(2): 239245. 14. Erdogan B, Sen O, Aydin VM, et al. Multi-organ cavernous hemangiomas: case report. Neurol Res 2003; 25(1): 9294. 15. Farges O, Daradkeh S, Bismuth H. Cavernous hemangiomas of the liver: are there any indications for resection? World J Surg 1995; 19(1): 1924. 16. el Dessouky M, Azmy AF, Raine PA, Young DG. Kasabach-Merritt syndrome. J Pediatr Surg 1988; 23(2): 10911. 17. Leslie DF, Johnson CD, Johnson CM, Ilstrup DM, Harmsen WS. Distinction between cavernous hemangiomas of the liver and hepatic metastases on CT: value of contrast enhancement patterns. AJR 1995; 164(3): 6259. 18. Krause T, Hauenstein K, Studier-Fischer B, Schuemichen C, Moser E. Improved evaluation of technetium99m-red blood cell SPECT in hemangioma of the liver. J Nucl Med 1993; 34(3): 37580. 19. Lerner SM, Hiatt JR, Salamandra J, et al. Giant cavernous liver hemangiomas: effect of operative approach on outcome. Arch Surg 2004; 139(8): 81821. 20. Longeville JH, de la HP, Dolan P, et al. Treatment of a giant haemangioma of the liver with Kasabach-Merritt syndrome by orthotopic liver transplant a case report. HPB Surg 1997; 10(3): 15962.
269
270
30 Liver trauma
introduction
The size and location of the liver account for its high susceptibility to both blunt and penetrating trauma. The type and severity of liver injuries vary greatly and associated organ injuries are common. The leading cause of death is hemorrhage, with road traffic accidents accounting for an ever increasing proportion of blunt liver injuries. It also presents a large target for penetrating injuries to the trunk and these, including gunshot wounds, can be difficult to manage. The intimate connections between the liver capsule, the major hepatic veins, and the retrohepatic inferior vena cava anchor the liver within the upper abdominal cavity and most of the venous return from the lower body flows within these thin-walled veins. Injuries to these vulnerable, high-volume-flow juxtahepatic vessels pose a uniquely challenging aspect of severe liver trauma. Dramatic advances in the management of liver trauma have been reported in recent years and algorithms of management continue to evolve. The last two decades have witnessed a major paradigm shift in the management of liver trauma, with Non-Operative Management of Liver Injury (NOMLI) now firmly established as the standard of care for the majority of patients. For those undergoing surgery, the philosophy of damage control at abbreviated laparotomy prevails and the technique of perihepatic packing has come to serve a dominant role. Multidisciplinary interventions are indispensible in managing both the inevitable consequences of NOMLI and as adjuncts to surgical intervention. Unsurprisingly, little or no Grade III evidence exists from randomized or controlled studies of liver trauma, and recommendations for management are based on large descriptive studies, including multiinstitutional prospective cohort studies, and the clinical experience of respected authorities in the field.
271
IV. V. VI.
a b
Advance one grade for multiple injuries to the same organ. Based on most accurate assessment at autopsy, laparotomy, or radiological study.
hemoperitoneum (17) and demonstration of associated intraperitoneal and retroperitoneal injuries (Fig. 30.2). Technical refinements such as the development of rapid spiral CT scanners, protocols optimizing vascular contrast enhancement, and CT-scanning suites adjacent to the emergency department and equipped for critical care monitoring have established the central role of CT in the management of all but the most unstable cases of liver trauma (16). Despite concerns regarding the reliability of CT in the detection of hollow vicious injuries (18), the incidence of missed injuries following non-operative management based on clinical and CT findings is reported to be as low as 0.2% (7). Although reliable predictors of failure of non-operative management are lacking, contrast extravasations (pooling or a blush) merits emphasis as a cardinal sign of active hemorrhage mandating prompt (angiographic and / or surgical) intervention (7,15,16,19,20) (Fig. 30.3). Fang and colleagues reported contrast pooling in eight out of 150 stable patients treated non-operatively, six of whom (75%) developed hemodynamic instability requiring liver-related laparotomy (20).
Figure 30.1 Selective hepatic angiography (right hepatic artery arising from superior mesenteric artery) demonstrates contrast extravasation (arrows). Angioembolization was performed.
were successfully managed by hepatic embolization as definitive therapy. The alternative management of hemorrhage from Grade V juxtahepatic venous lacerations by percutaneous hepatic venous stenting has also been reported (14). Clearly much depends on the timing of such intervention and the prompt availability of appropriate expertise (with an operating room on standby) (12,15). Abdominal CT is established as the primary screening modality for the hemodynamically stable patient with suspected blunt liver trauma (16). Detailed cross-sectional imaging of the abdominal organs permits precise delineation of the type and extent of the liver injury, estimation of the volume of
Non-operative Management of Blunt Liver Trauma (NOMLI) Non-operative management of the majority of patients presenting with blunt liver injury (NOMLI) represents a major paradigm shift in liver trauma management during the last two decades (Fig. 30.2). Analysis of 35,510 hepatic injuries documented in the American College of Surgeons National Trauma Databank revealed a highly significant increase in NOMLI from 75% to 87% between 1994 and 2003 (95.1% for blunt liver injuries) (21). Factors heralding this change include (i) the recognition that as many as two-thirds of patients undergoing surgery on the basis of positive diagnostic peritoneal lavage were found to have relatively trivial injuries during non-therapeutic laparotomy (2224), (ii) the improved imaging with abdominal CT and less concern regarding missed injuries (15,25), (iii) the precedents for successful nonoperative management of solid organ injuries documented in
272
LIVER TRAUMA
Figure 30.2 Grade V blunt liver trauma associated with right renal hematoma in a hemodynamically unstable patient responding to fluid resuscitation and angioembolization.
Figure 30.3 Abdominal CT performed after perihepatic packing for blunt liver trauma showing intra-parenchymal contrast extravasation (arrow). The patient was transferred from the referring hospital and underwent day 1 relaparotomy because of deteriorating LFTs and evidence of the abdominal compartment syndrome.
the pediatric literature (2630), (iv) a better understanding of the pathophysiology and natural history of the injured and healing liver (31), and (v) the availability of adjunctive interventional techniques to deal effectively with the inevitable consequences of the non-operated liver injury (15). High success rates with NOMLI have been reported. Pachter and Hofstetters multi-center study of 404 patients in 1995 reported NOMLI in 98.5% of patients with just two liverrelated deaths (32). A collective review of 16 published series comprising 609 adult patients with liver trauma managed non-operatively between 1988 and 1997 reported success rates of 84% to100%, mean hospital stays of 11.5 to 16.6 days and mean transfusional requirements of 1 to 4 units (19). Others confirm that NOMLI may be undertaken in 85% to 95% of all adult patients with blunt liver trauma (15,23,24,30,33,34). It is generally accepted that the adoption of non-operative management, in place of the pre-1990s practice of liberal operative intervention, has heralded a substantial reduction in the mortality historically, associated with severe blunt liver injuries (7,15). Although it remains difficult to predict in whom NOMLI will fail, increased experience and confidence has lowered the threshold for attempting non-operative treatment to include all hemodynamically stable patients (i.e., systolic blood pressure >90 mmHg) without the signs of peritonitis, regardless of age, injury grade, or associated injuries (35). It should be emphasized that it is hemodynamic status and not the grade of liver injury which determines decision making. The patient typically at risk of failure of NOMLI, most often because of intra-abdominal bleeding, has been characterized as having a high-grade liver injury and remaining dependent on ongoingfluid resuscitation with persisting acidosis (35). Complications of Non-operative Management Contamination of the peritoneal cavity with blood and bile is an inevitable consequence of non-operative management of the fractured liver and both localized peritoneal signs and a
systemic inflammatory response may be expected. The anticipation and management of specific complications is integral to the successful non-operative management of severe liver injuries. Typically these include arterio-venous fistulas, bile leaks, intra- or peri-hepatic abscesses, and vascular-biliary communications (bilhemia and hemobilia). Such complications should be regarded as virtually obligatory consequences of non-operative management (36). This re-defines the philosophy of surgical abstention recognizing that delayed surgery and/or interventional procedures should be deemed an inherent part of the overall management plan rather than treatment failure. Carillo and colleagues reported that 32 patients out of 135 (24%) with severe blunt liver trauma managed non-operatively during 1995 to 1997 developed such complications (15). Strategies employed in their treatment included angioembolization (37%), CT-guided drainage of collections (31%), ERCP (25%), and laparoscopic drainage of collections (7%). A more recent multicenter study of 453 patients with Grades 3 to 5 blunt liver trauma managed by NOMLI at seven urban level 1 American trauma centers between 2000 and 2003 revealed 87 complications in 61 patients (13%)(37). Similarly, these comprised bleeding, biliary complications, abdominal compartment syndrome, and infective complications, which required 86 multimodality interventions. Hemorrhage Ongoing or recurrent bleeding in the non-operatively managed patient is typically recognized by hemodynamic instability with a gradually declining hematocrit and the requirement for repeated transfusions at an early stage. Angioembolization is usually effective for the relatively small proportion of patients who exhibit the signs of early ongoing hemorrhage or late re-bleeding, though this is unusual beyond 3 days postinjury (37). Liver enzyme derangement is common in the
273
274
LIVER TRAUMA
Angioembolization plays an important role in this group of patients for treatment of false aneurysms or active bleeding (56,57). It remains to be seen whether diagnostic laparoscopy will be increasingly adopted to identify the isolated non-bleeding LGSW as suggested by some (6164). Early Decision Making During Laparotomy Arrest of hemorrhage is the priority at initial operation and rapid decision making is required of the surgeon who encounters major liver injury at laparotomy. Most liver injuries are relatively minor and can be dealt with by simple maneuvers such as bimanual compression of the adjacent parenchyma, diathermy or suture ligation of visible bleeding points. Ongoing bleeding which is not easily controlled in this way requires temporary vascular inflow control by the Pringle maneuver, which serves both therapeutic and diagnostic roles. Grade IVV injuries with hepatic venous/caval lacerations may not respond to inflow occlusion and any attempts to mobilize the liver or inspect the retrohepatic space may be met with profuse venous bleeding. Consideration of perihepatic packing as the mainstay of the Damage Control Laparotomy (DCL) should now occur (6567). Perihepatic Packing Perihepatic packing is acknowledged as one of the most important factors in reducing the mortality following liver trauma in recent years (7). Temporary resuscitative packing may be distinguished from definitive therapeutic packing. The former aims to achieve hemodynamic stability, allows the surgeon to regain his composure, repair other priority vascular injuries, await more experienced surgical assistance, and/or facilitate transfer to a major trauma or hepatobiliary center for definitive treatment (67,68). Pack tamponade is the key maneuver underpinning the philosophy of surgical restraint and damage control during abbreviated laparotomy (69). Its judicious use may pre-empt the rapid cascade of events leading to refractory hypotension, dilutional coagulopathy, hypothermia, acidosis, and metabolic failure. A decision can then be taken either to attempt definitive control of bleeding or to proceed with therapeutic packing with abdominal closure and staged reoperation. The timing of the decision to pack is critical and the avoidance of packing as a desperate last resort when all other measures have failed should be emphasized (70). Indeed, a multicenter study identified failure to recognize the value of timely packing as the most common scenario in which patients died from fatal exsanguinations in the operating room (10). Furthermore, initially effective packing may engender a false sense of security when a pack and peek sequence develops and it is important to avoid the vicious cycle of repeated packing, resuscitation, unsuccessful attempts at definitive hemostasis, and repeated re-bleeding into shock (71). Perihepatic packing requires careful insertion of large, folded, dry gauze laparotomy packs around the diaphragmatic surfaces of liver and aims to restore its external contours (66,67) (Fig. 30.3). Sufficient packs must be inserted to provide adequate external counterpressure to achieve tamponade (without causing abdominal compartment syndrome), most of this external force being provided by the body wall and rib cage following wound closure. In this regard, Krige and colleagues describe a six-pack technique(72). The patient is later returned to the operating room for re-laparotomy and pack removal according to the progress of metabolic recovery. The Cape Town experience supports delay of liver pack removal beyond 48 hours without increased risk of septic complications or bile leaks, whereas early re-look laparotomy performed within 24 hours was associated with re-bleeding (73). A refinement in therapeutic perihepatic packing is the mesh hepatorrhaphy technique which employs a synthetic (polyglycolic acid or polygalactin) absorbable mesh and obviates the need for re-laparotomy (74). The technique seems logical for extensive lobar stellate lacerations, but unsurprisingly is ineffective in instances of juxtahepatic or caval injury and does not seem to have achieved widespread acceptance. Similarly, the use of a non-permeable liver bag following failure of conventional packing has been described (75). Refractory Bleeding Following Perihepatic Packing Continued bleeding through the packs that ceases with the Pringle manouevre and recurs with its release indicates hepatic arterial bleeding. Selective hepatic artery ligation remains an option although is regarded by some authorities as obsolete (76,77) and of historical interest only (78). Rather, postoperative transfer to the angiography suite for selective angioembolization has been identified as a major advance in this scenario (42,79). Asensio and colleagues reported early angioembolization as an adjunct to surgical intervention in 23 out of 57 survivors (40%) with grades IVV liver trauma, and the use of angiography in this way was identified as a significant independent predictor of outcome associated with decreased mortality (80). Persistent bleeding despite inflow occlusion suggests retrohepatic caval or hepatic venous injury and critical decisions must be made regarding the next level of intervention and whether to attempt definitive control of parenchymal / vascular bleeding with or without debridement of devascularized parenchyma (Fig. 30.4). Definitive Surgical Procedures in Complex Liver Trauma The latter option requires the use of one or more recognized manouevres. Although these techniques all have their proponents and detractors, they are nevertheless not mutually exclusive. No controlled trials exist to provide an evidence base for the superiority of one particular method over the other and much depends on anecdote, local expertise, and individual experience. Hepatotomy and Selective Vascular Ligation Rapid exposure and selective vascular suture/ligation of deepseated, actively bleeding, intra-hepatic vessels under hepatic inflow control have long been advocated as a mainstay in some centers (7). In the series of 107 patients with Grade IIIIV liver injuries reported from New York, finger-fracture hepatotomy technique was successful in controlling hemorrhage in no less than 100 cases (93.5%) for a cumulative mortality of 15% (81). It should be noted, however, that 83% of these patients had penetrating injuries. Similarly, Beal reported the use of
275
Figure 30.4 Laparotomy and perihepatic packing was performed for postangioembolization hemodynamic instability. The patient continued to bleed and re-laparotomy with hepatic segmentectomy 7/8 and repair of a middle hepatic vein laceration was performed.
hepatotomy in 53 out of 121 patients (44%) with complex liver trauma, citing success in 87% of cases (71). The popularity of the technique in large North American trauma centers during the 1980s is evidenced by its reported use in approximately 43% of nearly 3000 collected cases of complex hepatic trauma (71,82,83), and in 28 out of 85 (33%), such cases reported from Cape Town (72). Non-anatomic Resection In the nomenclature of non-anatomic liver resection for trauma, Strong and colleagues emphasized that such procedures are appropriately defined as either partial resections, where devascularized liver peripheral to the fracture line is removed, or resectional debridement, which involves limited removal of non-viable liver bordering the injury (76). Such atypical liver resections may be performed during the index operation after hemostasis has been achieved, or during subsequent staged re-operations following therapeutic perihepatic packing. The limited removal of non-viable tissue in this way has gained popularity as part of the philosophy of surgical restraint in the management of severe liver trauma, as distinct from the more aggressive approach of definitive anatomical hepatic resection. Specific Manouevres for Control of Hemorrhage from Juxtahepatic/Caval Injuries Liver injuries involving the retrohepatic vena cava and hepatic veins are the most difficult and deadly, and are associated with mortality rates of 50% to 80% (81,8386). Buckman and colleagues have classified two patterns of juxtahepatic injury: Type A intra-parenchymal hepatic venous injuries, and Type B extraparenchymal venous wounds (86). Type A injuries are probably more common, with predominant bleeding through the associated disrupted hepatic parenchyma and capsule. Restoration of containment by perihepatic packing may achieve tamponade of hemorrhage from high flow or low pressure intra-parenchymal veins in such cases. Thus, Beal reported success with packing in 20 patients with Grade 5 venous injuries (71). Similarly, Strong and colleagues observed that this manouevre, while not
276
LIVER TRAUMA
Figure 30.5 Hemodynamically unstable patient with severe blunt liver trauma underwent laparotomy, common hepatic artery ligation, liver suture, perihepatic packing, and was transferred for definitive management. Re-laparotomy and pack removal on day 1 revealed that active bleeding had stopped but the gall bladder was necrotic and there was a major bile leak from the sutured right liver laceration.
Figure 30.7 Abdominal CT performed 2 weeks later shows satisfactory hypertrophy of the remnant left hemiliver and no complications.
tion was still <1%, and the availability of experienced hepatobiliary and liver transplant surgeons at this institution was again a significant factor (95). It remains to be seen whether such results are reproducible widely, or whether the role of major resections in this context will remain the preserve of the surgical virtuoso. For deep penetrating liver injuries, including central bilobar LGSWs, balloon tamponade is an innovation which offers the chance of salvage (9698). Total hepatectomy is the ultimate strategy in desperate circumstances when hemorrhage from a shattered liver cannot be controlled, or when a Grade VI avulsion injury renders the liver remnant non-viable. However, the logistical and ethical dilemmas presented by this scenario are daunting as the future survival of the patient depends at the very least on the availability of a suitable donor organ. While an increasing number of reports have testified to the feasibility of this approach (99,100), the reality was illustrated by the Hannover experience in which six out of eight such patients died (101). The authors emphasize the importance of the (early) timing of hepatectomy, but stress that this approach can only be justified in exceptional circumstances.
references
1. Moore EE, Shackford SR, Pachter HL, et al. Organ injury scaling: spleen, liver, and kidney. J Trauma 1989; 29: 16646. 2. Moore EE, Cogbill TH, Jurkovich GJ, et al. Organ injury scaling: spleen and liver (1994 revision). J Trauma 1995; 38: 3234. 3. Croce MA, Fabian TC, Kudsk KA, et al. AAST organ injury scale: correlation of CT-graded liver injuries and operative findings. J Trauma 1991; 31: 80612. 4. Rizoli SB, Brenneman FD, Hanna SS, et al. Classification of liver trauma. HPB Surgery 1996; 9: 2358. 5. Tinkoff G, Esposito TJ, Reed J, et al. American Association for the Surgery of Trauma Organ Injury Scale I: spleen, liver, and kidney, validation based on the National Trauma Data Bank. J Am Coll Surg 2008; 207: 64655. 6. Alexander RH, Proctor HJ. Advanced Trauma Life Support Program for Physicians. 5th edn. Chicago: American College of Surgeons, 1993.
Figure 30.6 Formal right hepatectomy was performed and the patient made an uncomplicated post-operative recovery.
Subsequent reports by Tsugawa and colleagues (94), and the University of Pittsburgh group (95), support further the role of hepatic resection in selected patients with severe liver trauma requiring operative intervention. A mortality of 9% and hepatic-related morbidity of 30% were achieved in the latter series. However, the overall rate of formal major hepatic resec-
277
278
LIVER TRAUMA
63. Simon RJ, Ivatury RR. Current concepts in the use of cavitary endoscopy in the evaluation and treatment of blunt and penetrating truncal injuries. Surg Clin N Am 1995; 75: 15774. 64. Ditmars ML, Bongard F. Laparoscopy for triage of penetrating trauma: the decision to explore. J Laparoendosc S 1996; 6: 28591. 65. Feliciano DV, Mattox KL, Burch JM, et al. Packing for control of hepatic haemorrhage. J Trauma 1986; 26: 73843. 66. Krige JEJ. Perihepatic packing in the management of liver trauma. HPB Surg 1991; 3: 1414. 67. Krige JEJ, Bornman PC, Terblanche J. Therapeutic perihepatic packing in complex liver trauma. Br J Surg 1992; 79: 436. 68. Watson CJE, Calne RY, Padhani AR, et al. Surgical restraint in the management of liver trauma. Br J Surg 1991; 78: 10715. 69. Rotondo MF, Schwab CW, McGonigal MD, et al. Damage control: an approach for improved survival in exsanguinating penetrating abdominal injury. J Trauma 1993; 35: 37583. 70. Garrison JR, Richardson JD, Hilakos AS, et al. Predicting the need to pack early for severe intra-abdominal hemorrhage. J Trauma 1996; 40: 9239. 71. Beal SL. Fatal hepatic hemorrhage: an unresolved problem in the management of complex liver injuries. J Trauma 1990; 30: 1639. 72. Krige JEJ, Bornman PC, Terblanche J. Liver trauma in 446 patients. S Afr J Surg1997; 35: 105. 73. Nicol JA, Hommes M, Primrose R, et al. Packing for control of haemorrhage in major liver trauma. World J Surg 2007; 31: 56974. 74. Reed RL, Merrell RC, Meyers WC, et al. Continuing evolution in the approach to severe liver trauma. Ann Surg 1992; 216: 52438. 75. Sattler S, Gentilello LM. The liver bag: report of a new technique for treating severe, exsanguinating hepatic injuries. J Trauma 2004; 57: 8846. 76. Strong RW, Lynch SV, Wall DR, et al. Anatomic resection for severe liver trauma. Surgery 1998; 123: 2517. 77. Krige JEJ, Nicol JA. Treating major liver injuries. SAJS 2006; 44: 12830. 78. Mays ET. Hepatic trauma. Curr Probl Surg 1976; 13: 673. 79. Fang J-F, Chen R-J, Lin B-C, et al. Blunt hepatic injury: minimal intervention is the policy of treatment. J Trauma 2000; 49: 7228. 80. Asensio JA, Roldan G, Petrone P, et al. Operative management and outcomes in 103 AAST-OIS grades IV and V complex hepatic injuries: trauma surgeons still need to operate, but angioembolization helps. J Trauma 2003; 54: 64754. 81. Pachter HL, Spencer FC, Hofstetter SR, et al. Significant trends in the treatment of hepatic trauma. Experience with 411 injuries. Ann Surg 1992; 215: 492502. 82. Feliciano DV, Mattox KL, Jordan GL, et al. Management of 1000 consecutive cases of hepatic trauma (19791984). Ann Surg 1986; 204: 43842. 83. Cogbill TH, Moore EE, Jurkovich GJ, et al. Severe hepatic trauma: a multicenter experience with 1,335 liver injuries. J Trauma 1988; 28: 14338. 84. Rovito PF. Atrial caval shunting in blunt hepatic vascular injury. Ann Surg 1987; 205: 31821. 85. Burch JM, Feliciano DV, Mattox KL. The atriocaval shunt. Facts and fiction. Ann Surg 1988; 207: 55568. 86. Buckman RF, Miraliakbari R, Badellino MM. Juxtahepatic venous injuries: a critical review of reported management strategies. J Trauma 2000; 48(5): 97884. 87. Bismuth H, Castaing D, Garden OJ. Major hepatic resection under total vascular exclusion. Ann Surg 1989; 210: 139. 88. Khaneja SC, Pizzi WF, Barie PS, Ahmed N. Management of penetrating juxtahepatic inferior vena cava injuries under total vascular occlusion. J Am Coll Surg 1997; 184: 46974. 89. Richardson JD, Franklin GA, Lukan JK, et al. Evolution in the management of hepatic trauma: a 25 year perspective. Ann Surg 2000; 232: 32430. 90. Chen R-J, Fang J-F, Lin B-C, et al. Surgical management of juxtahepatic venous injuries in blunt hepatic trauma. J Trauma 1995; 38: 88690. 91. Moore FA, Moore EE, Seagraves A. Nonresectional management of major hepatic trauma. An evolving concept. Am J Surg 1985; 150: 7259. 92. Kasai T, Kobayashi K. Searching for the best operative modality for severe hepatic injuries. Surg Gynecol Obstet 1993; 77: 5515. 93. Menegaux F, Langlois P, Chigot J-P. Severe blunt trauma of the liver: a study of mortality factors. J Trauma 1993; 35: 8659. 94. Tsugawa K, Koyanagi N, Hashizume M, et al. Anatomic resection for severe blunt liver trauma in 100 patients. World J Surg 2002; 26: 5449. 95. Polanco P, Leon S, Pineda J, et al. Hepatic resection in the management of complex injury to the liver. J Trauma 2008; 65: 126470. 96. Poggetti RS, Moore EE, Moore FA, et al. Balloon tamponade for bilobar transfixing hepatic gunshot wounds. J Trauma 1992; 33: 6947. 97. Seligman JY, Egan M. Balloon tamponade: an alternative in the treatment of liver trauma. Am Surg 1997; 63: 10223. 98. Demetriades D. Balloon tamponade for bleeding control in penetrating liver injuries. J Trauma 1998; 44: 5389. 99. Jeng LB, Hsu CH, Wang CS, et al. Emergent liver transplantation to salvage a hepatic avulsion injury with a disrupted suprahepatic vena cava. Arch Surg 1993; 128: 10757. 100. Demirbas A, Fragulidis GP, Karatzas T, et al. Role of liver transplantation in the management of liver trauma. Transpl Proc 1997; 29: 2848. 101. Ringe B, Pichlmayr R. Total hepatectomy and liver transplantation: a life-saving procedure in patients with severe hepatic trauma. Br J Surg 1995; 82: 8379.
279
31
introduction
Portal hypertension has undergone major changes in understanding its pathophysiology, investigation, and management over the past 3 decades. It has moved from a dominantly surgical syndrome to a predominantly medical one, but in day-today practice includes a broad group of disorders that require a multidisciplinary team for evaluation and management. Basic science has defined the pathophysiology, allowing the introduction of pharmacologic therapies for treating many of the complications of portal hypertension. Technology advances in endoscopic therapies and endovascular stenting have changed the treatment options for variceal bleeding. The coming of age of liver transplantation has dramatically altered the management of patients with end stage liver disease and portal hypertension, and is now the dominant surgical option for suitable patients. This chapter will address these changes and present the evidence supporting management choices for the main clinical presentations of portal hypertension.
clinical manifestations
Variceal Bleeding Variceal bleeding is one of the major complications of portal hypertension requiring medical and surgical therapies (14). Screening endoscopy in cirrhotics shows that patients with more advanced liver disease and a lower platelet count are more likely to have varices (15). Epidemiologic studies have shown linear progression of varices over time (16). All patients with cirrhosis should undergo an initial screening upper endoscopy for varices: if none are present this should be repeated every 2 years. If present, intervention with prophylactic therapy to prevent bleeding (primary prophylaxis) should be considered. Ascites Ascites is a marker of advanced liver disease that develops later than varices. Refractory ascites which does not respond to salt restriction and diuretics and has consistently been linked to increased mortality (17). In addition, refractory ascites is potentially complicated by fluid and electrolyte imbalances, spontaneous bacterial peritonitis, and a higher incidence of abdominal wall hernias (18). Hypersplenism Portal hypertension can lead to splenomegaly and hypersplenism, with anemia, leukopenia, and thrombocytopenia. Blood is sequestered and destroyed in the spleen due to morphologic changes (19). Hypersplenism improves with decompression of the portal hypertension and rarely is splenectomy needed. Partial splenic embolization has been advocated by some (20), but is less effective. Pulmonary Syndromes Hepatopulmonary syndrome (HPS) is characterized by hypoxemia with the development of right-to-left intrapulmonary
etiology
Portal hypertension can be divided into prehepatic, intrahepatic, and posthepatic causes based on the location of obstruction to portal blood flowTable 31.1. Most of the prehepatic causes have a normal liver which improves overall prognosis for this group. Portal vein thrombosis should prompt a workup for hypercoagulable states (1). Rarely, a procedural induced arteriovenous fistula or functional fistulae associated with Osler Weber Rendu disease (Hereditary hemorrhagic telangiectasia) (2,3), can cause portal hypertension. Intrahepatic portal hypertension is usually secondary to cirrhosis with its multiple causes. The severity of the liver disease is the most important factor in determining prognosis. Intrahepatic presinusoidal obstruction occurs in congenital hepatic fibrosis and schistosomiasis, and liver function is well preserved. Schistosomiasis accounts for 200 million cases of portal hypertension worldwide (4,5). Posthepatic portal hypertension is rare and includes Budd Chiari Syndrome (BCS) and veno-occlusive disease. BCS results from obstruction of either the hepatic veins or suprahepatic vena cava, and is often associated with a myeloproliferative or hypercoagulable disorder. Outcome is determined by the extent of hepatic vein involvement, the rapidity of development, and the underlying liver function (6,7).
pathophysiology
Portal hypertension occurs when portal venous pressure rises above the normal pressure of 8 mmHg and becomes clinically important above 10 to 12 mmHg. The cascade of events that follow portal flow obstruction are illustrated in Figure 31.1. As portal pressure rises, additional dynamic factors come into play as a result of neurohormonal changes. Vasoconstriction
280
PORTAL HYPERTENSION
shunts and a widened alveolar-arterial oxygen gradient (21). Treatment is with liver transplantation which usually reverses the syndrome with survival rates similar to non-HPS cohorts (22). Pulmonary hypertension is also seen in patients with portal hypertension and carries a more sinister prognosis than HPS. Unless pulmonary arterial pressure can be reduced to normal ranges, liver transplant is contraindicated in these patients. Hepatocellular Carcinoma (HCC) Hepatocellular carcinoma is a common cause of death among patients with cirrhosis and has increased in importance as other causes of mortality have declined (23). The most common conditions leading to HCC are hepatitis B and C and alcoholism. Screening is recommended for patients with cirrhosis using hepatic ultrasound. However effectiveness of this approach has been questioned (24). Early detection of HCC in patients with well-compensated cirrhosis who are eligible for resection or can be prioritized for transplantation is the goal. Radiologic Imaging includes ultrasound as a versatile, low cost, low-risk tool for imaging of the liver parenchyma and the portal and hepatic venous systems. The addition of Doppler allows portal venous velocity assessment. Ultrasound can aid to guide percutaneous liver biopsy and paracentesis, screen for hepatocellular carcinoma, and define vessels. Computed tomography (CT) provides better anatomic detail, especially with newer multidetector array scanners and digital reconstruction of images in different planes and in three dimensions. Magnetic resonance imaging (MRI) is an imaging modality that may be preferred by some over CT scan, and can provide more information about the bile and pancreatic ducts. Visceral angiography and hepatic venography are occasionally indicated. The Hepatic Venous Pressure Gradient (HVPG) is calculated by measuring the hepatic venous wedge pressure with a balloon occlusion catheter minus the free hepatic vein pressure. In patients treated with pharmacotherapy, it has been shown that variceal bleeding rarely occurs when the HVPG is below 10 mmHg and if the HVPG can be reduced to below 12 mmHg or by 20% from baseline after an initial variceal bleed (29,30).
evaluation
The three essential components in evaluating patients with portal hypertension are (i) assessment of liver function, (ii) endoscopic study, and (iii) radiologic imaging. Liver Function is assessed from clinical and laboratory parameters. Ascites, jaundice, muscle wasting, and encephalopathy are markers for advanced liver disease. Biochemical and hematologic lab profiles include a complete blood count, prothrombin time, serum electrolytes, and liver chemistries. Specific markers of liver disease include hepatitis panels, antinuclear antibody, antimitochondrial antibody, iron and copper levels, alpha 1 antitrypsin, and alpha fetoprotein for HCC screening. The Child-Pugh and MELD scoring systems combine clinical and laboratory variables to determine prognosis in chronic liver disease. Endoscopy focuses on the presence, extent and size of esophageal and/or gastric varices and Portal Hypertensive Gastropathy (PHG). Grading of varices, using, for example, the North Italian Endoscopic Club (NIEC) system, risk-stratify based on variceal size, severity of red wale markings. When combined with ChildPugh class, such grading can help to guide therapy (25,26). Similar grading systems have been developed and validated for PHG and gastric varices (27,28).
Increased production vasoconstrictors Increased hepatic vascular tone Increased hepatic vascular resistance
Peripheral, BP
Splanchnic hyperemia
Activate neurohumoral
Intrahepatic
Post hepatic
Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.1 Pathophysiology of portal hypertension demonstrating complex vascular and neurohormonal responses. BP, blood pressure; CO, cardiac output; PVT, portal vein thrombosis. Source: From Ref. (97).
281
administration of intravenous antibiotics should precede endoscopy (37,38) (Grade 1a evidence). Terlipressin, a longacting synthetic vasopressin, in a meta-analysis of seven randomized controlled trials afforded a 34% relative risk reduction in all-cause mortality compared to placebo (39). Octreotide, was compared to terlipressin in two randomized controlled trials and both agents were found to be similarly effective (40,41). Endoscopy should be performed early for diagnosis and treatment. EVL and injection sclerotherapy are effective at controlling acute bleeding, especially when combined with pharmacologic treatment (42). When compared to sclerotherapy, banding is associated with a lower rate of rebleeding with fewer complications and endoscopy sessions (43) (Grade 1b evidence). In the 5% to 10% of patients not responding to the above measures, balloon tamponade may be necessary as a rescue measure until emergency Transjugular Intrahepatic Portosystemic Shunt (TIPS) can be performed. In-hospital mortality from acute variceal hemorrhage has steadily declined over the last couple of decades to 14.5%, thanks in large part to better resuscitation strategies, lower rates of rebleeding, and prevention of infectious complications (44). Prevention of Recurrent Variceal Bleed A first variceal bleed changes the odds of subsequent bleeding. Without specific therapy, approximately 60% of patients will rebleed within 1 to 2 years (31,45). This emphasizes the need for optimal strategies to prevent rebleeding and at the same time not accelerate the rate of progression of any underlying liver disease (46). Figure 31.4 illustrates a management algorithm. Pharmacologic and Endoscopic Therapy The best results for prevention of rebleeding have been obtained using a combination of pharmacologic therapy with non-selective beta-blockers (sometimes in combination with
Endoscopy
Endoscopy
Intolerance to -blockers or high-risk varices Continued bleed or rebleed Band ligation Figure 31.2 Primary prophylaxis to prevent an initial variceal bleed. Management algorithm based on variceal size. Source: From Ref. (97). -Balloon tamponade -TIPS
Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.3 Acute variceal bleed. A management algorithm for diagnosis and management of acute variceal bleeding. Source: From Ref. (97).
282
PORTAL HYPERTENSION
nitrates) and EVL (Grade 1b evidence). The latter should be performed in 2 to 4 sessions, 7 to 10 days apart until variceal obliteration is achieved. Combination therapy has succeeded in lowering rebleeding rates to as low as 14% at 2 years (47). The lowest rates of rebleeding are found in patients deemed responders based on HVPG measurements as mentioned earlier. Patients with a HVPG < 12 mmHg or a 20% decrease in HVPG have a 10% rebleeding rate (4850). Some have argued that pharmacologic therapy should be tried first, with EVL added for non-responders. In a meta-analysis of 12 randomized controlled trials comparing TIPS to endoscopic therapy for preventing variceal rebleeding, TIPS performed better in the prevention of rebleeding and deaths due to rebleeding, albeit with a higher rate of encephalopathy (51) (Grade 1a evidence). However, half of the studies used sclerotherapy alone for secondary prophylaxis. Subgroup analysis showed EVL was statistically equivalent to TIPS in terms of rebleeding, mortality, and encephalopathy. The data suggest TIPS should be used only once the combination of pharmacologic and endoscopic therapies has failed. Variceal Decompression Variceal decompression, either with a radiologic shunt (TIPS) or a surgical shunt, is indicated in patients that continue to bleed despite adequate medical and endoscopic therapy. TIPS has largely replaced surgical shunts both for patients with good hepatic reserve, and as a bridge to transplantation. TIPS Since its introduction in the 1990s TIPS has undergone a number of modifications, allowing it to become the primary means of portal decompression with a rebleeding rate at 1 year of about 13% (52). It is functionally an intrahepatic side-toside portocaval shunt which lowers the portal venous pressure and sinusoidal pressure. Initially, the main limitation of TIPS was stenosis, with the need for frequent surveillance and reintervention in the first year (50 % to 80%). The use of polytetrafluoroethylene (PTFE)-covered stents has markedly reduced the need for reintervention to <25%. Two randomized trials demonstrated improved primary patency rates with no impact on rate of encephalopathy or survival (53,54) (Grade 1b evidence). The other main side effect of TIPS is the development or worsening of encephalopathy which occurs in approximately 30% of patients (52). This is often amenable to medical management or modification of the TIPS itself. TIPS Procedure Venous access is usually obtained through the right internal jugular vein into the right or middle hepatic veins. The main right portal vein is identified by a retrograde hepatic venogram, and the portal venous system is entered above the bifurcation. After a contrast portal venogram confirms correct positioning, the TIPS is placed with a gentle curve to the prosthesis to prevent kinking. It is also important to choose a stent of the correct length, not extending too far into either the hepatic vein or the portal vein. At the same time, the entire hepatic vein segment should be covered to prevent the development of a stenosis at this end. Portal venous pressures are measured before and after the TIPS is deployed, and a completion venogram is obtained. The goal is a portal vein to right atrial gradient of <10 mmHg. Recurrence of variceal bleeding often heralds TIPS dysfunction and warrants recatheterization of the shunt to assess for patency and measure the gradient. Surgical Shunts Surgical shunts can be classified as total, partial, or selective. Total shunts divert all portal venous blood flow either a direct side-to-side portocaval shunt or an H-graft shunt using a 10-mm or greater PTFE graft. Portal decompression and resolution of variceal bleeding are excellent at greater than 90%; however, encephalopathy develops in up to 45% (55). Partial shunts use an 8 mm graft to partially decompress the portal venous system while preserving some hepatopedal blood flow. Prevention of variceal rebleeding remains greater than 90% with lower rates of encephalopathy compared to total shunts (56,57) (Grade 3 evidence). Selective shunts, such as the Distal Splenorenal Shunt (DSRS), selectively decompress gastroesophageal varices while maintaining portal hypertension (Fig. 31.5). These became the most widely used surgical shunts from 1980s to 1990s. Most series demonstrated rebleeding rates from 5% to7% and encephalopathy in 5% to 19% range. An NIH-funded prospective, randomized trial (1997 to 2003) compared DSRS to TIPS in patients with Childs class A and B cirrhosis (58) (Grade 1b evidence). At the close of this study (mean follow-up of 46 26 months with a range 24 to 96 months), the survival rates were not different at 2 and
Evaluation
Varices obliterated
-blocker
Transplant Copyright 2007 by Saunders, an imprint of Elsevier Inc. Figure 31.4 Prevention of recurrent variceal bleeding with cascading therapy options. TIPS, transjugular intrahepatic portosystemic shunt; DSRS, distal splenorenal shunt. Source: From Ref. (97).
283
ascites
This is the most common complication of cirrhosis and portal hypertension and is an important source of morbidity and mortality. Figure 31.6 presents a management algorithm. Ascites develops as a result of sinusoidal portal hypertension and the concomitant vasodilatation within the splanchnic circulation with an imbalance between hepatic lymph production and return to the systemic circulation. A relative hypovolemia is sensed by the kidneys due to reflex systemic vasoconstriction that, in turn, activates the reninangiotensin system leading to sodium and water retention. Paracentesis is used in the diagnosis and management of ascites. For diagnosis, a Serum-Ascites Albumin Gradient
Mild/moderate
1. Diet, sodium restriction (2 gm/day) 2. Spironolactone (100 mg/day) 3. May add Lasix (40 mg/day)
Refractory Persistent ascites Large volume paracentesis albumin infusion Increased frequency TIPS
? Transplant Figure 31.5 Distal splenorenal shunt selectively decompresses gastroesophageal varices while maintaining portal perfusion through the superior mesenteric and portal veins. Source: From Ref. (97). Figure 31.6 Ascites. A management algorithm based on severity and response to therapy. TIPS, transjugular intrahepatic portosystemic shunt. Source: From Ref. (97).
284
PORTAL HYPERTENSION
(SAAG) greater than 1.1 is highly suggestive of cirrhosis. Other causes of ascites (malignancy, infection, pancreatic ascites) usually have a SAAG less than 1.1. In the cirrhotic patient with ascites, abdominal pain and signs of infection, paracentesis should be performed to evaluate for possible spontaneous bacterial peritonitis, which carries a mortality of around 37% (63). Diagnosis of SBP requires the presence of at least 250 polymorphonuclear cells per cubic millimeter of ascitic fluid (64). As with gastroesophageal varices, a systematic approach should be taken in the management of ascites. The cornerstones of treatment of mild to moderate ascites are sodium restriction, to less than 2 g/d and diuretics (65). Spironolactone is the first-line diuretic acting as an aldosterone antagonist. Therapy starts with 100 mg daily and can be titrated up to a maximum dose of 400 mg daily. Furosemide can be added to assist with natriuresis and reduction of peripheral edema, but caution must be exercised to prevent overdiuresis. Refractory ascites fails to respond to maximum medical management and carries a poor prognosis. It interferes significantly with quality of life and requires a more aggressive approach that may include Large Volume Paracentesis (LVP), TIPS, or transplant. LVP removes 5 or more liters of ascites, with or without concomitant albumin infusion. A metaanalysis of four randomized trials comparing LVP to TIPS, showed that TIPS was superior to LVP in terms of control of ascites and transplant-free survival but carried a higher risk of hepatic encephalopathy (66) (Grade 1a evidence). Patients with refractory ascites are best served with transplantation for long-term survival. be made with the use of contrast-enhanced transthoracic echocardiography with agitated saline to produce microbubbles. In the presence of the abnormally dilated pulmonary vascular bed typical of HPS, microbubbles can be seen in the left atrium within 3 to 6 cardiac cycles. Alternatively, a more sensitive method involves the injection of technetium-99m-labeled microaggregated albumin into a peripheral vein with quantitative uptake in the brain. Liver transplantation is the only known definitive treatment for HPS with a 5-year survival of 76% in one series compared to 23% for patients not undergoing transplant (22) (Grade 3 evidence). Given the progressive nature of the disease and inferior outcome after transplant for those with severe hypoxemia (PaO2 < 50 mmHg), patients diagnosed with HPS should be prioritized for transplantation. Portopulmonary hypertension is defined by the presence of the following in the setting of portal hypertension: elevated pulmonary artery pressures (>25 mmHg), elevated pulmonary vascular resistance (>240 dyne s1 cm5), and pulmonary artery occlusion pressures <15 mmHg (68). As with HPS, the presence or severity of PPH does not seem to correlate with the degree of liver disease or portal hypertension. The hyperdynamic circulation that accompanies portal hypertension leads to increased sheer stress and vascular remodeling in the pulmonary vasculature which, in turn, leads to elevated resistance. The most common symptom is dyspnea on exertion but fatigue, syncope, palpitations, and chest pain can also be seen. Transthoracic echocardiography is a good initial screening test to perform if PPH is suspected with right-heart catheterization used to confirm the diagnosis along with its severity. Milder cases of PPH may be reversible with liver transplant, but severe PPH is associated with high post-transplant mortality (69) (Grade 3 evidence). Aggressive medical therapy with prostanoids and other pulmonary vasodilators is mandatory prior to considering patients for transplantation.
portopulmonary syndromes
Lung dysfunction may develop for a variety of reasons in patients with cirrhosis and portal hypertension, with the two main clinical entities of hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). (Figure 31.7 summarizes key features of these two syndromes. HPS is characterized by a defect in arterial oxygenation in the setting of liver disease due to arteriovenous shunting in the pulmonary vascular bed (21). HPS manifests most commonly with dyspnea, digital clubbing, cyanosis, and hypoxemia. Diagnosis of this syndrome requires (1) advanced liver disease, (2) arterial hypoxemia (PaO2 < 80 mmHg or alveolar-arterial oxygen gradient > or = 15 mmHg), and (3) pulmonary vascular dilatation (67). The precise etiology for the pulmonary vascular changes that take place are not entirely known, but are thought related to elevated pulmonary nitric oxide levels. Diagnosis can
Hepatopulmonary Syndrome (pO2 < 70) 820% Vasodilatation Liver dysfunction portal hypertension Curative
Portopulmonary Hypertension (RVSP > 40) 312% Vasoconstriction Portal hypertension Contraindicated
Figure 31.7 Pulmonary syndromes in liver disease: characteristics and management. RVSP, right ventricular systolic pressure. Source: From Ref. (97).
285
references
1. Valla DC, Condat B, Lebrec D. Spectrum of portal vein thrombosis in the West. J Gastroenterol Hepatol 2002; 17 (Suppl 3): S2247. 2. Matsumoto S, Mori H, Yamada Y, et al. Intrahepatic porto-hepatic venous shunts in Rendu-Osler-Weber disease: imaging demonstration. Eur Radiol 2004; 14: 5926. 3. Gabriel S, Maroney TP, Ringe BH. Hepatic artery-portal vein fistula formation after percutaneous liver biopsy in a living liver donor. Transplant Proc 2007; 39(5): 17079. 4. Souza MR, Toledo CF, Borges DR. Thrombocytemia as a predictor of portal hypertension in schistosomiasis. Dig Dis Sci 2000; 45(10): 196470. 5. Rodrigues de Araujo Souza M, Fischer de Toledo C, Borges DR. Thrombocytemia as a predictor of portal hypertension in schistosomiasis. Dig Dis Sci 2000; 45 (10): 196470.
286
PORTAL HYPERTENSION
32. Garcia-Pagan JC, Bosch J. Endoscopic band ligation in the treatment of portal hypertension. Nat Clin Pract Gastroenterol Hepatol 2005; 2(11): 52635. 33. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99(5): 14017. 34. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent varicela haemorrhage in patients with cirrhosis. Lancet 1995; 346(8982): 10569. 35. Escorsell A, Bordas JM, Castaneda B, et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension. Hepatology 2000; 31(5): 10617. 36. Merkel C, Bolognesi M, Sacerdote D, et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectives in the primary prophylaxis of varicela bleeding in cirrhosis. Hepatology 2000; 32(5): 9304. 37. Morales GF, Pereira Lima JC, Hornos AP, et al. Octreotide for esophageal variceal bleeding treated with endoscopic sclerotherapy: a randomized, placebo-controlled trial. Hepatogastroenterology. 2007; 54(73):195200. 38. Soares-Weiser K, Brezis M, Tur-Kaspa R, et al. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Cochrane Database Syst Rev 2002; (2): CD002907. 39. Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal varicela hemorrhage. Cochrane Database Syst Rev 2003; (1): CD002147. 40. Feu F, Ruiz del Arbol L, Banares R, et al. Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Variceal Bleeding Study Group. Gastroenterology 1996; 111(5): 12919. 41. Walker S, Kreichgauer HP, Bode JC. Terlipressin (glypressin) versus somatostatin in the treatment of bleeding esophageal varicesfinal report of a placebocontrolled, double-blind study. Z Gastroenterol 1996; 34(10): 6928. 42. Krige JE, Kotze UK, Bornman PC, et al. Variceal recurrence, rebleeding, and survival after endoscopic injection sclerotherapy in 287 alcoholic cirrhotic patients with bleeding esophageal varices. Ann Surg 2006; 244(5):76470. 43. Lo GH, Lai KH, Cheng JS, et al. Emergency Banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997; 25(5): 11014. 44. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival alter varicela bleeding in patients with cirrhosis over the past two decades. Hepatology 2004; 40(3): 6529. 45. Yang MT, Chen HS, Lee HC, et al. Risk factors and survival of early bleeding after esophageal variceal ligation. Hepatogastroenterology 2007; 54(78):17059. 46. Kravetz D. Prevention of recurrent esophageal variceal hemorrhage: review and current recommendations. J Clin Gastro 2007; 41 (Suppl 3): S31822. 47. de la Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005; 41(3): 5728. 48. Bosch J, Garcia-Pagan JC. Prevention of variceal bleeding. Lancet 2003; 361(9361): 9524. 49. Turnes J, Garcia-Pagan JC, Abraldes JG, et al. Pharmacological reduction in portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis. Amer J Gastroenterol 2006; 101(3): 50612. 50. Abraldes JG, Villanueva C, Banares R, et al. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol. 2008; 48(2): 22936. 51. Zheng M, Chen Y, Bai J, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic therapy in the secondary prophylaxis of variceal rebleeding in cirrhotic patients: meta-analysis update. J Clin Gastroenterol 2008; 42(5): 50716. 52. Tripathi D, Helmy A, Macbeth K, et al. Ten-years follow-up of 472 patients following transjugular intrahepatic portosystemic stent-shunt insertion at a single centre. Eur J Gastroenterol Hepatol 2004; 16(1): 918. 53. Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126(2): 46975. 54. Bureau C, Garcia-Pagan JC, Layrargues GP, et al. Patency of stents covered with polytetrafluoroethylene in patients treated by transjugular intrahepatic portosystemic shunts: long-term results of a randomized multicentre study. Liver Int 2007; 27(6): 7427. 55. Stipa S, Balducci G, Ziparo V. Total shunting and elective management of variceal bleeding. World J Surg 1994; 18(2): 2004. 56. Collins JC, Ong J, Rypins EB, et al. Partial portocaval shunt for variceal hemorrhage; longitudinal analysis of effectiveness. Arch Surg 1998; 133: 5903. 57. Rosemurgy AS, Serafini FM, Zweibel BR, et al. Transjugular intrahepatic portosystemic shunt vs. small-diameter prosthetic H-graft portocaval shunt: extended follow-up of an expanded randomized prospective trial. J Gastrointest Surg 2000; 4: 58997. 58. Henderson JM, Boyer TD, Kutner MH, et al. Distal splenorenal shunt versus transjugular intrahepatic portosystemic shunt for variceal bleeding: a randomized trial. Gastroenterology 2006; 130(6):164351. 59. Sugiura M, Futagawa S. A new technique for treating esophageal varices. J Thorac Cardiovasc Surg 1973; 66(5): 67785. 60. Selzner M, Tuttle-Newhall JE, Dahm F, et al. Current indication of a modified sugiura procedure in the management of variceal bleeding. J Am Coll Surg 2001; 193(2): 16673. 61. Orozco H, Mercado MA, Takahashi T, et al. Elective treatment of bleeding varices with the Sugiura operation over 10 years. Am J Surg 1992; 163(6): 5859. 62. 2007.Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1997-2006. Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD. Available from: URL: http://www.ustransplant.org/annual_reports/current/914a_cv_li.htm 63. Nobre SR, Cabral JE, Gomes JJ, et al. In-hospital mortality in spontaneous bacterial peritonitis: a new predictive model. Eur J Gastroenterol Hepatol. 2008; 20(12): 117681. 64. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000; 32(1): 14253. 65. Sandhu BS, Sanyal AJ. Management of ascites in cirrhosis. Clin Liver Dis 2005; 9(4): 71532. 66. Salerno F, Camma C, Enea M, et al. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007; 133 (3): 82534. 67. Krowka MJ. Hepatopulmonary syndrome versus portopulmonary hypertension: distinctions and dilemmas. Hepatology 1997; 25(5): 12824. 68. Hoeper MM, Krowka MJ, and Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363: 14618. 69. Krowka MJ, Plevak DJ, Findlay JY, et al. Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transpl 2000; 6: 44350. 70. Mansour A, Watson W, Shayani V, et al. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 1997; 122(4): 7305. 71. del Olmo JA, Flor-Lorente B, Flor-Civera B, et al. Risk factors for nonhepatic surgery in patients with cirrosis. World J Surg 2003; 27(6): 64752. 72. Puggioni A, Wong L. A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis. J Am Coll Surg 2003; 197(6): 9216. 73. Meunier K, Mucci S, Quentin V, et al. Colorectal surgery in cirrhotic patients: assessment of operative morbidity and mortality. Dis Colon Rectum 2008; 51(8): 122531. 74. Northrup PG, Wanamaker RC, Lee VD, et al. Model for end-stage liver disease (MELD) predicts nontransplant surgical mortality in patients with cirrhosis. Ann Surg. 2005; 242(2): 24451. 75. Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology 2007; 132(4):12619. 76. Slakey DP, Benz CC, Joshi S, et al. Umbilical hernia repair in cirrhotic patients: utility of temporary peritoneal dialysis catheter. Am Surg 2005; 71(1): 5861. 77. Henderson JM. Multidisciplinary approach to the management of portal hypertension. In: Yeo CJ, Dempsey DT, Klein AS, Pemberton JH, Peters JH, eds. Shackelfords Surgery of the Alimentary Tract, 6th edn. Philadelphia: Saunders, 2007: 175170.
287
32
Liver transplantation for acute and chronic liver failure Vincent Kah Hume Wong and J. Peter A. Lodge
UKELD score of > 49 needs to be achieved which predicts a 1-year mortality risk of greater than 9% (7). Exceptions to this rule are patients with HCC (discussed in Chapters 20 and 21), and variant syndromes consisting of diuretic-resistant ascites, intractable pruritus, hepatopulmonary syndrome, chronic hepatic encephalopathy, familial amyloidosis, primary hyperlipidemias, and polycystic liver disease (7). Patients with Acute Liver Failure Etiology (5,15), grade of encephalopathy (16,17), serum pH (18), and serum lactate (1921) are among the important prognostic indicators for acute liver failure (ALF) and in the United Kingdom, these factors are incorporated into the selection criteria for super-urgent LT (Table 32.2) (7). Timing of LT for ALF patients is vital as clinical deterioration can occur rapidly such that LT may be too risky. Therefore, patients listed on the super-urgent liver transplant waiting list are prioritized to be offered a deceased donor liver from any region within the United Kingdom, increasing the chances of receiving a deceased donor liver. Similarly, patients with ALF or primary nonfunction graft requiring retransplantation in the United States are exempted from MELD allocation and are listed with highest priority for available organs (22). Patients with Viral Hepatitis Hepatitis B virus (HBV)-associated liver cirrhosis was a relative contraindication for LT in the past but the introduction of potent antiviral agents and hepatitis B surface antigen antibody has resulted in a markedly reduced rate of recurrence post-LT (recurrence rate 58% in 5 years) (23,24) with concomitant improved patient and graft survival outcome comparable to that of non-viral hepatitis LT (25). In contrast, outcomes for hepatitis C virus (HCV)-related LT remain poorer in comparison with LT for other non-viral causes (26). Unlike HBV, there is no medication as yet for HCV able to provide excellent control of the virus and eventual recurrence of HCV in graft is inevitable. Risk factors for HCV recurrence include donor age >40 years (27), high viral load pre- and early post-LT, cytomegalovirus (CMV) and human immunodeficiency virus (HIV) co-infection (28), HCV genotype 1b (29), and over-immunosuppression or abrupt changes to the immunosuppression (30). Patients with HIV The improved prognosis of HIV (31) in the recent years with the advent of highly active anti-retroviral therapy (HAART), combined with effective prophylaxis of HBV re-infection, and a deeper understanding of HCV recurrence in LT, have made LT possible for HIV patients. HIV itself does not directly damage the liver parenchyma but rather the co-infection with HBV and HCV, HAART-related hepatotoxicity, and malignancies
introduction
Since the first successful liver transplant in 1963, liver transplantation (LT) has become an established form of therapy for patients with acute and chronic liver failure. With reported 5and 10-year survival rates for patients with liver transplant of 70% and 60%, respectively (1), indications for LT have expanded resulting in an increasing demand in this era of donor shortage. To augment the donor pool, expanded donor criteria and novel LT techniques are utilized increasingly. Artificial liver systems and hepatocyte cell transplantation, while still much in development, are exciting potential therapies to reduce the organ shortage burden. This chapter will look at the latest development in LT for acute and chronic liver failure and their indications.
288
account for the majority of the LT indications in HIV patients. In addition to the selection criteria mentioned previously, criteria specific to HIV in the United Kingdom (32) include 1. CD4 counts >200 cells/l or >100 cells/l in the presence of portal hypertension 2. Absence of viremia 3. Absence of AIDS dening illness after immune reconstitution 4. Anti-retroviral therapeutic options available if HIV disease reactivates.
Table 32.2 Current UK Blood and Transplant Criteria for Listing as a Super-Urgent Transplant
Category 1: Etiology: AOD: pH <7.25 more than 24 hrs after overdose and after fluid resuscitation Category 2: Etiology: AOD: Co-existing PT >100 sec or INR >6.5, and serum creatinine >300 mol/l or anuria, and grade 34 encephalopathy Category 3: Etiology: AOD: Serum lactate more than 24 h after overdose >3.5 mmol/l on admission or >3.0 mmol/l after fluid resuscitation Category 4: Etiology: AOD: Two of the three criteria from category 2 with clinical evidence of deterioration (eg, increased ICP, FiO2 >50%, increasing inotrope requirements) in the absence of clinical sepsis Category 5: Etiology: Seronegative hepatitis, hepatitis A, or hepatitis B or an idiosyncratic drug reaction. PT >100 sec or INR >6.5, and any grade of encephalopathy Category 6: Etiology: Seronegative hepatitis, hepatitis A, or hepatitis B, or an idiosyncratic drug reaction. Any grade of encephalopathy and any three from the following: unfavorable etiology (idiosyncratic drug reaction, seronegative hepatitis), age >40 yrs, jaundice to encephalopathy time >7 days, serum bilirubin >300 mol/l, PT >50 sec or INR >3.5 Category 7: Etiology: Acute presentation of Wilsons disease, or BuddChiari syndrome. A combination of coagulopathy and any grade of encephalopathy Category 8: Hepatic artery thrombosis on days 021 after liver transplantation Category 9: Early graft dysfunction on days 07 after liver transplantation with at least two of the following: AST >10,000 IU/l, INR >3.0, serum lactate >3 mmol/l, absence of bile production Category 10: Any patient who has been a live liver donor who develops severe liver failure within 4 wks of the donor operation
AOD Acetaminophen overdose, PT Prothrombin time, INR International Normalized Ratio, ICP Intracranial Pressure, FiO2 inspired oxygen concentration
selection of donor
The ideal deceased donor profile is as follows: age <40 years, trauma as the cause of death, donation after brain death, hemodynamic stability at the time of procurement, no steatosis or any other underlying chronic liver lesions, and no transmissible disease (33). This implies a very low risk of initial poor graft function or primary graft failure resulting in death or retransplantation. However, the profile of deceased donors is changing and the past decade has seen an increasing proportion of donors >50 years of age with cerebrovascular disease as cause of death (34,35). Expanded Criteria Donor The impact of changing deceased donor characteristics and widening gap between the donor pool and the waiting list means that deceased donors with features deviating from the donor profile are increasingly utilized (36,37). The term extended or expanded criteria donor (ECD) has been coined for such donors (Table 32.3), which suggests a higher risk of graft failure and decreased survival. Rather than a clear good or bad liver graft, ECD represents a spectrum of cumulative donor risks which should be taken into consideration (33,38,39). Steatosis and Abnormal Liver Function A recent international consensus meeting on ECD grafts (40) recommended against using liver allografts with severe steatosis (>60%) and from elderly donors in HCV-infected recipients. Abnormal liver function tests are not contraindications but careful assessment of other donor factors is essential, especially if there is a marked rise in gamma glutamyl transpeptidase level (>200 UI/L). Elderly Donors Patients with liver transplant from elderly donors have shown comparable survival, provided that there are no additional risk factors (41,42). While there is no clear age limit in utilizing an
289
Donors with Hepatitis C Infection Livers from donors infected with HCV represent 2% to 6% of the donor pool. As the risk of HCV transmission is high, HCVinfected liver grafts should be limited to HCV-positive recipients only. Ideally, a biopsy of the HCV-positive graft should be obtained prior to transplantation to assess fibrosis (47). Using HCV-positive grafts with minimal inflammation and fibrosis does not negatively impact outcome. Several studies (5558) have shown comparable 5-year graft and patient survival between HCV-positive and HCV-negative liver grafts in HCVinfected patients. Donors with Malignancy As the age of donors increases, the risk of cadaveric donors with previous malignancy increases. Currently, the incidence of donors having either an active or treated malignancy is 3% (59) and the risk of transmitted cancer is between 0.02% (60) and 0.2% (61). The most common cancer in an organ donor is skin malignancy followed by brain tumor (59). The risk of donor transmitted malignancy increases with tumor grade (Table 32.4) and any donors with a history of metastatic cancer should be excluded. Split-Liver Split-liver transplantation (SLT) in adults is associated with increased graft failure and recipient morbidity (33,62,63). Current UNOS criteria for potential splittable donors are donor age <40 years, on not more than a single vasopressor, rise in transaminases not more than three times of normal range, and BMI 28 (64). A recent study (65) interrogated the UNOS/OPTN data base and suggested two further risk criteria for considering donors for SLT: donor weight 40 kg and history of cardiac arrest after declaration of death. In our unit, criteria for splitting a deceased donor liver are (i) donor age <50 years, (ii) body weight >40 kg, (iii) ICU stay <5 days, (iv) minimal inotropic support, (v) good liver function, (vi) minimal hepatic steatosis, and (vii) suitable anatomy. Donation after Cardiac Death In donation after cardiac death (DCD), also called nonheart-beating donation, grafts can be procured either in a controlled setting, after a planned withdrawal of life support, or in an uncontrolled situation with the onset of sudden cardiac arrest. This can be classified into five categories, according to the Maastricht criteria (66) ( Table 32.5). DCD grafts are associated with a significantly increased risk of graft failure (67,68) and biliary complications (6972), although recent large studies (73,74) have shown that with judicious selection of DCD donors and recipients, comparable results to donation after brain death (DBD) liver allografts can be achieved. In the United Kingdom, guidelines on the use of solid organ transplants from DCD donors were drawn up by the British Transplantation Society (Table 32.6) (75). Our unit practices controlled DCD with planned withdrawal treatment of patient in the ICU, with regular reassessment of success rates. Thus, our current criteria are donor age less than 50 years, asystole
elderly donor liver, there are two caveats: (i) liver grafts of advanced age have reduced regenerative capacity and synthetic function, and are more susceptible to cold ischemic injury and (ii) elderly liver grafts should not be used for HCV-positive patients because of the high risk of severe HCV recurrence (43) and reduced graft and patient survival (44). Donors with Infection The use of donors with bacteremia or bacterial meningitis seems safe as the risk transmission is low (4%) (40,45), especially when appropriate prophylactic antibiotic therapy is instituted (46). However, donors with systemic sepsis, multiorgan failure, tuberculosis, or infected with multi-resistant organisms should be avoided (46,47). Donors with Hepatitis B Core Antibody Positive The use of hepatitis B core antibody (anti-HBc) positive donor livers and post-operative management remain controversial. Recipients who receive anti-HBc-positive livers are at a greater risk of developing de novo HBV with reported incidences of 72% (48) to 78% (49), compared to candidates who had antiHBc-negative livers (0.5%) (49). This is due to detectable levels of HBV DNA in serum and/or liver tissues of anti-HBc-positive donors, despite no other serological markers of HBV being present (50,51). Interestingly, studies have shown that recipients who are anti-HBc and/or anti-HBs-positive are protected with a much lower risk of de novo HBV from an anti-HBcpositive liver (48,52). Management strategies to prevent de novo HBV in recipients of anti-HBc-positive livers involve using lamivudine and/ or hepatitis B immunoglobulin (HBIG) depending on the serological status of the donor and recipient. Recently, adefovir dipivoxil was proposed as an alternative to HBIG (23). There is no consensus as yet on the prophylactic strategies with some units preferring HBIG monotherapy (53) and others using lamivudine only (54). Our units protocol comprises of long-term lamivudine for recipients of anti-HBc-positive livers. For patients receiving hepatitis B surface antigen-positive livers, long-term lamivudine and adefovir regimens are used.
290
0 40 39 19 29 61 93
Use with caution Reject Reject Dependent on tumor stage and interval from diagnosis. Dependent on tumor stage and interval from diagnosis. Use with caution as transmission has been often limited to the kidney graft Reject
Table 32.5 First International Workshop on Donation after Cardiac Death, Masstricht, 1994
Categories of Donation After Cardiac Death (categories 1 and 2 for uncontrolled DCD, 3 and 4 for controlled DCD) Dead on arrival Unsuccessful resuscitation Awaiting cardiac arrest-ventilator switch off Cardiac arrest while brain-dead Unexpected cardiac arrest while in ITU/ or critical care unita
a Category 5 is an addition to the original four categories of the Maastricht criteria.(155)
cell-mediated rejection. Early reports (77,78) showed much reduced graft survival for ABO-incompatible (ABO-I) LT with 1-, 2-, and 5-year graft survival of 66%, 30%, and 20% but recent reports (7981) have demonstrated that comparable short- and long-term patient and graft survival with blood-matched LT is achievable. Various treatment strategies to reduce risk of rejections have been advocated including plasmapheresis, immunoadsorption, splenectomy, quadruple immunosuppression, rituximab, and hepatic artery or portal vein infusion of prostaglandin E1 (80,82).
Table 32.6 British Transplantation Society Selection Criteria for Potential DCD Donor for Liver Allografts (75)
Age < 70 yrs Warm ischemia timea 20 min No history of renal impairment No uncontrolled hypertension or complicated insulin dependent diabetes No uncontrolled systemic sepsis or malignancy using the same criteria as for potential DBD donors
a This time is defined as starting when there is hypotension below a systolic BP of 55 mmHg and is measured up to the point of the cold perfusion of the organ.
within 45 minutes after treatment withdrawal, and traveling time less than 2 hours. A 10 minutes stand off period is instituted from time of asystole to confirm cardiac death. Failure of rapid asystole results procedure abandonment and a resultant increased unit workload without impacting the transplant rate. ABO-Incompatible Liver LT across the ABO barrier remains rare in the West and is used only in the setting of super-urgent need or as a bridging transplantation (76) because of the risk of antibody and
291
292
If normal renal function: 1 mg per kg amphotericin maximum 50 mg standard preparation (Change to liposomal amphotericin if renal function deteriorates). If established renal failure on renal dialysis: 1 mg per kg amphotericin to maximum 50 mg or liposomal amphotericin at the teams discretion. If impaired renal function but not requiring dialysis: 1 mg per kg liposomal amphotericin rounded off to nearest ampoule All patients receiving amphotericin prophylaxis should have regular fungal cultures including weekly aspergillus antigen.
293
294
295
296
Native Liver Operation Retransplant 3 4 11 80 4 69 Mortality 1-yr Survival R Trix 13 NR 2 NR 1 Whole 13 2 0 2 Donor Liver Transplant Vascular Complication Biliary Complication Primary Nonfunction ALT Off IS (%) 100 53 NR 1 1 0 2 6 0 0 NR Whole 5 R Tri 16 RL 7 LL 4 LLS 8 (only 40 recorded op) LLS 2 LL 3 RL 1 LL 6 RL 9 1 0 1 2 5 67 60 0 3 5 1 0 0 0 3 1 4 66 66 80 25 L Hep 2 R Hep 4 LLSx 1 L Hep 4 R Hep 7 LL 2 RL 4 LLS 1 LL 4 RL 7 LLSx 17 L Hep 11 R Trix 2 R trix + caudate 1 R Hep 4 11 APOLT 6 HALT 5 NR 6 APOLT 3 HALT 3 7 18 APOLT 10 HALT 8 62 APOLT 71 HALT 33 38
Studies
Patients
Indications
13
AOD 13
49
HBV 1 Unknown 5
15
12
47 (includes 12 HALT)
57
100
Contains both adult and children recipients; bLiving donors; Abbreviations: LLSx indicates left lateral sectionectomy; R Hep, Right hepatectomy; L Hep, Left hepatectomy; R Trix, Right trisectionectomy; L Trix, Left trisectionectomy; LLS, Left lateral section; LL, Left lobe; RL, Right lobe; R Tri, Right Trisectional graft; AOD, Acetominophen overdose; AIH, Autoimmune hepatitis; HAV, Hepatitis A virus; HBV, Hepatitis B virus; EBV, Epstein-Barr virus; HALT, Heterotropic auxiliary liver transplantation; APOLT, Auxiliary partial orthotopic liver transplantation; Whole, Auxiliary whole orthotopic liver graft transplantation; NR, Not recorded. Source: From Ref. 157.
references
1. European Liver Transplant Registry. (Accessed 19th December, 2008, at http://www.eltr.org.) 2. Berlakovich G. Wasting your organ with your lifestyle and receiving a new one? Ann Transplant 2005; 10: 3843. 3. Bernal W. Changing patterns of causation and the use of transplantation in the United Kingdom. Semin Liver Dis 2003; 23: 22737. 4. OGrady JG. Acute liver failure. Postgrad Med J 2005; 81: 14854. 5. Lee WM, Squires RH, Jr., Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: summary of a workshop. Hepatology 2008; 47: 140115. 6. Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007. Curr Opin Gastroenterol 2008; 24: 28797. 7. Neuberger J, Gimson A, Davies M, et al. Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut 2008; 57: 2527. 8. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The Liver and Portal Hypertension. Philadelphia: Saunders; 1964: 5064. 9. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 6469. 10. Santori G, Andorno E, Antonucci A, et al. Potential predictive value of the MELD score for short-term mortality after liver transplantation. Transplant Proc 2004; 36: 5334. 11. Broering DC, Walter J, Braun F, Rogiers X. Current status of hepatic transplantation. Anatomical basis for liver transplantation. Curr Probl Surg 2008; 45: 587661. 12. Ruf AE, Kremers WK, Chavez LL, et al. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl 2005; 11: 33643. 13. Biggins SW, Kim WR, Terrault NA, et al. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology 2006; 130: 165260. 14. Huo TI, Lee SD, Lin HC. Selecting an optimal prognostic system for liver cirrhosis: the model for end-stage liver disease and beyond. Liver Int 2008; 28: 60613. 15. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137: 94754. 16. Polson J. Assessment of prognosis in acute liver failure. Semin Liver Dis 2008; 28: 21825. 17. Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End-Stage Liver Disease (MELD) and Kings College Hospital criteria. Liver Transpl 2007; 13: 81421. 18. OGrady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 43945. 19. Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002; 359: 55863. 20. Cholongitas E, OBeirne J, Betrossian A, et al. Prognostic impact of lactate in acute liver failure. Liver Transpl 2008; 14: 1212; author reply 3. 21. Hadem J, Stiefel P, Bahr MJ, et al. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Clin Gastroenterol Hepatol 2008; 6: 33945. 22. Ahmed A, Keeffe EB. Current indications and contraindications for liver transplantation. Clin Liver Dis 2007; 11: 22747. 23. Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology 2008; 48: 14606. 24. Degertekin B, Lok AS. What is the optimal regimen for preventing hepatitis B recurrence after liver transplantation? Nat Clin Pract Gastroenterol Hepatol 2009; 6: 689 25. Gaglio P, Singh S, Degertekin B, et al. Impact of the hepatitis B virus genotype on pre- and post-liver transplantation outcomes. Liver Transpl 2008; 14: 14207. 26. Hong Z, Smart G, Dawood M, et al. Hepatitis C infection and survivals of liver transplant patients in Canada, 19972003. Transplant Proc 2008; 40: 146670.
297
51.
52.
53.
54.
55.
56.
57.
58.
59. 60.
61.
62. 63.
64.
65.
66. 67.
68. 69.
70.
71.
72.
73.
298
299
300
33
Benign cystic disease of the liver Stephen W. Fenwick and Dowmitra Dasgupta
1.6% and 18% (59). Females are affected more than males (6). The frequency of diagnosis increases with age with the peak incidence occurring between the ages of 50 and 60 years (10,11). Typically, patients with simple hepatic cysts have no symptoms. However, larger cysts may exert a mass effect and cause upper abdominal discomfort and early satiety. Symptoms are more common with right sided cysts (10). Complications are rare but include intra-cystic hemorrhage (12), biliary obstruction due to compression of the biliary tree (13,14), vascular compression (15), cyst rupture (16), and cyst torsion. Bacterial infection can occur within a cyst, particularly when there is communication with the biliary tree (17).
introduction
Benign cystic lesions of the liver were historically an uncommon clinical entity, presenting only when symptoms or complications occurred. However, with the wider availability of sophisticated radiological techniques, these lesions are being recognized more commonly. In spite of this they sometimes represent a diagnostic challenge. Common cystic lesions range from the single, simple, small liver cyst to the florid appearance of polycystic liver disease. More uncommon lesions are mesenchymal hamartomas (in pediatric patients), biliary hamartomas, and ciliated foregut hepatic cysts. Once a firm diagnosis is made, management is usually expectant unless symptoms worsen.
simple cysts
Simple biliary hepatic cysts are congenital lesions which are thought to result from progressive dilatation of biliary microhamartomas, otherwise known as von Meyenbergs complexes. They are lined by flattened biliary epithelium which rests on a thin underlying rim of fibrous stroma, without a distinct separation from adjacent hepatic parenchyma. They may be solitary or multiple, and do not normally communicate with the biliary tree (1). The cysts contain serous fluid which is continuously excreted by the lining epithelial cells.
treatment
The vast majority of simple hepatic cysts are incidental and, once the diagnosis is established, require no treatment. Even for those patients with abdominal symptoms the possibility of another underlying cause must always be considered and investigated.
aspiration
Ultrasound-guided percutaneous cyst aspiration has little role in the treatment of symptomatic simple cysts as the recurrence rate is high (78100%) (1820), sometimes as rapid as 2 weeks (18). However, cyst aspiration can be used as a trial of therapy. If symptoms persist after needle aspiration then the cyst is unlikely to be the cause, and other pathology must be sought. Conversely, if symptoms abate after cyst aspiration, and return with recurrence of the cyst, then a definitive treatment of the cyst is indicated.
clinical presentation
Most simple hepatic cysts are asymptomatic and are detected as an incidental finding during imaging of the abdomen for other indications. Ultrasound scanning demonstrates a rounded, anechoic intra-hepatic mass with good-through transmission and an imperceptible wall (2). On unenhanced computed tomography (CT) imaging a simple cyst appears as a homogenous lesion of low attenuation, with no enhancement of the wall or content following the administration of contrast (3) (Fig. 33.1). With magnetic resonance (MR) scanning, simple cysts show low attenuation on T1-weighted images (Fig. 33.2A) and homogeneous, very high signal intensity on T2-weighted images (Fig. 33.2B). The differential diagnosis includes multiple cysts arising as a result of polycystic liver disease, juvenile hydatid cysts, parasitic liver cysts, and biliary cystadenomas or cystadenocarcinomas. The differentiation between these lesions can largely be made on imaging characteristics. Hepatic metastases can occasionally appear cystic, particularly neuroendocrine tumors and sarcomas.
aspiration sclerotherapy
Aspiration sclerotherapy is a well-tested therapeutic technique for the treatment of simple hepatic cysts. The procedure involves the aspiration of cyst fluid followed by the instillation of a sclerosant. A number of sclerosing agents have been used including tetracycline (21,22), minocycline (23,24), pantopaque (25), and alcohol (11,2629). The procedure is performed under ultrasound or CT guidance. A pigtail catheter is inserted into the cyst, and the cyst fluid aspirated. The fluid is usually clear and should be sent for cytology to exclude malignancy, culture to exclude infection, and microscopy to look for hydatid scolices. In addition the fluid should be assessed for the tumor marker CA199 which, if elevated, suggests an underlying diagnosis of cystadenoma or cystadenocarcinoma (30). Any bile staining of the fluid would suggest a communication with the biliary tree and would mandate abandoning the procedure and further assessment with cholangiography. The consequence of inadvertent injection of sclerosant into the biliary tree is devastating, and following cyst drainage a contrast cystogram should always be performed (28).
natural history
An early series, based on findings at laparotomy, estimated a low prevalence of simple hepatic cysts of 0.17%, although many small cysts were probably missed (4). More recent data based on imaging studies suggests the prevalence is between
301
surgical treatment
Figure 33.1 Multidetector computed tomography (MDCT) image with iodinated intravenous contrast media. A large simple cyst is seen in segments 6 and 7. A small cyst is noted on the periphery of segment 2.
There are three surgical techniques that have been employed in the management of simple benign liver cysts. These are fenestration (deroofing of the cyst), local excision of the cyst (cystectomy), and anatomic or non-anatomic liver resection.
(A)
(B)
Figure 33.2 (A) T1-weighted MRI image through the upper abdomen showing multiple cysts throughout the liver. Fluid is dark on T1-weighting (B) T2-weighted coronal view of the abdomen of the same patient as in Figure 33.2A. The cysts are clearly seen as bright throughout the liver. This section is taken through the vascular pedicle of the liver.
302
open surgery
With the development of the laparoscopic technique, the procedure of open cyst fenestration for benign simple cysts should be reserved for those patients with recurrent disease or with extensive abdominal adhesions that preclude the laparoscopic technique. More radical procedures, including cystectomy and liver resection, carry a greater morbidity and mortality than cyst fenestration (44). Cystectomy can be particularly dangerous as the adjacent parenchyma is compressed and major vascular structures are often within the walls of the cyst. The main indication for resection is when there is suspicion that the cyst may be neoplastic in nature.
laparoscopic surgery
In recent years, the technique of laparoscopic cyst fenestration has developed and should now be the first-line surgical approach for patients with symptomatic simple cysts. Laparoscopic cyst fenestration has all the advantages of minimally invasive surgery including reduced postoperative pain, shorter hospital stay, and quicker recovery. The laparoscopic procedure was initially recommended for cysts in segments II, III, IVb, and V. However, with increasing experience, location should not be considered a contraindication to laparoscopic surgery (40). A standard 4 port laparoscopic technique is used with the patient in a supine position, although for right-sided posteriorly placed cysts a left lateral position can give superior access. An angled laparoscope (30 or 45 degrees) gives superior views of the cyst cavity. The cyst can be punctured by insertion of a trocar through the exposed wall. The contents are sent for analysis. A wide excision of the cyst wall is then made, taking great care not to venture into the hepatic parenchyma. Various techniques have been employed to achieve hemostasis of the remnant cyst wall including diathermy, over sewing of the remnant cyst wall edge and using a laparoscopic linear cutting vascular stapler to excise the cyst wall. The authors preference is to use harmonic shears. The resected cyst wall is removed in an endoscopic retrieval bag, and the remnant cyst wall is inspected. Although unusual, if a bile leak is identified it must be controlled either with a suture or with a laparoscopic clip. Some authors advocate obliteration of the residual cyst wall with electrocautery. If this is attempted it should be done without breaching the cyst wall as major vascular structures, distorted by the cyst, can lie just underneath. The argon beam coagulator is probably best suited to the task (41) as the burn is very superficial. There is the potential risk of gas embolus and careful control of intraperitoneal pressure must be maintained. To prevent recurrence of the cyst, particularly when the exposed cyst cavity will come to lie against the abdominal wall, an omentoplasty should be performed. A pedicle of omentum is mobilized from the transverse colon and advanced into the cyst cavity. It can be secured either with sutures or with laparoscopic clips. A cholecystectomy is not routinely performed unless there is evidence of cholecystolithiasis, or where the cyst drainage leaves the gallbladder excessively mobile and at risk of subsequent torsion.
clinical presentation
The majority of patients with PCLD are asymptomatic and, as with simple cysts, the diagnosis is made during routine investigation (50). Laboratory tests of liver function including bilirubin, alkaline phosphatase, alanine aminotransferase, and prothrombin time are usually normal. Symptoms tend to occur in patients with longstanding disease and are related to liver enlargement and compression of adjacent organs. Patients may complain of an increase in abdominal girth, upper abdominal pain, early satiety, nausea, respiratory compromise, and limitation in physical ability. More significant complications include hemorrhage into a cyst, infection within a cyst and compression of vascular and
303
Type III
Figure 33.3 Portal venous phase MDCT image showing multiple large cysts throughout the liver. Cysts are also noted within the kidneys.
due to PCLD. The aim of treatment should be to reduce the size of the cystic component of the liver, whilst preserving parenchymal liver function, leading to long-term relief of symptoms.
aspiration sclerotherapy
The techniques of serial cyst aspiration (55) and serial aspiration sclerotherapy (56) have been used with success in the treatment of PCLD. However, there is a higher rate of recurrence in PCLD than seen in the treatment of simple hepatic cysts, one explanation being that the more rigid hepatic parenchyma prevents complete collapse of the cysts (27). As a result, this technique is probably best suited to patients with Gigot type I disease in whom more aggressive surgical options would be contraindicated. One exception would be in treating the life-threatening complication of cyst infection where a combination of antibiotic therapy and cyst drainage is required to reduce mortality (52).
surgical treatment
Surgical options for the treatment of PCLD include cyst fenestration, liver resection, a combination of cyst fenestration and liver resection, and liver transplantation. The procedure of cyst fenestration, either by an open or by a laparoscopic approach, involves the progressive deroofing of liver cysts, starting superficially and working through to cysts placed deeper within the liver parenchyma. This approach is best suited to patients with Gigot type I disease. The resulting decrease in liver volume can lead to a significant improvement in symptoms for the majority of patients (57,58). For patients with more severe parenchymal involvement, classified as Gigot types II and III, fenestration alone is rarely successful. A combination of hepatic resection with fenestration may, however, offer alleviation of symptoms through a reduction in liver volume and mass (5961). The procedure typically involves a non-anatomical resection of either the right or left hemi-liver with fenestration of accessible cysts on the remnant side. The preservation of hepatic parenchyma is crucial when planning the resection. The procedure can be technically challenging as the hepatic anatomy is distorted by the cysts. The absence of landmarks predisposes to injury of the remnant liver inflow or outflow. The major vasculo-biliary structures are often compressed between adjacent cyst walls,
Figure 33.4 T2-weighted MRI image of the upper abdomen showing the appearance of multiple fluid filled simple cysts both in the liver and in the left kidney of a patient with PCLD. Fluid is bright on T2-weighting.
biliary structures. Infection within a cyst is a rare but serious complication and the patient will usually present with abdominal pain and raised inflammatory markers. Awareness of the diagnosis along with prompt treatment with antibiotics and a drainage procedure are necessary to reduce morbidity and mortality (51,52). Jaundice can occur in PCLD due to direct compression of the extrahepatic biliary tree by cysts (53). Most patients with PCLD have well-preserved parenchyma and hepatic failure is rarely reported. Gigot et al. produced a useful classification of adult PCLD according to the number and size of liver cysts and the amount of remaining liver parenchyma (54) (Table 33.1). This classification of PCLD is of use in determining treatment algorithms for patients.
treatment
Therapeutic intervention should only be considered for those patients with significant symptoms or complications
304
summary
Benign cystic lesions of the liver are being increasingly recognized due to improvements in and wider availability of radiological techniques. They only require treatment if they produce symptoms or if there is a diagnostic uncertainty. Treatment is usually in the form of percutaneous aspiration, aspiration sclerotherapy or surgery. Surgical treatment ranges from fenestration of the cyst wall, cystectomy, or liver resection. These can be performed as open or laparoscopic procedures according to the surgeons expertise. PCLD may rarely require liver transplantation. As yet there are no randomized or case control studies comparing different treatment options. Therefore, treatment decisions have to be based on level 3 evidence (the case report or small case series) and the experience of the treating physician.
novel treatments
Medical treatments have in the past had little role in the treatment of PCLD. There are reports of a reduction in cyst volume using the somatostatin analog octreotide. The effect is thought to be due to a direct reduction of fluid secretion by cholangiocytes (72). In one recent clinical trial, the treatment
305
key points
The vast majority of benign cystic lesions of the liver do not require treatment. Rarer forms of these lesions may have an element of diagnostic uncertainty. Indications for treatment are
Increase in size in surveillance scans Pain affecting quality of life Symptoms due to compression of the stomach, duodenum, biliary tree, portal venous system or inferior vena cava Intracystic hemorrhage Spontaneous/traumatic rupture Evidence of infection in the cyst Diagnostic uncertainty
acknowledgments
The authors would like to acknowledge and thank Dr David White, Consultant Radiologist, University Hospital Aintree, Liverpool, for contributing the images reproduced in this chapter.
references
1. Dhumeaux D. Congenital cystic diseases of the intra and extrahepatic bile ducts. Gastroenterol Clin Biol 2005; 29: 87882. 2. Mergo PJ, Ros PR. Benign lesions of the liver. Radiol Clin N Am 1998; 36: 31931. 3. Mortel KJ, Ros PR Cystic focal liver lesions in the adult: differential CT and MR imaging features. Radiographics 2001; 21: 895910. 4. Sanfelippo PM, Beahrs OH, Weiland LH. Cystic disease of the liver. Ann Surg 1974; 179: 9225. 5. Chang CS, Lin KC, Hwang SL, et al. Nonparasitic hepatic cysts detected in ultrasonographic examination: analysis of 95 cases. Taiwan Yi Xue Hui Za Zhi 1989; 88: 3949. 6. Gaines PA, Sampson MA. The prevalence and characterization of simple hepatic cysts by ultrasound examination. Br J Radiol 1989; 62: 3357. 7. Caremani M, Vincenti A, Benci A, et al. Ecographic epidemiology of nonparasitic hepatic cysts. J Clin Ultrasound 1993; 21(2):1158. 8. Carrim ZI, Murchison JT. The prevalence of simple renal and hepatic cysts detected by spiral computed tomography. Clin Radiol 2003; 58: 6269. 9. Larssen TB, Rrvik J, Hoff SR, et al. The occurrence of asymptomatic and symptomatic simple hepatic cysts. A prospective, hospital-based study. Clin Radiol 2005; 60: 10269. 10. Sanchez H, Gagner M, Rossi RL, et al. Surgical management of nonparasitic cystic liver disease. Am J Surg 1991; 161: 1138. 11. Erdogan D, van Delden OM, Rauws EA, et al. Results of percutaneous sclerotherapy and surgical treatment in patients with symptomatic simple liver cysts and polycystic liver disease. World J Gastroenterol 2007; 13: 3095100. 12. Takahashi G, Yoshida H, Mamada Y, et al. Intracystic hemorrhage of a large simple hepatic cyst. J Nippon Med Sch 2008; 75: 3025. 13. Ishikawa H, Uchida S, Yokokura Y, et al. Nonparasitic solitary huge liver cysts causing intracystic hemorrhage or obstructive jaundice. J Hepatobiliary Pancreat Surg 2002; 9: 7648. 14. Kanai T, Kenmochi T, Takabayashi T, et al. Obstructive jaundice caused by a huge liver cyst riding on the hilum: report of a case. Surg Today 1999; 29: 7914. 15. England RA, Wells IP, Gutteridge CM. Benign external compression of the inferior vena cava associated with thrombus formation. Br J Radiol 2005; 78: 5537. 16. Poggi G, Gatti C, Delmonte A, et al. Spontaneous rupture of non-parasitic hepatic cyst. Int J Clin Pract 2006; 60: 99103.
17. Klingler PJ, Gadensttter M, Schmid T, et al. Treatment of hepatic cysts in the era of laparoscopic surgery. Br J Surg 1997; 84: 43844. 18. Saini S, Mueller PR, Ferrucci JT Jr, et al. Percutaneous aspiration of hepatic cysts does not provide definitive therapy. Am J Roentgenol 1983; 141: 55960. 19. Koperna T, Vogl S, Satzinger U, et al. Nonparasitic cysts of the liver: results and options of surgical treatment. World J Surg 1997; 21: 8504. 20. Regev A, Reddy KR, Berho M, et al. Large cystic lesions of the liver in adults: a 15-year experience in a tertiary center. J Am Coll Surg 2001; 193: 3645. 21. Lopes HM, Portela FA, e Silva Pontes JM, et al. Treatment of benign hepatic cysts by instillation of tetracycline hydrochloride. Hepatogastroenterology 1998; 45: 4969. 22. McFarlane ME, Venugopal R, McDonald A, Ewing, et al. Management of hepatic cysts by percutaneous drainage and instillation of tetracycline hydrochloride. Indian Med J 2001; 50: 2303. 23. Cellier C, Cuenod CA, Deslandes P, et al. Symptomatic hepatic cysts: treatment with single-shot injection of minocycline hydrochloride. Radiology 1998; 206: 2059. 24. Yoshida H, Onda M, Tajiri T, et al. Long-term results of multiple minocycline hydrochloride injections for the treatment of symptomatic solitary hepatic cyst. J Gastroenterol Hepatol 2003; 18: 5958. 25. Goldstein HM, Carlyle DR, Nelson RS. Treatment of symptomatic hepatic cyst by percutaneous instillation of Pantopaque. Am J Roentgenol 1976; 127: 8503. 26. Bean WJ, Rodan BA. Hepatic cysts: treatment with alcohol. Am J Roentgenol 1985; 144: 23741. 27. Kairaluoma MI, Leinonen A, Sthlberg M, et al. Percutaneous aspiration and alcohol sclerotherapy for symptomatic hepatic cysts. An alternative to surgical intervention. Ann Surg 1989; 210: 20815. 28. Larssen TB, Jensen DK, Viste A, et al. Single-session alcohol sclerotherapy in symptomatic benign hepatic cysts. Long-term results. Acta Radiol 1999; 40: 6368. 29. Blonski WC, Campbell MS, Faust T, et al. Successful aspiration and ethanol sclerosis of a large, symptomatic, simple liver cyst: case presentation and review of the literature. World J Gastroenterol 2006; 12: 294954. 30. Horsmans Y, Laka A, Gigot JF, et al. Serum and cystic fluid CA 19-9 determinations as a diagnostic help in liver cysts of uncertain nature. Liver 1996; 16: 2557. 31. Yang CF, Liang HL, Pan HB, et al. Single-session prolonged alcohol-retention sclerotherapy for large hepatic cysts. Am J Roentgenol 2006; 187: 9403. 32. vanSonnenberg E, Wroblicka JT, DAgostino HB, et al. Symptomatic hepatic cysts: percutaneous drainage and sclerosis. Radiology 1994; 190: 38792. 33. Andersson R, Jeppsson B, Lunderquist A, et al. Alcohol sclerotherapy of non-parasitic cysts of the liver. Br J Surg 1989; 762545. 34. McCullough KM. Alcohol sclerotherapy of simple parenchymal liver cysts. Austr Radiol 1993; 37: 17781. 35. Simonetti G, Profili S, Sergiacomi GL, et al. Percutaneous treatment of hepatic cysts by aspiration and sclerotherapy. Cardiovasc Intervent Radiol 1993; 16: 814. 36. Montorsi M, Torzilli G, Fumagalli U, et al. Percutaneous alcohol sclerotherapy of simple hepatic cysts. Results from a multicentre survey in Italy. HPB Surg 1994; 8: 8994. 37. Tikkakoski T, Mkel JT, Leinonen S, et al. Treatment of symptomatic congenital hepatic cysts with single-session percutaneous drainage and ethanol sclerosis: technique and outcome. J Vasc Interv Radiol 1996; 7: 2359. 38. Zerem E, Imamovic G, Omerovic S. Percutaneous treatment of symptomatic non-parasitic benign liver cysts: single-session alcohol sclerotherapy versus prolonged catheter drainage with negative pressure. Eur Radiol 2008; 18: 4006. 39. Lin TY, Chen CC, Wang SM. Treatment of non-parasitic cystic disease of the liver: a new approach to therapy with polycystic liver. Ann Surg 1968; 168: 9217. 40. Fabiani P, Iannelli A, Chevallier P, et al. Long-term outcome after laparoscopic fenestration of symptomatic simple cysts of the liver. Br J Surg 2005; 925967. 41. Tan YM, Chung A, Mack P, et al. Role of fenestration and resection for symptomatic solitary liver cysts. ANZ J Surg 2005; 75: 57780.
306
307
34
308
BC P DC
Figure 34.1 Structure of the liver hydatid cyst. Abbreviations: L, liver; P, pericyst; C, chitinous layer; G, germinal layer; BC, brood capsules or vesicles; P, protoscoleces; DC, daughter cysts (similar to mother cyst).
thin residual septum (sand-glass-like cyst), or with the collapse of separating septum, the two cavities communicate through a more or less wide operculum (sacculations). As for the presence and frequency of ectogenic vesiculation, the phenomenon is either ignored or largely underestimated (59), because of the preference for conservative operations which do not allow their identification, and because in all reported series the recurrence rates of clear and multivesicular cysts are calculated together, thus leading to an under-reporting of the real incidence of recurrence in multivesicular cysts. However, ectogenic vesiculation is recognized in about 30% of radical operations for multivesicular cysts (10,11). Once this phenomenon was identified and quantitatively assessed, its importance was recognized beyond just biological and pathological interest. Consequently, in a large number of patients in whom procedures performed including no removal of the pericyst, this could not be considered effective: actually, only the cyst was resected. Viable, vital parasite foci remained, bound to lead to disease progression. This was incorrectly considered a recurrence attributed to implantation from accidental dissemination of the operating field or reinfection. The latter interpretations, already unconvincing, have lost credibility, based on the observation that the findings of ectogenic vesiculation, compared with the incidence of recurrence in series of conservative surgery, interestingly enough, were similar, at about 30%. This was furthermore confirmed by the fact that the so-called recurrences were practically absent in series of radical surgery (1214).
(A)
(B)
(C)
(D)
Figure 34.2 Cyst features (total pericystectomy specimens). (A) Multivesicular cyst; (B) yellow-colored cystic membrane for biliary infiltration; (C) calcific cyst of jelly-like necrotic contents and intense biliary infiltration; (D) calcific coarctate cyst of chalk-colored contents and dry clay consistency.
309
(A)
(B)
(C)
(D)
Figure 34.3 Exogenous vesiculation: microscopic appearance. (A) Brood capsules and protoscoleces contained in a protrusion of germinal layer within the cuticle; (B and C) intrapericyst exogenous vesiculation hydatid membranes within the pericyst of primary cyst; (D) extrapericyst exogenous vesiculation encircled by a new pericyst and protruding in the liver parenchyma adjacent to the mother cyst.
(A)
(B)
(C)
(D)
Figure 34.4 Intra- and extrapericyst exogenous vesiculation. Macroscopic appearance in four total pericystectomy specimens. (A and B) Within the pericyst of open cysts viable daughter cysts are observed, separated from the mother cyst cavity; (C and D) clusters of pedunculated pseudodiverticula, non-communicating with the mother cyst cavity, covered with a thin pericyst and containing daughter cysts.
310
diagnosis
Hydatid cyst of the liver may be asymptomatic for years, sometimes for decades. Diagnosis may be accidental, based on an incidental clinical exam that detects swelling when the cyst is located in a palpable abdominal area or, in the case of hepatomegaly, subsequently assessed with other examinations. Liver hydatidosis may be an incidental finding in a plain radiograph of the hepatic region when the cyst is calcified, during a chest radiograph for a raised hemidiaphragm or during US examination performed for other reasons such as gallstones. In children, large hepatic swellings from hydatid cysts are accompanied by evident deformities of the chest involving the last ribs and arches. Apart from a sensation of pressure, a cyst of the liver may cause deep-seated pain at the chest base because of diaphragmatic pleural or peritoneal reactive process. Dyspepsia, possibly from reflexes originating in the periductal nervous network, is not unusual. Cholestasis from major bile duct compression may be responsible for fever, also of high grade. Liver function tests remain normal for a long time. Diagnosis is established using several investigations. Conventional radiology may show a raised hemidiaphragm. In calcific cysts, high-density roundish shadows are readily visualized (Fig. 34.5). Diagnostic Imaging Ultrasonography (US) Ultrasound is the preferred first-line imaging method for hydatid liver cysts. It is non-invasive, low-cost and reproducible, thus suitable for postoperative follow-up or during medical therapy. US supplies precise information on the size, number, location, and vascular and biliary relationships of the cyst as well as on its structure. Cysts are staged according to the content patterns. Based on several studies and classifications (1518), liver hydatid cysts can be divided into six types:
CE 1 type, a concentric hyperechogenic halo around the cyst containing free-floating hyperechogenic foci corresponding to hydatid sand CE 2 type includes multivesicular cysts that have the most characteristic appearance with daughter cysts identified by honeycomb, rosette, spoke wheel, or cluster images (Fig. 34.6) CE 3 type is characterized by a partial or total detachment of the chitinous layer showing the dual wall, water-lily, and water snake signs. CE 4 type includes cysts containing cystic and solid components without visible daughter cysts. CE 5 includes cysts with a matrix or amorphous mass with a solid or semisolid appearance. Calcification in the rim of the host adventitial tissue is common.
Staging is important to allow more objective comparison of different management strategies. US is also useful in postoperative follow-up. Computed Tomography (CT) CT is the procedure of choice when considering radical surgery. Besides precise information on the cyst features, similar to those acquired by US (Fig. 34.7), CT is fundamental in identifying vascular relationships, number, site, and type of the cysts: dual, sand-glass like, with vesiculations (Fig. 34.8). CT is invaluable for the diagnosis of recurring patterns. Spiral CT is presently the gold standard investigation (19). Magnetic Resonance Imaging (MRI) A low-signal intensity rim on T2-weighted magnetic resonance imaging is a characteristic sign of hydatid liver disease that represents the outer collagen-rich laminated membrane of the cyst. When present, daughter cysts are seen as cystic structures attached to the germinal layer that are hypointense relative to intracystic fluid on T1-weighted images and hyperintense on T2-weighted images (20). MRI cholangiography can provide good visualization of the intrahepatic and extrahepatic biliary tree and its relationship with the hydatid cysts and cystobiliary communication (21,22) (Fig. 34.9).
CL type (univesicular cyst), a well circumscribed, round liquid, anechogenic image with a clearly defined wall.
(A)
(B)
Figure 34.5 Plain radiographs. (A) Partial en brioche image of diaphragm profile; (B) calcific image pathognomonic of hydatid cyst.
311
(A)
(B)
Figure 34.6 US image. (A) Total detachment of parasite membrane from pericyst; (B) multivesicular hydatid cyst: rosette sign.
(A)
(B) Figure 34.7 CT image. (A) Univesicular cyst; (B) water-snake sign of membrane detachment.
(A)
(B)
Figure 34.8 CT image. (A) Multivesicular cyst: honeycomb or rosette sign; (B) calcific cyst of segment VII in contact with the caval vein and causing intrahepatic duct dilation stasis.
312
(A)
(B)
Figure 34.9 (A) MRI coronal T1-weighted sequence after DTPA gadolinium injection with visualization of a cyst, about 2 cm in diameter, of segment IV at the level of portal vein bifurcation (in the same patient a bulky hydatid cyst of segments VII, VIII, and V is present); (B) same technique in another patient. Inferior caval vein compression with marked stenosis caused by a bulky cyst of right hemiliver.
Angiography Hepatic artery angiography, inferior caval vein, and hepatic vein venography have been progressively abandoned following the introduction of US and CT-angiography. They may be still of some use in the case of huge cysts to define their relationships with the main parenchymal vessels. Percutaneous cholangiography is contraindicated in liver hydatidosis because of the risk of perforation of the cystic wall and dissemination of hydatid contents. Endoscopic retrograde cholangiopancreatography (ERCP) can be considered the most suitable procedure for the characterization of the common bile duct and the biliary relationships and communication of the cyst. It allows pre- or postoperative papillotomy and bile duct clearing (2325). Perioperative cholangiography through the remnant of the cystic duct may be of great use to detect the site of cystobiliary fistulas. Radioisotope Imaging Scintigraphic imaging of the liver has been practically abandoned as a preoperative exam. Its use is presently restricted to monitor postoperative liver function. Serology The hydatid cyst secretes and exposes numerous immunomodulatory molecules to the hosts immune system. These molecules modulate both the innate and the adaptive arms of the immune response and appear to target cellular and humoral response. Several techniques for biologic diagnosis and follow-up of human cystic hydatidos are used and there are significant differences in specificity and sensitivity among various tests (26). The diagnostic value of hydatidosis with immunoelectrophoresis ranges between 91% and 94%. Immunoelectrophoresis can be used for post-treatment followup (27). Sensitivities for enzyme-linked immunosorbent assay (ELISA) vary from 64% to 100% depending on the antigens
used (28,29). This test is not suitable for post-treatment follow-up because of its longstanding positivity after successful treatment (30). Western blotting proved to be highly useful in the diagnosis and postsurgical monitoring of hydatidosis patients. Purification of antigens strongly affects the diagnostic value of the test which, however, when using purified fractions enriched in antigens 5 and B and glycoprotein, yield sensitivity and specificity close to 100% (31,32).
complications
During its development, hydatid cysts of the liver may undergo a number of complications, some of them clinically dramatic. Infection Infection of the cystic cavity and its contents is an ill defined and frequently asymptomatic complication (33). It is most likely caused by the penetration of bile into the cavity. Together with the contents, the mother membrane can be destroyed and consequently the altered escavated pericystic wall loses its function of delimiting the infectious process which reaches the hepatic parenchyma. Clinical course and related treatment are, in this case, those of a hepatic abscess (34,35). Rupture Frank rupture (major communication) into the bile ducts should be distinguished from simple biliary communication (minor communication). Minor communications are usually asymptomatic, revealed intraoperatively by a yellowish staining of the cystic content and the finding of biliary leakage in the residual cavity. The true incidence of minor communication is ill defined; and the reported rates range between 28.6% and 70% (36,37). The risk of biliary cyst communication has been reported to be higher in patients with multiple cysts, in patients to multilocular and degenerated cysts, and in patients with cysts near the biliary bifurcation (38). Cyst diameter
313
(A)
(B)
Figure 34.10 Residual surfaces after removal of deep or vasculobiliary cysts: dissected and preserved vascular and biliary elements are indispensable for the survival and function of parenchymal structures adjacent to the cyst. (A) The caval vein (c) and right hepatic vein with branchings are well visualized; (B) vasculobiliary network of hilar origin distribution.
314
parasites biology and interrelationship between the cyst and liver represent the scientific basis for a rational approach to surgery for hydatid liver disease. The choice of the procedure should not be at the surgeons discretion but determined by the cysts characteristics. For the two different types of sterile and fertile cysts, indications for surgery are as follows:
Univesicular (sterile), clear cysts, lacking of the pericyst, can be safely treated by conservative surgery. Multivesicular (fertile) cysts at different developmental stage should be treated by radical surgery because of the risk of exogenous vesiculation and because of high rates of postoperative complications.
Hepatic venous cysts Right or caval intermediate cysts (segments VII, VIII, VI, V) Hilar cysts Central cysts (interportohepatic) (VIII, IV and V) (55).
With the concept of radicality, surgery of liver hydatidosis becomes demanding and therefore selective surgical experience is required as the only means of ensuring a good chance of recovery.
approaches
Access must be generous for two main reasons: first, because of the frequent presence of adhesions of the protruding cyst to adjacent structures and organs, in particular the diaphragm. Second, because of the need for extended liver mobilization to control the vessels and exploit the liver flexibility to reduce the cavities or residual surfaces after pericyst removal. The bilateral subcostal approach, possibly extended depending on the location and size of the cyst(s), to the right as far as the midaxillary line, to the left as far as the lateral end of the rectus muscle, and medially upward as far as the xiphoid process of the sternum (mercedes incision) is the classic approach for liver surgery and hence for the surgical treatment of liver hydatidosis. Median laparotomy may be adequate for cysts located in the left lobe, when the right liver is known to be unaffected. The thoraco-abdominal approach is a no longer used, except in case of hydatid cysts involving the right lung base. Intraoperative General Concerns Protection of the operating field is mandatory before the planned operation on the cyst or before the cyst is emptied. A cautious approach is to apply protection before liver dissection, and when the cyst is protruding from the liver surface and adhering to the adjacent structures and organs. Isolation of the peritoneal and/or pleural cavity to limit the access to the operative field is achieved with dry gauze, preferred by the authors, or soaked in a parasiticidal or hypertonic saline solution, not unanimously considered harmless. During prior emptying of the cyst the gauze pads should be placed around the site of puncture by the trocar. When emptying the cyst, a large caliber trocar is connected with an aspirator by a similarly large non-collapsible tube. As soon as the cyst pressure is relieved and the protruding pericyst tends to collapse, two of its folds are grasped and raised with Allis or ovum forceps. The amount emptied depends on the contents: it will be practically complete in univesicular cysts, more or less partial in multilocular cysts where the hydatid material is abundant and dense. If the pericyst wall is opened with electric cautery, direct emptying is completed through a large tube with a frontal
In turn, hepatic venous cysts are divided into right (VII and VIII), median (IV), left (II); hilar cysts are divided into right (V), anterior median (IV), and posterior (I), left (II and/ or III) (Fig. 34.11). Clearly, there may be some overlap between locations. For example, right hepatic cysts may extend to the midright lobe and left hepatic cysts may be located across the hilum. Obviously, these possibilities do not affect the principles on which the classification is based.
treatment
The desired goals of treatment of liver hydatidosis include complete elimination of the parasite, prevention of recurrent disease, achieved with minimum mortality. In spite of other proposed techniques, surgery remains the first-line treatment. There is, however, considerable disagreement about the surgical technique to be adopted. The major issue of debate is whether complete removal of the pericyst is necessary for the proper care of the disease. The focused concepts about the
7 2 5 3 6 9
Figure 34.11 Topography of vasculobiliary hydatid cysts. 1, 4, 8: Right, median, left hepatic cysts; 3, 5, 6, 9: right, anterior median, posterior median, left hilar cysts; 2: intermediate cyst; 7: interportohepatic cyst.
315
Figure 34.12 Resection of protruding pericyst during conservative surgery. The left-hand fingers protect the inferior caval vein.
316
(A)
(B)
(C)
(D)
Figure 34.13 Right hepatectomy extended to segment IV and caudate lobe. (A) Bulky cyst mass; (B) the residual surface is sutured; (C) surgical specimen; (D) the gallbladder is packed with hydatid material.
317
Figure 34.14 Total pericystectomy. Dissection of pericyst from vasculobiliary structures should be along the presumed centriperipheral direction (following the direction of emerging and merging branches).
318
Figure 34.15 Total open pericystectomy. Stripping of pericyst and traction on each strip by folding facilitates deep dissection of vasculobiliary structures also in case of calcific pericyst. Figure 34.17 Total pericystectomy. In deep, non-emerging cysts, opening of the corresponding fissure is very useful. The cyst becomes accessible from several sides, somewhat similar to more superficial cysts.
Figure 34.16 Total open pericystectomy. Cautious full depth incision of pericyst with a lancet on the cavity bottom allows access to vessel dissection from several directions, even in the case of very thick cysts.
Figure 34.18 Total pericystectomy of deep cysts with multiple vasculobiliary relationships such as interportohepatic cysts is facilitated by opening the median fissure. Venous stasis from compression and compensatory collaterals may be present.
319
Figure 34.19 Exploration and cleansing of biliary tract. Through papillosphincterostomy the spoon for stones or a probe can be carefully advanced to identify the biliary breach and specify the type of communication, whether lateral or terminal, with the cyst cavity.
320
key points
Complications of hepatic hydatidosis include: Metastatic hydatid Secondary bacterial infection Intrabiliary rupture Intraperitoneal rupture Bronchobiliary fistula Diagnosis of hepatic hydatidosis: Incidental finding (in patient from endemic region) Abdominal mass Calcified hepatic cyst on the plain abdominal photograph (AXR) Ultrasound/CT/MRI Hydatid serology/Casoni skin test. Preoperative management: Systemic albendazole/mebendazole ERCP (exclude cystobiliary fistula) Protection of operative field before surgical emptying of cyst contents Sterilization of cyst cavity
references
1. Akinoglu A, Arparslan, Kaza K. Hydatid disease of the liver: prevention of postoperative biliary fistula. Arch Hidatid 1991; 30: 64955. 2. Chigot JP, Langlois P, Teboul F, et al. Le traitement des kystes hydatiques du foie. Ann Chir 1986; 40: 17782. 3. Euzeby J. Lechinococcose larvaire. Rev Med Vet 1955 ; 106 : 456-468. 4. Kalovidouris A, Voros D, Gouliamos A, Vlachos L. Papavasiliou C. Extracapsular (satellite) hydatid cysts. Gastrointest Radiol 1992; 17: 3536. 5. Bourgeon R, Catalano H, Guntz M. La pE9rikystectomie dans le traitement des kystes hydatiques du foie. J Chir 1961; 81: 15374. 6. Belli L, Del Favero E, Marni A, Romani F. Resection versus pericystectomy in the treatment of hydatidosis of the liver. Am J Surg 1983; 145: 23942. 7. Moreno Gonzales E, Jovez Navalon JM, Landa Garcia JI, et al. Surgical management of liver hydatidosis. 10-year experience with 269 patients. It J Surg Sci 1985; 15: 26773. 8. Debesse B, Dujon A. La pE9rikystectomie au plus prE8s dans le traitement du kyste hydatique du foie. Ann Chir 1987; 41: 64651. 9. Moreno Gonzales E, Rico Selas P, Bercedo Martinez J, et al. Results of surgical treatment of hepatic hydatidosis: current therapeutic modifications. World J Surg 1991; 15: 25463. 10. Tagliacozzo S, Daniele GM, Pisano G. Pericistectomia totale per echinococco epatico. Arch Atti Soc It Chir 1979; 1: 657712. 11. Tagliacozzo S, Daniele GM, Pisano G. Total pericystectomy for hydatid disease of the liver. 6B0 World Congr Coll Int Chir Dig, Lisbona 1980, abst SP503. 12. Magistrelli P, Masetti R, Coppola R, et al. Surgical treatment of hydatid disease of the liver. A 20 year experience. Arch Surg 1991; 126: 51823. 13. Moreno Gonzales E, Rico Selas P, Martinez B, et al. Results of surgical treatment of hepatic hydatidosi: current therapeutic modifications. World J Surg 1991; 15: 25463. 14. Aydin U, Yazici P, Onen Z, et al. The optimal treatment of hydatid cyst of the liver: radical surgery with a significant reduced risk of recurrence. Turk J Gastroenterol 2008; 19: 339.
321
322
323
35
Surgical management of primary sclerosing cholangitis Jason A. Breaux and Steven A. Ahrendt
IBD and because PSC patients may harbor a higher risk of colorectal cancer (7).
overview
Primary sclerosing cholangitis (PSC) is a chronic, progressive disease characterized by inflammation and fibrotic strictures of the biliary tree. Strictures are usually multi-focal, with 75% of patients demonstrating both intra- and extrahepatic duct involvement. Only 10% of patients have isolated extrahepatic duct involvement (13). The incidence of dominant strictures accounting for the majority of symptoms is approximately 45% and most (up to 80%) of these occur at or near the hilum (4). PSC is not only associated with inflammatory bowel disease (IBD) in 70% of cases, most commonly ulcerative colitis, but also occurs in the setting of autoimmune diseases such as ankylosing spondylitis, celiac sprue, autoimmune pancreatitis, thyroiditis, and others. The overall risk of developing PSC in patients with ulcerative colitis approaches 10%, for patients with Crohns disease the risk is lower, approximately 2%. As with inflammatory bowel disease there is an approximate 2:1 male to female predominance and most patients present in young adulthood or middle age (5,6).
natural history
The natural history of primary sclerosing cholangitis is variable but generally involves progression from cholestasis to biliary cirrhosis and ultimately hepatic failure leading to liver transplant or death. Many more patients are being diagnosed in the asymptomatic stage as screening for IBD patients with serum liver studies has become routine. PSC generally follows an insidious course and some patients remain asymptomatic for many years. However, others progress rapidly or present initially with high-grade obstruction, cirrhosis, or cholangiocarcinoma. The median time from diagnosis to death or need for liver transplantation is 12 to 18 years. Liver failure and cholangiocarcinoma are the leading causes of death, in order of frequency (6). The Mayo Clinic developed a mathematical model to stratify patients risk, which has recently been updated. It utilizes data on patient age, total bilirubin level, aspartate aminotransferase level, presence of variceal bleeding, and serum albumin level to predict survival and assign a Mayo Risk Score (8). This can be used to prioritize treatment plans for individual patients. Unfortunately, surgical treatment for inflammatory bowel disease such as proctocolectomy for ulcerative colitis does not alter the natural course of PSC and patients may even present years after successful treatment for IBD.
diagnosis
Patients with PSC usually present with signs of cholestasis including right upper quadrant abdominal pain, jaundice, pruritis, and/or abnormal serum liver studies. Some IBD patients are diagnosed during routine screening for liver disease revealing elevated liver function tests particularly an elevated serum alkaline phosphatase (2,6). In the absence of alternative etiologies of cholestatic liver disease, the diagnosis is usually confirmed with high-quality imaging of the biliary tree utilizing endoscopic retrograde cholangiography (ERC), or more recently, magnetic resonance cholangiography (MRC). Both methods effectively demonstrate the characteristic beads-on-a string strictures (Fig. 35.1) of PSC making diagnosis possible in over 95% of cases using image criteria alone (3). ERC offers the ability to perform concurrent intervention, with the disadvantage of the low (38%) but welldefined incidence of complications related to this invasive procedure. MRC is diagnostic only, but has the advantage of minimal risk. MRC is also superior for visualization of ductal anatomy proximal to dominant strictures, and the two modalities may be used in complimentary fashion. Percutaneous transhepatic cholangiography (PTC) and intervention can also be utilized where the expertise exists, but PTC is notoriously difficult in patients with the altered ductal anatomy inherent to PSC. Regardless of imaging modality, detailed knowledge of a patients ductal anatomy is essential prior to any surgical intervention. Liver biopsy should be obtained at the time of diagnosis to assess the hepatic parenchyma for the presence and degree of fibrosis, which can alter treatment plans. Colonoscopy should also be performed to identify patients with subclinical
cholangiocarcinoma
Cholangiocarcinoma (CCA) develops in 10% to 30% of patients with PSC, and the incidence of CCA increases with the length of follow-up (510 years). The incidence of 10% at 5 years correlates with an increased risk of 160-fold over the general population. It is an ominous finding as the majority of patients have unresectable disease at the time of diagnosis and an overall median survival of only 5 to 11 months. A high index of suspicion is warranted, as just over half of patients with CCA related to PSC are diagnosed concurrently or within 1 year of their initial presentation (9,10). The diagnosis of cholangiocarcinoma in PSC can be challenging. Imaging techniques such as CT, MR, and positron emission tomography have proven largely unreliable in distinguishing benign from malignant biliary strictures. The majority (approximately 80%) of CCAs in PSC occur at the liver hilum, corresponding with the most frequent location for dominant strictures in this disease. Brushings and/or biopsies for cytology taken at the time of ERC have only up to 43% sensitivity in detecting malignancy (11). Recently, advanced cytologic techniques that identify chromosomal abnormalities including digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have shown promise, but further study is warranted before widespread application is possible (12).
324
(A)
(B) Figure 35.1 Cholangiograms (A and B) demonstrating the characteristic beads on a string strictures of PSC.
Tumor markers are moderately helpful in distinguishing benign from malignant strictures in PSC. Serum CEA and CA19-9 levels may both be elevated in CCA. Of the two tests, CA19-9 is the most useful and is relatively sensitive and specific in the diagnosis of CCA (78% and 98%, respectively) when elevated greater than 129 U/ml in the setting of PSC, based on a recent Mayo Clinic study. However, the majority of patients diagnosed by an elevated serum CA 19-9 level have unresectable disease and the utility of CA19-9 as a screening tool to identify early-stage disease in PSC patients is lacking. The best approach to diagnosis in patients with suspicious history or imaging findings seems to include the combination of a high index of suspicion, high-quality imaging, endoscopic brushings/biopsy, and CA19-9 levels. However, the diagnosis often remains in question and surgical excision with histopathologic examination is the only option in many cases to definitively rule out malignancy. Margin-negative surgical resection, when possible, also offers the only chance for longterm survival as traditional chemotherapeutic agents and radiation have poor efficacy in cholangiocarcinoma (1013). Recent trials indicating improved survival with newer agents such as gemcitabine given neoadjuvantly followed by resection or transplantation have shown promise, but these approaches await validation and can only be recommended in the protocol setting (14,15).
endoscopic management
Endoscopic treatment involving balloon dilation to relieve symptomatic obstruction has become first-line treatment for benign dominant biliary strictures in primary sclerosing cholangitis. Stents were routinely employed in the past but have fallen out of favor due to studies identifying an increased risk of bacterial cholangitis with their use (19,20). Dominant strictures are defined as common bile duct or common hepatic duct stricture with a cross-sectional diameter of <1.5 mm and/ or a hepatic duct stricture with a diameter <1.0 mm within 2 cm of the hepatic duct bifurcation (21). Dilation of dominant strictures relieves symptoms, improves serum liver studies, and can produce durable improvement in imaging findings. Most patients require multiple interventions for adequate biliary drainage (20). The effect of endoscopic treatment on disease progression and survival is controversial. Two studies by Stiehl et al. and Baluyut et al. demonstrated improved overall survival and transplant-free survival with repeated endoscopic dilation, compared to that which would be predicted using the Mayo mathematical model. The incidence of cholangiocarcinoma developing during the follow-up period in the two series was 3% and 8%, respectively (Table 35.1) (21,22).
medical treatment
The inflammation and strictures of primary sclerosing cholangitis are thought to be immune-mediated and various immunosuppressive medications have been used in an attempt to slow the progression of PSC. However, numerous prospective randomized trials have failed to identify an agent that slows progression or improves outcome in patients with PSC (6). The most extensively studied drug, ursodeoxycholic acid, has been shown anecdotally to improve bile acid transport and have immuno-modulatory effects. However, despite initial encouraging studies showing improvement in serum liver studies and histologic findings on liver biopsy in PSC patients, no definitive improvement in survival or outcome has been observed in two large randomized trials (16,17). The National Institute of Health has sponsored a multicenter trial
surgical management
Surgical resection for primary sclerosing cholangitis was the only therapeutic option for patients with dominant strictures before the development of advanced endoscopic techniques and liver transplantation (2325). The fact that most of the dominant strictures in PSC occur at or near the hepatic bifurcation makes resection and biliary-enteric drainage feasible and effective therapy (26). However, morbidity and mortality are high in patients with advanced disease and cirrhosis. Liver transplant is the treatment of choice for these patients and PSC has become a leading indication for transplantation. However, although advancements in endoscopy and transplantation have made resection of dominant strictures in PSC less common, there is still a role for this approach in select patients.
325
60%
95% 95%
Table 35.2 Transplant-free Survival in Recent Studies on Endoscopic and Surgical Treatment of Dominant Strictures in Noncirrhotic Patients with Primary Sclerosing Cholangitis
1 year Endoscopic therapy Stiehl et al. Ahrendt et al. Surgical therapy Ahrendt et al. 85% 95% 3 year 93% 59% 92% 5 year 89% 46% 82%
Table 35.3 Survival of Patients with Primary Sclerosing Cholangitis Without Cholangiocarcinoma Treated by Surgical Resection (Extrahepatic Bile Duct Resection) Versus Transplantation
3 year Surgical resection Overall Noncirrhotics Cirrhotics Transplantation Source: Adapted from Ref. (31). 85% 95% 60% 87% 5 year 76% 83% 36% 67% 10 year 52% 60% 12% 57%
The indications for surgical resection in noncirrhotic PSC patients include symptomatic dominant strictures not amenable or recalcitrant to endoscopic dilation, failure to rule out malignancy in suspicious lesions, the finding of dysplasia or atypia on endoscopic brushings/biopsies and when resectable cholangiocarcinoma is identified (2729). Biliary strictures that persist or recur despite dilation raise suspicion for malignancy and resection should be considered. High-quality preoperative imaging to define biliary and hepatic vascular anatomy is essential for operative planning. Broad-spectrum antibiotics covering biliary-enteric organisms should be administered preoperatively and continued postoperatively for 24 to 48 hours or until postoperative fever and cholangitis resolve. Surgical treatment involves resection of the extrahepatic biliary tree including the biliary bifurcation at the hilum, cholecystectomy, division and oversewing of the distal common
bile duct at the pancreatic head, and reconstruction with Roux-en-Y bilateral hepaticojejunostomies. Bile cultures should be obtained intraoperatively to guide therapy if postoperative cholangitis persists. Bilateral percutaneous transhepatic biliary stents are usually placed preoperatively to aid in portal dissection, and these are exchanged intraoperatively for silastic stents which are placed across the anastamosis and remain in long term to provide drainage and access to the biliary tree (2328,3033). There is some debate on the duration of post-operative drainage, but most experts advocate removal of the stents at approximately 1 year if the biliary-enteric anastamosis is widely patent. Major hepatic resection may also be included, using standard techniques, to achieve margins in the case of cholangiocarcinoma or extensive hilar fibrosis (11,30). Postoperative mortality following extrahepatic biliary resection for PSC is low (24%) as reported by centers with a high volume of hepatobiliary surgical experience. Morbidity is approximately 35%, with the majority of postoperative complications being mild and related to cholangitis. The effect of surgical resection on long-term outcome remains controversial. Early series suggested an overall and transplant-free survival benefit in favor of resection, when compared with similar series on endoscopic management (Tables 35.1 and 35.2). The most extensive investigation into this subject to date has come from data collected and published from The Johns Hopkins Hospital. This was recently expanded and updated by Pawlik et al. to include data from multiple centers with an extended follow-up of 10 years (31). They observed overall survival in noncirrhotic PSC patients undergoing resection of 95%, 83%, and 60% at 1 year, 5year and 10 year follow-up, respectively. They also reported favorable results resection, especially in noncirrhotic patients, when compared with liver transplantation (Table 35.3). Only 4 of 66 patients (6%) in the resection group went on to require transplant in this series. They also reported a relatively low rate of readmission following resection for PSC, with over half of patients requiring no readmissions for PSC-related problems at 3-year follow-up. The most common indication for readmission was for stent change and/ or treatment of cholangitis. Most significantly, no patients developed cholangiocarcinoma during the median follow-up time of 10.5 years (Table 35.1). This is likely due to the removal of the most common source of malignancy with this approach,
326
summary
Primary sclerosing cholangitis is a chronic, stricturing disease of the bile ducts leading to progressive cholestatic liver disease and a dramatic increase in risk for cholangiocarcinoma. Dominant strictures are common and usually involve the hepatic bifurcation. Medical therapy is ineffective in preventing progression of disease or improving outcomes. Optimal management of symptomatic noncirrhotic patients with dominant strictures has been somewhat controversial. Endoscopic therapy palliates symptoms and is relatively low risk and outcomes seem to be improved over mathematical predictions. However, the risk of cholangiocarcinoma remains in endoscopically treated patients and close follow-up is necessary. Surgical resection of the extrahepatic biliary tree also improves survival over predicted, and the primary site for the development of cholangiocarcinoma is removed. Therefore, a treatment strategy for symptomatic, noncirrhotic patients with PSC should involve a multi-disciplinary approach. High-quality imaging and a high index of suspicion for cholangiocarcinoma with appropriate screening measures are essential after diagnosis. Initially, endoscopic dilation of seemingly benign dominant strictures should be undertaken. Recurrent or suspicious lesions should be strongly considered for resection due to the risk of CCA. The surgical approach should involve resection of the extrahepatic biliary tree including the hepatic bifurcation with hepaticojejunostomy. PSC patients that progress to cirrhosis are best treated with orthotopic liver transplant.
references
1. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995; 332: 92433. 2. Zyromski NJ, Pitt HA. Primary sclerosing cholangitis. In: Cameron JL, ed. Current Surgical Therapy, 9th edn, Philadelphia: Mosby/Elsevier, 2008: 43842. 3. LaRusso NF, Shneider BL. Primary sclerosing cholangitis: summary of a workshop. Hepatology 2006; 44: 74664. 4. Bjornsson E, Lindquist-Ottosson J, Asztely M, et al. Dominant stricture in patients with primary sclerosing cholangitis. Am J Gastroenterol 2004; 99: 5028. 5. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel Dis 2005; 11: 6272. 6. Silveria MG, Lindor KD. Clinical Features and management of primary sclerosing cholangitis. World J Gastroenterol 2008; 14(21): 333849.
327
328
36
Gallbladder cancer is uncommon disease, although it is not rare. Indeed, gallbladder cancer is the fifth most common gastrointestinal cancer and the most common biliary tract cancer in the United States. The incidence is 1.2 per 100,000 persons per year (1). It has historically been considered as an incurable malignancy with a dismal prognosis due to its propensity for early invasion to liver and dissemination to lymph nodes and peritoneal surfaces. Therefore, clinical attitudes toward gallbladder cancer were pervaded with pessimism and nihilism. Population data in United States from 1988 through 2003 suggested >95% of surgically resectable gallbladder cancer has been treated with only simple cholecystectomy (2). Although recent advances in surgical technique and perioperative management have allowed an increased role for radical surgery in appropriately selected cases, the outcomes of majority of patients with advanced gallbladder cancer remains poor. Patients with gallbladder cancer usually present in one of three ways: (1) advanced unresectable cancer; (2) detection of suspicious lesion preoperatively and resectable after staging work-up; (3) incidental finding of cancer during or after cholecystectomy for benign disease. In this chapter, we describe a contemporary approach to advanced gallbladder cancer in the former two scenarios. We define advanced cancer as tumor penetrating through gallbladder wall (T3 or greater), metastasizing to regional lymph node (N1) or distant organ (M1). In the AJCC staging system, this is staged as II or higher on 6th edition (3) and as III, IVa, or IVb on 5th edition system (4). Refer previous chapter for more detailed discussion for staging systems of gallbladder cancer.
329
surgical management
Although, many studies have suggested improved survival in patients with early gallbladder cancer with radical surgery including en bloc resection of gallbladder fossa and regional lymphadenectomy, its role for those with advanced gallbladder cancer remains controversial. First, patients with more advanced disease often require more extensive resections than early stage tumors, and operative morbidity and mortality rates are higher (24). Second, the long-term outcomes after resection, in general, tend to be poorer; long-term survival after radical surgery has been reported only for patients with limited local and lymph node spread. Therefore, the indication of radical surgery should be limited to well-selected patients based on thorough preoperative and intra-operative staging and the extent of surgery should be determined based on the area of tumor involvement. Surgical resection is warranted only for those who with locoregional disease without distant spread. Because of the limited sensitivity of current imaging modalities to detect metastatic lesions of gallbladder cancer, staging laparoscopy prior to proceeding to laparotomy is very useful to assess the abdomen for evidence of discontinuous liver disease or peritoneal metastasis and to avoid unnecessary laparotomy. Weber et al. reported that 48% of patients with potentially resectable gallbladder cancer on preoperative imaging work-up were spared laparotomy by discovering unresectable disease by laparoscopy (25). Laparoscopic cholecystectomy should be avoided when a preoperative cancer is suspected because of the risk of violation of the plane between tumor and liver and the risk of port site seeding.
Figure 36.1 ERCP of an advanced gallbladder cancer showing mid-bile duct obstruction.
Figure 36.2 Axial, contrast-enhanced computed tomogram of an advanced gallbladder cancer showing invasion into the liver parenchyma (arrowhead) and involvement of the stomach and first portion of the duodenum (arrow).
330
outcomes
Although advances in surgical technique and improvement in perioperative care allow us to perform radical resection for patients with gallbladder cancer safely, the outcomes for those with advanced cancer remain disappointing. The 5-year survival rates for patients having radical surgery ranged from 0% to 51%, most of them fall in 20% to 30% (Table 36.1). Nodal status and histological margin have been reported as predictive factors of survival after radical resection for this group of patients throughout the literature. For example, Behari and his colleague reported that positive node was associated with incomplete resection and none of the patients with N1 disease survived beyond 5 years (30). Endo and his colleague reported in their analysis of 55 patients who underwent complete resection, a 77% 5-year survival for patients without nodal involvement, 33% for those with single lymph node involvement, and 0% for those with two or more lymph nodes involvement (35). These findings suggest that radical resection should not be performed for patients with gross lymph nodes involvement or extensive tumor infiltration to adjacent structure on perioperative evaluation, both of which make complete resection with histological negative margin unlikely.
palliative care
Most patients with gallbladder cancer present with advanced, incurable disease and many are not candidates for surgical resection. The median survival of patients with advanced gallbladder cancer who are deemed inoperable ranges between 2 and 4 months (6,9,40) and palliation of symptoms should be the primary goal. Symptoms and conditions associated with incurable gallbladder cancer include jaundice, cholangitis, pain, and gastrointestinal obstruction. For obstructive jaundice or gastrointestinal obstruction, palliative intervention may be required. The common procedure for biliary obstruction due to gallbladder cancer is a segment III bypass (41). In their series of 41 consecutive segment III bypass for patients with advanced gallbladder cancer, Kapoor and his colleagues reported 87% success rate with 12% mortality and 51% morbidity rate (42). Because of poor survival, biliary stent is a preferred option for most of the patients. It can be placed via either percutaneous transhepatic route or endoscopic approach with minimal morbidity. Intestinal bypass should be performed only in patients who have symptomatic obstruction. Systemic chemotherapy and radiation therapy have, in general, little impact on unresectable gallbladder cancer. Multiple
adjuvant therapy
Because of its propensity to spread to regional lymph nodes at early stage and high rate of locoregional recurrence, adjuvant chemotherapy and/or chemoradiation therapy seems a rational therapeutic option for gallbladder cancer. Traditionally 5-FU based chemotherapeutic regimen has been used with or without combination of chemoradiation. However, there are few data to support its efficacy. The rarity of gallbladder cancer and further limitation of patients who can undergo complete resection make the randomized trial difficult to conduct. To date, there is only one randomized trial examining the efficacy of adjuvant chemotherapy for gallbladder cancer. This study
N 58 38 24 39 631 72
Note
Multi-institutional study
331
references
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2): 7196. 2. Coburn NG, Cleary SP, Tan JC, et al. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg 2008; 207(3): 37182. 3. Greene F, Page D, Fleming I, et al. AJCC Cancer Staging Manual, 6th edn. New York: Springer-Verlag, 2002. 4. Fleming I, Cooper J, Henson D, et al. AJCC Cancer Staging Manual, 5th edn. Philadelphia: Lippincott-Raven, 1998. 5. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000; 232(4): 55769. 6. Hawkins WG, DeMatteo RP, Jarnagin WR, et al. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol 2004; 11(3): 3105. 7. Chan SY, Poon RT, Lo CM, et al. Management of carcinoma of the gallbladder: a single-institution experience in 16 years. J Surg Oncol 2008; 97(2): 15664. 8. Dixon E, Vollmer CM, Jr., Sahajpal A, et al. An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg 2005; 241(3): 38594. 9. Ito H, Matros E, Brooks DC, et al. Treatment outcomes associated with surgery for gallbladder cancer: a 20-year experience. J Gastrointest Surg 2004; 8(2): 18390. 10. Gandolfi L, Torresan F, Solmi L, et al. The role of ultrasound in biliary and pancreatic diseases. Eur J Ultrasound 2003; 16(3): 14159. 11. Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics 2001; 21(2): 295314; questionnaire, 54955. 12. Onoyama H, Yamamoto M, Takada M, et al. Diagnostic imaging of early gallbladder cancer: retrospective study of 53 cases. World J Surg 1999; 23(7): 70812. 13. Komatsuda T, Ishida H, Konno K, et al. Gallbladder carcinoma: color Doppler sonography. Abdom Imaging 2000; 25(2): 1947. 14. Gourgiotis S, Kocher HM, Solaini L, et al. Gallbladder cancer. Am J Surg 2008; 196(2): 25264. 15. Ohtani T, Shirai Y, Tsukada K, et al. Carcinoma of the gallbladder: CT evaluation of lymphatic spread. Radiology 1993; 189(3): 87580. 16. Ohtani T, Shirai Y, Tsukada K, et al. Spread of gallbladder carcinoma: CT evaluation with pathologic correlation. Abdom Imaging 1996; 21(3): 195201. 17. Kumaran V, Gulati S, Paul B, et al. The role of dual-phase helical CT in assessing resectability of carcinoma of the gallbladder. Eur Radiol 2002; 12(8): 19939. 18. Yoshimitsu K, Honda H, Shinozaki K, et al. Helical CT of the local spread of carcinoma of the gallbladder: evaluation according to the TNM system in patients who underwent surgical resection. AJR Am J Roentgenol 2002; 179(2): 4238. 19. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J Comput Assist Tomogr 2002; 26(3): 40510. 20. Petrowsky H, Wildbrett P, Husarik DB, et al. Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 2006; 45(1): 4350. 21. Rodriguez-Fernandez A, Gomez-Rio M, Llamas-Elvira JM, et al. Positronemission tomography with fluorine-18-fluoro-2-deoxy-D-glucose for gallbladder cancer diagnosis. Am J Surg 2004; 188(2): 1715. 22. Anderson CD, Rice MH, Pinson CW, et al. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg 2004; 8(1): 907.
332
37
preoperative managements
Staging of Cholangiocarcinoma Recent developments in diagnostic modalities have changed the preoperative staging system, with invasive techniques being replaced by non-invasive diagnostic procedures. Extracorporeal ultrasonography (US) is first used to detect biliary dilation proximally to a possible biliary lesion, and magnetic resonance cholangiopancreatography (MRCP) is performed to demonstrate gross anatomy of the biliary tree and the variation of the intrahepatic bile ducts. Surgical anatomy and the extent of the cancer along the involved intrahepatic segmental ducts also have to be clarified in patients with hilar cholangiocarcinoma (Fig. 37.4A). Multi-detector row CT (MDCT) is helpful not only to assess the depth of invasion and longitudinal extension of cholangiocarcinoma but also to find lymph node and distant organ metastases. Furthermore multiplanar reformation (MPR) images provide more useful information about complex structures at the hepatic hilus and display the entire length of the involved bile duct, and show ductal thickening and intraductal masses (Fig. 37.4B). Also volume
333
6b 5b
5b 6a 6a 6b
Figure 37.1 Cholangiographic anatomy of the intrahepatic subsegmental bile duct. Numerals refer to Couinauds segments. 3a, Superior branch; 3b, inferior branch; 4a, inferior branch; 4b, superior branch; 4c, dorsal branch; 5a, ventral branch; 5b, dorsal branch; 5c, lateral branch; 6a, ventral branch; 6b, dorsal branch; 6c, lateral branch; 7a, ventral branch, 7b, dorsal branch; 8a, ventral branch; 8b, lateral branch; 8c, dorsal branch.
curative hepatobiliary resection (2936). These invasive diagnostic procedures are carried out during the preoperative period of biliary drainage.
1r 1r 1ls
2 A U P 4 3
P 1li
1c
Portal Vein Embolization At the final stage of preoperative BD, liver function tests including indocyanine green (ICG) test are performed. Also the functional capacity of each section of the liver is carefully estimated by both the CT volumetric study and the ICG test (37,38). PE is performed safely before extended hepatectomy to prevent postoperative liver failure for patients with marginal functional capacity of the future remnant liver and to increase the resectability rates for patients with advanced hilar cholangiocarcinoma (39,40). At a minimum of 2 weeks later, liver resection volume and functional capacity of the future remaining liver are estimated again by CT volumetry and ICG test to decide the timing of the definitive surgery (Fig.37.7). Clinical studies on PE offered revolutionary progress in hepatobiliary surgery and have actually increased resectability and the safety of major liver resection for locally advanced hilar cholangiocarcinoma (41,42). Synbiotics Treatments with Bile Replacement Obstructive jaundice is associated with an increased incidence of bacterial translocation and infectious complications after hepatectomy for biliary cancer patients still remain a major problem, although surgical techniques and perioperative care have been improved. External BD alone cannot re-establish the defense system against bacterial translocation and absence of intestinal bile plays an important role in the development of infectious complications related to biliary obstruction. On the contrary, internal BD prevents the loss of bile from the gastrointestinal tract, preserves the enterohepatic biliary circulation, and normalizes the enhanced intestinal permeability in obstructive jaundice. Therefore bile replacement should be carried out during external BD to
Figure 37.2 Surgical anatomy of the hepatic hilus, including the biliary and portal branches of the caudate lobe. U, Umbilical portion of the left portal vein; P, right posterior branch; A, right anterior branch; 1ls, superior branch of the left caudate lobe; 1li, inferior branch of the left caudate lobe; 1r, branch of the right caudate lobe; 1c, branch of the caudate process; 2, left lateral posterior branch; 3, left lateral anterior branch; 4, left medial branch.
cholangiocarcinoma, per-oral cholangioscopy (POC) or percutaneous transhepatic cholangioscopy (PTCS), followed by mapping biopsy is useful to detect minor mucosal changes and define the proximal mucosal extension of the cancer into the intrahepatic segmental ducts, and so design an appropriate
334
EXTRAHEPATIC CHOLANGIOCARCINOMA
Round ligament Round ligament Round ligament
S4 P4 B4
S3 P3 B3 B2 P2 P4 B4
S4
S3 P3 B3 B2 P2 P4 B4
S4
S3 B3a P3 B3b B2 P2
Figure 37.3 Schema of the infraportal variation of the anterior branch of the left lateral section (B3). (A) Normal anatomy, (B) infraportal B3 joining B4, (C) supraportal B3d (superior branch) and infraportal B3b (inferior branch).
(A)
(B)
(C)
Figure 37.4 (A) MRCP shows biliary stricture at the hepatic hilus. A possible diagnosis is hilar cholangiocarcinoma separating the hepatic confluence. (B) Coronal images of multiplanar reformation (MPR) show a soft tissue tumor at the hepatic confluence separating the right and left hepatic duct (arrow). (C) The soft tissue tumor separates the confluence of the right anterior and posterior sectional ducts (arrow).
(A)
(B)
Figure 37.5 Volume rendered (VR) images of the hepatic artery (A) and portal vein (B). 3D images can be obtained. (A). Irregular encasement is demonstrated on the right hepatic artery (arrow). (B) The left portal vein is obstructed and the right portal vein is involved (arrow). P, right posterior sectional branch; 7d, paracaval branch of the segment 7.
335
operative procedures
Pancreatoduodenectomy for Mid-third and Distal Cholangiocarcinoma PD and pylorus-preserving pancreatoduodenectomy (PPPD) have been used as the standard operation not only for pancreatic cancer but also for distal cholangiocarcinoma. Although the details of this surgical procedure are presented in the chapter of pancreatic cancer, an important part of the procedure as related to cholangiocarcinoma is presented to avoid an overlap of description. PD versus PPPD PPPD is preferably used in biliary tract cancer surgery to preserve the important organs as much as possible. Also, as the risk of peripyloric lymph node metastasis is low in extrahepatic
L B4b
B2
B1 B3 P B4a1
(A) (B)
B4a2
Figure 37.6 (A) PTBD tube cholangiography in a supine position. A tip of the PTBD catheter (arrow) is introduced from the right anterior sectional duct into the left hepatic duct across the hepatic confluence occupied by the tumor to drain bile from the future remnant hepatic lobe. Another PTBD catheter (arrow head) is placed in the right posterior sectional duct. A: right anterior sectional duct, P: right posterior sectional duct, L: left hepatic duct. (B) PTBD tube cholangiography in a right anterior and cranioanterior oblique position. Selective cholangiography of the left hepatic duct clearly demonstrates each segmental duct and the expected resection line can be defined at the confluence of the left medial segmental duct proximally to the confluence of the caudate lobe branch. B1: caudate lobe branch, B2: lateral posterior branch, B3: lateral anterior branch, B4a: medial inferior branch, B4b: medial superior branch.
Before
After
Figure 37.7 Volumetric changes of the liver sections before and after right trisectional portal vein embolization. Hypertrophy of the left lateral section is observed after portal vein embolization.
336
EXTRAHEPATIC CHOLANGIOCARCINOMA
cholangiocarcinoma, PPPD is advisable as appropriate surgery for distal cholangiocarcinoma. Extent of Lymph Node Dissection Lymph node metastasis, perineural invasion, surgical resection margins, and pancreatic invasion are prognostic factors after curative resection for middle and distal cholangiocarcinoma (4651). Therefore regional lymph node dissection is necessary, including the nodes in the hepatoduodenal ligament and along the common hepatic and superior mesenteric arteries. Proximal Extension of Resection In cases of distal cholangiocarcinoma with proximal extension close to the hepatic confluence, the proximal bile duct is carefully dissected while detaching the portal bifurcation and the left hepatic duct is transected on the left extremity of the hilar plate along the right wall of the umbilical portion of the left portal vein (UP). At the resected margin of the left hepatic duct, the openings of the resected segmental ducts (B2, B3, and B4) are identified according to their anatomical variation. On the right extremity of the hilar plate, the right hepatic artery is carefully skeletonized in Rouvieres sulcus and the right posterior sectoral duct is carefully divided with a negative margin. Next, the right anterior sectoral duct is divided. The caudate lobe branches are sometimes identified and divided according to their anatomical variation (Fig. 37.8). Hepaticojejunostomy After resecting the proximal bile duct, each individual sectional or segmental bile duct should be anatomically identified and sutured side by side to complete the hepaticoplasty and to minimize the number of hepaticojejunostomies with a Roux-en-Y jejunal limb. A running suture of 5-0 PDS is preferably used for both posterior and anterior wall anastomosis. Hepatobiliary Resection for Hilar Cholangiocarcinoma Most of hilar cholangiocarcinoma involving the hepatic confluence are indicated for liver and extrahepatic bile duct resection with caudate lobe resection, because the caudate lobe branches join the right and left hepatic ducts and/or their confluence and mostly be involved by carcinoma at the hepatic confluence (46). In this section, important parts of the surgical procedures for cholangiocarcinoma are described. Left Hepatectomy, Caudate Lobectomy, and Extrahepatic Bile Duct Resection Left-sided hepatectomy is indicated for hilar cholangiocarcinoma predominantly involving the left hepatic duct (51). After regional node and connective tissue dissection, the distal bile duct is resected in the pancreas with a histologically free margin. After dividing the vascular structures for the left liver and the caudate lobe, the left lateral section of the liver is mobilized toward the right anteriorly and the caudate lobe is also mobilized to the right anteriorly, while ligating and dividing all the short hepatic veins. Then the caudate lobe is completely detached from the inferior vena cava (IVC). Next, the liver is transected along the demarcation line and this dissection progressed toward the hepatic hilus to identify the right hepatic duct and the right anterior sectional duct crossing behind the middle hepatic vein (MHV). The dorsal aspect of liver dissection is aligned along the right lateral edge of the IVC and the caudate process is detached from the segment 7 to remove the entire caudate lobe. Then the isolated right anterior sectional duct or segmental ducts are divided with free margins. Next, the right posterior sectional duct is exposed cranially to the right portal vein and divided with a negative margin; and the left liver, caudate lobe, and extrahepatic duct are removed en bloc.
4 3 A P A 1 1 2
LH M HA
RH
Figure 37.8 Hilar bile duct resection. The right and left sectional or segmental ducts and caudate lobe branches are identified and divided with free margins. Numerals refer to Couinauds segments. A, anterior sectional duct; P, posterior sectional duct; RHA, right hepatic artery; MHA, middle hepatic artery; LHA, left hepatic artery.
337
Figure 37.9 The right posterior segmental and subsegmental ducts are identified at the resected margin of the right posterior sectional duct. P6, posterior inferior portal branch; P7, posterior superior portal branch; B6a, ventral biliary branch; B6bc, dorsal and lateral biliary branch; B7, posterior superior biliary branch; RHV, right hepatic vein..
338
EXTRAHEPATIC CHOLANGIOCARCINOMA
caudate lobe from the IVC. At the cranial part of this procedure, the distal end of the RHV is divided and closed at the confluence of the IVC. Next, liver transection is started from the right edge of the attachment of the round ligament and progressed dorsally along the right edge of the UP and the portal branches for the left medial section (S4) are ligated and divided. During this procedure, the lumen of the divided portal branches must be carefully observed not to overlook portal thrombi at the bifurcation if the right trisectional PE has already been carried out. When medial branches of the left portal vein are divided, the demarcation is observed more clearly along the right edge of the falciform ligament. Then liver transection is advanced cranially along the demarcation and reaches the distal end of the MHV at the confluence of the LHV or the IVC. And the MHV is divided and closed at the confluence. Finally the left lateral sectional duct is exposed and isolated cranially close to the UP and divided with a free resection margin, and the right trisection of the liver, caudate lobe and the extrahepatic bile duct are removed en bloc. Anatomic Right Trisectionectomy Anatomic right trisectionectomy is a more extensive hepatectomy than traditional right trisectionectomy and this more aggressive procedure is indicated for more advanced hilar cholangiocarcinoma which involves not only the right hepatic duct and the left medial sectional duct but also the confluence of the left medial and lateral sectional ducts (52). The actual surgical procedure is slightly different from that of traditional right trisectionectomy in dividing all the portal branches for the left medial section (S4), including the main superior and inferior branches and the dorsal branches which ramify from the dorsal aspect of the UP. By progressing this procedure, the UP is gradually turned counterclockwise to expose the left lateral sectional duct more proximally on the left of the UP (Fig. 37.10). Then a clear demarcation appears on the umbilical fissure behind or left laterally to the falciform ligament. Then liver transection along the umbilical fissure reaches left laterally to the UP or just behind the UP, and the left lateral sectional duct or segmental ducts can be divided more proximally with free margins (Fig. 37.11). Intrahepatic Cholangiojejunostomy After hepatobiliary resection and removal of the tumor, the resected margins of the intrahepatic ducts must be identified anatomically and sutured side by side to complete the hepaticoplasty and to minimize the number of anastomotic orifices for intrahepatic cholangiojejunostomy with a Roux-en-Y jejunal limb lifted via the retrocolicretrogastric route (12,53). Previously, single layer cholangiojejunostomy was performed using interrupted sutures of 5-0 or 6-0 PDS and all anastomosed bile ducts drained externally with 6 Fr. polyvinyl chloride tubes. However, a continuous suture of 5-0 or 6-0 PDS has recently been used for each anterior and posterior wall anastomosis of all cholangiojejunostomies and external biliary drainage tube(s) has not been used routinely. Thus, difficult and time-consuming hepatobiliary resectional and reconstructional surgery became simplified. Combined Liver and Portal Vein Resection for Advanced Cholangiocarcinoma Combined liver and portal vein resection is indicated for locally advanced cholangiocarcinoma, and several types of liver resection and combined portal vein resection and reconstruction have been reported as an aggressive surgical approach which provides both negative surgical margins and contributes to prolonged survival for resected patients compared to non-resected patients (5458). The portal vein is usually resected at the final step of hepatobiliary resection and is reconstructed after removal of the
Figure 37.10 All left medial branches of the portal vein are divided to turn the umbilical portion of the vein and to expose the left lateral sectional duct more proximally and left laterally to the vein. B2: lateral posterior branch, B3: lateral anterior branch, B4, P4: medial branch, P4c: dorsal branch, RPV: right portal vein.
339
discussion
Recent improvement in preoperative staging system and managements of difficult biliary cancer patients, as well as technical developments in hepatobiliary surgery have increased the rate of potentially curative resection and decreased postoperative morbidity and mortality (13,14,3640,4244). Although preoperative BD has recently not been used prior to PD, the value of preoperative BD before cholestatic liver resection has not been clarified by RCTs (28). As the HPD is the ultimate surgery for the visceral organs, unexpectedly high morbidity and mortality have been encountered (63); however, recent progress in surgical techniques and perioperative management for biliary cancer patients with difficult preoperative complications improved the outcome of this surgery and an increasing number of operations and 5-year survivors have been reported not only from aggressive surgeons in Japan but also from the United States (6468). It is expected that an increasing number of patients with locally advanced cholangiocarcinoma will be considered for difficult surgeries employing HPD with or without vascular resection, which should be justified by improved outcome (6972). Recent retrospective analysis of the impact of future liver remnant (FLR) volume and preoperative BD on postoperative hepatic insufficiency and mortality rates revealed that preoperative BD did not appear to improve perioperative outcome in patients with FLR 30% and PVE is likely to offer little benefit (73). According to the continued and utmost efforts of aggressive hepatobiliary surgeons, favorable results of PD and hepatectomy have been reported and prognostic factors after curative resection of extrahepatic cholangiocarcinoma have been revealed (2227,42,4651). Although preoperative BD followed by PE has been used prior to major hepatectomy for biliary cancer patients with obstructive jaundice in many centers all over the world, it may be difficult to clarify the value of this strategy by RCTs.
Figure 37.11 The left lateral sectional or segmental ducts ( ) are resected left dorsally to the umbilical portion of the left portal vein. In this case, right hepatopancreatoduodenectomy with portal vein resection and reconstruction (arrow) are performed. P, pancreas; RL, round ligament.
tumor. However, in case of right-sided hepatectomy, the portal bifurcation can be resected and reconstructed prior to liver dissection using an end-to-end anastomosis between the left portal vein and the main trunk to establish the non-touch resection of hilar cholangiocarcinoma (59). Several techniques have been reported for portal vein reconstruction. In addition to the end-to-end anastomosis which is commonly used, a graft interposition using an external iliac vein (54,60), a hepatic vein segment (61), a saphenous vein (54), or a left renal venous patch (62) are used for difficult portal vein reconstruction after segmental or wedge resection of the portal bifurcation. Hepatopancreatoduodenectomy for Advanced Cholangiocarcinoma Hepatopancreatoduodenectomy (HPD) has been used as the most extensive surgery for advanced carcinoma of the biliary tract (63). Recent development of diagnostic modalities has increased the opportunity to demonstrate the extent of cholangiocarcinoma precisely by MDCT, selective cholangiography, and cholangioscopy, and increasing numbers of patients with cholangiocarcinoma have been considered for HPD. Distal or middle bile duct cancer with superficial spread to the intrahepatic bile duct or intrahepatic cholangiocarcinoma with superficial spread to the distal bile duct are indications for HPD (33,64,65). As HPD is composed of PD or PPPD for distal bile duct cancer and hepatectomy for proximal cholangiocarcinoma, PD or PPPD is carried out at the first step of this operation, and the hepatoduodenal ligament is dissected upward to skeletonize the hepatic arteries and portal bifurcation. As the next step, hemihepatectomy or hepatic sectionectomy is performed according to the preoperative diagnosis of
references
1. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human liver, analysis of the prevailing pattern of branchings and the major variations of the biliary ducts. AMA Arch Surg 1953; 66: 599616. 2. Couinaud C. Surgical anatomy of the liver revisited. Paris: Couinaud C, 1989: 6174. 3. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with special reference to the caudate lobe. World J Surg 1988; 12: 210. 4. Nimura Y, Hayakawa N, Kamiya J, Kondo S, Shionoya S. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 1990; 14: 53544.(Category III) (Grade C). 5. Kamiya J, Nimura Y, Hayakawa N, et al. Preoperative cholangiography of the caudate lobe: Surgical anatomy and staging for biliary carcinoma. J Hepatobiliary Pancreat Surg 1994; 1: 3859. 6. Nimura Y, Hayakawa N, Kamiya J, et al. Hilar cholangiocarcinoma surgical anatomy and curative resection. J Hepatobiliary Pancreat Surg 1995; 2: 23948. (Category III) (Grade C). 7. Nimura Y. Surgical anatomy of the biliary ducts. In: Rossi P, ed. Biliary Tract Radiology. Berlin, Heidelberg, Springer-Verlag, 1997: 2130. 8. Nimura Y. Living donor liver transplantation: importance of anatomical variations of biliary tree and vascular systems. Transpl Proc 2003; 35: 955.
340
EXTRAHEPATIC CHOLANGIOCARCINOMA
9. Ozden I, Kamiya J, Nagino M, et al. Clinicoanatomical study on the infraportal bile ducts of segment 3. World J Surg 2002; 26: 14415. 10. Ohkubo M, Nagino M, Kamiya J, et al. Surgical anatomy of the bile ducts at the hepatic hilum as applied to living donor liver transplantation. Ann Surg 2004; 239: 826. 11. Sugiura T, Nagino M, Kamiya J, et al. Infraportal bile duct of the caudate lobe: a troublesome anatomic variation in right-sided hepatectomy for perihilar cholangiocarcinoma. Ann Surg 2007; 246: 7948. 12. Nagino M, Nishio H, Ebata T, et al. Intrahepatic cholangiojejunostomy following hepatobiliary resection. Br J Surg 2007; 94: 707. (Category III) (Grade C). 13. Choi JY, Lee JM, Lee JY, et al. Assessment of hilar and extrahepatic bile duct cancer using multidetector CT: value of adding multiplanar reformations to standard axial images. Eur Radiol 2007; 17: 31308. (Category III) (Grade C). 14. Senda Y, Nishio H, Oda K, et al. Value of multidetector row CT in the assessment of longitudinal extension of cholangiocarcinoma-correlation between MDCT and microscopic findings. World J Surg 2009; 33: 1459 67. (Category III) (Grade C). 15. Fukuda Y, Tsuyuguchi T, Sakai Y, Tsuchiya S, Saisyo H. Diagnostic utility of peroral cholangioscopy for various bile-duct lesions. Gastrointest Endosc 2005; 62: 37482. (Category IV) (Grade D). 16. Itoi T, Sofuni A, Itokawa F, et al. Peroral cholangioscopic diagnosis of biliary-tract diseases by using narrow-band imaging (with videos). Gastrointest Endosc 2007; 66: 7306. (Category IV) (Grade D). 17. Nishio H, Hidalgo E, Hamady ZZ, et al. Left hepatic trisectionectomy for hepatobiliary malignancy: results and an appraisal of its current role. Ann Surg 2005; 242: 26775. (Category III) (Grade C). 18. Hochwald SN, Burke EC, Jarnagin WR, Fong Y, Blumgart LH. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 1999; 134: 2616. (Category III) (Grade C). 19. Figueras J, Llado L, Valls C, et al. Changing strategies in diagnosis and management of hilar cholangiocarcinoma. Liver Transpl 2000; 6: 78694. (Category III) (Grade C). 20. Cherqui D, Benoist S, Malassagne B, et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000; 135: 3028. (Category III) (Grade C). 21. Ferrero A, Lo Tesoriere R, Vigan L, et al. Preoperative biliary drainage increases infectious complications after hepatectomy for proximal bile duct tumor obstruction. World J Surg 2009; 33: 31825. (Category III) (Grade C). 22. Nimura Y, Kamiya J, Kondo S, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg 2000; 7: 15562. (Category III) (Grade C). 23. Lee SG, Lee YJ, Park KM, Hwang S, Min PC. One hundred and eleven liver resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg 2000; 7: 13541. (Category III) (Grade C). 24. Seyama Y, Kubota K, Sano K, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003; 238: 7383. (Category III) (Grade C). 25. Kawasaki S, Imamura H, Kobayashi A, et al. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 2003; 238: 8492. (Category III) (Grade C). 26. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005; 241: 693702. (Category III) (Grade C). 27. Sano T, Shimada K, Sakamoto Y, et al. One hundred two consecutive hepatobiliary resections for perihilar cholangiocarcinoma with zero mortality. Ann Surg 2006; 244: 2407. (Category III) (Grade C). 28. Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB 2008; 10: 1303. (Category III) (Grade C). 29. Nimura Y, Shionoya S, Hayakawa N, et al. Value of percutaneous transhepatic cholangioscopy (PTCS). Surg Endosc 1988; 2: 2139. (Category III) (Grade C). 30. Nimura Y, Kamiya J, Hayakawa N, Shionoya S. Cholangioscopic differentiation of biliary strictures and polyps. Endoscopy 1989; 21(Suppl 1): 3516. (Category IV) (Grade D). 31. Nimura Y. Staging of biliary carcinoma: cholangiography and cholangioscopy. Endoscopy 1993; 25: 7680. (Category IV) (Grade D). 32. Seo DW, Lee SK, Yoo KS, et al. Cholangioscopic findings in bile duct tumors. Gastrointest Endosc 2000; 52: 6304. (Category IV) (Grade D). 33. Kato M, Nimura Y, Kamiya J, et al. Carcinoma of the common bile duct with superficial spread to the intrahepatic segmental bile ducts: a case report. Am Surg 1997; 63: 9437. 34. Itoi T, Shinohara Y, Takeda K, et al. Detection of telomerase activity in biopsy specimens for diagnosis of biliary tract cancers. Gastrointest Endosc 2000; 52: 3806. (Category III) (Grade C). 35. Murata T, Nagasaka T, Kamiya J, et al. P53 labeling index in cholangioscopic biopsies is useful for determining spread of bile duct carcinomas. Gastrointest Endosc 2002; 56: 68895. (Category III) (Grade C). 36. Nimura Y. Staging cholangiocarcinoma by cholangioscopy. HPB 2008; 10: 1135. (Category IV) (Grade D). 37. Uesaka K, Nimura Y, Nagino M. Changes in hepatic lobar function after right portal vein embolization: an appraisal by biliary indocyanine green excretion. Ann Surg 1996; 1: 7783. (Category III) (Grade C). 38. Nagino M, Nimura Y, Kamiya J, et al. Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. Hepatology 1995; 21: 4349. (Category III) (Grade C). 39. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107: 5217. 40. Nagino M, Nimura Y, Kamiya J, Kondo S, Kanai M. Selective percutaneous transhepatic embolization of the portal vein in preparation for extensive liver resection: the ipsilateral approach. Radiology 1996; 200: 55963. (Category III) (Grade C). 41. Nagino M, Kamiya J, Kanai M, et al. Right trisegment portal vein embolization for biliary tract carcinoma: technique and clinical utility. Surgery 2000; 127: 15560. (Category III) (Grade C). 42. Nagino M, Kamiya J, Nishio H, et al. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006; 243: 36472. (Category III) (Grade C). 43. Kamiya S, Nagino M, Kanazawa H, et al. The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, and microflora. Ann Surg 2004; 239: 5107. (Category Ib) (Grade A). 44. Kanazawa H, Nagino M, Kamiya S, et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005; 390: 10413. (Category Ib) (Grade A). 45. Sugawara G, Nagino M, Nishio H, et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006; 244: 70614. (Category Ib) (Grade A). 46. Bhuiya MR, Nimura Y, Kamiya J, et al. Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 1992; 215: 3449. (Category III) (Grade C). 47. Kayahara M, Nagakawa T, Ohta T, et al. Role of nodal involvement and the periductal soft-tissue margin in middle and distal bile duct cancer. Ann Surg 1999; 229: 7683. (Category III) (Grade C). 48. Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 2005; 103: 12106. (Category III) (Grade C). 49. Jang JY, Kim SW, Park DJ, et al. Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. Ann Surg 2005; 241: 7784. (Category III) (Grade C). 50. Cheng Q, Luo X, Zhang B, et al. Distal bile duct carcinoma: prognostic factors after curative surgery. A series of 112 cases. Ann Surg Oncol 2007; 14: 12129. (Category III) (Grade C). 51. Murakami Y, Uemura K, Hayashidani Y, et al. Pancreatoduodenectomy for distal cholangiocarcinoma: prognostic impact of lymph node metastasis. World J Surg 2007; 31: 33742. (Category III) (Grade C). 52. Nagino M, Kamiya J, Arai T, et al. Anatomic right hepatic trisectionectomy (extended right hepatectomy) with caudate lobectomy for hilar cholangiocarcinoma. Ann Surg 2006; 243: 2832. (Category III) (Grade C).
341
342
38
Endoscopic management of malignant biliary obstruction Nick Stern and Richard Sturgess
ultrasound
One of the first investigations important in the jaundiced patient is an ultrasound of the liver and biliary tree. This will determine whether the jaundice is obstructive or whether it is due to a parenchymal liver disease or pre-hepatic cause (10,11). Obstructive jaundice cannot be diagnosed without imaging of the biliary tree. It is worth noting that abnormal LFTs in a cholestatic pattern do not necessarily equate to biliary obstruction. Trans-abdominal ultrasound will be able to confirm whether the patient has gall bladder calculi, which can cause obstructive jaundice if they migrate to the bile ducts. It can also detect whether there are intra-hepatic lesions, such as liver metastases or primary liver malignancies (12,13). The main role in this context, however, is to detect whether there is biliary obstruction. A mildly dilated common bile duct is expected in patients with prior cholecystectomy. It is not abnormal for the common bile duct to increase in size slightly with age. Should there be dilatation of the intra-hepatic ducts, this almost always suggests pathology and biliary obstruction.
background
There are many aspects of diagnosis, staging, and therapy in biliary malignancies that are managed by the endoscopist. As different imaging modalities of the biliary system have advanced, there has been a move in recent years away from using endoscopic retrograde cholangio-pancreatography (ERCP) as a diagnostic tool. High-quality diagnostic images of the biliary tree can now be obtained with modern radiological techniques. Newer MRI scanners using an MRCP protocol (13) can provide highquality cholangiography and cross-sectional imaging. Endoscopic ultrasound (4,5) allows sonographic views from the lumen of the upper GI tract, particularly of the distal biliary system and pancreas. These, along with the improved quality of CT scanning (68) can provide safe diagnosis and staging of biliary malignancies, saving potentially risky ERCP for appropriate therapeutic procedures.
ct scanning
For detailed information about potential causes of obstructive jaundice, a high-quality, contrast-enhanced CT scan is often necessary. CT scanning can give important information about the pancreas (often obscured by bowel gas on ultrasound scanning). Heads of pancreas tumors, that often present with obstructive jaundice, are normally visible on targeted, enhanced CT scans of the pancreas (14,15). The degree of biliary dilatation and the site of any caliber change in the biliary tree can provide additive information about the tumor. Segmental intra-hepatic dilatation of the bile ducts can suggest cholangiocarcinoma. Lymphadenopathy can cause malignant biliary obstruction and when this occurs this tends to be at the porta hepatis. This is normally well seen on CT scans with the opportunity to get information about a possible site of primary tumor. Large colonic masses or widespread lymphadenopathy with splenomegaly may suggest a possible cause of the malignancy. The importance of CT scanning is that of diagnosing the primary tumor, as well as providing information for staging and operability. CT scanning should ideally be performed prior to any endoscopic intervention of the biliary tree (ERCP) as the complication of pancreatitis can interfere with accurate staging of the disease. While CT may give a good indication of the site of biliary obstruction and the cause, detailed views of the biliary tree are better obtained with MR scanning.
mr scanning
Magnetic Resonance Imaging (MRI scanning) is increasingly important in providing good imaging of the biliary tree (13).
343
endoscopic assessment
Endoscopic Intervention The anatomy of the biliary tree allows good access to the biliary system with an endoscope. The bile ducts drain, via the common bile duct, through the ampulla of Vater and sphincter of Oddi into the second part of the duodenum. This allows an accessible port of access to the biliary system by use of an endoscope designed to sit opposite the ampulla within the duodenum. The use of endoscopy in the management of malignant biliary obstruction can be in the diagnosis, staging, and therapy of the disease. Endoscopic Ultrasound (Endosonography, EUS) A relatively new and very useful part of diagnosis and staging is the method of endoscopic ultrasound (EUS) (4). This involves an endoscope designed with an ultrasound probe at the tip (Fig. 38.2). The imaging can be either a radial EUS that provides a 360 degree image around the probe at the tip of the endoscope or a linear EUS that gives an ultrasound picture in the plane of the scope.
ercp
Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is an endoscopic method of accessing the biliary tree. ERCP is performed using a side-viewing endoscope, passed normally to the second part of the duodenum, sitting opposite the ampulla of Vater (Fig. 38.4).
344
(A)
(B) Figure 38.3 (A) EUS cholangio. (B) A Eus Ca Panc (arrow indicates the pancreatic tumor).
345
this risk is much smaller than the risk of a non-draining, obstructed biliary system. ERCP Complications Pancreatitis Perforation Bleeding Cholangitis Drug reactions/effects Aspiration pneumonia
Confirmed/strongly suspected bile duct calculi (EUS/MRCP would often be used prior to ERCP) Severe gallstone pancreatitis (particularly with jaundice and cholangitis) Cholangitis Bile leak post cholecystectomy Cytological sampling of strictures Pancreatic duct dilatation/stenting Sphincter of Oddi manometry
direct cholangioscopy
A technique that has developed for the assessment of intrabiliary pathology is that of direct, per oral cholangioscopy. Whereas traditional ERCP provides detailed information about intra-biliary pathology, this is normally part of a contrastenhanced radiological cholangiogram performed with the assistance of an endoscope rather than direct vision. Strictures may be misclassified as malignant rather than benign, particularly with the relatively poor yield of biliary brushings (25,26). Direct cholangioscopy provides the user the opportunity to see directly into the biliary tree to the second- or third-order ducts. A clearer impression about the nature of a stricture, be it benign or malignant can be obtained and the cause of the stricture can be biopsied as well as brushed, and this can be done under direct vision, thereby improving the yield of diagnostic histology to about 80% (27,28). The original cholangioscopy via ERCP scopes, were the mother and baby scopes that required two operators to use with one controlling the duodenoscope (mother) and the second operating the smaller cholangioscope (baby). The baby scope passed through the working channel of the duodenoscope. As well as being clumsy, irrigation and visualization were poor and newer technologies have enabled improved and constant irrigation improving cholangioscopic views.
Given the potential complications of ERCP (see below), it is now almost totally used as a method of providing therapy to the biliary tree and pancreatic duct. In the context of malignant biliary obstruction, therapy is often targeted at the relief of jaundice. With malignancy, drainage of jaundice normally involves the insertion of one of the variety of stents. When planning to drain jaundice in the patient with malignancy, consideration needs to be given to the choice of stent type, the site of stenting whether unilateral in hilar strictures, or bilateral and the method of approaching this. It is because of this reason that reviewing good quality imaging prior to the procedure and planning the procedure in advance is of paramount importance. Additional diagnostic information can be obtained using direct cholangioscopy. This is an emerging technology and its current availability is limited. It is being used for those strictures that cant be classified with conventional imaging.
complications of ercp
The reason to limit the use of ERCP for therapy rather than diagnosis, unlike most other modalities of endoscopy, is the risk profile. Because of the anatomy of the biliary tree, and the distal portion of the common bile duct passing through the head of the pancreas, the main risk of ERCP is that of acute pancreatitis. A lot of effort has been put into reducing the risk as much as possible. This includes the improved training of ERCP endoscopists, as well as the development of guidance suggesting that a fewer number of endoscopists perform ERCP to increase the numbers performed by each individual. The technical changes of wire-guided cannulation are also thought to reduce pancreatitis risk as wire cannulation of the pancreatic duct should result in lower rates of ERCP-induced pancreatitis than opacification with contrast (18). Rates of pancreatitis have been quoted very variably as 1% to 30% (1822); however, the recent large volume British Society of Gastroenterology (BSG) audit of ERCP practice in the United Kingdom reported pancreatitis rates of 1.5% with an overall complication rate of 5.1% (23). Other ERCP complications are those for standard endoscopy, namely bleeding and perforation. Another risk following stenting of the ampulla is the risk of cholangitis (24); however,
346
347
348
radiotherapy
Brachytherapy Intraductal radiotherapy, brachytherapy has been used in a small number of studies in an attempt to improve survival in patients with nonresectable cholangiocarcinoma. A retrospective study comparing brachytherapy to stenting alone did show some survival benefit, that didnt achieve statistical significance (p = 0.06) in patients with type II or III tumors treated with brachytherapy, but this was associated with more stent changes and longer hospital stays. The authors felt that the benefit was limited to those with type II or III tumors treated within 10 months of diagnosis (86). A more recent study looking at external beam radiotherapy in conjunction with expandable metal stents in patients with cholangiocarcinoma, showed longer survival in those than in stents alone (10.6 vs. 6.4 months, p < 0.05) and longer stent patency than metal stents alone (9.8 vs. 3.7 months, p < 0.001);
hilar strictures
Unilateral Versus Bilateral The more difficult scenario is in strictures that affect the bifurcation of the common hepatic duct, the hilar strictures. These are commonly caused by cholangiocarcinomas and if extend beyond the hilum a decision has to be made about the best approach to drainage (Fig. 38.12). While the optimal drainage is achieved by bi-lobar drainage, this can prove technically difficult, and the great danger in this group of patients is in failing to drain an opacified area. This has been shown in various series to increase morbidity and mortality due to cholangitis (80,81). Adequate palliation of jaundice is likely to be obtained with drainage of 30% of the liver volume and this can normally be achieved through unilobar stenting (8285). Due to these problems, in some centers PTC is preferred to ERC as at PTC the obstructed area is targeted first and this can easily be drained.
349
photodynamic therapy
The greater majority of patients with cholangiocarcinoma do not undergo resection (88). The disease has a particularly poor prognosis, especially if the disease is advanced with a median survival time of 62 days if there is bilateral intrahepatic disease (81). Photodynamic therapy (PDT) has emerged as a promising new modality of treatment for patients who do not undergo resection. PDT uses the combination of two non-toxic moieties; light and a photosensitizing chemical, which when combined together produce a cytotoxic effect. The photosensitizer tends to accumulate in proliferating tissue. This tissue is then illuminated with light of a wavelength appropriate to the absorption spectrum of the photosensitizer. A photochemical reaction generates cytotoxic reactive oxygen species resulting in apoptosis or necrosis of tumor cells. PDT may also cause thrombosis in tumor blood vessels and induce a tumor-specific immune reaction with more distant effects from the site of illumination. Photofrin (Axcan Pharma Inc.) has been the most widely used photosensitizer in this application and is a complex mix of compounds derived from hematoporphyrin. It is activated at a wavelength of 630 nm. The depth of necrosis obtained is 4 to 6 mm. The technique of ERC-PDT involves the prior administration of Photofrin at a dose of 2 mg/kg, optimally 48 hours before the procedure. A cylindrical laser diffuser fiber is positioned across the malignant stricture through a standard cannula. Concurrent oxygen administration (4 l/min) optimizes the PDT effect. A light dose of 180 to 200 J/cm is delivered. Stents, preferably plastic, are inserted after the
Refer to gastroenterology/ hepatology
Jaundiced patient
Biliary ultrasound
Inoperable
350
conclusions
The management of biliary malignancy can be a complex issue. There are various treatment options that are appropriate and the choice of optimal treatment may depend on local expertise. We have found that in patients with proximal biliary neoplasia, the risks of cholangitis are higher than in other groups, particularly when the biliary system has been previously instrumented. Our group strongly advocates that patients with a proximal biliary malignancy should be transferred to the regional specialist center for a review of the imaging and an appropriate method of biliary decompression to be arranged and performed there. Local data suggest that this reduces the rate of cholangitis in this cohort of patients. We have found that the drainage of biliary disease can be optimized with the use of SEMS as opposed to 10 F plastic stents and that patients can still be operable following this. Carefully sited SEMS can allow biliary drainage and a welldecompressed system without interfering in the surgical field. We have also started using fully covered SEMS which have proved safe to remove up to 3 months following deployment.
references
1. Ishizaki Y, Wakayama T, Okada Y, Kobayashi T. Magnetic resonance cholangiography for evaluation of obstructive jaundice. Am J Gastroenterol 1993 Dec; 88(12): 20727. 2. Pavone P, Laghi A, Passariello R. MR cholangiopancreatography in malignant biliary obstruction. Semin Ultrasound CT MRI 1999 Oct; 20(5): 31723. 3. Vaishali MD, Agarwal AK, Upadhyaya DN, et al. Magnetic resonance cholangiopancreatography in obstructive jaundice. J Clin Gastroenterol 2004; 38(10): 88790.
351
352
353
39
presentation
The clinical triad of abdominal pain, mass, and jaundice is seldom seen in adults (3,25). Clinical symptoms in most cases are intermittent and nonspecific resulting in delayed diagnosis. Also the majority of these patients do not have consistent abnormalities in liver function tests (LFTs) (27). Abdominal pain and recurrent cholangitis are the most common presentation (3,2830). The abdominal pain usually mimics that of calculus cholecystitis and many patients do have gallstones either in the cyst and/or in the gallbladder. This might lead to misdiagnosis of calculus cholecystitis and or choledocholithiasis with biliary ductal dilatation. Subsequently, a number of these patients who genuinely have cystic dilatation of the biliary tree end up treated inadequately by simple cholecystectomy and or common bile duct (CBD) exploration or occasionally treated by biliary enteric bypass (31). In areas where incidence of choledochal cysts is relatively high, it is prudent to consider choledochal cyst in the differential diagnosis in patients who present with biliary colic, recurrent cholangitis, and evidence of dilated biliary tree (32,33). However, in areas where incidence of choledochal cysts is rare, this might represent a real-diagnostic dilemma requiring careful management of these patients at a specialist unit to ensure correct and adequate treatment tailored to each individual. Other presentations include those related to complications that might develop secondary to cystic dilatation of the biliary tree such as calculi, recurrent hepatic abscesses, recurrent pancreatitis, bleeding, cyst erosion into surrounding structure, cirrhosis, portal hypertension, and cholangiocarcinoma (6,34). Such presentations may obscure the primary problem and may increase the complexities of treatment (32,35). Indeed, studies in adults have shown that nearly 80% of them present with one or more of these conditions (5,6,27).
diagnosis
Correct diagnosis of true cystic dilatation of the biliary tree in adults depends mainly on the use of imaging studies and some times can be quite challenging. In indeterminate cases, careful evaluation for anomalous pancreaticobiliary ductal confluence may be useful.
354
IVa
IVb
Figure 39.1 Tandoni classification of choledochal cysts: Type 1 extra-hepatic bile duct cystic dilatation, Type II common bile duct diverticulum, Type III choledochocele, Type IVa intra- and extra-hepatic bile duct dilatation, Type IVb multiple cysts (extra-hepatic only), and Type V intra-hepatic cysts only.
considered to be more accurate than ultrasonography in demonstrating the biliary tree anatomy especially when using the most recent spiral CT cholangiography technology which allows three-dimensional reconstructions (38,39). CT scan and ultrasonography can be sometimes of limited value in demonstrating the biliary origin of choledochal cyst. However, hepatobiliary scintigraphy with technetium-99 labeled iminodiacetic acid (IDA) derivatives will often show the cyst and in particular helpful at establishing that the cystic structure is an intrinsic part o the biliary tree. IDA scanning is also helpful at assessing hepatobiliary function and anastomotic patency postoperatively (33,36,40). Magnetic resonance imaging (MRI) is non-invasive and produces clear images of the biliary tree. Also, it may even demonstrate APBDC similar to endoscopic retrograde cholangiopancreaticograpgy (ERCP), but without the complications of ERCP (3,4143). Several studies reported that MRI has an estimated diagnostic accuracy of 82% to 100% (43,44). Hence, MRI is widely held as the imaging modality of choice for choledochal cysts (Figs. 39.2A and 39.3A). ERCP defines the anatomy of the biliary tree accurately and reveals the presence of any associated intra-ductal pathology or an APBDC (Figs. 39.2B and 39.3B) (3,41). Also, ERCP allows dealing with coexisting ductal stones in patients present with jaundice and in the rare instance of type III cyst; it facilitates a therapeutic papillotomy simultaneously (45). However, this is invasive investigation with a significant complication rate and although it provides excellent anatomic delineation, it rarely produces information which alters the subsequent management of the choledochal cysts. More over cholangiography can always be performed intra-operatively by injecting contrast directly into the bile duct to display the ductal anatomy (6). Endoscopic ultrasound scan and cholangioscopy are relatively more recent investigations that can be of great use in the diagnosis of extra-hepatic biliary cystic dilatation and more important in the diagnosis of early malignant changes within the cyst wall where biopsies can also be taken to confirm abnormal tissue findings (46).
(A)
(B)
Figure 39.2 (A) MRCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V). (B) ERCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V).
355
complications
The most common complication associated with choledochal cysts is stones in the gallbladder, within the cysts or in the pancreatic duct (6). The calculi in the cysts are of the type seen in biliary stasis (47). In choledochal cysts the calculi can be mistaken for choledocholithiasis in a dilated bile duct secondary to obstruction. The main distinguishing features are nondilated proximal and intra-hepatic biliary radicles in the case of type I cysts and non-dilated intervening ducts in the case of type IV cysts. Biliary strictures are another recognized complication associated with adult choledochal cysts. This is most often related to earlier surgical intervention but also can occur secondary to chronic inflammation or rarely related to congenital etiology (47,48). Cirrhosis and liver abscesses are often associated with longstanding biliary obstruction and recurrent cholangitis (48,49). Some patients develop portal hypertension due to compression of the portal vein by a large choledochal cyst or more often secondary to biliary cirrhosis (50). Pancreatitis is a well-recognized complication related to choledochal cysts. Incidence (1070%) has been reported in the literature by several authors (3,51,52). The pathophysiology of pancreatitis in these patients is not well understood but most authors believe that it is due to activation of pancreatic enzymes associated with biliary reflux especially in patients with APBDC (51,53). Choledochal cysts are associated with an increased risk of developing cholangiocarcinoma and gallbladder tumors (5456). The risk is about 20 times higher than that in the general population ranging from 2.5% to 30% (3,5658). The risk is age related: 0.7% in children under the age of 10, 6.8% in patients 11 to 20 years of age, and 14.3% in patients over the age of 20 years (57). Carcinoma occurs not only in the cyst wall but also in the remainder of the hepatobiliary and pancreatic tree (57,59). Therefore, long-term follow-up is indicated in all
patients with choledochal cysts even after complete excision of the cysts. The pathogenesis of malignant change in biliary cysts is unknown. It has been thought to be related to bile stasis and/or reflux of pancreatic juice, which give chronic irritation and metaplasia (59).
treatment
Management of choledochal cysts in adults should be performed at specialist unit and tailored according to each patients circumstances. Cyst type and more important patients general health, presenting symptoms and risk of developing complications related to the choledochal cysts are major factors that should be considered when deciding upon which type of treatment to be adapted. Total cyst excision when possible remains the gold standard treatment for choledochal cysts. This has been recommended by many investigators because of lower incidence of both early and late postoperative complications. Therefore, this approach has gained popularity worldwide (10,27,33,60,61). In choledochal cysts types I and IVb involve complete excision of the bile duct from the confluence of the hepatic ducts proximally up to the pancreaticobiliary junction distally. Cholecystectomy at the same time is a necessity, as the gallbladder usually arises from or adheres to the cyst wall and may contain stones or occasionally even tumor. Reconstruction of the biliary-enteric communication in these patients is usually achieved by Roux-en-Y hepaticojejunostomy or less commonly by hepaticoduodenectomy. For type IVa choledochal cyst, the extrahepatic component should be treated in the same way as for types I and IV cysts. The management of the intra-hepatic component depends on the severity of the disease and extent of involvement. This could range from percutaneous drainage through stricture dilatation and stone removal to partial hepatectomy (Fig. 39.4) or liver transplantation (3). More radical surgery is required if malignancy is confirmed on preoperative or fresh frozen biopsies. This might involve
(A)
(B)
Figure 39.3 (A) MRCP image demonstrating intra- and extra-hepatic bile duct dilatation (Type IVa). (B) ERCP image demonstrating intra- and extra-hepatic bile duct dilatation (Type IVa).
356
Figure 39.4 Intra-operative view following surgical resection of type IVa choledochal cyst seen in Figure 3A,B. Surgery involved left hepatectomy, total excision of the bile duct and cholecystectomy.
(A)
(B)
Figure 39.5 (A) Demarcation of right anterior sector (segments 5 and 8) following extra-hepatic division of the right anterior sectoral hepatic artery and portal vein. (B) Intra-operative view following segmental (central) liver resection (segments 5 and 8) for localized intra-hepatic segmental dilatation of the biliary tree seen in Figure 2A,B.
357
summary
Diagnosis and treatment of adult choledochal cysts can be quite challenging. Therefore, management of these patients should be carried out at specialist units. Choledochal cysts rarely present for the first time in adulthood. However when they do, the presentation is variable and most often due to presence of associated disease. Also they can be totally asymptomatic. The appropriate treatment strategy should be selected based on the type of the cyst and more important on the individuals general health and presenting symptoms. Total cyst excision and Roux-en-Y hepaticojejunostomy are the current recommended surgical options world wide for type I and IV choledochal cysts while for type V cyst (diffuse Carolis disease) with frequent recurrent cholangitis, liver transplantation should be considered. Patients with previous cyst drainage procedures should undergo revisional surgery if appropriate to reduce recurrent symptoms and the risk of developing malignancy. Conservative treatment might be the most appropriate strategy in asymptomatic individuals with poor general health and significant co-morbidities. All patients with choledochal cysts including those who had complete choledochal cyst excision should be kept under long-term surveillance.
key points
Choledochal cysts are increasingly diagnosed in adult population Etiology of choledochal cysts remains speculative Adults with choledochal cysts most commonly present with complications related to their choledochal cysts Choledochal cysts are associated with an increased risk of developing cholangiocarcinoma and gallbladder tumors MRI is widely held as the imaging modality of choice for choledochal cysts Patients with choledochal cysts should be managed at a specialist unit to ensure correct and adequate treatment tailored to each individual Total cyst excision when possible remains the gold standard treatment for choledochal cysts
references
1. Gigot JF, Nagorney D, Farnell M, Moir C, Ilstrup D. Bile duct cysts: a changing spectrum of disease. J Hepato-Biliary-Pancreatic Surg 1996; 3(4): 40511. 2. Lenriot JP, Gigot JF, Segol P, et al. Bile duct cysts in adults: a multi-institutional retrospective study. French Associations for Surgical Research. Ann Surg 1998; 228(2): 15966. 3. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg 1994; 220(5): 64452.
358
359
360
Figure 40.1 A classification of laparoscopic injuries to the biliary tract. The injuries Type A to E are illustrated. Type A injuries originate from small bile ducts in the liver bed that or from the cystic duct. Type B and C injuries almost always involve aberrant right hepatic ducts. The notations >2 cm and <2 cm in Type E1 and Type E2 indicate the length of common hepatic duct remaining. The corresponding Bismuth classification numbers are given when possible as B1-5. Note that Types A and D do not exist in the Bismuth classification, which is a classification of bile duct strictures rather than injuries. Note that B,C and E5 injuries would be classified as B5. They are separated in our classification because of the increase incidence of B and C injuries in the laparoscopic era.
Figure 40.2 Type A (left) and Type D injuries (right) are much more common in the laparoscopic era and were given separate categories in our classification. The Type A injury figure demonstrates extravasation of contrast from the liver bed of the gallbladder due to injury to a bile duct in that location. The Type D injury figure demonstrates an injury which was incompletely repaired over a t-tube (arrow). There is extravasation of contrast from the common bile duct when T tube is injected. A percutaneous drain (arrowhead) was inserted to drain postoperative bilomas. The injury healed without further treatment.
although this was not borne out in a Cochrane review of randomized trials (18) (evidence level 1a). However, in the latter, conclusions were drawn from a total of four bile duct injuries among 438 patients (0.9%) (18). Acute inflammation causes thickening of tissues, increases friability and vascularity, and promotes adhesions. These factors obscure normal anatomical relationships (Fig. 40.3A) and increase difficulty of exposure
and dissection. The inflammatory mass may effectively obliterate the triangle of Calot and hide the cystic duct (19) (Fig. 40.3B). Severe inflammation is more likely to be encountered when the time between onset of symptoms and surgery for acute cholecystitis is greater than 72 hours (20,21), when the white blood cell count is greater than 18,000 cells/cu mm (20,22), or if the patients age is over 60 years (20,23,24). The Tokyo Severity
361
Triangle of Calot
(A)
(B)
(C)
(D)
(E)
(F)
Figure 40.3 Conditions which predispose to the deception that the common bile duct is the cystic duct especially when the infundibular techniques is used. (A) Situation in which the infundibular technique is effective. There is mild inflammation. The triangle of Calot is open and the funnel shape of the junction between the gallbladder and cystic duct (heavy line) is readily apparent. (BF) Conditions which may give a misleading funnel shape (heavy lines) due to concealment or obliteration of the triangle of Calot. In these cases the common bile duct is dissected by a surgeon who thinks it is the cystic duct widening to become the gallbladder. (B) Severe acute cholecystitis. (C) Severe chronic inflammation. (D) Parallel cystic duct insertion. (E) Congenital bands. (F) Large impacted stone.
362
(A)
(B)
(C)
(D)
(E)
(F)
Figure 40.4 Patterns of biliary injury due to misidentification. (A). The classical type E injury in which the common duct is divided between clips at point x. The ductal system is later divided again to remove the gallbladder either at point y1 producing E1 or E2 injuries, or at point y2 producing E3 or E4 injuries. (B) Variant of Type E injury which leads to bile leakage into the operative field and thereby an increased chance of recognition before the entire injury evolves. (C) Variant of Type E injury leading to clipping but not excision of the duct. This injury also causes intraoperative bile leakage, except when cystic and common bile ducts are both occluded, as shown in the inset. D,E, and F represent variants of injury to aberrant right hepatic duct, producing Type B or Type C injuries. The injuries shown in D, E, and F correspond to the injuries shown in A, B, and C, but affect the aberrant right duct.
363
Cystic plate
Figure 40.5 The critical view of safety. The triangle of Calot is dissected free of all tissue except for cystic duct and artery and the base of the liver bed is exposed. When this view is achieved, the two structures entering the gallbladder can only be the cystic duct and artery. It is not necessary to see the common bile duct.
(A)
(B)
Figure 40.6 (A) Intraoperative cholangiogram which was interpreted as normal with only a wisp of dye entering right hepatic ducts. Note stone at ampulla. (B) Postoperative ERCP in same patient done to remove stone. Note retrograde filling of aberrant right hepatic duct, made stenotic by clips. Note how the point of union of the aberrant duct with the common hepatic duct looks like a cystic duct- common duct junction. Problem successfully treated by stenting.
364
(A)
(B)
Figure 40.7 Cause of bile duct injury in top down cholecystectomy in the face of severe inflammation with obliteration of triangle of Calot which draws the side of the common hepatic duct to the side of the gallbladder. (A) Real anatomical situation. (B) Apparent anatomical situation is shown by heavy line. The surgeon sees the anatomy bounded by the heavy line as the gallbladder and the cystic duct and as the gallbladder is excised top-down (arrow) the common hepatic duct is transected. Vascular injuries are also common with this mechanism of injury.
365
Figure 40.8 Intraoperative photo (left) and diagram (right) showing transection of multiple hepatic ducts during open cholecystectomy by the fundus down technique in a very inflamed gallbladder. The right anterior sectional duct (Sg 5,8), the right posterior sectional duct (Sg 6,7) and the left hepatic duct (LHD) were transected in this high E4 injury.
Thermal Injuries (Fig. 40.9) Thermal injuries are more likely to occur in the presence of severe inflammation, because hemorrhage is more common when dissecting in the face of acute inflammation and higher power settings may be used to control hemorrhage. These injuries are often not recognized at surgery and usually result in bile duct stenosis rather than loss of continuity. Tenting Injuries The junction of the common bile duct and hepatic bile ducts may be occluded when clipping the cystic duct while pulling up forcefully on the gallbladder. This is a very uncommon laparoscopic injury perhaps due to the magnification afforded by laparoscopy. Surgeon/Hospital-Related Factors Learning Curve Effect Inexperience with laparoscopic cholecystectomy was a well documented cause of bile duct injuries in the 1990s. The likelihood of biliary injury was much greater during the early experience of a surgeon than subsequently. It is possible that inexperience in the procedure during acute cholecystitis is still contributing to injury. The Psychology of Human Error Hugh (32) and then Way et al. (33) described traits of human behavior that cause or contribute to biliary injury. Surgery is a complex task in which visual disorientation will occur occasionally and persistence in error due to the deadly mind set error is a common human failing. The mind set error is the tendency to interpret information incorrectly after one has first made a decision. The point of departure of the author with this view is that the visual disorientation is more likely to occur with certain methods of procedure and can be greatly diminished with the use of routine cholangiography or the critical view technique of identification.
Figure 40.9 T-tube cholangiogram in a patient 2 months after a thermal injury. The common hepatic duct (arrow) appears shrink wrapped over the T-tube. At the time of reconstruction the common hepatic duct was replaced by scar.
Equipment Laparoscopic equipment must be regularly maintained. Focal loss of insulation on cautery instruments can result in arcing and thermal injuries to bile ducts or bowel.
366
technical problems
Injury to a Bile Duct in the Course of Dissection Avoidance depends on the principles of careful dissection and experience, as well as recognition of circumstances in which the potential hazard in continued dissection may outweigh the benefit of completing a cholecystectomy. Also the author recommends not using the top-down technique in the face of severe inflammation either in open or laparoscopic surgery. Failure to Obtain Secure Closure of the Cystic Duct Tips of clips should be noted to project beyond the cystic duct. Pre-formed ligature loops should be used for closure of the cystic duct if the cystic duct is thick, rigid or wide. Two loops should be applied on the side of the cystic duct to be retained. Thermal Injuries Cautery should be used with great care in the porta hepatis. Low cautery settings are essential, characteristically 30 W or less. Attempts to stop hemorrhage by blind application of cautery clamps, or clips are very unwise. Brisk bleeding requires conversion. Adhesions should be divided sharply or with minimum application of power. Tenting Injuries The injury is avoided by not lifting the gallbladder forcefully when applying clips to the cystic duct. It is recommended that the surgeon sees that a length of cystic duct will remain below the clip closest to the common bile duct end of the cystic duct before applying that clip.
367
Figure 40.10 An E4 injury in which the confluence of the right and left hepatic ducts has been resected. Note the wide separation of the ducts indication a very high injury. Also note multiple clips. Preoperative placement of percutaneous transhepatic tubes facilitated identification of anatomy at surgery.
368
Step 1
Step 2
C. Core or lift liver off right Portal pedicle
Gallbladder plate
A. Identify left duct by HeppCouinaud technique D. Open bile duct on anterior surface
(A)
(B)
Figure 40.11 (A) Technique for identifying isolated right ducts. Step 1: Finding and dividing cystic plate to expose right pedicle. (B) Technique for identifying isolated right ducts. Step 2: Elevating right portal pedicle, identifying and incising right duct.
369
references
1. Keus F dJJ, Gooszen HG, van Laarhoven CJHM. Laparoscopic versus open cholecystectomy for patients with symptomatic cholecystolithiasis. The Cochrane Library 2008, Issue 2 2008: 1133. 2. Adamsen S, Hansen OH, Funch-Jensen P, Schulze S, Stage JG, Wara P. Bile duct injury during laparoscopic cholecystectomy: a prospective nationwide series. J Am Coll Surg 1997; 184: 5718. 3. Russell JC, Walsh SJ, Mattie AS, Lynch JT. Bile duct injuries, 19891993. A statewide experience. Connecticut Laparoscopic Cholecystectomy Registry. Arch Surg 1996; 131: 3828.
370
371
372
41
Gallstones and common bile duct stonessurgical and non-surgical approaches Matthew P. Dearing and Michael Rhodes
with radiation to the right lower chest or the lower pole of the scapula. This can be explained by the origin of the gallbladder from the lower thoracic segments, and transmission of visceral sensation through splanchnic nerves to the lower thoracic spinal cord. Some pain afferents may travel within the right phrenic nerve and peritoneum below the right diaphragm, accounting for the radiation of pain to the right shoulder tip. The pain of biliary colic often has a slower periodicity than ureteric colic, lasting between 30 minutes and 2 hours, but sometimes persisting for up to 8 hours. Although it is a commonly held belief that the consumption of fatty food is likely to provoke an attack, there is little evidence to support this (6). The pain may resolve spontaneously but often requires parenteral analgesia and anti-emetics. Acute Cholecystitis This is characterized by the presence of right upper quadrant or epigastric pain lasting for more than 8 hours, accompanied by systemic signs of infection such as fever and leukocytosis. The condition arises after impaction of a stone in the neck of the gallbladder or cystic duct, leading to sustained high pressure in the gallbladder. This leads to a reduction in the blood flow to the mucosa with subsequent ischemic injury (6). As a result of this, a chemical cholecystitis develops with inflammatory infiltrate and edema of the gallbladder wall. In the first 48 hours it is unusual for bacterial infection to occur but the incidence of infection after 1 week is in the order of 70% (6). Traditionally patients were admitted to hospital for a period of intense medical therapyanalgesia, intra-venous fluid rehydration and broad-spectrum antibiotics, with cholecystectomy deferred for 6 to 12 weeks (12). This used to be common practice across the United Kingdom. In one survey, 88% of surgeons reported routinely managing patients in this manner (13). However, it has been shown that early surgery (laparoscopic or open) is preferable to delayed surgery and is not associated with any additional morbidity or mortality (1214). Laparoscopic cholecystectomy, widely accepted as the gold standard of treatment, has been shown to be safe and effective in acute cholecystitis, with shortened length of hospital stay (15).
introduction
About 10% to 15% of the adult Western population has gallstones (1,2). This equates to 7.5 million Britons and 20 million Americans with gallstones, with between 1% and 4% a year developing symptoms (2,3). Cholecystectomy is not recommended in asymptomatic patients (4). However, symptomatic gallstone disease is one of the most common conditions in the United Kingdom requiring surgery (5,6). Up to 35% of patients with gallstones will ultimately become symptomatic, requiring cholecystectomy (7). In England, 49,077 cholecystectomies were performed between April 2005 and March 2006 (3). It is estimated that over half a million cholecystectomies are performed each year in the United States (5). Gallstones are seen in all age groups but incidence increases with age, with over one-third of the population over the age of 70 years affected (3,5). The development of gallstones is a multifactorial process, but has been shown to be associated with family history, pregnancy, obesity, rapid weight loss (such as after bariatric surgery), hemolytic anemias, parenteral nutrition, loss of bile salts (as seen in terminal ileitis and after terminal ileal resection), and diabetes mellitus (via the metabolic syndrome) (8).
classification of gallstones
There are three common types of gallstone. 1. Cholesterol (20%) 2. Bile Pigment (5%) 3. Mixed (75%) In western populations the consumption of a diet which is high in cholesterol and fat leads to the supersaturation of bile, with resultant precipitation and crystal growth (Fig. 41.1). Pure cholesterol stones are often solitary or exist as clusters of mulberries (9). Bile pigment stone are multiple, irregular, small, black, and fragile. They are seen in patients with chronic hemolysis (hereditary spherocytosis and sickle cell disease) and cirrhosis, where there is an increase in bilirubin (10). Mixed stones, composed of varying proportions of the above ingredients, are usually multiple.
empyema
The contents of the gallbladder become purulent, as a result of bacterial proliferation and exudation of neutrophils. The resultant collection of pus is termed an empyema. The adjacent omentum often becomes involved in the inflammatory process encasing the gallbladder and leading to the development of large tender mass in the right upper quadrant. The patient will be systemically unwell with a high swinging temperature and leukocytosis. Treatment involves controlling the sepsis with broad-spectrum antibiotics and percutaneous ultrasound-guided drainage, prior to definitive surgery. Most
373
Liver
XXX
These may demonstrate small bowel obstruction, a gallstone in the bowel lumen and gas in the biliary tree. Often the diagnosis is made at laparotomy. These conditions are rare but important causes of bowel obstruction, particularly in the elderly, where gallstones and cholecystenteric fistula are more common. Gallstones are implicated in 20% of cases of small bowel obstruction where there is no history of a hernia or previous abdominal surgery (17).
obstructive jaundice
Gall bladder Bile supersaturated with cholesterol
Cholesterol gallstone
patients can be managed in this way, although in severe cases the inflammatory process produces patchy necrosis of the gallbladder wall, which can result in perforation. Often the omentum is adherent around the gallbladder and this contains the perforation, leading to the formation of a peri-cholecystic abscess. In a small proportion of patients, usually the elderly, the perforation is not contained and generalized peritonitis develops with associated high morbidity and mortality (16).
Gallstones can migrate through the cystic duct into the common bile duct. Sometimes they will pass spontaneously causing no symptoms. The likelihood of stones passing spontaneously is related to their size (18). Stones up to 8 mm in diameter may pass without problems (19,20). When a stone impacts at the lower end of the common bile duct this can lead to obstructive jaundice. The impacted stone prevents the normal flow of bile resulting in biliary colic as the gallbladder contracts against the obstruction. The jaundice may be transient, resolving in 24 to 48 hours, as the stone either disimpacts and floats free in the bile duct or passes into the duodenum (6). If the stone remains impacted then the jaundice will persist and deepen. The diagnosis is based on analysis of the liver function tests, showing a characteristic rise in alkaline phosphatase and only minor derangement of transaminases, together with finding dilated extra-hepatic bile ducts on ultrasound. This can be confirmed with magnetic resonance cholangiopancreatography, endoscopic ultrasound, or ERCP (21). The prevalence of asymptomatic bile duct stones has been estimated between 5.2% and 12% (2224). Common bile duct stones have been found in between 10% and 18% of patients undergoing cholecystectomy (25).
acute cholangitis
Acute cholangitis results when bacterial infection develops within a partially or completely obstructed biliary system. Stasis leads to an increase in the resident bacterial flora, which are often found when gallstones are present in the biliary tract. Classically the condition presents with Charcots Triad of symptomsright upper quadrant pain, rigors, and jaundice. Ascending infection of the biliary tree can lead to septicemia and multiple hepatic abscesses. One-fifth of patients presenting with cholangitis have a bacteremia, with gram negative organisms mainly responsible (26). Treatment is with broad spectrum antibiotics, such as second generation cephalosporins or ciprofloxacin. ERCP is performed at an early stage allowing both confirmation of the diagnosis and decompression of the bile ducts. Biliary stents can be placed to encourage further drainage prior to definitive treatment.
mucocele
In this situation the obstructed gallbladder remains free of infection. Although the mucosa remains inflamed, it continues to function, absorbing water from bile and secreting mucus. The gallbladder fills with clear or bile-stained mucus. The patient will often report an episode of severe pain, consistent with cholecystitis. The symptoms may resolve partly, but there will be some persisting right upper quadrant pain and tenderness.
acute pancreatitis
Gallstones are responsible for up to 60% of all cases of pancreatitis. Between 4% and 8% of patients with gallstones will develop acute pancreatitis due to migratory stones (27). Small stones, with mean diameter of 4 mm, are more likely to cause pancreatitis than larger stones (28). The condition develops when a small gallstone, traveling from gallbladder to the bowel, impacts in the biliopancreatic duct
374
mirrizi's syndrome
This occurs when a gallstone, impacted in the neck of the gallbladder, causes inflammation to the surrounding tissue thereby compressing the adjacent bile duct. The stone induces fibrosis leading to obliteration of the cystic duct. Ongoing inflammation results in adherence of the gallbladder to the common hepatic duct, causing partial obstruction and jaundice. Mirrizis syndrome has been classified into two types. In type 1, there is no communication between the gallbladder and the bile duct. In type 2, the gallstone has eroded into the bile duct, resulting in a cholecystcholedochal fistula.
biliary dyspepsia
This represents a set of vague abdominal symptoms which have been attributed to gallstones. These include non-specific upper abdominal pain, nausea, belching, and food intolerance. These symptoms have been found to occur with equal frequency in patients with or without gallstones (34). In fact, symptoms other than typical biliary colic are rarely due to gallstones (6). Cholecystectomy in these situations is often ineffective with up to 30% of patients continuing to suffer dyspeptic symptoms (35,36).
375
Figure 41.2 Laparoscopic cholecystectomy. The gallbladder fundus is grasped and pushed cephalad.
Figure 41.4 A window is created behind the cystic duct and artery.
technique. During dissection, the gallbladder neck is retracted to the patients right. This stretches the peritoneum overlying the cystic duct and common duct, facilitating safe dissection. The cystic duct, cleared of peritoneum, can be cannulated in order to perform operative cholangiography. Following this the duct can be clipped and ligated. The cystic artery should be clipped and ligated similarly. The gallbladder can be removed from the liver bed using diathermy. The rectus sheath should be closed in 2 layers with continuous monofilament suture. Laparoscopic Cholecystectomy Laparoscopic cholecystectomy, which was first performed in 1985 (50), is well established as the preferred method of treatment (45). These procedures are routinely performed as day cases (51) and during the index admission for cholecystitis (12). This has been shown to be both safe and efficacious. The standard procedure involves four ports and will be described below. Operative Technique The patient is positioned supine on the operating table. The pneumoperitoneum is established via an open longitudinal
incision below the umbilicus, followed by insertion of a blunt 10 mm trocar and insufflation of carbon dioxide. This technique is preferable to the use of the Veress needle which has a higher incidence of bowel and vascular injuries (52). Further ports can then be inserted under direct vision. Two 5 mm ports are placed in the right flank (in the anterior axillary and midclavicular lines) and a further 10 mm port is placed in the midline about 5 cm below the xiphisternum. The usual setup requires the surgeon to stand on the patients left side with the monitor positioned on the right. The gallbladder fundus is grasped atraumatically and pushed cephalad (Fig. 41.2). The assistant is required to hold the grasper with the left hand, maintaining traction, and the camera with the right hand. Adhesions can be taken down with either blunt or sharp dissection. Another grasper, inserted via the medial 5 mm port, is used to apply lateral and caudal traction to Hartmanns pouch. This allows Calots triangle to be identified. The peritoneum overlying Calots triangle is opened with diathermy. The cystic duct and artery are carefully dissected and identified (Fig. 41.3). This can be done with either blunt dissection or with cautious and sparing use of the diathermy hook. By moving the gallbladder medially the surgeon can continue the dissection, developing a window behind the cystic artery (Fig. 41.4). Having identified the cystic duct, cholangiography can be performed. Although this is not routinely performed in all cases it should be available, particularly if bile duct stones are suspected or there is difficulty in defining the biliary anatomy. Scissors are used to open the cystic duct and a 4 Fr catheter is inserted and held in place with a clip. Contrast media is injected via the catheter and real-time images are obtained using the image intensifier. A normal cholangiogram must demonstrate flow of contrast in the main bile duct and right and left hepatic ducts. There must be flow distally into the duodenum, and no stones present in the duct. After obtaining a cholangiogram and removing the catheter, the cystic duct and artery can be clipped and divided (Fig. 41.5). The gallbladder can then be removed with the diathermy hook. The gallbladder fossa is inspected thoroughly at the end
376
of the procedure for bleeding and bile leaks, as are the cystic duct and artery clips. The area can be gently irrigated with saline and then suctioned. The camera is moved to the top port and the gallbladder is grasped via the umbilical port and delivered. The linea alba can be closed with absorbable sutures and the skin with steristrips or sutures. Future Developments Advances in surgical technology and innovation have made possible the advent of 2 port (53) and single port laparoscopic cholecystectomy (54) and the development of NOTESnatural orifice transluminal endoscopic surgery (55). This will allow the surgeon to undertake major intraperitoneal surgery without the need for skin incisions, with access to the peritoneal cavity via the mouth (via the stomach), the rectum and the vagina, using flexible endoscopes. There is, to date, no research published on resections in humans but the first transvaginal cholecystectomy in a porcine model was carried out in 2005 (55). Progress in this area is likely to be rapid since the set up of working groups, dedicated to advancing the concept (56).
377
references
1. NIH Consensus Statement on gallstones and laparoscopic cholecystectomy. National Institute of Health Consensus Development Conference Statement Sep 1416, 1992. 2. Halldestam I, Enell EL, Kullman E, et al. Development of symptoms and complications in individuals with asymptomatic gallstones. Br J Surg 2004; 91(6): 7348. 3. Sanders G, Kingsnorth AN. Gallstones. BMJ 2007; 335: 2959. 4. Gurusamy KS, Samraj K. Cholecystectomy versus no cholecystectomy in patients with silent gallstones. Cochrane Database Syst Rev 2007. CD 006230. 5. Geibel J, Longo W. Cholelithiasis: evolving standards for diagnosis and management. World J Gastroenterol 2006 May 28; 12(20): 31627. 6. Johnson CD. Gallstones. Surg J 21: 5 May 2003. 7. Schirmer BD, Winters KL, Edlich RF. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants 2005; 15: 32938. 8. Shaffer EA. Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res Clin Gastrenterol 2006; 20: 98196. 9. Ellis H, Calne R, Watson C. Lecture Notes on General Surgery, 9th edn. 25664. 10. Kumar P, Clark M. Clinical Medicine, 5th edn. Edinburgh: W B Saunders, 2002: 9816. 11. Glasgow RE, Cho M, Hatter MM, et al. The spectrum and cost of complicated gallstone disease in California. Arch Surg 2000; 135: 10215. 12. Papi C, Catarci M, DAmbrosio L, et al. Timing of cholecystectomy for acute calculous cholecystitis: a meta-analysis. Am J of Gastroenterol 2004; 99(1): 14755. 13. Cameron IC, Chadwick C, Phillips J, et al. Current practice in the management of acute cholecystitis. Br J Surg 2000; 87: 3667. 14. Gurusamy KS, Samraj K. Cholecystectomy for acute cholecystitis. Cochrane Database Syst Rev 2006 CD 005440. 15. Keus F, deJong JA, Gooszen HG, et al. Laparoscopic versus open cholecystectomy for patients with symptomatic cholecystolithiasis. Cochrane Database Syst Rev 2006 CD 006231. 16. Stefandis D, Kirinek KR, Bingener J. Gallbladder perforation: risk factors and outcome. J Surg Res. 2006; 131(2): 2048. 17. Clavien PA, Richon J. Gallstone ileus. Br J Surg 1990; 77(7): 73742. 18. Fisher EJ, Sherman S. The interface of ERCP and laparoscopic cholecystecomy. Gastrointest Endosc Clin N Arm 1996; 6(1): 5780. 19. Chung RS, Chad V, Eisenstat M. Choledocholithiasis treated with endoscopic stenting of the papilla followed by stent guided sphincterotomy. Gastrointest Endosc 1997; 45: 12130. 20. Frossard JL, Hadengue A, Amouyal G, et al. Choledochlithiasis: a prospective study of common bile duct stone migration. Gastrointest Endosc 2000; 51(2): 1759. 21. Beckingham IJ. MRCP versus ERCP in the diagnosis of choledochlithiasis. Eur J Gastro Hepatol 2003; 15(7): 80913. 22. Murison MS, Gartell PC, McGinn FP. Does selective preoperative cholangiography result in missed bile duct stones? J R Coll Surg Edin 1993; 38(4): 2204. 23. Rosseland AR, Stomsaker TB. Asymptomatic common bile duct stones. Eur J Gastr Hepatol 2000; 12(11): 11713. 24. Sarli L, Pietra N, Franze A, et al. Routine intravenous cholangiography; selective ERCP and endoscopic treatment of bile duct stones before laparoscopic cholecystectomy. Gastrointest Endosc 1999; 50(2): 2008. 25. Martin DJ, Vernon DR, Toouli J. Cochrane Database of Systematic Review 2006 CD 003327. 26. Leung JW, Ling TK, Chan RL, et al. Antibiotics, biliary sepsis and bile duct stones. Gastrointest Endosc 1994; 40(6): 71621. 27. Ayub K, Imada R, Slavis J. ERCP in gallstone associated pancreatitis. Cochrane Database of Systematic Review 2004; CD 003630. 28. Caddy GR, Tham TC. Gallstone disease: Symptoms, diagnosis and endoscopic management of common bile duct stones. Best Prac Res Clin Gastr 2006; 20(6): 1085101. 29. Mayer AD, McMahon MJ, Benson EA, et al. Operations on the biliary tract in patients with acute pancreatitis; aims, indications and timing. Ann R Coll Surg Engl 1984; 66: 17983. 30. Neoptolemos JP, Hall AW, Finlay DF, et al. The urgent diagnosis of gallstones in acute pancreatitis: a prospective study of 3 methods. Br J Surg 1984; 71: 2303.
key points
10% to 15% of the adult Western population have gallstones. Between 1% and 4% of patients a year develop symptoms. Cholecystectomy is not recommended for asymptomatic gallstones (4)Grade A. Cholecystectomy is recommended for all patients with symptomatic gallbladder stones and CBDS (except where surgery is considered inappropriate). Grade A. Laparoscopic cholecystectomy is the gold standard of treatment for symptomatic gallstone disease (45)Grade A. Laparoscopic cholecystectomy is safe and effective in the management of acute cholecystitis (12,14))Grade A. Cholecystectomy during the index admission for cholecystitis is recommended (12) Grade A. Symptomatic patients with suspected ductal stones should undergo stone extraction where possibleGrade B. ERCP is not recommended solely as a diagnostic test, it should only be done in patients for whom an intervention is planned. Grade B Biliary sphincterotomy and endoscopic stone extraction are recommended for patients with bile duct stones post cholecystectomy. Biliary stenting should only be used as a sole treatment in patients with limited life expectancy or very high-surgical risk. Grade A. Patients with ductal stones undergoing laparoscopic cholecystectomy may be managed by laparoscopic common bile duct exploration at the time of surgery, or undergo peri-operative ERCP. Transcystic and transductal exploration of the common bile duct are both recommended approaches for removal of stones. Grade A. In patients with bile duct stones that have not been extracted, short term use of a biliary stent is recommended, followed by further endoscopy or surgery. Grade B. If duct clearance is not achieved by minimally invasive methods then open surgical exploration is recommended as an important treatment option. Grade B.
378
379
epidemiology
PDAC is the tenth most common type of cancer in the United States and the United Kingdom but accounts for the fourth and sixth most frequent type of cancer-related death in these countries (24), respectively. Due to its aggressive nature, the number of new cases per year (an estimated 37,680 in the U.S. in 2008 and 7,632 in the UK in 2005) almost equals the number of deaths per year (34,290 in the U.S. and 7315 in the UK) (36). PDAC has an overall median survival of less than 6 months and one of the lowest overall 5-year survival rates of any malignant disease with 0.4% to 5% (7,8). Furthermore, these dismal figures seem to have improved little compared to the 1950s (5). The incidence rate peaks between 65 and 75 years of age (9) and only 15% to 20% of patients initially present with localized disease suitable for potential curative surgical resection.
380
mucus production in exocrine glands. Several studies have analyzed the association between cystic fibrosis and PDAC showing a 2.3- to 32-fold increase in relative risk (61,62). Finally, a number of hereditary tumor syndromes are associated with an increased risk for PDAC. Table 42.2 gives an overview of hereditary pancreatic cancer disorders.
argued that the lack of efficient diagnostic tools to detect pancreatic cancer early does not warrant further diagnostic measures in patients with late-onset diabetes as their sole symptom (63). Although PDAC contributes only marginally to the overall number of acute pancreatitis cases, idiopathic acute pancreatitis in patients over 50 of age justifies further diagnostic workup, since up to 5% of PDAC patients are present with idiopathic pancreatitis as their first clinical manifestation (63,71).
381
Recurrent acute pancreatitis in young patients Exocrine pancreas insufficiency DIOS COPD Biliary cirrhosis Reduced fertility Intestinal hamartomatous polyps Mucocutaneous pigment spots FAMM: multiple dysplastic naevi/melanoma in two or more first-degree relatives 25% of FAMM families show association with PDAC MPCS: melanoma and PDAC Breast cancer Ovarian cancer Early-onset right-sided colorectal cancer Carcinoma of the pancreas, hepatobiliary tract, endometrium, ovary, stomach, small bowel, brain, upper uroepithelial tract Multiple colonic polyps and colon cancer Duodenal tumors Desmoids and others Breast cancer, Sarcoma, leukemia Brain tumors and others
40% <5%
STK11 CDKN2A
36% 17%
FBOC HNPCC
38% <5%
FAP
APC
<5%
LiFraumeni
TP53
<5%
Familial pancreatic cancer syndrome (FPC), hereditary pancreatitis and cystic fibrosis as well as hereditary tumor syndromes with PDAC association are listed. The causative genes are listed as well as the cumulative risk to develop PDAC the age of 70. Abbreviations: DIOS, distal intestinal obstruction syndrome; COPD, chronic obstructive pulmonary disease; STK11, serine-threonine protein kinase 11; PDAC, pancreatic ductal adenocarcinoma; FPC, familial pancreatic cancer; BRCA1/2, breast-cancer gene 1/2; PRSS1, Protease Serine 1; SPINK1, serine protease inhibitor Kazal-type 1; CFTR, cystic fibrosis transmembrane regulator; FAMM, familial atypical multiple mole melanoma syndrome; MPCS, melanoma pancreatic cancer syndrome; CDKN2A, cyclin-dependent kinase inhibitor 2A; HNPCC, hereditary non-polyposis colon cancer; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; FBOC, familial breast and ovarian cancer syndrome; MLH1, MutL homolog 1; MSH2/6, MutS homolog 2/6; PMS2, postmeiotic segregation 2; TP53, tumor protein 53.
Following the initial suspicion of a pancreatic malignancy after taking the patients history and conducting a thorough physical exam, a laboratory work-up and a transabdominal ultrasound are the first steps to be taken. Laboratory values should include amylase and lipase, cholestasis parameters (GT, direct and indirect bilirubin, alkaline phosphatase), the transaminases ALT and AST, a blood count to evaluate tumor anemia, coagulation parameters, and the tumor marker carbohydrate antigen 19-9 (CA199). None of these parameters are specific for pancreatic cancer and none can be used as a screening tool. The tumor-associated antigen CA19-9 specifically has been tested in two large studies and found to be ineffective as a screening tool in asymptomatic patients because of its low positive predictive value (72,73). Furthermore, controversies exist regarding the correct cut-off value for CA19-9.
However, in the context of suspected pancreatic malignancy, CA19-9 remains a valuable adjunct since in combination with computed tomography (CT) a positive predictive value of 99% can be achieved when levels are over 120 U/ml (74). In addition, high levels of CA19-9 (over 150 U/ml) were shown to serve as an indicator for irresectability with a positive predicitive value of 88% and might justify further staging procedures (75). Finally, CA19-9 can be used as a parameter of therapeutic response and as an indicator of recurrence in patients with PDAC. Transabdominal ultrasonography is a fast and cost-effective measure and provides valuable information. The presence of ascites, hepatic metastasis as well as dilated intrahepatic and extrahepatic bile ducts can be evaluated with high accuracy, whereas the visualization of the primary tumor is achieved
382
High
>50 >50
Pain plus Loss of appetite/loss of weight/fatigue Pain onlya Pain plus Loss of appetite/loss of weight/fatigue
Epigastric pain that radiates to the back and persists at night should trigger further investigations independent of age. Abbreviations: US, abdominal ultrasound; EUS, endoscopic ultrasound; CT, computed tomography.
Abbreviations: Tis: carcinoma in situ; T1, tumor limited to the pancreas <2 cm; T2, tumor limited to the pancreas >2 cm; T3: tumor extending beyond the pancreas but without involvement of the coeliac axis or the superior mesenteric artery; T4, tumor involving coeliac axis or superior mesenteric artery; N0, no regional lymph node metastasis; N1, regional lymph node metastasis; M0, no distant metastasis; M1, distant metastasis.
with less sensitivity (95% in tumors greater than 3 cm, 81% in tumors 13 cm, and 50% in tumors less than 1 cm) (76). Subsequently, a qualified imaging procedure should be performed to clarify local resectability and the presence of potential metastasis. CT is now widely regarded as the gold standard for this purpose although based on local experience and availability, magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreaticography (MRCP) or endoluminal ultrasound (EUS) may be applied without compromising sensitivity and specificity (evidence grade 3, recommendation C). CT diagnostic should be performed with a multidetector row CT (MDCT) with arterial and portal venous phases of contrast enhancement and a maximum section thickness of 3 mm. In this setting, MDCT will accurately predict respectability in 80% to 90% of cases (7779), but sensitivity drops below 80% when tumors are smaller than 2 cm (80). It should be mentioned, however, that PDAC induces a heavy desmoplastic reaction in the surrounding stroma tissue
(81) that is difficult to distinguish from the actual tumor on CT imaging which may lead to the false positive diagnosis of irresectability. Using a cut-off value of 180 of vascular involvement on CT yielded a sensitivity of 84% and a specificity of 98% for unresectable disease in one study (82), but recent data suggest that greater tumor involvement of arteries is necessary to accurately identify arterial invasion (83). Furthermore, enlargement of lymph nodes on CT is a poor indicator for metastasis and irresectability (84). Finally, the sensitivity of CT imaging to detect hepatic metastasis varies depending on the size of the lesion, but is considered to range between 38% and 73% (76). MRI should be performed with a field volume of at least 1.5 T, with sections of 5 mm and T1 and T2 weighted as well as MRCP images. In this setting, MRI/MRCP yields similar accuracy in diagnosis and staging of PDAC than CT imaging and might be superior in the diagnosis of hepatic lesions (85 87). As with endoscopic retrograde cholangio-pancreaticography (ERCP), a double-duct sign (obstruction of both the pancreatic and the bile ducts) strongly suggests pancreatic malignancies (88). Recent reports foster the hope that special MRI sequences may be superior to other imaging techniques in detecting early PDAC lesions (89). EUS is highly sensitive in the diagnosis of pancreatic cancer as well as in the evaluation of vascular involvement (90). It has a sensitivity of 95%, a specificity of 80%, a positive predictive value of 95%, and a negative predictive value of 80% for pancreatic tumors in experienced hands (9193). It was reported to be superior to CT imaging in detecting small tumors (93,94), but less effective in assessing vascular involvement and distant metastasis (91,95). Furthermore, EUS is a sensitive (over 90%) and highly specific (over 90%) method to obtain fine-needle aspirates (FNA) for pathological analysis (9699). In most cases, however, a histological verification before surgery is not necessary since any potentially malignant lesions of the pancreas should be resected (evidence level 2; recommendation B) (63). Histological verification should, therefore, only be sought if the result would influence further treatment, which is particularly important in the palliative setting. In order to complete staging procedures, a chest X-ray or thoracic CT scan should be performed to rule out potential pulmonary metastasis. Further diagnostic procedures that may be employed in specific clinical settings include ERCP, positron emission tomography with CT (PET-CT), and diagnostic laparoscopy. PET-CT does not play a role in the routine evaluation of pancreatic cancers, although it may be used in the context of equivocal radiographic findings, detection of occult metastasis, or in the case of recurrent disease (100,101). Similarly, diagnostic laparoscopy may detect peritoneal carcinosis and occult organ metastasis not previously visible on imaging studies. Early studies demonstrated a 15% to 25% incidence of such lesions when compared with preoperative imaging studies (102104) leading to the routine employment of diagnostic laparoscopy in some centers. Advances in the accuracy of imaging techniques, however, reduced the incidence of newly diagnosed lesions detected by diagnostic laparoscopy to 5% to 15% (105107). In addition, diagnostic laparoscopy
383
(pylorus or antrum)
: must be absent. : must be present. : may or may not be present (in brackets the maximum extent of involvement). For locally irresectabe tumors: one -criterion is enough to classify the tumor as locally irresectable. Abbreviations: SMV: superior mesenteric vein.
Labs transabd. US
Resectable
Borderline
Locally irresectable
Metastatic disease
Figure 42.1 Preoperative diagnosis pathway in patients with pancreatic cancer. The aim is to determine surgical respectability. Abbreviations: US, ultrasonography; MDCT, multidetector-computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreaticography; EUS, endoluminal ultrasound; ERCP, endoscopic retrograde cholangiopancreaticography; PET, positron emission tomography.
384
management
Management of PDAC depends on the clinical tumor stage (Fig. 42.2): 1. Patients with resectable tumors should undergo surgery as soon as possible followed by adjuvant chemotherapy. 2. Patients with borderline tumors should undergo exploration and resection if possible. If resection is not possible the decision to perform a (double) bypass operation (gastrojejunostomy and/or hepaticojejunostomy) must be made. The patient can then either be enrolled in a neoadjuvant treatment protocol to achieve respectability or undergo palliative care. 3. Patients with locally advanced, unresectable tumors can be enrolled in a neoadjuvant treatment trial or be treated palliatively. 4. Patients with distant metastasis should be offered palliative treatment. The rational to perform surgical resection whenever possible is the vastly improved prognosis and quality of life following a macroscopic complete (R0/R1) removal of the tumor (see below). It should be mentioned that age should not be a contraindication for surgery since several studies have demonstrated comparable outcomes between young and old patient cohorts (evidence grade 4, recommendation D) (121123).
surgical resection
The objective of surgical management of PDAC is the macroscopic complete resection of the primary tumor, complete regional lymphadenectomy, and reconstruction of the gastrointestinal tract. Depending on the localization of the tumor this goal can be achieved either by left (distal) pancreatectomy, pancreatoduodenectomy (PD) or by total pancreatectomy. A standard PD (KauschWhipple operation) (124) involves resection of the pancreatic head, the duodenum, the distal common bile duct, the distal stomach, the gall bladder, and regional lymph nodes. A variant of this standard PD procedure preserves the stomach and is thus termed pylorus-preserving pancreatoduodenectomy (ppPD, Traverso-Longmire operation) (125). Resections as well as the extent of lymphadenectomy (standard and extended) have been defined in order to allow for better comparison of data (126,127). For details concerning the surgical resection procedures see the chapter on pancreatic resection in this book. Standard Versus Pylorus-Preserving Pancreatoduodenectomy The question whether standard or pylorus-preserving pancreatoduodenectomy (PD vs. ppPD) is superior in the treatment of PDAC has been a matter of debate for some time. The main areas of concern were the oncological completeness of the ppPD procedure as well as the potential physiological side
385
Laparotomy
Histology
-CT/US/EUS: biopsy
Histology
-CT/US/EUS: biopsy
Resection
-PD -ppPD -Left resection -total pancreatecotmy
Irresectable
Neoadjuvant (R)CTx
Adjuvant CTx
(Double bypass)
Resectable
Irresectable
Neoadjuvant (R)CTx
Laparotomy
Figure 42.2 Treatment of PDAC dependent on clinical tumor stage. Abbreviations: CTx, chemotherapy; RCTx, radio-chemotherapy; EUS, endoluminal ultrasound; US, ultrasound; PD, pancreaticoduodenectomy; ppPD, pylorus-preserving pancreaticoduodenectomy.
effects of the distal gastrectomy performed during PD. A number of series have compared the two procedures; however, results were inconclusive or conflicting (128131). A recent meta-analysis of seven randomized controlled trials including a total of 496 patients, however, found no difference between the two procedures concerning in-hospital mortality, overall survival, and overall morbidity. Merely intra-operative blood loss and operation time were significantly reduced in the ppPD procedure (132). Although the authors pointed out that the analyzed studies were of clinical and methodological heterogeneity, currently both procedures seem to be equally appropriate in treating tumors of the pancreatic head (evidence grade Ia, recommendation A). PancreaticEnteric Anastomosis One of the most common and feared complications of pancreatic surgery is the development of a pancreatic fistula which was historically associated with mortality rates of up to 40% (133135). Mortality rates have dropped significantly with the advent of CT-guided drainage, modern antibiotic regimes, and nutritional support, but the question which anastomotic techniques are associated with the lowest possible leakage rate remains.
Several studies have investigated whether pancreaticogastrostomy might be superior to the traditional pancreaticojejunostomy. A recent meta-analysis of three randomized controlled trials and 13 nonrandomized observational studies found no significant differences between the two procedures regarding overall postoperative complications, pancreatic fistula, intra-abdominal fluid collection, or mortality when analyzing the randomized controlled trials (136). On the contrary, analysis of the 13 nonrandomized observational studies showed significant results in favor of pancreaticogastrostomy, a result which was most likely due to publication bias. Therefore, neither pancreaticogastrostomy nor pancreaticojejunostomy seems to be superior in reconstruction after PD (evidence grade Ia; recommendation A). Further areas of research concern technical aspects of the pancreaticojejunostomy. Specifically the question whether the anastomosis should be performed with invagination (end of the pancreas invaginated into either the end or the side of the jejunum) or whether a duct-to-mucosa approach leads to less pancreatic fistulas has been investigated. All have been proven to be safe and feasible with no clear advantage of one over the other (137,138). Similarly, the use of anastomotic stents has failed to affect fistula rates (137,139).
386
neoadjuvant treatment
Currently, no randomized controlled trial comparing neoadjuvant therapy (radiochemotherapy or chemotherapy alone) with direct resection for locally advanced pancreatic cancer exists. A number of phase I/II trials or retrospective studies, however, have demonstrated that neoadjuvant treatment is safe and may result in down-sizing in a number of cases resulting in resection rates as high as 51% for tumors that deemed unresectable at presentation (160162). These patients might benefit from the improved prognosis of an R0/R1 resection, although data to confirm this notion are lacking. Due to the lack of evidence, however, neoadjuvant treatment for pancreatic cancer should be confined to clinical trials. In this context, it should be pointed out that specialized, high-volume centers have markedly improved resection rates compared to low-volume centers (over 50%), i.e., patients that might be classified as unresectable in one hospital might undergo successful resection at a specialized center (163,164).
387
Group 1 2 3 4 5 6 7 8 9 10 11 12 12h 12a1 12a2 12p1 12p2 12b1 12b2 12c 13 13a 13b 14 14a 14b 14c 14d 15 16 16a1 16a2 16b1 16b2 17 17a 17b 18
Lymph nodes Right cardial Left cardial Along the lesser curvature of the stomach Along the greater curvature of the stomach Suprapyloric Infrapyloric Along the left gastric artery Along the common hepatic artery Around the celiac artery Splenic hilum Along the splenic artery In the hepatoduodenal ligament Hepatic hilum Superior to hepatic artery Inferior to hepatic artery Superior to portal vein Inferior to portal vein Superior to bile duct Inferior to bile duct Around cystic duct Posterior pancreatoduodenal nodes Superior to ampulla of Vater Inferior to ampulla of Vater Along the superior mesenteric artery Origin of the SMA Origin of the pancreatoduodenal artery Origin of the middle colic artery Origin of the jejunal arteries Along the middle colic artery; Around the abdominal aorta Above the origin of the coeliac axis Between coeliac axis and left renal artery Between left renal artery and IMA Between IMA and aortic bifurcation On the anterior surface of the pancreatic head Superior to ampulla of Vater Inferior to ampulla of Vater Along the inferior margin of the pancreatic body/tail
Figure 42.3 Japanese Pancreatic Society lymph node groups (140). Only the lymph node groups relevant for pancreatic surgery are shown in the figure, while the table lists all abdominal lymph node groups. 13 and 17 are first-order lymph nodes. 6, 8, 12 and partly 9 are second-order lymph nodes. 10, 11, 15, 16, 18 and partly 9 are third-order lmyph nodes. Abbreviations: SMA, superior mesenteric artery; IMA, inferior mesenteric artery. Opaque numbers indicate posteriorly positioned lymph nodes.
388
complications are surgical but frequently they can be handled by pharmaceutical, radiological, and/or endoscopic interventions. Complications that require reoperation are still associated with high-mortality rates between 23% and 67% (184186). The most common surgical complications in order of frequency are (the percentages given indicate the frequencies reported at two specialized high-volume centers and should be regarded as minimum numbers) (181,187):
been reported to alleviate the symptoms of DGE in up to 37% of patients (192). Postoperative Pancreatic Fistula (POPF) As for DGE, the rate of POPF in reports varies depending on the definition used and the experience of the team, but is approximately 5% in specialized centers (181,187). POPF is a feared complication since it is associated with a significant mortality rate of up to 28% secondary to sepsis and hemorrhage (189,193,194). An early sign of POPF may be a persistently elevated CRP level after postoperative day 4 (187). Surgical risk factors for POPF have been discussed in section Pancreatic-Enteric Anastomosis. Recently, POPF have been defined and graded according to their clinical relevance ( Table 42.7) (195). It should be mentioned that imaging studies are not necessary for diagnosis, although helpful in deciding further treatment options. Treatment should be tailored to the grade of POPF (all recommendations are grade D): Grade A fistulas have little or no clinical impact. The patient does well and can continue to be fed orally. Neither antibiotics nor total parenteral nutrition or somatostatin analogs are indicated. Most surgeons would leave the intraoperatively placed drains in situ and remove them slowly. Grade B fistulas require an adaption of the clinical management. Pancreatic fluid should be drained effectively. If this cannot be achieved via the intraoperative drains visualization by radiologic imaging and effective percutaneous drainage of any pancreatic fluid collection should be sought. Frequently, the patient is kept with nil by mouth and has to be supported by parenteral or enteral nutrition. Frequently, grade B fistulas are associated with fever and leucocytosis in which case antibiotics should be applied. Grade C fistulas constitute a worrisome clinical setting and demand immediate action since clinical stability of the patient is often compromised. Patients should be transferred to an ICU or at least intermediate care unit for better observation. The patient is kept with nil by mouth and is supported by parenteral or enteral nutrition. Intravenous antibiotics as well as somatostatin analogs are usually instituted. Radiologic imaging should be sought quickly and any peripancreatic fluid collection
Delayed gastric emptying (DGE) 9% to 15% Postoperative pancreatic fistula (POPF) 5% Wound infection 3% to 8% Intraabdominal abscess 1% to 4% Postpancreatectomy hemorrhage (PPH) 1% to 3%
The reported incidence rates for these complications vary widely since up to recently standardized definitions for these entities were lacking. In order to facilitate the reporting and comparison of morbidity data between different institutions, consensus definitions and classifications have been achieved recently and should be used in all future reports ( Table 42.7). Delayed Gastric Emptying (DGE) DGE has been reported in 14% to 70% of cases without application of a standardized definition (186,188,180), but seems to be considerably lower in specialized centers (915%) (181,187). DGE is graded according to an international consensus definition ( Table 42.7). A number of studies have demonstrated an association between DGE and other postpancreatectomy complications like intraabdominal abscesses or pancreatic fistulas (186). A relationship between DGE and the pylorus preserving Whipple procedure reported in one trial (189) could not be verified in consecutive randomized trials (128,190). However, the route of reconstruction, i.e., antecolic versus retrocolic gastrojejunostomy is associated with a significant lower DGE rate (191). Furthermore, early initiation of enteral feeding via an intraoperatively placed jejunal feeding tube after Whipple resections resulted in significantly higher rates of DGE as compared to patients not receiving early enteral nutrition (267). Intravenous erythromycin has
389
Postoperative Pancreatic Fistula (POPF) (195) Definition: Output via an operatively placed drain (or a subsequently placed, percutaneous drain) of any measurable volume of drain fluid on or after postoperative day 3, with an amylase content greater than three times the upper normal serum value Grade A Clinical condition Specific treatmenta CT/US findings Persistent drainage >3 weeks Reoperation Death related to POPF Signs of infection Sepsis Well No Negative No No No No No Grade B Often well Yes/no Negative/positive Usually yes No No Yes No Grade C Ill appearing/bad Yes Positive Yes Yes Possible Yes Yes
Postpancreatectomy Hemorrhage (PPH) (200) Time of onset (early <24 hr, late >24 hr) Location: intraluminal vs. extraluminal Severity: mild vs. severe b Grade A Time of onset, location, severity and clinical impact Clinical condition Diagnostic consequence Therapeutic consequence Early, mild, intra-/extraluminal Grade B Early, severe, intra-/extraluminal or late, mild, intra-/extraluminal Grade C Late, severe, intra-/extraluminal
Often well, intermediate, very rarely Severely impaired, life-threatening life-threatening abservation, blood count, US, CT, Angiography, CT, endoscopy, angiography, endoscopy transfusion, ICU, therap. endoscopy, Localization of bleeding, embolization, relaparotomy angiography and embolization, endoscopy, relaparotomy, ICU
Partial (peripheral) or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin analog and/or minimal invasive drainage; bFor the definition of mild and severe PPH see text. Abbreviations: delayed gastric emptying (DGE) (261), postoperative pancreatic fistula (POPF) (195), and postpancreatectomy hemorrhage (PPH) (200). CT, computed tomography; US, ultrasound; POD, postoperative day; NPO, nothing by mouth.
should be adequately drained percutaneously. Deteriorating clinical status (e.g., sepsis and organ dysfunction) may require re-exploration in order to attempt either to repair the site of leakage, convert to alternative means of pancreaticenteric anastomosis (e.g., conversion of pancreaticojejunostomy to pancreaticogastrostomy), or to resect the pancreatic remnant. Intraabdominal Abscess Intraabdominal abscesses have been reported in 1% to 12% of patients following pancreatic resection (186,188,180,196). The usual cause is a persistent leak from the pancreatojejunostomy (see pancreatic fistula) or any other anastomosis. Intraabdominal abscesses following pancreatic surgery typically present as subhepatic or left subdiaphragmatic collections (182) and can usually be managed by CT-guided percutaneous drainage and intravenous antibiotic application (197). Postpancreatectomy Hemorrhage (PPH) PPH occurs in 1% to 8% of pancreatic resections and accounts for approximately 11% to 38% of overall mortality
(189,198,199). Again the variation seems to be in part due to a lack of a uniform definition, which has recently been achieved (Table 42.7) (200). PPH should henceforth be classified according to: (1) time of onset, (2) location and cause, and (3) severity. Early onset PPH (<24 hours) seems to be due to insufficient intraoperative hemostasis or an underlying coagulopathy while late PPH (>24 hours) may occur from: (a) erosion of (peripancratic) vessels due to pancreatic fistulas or intraabdominal drains, (b) gastric or duodenal ulcers, (c) anastomotic suture lines, (d) the resected area, (e) intraabdominal abscesses, or (f) the formation and rupture of pseudoaneurysms in the peripancreatic vasculature (201203). It is important to distinguish between intraluminal and extraluminal PPH with markedly different clinical presentation. While the former is characterized by melena, hematemesis, or blood flow from the nasogastric tube, the latter is more often characterized by hemorrhage from the abdominal drains. The severity of the PPH should be determined clinically.
390
Small or medium volume blood loss, decrease in hemoglobin level by <3 g/dl Mild clinical impairment of the patient, no therapeutic consequence, or at most the need for noninvasive treatment with volume resuscitation or blood transfusions (23 units packed cells within 24 hr of end of operation or 13 units if later than 24 hr after operation) No need for reoperation or interventional angiographic embolization; endoscopic treatment of anastomotic bleeding may occur provided the other conditions apply
the analysis was, however, limited by the lack of any standardized definition for pancreatic fistulas between different trials (see above). As a result a meaningful subgroup analysis was not possible to elucidate which patients benefit from prophylactic application. Therefore, currently, prophylactic use of somatostatin analogs cannot be recommended indiscriminately.
adjuvant treatment
Two recent randomized controlled trails (CONKO-1 (210); ESPAC-1 (211)) as well as one meta-analysis (212) have demonstrated a significant benefit of adjuvant chemotherapy on outcome following pancreatic cancer resection compared to observation. Therefore, all patients undergoing curative resection should receive adjuvant chemotherapy (evidence grade 1b, recommendation A). The current data suggest that tumor-specific risk factors like grading or T-stage as well as age (even >80) are no contraindication for adjuvant chemotherapy (210,211). Poor postoperative performance status should be regarded as only a relative contraindication since in the trial of Oettle et al. even patients with Karnofsky index 50 were included (210). Currently, both 5-FU/folic acid (211) and gemcitabine (210) chemotherapy schemes are accepted after curative resection. A direct comparison of gemcitabine with 5-FU/folinic acid was recently conducted in the randomized, multicenter ESPAC-3 trial (270). Both groups had comparable overall survival rates after a median of 34.2 months of follow-up. While the treatment-related serious adverse events were significantly more frequent in the 5-FU/folinic acid group compared to gemcitabine, this did not translate into a difference in overall quality of life, which was comparable between the two groups. Based on the data from the currently available studies, adjuvant chemotherapy should be initiated within 6 weeks of surgery and be applied for 6 months. Table 42.8 lists all available randomized controlled trials of adjuvant treatment after resection of pancreatic carcinoma. Furthermore, based on subgroup analysis of the CONKO-1 trial (210), patients receiving a gemcitabine-based adjuvant chemotherapy demonstrated a significantly longer disease-free survival compared to observation alone after R1 resection of pancreatic cancer. Therefore, even in the setting of an R1 resection postoperative chemotherapy has been proven beneficial (evidence grade 1b, recommendation A). In contrast, the evidence for a combination of radiochemotherapy with chemotherapy is less clear, although this treatment is common in the United States (213). Most adjuvant trials have been underpowered and the randomized controlled ESPAC-1 (211) trial as well as one meta-analysis (212) failed to show any benefit for radiochemotherapy ( Table 42.8). Radiochemotherapy actually seemed to have a detrimental, albeit nonsignificant, effect on outcome. Therefore, currently, radiochemotherapy cannot be recommended as adjuvant treatment for PDAC outside trials (evidence grade 1b, recommendation A). Shortly data of the randomized controlled CAPRI trial (combination of radio-, chemo- and immunotherapy) (214) should be available to see if the promising data from previous reports on this combination can be confirmed (215).
Large volume blood loss (drop of hemoglobin level by >3 g/dl) Clinically significant impairment (e.g., tachycardia, hypotension, oliguria, hypovolemic shock), need for blood transfusion (>3 units packed cells) Need for invasive treatment (interventional angiographic embolization, or relaparotomy
Time of onset, localization, and severity allow an exact classification of PPH into three grades and thus define further diagnostic and therapeutic measures (Table 42.7).
postoperative treatment
In addition to the management of complications, standard postoperative treatment should include nutritional support which is vital since many patients suffer from tumor cachexia going into the surgery and the return of normal bowl function may be delayed because of postoperative complications like DGE. However, early total parenteral nutrition after pancreatic resection was associated with an increased risk of complication (204). Enteral feeding is recommended after pancreatic resection whenever possible, however, early initiation of enteral feeding via an intraoperatively placed jejunal feeding tube after Whipple resections resulted in significantly higher rates of DGE as compared to patients not receiving early enteral nutrition in one study (267). Another study evaluating continuous enteral feeding to cyclic enteral nutrition after ppPD showed significant benefits for the latter with earlier commencement of normal oral diet and shorter hospital stay (205). Increasingly, components of fast-track surgery are applied to pancreatectomized patients including early postoperative mobilisation, oral diet, and modern forms of analgesia (206). Intraoperatively placed drains for example can be removed on the second postoperative day if inconspicuous to avoid bacterial contamination of the abdominal cavity (207,208). The benefit of prophylactic application of somatostatin analogs to prevent pancreas-specific complications has been controversial with some studies arguing for and some against it. A recent meta-analysis of 10 randomized trials including 1918 patients showed no benefit of somatostatin analogs to reduce mortality, but did show a significant reduction in morbidity in the treatment group (209). The external validity of
391
392
Treatment 20.1 15.5 39.7 30.0 0.71 (0.55, 0.92) p = 0.009) Comparison Median survival (months) Conclusion Significant increase in survival for CT (P = 0.009) in 289 eligible patients Overall 2-year survival rate Hazard ratio (95% CI), p-value Ref. (211) 13.4 6.9 34% 20.5% estimated overall 3-year survival NN 23.0(fluorouracil) vs. 23.6 (gemcitabine) 48.1% vs. 49.1% 0.94 (0.811.08) p=0.39 Median disease-free survival was (210) 13.4 months in the gemcitabine group (95% CI, 11.415.3) and 6.9 months in the control group (95% CI, 6.17.8; p = 0.001, log-rank). Estimated diseasefree survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group. (270) No significant difference in overall survival between the two groups. Treatment-related serious adverse events were more frequent in the fluorouracil group. Both groups had comparable overall QoL. 24.2 29.6 1.18 (0.84, 1.66) p = 0.33 12.8 12.4
Table 42.8 Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
Year
Chemotherapy ESPAC-1a
19942000
CONKO-1
19982004
CTx vs. no CT 2x2 factorial design 2x(20 Gy in 10 fractions+500 mg/m2 5FU/FA days 13) (20 mg/m2 FA+425 mg/m2 5FU days 15) x 6 cycles CTx vs. OBS 6 cycles of gemcitabine every 4 weeks. Each cycle consisted of 3 weekly infusions of i.v. gemcitabine 1000 mg/m2 followed by a 1-week pause.
ESPAC-3
20002007
Takade et al.
19861992
Fluorouracil (425 mg/m2 Fluorouracil/ folinic acid intravenous bolus injection vs. given 15 days every 28 days) gemcitabine plus folinic acid (20 mg/m2, intravenous bolus injection ) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks) for 6 months 6 mg/m2 mytomycin C day1 CTx vs. OBS +310 mg/m2 5FU days 15 and days 1520 followed by 100 mg/m2 oral 5FU daily to recurrence CTx vs. OBS 17.7 10.4 30.6% 24.3%
Bakkevold et al.
19841987
AMF (40 mg/m2 doxorubicin, 6 mg/m2 mytomycin C,500 mg/m2 5FU) once every 3 weeks for six courses
(262) Significant survival benefit in gallbladder cancer patients. No difference in 158 eligible pancreatic cancer patients. No difference in 48 eligible ampullary cancer patients (263) Significant increase in median survival (23 vs. 11 mo, P1/40.02) in 60 pancreatic and ampullary patients combined (Continued)
Table 42.8 (Continued) Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
Treatment RCTx vs. No RCTx 15.9 17.9 28.5 41.4 1.28 (0.99, 1.66) p = 0.053 Comparison Median survival (months) Overall 2-year survival rate Hazard ratio (95% CI), p-value Conclusion Non-significant decrease in survival for RCTx (P=0.053) in 289 patients. Ref. (211)
Year
2x2 factorial design 2x (20 Gy in 10 fractions+500 mg/m2 5FU/FA days 13) (20 mg/m2 FA+425 mg/m2 5FU days 15) x 6 cycles RCTx vs. No RCTx 17.5 12.6 35.7 23.2 0.70 (0.46, 1.06) p = 0.088
EORTC
19871995
(264)
19982002
19741982
CTx with either 5FU (i.v. 250 mg/m2 per day) or gemcitabine (1000 mg/m2 once per week) for 3 weeks prior to and for 12 weeks after chemoradiation. Chemoradiation with 50.4 Gy + 5FU (250 mg/m2 per day) 2x (20 Gy in 10 fractions + 500 mg/m2 5FU days 13) + weekly 5FU to recurrence 20.0 10.9
42% 15%
Non significant increase in median survival (25 vs. 19 mo, P=0.21) in 207 eligible patients Non significant increase in median survival in 114 eligible pancreatic (17 vs. 13 mo, P = 0.099) The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant Significant increase in median survival (20 vs. 11 mo, p = 0.035) in 43 eligible patients
(266)
Trials addressing chemotherapy (CTx) and radiochemotherapy (RCTx) are listed. aThe ESPAC-1 trial had a factorial 2x2 design, meaning that patients were initially randomized into one of the four groups: observation, chemotherapy, radiochemotherapy, or a combination of both. Comparisons were made between (1) patients receiving chemotherapy (chemotherapy alone or radiochemotherapy + chemotherapy) and those not receiving it (observation or radiochemotherapy only) or (2) patients receiving radiation therapy (radiochemotherapy or radiochemotherapy + chemotherapy) and those not receiving it (observation or chemotherapy alone). Abbreviations: OBS, observation; NN, not reported.
393
prognosis
Curative surgical resection in patients with PDAC is the single most important factor influencing survival and the quality of life (216). Advanced age (>80 years) is no contraindication for resection which can be performed with similar mortality and morbidity rates and offers the same advantages than in the young (217). Although mortality rates for pancreatic surgery decreased significantly in the last years (see above) the overall 5-year survival rate for all patients with PDAC remains dismal (around 5%) (7,8). This number can be explained in part by the low incidence of resectable PDAC at presentation, but might also reflect a failure of adequate treatment. A recent nationwide study in the United States including over 9,500 patients with early, potentially resectable (stage I, T1/2N0M0) PDAC demonstrated that 71% of these patients did not undergo resection, mostly because they were not offered surgery (218). Following curative resection and adjuvant chemotherapy, patients have a 5-year survival rate of 20% to 25% and a median survival of 17 to 28 months (181,201,210,211,217,219 223). Even after 5 years, recurrence does occur meaning that true long-term survivors are rare (224,225). These numbers, however, compare favorable to the devastating prognosis of patients with inoperable, locally advanced, or metastatic disease that have a median survival of 8 to 12 and 3 to 6 months, respectively (226). In certain subgroups (R0 resection, negative lymph node status, and specialized center), the 5-year survival might actually be as high as 40% (227). Multiple pre-, intra-, and postoperative factors influencing prognosis have been studied, but consistently negative resection margins (R0), negative lymph node status (N0), favorable tumor grading, primary tumor size under 2 cm, and absence of perineural invasion have been identified as favorable prognostic markers. Tumor size under 2 cm seems to improve median survival dramatically from an average of 14 months to 35.5 months and significantly improves 5-year survival (201,228232). Similarly, a positive lymph node status (N1) has been demonstrated to be a negative prognostic factor (181,233235), a finding confirmed by data from the ESPAC-1 trial (211,212). Finally, poor tumor grading significantly worsens median as well as overall survival in a number of studies (181,223,236), as does perineural invasion (237239), although in the latter case a significant association could not be verified in other studies (231,240). Similarly, the results concerning the influence of microscopic tumor-free resection margins (R0) on prognosis have been ambiguous. While a number of studies have demonstrated a significant improvement in median as well as 5-year survival following R0 resection as compared to R1 resection (181,227,236,241) others have failed to confirm this association (240,242244). This observation is confirmed by data from the ESPAC-1 trial in which only tumor grade and lymph node status were identified as significant prognostic factors (245). The reason for this apparent disparity is that the pathological handling and reporting of pancreatic specimens vary widely between different institutions and guidelines concerning this matter have not been standardized (246). Consequently, the rate of R0 resections dropped from 86% to 24%
conclusion
All patients with PDAC should be evaluated for potential surgical resection given the improved prognosis and quality of life following resection compared to palliative treatment only. In case of questionable local respectability determined by the radiologist, an experienced pancreatic surgeon should evaluate the radiographic images to determine whether a tumor is resectable or not. Surgery can nowadays be carried out with low mortality and acceptable morbidity rates at high-volume specialized centers. Extended resections are justified if this results in macroscopic complete resection of the tumor. Surgical resection as the mainstay of treatment should be complemented by adjuvant chemotherapy in order to improve survival in patients suffering from PDAC.
references
1. Alexakis N, Halloran C, Raraty M, et al. Current standards of surgery for pancreatic cancer. Br J Surg 2004; 91(11): 141027. 2. Jemal A, Siegel R, Ward E, et al. Cancer Statistics. CA Cancer J Clin 2007; 57(1): 4366. 3. Cancer Research UK: UK cancer mortality statistics for males. 2005. [Available from: http://info.cancerresearchuk.org/cancerstats/mortality/ males/?a=5441] 4. Cancer Research UK: UK cancer mortality statistics for females. 2005. [Available from: http://info.cancerresearchuk.org/cancerstats/mortality/ females/?a=5441] 5. SEER Cancer Statistics Review 19752005. Available from: http://seer. cancer.gov/cgi-bin/csr/1975_2005/search.pl#results 6. Cancer Research UK: UK cancer incidence statistics by country. 2005. Available from: http://info.cancerresearchuk.org/cancerstats/incidence/ site/?a=5441 7. Bramhall SR, Allum WH, Jones AG, et al. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br J Surg 1995; 82(1): 1115. 8. Hedberg M, Borgstrm A, Genell S, Janzon L. Survival following pancreatic carcinoma: a follow-up study of all cases recorded in Malm, Sweden, 19771991. Br J Surg 1998; 85(12): 16414. 9. Lankisch PG, Assmus C, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic diseases in Lneburg County. A study in a defined german population. Pancreatology 2002; 2(5): 46977. 10. Glade MJ. Food, nutrition, and the prevention of cancer: a global perspective. American Institute for Cancer Research/World Cancer Research Fund, American Institute for Cancer Research, 1997. Nutrition 1999; 15(6): 5236. 11. Soler M, Chatenoud L, La Vecchia C, et al. Diet, alcohol, coffee and pancreatic cancer: final results from an Italian study. Eur J Cancer Prev 1998; 7(6): 45560. 12. Ji BT, Chow WH, Gridley G, et al. Dietary factors and the risk of pancreatic cancer: a case-control study in Shanghai China. Cancer Epidemiol Biomarkers Prev 1995; 4(8): 88593. 13. Chow WH, Gridley G, Nyrn O, et al. Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst 1995; 87(12): 9301. 14. Nthlings U, Wilkens LR, Murphy SP, et al. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst 2005; 97(19): 145865. 15. Michaud DS, Giovannucci E, Willett WC, et al. Dietary meat, dairy products, fat, and cholesterol and pancreatic cancer risk in a prospective study. Am J Epidemiol 2003; 157(12): 111525. 16. Michaud DS, Skinner HG, Wu K, et al. Dietary patterns and pancreatic cancer risk in men and women. J Natl Cancer Inst 2005; 97(7): 51824. 17. Patel AV, Rodriguez C, Bernstein L, et al. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev 2005; 14(2): 45966.
394
395
67.
68.
69. 70.
71. 72.
73.
74.
75.
76. 77.
78. 79.
80. 81.
82.
83.
84.
85.
86.
87.
88. 89.
396
397
398
227. 228.
229.
230. 231.
232.
233. 234.
235.
236.
237.
238.
239.
240.
241. 242.
243.
244.
245.
249.
250.
399
400
43
The surgical management of pancreatic adenocarcinoma is focused largely on complete tumor extirpation in patients with resectable tumors. Unfortunately, the majority of patients with pancreatic adenocarcinoma have advanced stage disease at the time of diagnosis and are not eligible for resection. Detectable metastases and/or extensive locoregional disease is frequently recognized during preoperative staging, thus consideration for a potentially curative resection is appropriate in less than onefourth of all patients with pancreatic adenocarcinoma (14). Even though high-resolution cross-sectional imaging and other dedicated staging modalities (e.g., pancreatic endoscopic ultrasound) have obviated the need for routine operative exploration to assess resectability in most patients, occult metastases or celiac/mesenteric vascular invasion precluding complete resection will be discovered at the time of exploration in approximately 20% of patients with localized, apparently resectable tumors on preoperative imaging (5,6). Symptom palliation becomes the goal of therapy for the majority of patients with pancreatic adenocarcinoma whose disease is not amenable to a potentially curative resection. Depending on individual performance status and medical co-morbidities, the life expectancy for all patients with unresectable cancer is typically less than 1 year. Patients with nonmetastatic, locally advanced cancer experience a median survival on the order of 9 to 12 months, whereas metastatic pancreatic adenocarcinoma is typically associated with a median survival of less than 6 months (1,710). Adequate palliation of biliary and duodenal obstruction, and most importantly control of cancer-related pain, has been shown to improve quality of life (1018). Therefore, every attempt, whether nonoperative or operative, should be made to palliate obstruction and relieve pain in virtually all patients with unresectable pancreatic cancer who have a reasonable life expectancy. Contrarily, the benefits of palliative treatments must be weighed against the potential morbidity associated with them. Therefore, it is difficult to advocate prophylactic palliative procedures for asymptomatic patients, many of whom are at uncertain risk for developing symptoms prior to death. Operative treatment has served as the traditional modality for palliating the symptoms associated with locally advanced pancreatic cancer. However, nonoperative therapies offered by endoscopists and interventional radiologists have proved to be reliable and durable in select patients with biliary and/or duodenal obstruction (19,20). A decision to pursue operative versus nonoperative palliation typically arises in two clinical scenarios. For patients undergoing open exploration for equivocal radiographic signs of unresectability, operative palliation is almost always indicated for those found to have nonmetastatic (or low-volume metastatic), locally unresectable disease intraoperatively. In experienced hands, operative biliary and gastric bypass procedures should not add
401
402
palliation of pain
The last step of surgical palliation for unresectable pancreatic cancer includes chemical splanchnicectomy which can be readily accomplished with the injection of 20 ml of 50% alcohol on each side of the aorta at the level of the celiac axis at the time of laparotomy (Fig. 43.3). Chemical splanchnicectomy can be performed similarly at the time of staging laparoscopy or other laparoscopic palliative procedures (46). Celiac plexus blocks under endoscopic ultrasound or computed tomography guidance have also been described, and thoracic splanchnicectomy although used infrequently can provide adequate pain relief for patients with unresectable pancreatic cancer (47,48). Long-term, pain related to pancreatic cancer is perhaps the most debilitating symptom associated with this disease and can lead to the deterioration of quality of life rather quickly. While only 30% to 40% of patients with pancreatic cancer report moderate to severe pain at the time of diagnosis, over 80% of patients with advanced cancer experience severe pain prior to death (4952). A single institution prospective randomized controlled trial (Level Ib) has demonstrated that chemical splanchnicectomy can achieve acute pain relief in over 80% of patients and can prevent the subsequent onset of
Figure 43.1 Illustration of one operative technique for a palliative double bypass procedure for unresectable pancreatic cancer. Here, the hepaticojejunostomy (HJ) is shown as an end-to-side anastomosis with a retrocolic Roux-en-Y jejunal limb. The gastrojejunostomy (GJ) is depicted as a retrocolic side-to-side anastomosis between the most dependent aspect of the stomach and an isoperistaltic loop of proximal jejunum just beyond the ligament of Treitz.
(A)
(B)
Figure 43.2 Coronal section of a representative CT scan showing a metallic endostent providing adequate relief of duodenal obstruction from a pancreatic head cancer (A). Plain film radiography demonstrating the long-term patency of palliative metallic biliary and duodenal stents which can be deployed serially as combined or separate endoscopic procedures (B).
403
Figure 43.3 A chemical splanchnicectomy can be accomplished by injecting 20 ml of 50% alcohol into the celiac ganglia on each side of the aorta (A) at the level of the celiac axis (CA). The use of a 22 gauge or smaller caliber spinal needle ensures containment of the injection wheal within the retroperitoneum.
Table 43.1 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Biliary Obstruction
Study Shepherd et al. Surgery Stent Andersen et al. Surgery Stent Smith et al. Surgery Stent Overall Surgery Stent
a
Year 1988
No. of patients 25 23
Table 43.2 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Gastroduodenal Obstruction
Study Mehta et al. Laparoscopic GJ Stent Fiori et al. Open GJ Stent Overall Surgery Stent
a
Year 2006
No. of patients 14 13
2004 9 9 23 22
404
80 60
7. 8.
40 20 0 0 3 6 9 12
p = 0.0001
9.
10.
15 18 21 24 27 30 33 36
11.
Months of survival
Figure 43.4 In a prospective, randomized, double-blind study by Lillemoe et al. (53), chemical splanchnicectomy (alcohol) in patients with unresectable pancreatic cancer and preoperative pain resulted in a significant reduction in pain at 2-, 4-, and 6-month follow-up and a significant improvement in overall survival compared to placebo (saline) injection.
12.
13.
stenting versus surgical gastrojejunostomy have shown that while endoscopic stenting for the palliation of malignant gastroduodenal obstruction is associated with higher early clinical success (i.e., shorter time to oral intake and shorter length of hospital stay), operative gastric bypass procedures are preferable in patients with a prolonged prognosis who are likely to benefit from the reliable durability of surgical palliation that is less likely to require reintervention (Table 43.2) (41,5759).
14.
15.
16.
17.
summary
Based on the existing clinical evidence, we advocate operative biliary decompression, gastric bypass, and chemical splanchnicectomy for all patients who undergo laparotomy without an indwelling metallic biliary stent and are found to have locally unresectable pancreatic carcinoma in the periampullary region. Even though this has not been studied directly, the durability of operative palliation should influence patients quality of life positively by decreasing the need for reinterventions and future hospitalizations. Symptomatic patients with preoperatively confirmed locally unresectable cancer or metastatic disease can be palliated reliably with nonoperative techniques. Such patients should be offered surgical palliation only when nonoperative procedures are unsuccessful and they have a reasonable life expectancy. To take advantage of the longterm benefits of surgical palliation, operative bypass procedures must be performed with acceptable morbidity.
18.
19. 20.
references
1. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004 Mar 27; 363(9414): 104957. 2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995 Nov 1; 76(9): 16717. 3. Schneider G, Siveke JT, Eckel F, Schmid RM. Pancreatic cancer: basic and clinical aspects. Gastroenterology 2005 May; 128(6): 160625. 4. Wray CJ, Ahmad SA, Matthews JB, Lowy AM. Surgery for pancreatic cancer: recent controversies and current practice. Gastroenterology 2005 May; 128(6): 162641. 5. House MG, Yeo CJ, Cameron JL, et al. Predicting resectability of periampullary cancer with three-dimensional computed tomography. J Gastrointest Surg 2004 MarApr; 8(3): 2808. 6. Soriano A, Castells A, Ayuso C, et al. Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing
25. 26.
27.
28.
29.
endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol 2004 Mar; 99(3): 492501. de Rooij PD, Rogatko A, Brennan MF. Evaluation of palliative surgical procedures in unresectable pancreatic cancer. Br J Surg 1991 Sep; 78(9): 10538. Di Fronzo LA, Cymerman J, Egrari S, OConnell TX. Unresectable pancreatic carcinoma: correlating length of survival with choice of palliative bypass. Am Surg 1999 Oct; 65(10): 9558. Gouma DJ, Nieveen van Dijkum EJ, van Geenen RC, van Gulik TM, Obertop H. Are there indications for palliative resection in pancreatic cancer? World J Surg 1999 Sep; 23(9): 9549. Moore MJ. Pancreatic cancer: what the oncologist can offer for palliation. Can J Gastroenterol 2002 Feb; 16(2): 1214. Cubiella J, Castells A, Fondevila C, et al. Prognostic factors in nonresectable pancreatic adenocarcinoma: a rationale to design therapeutic trials. Am J Gastroenterol 1999 May; 94(5): 12718. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 1999 Sep; 230(3): 3228; discussion 830. Lillemoe KD, Cameron JL, Yeo CJ, et al. Pancreaticoduodenectomy. Does it have a role in the palliation of pancreatic cancer? Ann Surg 1996 Jun; 223(6): 71825; discussion 258. Nieveen van Dijkum EJ, Kuhlmann KF, Terwee CB, et al. Quality of life after curative or palliative surgical treatment of pancreatic and periampullary carcinoma. Br J Surg 2005 Apr; 92(4): 4717. Ridwelski K, Meyer F, Ebert M, Malfertheiner P, Lippert H. Prognostic parameters determining survival in pancreatic carcinoma and, in particular, after palliative treatment. Dig Dis 2001; 19(1): 8592. van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al. Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg 1994 Jan; 219(1): 1824. van der Schelling GP, van den Bosch RP, Klinkenbij JH, Mulder PG, Jeekel J. Is there a place for gastroenterostomy in patients with advanced cancer of the head of the pancreas? World J Surg 1993 JanFeb; 17(1): 12832; discussion 323. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophylactic gastrojejunostomy for unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on assessment of quality of life. Ann Surg 2003 Dec; 238(6): 894902; discussion5. Costamagna G, Pandolfi M. Endoscopic stenting for biliary and pancreatic malignancies. J Clin Gastroenterol 2004 Jan; 38(1): 5967. Taylor MC, McLeod RS, Langer B. Biliary stenting versus bypass surgery for the palliation of malignant distal bile duct obstruction: a metaanalysis. Liver Transpl 2000 May; 6(3): 3028. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of the pancreas. Surgery 1982 Feb; 91(2): 12333. Singh SM, Longmire WP Jr., Reber HA. Surgical palliation for pancreatic cancer. The UCLA experience. Ann Surg 1990 Aug; 212(2): 1329. Watanapa P, Williamson RC. Surgical palliation for pancreatic cancer: developments during the past two decades. Br J Surg 1992 Jan; 79(1): 820. Espat NJ, Brennan MF, Conlon KC. Patients with laparoscopically staged unresectable pancreatic adenocarcinoma do not require subsequent surgical biliary or gastric bypass. J Am Coll Surg 1999 Jun; 188(6): 64955; discussion 557. Gentileschi P, Kini S, Gagner M. Palliative laparoscopic hepatico- and gastrojejunostomy for advanced pancreatic cancer. JSLS 2002 OctDec; 6(4): 3318. Hamade AM, Al-Bahrani AZ, Owera AM, et al. Therapeutic, prophylactic, and preresection applications of laparoscopic gastric and biliary bypass for patients with periampullary malignancy. Surg Endosc 2005 Oct; 19(10): 133340. Nieveen van Dijkum EJ, Romijn MG, Terwee CB, et al. Laparoscopic staging and subsequent palliation in patients with peripancreatic carcinoma. Ann Surg 2003 Jan; 237(1): 6673. Rhodes M, Nathanson L, Fielding G. Laparoscopic biliary and gastric bypass: a useful adjunct in the treatment of carcinoma of the pancreas. Gut 1995 May; 36(5): 77880. Rothlin MA, Schob O, Weber M. Laparoscopic gastro- and hepaticojejunostomy for palliation of pancreatic cancer: a case controlled study. Surg Endosc 1999 Nov; 13(11): 10659.
405
406
A cystic tumor of the pancreas is a radiographic finding that has a broad histologic differential. This differential includes non-neoplastic pseudocysts, benign neoplastic cysts (serous cysts), pre-malignant cysts (mucinous cysts), and cystic lesions with invasive carcinoma (Table 44.1) (1). The current ability to determine the histologic diagnosis of these lesions without resection is improving but limited (2,3). Serum testing, radiographic imaging, endoscopic ultrasound, cyst fluid cytology, and cyst fluid marker analysis (CEA) have a combined overall accuracy of approximately 70% to 85% (4). This diagnostic limitation can make treatment decisions difficult: resection may provide the only form of cure in those patients with highrisk mucinous cysts or very early invasive disease; however, resection has a major morbidity rate of approximately 20% and mortality rate of 2% to 10%. Resection of benign cysts will expose the asymptomatic patient to all the risks of resection without identified benefit. As cross-sectional imaging improves this diagnostic and treatment dilemma will become more common. The increased use of high-quality cross-sectional imaging has resulted in an increasing number of patients identified with small (<3 cm) asymptomatic cysts, and the ability to determine histology in these patients is even more difficult (57). The natural history of these small, incidentally discovered lesions is unknown. Even in a patient with a small and asymptomatic pre-malignant cyst (mucinous) the future risk of progression to malignancy has not been determined with respect to both frequency and duration. The decision to resect a small, asymptomatic mucinous lesion, particularly in someone who is elderly or with significant comorbidities, must take into account the fact that the natural history of that lesion is unknown.
407
Non-epithelial tumors
Pseudotumors
Figure 44.2 Cystic lesion in the tail of the pancreas (solid arrow) and dilated main pancreatic duct (broken arrow) in an otherwise healthy 63-year-old female.
Figure 44.1 Cystic lesion in the tail of the pancreas (arrow) in otherwise healthy 66-year-old female.
Figure 44.3 Cystic lesion in the body of the pancreas (arrow) in an otherwise healthy 60-year-old female.
408
(A)
(B) Figure 44.4 Gross and microscopic characteristics of serous cystadenoma. Arrow notes central scar.
BD
PD
(A)
(B) Figure 44.5 Gross and microscopic characteristics of main duct IPMN. Abbreviations: PD, pancreatic duct; BD, bile duct.
409
PD
Cyst
(A)
(B) Figure 44.6 Gross and microscopic characteristics of MCN. Abbreviation: PS, pancreatic duct.
410
diagnostic evaluation
High-quality cross-sectional imaging is essential for the evaluation of patients with cystic lesions of the pancreas. Multidetector CT (MdCT) allows thin section scanning of the pancreas and has become the most common method for assessing pancreatic cysts (28). MdCT has the ability to provide excellent visualization of septa, mural nodules, and calcifications. MdCT also allows excellent visualization and characterization of the pancreatic parenchyma. Evaluation of the parenchyma adjacent to the cyst is critical as we have recently reported on several patients with pancreatic adenocarcinoma who presented with isolated small retention cysts adjacent to a radiographically occult malignancy (14). MRCP also provides excellent characterization of cyst morphology (4). MRCP may also allow for the ability to diagnose branch duct IPMN through identification of communication between the cyst and the pancreatic duct (29). Endoscopic evaluation with endoscopic ultrasound (EUS) has played an increasingly important role in the evaluation of pancreatic cysts. In general, endoscopy with or without endoscopic retrograde cholangiopancreatography (ERCP) has a limited role in the evaluation of pancreatic cysts; however, these tests may have indications in the evaluation of suspected IPMN. Endoscopic ultrasound (EUS) with or without cyst aspiration is highly operator dependent, but the information gained from EUS by an experienced gastroenterologist can be very valuable. EUS can provide detailed images of the cyst wall as well as internal cyst architecture and can be used to perform fine needle aspiration biopsy. The fluid obtained by EUS FNA can be used both for cytologic analysis as well as for various tumor marker analyses. The diagnostic utility of cyst fluid analysis has been studied extensively (4,3032). A variety of tumor markers including CA19-9, CEA, CA15-3, M1 mucin, and amylase have been evaluated. The most consistent results have been reported for cyst fluid CEA levels. In a prospective study by Brugge et al. of 112 patients with cystic lesions, an elevated cyst fluid CEA level (>192 ng/ml) was the best predictor of a mucinous lesion and accurately identified these lesions in 79% of cases (3). Elevated CEA levels and the presence of extracellular mucin have been shown to have a positive predictive value for mucinous lesions as high as 85% (4,33,34). The degree to which the cyst fluid CEA level is elevated has not been found to be predictive of malignancy within mucinous cysts. Serous cystadenomas and retention cysts have been shown to have almost uniformly undetectable cyst fluid CEA levels (4,34,35). The ability of cyst fluid cytology to differentiate between serous versus mucinous cysts as well to identify malignancy within the mucinous sub-group is limited. Most studies have shown accuracy rates of cyst fluid cytology in the range of 50% and thus cytology is probably inferior to cyst fluid CEA alone in discriminating between serous and mucinous cysts (3).
treatment recommendations
Because of the frequent inability to determine histology without resection, and because of the unknown natural history of some cystic sub-types, many authors have recommended routine resection of all pancreatic cysts (2,37,38). These authors argue that because the preoperative distinction between benign and malignant is unreliable, and because the potential adverse consequences of not resecting a pre-malignant or malignant cyst are significant, all medically fit patients should undergo resection. Although this approach provides a guarantee to patients that no pre-malignant or malignant lesions will be observed, it exposes patients with benign lesions to the risks of pancreatectomy. Several recent reports, including a study from our own institution, have recommended a more selective approach to resection (3941). Proponents of this approach argue that with current imaging techniques, and with an improved understanding of the various histologic entities, a group of patients can be identified who have an extremely low risk of malignancy. Most reports evaluating this approach have recommended non-operative management (radiographic follow-up) for selected patients with small, incidentally discovered cysts of the pancreas that do not have a solid component or other concerning clinical or radiographic features of malignancy
411
summary
In summary, many institutions are now reporting a selective approach to resection in patients with cystic lesions of the pancreas. Routine resection of all pancreatic cysts is currently impractical, and given the large numbers of patients being identified with <2 cm lesions this approach would result in a mortality rate that is much higher than the rate of malignancy. Most studies that have advocated a selective approach have reported the radiographic characteristics of main duct dilatation, a solid component, cyst size, and symptoms to be associated with treatment recommendations. In the absence of these findings we feel that radiographic follow-up is warranted. In the young patient with a small mucinous tumor the additional factors are the likelihood of progression to malignancy and the patient anxiety about radiographic follow-up. No data are available for the former. Efforts should be made to improve the ability to distinguish histopathologic sub-types without resection. The current challenges are to improve the sensitivity and specificity for the identification of mucinous sub-type, to better characterize the progression of IPMN and mucinous cystic tumors, and to develop better methods for identifying the presence of in situ or invasive disease in these patients. Continued improvements in cross-sectional imaging and endoscopic techniques, and further investigation into markers in the serum and cyst fluid, should allow better stratification of mucinous sub-types.
412
references
1. Kloppel G, Kosmahl M. Cystic lesions and neoplasms of the pancreas. The features are becoming clearer. Pancreatology 2001; 1: 64855. 2. Ooi LL, Ho GH, Chew SP, et al. Cystic tumours of the pancreas: a diagnostic dilemma. Aust N Z J Surg 1998; 68: 8446. 3. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004; 126: 13306. 4. Brugge WR, Lauwers GY, Sahani D, et al. Cystic neoplasms of the pancreas. N Engl J Med 2004; 351: 121826. 5. Gorin AD, Sackier JM. Incidental detection of cystic neoplasms of the pancreas. Md Med J 1997; 46: 7982. 6. Fernandez-Del CC, Targarona J, Thayer SP, et al. Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003; 138: 4273. 7. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR 2008; 191: 8027. 8. Le Borgne J., De Calan L., Partensky C. Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association. Ann Surg 1999; 230: 15261. 9. Grace PA, Williamson RC. Modern management of pancreatic pseudocysts. Br J Surg 1993; 80: 57381. 10. OMalley VP, Cannon JP, Postier RG. Pancreatic pseudocysts: cause, therapy, and results. Am J Surg 1985; 150: 6802. 11. Compagno J, Oertel JE. Microcystic adenomas of the pancreas (glycogenrich cystadenomas): a clinicopathologic study of 34 cases. Am J Clin Pathol 1978; 69: 28998. 12. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). A clinicopathologic study of 41 cases. Am J Clin Pathol 1978; 69: 57380. 13. Matsumoto T, Hirano S, Yada K, et al. Malignant serous cystic neoplasm of the pancreas: report of a case and review of the literature. J Clin Gastroenterol 2005; 39: 2536. 14. Allen PJ, DAngelica M, Gonen M, et al. A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive patients. Ann Surg 2006; 244: 57282. 15. Tseng JF, Warshaw AL, Sahani DV, et al. Serous cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg 2005; 242: 4139. 16. Kloppel G, Solcia E, Longnecker DS. World Health Organization International Classification of Tumors. Berlin: Springer, 1996. 17. DAngelica M, Brennan MF, Suriawinata AA, et al. Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004; 239: 4008. 18. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004; 239: 78897. 19. Salvia R, Fernandez-Del CC, Bassi C, et al. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004; 239: 67885. 20. Sahani DV, Saokar A, Hahn PF, et al. Pancreatic cysts 3 cm or smaller: how aggressive should treatment be? Radiology 2006; 238: 91219. 21. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 2001; 234: 31321. 22. Chari ST, Yadav D, Smyrk TC, et al. Study of recurrence after surgical resection of intraductal papillary mucinous neoplasm of the pancreas. Gastroenterology 2002; 123: 15007.
23. White R, DAngelica M, Tang L, et al. The fate of the remnant pancreas following resection of non-invasive intraductal papillary mucinous neoplasm. J Am Coll Surg 2007; 204(5): 98793. 24. Zamboni G, Scarpa A, Bogina G, et al. Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol 1999; 23: 41022. 25. Yamada M, Kozuka S, Yamao K, et al. Mucin-producing tumor of the pancreas. Cancer 1991; 68: 15968. 26. Erdogan D, Lamers WH, Offerhaus GJ, et al. Cystadenomas with ovarian stroma in liver and pancreas: an evolving concept. Dig Surg 2006; 23: 18691. 27. Warshaw AL, Compton CC, Lewandrowski K, et al. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990; 212: 43243. 28. Sahani DV, Kadavigere R, Saokar A, et al. Cystic pancreatic lesions: a simple imaging-based classification system for guiding management. Radiographics 2005; 25: 147184. 29. Koito K, Namieno T, Ichimura T, et al. Mucin-producing pancreatic tumors: comparison of MR cholangiopancreatography with endoscopic retrograde cholangiopancreatography. Radiology 1998; 208: 2317. 30. Sand JA, Hyoty MK, Mattila J, et al. Clinical assessment compared with cyst fluid analysis in the differential diagnosis of cystic lesions in the pancreas. Surgery 1996; 119: 27580. 31. Hammel PR, Forgue-Lafitte ME, Levy P, et al. Detection of gastric mucins (M1 antigens) in cyst fluid for the diagnosis of cystic lesions of the pancreas. Int J Cancer 1997; 74: 28690. 32. Hammel P, Levy P, Voitot H, et al. Preoperative cyst fluid analysis is useful for the differential diagnosis of cystic lesions of the pancreas. Gastroenterology 1995; 108: 12305. 33. Walsh RM, Henderson JM, Vogt DP, et al. Prospective preoperative determination of mucinous pancreatic cystic neoplasms. Surgery 2002; 132: 62833. 34. Lewandrowski KB, Southern JF, Pins MR, et al. Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993; 217: 417. 35. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005; 62: 3839. 36. Goh BK, Tan YM, Yap WM, et al. Pancreatic serous oligocystic adenomas: clinicopathologic features and a comparison with serous microcystic adenomas and mucinous cystic neoplasms. World J Surg 2006; 30: 15539. 37. Horvath KD, Chabot JA. An aggressive resectional approach to cystic neoplasms of the pancreas. Am J Surg 1999; 178: 26974. 38. Siech M, Tripp K, Schmidt-Rohlfing B, et al. Cystic tumours of the pancreas: diagnostic accuracy, pathologic observations and surgical consequences. Langenbecks Arch Surg 1998; 383: 5661. 39. Spinelli KS, Fromwiller TE, Daniel RA, et al. Cystic pancreatic neoplasms: observe or operate. Ann Surg 2004; 239: 6517. 40. Walsh RM, Vogt DP, Henderson JM, et al. Natural history of indeterminate pancreatic cysts. Surgery 2005; 138: 66570. 41. Allen PJ, Jaques DP, DAngelica M, et al. Cystic lesions of the pancreas: selection criteria for operative and nonoperative management in 209 patients. J Gastrointest Surg 2003; 7: 9707. 42. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6: 1732.
413
45
introduction
Pancreatic endocrine tumors are benign or malignant epithelial tumors that show evidence of endocrine cell differentiation. Pancreatic endocrine tumors are uncommon, representing <5% of pancreatic tumors in surgical series (1,2). Clinically silent endocrine tumors have been detected in 0.3% to 1.6% of unselected autopsies in which only a few sections of the pancreas were examined, and in up to 10% of autopsies the whole pancreas was systematically investigated both grossly and microscopically. Most tumors from these series are small (less than 1 cm), in elderly patients (mean age of 70 years), and benign (clinically silent microadenomas). Pancreatic endocrine tumors can be broadly classified as functional or non-functional. Despite changing trends, the majority of clinically relevant pancreatic endocrine tumors are functional (3). The proportion of non-functioning tumors, in series of islet cell neoplasms, has varied over time, ranging between 15% and 53% of cases (47). While the definition of non-functional has been inconsistent in many reports, increased use of more sophisticated imaging modalities has allowed clinically silent intra-abdominal masses to be identified incidentally and many series report an increased incidence of non-functioning neoplasms (8,9). Overall, the reported 35% to 50% incidence of non-functioning endocrine tumors suggest that non-functional tumors are at least as common as insulinomas and more common than all of the remaining pancreatic endocrine tumor types (2). Functional endocrine tumors of the pancreas are peptidesecreting neoplasms leading to clinical presentation with a defined syndrome related to the effects of an abnormally elevated plasma peptide level. These peptides may or may not occur naturally in the pancreas and a given tumor may secrete multiple peptides. It is on the basis of the primary functional peptide hormone secreted that each tumor is named; e.g., gastrinoma, insulinoma. Non-functioning islet cell tumors are pancreatic neoplasms with endocrine differentiation in the absence of a clinical syndrome of hormone hyperfunction. Despite the presence of hormones in tumor cells at immunohistochemistry, many of these tumors lack evidence of increased serum hormonal levels. Tumors releasing increased amounts of hormone in the blood stream without evidence of a hyperfunctional syndrome are also often reported as non-functioning tumors. Several explanations can be given for why these non-functioning tumors are hormonally silent. One reason is that the principal hormone secreted by the tumor may cause no specific clinical signs, although it is released in excess. In some situations, the tumor makes a functionally inert hormone, which is recognized by an antibody directed against a functional hormone. As the specificity of antibodies improves, such false positives should disappear. A second possibility is that the amount of
insulinoma
Insulinoma is a neoplasm that arises from the pancreatic insulin-producing beta-cells. Unlike other gastrointestinal endocrine tumors, which are malignant in more than 60% of cases, 90% of insulinomas are benign, solitary growths that occur almost exclusively within the pancreatic parenchyma (Table 45.1). They occur throughout the head, body, and tail of the pancreas with equal frequency (14). Three percent are in the uncinate and 2% to 3% are ectopic. Ectopic insulinomas are usually found in the duodenal mucosa, the hilum of the spleen, or in the gastrocolic ligament (13).
414
Transabdominal ultrasonography 26 11 40 15 59 64
CT 26 17 43 50 60 36 26
Angiography 44 35 54 44 75 53 47
MR imaging 0 25
Intraoperative ultrasonography 92
Palpation 64
100 90 16 95
82 90 90
415
gastrinoma
Gastrinomas are the second most common functioning islet cells tumors of the pancreas, occurring one-half as often as insulinomas (14). These tumors are generally small and occur more frequently (3:2) in males than in females (28,29). Gastrinomas may occur from childhood into old age, but the majority of cases occur between the fourth and the sixth decades of life (13). The ZollingerEllison syndrome (ZES), originally described in 1955, includes non-insulin-producing tumors of the
Figure 45.1 Spiral CT of insulinoma in body of pancreas. Arrow indicates tumor which is enhancing with contrast material. The patient underwent an enucleation of this tumor.
416
90%
10%
Figure 45.2 Anatomic triangle in which gastrinomas are most often found. Source: From Ref. (13).
417
Table 45.3 Sensitivity of Non-invasive Imaging Studies for Localization of Primary and Metastatic Gastrinoma
Imaging study Ultrasound CT MR SRS
Source: Adapted from Ref. (57).
Liver (%) 48 42 71 92
Liver (%) NA 62 NA 41
418
glucagonoma
Glucagonomas are usually large tumors (>5 cm) and occur most often in the body and tail of the pancreas and are rarely extrapancreatic (Table 45.1) (13,16). The incidence of glucagonoma is considerably less than insulinoma and gastrinoma and is estimated to be one in 20 million to one in 30 million. The exact incidence is unknown because glucagonomas may
Table 45.5 Results of Surgery for Localized Sporadic and MEN-1 Gastrinoma
Sporadic or MEN S S S S MEN MEN S/MENa No. with tumor found (%) 56 (77) 10 (91) 5 (100) 9 (41) 17 (90) 10 (100) 17 (100) No. diseasefree (%) 37 (50) 9 (82) 5 (100) 2 (9) 1 (5) 0 (0) 5 (30)b
Series Norton et al. (33) Howard et al. (48) Thompson et al. (49) McArthur et al. (108) Melvin et al. (109) MacFarlane et al. (53) Jaskowial et al. (110)
Figure 45.3 Location of 24 duodenal gastrinomas in patients with Zollinger Ellison syndrome. Seventeen tumors were in the first portion, five were in the second, and two were in the third. Source: From Ref. (47).
N 73 11 5 22 19 10 17
Source: Adapted from Ref. (37). a Reoperation for localized recurrent gastrinoma. b Each of the five patients who were disease-free had sporadic gastrinoma. Abbreviations: MEN, Multiple endocrine neoplasia type 1; S, sporadic.
419
vipoma
VIPoma syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria (WDHA) was first described in 1958 by Vemer and Morrison (59). Vasoactive intestinal peptide was first isolated from bovine intestine in 1970 and soon after it was shown that extracts of peptides from tumor and plasma of patients with WDHA produced similar symptoms in dogs (13,60). The first report of a surgical cure was in 1978 when excision of a VIPoma in a patient with WDHA syndrome completely relieved the symptoms as plasma VIP levels dropped to normal (13). Since that time, 201 cases have been reported in the literature (61). VIPomas are predominantly in the pancreas (90%) and extrapancreatic tumors are very rare, except in children (14). Pancreatic VIPomas are usually solitary, small in diameter, and in the body or tail of the pancreas 75% of the time (Table 45.1) (61). Approximately 50% of pancreatic VIPomas are malignant and one-half of these are metastatic to the liver or regional lymph nodes at diagnosis. Less than 5% of patients with VIPoma of the pancreas have MEN-1 (14). The tumors have a bimodal distribution which is related to histologic type. In a study of 62 patients, 52 had pancreatic VIPomas and 10 had extrapancreatic ganglioneuromas. The extrapancreatic sites (adrenal, mediastinal, retroperitoneal) occur predominantly in the pediatric population and demonstrate a less aggressive course, with only a 10% rate of metastasis (61). Diagnosis includes an evaluation of the diarrhea for a secretory nature. This can be confirmed with a trial of fasting for 48 to 72 hours, which will have no major effect on the diarrhea due to VIPomas. The fecal content of potassium and sodium is determined. The sum of twice the sodium plus the potassium should equal isotonicity in a secretory diarrhea. All infectious causes of diarrhea must be excluded. A fasting plasma VIP level of more than 200 pg/ml is required to establish the diagnosis (14,62). Spiral CT scanning should be used to localize VIPomas. With small lesions, other modalities such as SRS or angiography may occasionally be necessary to help identify tumor location (63). Surgical excision remains the only effective method of cure. Preoperative restoration of extracellular volume status and correction of electrolyte abnormalities must be accomplished. The fluid and electrolyte imbalance should be reversed slowly because of its chronic nature. Octreotide acetate is useful in promptly inhibiting VIP secretion from the tumor and stopping the diarrhea (55) A careful surgical exploration including evaluation of the retroperitoneum, both adrenal glands, and the pancreas should be performed. Surgical therapy consists of enucleation or pancreaticoduodenectomy for pancreatic head tumors. Body and tail tumors are best managed by distal pancreatectomy. Complete resection of these tumors delivers full symptomatic relief. If all apparent tumor cannot be resected or if there is metastatic disease, surgical debulking remains a useful option. VIP levels are an excellent tumor marker for recurrence. If there is recurrence, repeat debulking may be a viable and therapeutic option (64). Survival of patients with malignancy and/or metastatic disease is disappointing. The average survival is approximately 1
420
somatostatinoma
Somatostatinomas are among the rarest of the functional endocrine tumors. There have been 41 males and 42 females reported with somatostatinomas. These patients have an average age of 54 years with a range of 24 to 84 years (64). The most common location for somatostatinomas was within the pancreas (68%); 19% occur in the duodenum and 3% each in the ampulla of Vater and the small bowel (Table 45.1) (68). Most commonly, pancreatic tumors are found in the head and body of the gland (13). The classic somatostatinoma syndrome has been characterized by the triad of diabetes, diarrhea/steatorrhea and gallstones. Diarrhea/steatorrhea occurs in approximately one-third of patients and results from an increase in stool osmolarity secondary to malabsorption of fats, sugars, and amino acids. Steatorrhea results from decreased pancreatic exocrine secretion and the associated impairment of fat absorption. Excessive somatostatin inhibits the release of cholecystokinin, which decreases gallbladder contraction and leads to malabsorption and cholelithiasis. Weight loss is one of the most common findings and is seen in about 40% of patients and may be attributable to malabsorption. Diabetes occurs in 25% of patients and may occur secondary to greater suppression of insulin secretion over glucagon release by somatostatin as well as indirectly by somatostatin suppression of gastric inhibitory peptide (13,14,68). Somatostatinomas are often large tumors at the time of presentation and imaging studies are associated with a high degree of accuracy. CT scanning correctly localized the somatostatinoma in 34 of 37 patients with pancreatic tumors. Angiography has also been used to localize difficult neoplasms (68). The diagnosis can be established by measuring an elevated fasting somatostatin level (normal, <100 pg/ml). When evaluated preoperatively, 34 of 35 patients had elevated levels of circulating somatostatin. Plasma somatostatin measurements may also be useful in evaluating the success of treatment and to follow patients for possible recurrence. Surgical resection is the preferred treatment for patients with somatostatinomas. Unfortunately, successful surgical management is difficult because of the high rate of metastases present at exploration (Table 45.1). Most tumors are large and enucleation is usually not possible. Pancreatic resection including a pancreaticoduodenectomy or distal pancreatectomy is often necessary. Debulking a large tumor or hepatic metastases may effectively palliate symptoms, often for prolonged periods of time. As with other islet cell cancer, somatostatinomas may have an indolent tumor biology and long-term survival can occur.
421
or gastrointestinal obstruction due to the primary tumor, that they present earlier (14). The duration of symptoms related to the tumor may be at least as long or longer in patients with functioning tumors as in non-functioning tumors. In a review of 64 patients with islet cell carcinomas (34 non-functional, 30 functional) treated at the Mayo Clinic, the duration of symptoms prior to diagnosis for all patients ranged from less than 1 to 120 months (median 10 months). For functional neoplasms the median duration of symptoms was 11 months versus 8 months for non-functional neoplasms (p > 0.1) (7). Others have also found that the median duration of symptoms was significantly longer for functional tumors (insulinomas: 22 months; gastrinomas: 36 months) as compared to nonfunctional neoplasms (6 months) (73). It appears that most patients with islet cell tumors undergoing surgical treatment have a lengthy duration of symptoms. A high index of suspicion is necessary in attempting to make the diagnosis of an islet cell tumor of the pancreas.
diagnosis
Since the clinical presentation of non-functioning islet cell tumors is similar to other pancreatic neoplasms, the major challenge is to distinguish this tumor from other forms of pancreatic neoplasia, especially from the much more common ductal adenocarcinoma. Non-functioning islet cell tumors tend to be larger than ordinary pancreatic adenocarcinomas at the time of diagnosis. Viable portions of islet cell tumors are typically well vascularized and often hypervascular relative to the unaffected portion of the pancreas. As a result this neoplastic tissue usually undergoes an appreciable degree of enhancement on images made with appropriate techniques of intravenous contrast enhancement (74). Other morphologic features that distinguish islet cell tumors include the lack of
Figure 45.4 Computed tomography of patient with large non-functioning tumor of tail of pancreas. Note area of cystic degeneration and hypodense areas of necrosis (arrows). This patient underwent a potentially curative resection of the tumor.
vascular encasement and lack of obstruction of the pancreatic duct as compared to adenocarcinoma of the pancreas. For non-functioning islet cell neoplasms, CT is the radiologic imaging modality of choice. Like other large, hypervascular neoplasms, islet cell carcinomas may have internal necrotic areas. These appear on CT as hypodense zones of low attenuation, sometimes with features of cystic degeneration or necrosis (Fig 45.4). Dystrophic calcification may develop within a tumor and is observed on CT in 20% of non-functioning islet cell tumors (75). The characteristic features on CT of nonfunctioning islet cell carcinomas, including large tumor mass, hyperenhancement, cystic degeneration, and calcification,
422
help distinguish them from ductal adenocarcinoma. Similar features are present and identified by CT in the metastatic lesions from these tumors. Metastases are found most often in the liver and in regional lymph nodes. Whereas metastases from ductal adenocarcinoma tend to be small, those from islet cell carcinoma are often large (74). Pancreatic tumors other than ductal adenocarcinomas can be difficult to distinguish from non-functioning islet cell tumors. In a study of 45 patients with 50 non-functioning islet cell tumors, 36 of the tumors had heterogeneous areas and over half (N = 27) had cystic degeneration visualized on CT or MRI. Only 14 of the 50 non-functioning tumors were solid homogeneous masses (76). Therefore, an islet cell carcinoma could resemble atypical forms of serous or mucinous cystic neoplasms. More likely, a partially necrotic tumor, such as solid and papillary epithelial neoplasm, might resemble an islet cell neoplasm with similar structure. Unlike solid and papillary epithelial neoplasms, however, non-functioning islet cell tumors are often associated with large metastases and they do not typically have visible capsules. Moreover, they tend to occur in older age groups and they do not have the predilection for female subjects (Table 45.8). While MEN-1 syndrome has been associated with functioning endocrine tumors of the pancreas, small clinically silent endocrine tumors are often numerous in the pancreas of patients with this syndrome. Non-functioning microadenomatoses of MEN-1 patients have been found mainly to be composed of glucagon and pancreatic polypeptide producing cells. In addition to the microadenomatosis, larger, discrete adenomas, mainly composed of pancreatic polypeptide producing cells, have been found (77). Although increased blood levels of glucagon and pancreatic polypeptide have been frequently detected in such patients, as a rule related clinical syndromes have not been observed. Most clinically non-functioning pancreatic tumors in patients with MEN-1 syndrome have benign histologic patterns and behavior (2). Metastatic tumors to the pancreas such as those from renal cell carcinoma are particularly likely to have appearances indistinguishable from those of islet cell carcinoma. In these cases, clinical correlation should predict the nature of the lesion. In addition to characteristic clinical presentations and radiologic findings, serum markers have been utilized in the diagnosis of non-functional endocrine tumors. To be able to detect a tumor by its secretion(s) implies that the tumor is no longer biochemically silent. Nonetheless, such neoplasms are not associated with any distinct clinical symptoms.
Pancreatic polypeptideoma (PPoma) is one such tumor and among the most common of the non-functional islet cell tumors. Human pancreatic polypeptide is frequently associated with other hormones in pancreatic endocrine tumors and pancreatic polypeptide cells are most often found in glucagonomas and in non-secreting tumors (11). In a series of eight patients with isolated pancreatic polypeptide producing islet cell tumors, clinical features included abdominal pain (N = 4), weight loss (N = 4), diarrhea (N = 2), gastrointestinal bleeding (N = 2), and jaundice in one patient. Serum basal pancreatic polypeptide was elevated in most patients with a marked response to secretin. Six of eight patients underwent tumor resection with two patients being not surgical candidates due to hepatic metastases (77). After curative resection, elevated serum pancreatic polypeptide levels fell to normal. Contrary to most reported nonfunctioning tumors, PPomas seem to have a benign course even when of large size and producing local symptoms, as found in six of eight cases reported above and in 10 of 10 cases reported elsewhere (11). Other markers which have been evaluated in non-functioning islet cell tumors include neuron-specific enolase (78). Its role in monitoring patient course or response to therapy is not known at present. The presence of hormones in tumor cells at immunochemical staining provides useful information for the diagnosis of non-functioning islet cell tumors. Multiple hormones can be produced by these neoplasms. In a series of 61 non-functioning tumors, pancreatic polypeptide immunoreactivity was detected in 35% of cases, with a mean of 33% of all tumor cells; glucagon was found in 30% of cases and 30% of cells; somatostatin in 15% of cases and 20% of cells; serotonin in 20% of cases and 36% of cells; calcitonin in 20% of cases and 10% of cells; neurotensin in 8% of cases and 8% of cells; and insulin in 15% of cases and 2% of cells. No gastrin or VIP immunoreactivity was detected (79). It seems clear that tumors producing pancreatic polypeptide, glucagon, somatostatin, calcitonin, and serotonin are more likely to be without an associated syndrome than are those producing clinically powerful hormones such as insulin, gastrin, or VIP.
423
Figure 45.5 Photograph of liver metastases of a non-functioning islet cell tumor (arrows) detected at laparoscopy. The primary tumor was in the head of the pancreas. The preoperative CT scan did not reveal metastatic disease.
scintigraphy was superior in detecting intra-abdominal and bony metastases. Conversely, tumor masses shown by conventional scanning techniques were missed by SRS in several patients. Since large tumor masses were missed by SRS in some cases, it is felt that the low density of somatostatin receptors on some tumors may be the major factor causing false negative results (88). Since somatostatin receptors appear to be present in similar concentrations in non-functioning and functioning tumors, SRS should be of equal accuracy in detecting both types of tumors. The advantage of radionuclide scintigraphy is that adenocarcinoma of the pancreas does not take up the tracer and therefore false positive rates are low (23). The disadvantage of this methodology is that the absence of tracer uptake by a tumor does not rule out an islet cell tumor. With rapid improvements in conventional imaging modalities (e.g., CT and MRI) in the visualization of the pancreas, liver and other intra-abdominal organs, the benefit of SRS in islet cell tumor identification may decrease. The capacity to take up and decarboxylate amine precursors such as 5-hydroxytryptophan (5-HTP) and l-dihydroxyphenylalanine (l-DOPA) and store their amine precursors is characteristic of neuroendocrine cells and tumors. Utilizing this concept, positron emission tomography (PET) has been evaluated in the diagnosis of pancreatic endocrine tumors. In a study utilizing l-DOPA, the ability to detect the pancreatic tumor and possible metastases was evaluated in 22 patients with islet cell tumors. In the six patients with non-functioning islet cell tumors, there was relatively lower uptake of l-DOPA and in two cases the primary tumor as well as the metastases were not identified with PET, despite the fact that they were large and clearly visible with CT (89). At present, with few available data, it appears that for localization of non-functioning endocrine tumors and their metastases, there is no general advantage of PET compared with CT. A larger patient population is needed to determine the usefulness of l-DOPA and 5-HTP as tracers for visualization of the various subgroups of pancreatic endocrine tumors.
424
(A)
(B)
(C) Figure 45.6 (A) CT scan of patient with cirrhosis and large non-functioning tumor of tail of pancreas (arrow). (B) Another image of the liver of the same patient shows a cystic lesion in the liver (arrow), which was suspicious for metastatic disease. (C) Octreotide scan of the same patient. Top panel demonstrates two intense areas of uptake in the left abdomen corresponding with the tumor and the spleen (arrowheads). In the bottom panel, the large cyst in the liver is visualized and there is no uptake within this cyst in the liver (arrowhead). At operation, these findings were confirmed, no liver metastases were identified and the patient underwent a distal pancreatectomy with splenectomy.
without actual invasion. The large tumor bulk may cause near obstruction of blood vessels via a compressive effect which can be relieved by tumor resection. For instance, tumors in the tail of the pancreas can compress the splenic vein leading to splenomegaly and even varices (Fig. 45.7A,B). Nevertheless, these tumors can be frequently resected with negative margins. Similarly, tumors in the head of the pancreas can compress the superior mesenteric vein. Again, in the absence of known metastatic disease, every attempt should be made at tumor resection. Tumors in the head of the pancreas should usually be treated by pancreaticoduodenectomy, while tumors in the body and tail should be treated with distal pancreatectomy. Extension of tumor from the pancreas into surrounding organs such as the stomach and colon should be resected en bloc. If the tumor is small (<2 cm) and located in the tail of the pancreas consideration should be given to distal pancreatectomy with splenic preservation. In patients with significant co-morbid conditions or for small lesions in the head of the pancreas, enucleation can be entertained. With endocrine tumors, some authors have advocated that surgical removal of involved lymph nodes should be performed
425
N 25 21 27 43 20 73 33 34 58
Study years 196078 194884 196584 195087 198291 195392 198388 198596 194996
Curative resection (%) 9 (36) 12 (57) 10 (37) 22 (51) 10 (50) 19 (26) 12 (36) 12 (35) 46 (79) 44% 63% 58% 40 30 4.8 76% 52%
Curativec (actuarial 5-yr) (actuarial 5-yr) (actuarial 3-yr) months (mean) months (median) yr (median) (actuarial 3-yr) (actuarial 5-yr)
Mean or median tumor size. Survival in entire study group: curative and non-curative resections. c Survival in curatively resected patients. d 18 of 25 tumors >5 cm in size.
(A)
(B)
Figure 45.7 (A) Large tumor in the tail of the pancreas with splenic vein obstruction and varices (arrows). This tumor was resected with negative margins. (B) Intraoperative picture of varices encountered at the time of resection (arrows).
as it may improve survival. Patients with malignant endocrine tumors whose disease is confined to regional lymph nodes have a greater chance of benefit by removal of tumor than patients who have distant metastases. Therefore, regional nodes which are involved with tumor should be resected as completely as possible in an attempt to eliminate all disease and decrease the probability of distant metastases (90). With non-functioning islet cell tumors, in the absence of metastases, it is controversial whether nodal disease outside the field of dissection should be resected. However, utilizing the data from neuroendocrine tumors of the small bowel in which extensive lymphadenectomy is recommended, it can be concluded that for non-functional islet cell neoplasms reasonable attempts should be made to remove all nodal disease.
be in the best interest of the patient, the primary disease and metastases must be completely resected. No data exist to validate this approach. It should only be considered if the metastatic lesion can be resected with acceptable morbidity and mortality. Patients with unresected hepatic metastases from gastrointestinal neuroendocrine tumors have been reported to have 5-year survival rates of between 13% and 43% (64). In an effort to improve survival and even cure patients who have failed other forms of therapy, liver transplantation has been applied in these patients. Reports of liver transplantation for metastatic neuroendocrine tumors have been confined to small numbers of patients and short follow-up, typically less than 3 years from the time of transplantation (91). In the best results published to date, 12 patients (five pancreatic islet cell tumors) received transplants at a single center. Long-term survival was achieved in most patients with a median survival of 55 months (92). However, in a multicenter report from France of 16 cases of liver transplantation for metastatic pancreatic islet cell tumors, the 4-year survival was 8%. The authors concluded that liver transplantation was not indicated for metastatic pancreatic islet cell tumors (93). Despite some
426
a Biliary and gastric bypass. Abbreviations: AWD, alive with disease; DOD, dead of disease.
encouraging results from individual groups, until larger numbers of patients and longer follow-up are accumulated, or until the supply of donor livers increases, liver transplantation for metastatic pancreatic islet cell carcinomas should be applied with great caution.
presence of liver metastases should be considered only in the presence of debilitating symptoms (e.g., pain) or in the presence of complications (e.g., bleeding). Resection of metastases for palliation of symptoms has been reported more often in functioning than in non-functional islet cell carcinomas. It may play a more important role in alleviating the effects of excess production of endocrine hormones in functioning tumors. For non-functioning tumors it is rarely indicated, especially when other less invasive modalities can be utilized for treatment of symptoms due to metastatic tumor growth. Hepatic artery embolization has been performed to palliate symptoms from metastatic disease. In a study of 22 patients with metastatic functional or non-functioning neoplasms, sequential hepatic artery embolization was performed. Patients underwent a median of four embolizations. Partial remission was achieved in 12 patients. Hormonal syndromes were frequently relieved. Moderately toxic reactions were incurred after each embolization, but they were brief. Median survival was 33.7 months (95). Sequential hepatic artery occlusion with microembolic material may provide prolonged palliation for selected symptomatic patients with islet cell carcinoma metastatic to the liver. Palliative biliary and/or enteric bypasses for patients presenting with unresectable disease and biliary or gastric outlet obstruction have been performed (Table 45.10). Prinz et al. (96) reported four of eight patients with unresectable tumors who underwent either a biliary bypass and gastrojejunostomy or a biliary bypass alone. The mean survival in these four patients was 4.5 years. For patients with obstructive jaundice secondary to a locally unresectable non-functioning islet cell neoplasm, operative biliary bypass should be strongly considered. The superiority of operative biliary bypass for long-term management of malignant biliary obstruction justifies this approach in patients who have islet cell tumors and potential for prolonged survival. Duodenal bypass via a gastrojejunostomy for lesions in the head of the pancreas should also be considered in these patients.
427
treatment: chemotherapy
Recommended chemotherapy for advanced islet cell tumors is based on the results of a multicenter randomized trial. In this trial, 105 patients were randomized to receive one of three regimens: streptozotocin plus fluorouracil, streptozotocin plus doxorubicin, or chlorozotocin alone. Patients with either nonfunctioning or functioning islet cell tumors were included in this study. Streptozotocin plus doxorubicin was superior to streptozotocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69% vs. 45%, p = 0.05, respectively), and the median length of time to tumor progression (20 vs. 6.9 months, p = 0.001, respectively). Streptozotocin plus doxorubicin also had a significant advantage in terms of survival (median 2.2 vs. 1.4 years, p = 0.004) (97). This regimen is now considered the standard treatment for advanced islet cell tumors, but should be considered in the context of each individual patient, as some may have prolonged survival untreated, and response to treatment is greater than the effect on overall survival.
treatment: octreotide
Octreotide is a synthetic octapeptide with structure and activities similar to those of the native hormone somatostatin, but with significantly longer half-life and duration of action that the native substance. Octreotide has been reported to be effective in controlling the hormone-induced symptoms of patients with functional islet cell tumors (100). Although rare reports of tumor regression to octreotide have been published, the drug has been primarily utilized to ameliorate the symptoms from hormonal excess in patients with functional islet cell tumors. In a study which included 13 patients with advanced, incurable non-functional islet cell tumors, octreotide was administered via subcutaneous injection. No patient experienced a major objective response. Of the 21 patients with functional tumors, 15 demonstrated either a symptomatic improvement or an objective decrease in hormone level. Octreotide is useful in controlling symptoms due to hormonal excess in functional islet cell tumors. There is no evidence that octreotide would benefit patients with non-functional islet cell tumors.
distant metastases and who did not undergo resection. These patients had a 38% 5-year survival with a median survival of 3.3 years. In addition, among patients with localized disease at presentation, the survival was significantly better in patients who were able to undergo tumor resection as compared to those who did not. Therefore, important predictors of survival are the ability to undergo curative resection and the degree of local spread. It is unclear whether non-functional tumors have a worse prognosis than functional islet cell tumors. Several studies have shown that the survival of patients with non-functional tumors is poorer than for those with functional tumors. In a report from the Cleveland Clinic, actuarial 10-year survival was 55% for non-functioning tumors while it was 92% for insulinomas and 68% for gastrinomas (73). In a study from Johns Hopkins, median survival was 121 months in functional tumors while it was 96 months in non-functional neoplasms (p < 0.025) (10). In an early report from the Mayo Clinic, survival was statistically better at 3 years in those patients with gastrinomas compared with patients with non-functioning tumors, 91% versus 58% (8). However, in a later report from the same institution, there was no survival difference between functional and non-functional neoplasms (7). Other studies have found no difference in survival between functioning and non-functioning tumors (101,102). Size of the primary tumor rather than functional status may be a more important prognostic variable. In the study by Phan et al. (10) the median tumor size in the non-functional tumors was 4.0 cm as compared to 1.9 cm in the functional neoplasms. In addition, the malignancy rates were correspondingly lower in the functional tumors (47%) as compared to the non-functional ones (60%). It may be that non-functional tumors are detected at larger tumor burdens because of the absence of an endocrine syndrome. This may account for poorer survival with non-functioning neoplasms seen in some studies. Efforts have been made to develop more sophisticated markers to determine prognosis in patients with non-functioning islet cell neoplasms. In a preliminary study of 61 non-functioning tumors, vascular or perineural microinvasion and Ki67 proliferative index were the most sensitive and specific variables that were predictive of malignancy. These variables were utilized in tumors lacking evidence of malignancy at the time of surgery, to separate cases with increased risk of malignancy from cases with limited risk, and were found to be somewhat predictive of survival (79). Rigorous studies in larger numbers of patients with islet cell neoplasms, which examine different immunohistochemical markers, may help identify prognostic variables in these tumors.
conclusions
Clinically, there are similarities and differences between the various functional endocrine tumors of the pancreas. These tumors vary with regard to size, location, age distribution, sex distribution, propensity for malignancy, and metastatic potential in accordance with the individual tumor type. The clinical morbidity and mortality associated with the tumor are due to peptide hypersecretion and not to tumor mass. In addition,
prognosis
Evans et al. (84) found that patients who underwent curative resection of their primary tumor in the absence of metastases had a 72% 5-year survival with a median survival of 6.8 years. This was in sharp contrast to patients who presented with
428
references
1. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas. Dig Dis Sci 1991; 36: 93342. 2. Solcia E, Sessa F, Rindi G, Bonato M, Capella C. Pancreatic endocrine tumors: general concepts; nonfunctioning tumors and tumors with uncommon function. In: Dayal Y, ed. Endocrine Pathology of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 10531. 3. Solcia E, Capella C, Kloppel G. Tumors of the endocrine pancreas. In: Anonymous Atlas of Tumor Pathology. Washington: AFIP, 1997: 145209. 4. Kent RB, Van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981; 193: 18590. 5. Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract 1988; 183: 15568. 6. Howard JN, Moss NH, Rhoads JE. Collective review: hyperinsulinism and islet cell tumors of the pancreas. Int Abstr Surg 1950; 90: 41755. 7. Lo CY, Van Heerden JA, Thompson GB, et al. Islet cell carcinoma of the pancreas. World J Surg 1996; 20: 87884 8. Thompson GB, Van Heerden JA, Grant CS, Carney A, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988; 104: 10117 9. Grant CS. Surgical management of malignant islet cell tumors. World J Surg 1993; 17: 498503 10. Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg 1998; 2: 47382 11. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors: immunocytochemical analysis of 125 tumors. Hum Pathol 1982; 13: 26371 12. Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a development lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 1988; 53: 295 13. Mozzell E, Stenzel P, Woltering EA, Rosch J, ODorisio TM. Functional endocrine tumors of the pancreas: clinical presentation, diagnosis, and treatment. Curr Probl Surg 1990; 27: 30386 14. Bieligk S, Jaffe BM. Islet cell tumors of the pancreas. Surg Clin N Am 1995; 75: 102540 15. Friesen SR. Tumors of the endocrine pancreas. N Engl J Med 1982; 306: 58090 16. Norton JA. Neuroendocrine tumors of the pancreas and duodenum. Curr Probl Surg 1994; 31: 77164 17. Grant CS. Insulinoma. Surg Oncol Clin N Am 1998; 7: 81944 18. Van Hoe L, Gryspeerdt S, Marchal G, Baert AL, Mertens L. Helical CT for the preoperative localization of islet cell tumors of the pancreas. AJR 1995; 165: 14379 19. Smelka RC, Cumming MJ, Shoenut JP, et al. Islet cell tumors: comparison of dynamic contrast-enhanced CT and MR imaging with dynamic gadolinium enhancement and fat suppression. Radiology 1993; 186: 799802 20. Muller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pancreatic tumors: evaluation with endoscopic US, CT and MR imaging. Radiology 1994; 190: 74551 21. Van Byck CHJ, Bruining HA, Reubi JC, et al. Use of isotope-labeled somatostatin analogs for visualization of islet cell tumors. World J Surg 1993; 17: 4447 22. Krenning EP, Kwekkeboom DJ, Reubi J, et al. 111In-octreotide scintigraphy in oncology. Metabolism 1992; 41: 836 23. Krenning EP, Kwekkeboom DJ, Oei HY, et al. Somatostatin-receptor scintigraphy in gastroenteropancreatic tumors. Ann NY Acad Sci 1994; 733: 41624 24. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasound in the localization of insulinomas and gastrinomas. Surgery 1994; 116: 11318 25. Pasieka JL, MeLeod MK, Thompson NW, et al. Surgical approach to insulinomas: assessing the need for preoperative localization. Arch Surg 1992; 127: 4427 26. Doppman JL, Miller DL, Chang R, et al. Intraarterial calcium stimulation test for insulinomas. World J Surg 1993; 17: 43943 27. Danforth DN, Gordon P, Brennan MF, et al. Metastatic insulin secreting carcinoma of the pancreas: clinical course and role of surgery. Surgery 1984; 96: 102737
key points
Clinically silent endocrine tumors have been found in up to 10% of detailed autopsy examinations. Functional islet cell tumors include Insulinoma Gastrinoma Glucagonoma VIPoma Somatostatinoma. Localization of pancreatic endocrine tumors: Helical CT: sensitivity 85% MRI: sensitivity not known Angiography: sensitivity 58% Somatostatin receptor scintigraphy: 82% PET scan: sensitivity not known. Surgical excision, usually with curative intent, is the major objective of treatment. Surgical debulking of primary and metastatic functional islet cell tumors often achieves good palliation of symptoms.
429
430
98. 99.
100.
101.
102. 103.
104.
109.
110.
431
Although ductal adenocarcinoma is the most common malignant neoplasm of the pancreas, there are multiple unusual tumors of the pancreas that surgeons must keep in mind. A thorough history and physical exam and a high-resolution dedicated pancreatic CT scan are crucial in differentiating these rare tumors from the more commonly seen tumors. At times, MRI/MRCP, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound can aid in making the diagnosis. Here, we discuss nine rare tumors of the pancreas and their distinguishing features (Table 46.1).
432
Imaging Large, well circumscribed, cystic or hemorrhagic degeneration Large, hypodense, exophytic, well demarcated Wide range of size Well circumscribed lesion or infiltrating lesion with poorly defined borders Often hypervascular spherical lesions Cysts, adenomas, and hypervascular neuroendocrine tumors Common local infiltration and metastases Similar to ductal adenocarcinoma
Treatment Resection
<1%
5th to 7th decade of life 2:1 M:F 6th decade of life 5th to 6th decade of life M > F
Resection
<14% <0.5%
<1% Rare
Variable M=F
Different for various Variable primaries Resection if Often determined by neuroendocrine other VHL lesions tumor Resection, if appropriate ?chemoradiation Resection Similar to adenocarcinoma Better than adenocarcinoma if positive for microsatellite instability Good
Rare
Medullary carcinoma
?<5%
Autoimmune pancreatitis
Uncommon
Steroid therapy
Note: Autoimmune pancreatitis (also termed lymphoplasmacytic sclerosing pancreatitis) is not a neoplasm, but may be mistaken for a neoplastic process.
Figure 46.1 CT scan showing a large heterogenous mass in the tail of the pancreas (arrow) with central calcification. The surgical specimen was consistent with a solid pseudopapillary neoplasm.
By definition, ASC must have both histologic components of squamous and adenocarcinoma (20). Some authors in the past had arbitrarily set 30% as the minimum amount of squamous carcinoma component required to diagnose ASC in a specimen.
However, Kardon et al. showed a wide range in the proportion of squamous carcinoma in individual specimens. Thus, it was their opinion that an adenocarcinoma showing any degree of malignant squamous cell differentiation should be considered as ASC. It has been hypothesized that ASC is the result of malignant squamous metaplasia (dedifferentiation) within an adenocarcinoma. To further support this theory, Kardon et al. studied K-ras oncogene mutation, which has been strongly linked to ductal adenocarcinoma (>95% have K-ras mutation). In their series of ASC, they found that greater than 50% of their specimen had K-ras mutation, even in the tumors that were almost exclusively squamous carcinoma. However, the presence of K-ras mutation did not have any prognostic implications. Recent molecular studies of ASC have shed more light on the pathogenesis of this aggressive tumor, indicating that K-ras mutations may be crucial for the development of ASC. ASC is a more aggressive tumor than ductal adenocarcinoma. Kardon et al. reported average survival of 11 months for ASC patients who underwent R0 resection versus a median survival of 18 to 20 months for resectable adenocarcinoma. Patients who underwent palliative procedures had short median survival of 3.8 months. Smoot et al. found similar survival data in their study; patients who underwent R0 resection had median survival of 14.4 months versus 4.8 months
433
without resection (21). Obviously, a complete surgical resection is recommended for ASC whenever possible. While the standard of care currently recommends adjuvant chemo- or chemoradiation therapy for resected ASC patients, no trials have proven a survival benefit in this patient cohort.
pancreatic lymphoma
Primary pancreatic lymphoma (PPL) is a rare disease, representing less than 0.5% of all pancreatic tumors and less than 2% of extra nodal non-Hodgkins lymphomas (NHL) (22,23). PPL occurs more frequently in men than women and usually presents in the 5th to 6th decade (median age 57.1 years) (24). The clinical presentation of PPL is often nonspecific. The most common presenting symptom is abdominal pain (83%), followed by abdominal mass (58%), weight loss (50%), jaundice (37%), acute pancreatitis (12%), small bowel obstruction (12%), and diarrhea (12%) (25). The classic B-symptoms of nodal NHL are seen in less than 2% of PPL patients (27). Laboratory studies are often non-diagnostic. Two different morphologic patterns of involvement are seen on CT: a well-circumscribed mass or an infiltrating lesion with poorly defined borders (27). Certain CT findings such as a bulky head of pancreas tumor without significant dilation of the bile duct or main pancreatic duct and enlarged lymph nodes below the level of the renal vein suggest PPL over adenocarcinoma (23,27). However, cytohistological examination of tissue, obtained by image-guided fine needle aspiration (FNA) or endoscopically guided FNA, is required to confirm the diagnosis of PPL (24,28). Surgery is usually reserved for rare cases where less invasive modalities fail to provide a tissue diagnosis. The treatment of PPL has varied, due to the lack of prospective randomized studies to delineate management. Chemotherapy has been the mainstay of treatment with CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone), CVP (Cyclophosphamide, Vincristine, Prednisolone), and MACOP-B (Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin) being used most commonly (26,29). Radiotherapy has been used variably, alone and as consolidation after chemotherapy (26). Recently rituximab has been used in combination with CHOP resulting in improved response rates (30). Surgical resection for stage I and II disease has been shown to increase cure rates and may be used as part of multimodality therapy for resectable lesions (31). In general, the outcomes for pancreatic lymphoma are better than for ductal adenocarcinoma.
Figure 46.2 CT scan showing a large heterogenous mass involving the body and the tail of the pancreas (arrow) in a 70-year-old male who had previously undergone right upper lobectomy for lung adenocarcinoma. This mass was found during a follow-up PET CT scan. The pathology specimen confirmed the diagnosis of a metastasis from the lung primary.
isolated metastases to the pancreas are renal, lung, breast, colon, and melanoma (32). Metastases to the pancreas are usually identified during initial metastatic work-up of a primary tumor, during routine follow-up after resection of the primary cancer, or via the presence of symptoms secondary to the pancreatic lesion (32). On CT imaging, hypervascularity of the lesion, absence of enlarged lymph nodes, and multicentric lesions suggest metastatic disease to the pancreas over a primary neoplasm (Fig. 46.2) (33). Treatment options (both surgical and nonsurgical) depend on the type of primary tumor, location of the metastasis, the extent of disease, and the presence or absence of symptoms related to the metastatic tumor (32). Renal cell carcinoma (RCC) is the most common cancer associated with isolated metastasis to the pancreas (34). Pancreatic metastasis from RCC is usually metachronous, occurring an average of 9.2 years after initial resection (32,35). Most patients are asymptomatic, with lesions detected through routine post-RCC surveillance (36,37). Surgical resection yields a 5-year survival between 53% and 75% compared to 5% to 30% for those with unresectable lesions (32). Metastectomy in patients with RCC does seem to confer a survival benefit and should be performed in eligible patients.
434
Isolated pancreatic metastases from lung cancer are rare. These patients have a poor prognosis and most do not benefit from metastectomy (32,38). Pancreatic metastasis from breast cancer usually occurs in the setting of diffusely metastatic disease; while controversial, surgical resection, in conjunction with multimodality therapy, may improve survival (32). Pancreatic metastasis from colon cancer often occurs secondary to local invasion; en bloc resection has been found to improve prognosis and is advocated in carefully selected cases (32). Pancreatic metastasis from malignant melanoma is generally found in conjunction with metastasis to other intraabdominal organs (39). Though the data are limited with regard to pancreatic resection for melanoma, improved survival has been documented when complete resection of all intra-abdominal sites of metastatic melanoma can be achieved (39,40). The different types of primary tumors metastatic to the pancreas and their recommended treatment are summarized in Table 46.3.
for pancreatic cysts or serous cystadenomas (43) but surgical resection is recommended for selected neuroendocrine tumors due to their malignant potential. The criteria for resection of VHL neuroendocrine tumors are (1) no metastatic disease and size greater than 3 cm in the body or tail, or greater than 2 cm in the head or (2) patient undergoing laparotomy for other lesions (47). Patients who do not meet criteria for resection should be successfully followed with yearly CT scan to assess for tumor enlargement (42). The most common sites of metastatic neuroendocrine tumor in VHL are the liver and peripancreatic lymph nodes; treatment consists of chemotherapy (and duodenal or biliary stenting as needed for palliation of space occupying lesions) (42).
435
Figure 46.3 Typical CT scan demonstrating the sausage-like appearance of the body and tail of the pancreas in autoimmune pancreatitis (arrow). The gallbladder is prominent and the intrapancreatic portion of the distal common bile duct is dilated.
medullary carcinoma
Initially described by Goggins et al. in 1998 as pancreatic adenocarcinomas with DNA replication errors (RER+), medullary carcinomas of the pancreas are poorly differentiated carcinomas that have been frequently grouped with conventional ductal carcinoma of the pancreas. However, they are histologically distinct, described by syncytial growth pattern, expanding tumor borders, and extensive necrosis (56). Furthermore, they have unique genetic features and tumor pathogenesis. Although not clearly known, up to 5% of pancreatic cancers may be medullary variants. Clinically, patients with these tumors present in the 6th and 7th decade of life with a slight male to female predominance and most patients have a family history of cancer in a first degree relative. On a molecular level, medullary carcinomas of the pancreas were initially reported to have a wild-type K-ras gene. However, later studies have not confirmed this as a universal finding. In addition, medullary cancers harbor microsatellite instability (MSI) in about 22% cases as compared to a lack of MSI in ductal adenocarcinomas (56). This suggested a distinct genetic pathway for medullary tumor development that is different from pancreatic adenocarcinoma (57). MSI is caused by mutations or methylation in such DNA repair genes as MLH1 and MSH2 (and others), which can be inherited or acquired (58). Patients with MSI-positive medullary tumors are observed to have better prognosis than those with ductal adenocarcinoma. Bunzo et al. examined the predictive value of MSI on prognosis of pancreatic cancer and found that MSI-positive tumors had significant longer survival times than their MSInegative counterpart (59,60). Such a beneficial association of MSI positivity with prognosis has been observed in other types of cancers including colorectal, gastric, and ampullary cancer. The treatment for localized disease is surgical resection. The optimal post-resection chemotherapy remains unknown, although this tumors unique molecular profile suggests a role for specifically targeted therapy.
436
Serology
Imaging
High serum gamma-globulins, IgG or IgG4, or the presence of autoantibodies such as antinuclear antibodies and rheumatoid factor Diffuse or segmental narrowing of the main pancreatic duct with diffuse or localized enlargement of the pancreas by imaging studies such as abdominal ultrasound, CT, and MRI
At least one of the following: (1) Elevated levels of IgG and/IgG4 (2)Detected autoantibodies (1) CT: diffuse enlargement (swelling) of the pancreas (2) ERCP: diffuse or segmental narrowing of the pancreatic duct
Not included
Not included
Common: diffusely enlarged gland with delayed (rim) enhancement; diffusely irregular, attenuated main pancreatic duct. Others: focal pancreatic mass/ enlargement; focal pancreatic duct stricture, pancreatic duct atrophy, pancreatic calcifications; or pancreatitis Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, parotid/lacrimal gland involvement, mediastinal lymphadenopathy, retroperitoneal fibrosis Resolution/marked improvement of pancreatic/extrapancreatic manifestation with steroids
synchronous AIP and ductal adenocarcinoma, treated via pancreatic resection (72).
references
1. Campbell F, Azadeh B. Cystic Neoplasms of the exocrine pancreas. Histopathology 2008; 52: 53951. 2. Adams AL, Seigal GP, Jhala NC. Solid pseudopapillary tumor of the pancreas. Adv Anat Pathol 2008; 15: 3945. 3. Liu X, Rauch TM, Siegal GP, et al. Solid-pseudopapillary neoplasm of the pancreas. Three cases with a literature review. Appl Immunohistochem Mol Morpho 2006; 14: 44553. 4. Mao C, Guvendi M, Domenico DR, et al. Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the worlds literature. Surgery 1995; 118: 8218. 5. Geers C, Moulin P, Gigot JF, et al. Solid and pseudopapillary tumor of the pancreasreview and new insights into pathogenesis. Am J Surg Pathol 2006; 30: 12439. 6. Shi C, Daniels JA, Hruban RH. Molecular characterization of pancreatic neoplasms. Adv Anat Pathol 2008; 15: 18595. 7. Tipton SG, Smyrk TC, Sarr MG, et al. Malignant potential of solid pseudopapillary neoplasm of the pancreas. Br J Surg 2006; 93: 7337. 8. Machado MCC, Machado MAC, Bacchella T, et al. Solid pseudopapillary neoplasm of the pancreas: distinct patterns of onset, diagnosis, and prognosis for male versus female patients. Surgery 2008; 143: 2934. 9. Riechelmann RP, Hoff PM, Moron RA, et al. Acinar cell carcinoma of the pancreas. Int J Gastrointest Cancer 2003; 23: 6772.
10. Holen KD, Klimsra DS, Hummer A, et al. Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors. J Clin Oncol 2002; 20: 46738. 11. Seth AK, Argani P, Campbell KA, et al. Acinar cell carcinoma of the pancreas: an institutional series of resected patients and review of the current literature. J Gastrointest Surg 2008; 12: 10617. 12. Wisnoski NC, Townsend CM Jr, Nealon WH, et al. 672 Patients with acinar cell carcinoma of the pancreas: a population-based comparison to pancreatic adenocarcinoma. Surgery 2008; 144: 1418. 13. Tatli S, Mortele KJ, Levy AD, et al. CT and MRI features of pure acinar cell carcinoma of the pancreas in adults. AJR 2005; 184: 5119. 14. Chiou YY, Chiang JH, Hwang JI, et al. Acinar cell carcinoma of the pancreas clinical and computed tomography manifestations. J Comput Assist Tomogr 2004; 28: 1806. 15. Mortenson MM, Katz MHG, Tamm EP, et al. Current diagnosis and management of unusual pancreatic tumors. Am J Surg 2008; 196: 10013. 16. Kitagami H, Kondo S, Hirano S, et al. Acinar cell carcinoma of the pancreas: clinical analysis of 115 patients from Pancreatic Cancer Registry of Japan Pancreas Society. Pancreas 2007; 35: 426. 17. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell of the pancreas in the United State: prognostic factors and comparison to ductal adenocarcinoma. J Gastrointest Surg 2008; 12: 207886. 18. Kardon DE, Thompson LDR, Przygodki RM, et al. Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod Pathol 2001; 14: 44351. 19. Hsu JT, Yeh CN, Chen YR, et al. Adenosquamous carcinoma of the pancreas. Digestion 2005; 72: 1048.
437
438
47
introduction
In the last 20 years, there are few disease processes where the understanding and the approach to management have changed more than that of acute pancreatitis. Acute pancreatitis presents a spectrum of disordered physiology, ranging from a mild and rapidly resolving attack (80%) requiring little more than analgesia and a short period of intravenous fluid resuscitation, to an overwhelming system illness characterized by multi-organ dysfunction refractory to aggressive resuscitation. Various clinical and biochemical scoring systems (14) have been used in an attempt to differentiate between mild or severe acute pancreatitis, but out-with the study environment, management is reactive aimed at normalizing altered physiology or the management of local complications. The majority of patients with severe early organ dysfunction will have pancreatic necrosis on CT scan. There is an association between the development of necrosis and the severity of organ dysfunction (5), although patients with edematous pancreatitis may manifest clinical features of a severe attack. Clinical practice has changed rapidly over the last decades, and the previous focus on parenchymal necrosis and particularly the role of prevention/treatment of infection are now considered in a wider concept tending toward organ support and less aggressive intervention. Most patients who develop organ failure have evidence of this at the time of admission or very shortly thereafter (6), and worsening or persistent organ failure is associated with an adverse outcome, and/or the development of late complications. There is no evidence that aggressive early surgical intervention to address the necrosis has a beneficial effect on outcome and indeed is potentially harmful. The majority of patients with acute pancreatitis will have a mild clinical course and other than maintenance of fluid volume and analgesia, subsequent treatment is aimed at prevention of a further attack. Early definitive treatment of cholelithiasis is recommended by cholecystectomy or endoscopic sphincterotomy as recurrent mild attacks are not uncommon (7). The main focus of this chapter is on the 15% to 20% of patients who present with severe disease and the options and rationale for clinical management.
etiology
Pancreatic inflammation was first reported in association with alcohol excess in 1878 by Freidrich, and 20 years later, Opie proposed the bile reflux theory potentially underlying the most common cause of gallstones. A detailed description of the pathophysiological mechanisms that are thought to be involved in the initiation of an attack is beyond the scope of this chapter. An attack may be initiated by obstruction of the duct either through passage of a
439
440
ACUTE PANCREATITIS
radiological assessment
Trans-abdominal ultrasound is often performed within 24 hours but in the absence of jaundice, this has little effect on clinical management. Bowel gas and a restless patient often compromise the examination and exclusion of cholelithiasis may require a repeated examination in the recovery period. Early post-admission CT may be appropriate where the diagnosis is in doubt or a complication suspected; however, as the evolution of necrosis is not complete until at least 72 hours, in some patients axial scanning is best delayed until this time. Subsequent management and need for further radiological assessment are determined by the clinical condition and the trend of biochemical and organ failure scores.
the pus surrounding the necrosis often resulted in at least a temporary improvement in organ failure challenged this dogma; however, further sepsis was common. The importance of maintaining a sustainable drainage system was recognized in the era of major open debridement leading to the techniques of open packing (42) and closed lavage (43). The solid component within these collections tends to block the lumen of small diameter drains but provided drainage is maintained, organ failure will resolve despite residual necrosis. The mortality that followed an open necrosectomy was common in the initial (72 hours) post-operative period due to overwhelming organ failure. This post-interventional escalation in organ failure is significantly less following all minimally invasive approaches, but often at the cost of multiple interventions and prolonged inpatient stay. A balanced approach is therefore able to utilize a number of techniques dependent on the clinical condition of the patient, the presence of sepsis, the degree of organ failure, the position of the collection, and the maturity of the collection.
management of necrosis
Until recently, sterile necrosis was considered to be a driver of organ dysfunction, leading to a necrosectomy for patients failing to progress after a few weeks. It was also considered essential to identify the development of infection as early as possible, leading to the popularization of protocol-driven radiologically guided fine needle bacterial aspiration (40), and pre-emptive necrosectomy following a positive result. Current opinion is that outcome can be improved by the avoidance of early major intervention, especially in patients with organ failure, utilizing minimally invasive approaches to sepsis control where possible. CT-guided fine needle aspiration no longer plays any role in our practice. For many years most specialist centers have addressed all collections utilizing a single surgical technique. This dogmatic procedure-based algorithm failed to address the changing requirements and risk profile with maturation of the collection. The indications for intervention vary with the dynamic evolution of pancreatic/peri-pancreatic collections (41). In the first 4 weeks, the solid necrotic phase, demarcation of devitalized tissue is incomplete and an attempt to remove the devitalized tissue often incomplete and associated with bleeding. By about 8 to 10 weeks demarcation results in formation of a walled off fluid collection containing a variable amount of solid necrosis. In the early weeks, achieving control of sepsisdriven organ failure is the primary consideration, whereas following maturation when organ failure is rare and morbidity low, indications include failure to thrive, SIRS, nutritional failure, gastric outlet obstruction, or pain. The presence of proven infection within necrosis (bacteria or gas on CT) was previously seen as a mandatory indication for urgent debridement, as it was believed until recently that recovery would only occur once the necrosis was completely removed. The observation that drainage of
441
442
Mean age in yrs (range) Mortality 6% 53 (3081) 64 (56%) 46 (100%) 14// 23 13% 9// 31 41 Number with infected necrosis (%) Mean AII/RS/ CT-SI Timing of intervention from onset (mean days) Mean postoperative length of stay (days) ITU preoperatively Morbidity Reoperations 17% ITU postoperatively 64 46 45% (median 6 days) 29 57 (2887) 29 (100%) 255 (75%) 16// 12 (131) 55a 13/4/ 22 85 24% 44% 26% 53 (1685) 39% 90% preoperative organ failure 79% (mean 2.2) 58b (1998) 140 (100%) 11/5/ 20 64 27% mean 3 days 78% 51% (median 1) Mean 27 days
Unit, year
Method
340
Necrosectomy with closed packing Necrosectomy with scheduled re-explorations Necrosectomy with closed lavage Necrosectomy with scheduled re-explorations or resection Necrosectomy with closed lavage
140
Survivors. Median. Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit.
ACUTE PANCREATITIS
packing and planned re-operation are, however, sometimes required to control blood loss from the retroperitoneum following the development of an intraoperative coagulopathy, a lavage system being created, following correction of the coagulopathy, at the time of interval pack removal. With Closed Lavage The Ulm group popularized the use of post-operative closed lavage and this remains the most popular method for postoperative sepsis control following open debridement. Several (46) large diameter tube drains are inserted in the lesser sac and throughout the abdomen and the abdomen closed. Continuous lavage is then commenced, the aim being the continuous removal of devitalized necrotic material and bacteria. The lavage is continued, for around 3 to 4 weeks on average, until the return fluid is clear, and the patient has no residual signs of systemic sepsis. Minimally Invasive Approaches A number of minimally invasive techniques have been developed over the last 15 years and these are often viewed as complimentary rather than exclusive. These will be initially described and then the potential advantages/disadvantages discussed. Percutaneous Catheter Drainage (Table 47.2) Interventional radiological drainage of abscesses has been commonplace for many years. The major difficulty in the acute pancreatitis patient is the tendency for these to block, leading to recurrent sepsis. Utilizing simple drainage as the primary modality of treatment is possible, but is extremely labor intensive and delayed surgical intervention is commonly required. Endoscopic Drainage (Table 47.3) Transmural drainage of lesser sac collections was initially performed for established pseudocyst. Baron first described extending the role into the management of pancreatic abscess, where the collections contained some solid component. Endoscopic ultrasoundguided drainage can increase the technical success rate and reduce the risk of bleeding. Small diameter stent drainage could lead to incomplete drainage, and the use of tract dilatation, multiple catheters, and intracystic lavage became commonplace. Seifert described the performance of a necrosectomy through the endoscopic cystgastrostomy and this is becoming increasingly popular. Potential advantages include that it can be performed without a general anesthetic, potentially performed as a day patient in suitable patients and the lack of an external drain, but inadequate drainage and hemorrhage are potential hazards. Percutaneous Necrosectomy (Table 47.4) This combines minimally invasive drainage with closed postoperative lavage. A CT-guided radiological drain in inserted ideally in the left flank to promote gravitational drainage. The drainage tract is dilated often releasing pus under pressure and the cavity explored using a rigid urological endoscope. Loose necrotic material can be removed in a piecemeal fashion as it is this that tends to block the drains. A wide bore 32FG drain (with a parallel catheter for post-operative lavage) is left within the cavity. Continuous lavage is maintained and further procedures performed when incomplete drainage is suspected. This is probably the easiest way of maintaining adequate drainage and sepsis control but results in a prolonged hospital stay and commonly late pancreatic fistula. In the 1980s Fagniez described an open minimally invasive approach utilizing a left flank incision and blind retroperitoneal debridement (Table 47.5). In 2001, Horvath modified this technique using video-assistance to allow direct visualization of the debridement through a 8 to 10 cm left flank incision. This minimally invasive technique is currently being assessed in the first randomized comparison of a minimally invasive approach against open surgery (PANTER trial, Dutch Acute Pancreatitis Study Group).
laparoscopy
Early attempts at laparoscopy attempted to mimic the open debridement, but proved technically challenging and has been superseded by the other surgical approaches. Laparoscopic cystgastrostomy has been reported for the management of late walled off necrosis. Initial descriptions involved intra-luminal laparoscopy but the position of the collection relative to the stomach is critical. Modification by performing a longitudinal anterior gastrostomy and then addressing the posterior cystgastrostomy greatly simplified the procedure and allows a onestep approach to organized necrosis. The procedure requires a well-formed cavity and complete separation of the necrotic tissue, so is less appropriate for collections in an early stage of the disease.
summary
The choice of primary procedure is determined by the relative importance of sepsis control and the stage of evolution of the necrosis-associated peri-pancreatic collection. Optimal sepsis control is obtained by percutaneous necrosectomy but completion of the process takes some time and requires multiple procedures. At the other end of the spectrum, where sepsis is not an issue but intervention demanded through pressure effects or failure to thrive, a single procedure laparoscopic cystgastrostomy expedites completion of treatment, particularly where a predominant solid component makes endoscopic clearance likely to require multiple procedures. Endoscopic cystgastrostomy has a role between these extremes. In the septic patient, initial endoscopic drainage is easy but maintenance of sepsis control often demands repeated intervention and adjuvant radiological drainage. A particular problem is that the first indication of a blocked internal cystgastrostomy drainage system is a clinical escalation of sepsis whereas a blocked external drain is easily recognized and addressed. Similarly large or para-colic collections are unsuitable. However, in the fluid-predominant
443
444
Number with infected necrosis managed percutaneously Technique 25152 3.3 Number of deaths in series 34 //8 9 (148) 16 Mean timing Mean AII/ of intervention from RS/CT-SI for patients onset days in series (range) Successful percutaneous management alone of those with infected necrosis 17 Average duration of drainage (days or range) Acute operative management Average catheter of those with infected exchanges per necrosis patient (range) 26 19 a 19 a /5/E 23 20 Average of 3 4 transperitoneal catheters per patient (1028 Fr) 816 Fr 5 43 1456 a 0.4b 6 6 15b 12 (231) 10 (158) 15 3 23 /4/8 a 2 Average of 1.4 drains per patient (1012 Fr) a 2 a a 0.1 a 12 3 80 18//6c >11c 42 37 (1260)c 2 (19)c 20
b
Author, year
34
56 (3171)
32
53
25
40 (1768)
15
59 (3678)
31
49
80
57 (1779)c
61
44 (2587)d
23/4/d
>4
7d
1 14 Fr catheter dilated to 20 Fr combined with irrigation 27 Median of (18/60 mantwo aged without catheters surgery) per patient (824 Fr) with active necrosectomy in 18 patients b a (10/61)d
15d
Data not stated. Limited/unclear data published. Median. d For entire reported series of patients with various diagnoses/treatments. Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; PA, pancreatic abscess; PC, post-operative collection.
ACUTE PANCREATITIS
63 (3884)
a 4
28
56 (3880)
0 (8 PA)
13
53 (3064)
11 (2 SN)
8//6
?24
15% 0
3
a
a a
Data not stated. Limited/unclear data published. Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; OPN, organized pancreatic necrosis; PA, pancreatic abscess; SN, sterile necrosis; RC, residual collection after endoscopic treatment.
445
446
Number with infected necrosis a 24 23 28 a 6 1 0 21(19%) 1
d
Author, yr
Early morbidity
Median number of reoperations per patient (range) 2.5 (14) 2.3 (14) a 3 (28) 8 3(16) 4 0
45 (3274) 10
46b (2378) 6
47
56 (1885) 38 (9 SN)
9 1 107
58 (4180) 7 (2 PA)
51
Carter, 2000 (33) Risse, 2004 (59) Connor, 2005 (60) Mui, 2005 (61) Shelat, 2007 (62) Carter2007
110
54(1889)
55%
Data not stated. Mean. c Total hospital stay. d Limited/unclear data published. Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; SN, Sterile necrosis; PA, Pancreatic abscess.
Author, year
40
46 (2680)
25
2.6
20
51 ()
13 (7 SN)
/3/E
13 (7 with IPN)
62
ACUTE PANCREATITIS
36 (1648)
2 percutaneous drainages
53 (2963)
18
//8
48 (0181)
2 1
2 (111) 1
15
52 (3466)
1015 cm left upper quadrant incision anterior to 12th rib including mobilization of descending colon 6 cm incision centered on 12th rib debridement, 23 cm mediastinoscope Percutaneous drainage, debridement through 45 cm flank incision, retroperitoneoscopy via ports placed through lumbotomy incision, CO2 insufflation Various left-sided approaches with videoscopic assistance 5 cm subcostal incision along percutaneous drain, initial blind debridement followed by videoscopic debridement
a For entire reported series of patients with various diagnoses/treatments. data not stated, ? limited/unclear data published Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit; ASIS, anterior superior iliac spine; IPN, infected pancreatic necrosis; SN, sterile necrosis.
447
(A)
(B)
(C)
(D)
Figure 47.1 (A) Early phase CT (48hrs) with head necrosis and peripancreatic edema. (B) CT at 6 weeks confirming extensive loss of parenchyma with early demarcation and no evidence of infection. (C) CT at 7 weeks with extensive gas indicating infectionclinical sepsis addressed by percutaneous necrosectomy x3. (D) CT at 12 weeks prior to discharge.
There are no comparative data between techniques, and our multimodal approach has evolved largely through experience, they should be seen as complimentary, and often combined in a single patient. There is undoubtedly a move away from open surgery, particularly in the septic patient. The complexity and need for a spectrum of interventional options demand that these patients are cared for within an organized multidisciplinary regional team network.
references
1. Ranson JH, Rifkind KM, Roses DF, et al. Objective early identification of severe acute pancreatitis. Am J Gastroenterol 1974; 61(6): 44351. 2. Blamey SL, Imrie CW, ONeill J. Prognostic factors in acute pancreatitis. Gut 1984; 25(12), 13406. 3. Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 1989; 2(8656): 2015. 4. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23(10): 163852. 5. Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology 2002; 223(3): 60313. 6. Buter A, Imrie CW, Carter CR, Evans S, McKay CJ. Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis. Br J Surg 2002; 89(3): 298302.
Figure 47.2
well-organized collection without organ failure, endoscopic cystgastrostomy, with dilatation and limited necrosectomy is potentially the procedure of choice.
448
ACUTE PANCREATITIS
7. Johnson CD, et al. UK guidelines for the management of acute pancreatitis. Gut 2005 May; 54 (Suppl 3): iii19. 8. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute pancreatitis. N Engl J Med 1974; 290(9): 4847. 9. Raraty MGT, Petersen OH, Sutton R, Neoptolemos JP. Intracellular free ionized calcium in the pathogenesis of acute pancreatitis. Baillieres Best Pract Clin Gastroenterol 1999; 13(2): 24151. 10. Imrie CW, McKay CJ. The scientific basis of medical therapy of acute pancreatitis: could it work, and is there a role for lexipafant? Gastroenterol Clin North Am 1999; 28(3): 5919. 11. Neoptolemos JP, London NJ, James D, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988; 2(8618): 97983. 12. Fan S-T, Lai ECS, Mok FPT, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. New Engl J Med 1993; 328(4): 22832. 13. Folsch UR, Nitsche R, Ludtke R, Hilgers RA, Creutzfeldt W. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. New Engl J Med 1997; 336(4): 23742. 14. Petrov MS, van Santvoort HC, Besselink MG, et al. Early endoscopic retrograde cholangiopancreatography versus conservative management in acute biliary pancreatitis without cholangitis: a meta-analysis of randomized trials. Ann Surg 2008; 247(2): 2507. 15. Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993; 176(5): 4803. 16. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet 1995; 346: 6637. 17. Dellinger EP, Tellado, J.M., Soto N.E., et al Early antibiotic treatment for severe acute necrotising pancreatitis: randomised double blind placebo controlled study. Ann Surg 2007; 245(5), 6845. 18. Isenmann R, Runzi M, Kron M, Kahl S, Kraus D, Jung N, et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004; 126(4): 9971004. 19. Bai Y, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials. Am J Gastroenterol 2008; 103(1): 10410. 20. Meir J., Luque-de Leon E, Castillo A, Robledo F, Blanco R. Early versus late necrosectomy in severe necrotising pancreatitis. Am J Surg 1997; 173: 715. 21. Al Bahrani AZ, Abid GH, Holt A, McCloy RF, Benson J, Eddleston J et al. Clinical relevance of intra-abdominal hypertension in patients with severe acute pancreatitis. Pancreas 2008; 36(1): 3943. 22. Zhang WF, Ni YL, Cai L, et al. Intra-abdominal pressure monitoring in predicting outcome of patients with severe acute pancreatitis. Hepatobiliary Pancreat Dis Int 2007; 6(4): 4203. 23. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos, CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg 1997; 84(12): 16659. 24. McClave SA, Greene LM, Snider HL, et al. Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN: J Parenter Enteral Nutr 1997; 21(1): 1420. 25. Nakad A, Piessevaux H, Marot J-C, et al. Is early enteral nutrition in acute pancreatitis dangerous? About 20 patients fed by an endoscopically placed nasogastrojejunal tube. Pancreas 1998; 17(2): 18793. 26. Abou-Assi S, Craig K, OKeefe SJ. Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study. Am J Gastroenterol 2002; 97: 225562. 27. Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol 2005; 100(2): 4329. 28. Eckerwall GE, Axelsson JB, Andersson RG. Early nasogastric feeding in predicted severe acute pancreatitis: a clinical, randomized study. Ann Surg 2006; 244(6): 95965. 29. Kumar A, Singh N, Prakash S, Saraya A, Joshi YK. Early enteral nutrition in severe acute pancreatitis: a prospective randomized controlled trial comparing nasojejunal and nasogastric routes. J Clin Gastroenterol 2006; 40(5): 4314. Windsor ACJ, Li A, Barnes E, et al. Feeding the gut in acute pancreatitis: a randomised trial of enteral vs parenteral nutrition. Br J Surg 1996; 83(Suppl. 1): 31. Windsor ACJ, Kanwar S, Li AGK, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42(3): 4315. Pearce CB, Sadek SA, Walters AM, et al. A double-blind, randomised, controlled trial to study the effects of an enteral feed supplemented with glutamine, arginine, and omega-3 fatty acid in predicted acute severe pancreatitis. JOP 2006; 7(4): 36171. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371(9613): 6519. Imrie CW, McKay AJ, Neill JO. Short duration megadosage IV Trasylol in primary acute pancreatitis a double-blind trial. Gut 1980; 21(5): 4315. Pederzoli P, Cavallini G, Falconi M, Bassi C. Gabexate mesilate vs aprotinin in human acute pancreatitis (GA.ME.P.A.): a prospective, randomized, double-blind multicenter study. Int J Pancreatol 1993; 14(2): 11724. Andriulli A, Leandro G, Clemente R, et al. Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis. Aliment Pharmacol Ther 1998; 12(3): 23745. McKay C, Baxter J, Imrie C. A randomized, controlled trial of octreotide in the management of patients with acute pancreatitis. Int J Pancreatol 1997; 21(1): 139. Uhl W, Buchler MW, Malfertheiner P, et al. A randomised double blind multicentre trial of octreotide in moderate to severe acute pancreatitis. Gut 1999; 45: 97104. McKay CJ, Curran F, Sharples C, Baxter JN, Imrie CW. Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis. British J Surg 1997; 84(9): 123943. Rau B, Pralle U, Mayer JM, Beger HG. Role of ultrasonographically guided fine-needle aspiration cytology in the diagnosis of infected pancreatic necrosis. British J Surg 1998; 85(2): 17984. Carter R. Percutaneous management of necrotizing pancreatitis. HPB (Oxford) 2007; 9(3): 2359. Bradley EL III. A fifteen year experience with open drainage for infected pancreatic necrosis. Surg Gynaecol Obstet 1993; 177: 21522. Rau B, Bothe A, Beger HG. Surgical treatment of necrotizing pancreatitis by necrosectomy and closed lavage: changing patient characteristics and outcome in a 19-year, single-center series. Surgery 2005; 138(1): 2839. Fernandez-Del CC, Rattner DW, Makary MA, et al. Debridement and closed packing for the treatment of necrotizing pancreatitis. Ann Surg 1998; 228(5): 67684. Bradley EL. Operative vs. Nonoperative therapy in necrotizing pancreatitis. Digestion 1999; 60(Suppl 1): 1921. Buchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg 2000; 232(5): 61926. Gotzinger P, Sautner T, Kriwanek S, et al. Surgical treatment for severe acute pancreatitis: extent and surgical control of necrosis determine outcome. World J Surg 2002; 26(4): 4748. Freeny PC, Hauptmann E, Althaus SJ, Traverso LW, Sinanan. Percutaneous CT-guided catheter drainage of infected acute necrotizing pancreatitis: Techniques and results. AJR 1998; 170(4): 96975. Gouzi JL, Bloom E, Julio C, et al. Percutaneous drainage of infected pancreatic necrosis: an alternative to surgery. Chirurgie 1999; 124(1): 317. Baril NB, Ralls PW, Wren SM, et al. Does an infected peripancreatic fluid collection or abscess mandate operation? Ann Surg 2000; 231(3): 3617. Olah A, Belagyi T, Bartek P, Poharnok L, Romics L Jr. Alternative treatment modalities of infected pancreatic necrosis. Hepatogastroenterology 2006; 53(70): 6037. Lee JK, Kwak KK, Park JK, et al. The efficacy of nonsurgical treatment of infected pancreatic necrosis. Pancreas 2007; 34(4): 399404. Bruennler T, Langgartner J, Lang S, et al. Outcome of patients with acute, necrotizing pancreatitis requiring drainage-does drainage size matter? World J Gastroenterol 2008; 14(5): 72530.
30.
31.
32.
33.
34. 35.
36.
37.
38.
39.
40.
44.
45. 46.
47.
48.
52. 53.
449
450
48 Chronic pancreatitis
introduction
Chronic pancreatitis (CP) is a common disorder of the gastrointestinal tract with enormous social and personal impact. The prevalence of CP is 10 to 30 per 100,000 population and it affects about eight new patients per 100,000 population per year in the United States (13). Autopsy series, however, suggest a higher prevalence of 0.04% to 5%. CP is an inflammatory disease characterized by the progressive conversion of pancreatic parenchyma to fibrous tissue. The most frequent causes are excessive alcohol consumption, cholelithiasis, autoimmune or individual genetic predisposition, and anatomic variants such as pancreas divisum. In up to 20% of the patients the reasons or predisposing factors are not identifiable. The peak of presentation of the disease occurs in patients between 35 and 55 years of age (4). Abdominal pain is the main symptom of CP leading to inability to work, early retirement, and addiction to analgesics. Severe pain attacks are the leading causes for hospitalization. The natural course is characterized by a consecutive loss of pancreatic parenchyma by fibrosis leading to exocrine insufficiency with maldigestion and finally in advanced stages endocrine insufficiency. The clinical course and histological morphological changes that characterize the disease are extremely variable. Overall the life expectancy is shortened by 10 to 20 years. The mortality is increased 3.6-fold, as compared with a population without CP (2). The annual treatment costs are approximately $17,000 per patient (2). Due to improvements in the treatment 20% to 50% of the patients live more than 20 years with chronic inflammation of the pancreas (5,6). Besides pain, exocrine and endocrine malfunction, mechanical complications occur such as stricture of the bile duct, duodenal stenosis (7), or the formation of pancreatic pseudocysts. The process of continuing organ destruction cannot be interrupted by abstinence from alcohol consumption, which seems to be the causative agent in most cases. Despite thousands of reports that have been published in the last decades dealing with this disease, pathogenesis and pathophysiology of CP are poorly understood and the clinical course is unpredictable. Therefore adequate treatment of CP and its complications remain a major challenge (8,9).
natural course of cp
In the past the main rationale for conservative approaches derives from the assumption, that most patients with longstanding CP will become pain free due to a progressive burning out of the organ (15). Recently it was shown that the natural course of CP is characterized by progressive loss of pancreatic function by fibrosis of the parenchyma with consecutive endocrine and exocrine insufficiency supplementary to pain (12,16,17). After an initial period without noticeable pain, the disease progresses into the next stage characterized by pain and exocrine, later endocrine insufficiency. In the third stage the burn-out pancreas with global insufficiency is found, and pain might subside. The pancreatic parenchyma is irreversibly converted to fibrous tissue with diabetes and steatorrhea (18). At time of onset of CP 8% of the patient had a at least moderate endocrine insufficiency, whereas in long-term follow-up approximately 80% had endocrine insufficiency (19,20). Studies revealed that it takes 10 to 20 years of a progressive inflammatory process to lead to exocrine insufficiency by destroying the pancreatic parenchyma (21). Ten years after onset of CP, 50% to 93% of the patients with CP were still suffering from abdominal pain (17,2022). At least 50% to 68% of the patients with CP need surgery for management of complications or for intractable pain (5,23). Reduction of alcohol intake did not influence the course of pain in chronic alcoholic pancreatitis, but continued alcohol abuse was associated with significantly lower survival rates (24,25). Patients that quit drinking showed improvement in exocrine function (20,24). Endocrine insufficiency did not alter the course of pain. For the individual patient the course of the disease is unpredictable (20,25).
definition of cp
The classification of CP as a separate disease was described in 1946 by Comfort et al. (10). Before, the term CP has been used for a variety of pancreatic diseases without a generally accepted definition (11,12). Since then, different classifications of CP have been presented. According to the Marseille Classification, CP is characterized by histological changes persisting after the etiologic agent has been removed (13). The Cambridge Classification (1983) defined CP as an
451
and colleagues in 1995 (33). Autoimmune pancreatitis can present with focal event or with multiple lesions. Pseudocysts and calculi are rarely found. Four histological features are characteristic for autoimmune pancreatitis. Lymphoplasmacytic infiltration, consisting of lymphocytes and plasma cells (often with high level of IgG4), macrophages, neutrophils, and eosinophils, result in an intestinal fibrosis (34). Additionally periductal inflammation and periphlebitis can lead to luminal strictures or obliterative venulitis, respectively. Obstructive jaundice is caused by an affection of the common bile duct (CBD) which may extend to the gallbladder and biliary tree. An increased level of IgG4 is a sensitive marker (35). Autoimmune pancreatitis is associated with other autoimmune disorders such as ulcerative colitis, Cohns disease, primary sclerosing cholangitis, Sjrgrens syndrome, lymphocytic thyroiditis, and primary biliary cirrhosis (36). Hereditary CP is a rare form with an incidence of approximate 3.5 to 10 per 100,000 inhabitants (3,37). The morphologic findings in HCP are irregular sclerosis with focal, segmental, or diffuse destruction of the parenchyma. Different mutations have been detected to be associated with hereditary CP, most common R122H, an N291 mutation of the PRSS1 gene, and mutations of the CFTR and SPINK1 gene (36,3840). The risk of developing pancreatic cancer is increased in HCP with PRSS1 mutation as compared with normal population and chronic alcoholic pancreatitis (41,42). Rare reasons for CP besides pancreatic duct obstruction due to tumors, strictures, diverticula, and pathoanatomical variations like pancreas divisum or annular pancreas are trauma and genetic mutation (14). In up to 20% of the patients the reason for CP remains unclear.
pathogenesis of pain in cp
Pain is the cardinal symptom in patients with CP. Together with the often ongoing consumption of alcohol it is most difficultly to treat. The permanent pain reduces the quality of life, leads to addiction of analgesics, and unemployment or early retirement. CP cannot be cured; therefore the aim of treatment is directed against symptoms (e.g. pain) and complications. Pain in CP is still only fragmentarily understood and a multifactorial nature is assumed, including inflammation, duct obstruction, high pancreatic tissue pressure, fibrotic encasement of sensory nerves, and a neuropathy characterized by both increased numbers and sizes of intrapancreatic sensory nerves and by inflammatory injury to the nerve sheaths allowing exposure of the neural elements to toxic substances. The pain is often localized in the upper part of the abdomen and is frequently nocturnal; sometimes it radiates to the back. Development of pain in the course of the disease is seen in 85% of the patients (43). It is described to be deep, penetrating, and debilitating and may increase after eating (44). In the initial stage of the disease the pain is intermittent and recurrent; later it is persistent. The painless pancreatitis is found rarely in alcoholinduced pancreatitis (<10%), while pain-free periods are seen in late-onset idiopathic pancreatitis. Pain pattern and histopathologic/radiologic findings have to be correlated in consideration of therapy especially surgery. Histological picture
452
CHRONIC PANCREATITIS
and diameter of the main pancreatic duct in CT scan, MRI/MRCP, and ERCP are necessary for optimal planning of the operation. Small duct disease requires other procedures compared to obstruction of the main pancreatic duct and inflammatory mass in the pancreatic head. The assessment of pain is very difficult. Most trials in CP use classifications for description of pre- and postoperative pain or outcome, such as excellent (no pain), good (better), fair (nil), poor (worse) (45), therefore no comparison between different trials is possible. Pain relief is more common in patients that quit drinking. The underlying mechanism for pain in CP is poorly understood. Different concepts have been hypothesized, but none of them can completely explain the pain in this disease. Present hypotheses include increased pressure on the ductal system and parenchyma by obstruction, neuritis, ischemia of the pancreatic tissue and intra- and extrapancreatic causes such as pseudocysts and CBDs or duodenal stenosis. The impact of the mentioned factors for the pathogenesis of the pain remains unclear and may vary between the patients. A higher intraductal pressure was measured in patients with CP compared to controls (46). The reason for increased pressure can be postinflammatory scarring of the pancreatic (main and side) ducts, pancreatic duct stones or strictures, or hemosuccus pancreaticus that leads to obstruction. Other reasons are pancreatic abscess, ascites, bile duct stenosis, or duodenal stenosis. The patients that were found to have a reduced intraductal pressure had a better pain relief compared to patients with higher intraductal pressure in the follow-up (46,47). Additionally it had been reported that phenotypic modification of primary sensory neurons may play a role in production of persisting pain (48). Focal release and uptake of mediators in the peptidergic nerves were changed by initial pancreatic inflammation. Previous trials revealed that number and diameter of the pancreatic nerves, as well as activity are significantly increased in CP (49,50). A correlation between pain and expression of growthassociated protein (43) and level of methionineenkephalin was detected (50). It is hypothesized that the increases in pressure facilitate the intox of pain mediators into the nerves and result in a neuritis and therefore causing the pain in CP. Another hypothesis is that pancreatic ischemia is responsible for the pain. The ischemia activates the xanthine oxygenase, leading to the production of toxic oxygen metabolites. An increased level of cytochrome P450 in CP was found in several trials (51,52), but treatment with an inhibitor of the xanthine oxygenase did not reduce the pain. Causal for the development of CBD stenosis is the close anatomical relationship of the distal common to the head of the pancreas; hereby the risk of CBD stricture is increased in patients with enlarged pancreatic head. In patients with CP bile duct stricture is found in 5% to 9% and in up to 35% after surgical procedures for CP (5558). Patients with CBD stricture can present asymptomatic with elevated liver enzymes, alkaline phosphatase, or bilirubin or being septic with cholangitis. In patients with CBD strictures secondary to CP interventional, i.e., surgical therapy is indicated. Ruling out a local malignancy is of greatest importance in patients with duodenal or CBD obstruction. Pancreatic ascites is found in approximately 4% of patients with CP and in 6% to 14% of those with pancreatic pseudocysts and is defined as massive accumulation of pancreatic fluid in the peritoneal cavity. The level of amylase in the ascitic fluid is typically above 1000 IU/L and the ascitic fluid to serum amylase ratio is approximately 6.0 (59,60). In those patients an endoscopic retrograde pancreatography (ERCP) should be performed to localize the site of leakage and to perform endoscopic stenting of the leak (61). Additional treatment with somatostatin or octreotide together with diuretics and repeated paracentesis may be beneficial for some patients (62,63). In patients with persistent or recurrent accumulation of ascites and/or sudden deterioration of clinical status surgery is indicated (64). Pancreaticopleural fistulas, result from a disruption of the pancreatic duct or leakage from a pseudocyst, are rare, but associated with a significant morbidity and mortality (65,66). Three main types of thoracic manifestations include mediastinal pseudocysts, pancreaticopleural fistulas, and pancreaticobronchial fistulas (67,68). Once a pancreaticopleural fistula is suspected, the concentration of amylase in the pleural effusion should be measured. Conservative treatment has an efficacy of 30% to 60%, a recurrence rate of 15%, and a mortality rate of 12% (69). If conservative therapy fails, endoscopic shincterotomy or stenting and surgical procedures should be considered aiming to reduce the hypertension intraductal or within pseudocyst, because the hypertension inhibits the spontaneous closure of fistula. Extrahepatic portal hypertension is a less common complication of CP; it may be confined to either the superior mesenteric or the splenic venous branch or may involve the whole splenomesentericoportal axis (70). It is defined as extrahepatic hypertension of the portal venous system in the absence of liver cirrhosis. The pathogenesis of extrahepatic portal hypertension in CP may include several factors. The inflammatory process is capable of causing initial damage to vascular walls and generating venous spasm, venous stasis, and thrombosis (71). A fibrosis of the pancreas can lead to progressive constriction of the splenomesentericoportal axis. Other reasons are considerable pancreatic head enlargement or compression by pancreatic pseudocysts or inflammatory swelling of the gland (72,73). At present an extrahepatic portal hypertension per se seems not to be an indication for surgical intervention in CP, because there was no evidence of hemorrhage (74) even though a potential risk of esophageal or gastric varices exists (75). Additionally it has to be mentioned that those patients have a
complications of cp
In the course of CP, several complications with less or more life-threatening potential may occur. In 12% of the patients that underwent surgery for CP, duodenal obstruction was detected; additionally it was found to be associated with CBD stenosis (53). Duodenal obstruction can also occur secondarily to pancreatic pseudocysts (54). The patients typically suffer from nausea, vomiting, upper abdominal pain, and weight loss. If duodenal obstruction does not resolve within 1 to 2 weeks of conservative therapy, an irreversible duodenal obstruction should be considered and therefore interventional/ surgical treatment is indicated.
453
454
CHRONIC PANCREATITIS
duodenum or CBD, intractable pain, pseudoaneurysm, or vascular erosion that cannot be controlled by radiological intervention, large pancreatic pseudocysts that cannot be endoscopically controlled, especially in conjunction with ductal pathology, and neither conservatively nor interventionally tractable internal pancreatic fistula (8,9,8789). The indication for surgical interventions in CP has seen its ups and downs over the last decades. Due to optimized surgical procedures, improvements in intensive care and in selection of the patients, the perioperative risk was reduced and the outcome has improved. In preoperative diagnostic it is a major challenge to differentiate a malignant tumor from an inflammatory mass in the pancreatic head (2). For sufficient histopathological examination it is necessary to provide an adequate specimen to exclude malignancy; only resections or limited resections and extended drainage procedures can provide this (8). In approximately 10% of the patients with pancreatic carcinoma even in experienced centers the initial diagnose of malignancy is based on the histological specimen at the time of operation. An optimal surgical intervention should manage the problems and complications of the CP (Fig. 48.1). Additionally it should guarantee a low relapse rate, preserve a maximum of endocrine and exocrine function, and most importantly, restore quality of life (8). A new drainage procedure was described by Puestow and Gillesby in 1956 (98). Decompression of the main pancreatic duct was performed by a longitudinal latero-lateral pancreaticojejunostomy after resection of the pancreatic tail and splenectomy. A modification of the PuestowGillesby procedure, performing a spleen-preserving longitudinal pancreaticojejunostomy without pancreatic tail resection, was introduced by Partington and Rochelle (99). The procedure described by DuVal (96) and Zollinger (97) proved to be effective only if there was a single dominant obstruction between pancreatic tail and the ampulla of Vater. A single dominant stricture is found rarely, especially in chronic alcohol-induced pancreatitis, which is common among the majority of patients in the western hemisphere. It has to be mentioned that recurrent episodes of severe pain were frequently observed even after sufficient drainage of the duct system. For many years the longitudinal pancreaticojejunostomy introduced by PartingtonRochelle was favored in surgical treatment of CP. Even in the presence of multiple strictures (chain of lakes) the main pancreatic duct could be effectively drained. No resection is included in this procedure, therefore it was associated with lower perioperative morbidity and mortality compared to resection procedures. The advantages of simple drainage procedures are the maximal preservation of pancreatic tissue. Performing drainage procedure, ruling out a malignancy, is not possible, because no adequate specimen is available for pathological examination. Pain relief was found in 80% to 90% of the patients with non alcohol-induced CP and only 50% to 60% of the patients with alcohol-induced pancreatitis because the inflammatory mass in the pancreatic head including its strictures as well as the local intraductal hypertension of the ducts of second and third order are left behind (8,91). In the long-term follow-up the failure rate of drainage procedure was found to be up to 45%. The reasons were inadequate duct decompression, biliary stenosis, and most importantly inflammatory mass of the pancreatic head. Studies have shown that drainage procedure can prevent or delay the loss of pancreatic function. The rationale for the wide-spread application of drainage procedures in CP was the considerable morbidity and mortality
Drainage
Cysto(gastro-)jejunostomy Pancreaticojejunostomy (Partington-Rochelle) Drainage and resection of pancreatic tail (Puestow-Mercadier) Left-resection of the pancreas (DuVal) Extended drainage (limited excision of pancreatic head (Frey) Duodenum preserving resection of pancreatic head (Beger) Pylorus-preserving partial duodenopancreatectomy Partial duodenopancreatectomy (Whipple) Pancreatectomy
Resection
Figure 48.1 Surgical armamentarium for the treatment of chronic pancreatitis.
455
456
CHRONIC PANCREATITIS
pylorus-preserving partial pancreatoduodenectomy after longterm follow up (117). A modification of the Beger procedure was presented by Frey in 1985. The Frey procedure (115,116,118) combines a longitudinal pancreaticojejunostomy according to Partington and Rochelle (99) with a local excision of the pancreatic head. It is marked by leaving a rim of pancreatic tissue across the portal vein and superior mesenteric vein (Fig. 48.3). Therefore this operation is easier to learn and perform; additionally only one pancreatojejunostomy is necessary. The drainage of the resection cavity of pancreatic head, body, and tail is performed with a longitudinal pancreatojejunostomy using a Roux-en-Y loop. The Frey procedure can be performed without mortality (<1%) and low morbidity (939%) (7,106,112). In these patients, 56% were free of pain, and 32% had substantial pain relief. The main complications are hemorrhage, pancreatic fistula (05%), and intra-abdominal abscess. After 5 years 78% suffered from exocrine and 60% from endocrine; 44% were professionally rehabilitated. By preserving the duodenum, the physiological gastroduodenal passage and the continuity of the CBD are sustained. Additionally exocrine and endocrine pancreatic functions are preserved and the procedure is able to control complications of adjacent organs such as CBD stenosis, duodenal stenosis, and internal pancreatic fistulas comparable to the Beger procedure (118,119). The Hamburg procedure is a modification of the Frey procedure and was proposed by Izbicki and coworkers. The extent of pancreatic head excision can be modified up to a subtotal excision including the uncinate process combined with a longitudinal V-shaped excision of the ventral aspect of the pancreas into the pancreatic duct (Fig. 48.4). If ductal irregularities are present in the pancreatic body and tail, the operation can be extended as a drainage operation much in the way of a PartingtonRochelle procedure into the pancreatic tail. Therefore the major advantage of this procedure is that the extent of the resection can be customized to the individual morphology of the pancreas (113). In a recently published trial, the mortality and morbidity of the Hamburg procedure were 0% and 19.6%, respectively; 89% of the patients were free of pain in the follow-up; the increase of the body weight was significantly better as compared with classic PPPD (31). The Berne procedure is combining the Frey and Beger procedure (120). A duodenum-preserving resection of the pancreatic head is performed according to the Beger technique. Compared to the Frey procedure the extent of the excision of the pancreatic is much larger and is therefore definitely decompressing the CBD and preventing a potential recurrence. According to the Frey procedure the hazardous dissection is avoided by leaving a small shape of the pancreatic tissue on the anterior wall of the portal vein (120,121). Performing the Berne procedure the mortality was found to be 0% and the morbidity 20% (108).
457
Frey procedure Perioperative mortality Perioperative morbidity 30-mo follow-up VAS Frequency of pain attacks Pain medications Inability to work Pain score 7-yr follow-up VAS Frequency of Pain attacks Pain medications Inability to work Pain score Late mortality Late mortality(chronic pancreatitis associated) Endocrine insufficiency Exocrine insufficiency Reoperation Professional rehabilitation
Source: From Ref. (106,124).
24-month follow-up (n = 61). In terms of morbidity rate the Frey procedure (19%) was superior to PPPD (53%). Additionally the Quality of Life was significantly higher (85.7 vs. 75.1) and the pain score better (6.1 vs. 18.1) after Frey procedure. In the long-term follow-up recently presented by Strate the favorable results still exists, but statistical significance is lost. Additionally no difference was found comparing late mortality, rate of endocrine and exocrine insufficiency, and need of reoperations (106,124) (Table 48.1). The only randomized trial comparing Frey and Beger procedure has been published by Izbicki 1995 (n = 42) (112). The perioperative mortality was 0 in both groups, while the morbidity rate was significantly lower after Frey (9%) compared to 15% after Beger procedure. In the 8-year follow-up published by Strate 2005 the rate of endocrine and exocrine insufficiency and rate of reoperation were comparable in both groups. No significant differences concerning Quality of Life and pain score were found at short-term and long-term follow-up (125) (Table 48.2). Recently a trial comparing Beger versus Berne modification was published (n = 65). The quality of life measured with the EORTC QLQ-PAN 26 was better, while no difference was found using the EORTC QLQ C30. The duration of hospital stay and the mean operating time were significantly shorter in the Berne group. No significant differences were found comparing the rates of reoperation, complications, and need of blood products. It had to be mentioned that the analysis was performed on an intention to treat basis, with 14 of the
65 patients were treated with other operation compared to randomization due to intraoperative findings (108). Short-term results favor the organ sparing operation, and additionally it is the easier operation to perform (easier to learn anyway) (106). In patients with small duct disease (diameter <3 mm), extended resection procedures are suggested (31). Additionally pain, nausea, and fatigue were significantly reduced. In terms of pain relief and quality of life and exocrine and endocrine function no significant differences were detected (7,125).
458
CHRONIC PANCREATITIS
references
1. Lohr JM. What are the useful biological and functional markers of earlystage chronic pancreatitis? J Gastroenterol 2007 January; 42(Suppl 17): 6671. 2. Mayerle J, Lerch MM. Is it necessary to distinguish between alcoholic and nonalcoholic chronic pancreatitis? J Gastroenterol 2007 January; 42(Suppl 17): 12730. 3. Andersen BN, Pedersen NT, Scheel J, Worning H. Incidence of alcoholic chronic pancreatitis in Copenhagen. Scand J Gastroenterol 1982 March; 17(2): 24752. 4. Ammann RW, Mullhaupt B. Do the diagnostic criteria differ between alcoholic and nonalcoholic chronic pancreatitis? J Gastroenterol 2007 January; 42(Suppl 17): 11826. 5. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Gastroenterology 1984; 86: 8208. 6. Thorsgaard PN, Nyboe AB, Pedersen G, Worning H. Chronic pancreatitis in Copenhagen. A retrospective study of 64 consecutive patients. Scand J Gastroenterol 1982 October; 17(7): 92531. 7. Pessaux P, Kianmanesh R, Regimbeau JM, et al. Frey procedure in the treatment of chronic pancreatitis: short-term results. Pancreas 2006 November; 33(4): 3548. 8. Knoefel WT, Eisenberger CF, Strate T, Izbicki JR. Optimizing surgical therapy for chronic pancreatitis. Pancreatology 2002; 2: 37985. 9. Warshaw AL. Pain in chronic pancreatitis patients, patience, and the impatient surgeon. Gastroenterology 1984; 86: 9879. 10. Kloppel G. Toward a new classification of chronic pancreatitis. J Gastroenterol 2007 January; 42(Suppl 17): 557. 11. Ammann RW. A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. Pancreas 1997; 14: 21521. 12. Strate T, Knoefel WT, Yekebas E, Izbicki JR. Chronic pancreatitis: etiology, pathogenesis, diagnosis, and treatment. Int J Colorectal Dis 2003 March; 18(2): 97106. 13. Banks PA. Classification and diagnosis of chronic pancreatitis. J Gastroenterol 2007 January; 42(Suppl 17): 14851. 14. Ammann RW. Diagnosis and management of chronic pancreatitis: current knowledge. Swiss Med Wkly 2006 March 18; 136(1112): 16674. 15. Ammann RW, Akovbiantz A, Largiader F. Pain relief in chronic pancreatitis with and without surgery. Gastroenterology 1984; 87: 74677. 16. Adler DG, Lichtenstein D, Baron TH, et al. The role of endoscopy in patients with chronic pancreatitis. Gastrointest Endosc 2006; 63(7): 9337. 17. Strate T, Yekebas E, Knoefel WT, Bloechle C, Izbicki JR. Pathogenesis and the natural course of chronic pancreatitis. Eur J Gastroenterol Hepatol 2002; 14: 92934. 18. Chari ST. Chronic pancreatitis: classification, relationship to acute pancreatitis, and early diagnosis. J Gastroenterol 2007 January; 42(Suppl 17): 589. 19. Malka D, Hammel P, Sauvanet A, et al. Risk factors for diabetes mellitus in chronic pancreatitis. Gastroenterology 2000; 119: 132432. 20. Lankisch PG, Happe-Loehr A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digest 1993; 54: 14855. 21. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different course of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107: 14817. 22. Ammann RW, Buehler H, Muench R, Freiburghaus AW, Siegenthaler W. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas 1987; 2(4): 36877. 23. Levy P, Milan C, Pignon JP, Baetz A, Bernades P. Mortality factors associated with chronic pancreatitis. Unidimensional and multidimensional analysis of a medical-surgical series of 240 patients. Gastroenterology 1989; 96: 116572. 24. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medicalsurgical series of 245 patients. Gastroenterology 1984; 86: 82088. 25. Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001; 1: 314.
If the pancreatitis is accompanied by an enlarged pancreatic head a pancreatic head resection should be performed.
salvage procedures
Due to improvement of surgical technique and selection of patients, pancreatic surgery for CP yields excellent results. In some cases recurrence develops; most frequently in the remnant of the pancreatic head indicating either insufficient surgical resection of the head of the pancreas or aggressive disease. In these patients re-do pancreas head resections are indicated. The procedures that should be considered are the partial pancreatoduodenectomy (Whipple procedure, PPPD) and in selected patients (i.e. re-recurrence) even total splenopancreatoduodenectomy. This procedure is indicated in patients that underwent partial pancreatoduodenectomy, and additional interventional nerve blocks or surgical denervation fail to achieve definitive pain relief. In patients that previously underwent duodenum-preserving resection of the pancreatic head or partial pancreatoduodenectomy with recurrence of the CP in the body or tail a V-shape drainage procedure is indicated.
conclusion
The aim of treatment of CP is mainly pain relief and improvement in the quality of life, which still poses a major challenge today. Duodenum-preserving pancreatic head resection is the ideal procedure for treatment of CP. If ductal pathology is present in the pancreatic body or tail the procedure can be combined with longitudinal duct drainage in various degrees which allows a tailored concept. Duodenum-preserving resections of the pancreas combine high safety with high efficacy and offer the best short-term outcome, while the long-term results of PPPD are comparable. In small duct pancreatitis (duct diameter <3 mm), a V-shape excision is the therapy of choice. Pancreatic surgery bears many pitfalls and potential complications and is technically demanding. It should be left to experts in high-volume hospitals in order to minimize mortality and morbidity.
459
53.
54.
55.
56.
60. 61.
62. 63.
64.
65.
66.
67.
68.
69.
70. 71.
72.
73.
74.
75.
460
CHRONIC PANCREATITIS
76. Warshaw AL, Jin GL, Ottinger LW. Recognition and clinical implications of mesenteric and portal vein obstruction in chronic pancreatitis. Arch Surg 1987; 122: 41045. 77. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic therapy. A randomised controlled trial. Gut 2007 Apr; 56(4): 54552. 78. Martin RF, Hanson BL, Bosco JJ, et al. Combined modality treatment of symptomatic pancreatic ductal lithiasis. Arch Surg 1995; 130(4): 3759. 79. Buscaglia JM, Kalloo AN. Pancreatic sphincterotomy: technique, indications, and complications. World J Gastroenterol 2007; 13(30): 406471. 80. Weber A, Schneider J, Neu B, et al. Endoscopic stent therapy for patients with chronic pancreatitis: results from a prospective follow-up study. Pancreas 2007; 34(3): 28794. 81. Heyries L, Sahel J. Endoscopic treatment of chronic pancreatitis. World J Gastroenterol 2007; 13(46): 612733. 82. Eleftherladis N, Dinu F, Delhaye M, et al. Long-term outcome after pancreatic stenting in severe chronic pancreatitis. Endoscopy 2005; 37(3): 22330. 83. Born P, Rosch T, Bruhl K, et al. Long-term results of endoscopic treatment of biliary duct obstruction due to pancreatic disease. Hepatogastroenterology 1998; 45(21): 8339. 84. Kahl S, Zimmermann S, Genz I, et al. Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study. Am J Gastroenterol 2003; 98(11): 244853. 85. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007; 356(7): 67684. 86. Dite P, Ruzicka M, Zboril V, Novotny I. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endosc 2003; 35(7): 5538. 87. Lankisch PG, Andren-Sandberg A. Standards for the diagnosis of chronic pancreatitis and for the evaluation of treatment. Int J Pancreatol 1993; 14: 20512. 88. Frey CF, Suzuki M, Isaji S. Treatment of chronic pancreatitis complicated by obstruction of the common bile duct or duodenum. World J Surg 1990; 14: 5969. 89. Saeger HD, Schwall G, Trede M. Standard Whipple in chronic pancreatitis. In: Beger HG, Buechler M, Malfertheimer P, eds. Standards in Pancreatic Surgery, 1st edn. Berlin: Springer, 1993, 38591. 90. Frey CF. Why and when to drain the pancreatic ductal system. In: Beger HG, Buechler MW, Ditschuneit H, Malfertheiner P, eds. Chronic Pancreatitis. Berlin: Springer, 1990, 41525. 91. Markowitz JS, Rattner DW, Warshaw AL. Failure of symptomatic relief after pancreaticojejunal decompression for chronic pancreatitis. Strategies for salvage. Arch Surg 1994; 129: 3749. 92. Gould AP. Pancreatic calculi: transactions of the Clinical Society of London. Lancet 1898; 2: 1532. 93. Moynihan SB. Pancreatic calculus. Lancet 1902; 4: 335. 94. Coffey R. Pancreaticojejunostomy and pancreatectomy. Ann Surg 1909; 50: 123864. 95. Link G. Treatment of chronic pancreatitis by pancreatectomy. Ann Surg 1911; 53: 76882. 96. DuVal MK. Caudal pancreatico-jejunostomy for chronic relapsing pancreatitis. Ann Surg 1954; 140: 77585. 97. Zollinger RM, Keith LM, Ellison EH. Pancreatitis. N Engl J Med 1954; 251: 497502. 98. Puestow CB, Gillesby WJ. Petrograde surgical drainage of pancreas for chronic pancreatitis. Arch Surg 1958; 76: 898906. 99. Partington PF, Rochelle REL. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960; 152: 103743. 100. Izbicki JR, Bloechle C, Knoefel WT, Rogiers X, Kuechler T. Surgical treatment of chronic pancreatitis and quality of life after operation. Surg Clin North Am 1999; 79: 91344. 101. Traverso LW, Tompkins RK, Urrea PT, Longmire WP, Jr. Surgical treatment of chronic pancreatitis. Twenty-two years experience. Ann Surg 1979 September; 190(3): 31219. 102. Beger HG, Buechler M. Duodenum preserving resection of the head of the pancreas in chronic pancreatitis with inflammatory mass in the head. World J Surg 1990; 14: 837. 103. Buechler M, Friess H, Isenmann R, Bittner R, Beger HG. Duodenumpreserving resection of the head of the pancreas: the Ulm experience. In: Beger HG, Buechler M, Malfertheimer P, eds. Standards in Pancreatic Surgery, 1st edn. Berlin: Springer, 1993, 43649. 104. Mobius C, Max D, Uhlmann D, et al. Five-year follow-up of a prospective non-randomised study comparing duodenum-preserving pancreatic head resection with classic Whipple procedure in the treatment of chronic pancreatitis. Langenbecks Arch Surg 2007; 392(3): 35964. 105. Schnelldorfer T, Lewin DN, Adams DB. Reoperative surgery for chronic pancreatitis: is it safe? World J Surg 2006; 30(7): 13218. 106. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic pancreatitis Prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus preserving pancreatoduodenectomy. Ann Surg 1998; 228: 7719. 107. Beger HG, Witte C, Krautzberger W, Bittner R. Experiences with duodenum-sparing pancreas head resection in chronic pancreatitis. Chirurg 1980; 51: 3037. 108. Koninger J, Seiler CM, Sauerland S, et al. Duodenum-preserving pancreatic head resectiona randomized controlled trial comparing the original Beger procedure with the Berne modification (ISRCTN No. 50638764). Surgery 2008; 143(4): 4908. 109. Izbicki JR, Bloechle C, Knoefel WT, et al. Complications of adjacent organs in chronic pancreatitis managed by duodenum-preserving resection of the head of the pancreas. Br J Surg 1994; 81(9): 13515. 110. Wilker DK, Izbicki JR, Knoefel WT, Geissler K, Schweiberer L. Duodenum-preserving resection of the head of the pancreas in treatment of chronic pancreatitis. Am J Gastroenterol 1990; 85(8): 10004. 111. Buechler MW, Friess H, Bittner R, et al. Duodenum-preserving pancreatic head resection: long-term results. J Gastrointest Surg 1997; 1: 139. 112. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum preserving resections of the head of the pancreas in chronic pancreatitis a prospective randomized trial. Ann Surg 1995; 221: 3508. 113. Izbicki JR, Bloechle C, Broering DC, Kuechler T, Broelsch CE. Longitudinal V-shaped excision of the ventral pancreas for small duct disease in severe chronic pancreatitis. Ann Surg 1998; 227: 21319. 114. Izbicki JR, Bloechle C, Knoefel WT, et al. Drainage versus Resektion in der chirurgischen Therapie der chronischen Kopfpankreatitis: eine randomisierte Studie. Chirurg 1997; 68: 36977. 115. Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg 1994; 220: 492507. 116. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987; 2: 7017. 117. Muller MW, Friess H, Martin DJ. Long-term follow-up of a randomized clinical trial comparing Beger with pylorus-preserving Whipple procedure for chronic pancreatitis. Br J Surg 2008 Mar; 95(3): 3506 118. Beger HG, Krautzberger W, Bittner R, Bchler M, Limmer J. Duodenumpreserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery 1985; 97: 46773. 119. Beger HG, Buechler M, Bittner R, Oettinger W, Roscher R. Duodenumpreserving resection of the head of the pancreas in severe chronic pancreatitis. Ann Surg 1989; 209: 2738. 120. Gloor B, Friess H, Uhl W, Buchler MW. A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg 2001; 18: 215. 121. Koninger J, Friess H, Muller M, et al. Duodenum-preserving pancreas head resection-an operative technique for retaining the organ in the treatment of chronic pancreatitis. Chirurg 2004; 75(8): 7818. 122. Muller MW, Friess H, Martin DJ, et al. Long-term follow-up of a randomized clinical trial comparing Beger with pylorus-preserving Whipple procedure for chronic pancreatitis. Br J Surg 2008; 95(3): 3506. 123. Farkas G, Leindler L, Daroczi M, Farkas G, Jr. Prospective randomised comparison of organ-preserving pancreatic head resection with pyloruspreserving pancreaticoduodenectomy. Langenbecks Arch Surg 2006; 391(4): 33842.
461
462
49 Pancreatic injury
history
The first reported case of pancreatic injury was discovered at an autopsy in 1827, in a woman who was hit and killed by a stagecoach (1). The first documented posttraumatic pancreatic fistula was published in 1905 (2). In 1904, Garre operated successfully on a patient with a transected pancreas (3). Advances over the next few decades led to significant improvements in the diagnosis and management of pancreatic injuries.
epidemiology
Pancreatic trauma remains fairly uncommon. The overall incidence in blunt trauma is reported to be 0.2% and in penetrating trauma about 1% (49). However, it is likely that some injuries, especially after blunt trauma may remain undiagnosed. Penetrating trauma accounts for the majority of injuries (7080%), with gunshot wounds being the most common mechanism (72%) (8). The location of the injury is evenly distributed among the head/neck and body of the pancreas (about 40% each), with the tail being less frequently injured (about 20%) (8,10). Because of the retroperitoneal location of the pancreas, significant force is mandated to lead to its injury. This fact, in combination with the proximity of the pancreas to vital structures, makes isolated pancreatic injuries rare. Overall, about 60% of patients with blunt trauma and about 90% with penetrating trauma have associated intra-abdominal injuries (7,1115). Pancreatic trauma should be considered as a marker of other intra-abdominal injuries. The most commonly associated injuries in blunt trauma are of the spleen (34%), liver (26%), and duodenum (6%). In penetrating trauma, first is the stomach (53%), followed by the liver (51%) (7). Associated intra-abdominal vascular injuries are of major concern since they are the most common cause of early mortality. More than 75% of penetrating injuries to the head of the pancreas are associated with a major vascular injury (8).
injury grading
There are numerous classification systems for pancreatic injuries. The most widely accepted grading system is the one proposed by the Organ Injury Scaling Committee of the American Association for the Surgery of Trauma (OIS-AAST) in 1990 (Table 49.1) (16). This classification scheme takes into account the type of injury (hematoma or laceration), the presence or absence of structural duct involvement, and the location of pancreatic injury (proximal or distal to superior mesenteric vein). OIS-AAST grades I and II are considered as low-grade and grades IIIV as high-grade pancreatic injuries (17). The classification may be based on computed tomography (CT) and intraoperative or autopsy findings. It is useful in the evaluation and management of patients with pancreatic injuries, and it is an excellent research tool for the comparison of the safety and efficacy of the various therapeutic approaches (15).
463
II
Table 49.2 Sensitivity and Specificity of the Diagnostic Adjunctive and Level of Evidence
Sensitivity (%) Amylase levels CT MRCP ERCP 4889 80 >95 >95 Specificity (%) 6481 80 >95 >95 Level of evidence (references) III (2024) III (10,3133) IIIIV (3739) IIIIV (40,41)
Figure 49.2 MRCP with detection of a pancreatic duct disruption (white arrow).
technique for the evaluation of pancreatic injuries and ductal status (Fig. 49.2). MRCP is diagnostic in 95% to 99% of cases of pancreatic ductal injuries, and complete visualization of normal-sized pancreatic ducts occurs in 97% of the patients (3739) (Table 49.2). Secretin administration may improve ductal visualization (39). However, MRCP is applicable only in those patients who are hemodynamically stable and have minimal other injuries and does not permit therapeutic intervention, such as stent placement. Endoscopic retrograde pancreatography (ERCP) is the gold standard in the evaluation of the pancreatic duct and may also have therapeutic application by placement of a stent over a ductal injury (4043). The procedure should be performed as early as possible, preferably within 12 to 24 hours of injury, to prevent abdominal septic complications (44). ERCP is often not available in an emergency setting and requires hemodynamic stability. The procedure may cause pancreatitis and the long-term results of stenting are still not well known (45,46). Intraoperative Exposure and Evaluation Many patients with pancreatic injury present with peritonitis or hemodynamic instability, requiring immediate abdominal exploration, before any preoperative diagnostic evaluation. A midline incision is the preferred approach in trauma because it provides an optimal exposure for the evaluation of other associated injuries. The pancreas is explored only after control of any bleeding and contamination due to a hollow viscus injury. A pancreatic injury should be suspected by the presence of lesser sac fluid collection, retroperitoneal bile staining, retroperitoneal hematoma, and fat necrosis of the omentum and retroperitoneum (47). Most of the pancreas can be visualized by opening the lesser sac. This maneuver can be easily and rapidly done by dividing
Figure 49.1 Grade IV pancreatic injury (white circle) and concomitant grade IV liver injury after blunt abdominal trauma.
to be around 80%, and the positive predictive value ranges from 80% to 100% (10,3133) (Table 49.2). The study tends to underestimate the severity of pancreatic injury (34). With the introduction of multidetector CT and improved techniques, the diagnostic accuracy is likely to improve (35,36). The sensitivity of detecting ductal injury with multidetector CT has been measured in a single study at 91% (32). However, to further assess the integrity of the pancreatic duct, additional investigations may be needed. Magnetic resonance imaging (MRI) with cholangiopancreatography (MRCP) is a noninvasive, alternative imaging
464
PANCREATIC INJURY
(A)
(B)
Figure 49.3 (A,B) Opening of the lesser sac allows exposure and evalutaion of the anterior surface of the body and tail of the pancreas. Kocher maneuver allows evaluation of the pancreatic head. Source : From Ref. 83.
the gastrocolic ligament between the stomach and the transverse colon. This maneuver exposes the anterior, inferior, and superior surfaces of the body and tail of the pancreas (Fig. 49.3A). Any attachments between the pancreas and the posterior wall of the stomach are divided. Exploration of the posterior portion of the pancreas can be performed by an incision in the peritoneum on the inferior border of the pancreas in the region of suspected injury. The avascular nature of the retropancreatic plane allows the index finger to be carefully slipped behind the pancreas where a laceration can often be felt. Improved access to the posterior portion of the body and tail can be achieved by dissecting the splenocolic, splenophrenic, and splenorenal ligament. The plane anterior to the kidneys usually can be developed with careful blunt dissection (48). To assess the head and uncinate process of the pancreas and the integrity of the duodenum and the bile duct, an extended Kocher maneuver should be performed. This includes the mobilization of the second and third portion of the duodenum, pancreatic head, and distal common bile duct from their retroperitoneal position. This procedure allows inspection and bimanual palpation of the anterior and posterior surfaces of the head and uncinate process (Fig. 49.3B). Intraoperative Evaluation of the Integrity of the Pancreatic Duct The major determinant of morbidity and mortality related to pancreatic trauma is the integrity of the main pancreatic duct (4951). Most trauma patients have normal-sized pancreatic ducts, which can be difficult to visualize. The use of magnifying glasses and administration of secretin may facilitate visualization of the duct. Several radiological and endoscopic methods of intraoperative pancreatography have been described (5256), but are rarely used in trauma. If there is a low probability of ductal injury or the patient is hemodynamically unstable, simple drainage of the peripancreatic space is the most appropriate
Figure 49.4 Duodenotomy and catheterization of the ampulla of Vater for intraoperative pancreatography. Source : From Ref. 83.
approach. Postoperative evaluation by means of CT or MRCP may be considered in patients with persistent elevation of the serum amylase or pancreatic leaks. Intraoperative pancreatography may be considered in selected stable patients with suspicious pancreatic head ductal injury. It can be performed by injecting contrast medium into the gallbladder after clamping the proximal common bile duct. The administration of morphine to cause contraction of the sphincter of Oddi may aid in visualizing the pancreatic duct. In about 10% of subjects, the common bile duct and pancreatic duct drain separately, and the pancreatic duct is not visible with this technique. However, the images obtained may be useful in assessing the intrapancreatic portion of the common bile duct and the integrity of the ampulla of Vater (57). If the duodenum is already open, the ampulla of Vater may be cannulated directly (Fig. 49.4). Identification of the ampulla of Vater can be difficult, especially in the presence of edema or hematoma, and magnifying glasses are strongly recommended in order to identify this structure. The major duct is cannulated
465
management
The rarity of these injuries precludes the development of evidence-based guidelines. Expert opinions and small series reports (levels III and IV evidence) constitute the major source of the knowledge gained throughout the years. Nonoperative Management (NOM) Selective NOM might have a place in the management of carefully selected patients with blunt abdominal trauma. Only hemodynamically stable patients without evidence of peritonitis are potential candidates for NOM. Experience of NOM in pediatric population showed that this approach is safe and effective. Keller et al. (58) in a National Pediatric Trauma Registry study reviewed 154 pancreatic injuries in children, 80% with low-grade and 20% with high-grade injuries. NOM was successful in about half of high-grade injuries and about 80% of low-grade injuries. The frequency of NOM increased significantly over the last year of the study. However, pediatric pancreatic trauma is different from adult trauma because of the much lower risk of pancreatic duct injury in children (less than 1% in children, about 15% in adults). Subsequent experience in adult blunt trauma patients confirmed the safety of this approach (5862). In a recent study there were no failures of NOM in grade I and 17.3% failure in grade II pancreatic injuries (61). In summary, NOM is safe for low grade injuries and may be acceptable in selected high-grade injuries. Early evaluation by means of ERCP or MRCP helps to visualize the integrity of the pancreatic duct. In addition ERCP might be used for stent placement, which can be an excellent adjunctive tool to NOM (63). The downside to NOM is the development of a pseudocyst or fistulae and occasionally severe pancreatitis (64). Most of these complications are treatable by percutanous CT-guided drainage. There is no evidence that the use of somatostatin analogs, such as octreotide, increases the success rate of NOM, although they might have a role in the treatment of posttraumatic pancreatic fistulae (65). Operative Management The surgical treatment plan of pancreatic injury should be determined by the overall condition of the patient, the grade and location of pancreatic injury, the concomitant injuries, and the experience of the surgeon. The strengths of management recommendations for pancreatic trauma are all of level C or D.
Figure 49.5 Anastomosis of the distal pancreatic stump to a Roux-en-Y jejunal loop. Source : From Ref. 83.
Low-grade injuries discovered intraoperatively are best managed with sparse debridement of nonviable tissue, hemostasis, and wide external drainage with closed suction drains. Although some authors advocate repair of the pancreatic capsule (66), this may lead to further parenchymal damage and pseudocyst formation and should only be done to control bleeding. Application of topical hemostatics on the pancreatic laceration may facilitate hemostasis and reduce the risk of postoperative leaks. When dealing with high-grade injuries (AAST-OIS grades III, IV, and V), the choice of procedure depends on the general condition of the patient and the location of duct injury, i.e., in the head, neck, or tail of the pancreas. Distal ductal injuries (AAST-OIS grade III) are best treated by distal pancreatectomy (67,68) often en bloc with the spleen. Spleen-preserving distal pancreatectomy should be considered in hemodynamically stable patients especially in children (6972). Splenic preservation is technically more challenging and may result in increased blood loss. After completion of the distal pancreatectomy, the main pancreatic duct is identified if possible and is suture-ligated with nonabsorbable suture. With the main duct ligated, the proximal parenchyma should be closed with a mattress sutures or a TA stapling device. Extensive pancreatic resection to the right side of the superior mesenteric vessels may lead to diabetes or exocrine insufficiency. In these cases, the distal pancreas may be preserved and anastomosed to a Roux-en-Y jejunal loop (Fig. 49.5). Closed suction drains should be placed around the remaining pancreas and left upper quadrant if the spleen has been removed.
466
PANCREATIC INJURY
Proximal ductal injuries and injuries to the head of the pancreas (AAST-OIS grade IV) are more challenging. In the presence of hemodynamic instability or major associated injuries, or if the surgeon has no experience with complex pancreatic surgery, no attempts should be made to evaluate the integrity of the duct or perform major resections. In these cases, the safest option is hemostasis and liberal external drainage (50,68). Damage control with packing and temporary abdominal closure may be necessary. In destructive injuries to the head of the pancreas or the duodenum, a pancreaticoduodenectomy may be necessary. It should only be performed as a primary procedure in hemodynamically stable patients by an experienced surgeon. In severely compromised patients the surgeon should opt for damage control and a two-stage procedure (7375). Primarily, damage control surgery should be performed to control the hemorrhage and any intestinal spillage. Major associated vascular injuries may be managed by ligation or temporary arterial shunts reinforced by abdominal packing. Complex gastrointestinal injuries may be stapled off and the common bile duct exteriorly drained. The abdominal wall is temporarily closed and the patient is transferred to the intensive care unit for stabilization. The definitive Whipples procedure should be deferred for 24 to 48 hours after restoration of the hemodynamic status, coagulability, and normalization of body temperature. The reconstruction, including pancreatico-jejunostomy or pancreatico-gastrostomy (76,77), choledochojejunostomy, and gastro-enterostomy, is similar to that in elective cases. Insertion of a jejunal feeding tube beyond the ligament of Treitz is strongly recommended to allow feeding in prolonged complicated cases. Overall, pancreaticoduodenectomy is rarely indicated in trauma. In a review at our center over 7.5 years, only 16 of 214 (7.4%) patients with pancreatic injuries required pancreaticoduodenectomy (73).
outcomes
Mortality Many patients with pancreatic injury die from associated exsanguinating injuries. The overall pancreas-related mortality is lower than 1% and is usually the result of sepsis and organ failure. In pancreatico-duodenal resection the overall mortality is about 30% to 40% (7,73). Complications Pancreas-related local complications occur in about 25% of patients. The complication rate depends on the severity of pancreatic injury and associated injuries. The most common complications include pancreatic fistulae, peripancreatic fluid collection, local sepsis, pseudocysts, and pancreatitis. Most of these complications can successfully be managed non-operatively, either expectantly or with percutaneous drainage or endoscopic stenting of the duct. Pancreatic Leaks and Fistulae Early pancreatic leaks are the most common complications after surgery for pancreatic trauma and occur in 10% to 35% of patients (7,78). The amylase levels of this fluid should be determined to confirm the pancreatic origin. The prognosis is excellent and the vast majority close spontaneously within days or
weeks (79). Administration of a somatostatin analog may accelerate the resolution of the pancreatic leaks (65). The role of prophylactic use of somatostatin following pancreatic trauma is controversial and there is no evidence to support its routine use. Routine parenteral nutrition is not necessary in this group of patients. Many of them tolerate oral or intestinal tube feeding well, without any significant increase of the drain output. Parenteral nutrition should only be considered in cases where enteral feeding is associated with an increase of the output. No invasive diagnostic procedures, such as ERCP, should be considered during the early postoperative period, because of the high rate of spontaneous healing. Specific investigations should be considered only after persistently high output which shows no evidence of improvement. An MRCP might delineate the anatomy of the pancreatic duct and select those patients who might benefit from ERCP duct stenting. The long-term experience with stenting of posttraumatic leaks is still limited but encouraging. Previous case series found a high incidence of long-term ductal stricture and therefore concluded that the role of pancreatic duct stenting remains uncertain (46). Other investigators however, have reported successful stent placement, even in complicated cases (8082). Peripancreatic Fluid Collection and Pseudocysts These complications are fairly common and may occur with either operative or non-operative management of pancreatic injuries. They are usually diagnosed during CT scan evaluation of the abdomen (Fig. 49.6). The nature of the fluid collection varies and it can be residual bleeding, serosanguinous fluid, pancreatic exudate, or true pancreatic juice. The natural history of truly pancreatic collections depends on the integrity of the main pancreatic duct. If the main duct is intact, the majority of these collections resolve spontaneously without any intervention. If the main duct is injured, the collection may persist and evolve to a pancreatic pseudocyst. Asymptomatic patients with small peripancreatic collections should be managed expectantly. Symptomatic patients, or those with large collections, may require CT-guided percutaneous drainage. If external drainage fails, as shown by persistently high drain output without any signs of improvement, an
467
summary
Pancreatic injuries remain fairly uncommon with penetrating trauma accounting for most cases. The diagnosis of isolated pancreatic injury due to blunt trauma may be missed on the initial evaluation and this delay increases morbidity and mortality. The diagnosis in these cases can be made timely by a high index of suspicion, serial clinical examinations, serial amylase levels, and repeat CT scan evaluation. All penetrating injuries to the pancreas require surgical interventions but a significant number of isolated injuries due to blunt trauma can safely be managed non-operatively, provided that the main pancreatic duct is intact and the patient is hemodynamically stable and has no signs of peritonitis. The type of operative management of the pancreatic injury depends on the severity and site of the injury, associated injuries, hemodynamic condition of the patient, and the experience of the surgeon. The majority of injuries can be managed by hemostasis and closed suction drainage. Distal injuries are best managed by distal pancreatectomy, with or without splenic preservation. Proximal injuries may be managed with hemostasis and drainage or extended distal pancreatectomy. In many pancreatic head injuries, if the duodenum is not severely damaged, hemostasis and external drainage may be sufficient. Pancreaticoduodenectomy is very rarely indicated and should be reserved only for destructive injuries to the head of pancreas or the duodenum. Damage control procedures should be considered in hemodynamically unstable, coagulopathic patients. Pancreas-related complications are common after severe trauma but they can usually be managed successfully with non-operative methods.
references
1. Travers B. Rupture of the pancreas. Lancet. 1827; 12: 384. 2. Korte W. The Pancreas: Its Surgery and Pathology. Philadelphia: Saunders, 1907. 3. Garre C. Totaler Querriss des Pankreas durch Naht geheilt. Beit Clin Chir 1904; 46: 233. 4. Wind P, Tiret E, Cunningham C, et al. Contribution of endoscopic retrograde pancreatography in management of complications following distal pancreatic trauma. Am Surg 1999 Aug; 65(8): 77783.
468
PANCREATIC INJURY
33. Ilahi O, Bochicchio GV, Scalea TM. Efficacy of computed tomography in the diagnosis of pancreatic injury in adult blunt trauma patients: a singleinstitutional study. Am Surg 2002 Aug; 68(8): 7047; discussion 78. 34. Akhrass R, Kim K, Brandt C. Computed tomography: an unreliable indicator of pancreatic trauma. Am Surg 1996 Aug; 62(8): 64751. 35. Shanmuganathan K. Multi-detector row CT imaging of blunt abdominal trauma. Semin Ultrasound CT MR 2004 Apr; 25(2): 180204. 36. Mullinix AJ, Foley WD. Multidetector computed tomography and blunt thoracoabdominal trauma. J Comput Assist Tomogr 2004 JulAug; 28(Suppl 1): S207. 37. Fulcher AS, Turner MA, Yelon JA, et al. Magnetic resonance cholangiopancreatography (MRCP) in the assessment of pancreatic duct trauma and its sequelae: preliminary findings. J Trauma 2000 Jun; 48(6): 10017. 38. Nirula R, Velmahos GC, Demetriades D. Magnetic resonance cholangiopancreatography in pancreatic trauma: a new diagnostic modality? J Trauma 1999 Sep; 47(3): 5857. 39. Ragozzino A, Manfredi R, Scaglione M, et al. The use of MRCP in the detection of pancreatic injuries after blunt trauma. Emerg Radiol 2003 Apr; 10(1): 148. 40. Hata M, Murao Y, Konobu T, Okuchi K, Nakajima Y. Laparoscopic treatment for peripheral pancreatic duct injury after blunt abdominal trauma: report of a case. Surg Today 2002; 32(7): 65962. 41. Wolf A, Bernhardt J, Patrzyk M, Heidecke CD. The value of endoscopic diagnosis and the treatment of pancreas injuries following blunt abdominal trauma. Surg Endosc 2005 May; 19(5): 6659. 42. Varadarajulu S, Noone TC, Tutuian R, Hawes RH, Cotton PB. Predictors of outcome in pancreatic duct disruption managed by endoscopic transpapillary stent placement. Gastrointest Endosc 2005 Apr; 61(4): 56875. 43. Telford JJ, Farrell JJ, Saltzman JR, et al. Pancreatic stent placement for duct disruption. Gastrointest Endosc 2002 Jul; 56(1): 1824. 44. Degiannis E, Glapa M, Loukogeorgakis SP, Smith MD. Management of pancreatic trauma. Injury 2008 Jan; 39(1): 219. 45. Harrell DJ, Vitale GC, Larson GM. Selective role for endoscopic retrograde cholangiopancreatography in abdominal trauma. Surg Endosc 1998 May; 12(5): 4004. 46. Lin BC, Liu NJ, Fang JF, Kao YC. Long-term results of endoscopic stent in the management of blunt major pancreatic duct injury. Surg Endosc 2006 Oct; 20(10): 15515. 47. Olah A, Issekutz A, Haulik L, Makay R. Pancreatic transection from blunt abdominal trauma: early versus delayed diagnosis and surgical management. Dig Surg 2003; 20(5): 40814. 48. Aird I, Helman P. Bilateral anterior transabdominal adrenalectomy. Br Med J 1955 Sep 17; 2(4941): 7089. 49. Cogbill TH, Moore EE, Kashuk JL. Changing trends in the management of pancreatic trauma. Arch Surg 1982 May; 117(5): 7228. 50. Degiannis E, Levy RD, Velmahos GC, et al. Gunshot injuries of the head of the pancreas: conservative approach. World J Surg 1996 Jan; 20(1): 6871; discussion 2. 51. Lewis G, Krige JE, Bornman PC, Terblanche J. Traumatic pancreatic pseudocysts. Br J Surg 1993 Jan; 80(1): 8993. 52. Barkin JS, Ferstenberg RM, Panullo W, Manten HD, Davis RC Jr. Endoscopic retrograde cholangiopancreatography in pancreatic trauma. Gastrointest Endosc 1988 MarApr; 34(2): 1025. 53. Beckingham IJ, Krige JE, Bornman PC, Terblanche J. Long term outcome of endoscopic drainage of pancreatic pseudocysts. Am J Gastroenterol 1999 Jan; 94(1): 714. 54. Berni GA, Bandyk DF, Oreskovich MR, Carrico CJ. Role of intraoperative pancreatography in patients with injury to the pancreas. Am J Surg 1982 May; 143(5): 6025. 55. Hayward SR, Lucas CE, Sugawa C, Ledgerwood AM. Emergent endoscopic retrograde cholangiopancreatography. A highly specific test for acute pancreatic trauma. Arch Surg 1989 Jun; 124(6): 7456. 56. Wisner DH, Wold RL, Frey CF. Diagnosis and treatment of pancreatic injuries. An analysis of management principles. Arch Surg 1990 Sep; 125(9): 110913. 57. Bornman PC, Krige JE. Management strategies in pancreatic trauma. Johannesburg: University of the Witwatersrand Press, 2006. 58. Keller MS, Stafford PW, Vane DW. Conservative management of pancreatic trauma in children. J Trauma 1997 Jun; 42(6): 1097100. 59. Holmes JHt, Wiebe DJ, Tataria M, et al. The failure of nonoperative management in pediatric solid organ injury: a multi-institutional experience. J Trauma 2005 Dec; 59(6): 130913. 60. Stringer MD. Pancreatic trauma in children. Br J Surg 2005 Apr; 92(4): 46770. 61. Duchesne JC, Schmieg R, Islam S, Olivier J, McSwain N. Selective nonoperative management of low-grade blunt pancreatic injury: are we there yet? J Trauma 2008 Jul; 65(1): 4953. 62. Kouchi K, Tanabe M, Yoshida H, et al. Nonoperative management of blunt pancreatic injury in childhood. J Pediatr Surg 1999 Nov; 34(11): 17369. 63. Lin BC, Fang JF, Wong YC, Liu NJ. Blunt pancreatic trauma and pseudocyst: management of major pancreatic duct injury. Injury 2007 May; 38(5): 58893. 64. Canty TG Sr, Weinman D. Management of major pancreatic duct injuries in children. J Trauma 2001 Jun; 50(6): 10017. 65. Phelan HA, Minei JP. Pancreatic trauma: diagnostic and therapeutic strategies. Curr Treat Options Gastroenterol 2005 Oct; 8(5): 35563. 66. Glancy KE. Review of pancreatic trauma. West J Med 1989 Jul; 151(1): 4551. 67. Patton JH Jr, Fabian TC. Complex pancreatic injuries. Surg Clin North Am 1996 Aug; 76(4): 78395. 68. Patton JH Jr, Lyden SP, Croce MA, et al. Pancreatic trauma: a simplified management guideline. J Trauma 1997 Aug; 43(2): 2349; discussion 941. 69. Cogbill TH, Moore EE, Morris JA Jr, et al. Distal pancreatectomy for trauma: a multicenter experience. J Trauma 1991 Dec; 31(12): 16006. 70. Pachter HL, Hofstetter SR, Liang HG, Hoballah J. Traumatic injuries to the pancreas: the role of distal pancreatectomy with splenic preservation. J Trauma 1989 Oct; 29(10): 13525. 71. Dawson DL, Scott-Conner CE. Distal pancreatectomy with splenic preservation: the anatomic basis for a meticulous operation. J Trauma 1986 Dec; 26(12): 11425. 72. Schein M, Freinkel W, DEgidio A. Splenic conservation in distal pancreatic injury: stay away from the hilum! J Trauma 1991 Mar; 31(3): 431. 73. Asensio JA, Petrone P, Roldan G, Kuncir E, Demetriades D. Pancreaticoduodenectomy: a rare procedure for the management of complex pancreaticoduodenal injuries. J Am Coll Surg 2003 Dec; 197(6): 93742. 74. Koniaris LG. Role of pancreatectomy after severe pancreaticoduodenal trauma. J Am Coll Surg 2004 Apr; 198(4): 6778; author reply 89. 75. Krige JE, Beningfield SJ, Nicol AJ, Navsaria P. The management of complex pancreatic injuries. S Afr J Surg 2005 Aug; 43(3): 92102. 76. McKay A, Mackenzie S, Sutherland FR, et al. Meta-analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy. Br J Surg 2006 Aug; 93(8): 92936. 77. Nakao A, Fujii T, Sugimoto H, et al. Is pancreaticogastrostomy safer than pancreaticojejunostomy? J Hepatobiliary Pancreat Surg 2006; 13(3): 2026. 78. Bassi C, Dervenis C, Bultirini G. Postoperativ pancreatic fistula an international study group (IS6PF) definition. Surgery 2005; 138: 8. 79. Subramanian A, Dente CJ, Feliciano DV. The management of pancreatic trauma in the modern era. Surg Clin North Am 2007 Dec; 87(6): 151532, x. 80. Hsieh CH, Liu NJ, Chen RJ, Fang JF, Lin BC. Endoscopically placed pancreatic stent in a patient with concomitant two locations of main pancreatic duct disruption following pancreatic trauma. Hepatogastroenterology 2003 JanFeb; 50(49): 26971. 81. Kim HS, Lee DK, Kim IW, et al. The role of endoscopic retrograde pancreatography in the treatment of traumatic pancreatic duct injury. Gastrointest Endosc 2001 Jul; 54(1): 4955. 82. Bagci S, Tuzun A, Erdil A, et al. Endoscopic treatment of pancreatic duct disruption due to blunt abdominal trauma: a case report. Mil Med 2007 May; 172(5): 54850. 83. Blumgart MD, ed. Surgery of the Liver, Biliary Tract and Pancreas. London: Elsevier, 2006.
469
50 Pancreas transplantation
Khalid Khwaja
Over the past four decades, the field of pancreas transplantation has seen much evolution, both through refinement in surgical techniques and improvement in immunosuppressive strategies. Pancreas transplantation is primarily performed in uremic, type I diabetics in conjunction with a kidney transplant, and when successful, results in freedom from exogenous insulin therapy, amelioration, or even reversal, of diabetesassociated complications and improved quality of life. Pancreas transplants, contrary to other organ transplants, are not considered essential to patient survival. For each individual recipient, the potential benefit of a pancreas transplant must be carefully weighed against the risk of a major surgical operation and lifelong immunosuppression. The first successful pancreas transplant was performed at the University of Minnesota in 1966 (1). Early outcomes were poor, largely due to technical and infectious complications and the lack of effective and safe immunosuppressive regimens. Over the next decade, the efforts of investigators at several centers in Europe and North America resulted in refinement of surgical techniques and improvement in results. With the introduction of cyclosporine into clinical practice, the field of pancreas transplantation blossomed in the 1980s and outcomes became comparable to those of other transplanted organs. To date, over 20,000 pancreas transplants have been performed worldwide, as reported by the International Pancreas Transplant Registry and about 75% of these have been in the United States (2). In 2006 alone, 1386 pancreas transplants were performed in the United States, with approximately 4000 people waiting for pancreas transplants at the end of that year (Fig. 50.1) (3). centers, involves performing a living-donor kidney transplant at the same time as a deceased donor pancreas transplant (7,8). SPK using a kidney and a partial pancreas graft and a kidney from the same living donor has also been reported (9). Pancreas After Kidney Transplant (PAK) Here, the pancreas transplant is performed after the kidney transplant in a separate operation. The benefits of preemptive (before the initiation of dialysis) kidney transplantation have been well established (10,11). When a uremic diabetic presents for transplant consideration, they are candidates for either a SPK or a living donor kidney transplant followed by a PAK. The approach varies depending on the region of the country and the availability of a living kidney donor. Type I diabetics on dialysis have a waitlist mortality of almost 10% per year, which is higher than that for people with other causes of ESRD (12). If a living donor is available, than kidney transplant should be performed as soon as possible, as outcomes after transplant worsen in direct proportion to time spent on dialysis (11). Some regions of the United States allocate waitlist priority to diabetics listed for SPK (over kidney alone candidates) and in these areas, SPK may be the better option. Pancreas Transplant Alone (PTA) The fewest pancreas transplants are performed in this category. A select group of non-uremic, type I diabetics who have failed insulin therapy can be considered for solitary pancreas transplantation. These patients usually have severe and life-threatening metabolic complications, such as hypoglycemia unawareness, justifying the risk of surgery and immunosuppression.
470
PANCREAS TRANSPLANTATION
SPK 3000 Number of new registrations PAK PTA All pancreas
2000
1000
Patients with symptomatic coronary artery disease or stenoses greater than 75% should undergo pretransplant revascularization (19). All candidates should have optimal management of hypertension, hyperlipidemias, and be counseled on weight loss and smoking cessation if indicated. A BMI > 30 kg/m2 is an independent risk factor for technical graft failure (20).
Figure 50.1 New registrations on pancreas waiting list by transplant type, 19952004. Data from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org December 2008. Abbreviations: SPK, simultaneous kidney and pancreas; PAK, pancreas after kidney; PTA, pancreas transplant alone.
PAK
PTA
All pancreas
1200 800
400
0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 50.2 Pancreas transplants in the United States by transplant type, 19972006. Data from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org December 2008.
The majority of transplanted pancreata are from deceased donors who meet criteria for brain death. Selective use of pancreata from donors after cardiac death (DCD) is increasing, with no compromise in outcomes (21). Living donor pancreas transplants are not widely performed. The distal half of the donor pancreas, based on the splenic vessels, is removed for implantation, as a segmental graft (22). However, given the donor risk, the relatively short waiting times for solitary pancreas transplants and the fact that these transplants are not necessarily life-saving, use of live donors is hard to justify (23). All potential donors undergo a thorough medical evaluation and are screened for transmissible diseases such as HIV and hepatitis B and C. The presence of active or recent malignancy is generally a contraindication to pancreas donation. Pancreata from donors with a BMI greater than 30 kg/m2, age greater than 45 years and a cerebrovascular cause of death have higher technical failure rates after transplant (20), and should be used very selectively. Hyperglycemia, per se, does not contraindicate donation, as it is often related to donor stress or use of vasoactive drugs or steroids. Organs from pediatric donors (311 years) have been used for SPK transplants with good long-term results (24). A donor risk index has been developed and will allow more informed selection of donors and matching with potential recipients (25).
surgical techniques
Procurement The various methods for recovery of the pancreas from the deceased donor have been well described (2628). Often, multiple recovery teams are present, and careful coordination between them is of paramount importance. Exposure is through a long midline or cruciate incision. The infrarenal and supraceliac aorta are controlled and looped and the pancreas is inspected through the lesser sac. The gland is assessed for quality, in particular, presence of edema, injury, fibrosis, and fat content. Pancreas dissection can be performed in the warm (prior to crossclamp) or in the cold (after crossclamp); other surgeons prefer some form of en bloc recovery technique, with separation of the pancreas from the liver ex situ (29,30). The supraceliac aorta is clamped and the infrarenal aorta flushed with preservation solution. Various solutions are available and in the United States, typically University of Wisconsin (UW) or HistidineTryptophanKetoglutarate (HTK) solutions are used; however, recent studies suggest that the rate of posttransplant pancreatitis and graft failure is higher with HTK use (31,32). After flush, the pancreas is mobilized, using the spleen as a handle. The duodenum is maintained intact with the gland and the mesenteric root stapled and divided
471
Figure 50.3 A pancreas allograft procured from a deceased donor, with the duodenum and spleen intact.
backtable preparation
A carefully performed backtable preparation is probably the single most important technical aspect of pancreas transplantation. All work is carried out in a basin of preservative solution, cooled to about 4C. The graft is received with the spleen and duodenum intact (Figs. 50.3 and 50.4). The spleen is removed by ligating the splenic vessels close to the distal end of the pancreas. Loose, fatty tissue on the upper and lower borders of the pancreas is carefully tied, the inferior mesenteric vein is ligated and the staple lines on the mesenteric stump and duodenal ends oversewn. On the posterior surface of the gland, the open ends of the PV, SMA, and SA are identified and any surrounding lymphatic and ganglionic tissue removed. The pancreatic head and duodenum will derive arterial supply from the SMA via the inferior pancreaticoduodenal arcade and the body and tail of the gland will be supplied by the SA. This dual supply is united by means of a Y-graft fashioned from the donor iliac vessels (Fig. 50.5), enabling a single arterial anastomosis during the recipient operation.
Figure 50.4 A procured pancreas allograft. The portal vein (PV), superior mesenteric artery (SMA), and splenic artery (SA) are preserved with the graft. The duodenal ends and the root of the small bowel mesentery are transected with a stapling device.
recipient operations
The recipient operation varies with respect to graft placement (intra- vs. extraperitoneal), venous drainage (systemic vs. portal), and exocrine drainage (bladder vs. enteric). Most grafts are placed intraperitoneally, although a few centers prefer extraperitoneal placement, similar to the approach used for kidney transplantation (34,35). Intraperitoneal placement allows placement of the kidney through the same incision in SPK transplants and may be associated with less wound problems (36). Systemic Venous Drainage Most pancreas transplants are drained systemically, usually into the iliac vein, on the right side (2). A lower midline incision is made and the cecum and right colon mobilized medially to expose the iliac vessels and ureter. The iliac vessels are completely mobilized, and all hypogastric venous branches ligated to allow full mobilization of the iliac vein and to reduce tension on the subsequent venous anastomosis. The graft is then brought into the operative field, with the head and duodenum directed caudally. The portal vein is anastomosed
Figure 50.5 Pancreas allograft after backtable preparation. The spleen is removed and the distal splenic vessels ligated. The inferior mesenteric vein is ligated. The duodenal staple lines are oversewn. A donor iliac artery Y graft is anastomosed to the SMA and SA.
472
PANCREAS TRANSPLANTATION
Figure 50.8 Pancreas transplant with portal venous drainage and enteric anastomosis. The graft PV is anastomosed, end-to-side, to the recipient superior mesenteric vein. The graft duodenum points cephalad.
Figure 50.7 A SPK transplant. The graft PV is anastomosed to the recipient right common iliac vein and the Y-graft to the recipient right common iliac artery. A side-to-side enteric anastomosis is depicted. The kidney is transplanted to the left external iliac vessels and a standard ureteroneocystostomy is constructed.
in an end-to-side fashion to the iliac vein and the long limb of the Y-graft to the iliac artery and the graft reperfused (Fig. 50.6). The graft duodenum is then drained into the bladder or bowel. Alternatively, the graft can be placed with the head cephalad, with venous drainage directly into the cava (37); this, however, precludes the option of bladder drainage. In an SPK transplant, the kidney is placed on the opposite side, either before or after the pancreas (Fig. 50.7).
Portal Venous Drainage About 20% to 30% of all pancreas transplants are currently drained into the portal venous system (2). Its proponents claim that this approach is more physiologic and associated with lower rates of rejection (38). Indeed, systemic transplants are associated with hyperinsulinemia, but the significance of this is unclear (39). Disadvantages of portal drainage are a graft that is less amenable to percutaneous biopsy and the inability to perform bladder exocrine drainage. However, registry data show no difference in graft survival between the two techniques (2). The author uses both methods, preferring portal drainage if a difficult pelvic dissection is anticipated or there is a prior kidney transplant on the right side. The approach is through an upper midline incision, and the SMV is exposed at the root of the small bowel mesentery and dissected as far proximally as possible. The right common iliac artery is exposed through a window in the mesentery. The graft is placed with the duodenum directed superiorly, and the graft portal vein anastomosed, end-to-side, to the SMV. The Y-graft, which is kept long, is anastomosed to the iliac artery through the mesenteric window. The graft is then reperfused and the enteric anastomosis completed (Fig. 50.8). Bladder Drainage Management of exocrine drainage has been the Achilles heel of pancreas transplantation. Over the years, numerous
473
Figure 50.9 Pancreas transplant with systemic venous drainage and exocrine drainage into the bladder. The graft duodenum points caudad.
techniques have been tried, including free drainage of the pancreatic duct into the peritoneum (40) and obliteration of the pancreatic duct with polymer injection (41,42). Currently, bladder or enteric drainage is the standard techniques. Bladder drainage of pancreatic exocrine secretions was first described in 1984 (43) and was the predominant technique in the 1990s (44). The graft duodenum is anastomosed directly to the dome of the bladder, using absorbable sutures (Fig. 50.9). A stapled technique, using an EEA device, has also been described (45). The main advantage of this technique is the early safety (small leaks, e.g., can be managed simply by catheter drainage of the bladder) and less technical failure when compared to enterically drained grafts (2). Urinary amylase output can also be monitored and this is a sensitive marker for pancreatic rejection (46). However, the technique is fraught with long-term complications, such as dehydration, metabolic acidosis, recurrent urinary tract infections, graft pancreatitis, and hematuria (47). About 20% to 30% of bladder drained grafts have to be converted to enteric drainage due to these complications (48). Enteric Drainage Most centers currently prefer enteric drainage, to avoid the metabolic complications associated with bladder drainage (2). The availability of better immunosuppressive agents and the lower rates of acute rejection have lessened the role of urinary amylase monitoring. The graft duodenum is anastomosed to a loop of proximal small bowel, either directly (Fig. 50.7) or using a Roux-en-Y technique. Technical complications are actually higher when a Roux limb is constructed (44). If the graft duodenum does not perfuse well or the ischemic time is long, it may be more prudent to use a Roux or perform bladder drainage.
outcomes
Historically, SPK transplant recipients have enjoyed much better pancreas graft survival than PAK and SPK recipients (54). Over the last decade, the 1-year survival for solitary grafts has been steadily improving. Current 1-year graft survivals for SPK, PAK, and PTA transplants are 86%, 79%, and 80%, respectively (Fig. 50.10) (3). At 10 years, 51% of SPK recipients still have functioning grafts, compared to only 28% of PAK recipients and 24% of PTA recipients (55). Chronic rejection and death with a functioning graft are responsible for most cases of late graft loss (56). Patient survival is similar for the three categories, and ranges from 95% to 97% at 1 year and 64% to 71% at 10 years (Fig. 50.11) (3). Recent studies have clearly demonstrated a survival advantage with SPK transplants (5759). However, one analysis of registry data suggested that survival after pancreas transplant was worse with solitary pancreas transplants, when compared to waitlisted people who received conventional therapy for diabetes (58). Some patients were registered on several waitlists and counted more than once, and patients who dropped off the list for medical reasons were censored, biasing the outcomes of this study. When these differences were accounted for, there was no difference in survival at 4 years between waitlisted patients and those receiving PAK or PTA transplants (level of evidence: III) (59).
474
PANCREAS TRANSPLANTATION
Unadjusted graft survival (%)
100% 80% 60% 40% 20% 0% 1-Year 3-Year 5-Year 10-Year SPK PTA PAK
and a lower incidence of death from cardiovascular causes compared to waitlisted patients (73). Several studies have demonstrated improvement in quality of life after pancreas transplant, using various survey instruments (level of evidence IIa to III) (76).
immunosuppression
Up to 80% of pancreas recipients receive some form of induction therapy at the time of transplant, usually a T-cell depleting agent such as thymoglobulin (77). Standard maintenance regimen consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil or sirolimus), and steroids. Outcomes with tacrolimus-based therapy are better overall (78,79) but one must be wary of the potential of nephrotoxicity with this agent (80). Steroid avoidance and steroid withdrawal protocols are also increasingly used, with good short-term results (81). Acute rejection rates in the first year after pancreas transplant are currently less than 25% for SPK transplants and somewhat higher for solitary transplants (78). A rise in serum amylase or lipase, a fall in urinary amylase output (for bladderdrained grafts), and hyperglycemia are suggestive of acute rejection, and should prompt a biopsy. The histologic features for diagnosis and grading acute pancreas allograft rejection were recently standardized (82).
Figure 50.10 Unadjusted pancreas graft survival by transplant type. Data from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org December 2008.
SPK
PTA
PAK
5-Year
10-Year
Figure 50.11 Unadjusted pancreas patient survival by transplant type. Data from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org December 2008.
conclusions
Combined kidney and pancreas transplant is an effective option for uremic patients with type I diabetes. A select group of type I diabetics, who have normal renal function, may benefit from a solitary pancreas transplant. In the current era, graft survivals are comparable to those of other solid organ transplants. There is much enthusiasm over islet cell transplantation as a less invasive alternative, but, at present, the results are not as durable as those of whole organ transplant (83). No doubt, both fields will continue to evolve, with ongoing advances in techniques and immunosuppression.
difficult to demonstrate benefit after transplant. The Diabetes Control and Complication Trial (DCCT) clearly showed the benefits of normalizing blood glucose concentrations in diabetics, with an almost 50% reduction in retinopathy, neuropathy, and nephropathy (60). Several, small, non-randomized, but controlled studies provide evidence (level IIa) of the beneficial effects of transplant on secondary diabetic complications. Reversal of diabetic nephropathy was seen 10 years (but not at 5 years) after PTA, with decreased thickness of glomerular and tubular basement membranes and decreased mesangial fraction volume (61). Most studies investigating the effects of transplantation on diabetic retinopathy are limited by the presence of advanced disease at baseline. Proteinuria also decreases after successful PTA when compared to matched controls at 1-year posttransplant (62). Stabilization of retinopathy after pancreas transplantation has been well demonstrated (6365) with less disease progression over time in comparison to controls (66). There is a sustained improvement in nerve conduction velocity and action potential amplitude after both SPK (67,68) and solitary pancreas transplantation (67). Recipients of SPK transplants have less progression of coronary atherosclerosis, (69) a better atherosclerotic risk profile (70), and significant improvement in cardiac geometry and function in comparison to kidney-alone recipients (7173). There is improvement in systolic and diastolic blood pressure (74,75) and other cardiovascular parameters (75) after combined pancreaskidney transplantation
references
1. Kelly WD, Lillehei RC, Merkel FK, et al. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1966; 61: 82737 2. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005; 19: 43355 3. Leichtman AB, Cohen D, Keith D, et al. Kidney and pancreas transplantation in the United States, 19972006: the HRSA Breakthrough Collaboratives and the 58 DSA Challenge. Am J Transplant 2008; 8(4 Pt 2): 94657. 4. Finne P, Reunanen A, Stenman S, et al. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294(14): 17827 5. Nishimura R, Dorman JS, Bosnyak Z, et al. Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a report from the Allegheny County Registry. Am J Kidney Dis. 200; 42(1): 11724. 6. Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States Renal Data System. J Am Soc Nephrol 2007; 18(10): 26448. 7. Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient. Ann Surg 2000; 232(5): 696703.
475
476
PANCREAS TRANSPLANTATION
56. Humar A, Khwaja K, Ramcharan T, et al. Chronic rejection: the next major challenge for pancreas transplant recipients. Transplantation 2003; 76(6): 91823. 57. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation 2001; 71(1): 8290. 58. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 2003; 290(21): 281723. 59. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004; 4(12): 201826. 60. The Diabetes Control and Complications Trial Research Group. the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 97786 61. Fioretto P, Steffes MW, Sutherland DER, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339; 6975. 62. Coppelli A, Giannarelli R, Boggi U, et al. Disappearance of nephrotic syndrome in type 1 diabetic patients following pancreas transplant alone. Transplantation 2006; 81(7): 10678. 63. Konigsrainer A, Miller K, Steurer W, et al. Does pancreas transplantation influence the course of diabetic retinopathy? Diabetologia 1991; 34(S1): S868. 64. Koznarova R, Saudek F, Sosna T, et al. Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy. Cell Transplant 2000; 9: 9038. 65. Giannarelli R, Copelli A, Sartini MS, et al. Early improvement of unstable diabetic retinopathy after solitary pancreas transplantation. Diabetes Care 2002; 25: 23589. 66. Ramsey RC, Goetz FC, Sutherland DE, et al. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1998; 318: 20814. 67. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997; 42: 72736. 68. Allen RD, Al-Harbi IS, Morris JG, et al. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation 1997; 63: 8308. 69. Jukema J, Wouter MD, Smets YF, et al. Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes. Diabetes Care 2002; 25: 90611. 70. Fiorina P, La Rocca E, Venturini M, et al. Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes. Diabetes 2001; 50(3): 496501. 71. Gaber AO, Wicks MN, Hathaway DK, Burlew BS. Sustained improvement in cardiac geometry and function following kidney-pancreas transplantation. Cell Transplant 2000; 9: 9138. 72. Fiorina P, La Rocca E, Astorri E, et al. Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients. Diabetes Care 2000; 23: 180410. 73. La Rocca E, Fiorina P, Di Carlo V, et al. Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation. Kid Int 2001; 60: 196471. 74. Elliot MD, Kapoor A, Parker MA, et al. Improvement in Hypertension in patients with diabetes mellitus after kidney/pancreas transplantation. Circulation 2001; 104: 5639. 75. Coppelli A, Giannarelli R, Mariotti R, et al. Pancreas Transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients. Transplantation 2003; 76: 9746. 76. Joseph JT, Baines LS, Morris MC, Jindal RM. Quality of life after kidney and pancreas transplantation: a review. Am J Kidney Dis 2003; 42(3): 43145. 77. Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, et al. Immunosuppression: evolution in practice and trends, 19942004. Am J Transplant 2006; 6(5 Pt 2): 111131. 78. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001 Apr; 233(4): 463501. 79. Saudek F, Malaise J, Boucek P, Adamec M; Euro-SPK Study Group. Efficacy and safety of tacrolimus compared with cyclosporin microemulsion in primary SPK transplantation: 3-year results of the Euro-SPK 001 trial. Nephrol Dial Transplant 2005; 20(Suppl 2): ii310, ii62. 80. Ojo AO. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007; 27(4): 498507 81. Cantarovich D, Vistoli F. Minimization protocols in pancreas transplantation. Transpl Int 2008 Aug 15. 82. Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. Am J Transplant 2008; 8(6): 123749. 83. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006; 355(13): 131830.
477
51
introduction
Advances in surgical technique have led various treatment options for patients with hepatobiliary and pancreatic disorders. There have also been advances in the understanding of pathogenesis and clinical behavior of specific diseases. This chapter addresses the common hepatobiliary and pancreatic disorders with a focus on surgical treatment modalities.
biliary atresia ba
Classification BA is an obstructive condition of the bile ducts. It is of unknown etiology but results from a progressive obliterative process of variable extent. It has a worldwide incidence of 1 in 5000 to 18,000 live births, and it is more common in girls than in boys (1,2). Two clinical forms are described: acquired and embryonic (3). The acquired form accounts for 80% of affected infants. They are asymptomatic and anicteric at birth and develop jaundice in the first postnatal weeks. These otherwise normal infants are born with a patent biliary system which undergoes progressive inflammation and fibro-obliteration initiated by a perinatal insult. Infants with the embryonic form have no jaundice-free interval and suffer from one or more congenital anomalies, such as interruption of the suprarenal segment of the inferior vena cava with azygous continuation, preduodenal portal vein, midline symmetric liver, intestinal malrotation, situs anomalies, bronchial anomalies, and polysplenia or asplenia (2,4). Pathology BA can be classified by using macroscopic appearance and cholangiography findings according to three main categories. Types I, II, and III are defined as atresia at the site of the common bile duct, at the site of the hepatic duct, and up to the porta hepatis, respectively. Type III is most common. A patent duct that can be anastomosed to the intestine at the porta hepatis is present in 5% of cases. In more than 90% of cases, no normal ductal structures are seen at the porta hepatis (5). Early in the course the liver is enlarged. There are portal tract edema, bile duct proliferation, portal and periductal inflammation, and associated areas of hepatic cell injury. This process develops into end stage cirrhosis. The pathologic changes are generally considered to be panductal, affecting intrahepatic as well as extrahepatic structures (68). The degree of damage present in the intrahepatic biliary system is responsible for much of the morbidity after hepatic portoenterostomy (HPE). Paucity or absence of intralobular bile ducts along with architectural disturbances, even in jaundice-free infants after successful HPE, has been observed by some (9).
478
The incidence is 1 in 13,000 to 15,000 in western countries, but rates as high as 1 in 1000 have been described in Japan (24). Choledochal cyst can be categorized according to their anatomic appearance into five types (25,26): I. Cystic or diffuse fusiform dilatation of the extrahepatic bile duct II. Diverticulum of the extrahepatic bile duct III. Choledochocele IV. Multiple cysts of the intra- or extrahepatic ducts (or both) V. Single or multiple intrahepatic cysts Type I accounts for at least 75% of all cases, and type IV accounts for most of the remainder. The other varieties are rare (27,28). Pathology Histologic sections of the wall of extrahepatic choledochal cysts have demonstrated a thick-walled structure of dense connective tissue interlaced with strands of smooth muscle. In most instances, some degree of inflammatory reaction is noted. The degree of histologic damage and the rate of epithelial metaplasia and dysplasia are related to the age of the patient (29). In a newborn, the histologic appearance of the liver is usually normal or having mild bile duct proliferation consistent with chronic biliary obstruction. Occasionally in older patients mild periportal fibrosis is noted. Choledochal cysts are congenital. There is predominance in females, suggesting a sex-linked defect, as well as a much higher incidence in Asian populations.
choledochal cyst
Classification Choledochal cysts are congenital anomalies of the biliary tract manifested by cystic dilatation of the extra hepatic biliary tree.
479
Survival with native liver 5 years: 59.7% (actual) 5 years: 30.1% (actuarial) 2 years: 55.8% (actual) 4 years: 42.7% (actuarial) 4 years: 51% (actuarial)
Survival after liver transplantation _ 2.4 years: 89% (actual) 2 years: 88% (actual) 4 years: 88.8% (actuarial) 2 years: 89% (actuarial)
Overall survival of patients 5 years: 75.5% (actual) 5 years: 85% (actuarial) 2 years: 91.3% (actual) 4 years: 87.1% (actuarial) 4 years: 89% (actuarial)
The most plausible etiology is obstruction of the distal common bile duct. Clinical Features In the infantile form, patients present with obstructive jaundice, acholic stools, and hepatomegaly at 1 to 3 months of age (30). Patients do not tend to have abdominal pain of palpable mass. Infants do not ordinarily become jaundiced until 1 to 3 weeks after birth. In the adult forms, the clinical manifestations do not become evident until the patient is 2 years old; and most of these patients have fusiform deformities of the common duct without high grade or complete obstruction. The classic triad of abdominal pain, a palpable abdominal mass, and jaundice may be noted (31). Only partial obstruction occurs in the adult form, so the symptoms are intermittent. The pattern of pain has been described as similar to that of recurrent pancreatitis. Imaging Ultrasonography may be the only screening required in infants. If a choledochal cyst is suspected on US, 99Tcdi-isopropylphenylcarbamoyl-methylimidodiacetic acid (DISIDA) scintigraphy can confirm the diagnosis and provide information about drainage, obstruction, and hepatic function. Prenatal ultrasonography of fetal choledochal cyst has been reported by a number of investigators (3234). A key question after prenatal diagnosis is the appropriate timing of surgical correction. Redkar suggests that asymptomatic patients are best operated around 3 months of age (35). Suita et al. noted that patients who undergo surgery within a month of life have a lower incidence of hepatic fibrosis than those operated on later (36). Treatment In 1970, Kasai et al. and Ishida et al. reported favorable results with cyst excision and Roux-en-Y jejunostomy (37,38). Outcome Radical cyst excision and hepaticojejunostomy yield consistently good results, even in small infants (27). In a large Japanese series of 200 children followed for a mean of
11 years, Roux-en-Y hepaticojejunostomy was performed in 188 patients. No operative mortality occurred, and 9% had complications including cholangitis, intrapancreatic terminal CBD calculi, pancreatitis, and bowel obstruction (39).
gallbladder disease
Cholelithiasis The prevalence of gallstones in children varies according to geography and age. The predominant factors in gallstone formation are biliary stasis, excess bilirubin pigment, and lithogenic bile. Hemolytic disorders, fasting and TPN, ileal resection/disease, cystic fibrosis, Down syndrome, childhood cancer, bone marrow transplantation, cardiac transplantation, spinal surgery, dystrophia myotonica, and chronic intestinal pseudo-obstruction have all been associated with increased incidence of cholelithiasis in children (40). Gallstones in infants occasionally resolve spontaneously. Early surgery can be deferred in the asymptomatic infant with gallbladder calculi. Management of asymptomatic cholelithiasis in older children is controversial. In children without hemolytic disorders, a conservative approach is recommended (41). Cholecystectomy is the standard treatment for symptomatic or complicated gallbladder stones. Hemolytic Cholelithiasis In the past, the usual cause of gallstones in children was hemolytic disease. Hereditary spherocytosis, sickle cell anemia, and thalassemia are the most common hemolytic disorders resulting in the development of gallstones. In patients with spherocytosis, ultrasound is indicated prior to splenectomy. If stones are present, cholecystectomy is performed. In sickle cell disease, only symptomatic patients require cholecystectomy, which should be preformed electively rather than emergently during a hemolytic crisis (42). Congenital Deformities Congenital deformities include a variety of abnormal configurations and locations of the gallbladder, such as gallbladder agenesis, duplication, bilobation, floating gallbladder, diverticula, and ectopia. They are usually of no clinical relevance; if
480
hepatoblastoma
Incidence Hepatoblastoma is the most common malignant hepatic tumor. Liver cancers constitute 0.5% to 2% of all pediatric solid tumors and about 5% of abdominal tumors in childhood (43). Hepatoblastomas are the most common primary hepatic tumors of childhood constituting 43% to 64% of all hepatic neoplasms in one large series (4345). Approximately twothirds of all liver masses occurring in children are malignant. Eighty percent of 123 children in the United States registered with malignant liver tumors in 2000 had hepatoblastoma and they accounted for 91% of primary hepatic malignancies in children less than 5 years of age (46). There are approximately 50 to 70 new cases per year in the United States with a male to female ratio of 1.7:1 (47). The median age at diagnosis is about 18 months, and most cases occur before age 2 to 3 years (48). Hepatoblastoma may occur in siblings (4951). It is most strongly associated with familial polyposis (52,53), Gardners syndrome (54), and BeckwithWiedemann syndrome (55,56). Pathology The five histologic subtypes observed in hepatoblastoma are fetal, embryonal, mixed mesenchymal, macrotubular, and anaplastic or small cell. The importance of subtyping in hepatoblastoma is the association between prognostic risk and subtype (57,58). Patients with small cell undifferentiated tend to do worse. Figure 51.1 illustrates imaging and pathology of a child with Beckwith-Wiedemann syndrome with hepatoblastoma. Clinical Features The most common presenting sign of hepatoblastoma is an asymptomatic abdominal mass. A mild anemia with a markedly elevated platelet count is observed in most patients at diagnosis. The cause is probably secondary to abnormal cytokine release. In an abstract from the 1993 Annual Meeting of the American Society of Clinical Oncology, Van Tournet et al. stated that measurement of serum alpha-fetoprotein is well established as an initial tumor marker in the diagnosis of hepatoblastoma and a means of monitoring the therapeutic response. The normal level in most laboratories is less than 20 ng/ml whereas the AFP level at diagnosis in hepatoblastoma patients can range from normal to 7.7 106 ng/ml. It is estimated that the AFP is elevated in 84% to 91% of patients with hepatoblastoma (58). In comparison, the mean in pediatric patients with HCC was about 200,000 ng/ml (59). Imaging The first imaging study is usually an abdominal ultrasound. Computed tomography (CT) is useful to identify pulmonary metastases, identify diffuse hepatic involvement, and determine respectability. MRI is useful for evaluating hepatic lesions and their relationship to vascular structures (60). It can show the hepatic veins, the vena cava, and bile ducts.
Incidence HCC accounts for 23% of pediatric liver tumors (64). The incidence is bimodal with an early peak that occurs before 5 years and a second peak that occurs between 13 and 15 years. HCC is the most common hepatic malignancy of adolescence (65). There is a male predominance of 1.3 to 3.2:1. Hepatitis B and C correlate with the incidence of HCC. In Asia 85% of these patients (adults and children) are hepatitis B surface antigen positive, whereas this is found in only 10% to 25% of patients in the United States. The relative risk for the development of HCC is 250:1 for patients with chronic active hepatitis compared with patients without hepatitis surface antigen positivity (66). Other conditions associated with the development of HCC include cirrhosis, 1-antitrypsin deficiency, tyrosinemia, aflatoxin ingestion, hemochromatosis, hepatic venous obstruction, androgen and estrogen exposure, Alagille syndrome, and thorotrast administration (67).
481
(A)
(B)
(C)
(D)
(E) Figure 51.1 Ten-month-old female with BeckwithWiedemann syndrome. (A,B) The hepatoblastoma is centered on the middle hepatic vein, with an extension into the right hepatic vein (arrow in A) and an encasement of the left hepatic vein (arrow in B). (C,D) Preoperative chemotherapy resulted in shrinkage of the tumor, with apparent involvement of a clear plane between the tumor and the right hepatic vein (arrow in C); panel D demonstrates the tumor encasing the left portal vein. An attempted extended left hepatic lobectomy was abandoned because of the presence of an occult tumor involvement of the right hepatic vein noted at surgery. (E) The patient underwent hepatic transplantation. Source: Reprinted from Ref. (104).
Pathology HCCs are highly invasive and often multicentric at diagnosis, with frequent hemorrhage and necrosis. Invasiveness, especially vascular invasion, is a hallmark of these tumors. Extrahepatic dissemination to portal lymph nodes, lungs, and bones is frequent at diagnosis and strongly affects survival.
Clinical Features Children and adolescents with HCC frequently present (68) with palpable abdominal masses (40%), but many are asymptomatic at diagnosis. Pain is common (38%) and may occur in the absence of an obvious mass. Constitutional disturbances such a as anorexia, malaise, nausea and vomiting, and significant
482
When encountered at laparotomy, they should usually be excised unless this would entail significant risk of morbidity. Annular Pancreas Annular pancreas is thought to be due to a faulty rotation of the ventral pancreatic bud in its course around the posterior aspect of the duodenal anlage during the sixth week of gestation. The duodenum is encircled by and obstructed with normal pancreatic tissue containing normal functioning acini, ducts, and islets of Langerhans (79,80). The theory is that half the ventral bud migrates anteriorly and half migrates posteriorly. Duodenal atresia and stenosis, intestinal malrotation, and trisomy 21 can often be found in combination with annular pancreas (81). The clinical symptoms relate to duodenal obstruction with bilious vomiting. Radiographic studies reveal the classic finding of the double bubble sign (82). Management consists of surgical bypass of the obstructing lesion with a duodenoduodenostomy. Resection or division of the annular pancreas should not be carried out. Pancreas Divisum Failure of the duct of Wirsung and the duct of Santorini to unite from the dorsal and ventral pancreas during development results in the anatomic variant known as pancreas divisum. In this disorder the duct of Wirsung is very small, and the duct of Santorini becomes the major ductal system and communicates with the duodenum through the minor papilla. If the orifice of the accessory papilla is stenotic, pancreatitis can occur. The goal of treatment is to establish adequate drainage of the duct of Santorini. Several reports show that adequate drainage can be obtained with accessory papilla sphincteroplasty (83). Acute Pancreatitis The causes of acute pancreatitis include trauma, biliary tract stone disease, choledochal cyst, ductal developmental anomalies, drugs, such as retrovirals, diuretics, anticonvulsants, as well as some chemotherapeutic agents, metabolic derangements, and infections. In children, trauma is the most common cause. Pancreas divisum is an anomaly present in 10% of the population, resulting from failure of the dorsal duct to fuse with the ventral duct. This relative obstruction may cause recurring episodes of pancreatitis (84). These patients should undergo a sphincteroplasty of the minor papilla. The pathogenesis entails the inappropriate activation of proenzymes, leading to autodigestion of the pancreas. Acute pancreatitis usually presents with the acute onset of midepigastric pain associated with back pain, severe vomiting, and low-grade fever (85,86). In severe cases of necrotizing or hemorrhagic pancreatitis, hemorrhage may dissect from the pancreas along tissue plans appearing as ecchymosis either in the flanks (GreyTurner sign) or at the umbilicus (Cullens sign). Lipase levels have been proposed as a more specific test of pancreatic tissue damage, although intestinal perforation does cause an elevation of lipase throughout reabsorption via the peritoneum. Lipase is produced only in the pancreas and its measurement is particularly helpful for distinguishing pancreatic trauma from salivary trauma (87). CT scan offers better resolution than other modalities to determine size of pancreas, degree of edema, and the presence of fluid collections (88). It
Stage III
Stage IV
Source: Reprinted from Ref. (104).
weight loss occur with greater frequency. AFP is elevated in approximately 85% of patients, with most levels greater than 1000 ng/ml (69). Treatment Long-term survival is impossible without complete resection. However, because of the high incidence of multifocality within the liver, extrahepatic extension to regional lymph nodes, vascular invasion, and distant metastases, complete resection is often impossible. Unresectable HCCs can be palliated with embolization with or without added chemotherapeutic agents or radioisotopes (70). Percutaneous intralesional injection of ethanol also has been of palliative benefit when lesions are small (71). Radiofrequency ablation of these tumors, percutaneously or at laparoscopy/laparotomy, has been associated with tumor resolution and prolonged survival (7275). Outcome The overall survival from HCC in childhood approaches zero and it remains a therapeutic problem. Occasionally, resection of localized lesions results in long-term survival. The trend is to separate HCC from hepatoblastoma in clinical studies because of its greatly differing biologic behavior.
pancreas
Congenital Anomalies Ectopic Pancreatic Rests The incidence of ectopic pancreatic rests in autopsy ranges from 1% to 2% (76) and is frequently encountered along foregut derivatives, such as the stomach and duodenum, as well as jejunum, ileum, and colon (77). They represent the most common anomaly of the gastric antrum and may cause a gastric outlet obstruction (78). Their origin is unknown, but one possible explanation suggests an aberrant epithelialmesenchymal interaction, leading to trans-differentiation of heterotrophic embryonic epithelium into pancreatic epithelium. Ectopic rests are usually asymptomatic and found incidentally at laparotomy.
483
KEY POINTS
Biliary atresia is marked by obstruction of the bile ducts. In infancy, jaundice that persists beyond 2 weeks is physiologic. Signs and symptoms include jaundice, clay-colored stools, and hepatomegaly. Treatment is a hepatic portoenterostomy. Choledochal cysts are congenital anomalies of the biliary tract. There are five types. They present with obstructive jaundice. Treatment is cyst excision and Roux-en-Y jejunostomy. Cholelithiasis, hemolytic cholelithiasis, and congenital deformities are gallbladder diseases seen in pediatrics. Treatment varies for each and depends on symptoms.
484
references
1. Mack CL, Sokol RJ. Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 2005; 57: 87R94R. 2. Carmi R, Magee CA, Neill CA, et al. Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations. Am J Med Genet 1993; 45: 68393. 3. Perlmutter DH, Shepherd RW. Extrahepatic biliary atresia: a disease or a phenotype? Hepatology 2002; 35: 1297304. 4. Silveira TR, Salzano FM, Howard ER, et al. Congenital structural abnormalities in biliary atresia: evidence for etiopathogenic heterogeneity and therapeutic implications. Acta Paediatr Scand 1991; 80: 11929. 5. ONeill JA, Rowe MI, Grosfeld JL, et al. Pediatric Surgery. 5th edn. St. Louis, MO: Mosby, 1998. 6. Raweily EA, Gibson AA, Burt AD. Abnormalities of intrahepatic bile ducts in extrahepatic biliary atresia. Histopathology 1990; 17: 5217. 7. Lilly JR, Altman RP. Hepatic portoenterostomy (the Kasai operation) for biliary atresia. Surgery 1975; 78: 7686. 8. Ito T, Horisawa M, Ando H. Intrahepatic bile ducts in biliary atresia--a possible factor determining the prognosis. J Pediatr Surg 1983; 18: 12430. 9. Sherlock S. The syndrome of disappearing intrahepatic bile ducts. Lancet 1987; 2: 4936. 10. Balistreri WF. Neonatal cholestasis. J Pediatr 1985; 106: 17184. 11. Brough AJ, Bernstein J. Conjugated hyperbilirubinemia in early infancy. A reassessment of liver biopsy. Hum Pathol 1974; 5: 50716. 12. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39: 11528. 13. Kasai M, Suzuki S. A new operation for non-correctable biliary atresia: hepatic portoenterostomy. Shujjutsu 1959; 13: 7339. 14. Shteyer E, Ramm GA, Xu C, et al. Outcome after portoenterostomy in biliary atresia: pivotal role of degree of liver fibrosis and intensity of stellate cell activation. J Pediatr Gastroenterol Nutr 2006; 42: 939. 15. Azarow KS, Phillips MJ, Sandler AD, et al. Biliary atresia: should all patients undergo a portoenterostomy? J Pediatr Surg 1997; 32: 16872; discussion 724. 16. Lang T, Kappler M, Dietz H, et al. Biliary atresia: which factors predict the success of a Kasai operation? An analysis of 36 patients. Eur J Med Res 2000; 5: 1104. 17. Davenport M, De Ville de Goyet J, Stringer MD, et al. Seamless management of biliary atresia in England and Wales (19992002). Lancet 2004; 363: 13547. 18. Chardot C, Carton M, Spire-Bendelac N, et al. Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996. Hepatology 1999; 30: 60611. 19. Laurent J, Gauthier F, Bernard O, et al. Long-term outcome after surgery for biliary atresia. Study of 40 patients surviving for more than 10 years. Gastroenterology 1990; 99: 17937.
485
486
487
Index
AAST. See American Association for Surgery of Trauma Abdominal compartment syndrome, 274 Abdominal pain, 451 Ablative techniques, 5758 ABO-incompatible liver, 291 ACC. See Acinar cell carcinoma Acinar cell carcinoma, 432 pancreatic lesions, 107 ACS. See Abdominal compartment syndrome Acute and chronic liver failure auxiliary liver transplantation auxiliary whole orthotopic liver transplantation, 294295 immunosuppression, 295 outcome of, 295 donor selection ABO-incompatible liver, 291 donation after cardiac death, 290291 donors with infection, 290 donors with malignancy, 290 elderly donors, 289290 hepatitis B core antibody positive donors, 290 hepatitis C infection donors, 290 split-liver, 290 steatosis and abnormal liver function, 289 future perspectives hepatocyte transplantation, 297 immune tolerance, 297 liver support devices, 295, 297 orthotopic liver transplantation immunosuppression, 292293 operative technique of, 292 outcomes in, 293294 post-operative management, 292293 recipient selection with acute liver failure, 288 end-stage liver disease, 288 with HIV, 288289 with viral hepatitis, 288 retrieval of deceased donor liver graft donation after cardiac death retrieval, 292 standard retrieval, 291 splitting of deceased donor liver graft, 292 Acute cholangitis, gallstone disease, 374 Acute cholecystitis bile duct injuries, 360362 gallstone disease, 373 Acute pancreatitis congenital anomalies, 483484 early management of, 439441 etiology of, 439 gallstone disease, 374375 laparoscopy, 443 necrosis management, 441 radiological assessment, 441 role for specific interventions, 440 surgical intervention endoscopic drainage, 443, 445 laparotomy/debridement, 441443 open surgery, 441 percutaneous catheter drainage, 443444 percutaneous necrosectomy, 443, 446 Acute variceal hemorrhage, 282 ADA. See American Diabetes Association Adenocarcinoma, congenital anomalies, 484 Adenosquamous carcinoma, 432434 Adjuvant chemotherapy, 391393 hepatic metastasectomy, 5859 Adjuvant intra-arterial chemotherapy, 123 Adjuvant regional chemotherapy, 141142 Adjuvant systemic chemotherapy after liver resection, 141 colorectal liver metastases, 122 Adjuvant therapy gallbladder cancer, 331 laparoscopically discovered disease, 204205 Adult hemangioma, 262 Adulthood, choledochal cyst clinical presentation, 354 complications, 355 diagnosis, 354355 etiology and classification, 354 incidence and pathophysiology, 354 treatment, 355358 Advanced cholangiocarcinoma combined liver and portal vein resection, 339340 hepatopancreatoduodenectomy, 340 Aging, 46 AIP. See Autoimmune pancreatitis AJCC. See American Joint Committee on Cancer ALT. See Auxiliary liver transplantation Amebiasis, 253 Amebic liver abscess diagnosis of, 253254 epidemiology of, 253 outcomes of, 255 pathogenesis of, 253 treatment of, 254255 American Association for Surgery of Trauma, 271272 American Diabetes Association, 470 American Joint Committee on Cancer, 192, 198 American Pancreas Club, 458 American Society of Anesthesiology, 47 American Society of Clinical Oncology, 137 Anatomic right trisectionectomy, 339 Anatomical hepatectomies, 56 Anatomical hepatic resection, 276277 Anatomy of pancreas arterial anatomy anterior and posterior inferior pancreaticoduodenal arteries, 19 caudal and great pancreatic arteries, 20 dorsal pancreatic artery, 1920 inferior pancreaticoduodenal artery, 19 posterior superior pancreaticoduodenal artery, 1819 superior pancreaticoduodenal artery, 18 venous drainage of pancreas, 2021 ductal anatomy of, 17 innervation of, 22 lymphatic drainage, 2122 topography of, 17 Angioembolization, 275 Angiography, hydatid cyst, 313 Angiomyolipoma, 267 Annular pancreas, congenital anomalies, 483 Anti-angiogenic therapies, 219220 ASA. See American Society of Anesthesiology ASC. See Adenosquamous carcinoma AschoffRokitansky sinuses, 40 Ascites, 280, 284285 ASCO. See American Society of Clinical Oncology Aspiration sclerotherapy, 301302 laparoscopic surgery, 303 open surgery, 303 surgical treatment, 302303 Associated intra-abdominal vascular injuries, 463 Autoimmune pancreatitis chronic pancreatitis, 452 rare tumors, 436437 Auxiliary liver transplantation auxiliary whole orthotopic liver transplantation recipient selection criteria, 294 surgical technique, 294295 immunosuppression, 295 outcome of, 295 Auxiliary whole orthotopic liver transplantation recipient selection criteria, 294 surgical technique, 294295 AWOLT. See Auxiliary whole orthotopic liver transplantation BA. See Biliary atresia Backtable preparation, 472 BCS. See BuddChiari syndrome BD. See Biliary drainage
489
INDEX
Benign cystic diseases aspiration sclerotherapy, 301303 polycystic liver disease, 303304 rare lesions, 305 simple biliary hepatic cysts, 301 Benign disease, 24 Benign inflammatory pseudotumors, 370 Benign solid tumors adult hemangioma, 262 capillary hemangioma, 262 cavernous hemangioma imaging features of, 263 management of, 263 pathology of, 262 classification of, 262 congenital hepatic fibrosis, 267 focal nodular hyperplasia imaging features of, 264 management of, 264 pathology of, 263 telangiectatic, 263 hepatocellular adenoma imaging features of, 265 management of, 265 pathology of, 264265 hepatocellular adenomatosis management of, 266267 pathology of, 265266 nodular regenerative hyperplasia, 266 pseudolipoma hereditary hemorrhagic telangiectasia, 268 heterotopic tissue, 268 inflammatory pseudotumor, 268 miscellaneous rare benign solid liver lesions, 268 peliosis hepatic, 267268 Benzimidazole, 321 Bevacizumab, 140, 176, 220 Bile duct hamartomas, 305 ultrasound applications, 3941 Bile duct injuries noniatrogenic bile duct strictures benign inflammatory pseudotumors, 370 biliary strictures secondary to pancreatitis, 369370 calculous disease, 370 sclerosing cholangitis, 370 patient-related factors acute cholecystitis, 360362 congenital abnormalities, 362363 procedure-related factors critical view technique, 365 misidentification concepts, 363365 technical problems, 365 surgeon/hospital-related factors laparoscopic equipment, 366 learning curve effect, 366 psychology of human error, 366 Bile ducts and liver, surgical anatomy anatomical hepatectomies, 56 anatomy of biliary exposure, 1213 arterial blood supply of, 1112 biliary anatomy, 1011 biliary tract, 6 caudate lobe, surgical approach, 6 cystic duct, 910 early application of functional anatomy, 1 extrahepatic biliary anatomy, 89 falciform ligament, 14 gallbladder, 910, 14 hepatic veins, 13 intrahepatic biliary anatomy, 78 ligamentum venosum, 14 morphological anatomy, 1 portal system, 1314 radiological anatomy of, 13 segmental anatomy of, 15 Bile fistula, 367 Bile leak, hepatectomy incidence, 65 prevention, 65 risk factors, 6566 Bile pigment stone, 373 Biliary adenoma, 267 Biliary atresia classification, 478 clinical features, 478 outcomes, 478 pathology, 478 surgical treatment, 478 Biliary colic, 373 Biliary decompression nonoperative technique, 402 operative technique, 402 Biliary drainage, 333334 Biliary dyspepsia, 375 Biliary hamartoma, 266267 Biliary injuries avoidance of, 366367 classification of, 360 iatrogenic, 360 incidence laparoscopic versus open cholecystectomy, 360 population-based studies, 360 management of intraoperative recognition, 367368 operative technique, 368369 preoperative preparation, 368 types of injuries, 368 outcome of treatment, 369 post-transplantation, 369 Biliary stricture, 356 after hepatectomy incidence of, 66 management of, 66 Bladder drainage, 473474 Bland embolization, 216218 Bleeding, hepatectomy incidence, 63 investigation and treatment, 65 presentation, 65 prevention, 6365 Body habitus, 363 Borderline tumors, 385 Brachytherapy, malignant biliary obstruction, 349350 Breast cancer, 54 noncolorectal, nonneuroendocrine metastases, 166 British Society of Gastroenterology, 346 BSG. See British Society of Gastroenterology BuddChiari syndrome, 280 CA19-9. See Carbohydrate antigen 19-9 Cambridge Classification of Chronic Pancreatitis, 451 Capecitabine, 173 Capillary hemangioma, 262 Carbamates, 321 Carbohydrate antigen 19-9, 382 Carcinoid symptom severity scale, 157 Carcinoid tumors, 154 Carcinoma fibrolamellar, 104 gallbladder, 104 hepatocellular, 104 Carolis disease, 357 Caspofungin, 259 Caudal pancreatic artery, 20 Caudate lobe, surgical approach, 6 Caval injury, 276 Cavernous hemangioma imaging features of, 263 management of, 263 pathology of, 262 CCA. See Cholangiocarcinoma CECT. See Contrast-enhanced computerized tomography Central pancreatectomy, 85 Cetuximab, 137, 176 CgA. See chromogranin A Charcots Triad of symptoms, 374 Chemical ablation, 195 Chemical splanchnicectomy, 403404 Chemo-embolization, 216218 Chemotherapeutic agents capecitabine, 173 irinotecan, 135 oxaliplatin, 135 Chemotherapeutic regimens, 173 Chemotherapy neuroendocrine tumors, 161 non-functional islet cell tumors, 428 Chemotherapy-associated hepatotoxicity diagnosis, 176177 monoclonal antibodies, 176 nonalcoholic fatty liver disease sinusoidal obstruction syndrome, 174176 steatohepatitis, 174 steatosis, 173174 preoperative chemotherapy, 178
490
INDEX
prevention, 177 Chemotherapy-associated nonalcoholic fatty liver disease diagnosis of, 173 sinusoidal obstruction syndrome, 174176 steatohepatitis, 174 steatosis, 173174 CHF. See Congenital hepatic fibrosis ChildTurcottePugh Score, 289 Chlorozotocin, 428 Cholangiocarcinoma liver and biliary tract lesions, 104 liver transplantation neoadjuvant chemoradiotherapy, 229231 organ allocation, 231 Cholecystenteric fistula, 374 Choledochal cysts adulthood clinical presentation, 354 complications, 355 diagnosis, 354355 etiology and classification, 354 incidence and pathophysiology, 354 treatment, 355358 classification, 479 clinical features, 480 imaging, 480 outcomes, 480 pathology, 479480 surgical treatment, 480 Choledochoduodenostomy, 91 Choledocholithiasis, 370 Choledochotomy, 9091 Cholelithiasis, 480 Cholestatic neonate, diagnostic evaluation in, 479 Cholesterol stones, 373 chromogranin A, 154 Chronic pancreatitis classification of, 451 comparison of different surgical approaches, 457458 complications of, 453454 congenital anomalies, 484 conservative treatment, 454 definition of, 451 duodenum-preserving resection Beger procedure, 456457 Berne procedure, 457 Hamburg procedure, 457 quality of life, 458 etiology pathomorphological findings, 452 indications for surgical intervention, 454455 interventional treatment, 454 natural course of, 451 pathogenesis of pain, 452453 rationale for drainage procedures, 455456 rationale for resectional procedures, 456 salvage procedures, 459 small duct disease, 458459 ultrasound findings in, 41 Ciliated foregut cysts, 305 Cirrhosis, 356 Cirrhotic liver, 266 cisPlatin, Interferon, Adriamycin, and 5-Fluorouracil, 219 Clinical risk score, 56 metastatic colorectal cancer, 120121 Clonorchis sinensis, 242 CMC. See Conventional Milan Criteria Color Doppler, 36 Colorectal cancer, 4748 Colorectal liver metastases, 4748 clinical risk scores, 120121 hepatic arterial infusion, 136137 multimodal strategies chemotherapy and surgery, 149150 computed tomography, 148149 magnetic resonance imaging, 149 management strategies, 150152 multidisciplinary team, 148 positron emission tomography, 149 preoperative staging, 148 resectability of, 149 resection margins, 149 strategies to improve respectability, 149 surgery, 149 tumor ablation, 150 natural history of, 118 patient evaluation patient selection, 118 preoperative imaging, 118119 tumor resectability, 118 postoperative management adjuvant intra-arterial chemotherapy, 123 adjuvant systemic chemotherapy, 122 nonresectable metastatic disease, 124126 outcomes of resection, 123124 repeat liver resection, 129130 resectability techniques, 126129 prognostic factors, 119120 resectable management preoperative management, 121 surgery approaches, 121122 thermal ablation CLOCC study, 184 cryotherapy, 180181 edge cryotherapy, 181 limitations of, 180 microwave coagulation, 183184 percutaneous ethanol injection, 184 radiofrequency ablation, 181183 Combined liver and portal vein resection, 339340 Common bile duct (CBD) stenosis, 453 Common bile duct stones non-surgical management drug dissolution therapy, 377 endoscopic removal of bile duct stones/biliary stenting, 377 lithotripsy, 377 surgical management laparoscopic common bile duct stone removal, 378 open choledocholithotomy, 377 Computed tomography choledochal cyst, 355 colorectal liver metastases, 148149 hydatid cyst, 311 liver and biliary tract lesions cholangiocarcinoma, 104 cross-sectional anatomy, 100 fibrolamellar carcinoma, 104 focal nodular hyperplasia, 102 gallbladder carcinoma, 104 hepatic hemangioma, 102 hepatocellular adenoma, 102, 104 hepatocellular carcinoma, 104 metastatic cancer to liver, 104 liver metastases, 109110 localization of insulinomas, 415 neuroendocrine tumors, 155 pancreatic ductal adenocarcinoma, 382383 pancreatic injuries, 463 pancreatic lesions acinar cell carcinoma, 107 cross-sectional anatomy, 100 metastatic cancer to pancreas, 107 pancreatic adenocarcinoma, 107 pancreatic neuroendocrine tumors, 106 solid pseudopapillary tumor, 106107 scanning, radiological anatomy of liver, 13 Congenital abnormalities, bile duct injuries, 362363 Congenital anomalies acute pancreatitis, 483484 adenocarcinoma, 484 annular pancreas, 483 chronic pancreatitis, 484 ectopic pancreatic rests, 483 pancreas divisum, 483 pancreatic abscess, 484 pancreatic pseudocyst, 484 persistent hyperinsulinemic hypoglycemia of infancy, 484 Congenital deformities, 480481 Congenital hepatic fibrosis, 267 CONKO-1, randomized controlled trail, 391392 Contrast-enhanced computerized tomography, 192 Contrast-enhanced ultrasound, liver metastases, 109 Conventional Milan Criteria, 193 Covered stents, 349 CP. See Central pancreatectomy; Chronic pancreatitis CRLM. See Colorectal liver metastases Cross-sectional imaging. See CT imaging, MRI characteristics CRS. See Clinical risk score Cryoablation, neuroendocrine tumors, 160
491
INDEX
Cryotherapy, 126 thermal ablation, 180181 Cryptogenic abscess, 256 CT. See Computed tomography Curative surgical resection, 394 Cyst aspiration, 301 Cyst fluid analysis, 411 Cystic dilatation. See Choledochal cyst Cystic fibrosis, 380381 Cystic lesions, 3637 Cystic metastases, 113 Cystic pancreatic neoplasms, 41 Cystic tumors clinical scenarios presentation and diagnostic evaluation, 407 treatment, 412 diagnostic evaluation, 411 pathologic sub-types and clinical behavior intraductal papillary mucinous neoplasm, 409410 mucinous cystic neoplasm, 410411 pancreatic pseudocyst, 407 serous cystadenoma, 407409 treatment recommendations intraductal papillary mucinous neoplasm, 412 mucinous cystic neoplasm, 412 DCCT. See Diabetes Control and Complication Trial DCD. See Donation after cardiac death DDLT. See Deceased donor liver transplantation Deceased donor liver graft retrieval of donation after cardiac death retrieval, 292 standard retrieval, 291 splitting of, 292 Deceased donor liver transplantation, 208213 Delayed gastric emptying, 81, 389 Detectable metastases, 401 Dexamethasone, 136 DGE. See Delayed gastric emptying Diabetes Control and Complication Trial, 475 Diabetic nephropathy, 475 Diagnostic laparoscopy palliation of pancreas cancer, 401402 pancreatic ductal adenocarcinoma, 383, 385 Diagnostic radiography, 402 Diarrhea, 417, 421 Diet, 380 Diffuse liver disease liver, 36 pancreas, 41 Diffusion-weighted MR imaging, 111 Direct cholangioscopy, 346 endoscopic therapy, 347 methods of therapy, 347 percutaneous drainage of jaundice, 348 Distal cholangiocarcinoma, 336337 Distal ductal pancreatic injuries, 466 Distal pancreatectomy, 7374, 416 Distal splenorenal shunt, 283284 Donation after cardiac death, 290291 Donor, pancreas, 471 Doppler ultrasound, 329 Dorsal liver dissection, 338 Dorsal pancreatic artery, 1920 DPPHR. See Duodenum-preserving pancreatic head resection Drug dissolution therapy common bile duct stones, 377 gallstone disease, 375 Drug-eluting microspheres, 218 DSRS. See Distal splenorenal shunt Ductal anatomy of pancreas, 17 Duodenal outlet obstruction, 402 Duodenal tumors, 419 Duodenum-preserving pancreatic head resection, 7576. See also Chronic pancreatitis Dysplastic nodules, 266 Eastern Cooperative Oncology Group, 421 EBRT. See External beam radiotherapy ECD. See Extended/Expanded criteria donor Echinococcal cysts, 102 ECOG. See European Cooperative Oncology Group Ectopic insulinomas, 414 Ectopic pancreatic rest, 483 Edge cryotherapy, thermal ablation, 181 EHD. See Extrahepatic disease Elderly patients, liver surgery age-related liver changes, 4647 colorectal liver metastases, 4748 financial cost, 50 hepatocellular carcinoma, 4850 surgical risk evaluation, 47 ELTR. See European Liver Transplant Registry Empyema, 373374 Endogenic vesiculation, 308 Endoluminal ultrasound cystic tumors, 411 pancreatic ductal adenocarcinoma, 383 Endoscopic assessment, malignant biliary obstruction causes of, 343 covered vs. uncovered stents, 349 CT scanning, 343 direct cholangioscopy, 346 endoscopic therapy, 347 methods of therapy, 347 percutaneous drainage of jaundice, 348 endoscopic intervention, 344 endoscopic retrograde cholangio-pancreatography, 344346 ERCP vs. PTC vs. surgery, 348 hilar strictures disease modifying treatment, 349 unilateral versus bilateral, 349 MR scanning, 343344 plastic vs. metal, 348349 radiological diagnostic imaging, 343 radiotherapy brachytherapy, 349350 photodynamic therapy, 350 ultrasound, 343 Endoscopic drainage, 443, 445 Endoscopic pancreatic sphincterotomy, 454 Endoscopic retrograde cholangiopancreatography acute pancreatitis antibiotics, 440 nutrition, 440 specific pharmacological intervention, 440 surgical intervention, 440 cystic tumors, 411 gallbladder cancer, 329 gallstone disease, 377 malignant biliary obstruction, 344346 pancreatic ductal adenocarcinoma, 383, 385 Endoscopic retrograde pancreatography, 464 Endoscopic therapy, 282283 Endoscopic ultrasound, 415416 malignant biliary obstruction, 344 Endoscopic variceal ligation, 282 End-stage liver disease, 288 Enteral feeding, 391 Enteric drainage, 474 Enucleation, 7677, 416 EORTC. See European Organization for Research and Treatment of Cancer EPIC. See Erbitux Plus Irinotecan in Colorectal Cancer Erbitux Plus Irinotecan in Colorectal Cancer, 137 ERCP. See Endoscopic retrograde cholangio-pancreaticography ESLD. See end-stage liver disease ESPAC-1, randomized controlled trail, 391393 ESWL. See Extracorporal shockwave lithotripsy European Cooperative Oncology Group, 137 European Liver Transplant Registry, 233 European Organization for Research and Treatment of Cancer, 141 EUS. See Endoluminal ultrasound EVL. See Endoscopic variceal ligation Exogenous vesiculation, 308, 310 Extended lymphadenectomy, 8485, 387 Extended resections, 387 Extended/Expanded criteria donor ABO-incompatible liver, 291 donation after cardiac death, 290291
492
INDEX
donors with infection, 290 donors with malignancy, 290 elderly donors, 289290 hepatitis B core antibody positive donors, 290 hepatitis C infection donors, 290 split-liver, 290 steatosis and abnormal liver function, 289 Extensive locoregional disease, 401 External beam radiotherapy, 230 Extracorporal shockwave lithotripsy, 454 Extrahepatic biliary anatomy, 89 Extrahepatic cholangiocarcinoma operative procedures combined liver and portal vein resection, 339340 distal cholangiocarcinoma, 336337 hepatobiliary resection for hilar cholangiocarcinoma, 337339 hepatopancreatoduodenectomy, 340 pancreatoduodenectomy, 336337 preoperative management biliary drainage, 333334 portal vein embolization, 334 staging of cholangiocarcinoma, 333 synbiotics treatments with bile replacement, 334336 surgical anatomy of bile duct, 333 Extrahepatic disease, 181183 Extrahepatic portal hypertension, 453 [18F] 2-fluoro-2-deoxyglucose, 111112 Familial pancreatic cancer syndrome, 380 Familial predisposition, 380 FAST. See Focused Assessment for Sonographic examination of Trauma patient FDA. See Food and Drug Administration FDG. See [18F] 2-fluoro-2-deoxyglucose; Fluorine-18-labeled fluoro-deoxyglucose Fertile cyst, 315 Fibrolamellar carcinoma, 104 Fine needle aspiration, 383, 440 FISH. See Fluorescent in situ hybridization FLC. See Fibrolamellar carcinoma Floxuridine, 136137 FLR. See Future liver remnant Fluorescent in situ hybridization, 229 Fluorine-18-labeled fluoro-deoxyglucose, 329 Fluorouracil, 135 5-Fluorouracil, 5859 FNA. See Fine needle aspiration FNH. See Focal nodular hyperplasia FNH-like lesions, 264 Focal fatty variants, 267 Focal hepatic lesions ultrasound applications cystic lesions, 3637 solid liver lesions, 3739 Focal nodular hyperplasia imaging features of, 264 liver and biliary tract lesions, 102 management of, 264 pathology of, 263 telangiectatic, 263 Focused Assessment for Sonographic examination of Trauma patient, 271 FOLFIRI, 121 FOLFOX, 121 Food and Drug Administration, 176, 218 FPC. See Familial pancreatic cancer syndrome FUDR. See Floxuridine Functional endocrine tumors comparison of, 415 definition, 414 Functional islet cell tumors definition of, 414 gastrinomas management of, 419 precise localization of, 417 preoperative evaluation, 418 sensitivity of invasive and non-invasive imaging studies, 418 symptoms of, 417 glucagonomas, 419420 insulinoma biochemical diagnosis of, 415 ectopic, 414 endoscopic ultrasound, 415416 intraoperative ultrasonography, 416 localization modalities for, 415416 symptoms, 415 somatostatinomas, 421 VIPomas, 420421 Fungal liver abscess, 258259 Future liver remnant, 67, 177 Gallbladder cancer adjuvant therapy, 331 clinical presentation and work-up, 329330 history of, 329 laparoscopically discovered disease adjuvant therapy, 204205 clinical presentation of, 199200 epidemiology of, 197198 palliative management, 205 pathology of, 198 patterns of spread, 198 radiologic workup, 200 staging systems, 198199 surgical management, 201204 liver and biliary tract lesions, 104 outcomes, 331 palliative care, 331332 surgical management, 330331 ultrasound applications, 3941 Gallbladder disease cholelithiasis, 480 congenital deformities, 480481 hemolytic cholelithiasis, 480 Gallstone acute cholangitis, 374 acute cholecystitis, 373 acute pancreatitis, 374375 biliary colic, 373 biliary dyspepsia, 375 cholecystenteric fistula, 374 classification of, 373 empyema, 373374 gallstone ileus, 374 ileus, 374 Mirrizis syndrome, 375 mucocele, 374 non-surgical management analgesia for biliary colic/ cholecystitis, 375 drug dissolution therapy, 375 percutaneous cholecystostomy, 375 obstructive jaundice, 374 surgical management, cholecystectomy laparoscopic cholecystectomy, 376 open cholecystectomy, 375376 operative technique, 376377 Gastric cancer, noncolorectal, nonneuroendocrine metastases, 167168 Gastric decompression nonoperative technique, 402403 operative technique, 403 Gastric outlet obstruction, 401402 Gastrinomas management of, 419 precise localization of, 417 preoperative evaluation, 418 sensitivity of invasive and non-invasive imaging studies, 418 symptoms of, 417 Gastrointestinal cancers, 55 Gastrojejunostomy, 402 isoperistaltic, 403 palliative, 403 Gelfoam, 216 Genitourinary tumors, 55 Giant cell tumors, 435 Giant hemangiomas, 37 -Glucuronidase, 242 Glucagonomas, 419420 Grade A fistulas, 389 Grade B fistulas, 389 Grade C fistulas, 389390 Great pancreatic artery, 20 Gynecological tumors, 166 HAE. See Hepatic artery embolization HAI. See Hepatic arterial infusion HALT. See Heterotopic auxiliary liver transplantation HAS. See Hepatic hemangiosarcoma HBV. See Hepatitis B Virus HCC. See Hepatocellular carcinoma Head and neck tumors, 168 HEHE. See Hepatic epithelioid hemangioendothelioma
493
INDEX
Hemangioma, 37 adult, 262 Hemolytic cholelithiasis, 480 Hemorrhage, 273274 Hepatectomy, 56 bile leak consequences of, 66 incidence, 65 management of, 66 presentation, 66 prevention, 65 risk factors, 6566 biliary stricture incidence of, 66 management of, 66 bleeding incidence, 63 investigation and treatment, 65 presentation, 65 prevention, 6365 cardiac complications, 69 hepatic insufficiency incidence, 66 optimization of venous drainage, 67 portal vein embolization, 67 prevention, 67 treatment, 6768 intra-abdominal infection abdominal drainage, 68 factors affecting, 68 pain relief, 6869 renal failure consequences of, 6970 etiology of, 69 renal impairment, 70 respiratory complications, 6869 wound complications, 70 Hepatic abscess. See Liver abscess Hepatic arterial infusion, 136137 Hepatic arterial infusional chemotherapy, 59 Hepatic artery embolization, 427 neuroendocrine tumors, 156158 Hepatic cryoablation, 160 Hepatic epithelioid hemangioendothelioma, 233235 Hepatic hemangioma, 102 Hepatic hemangiosarcoma, 237238 Hepatic infantile hemangioendothelioma, 235237 Hepatic metastasectomy adjuvant chemotherapy, 5859 colorectal metastases, 53 neuroendocrine metastases, 53 noncolorectal metastases, 5455 nonneuroendocrine metastases, 5455 patient selection colorectal metastases, 55 neuroendocrine tumors, 56 noncolorectal tumors, 56 nonneuroendocrine tumors, 56 resection techniques ablative techniques, 5758 morbidity and mortality, 57 segmental resections, 57 wedge resections, 5657 Hepatic metastases, neuroendocrine tumors clinical features, 154 cryoablation, 160 diagnostic imaging, 155 hepatic artery embolization, 156158 hepatic resection, 156 laboratory investigation, 154 liver transplantation, 160161 medical treatment, 161 radiofrequency ablation, 158, 160 radionuclide therapy, 161 WHO classification of, 155 Hepatic portoenterostomy, 478 Hepatic radiofrequency ablation, 158, 160 Hepatic resection basic principles anesthetic techniques, 25 benign disease, 24 malignant disease, 24 patient selection, 2425 preoperative imaging, 25 basic techniques exposure, 25 mobilization, 2527 positioning, 25 skin incision, 25 left hemihepatectomy, 32 left lateral sectionectomy, 3233 left trisectionectomy, 32 neuroendocrine tumors, 156 renal failure after consequences of, 6970 etiology of, 69 right hemihepatectomy, 3031 right trisectionectomy, 31 vascular isolation inflow control, 2728 outflow control, 2829 parenchymal transaction, 29 wedge vs. segmental resection central hepatectomy, 34 segment 4, 33 segmentectomy I, caudate resection, 33 segments 2/3, 33 segments 5 and 8, anterior sector, 33 segments 6 and 7, posterior sector, 3334 Hepatic steatosis, 36 Hepaticojejunostomy, 337 Hepatitis B virus, 208 Hepatobiliary resection for hilar cholangiocarcinoma, 337339 Hepatoblastoma clinical features, 481 imaging, 481 incidence, 481 outcomes, 481 pathology, 481 staging, 481 surgical treatment, 481 Hepatocellular adenoma imaging features of, 265 liver and biliary tract lesions, 102, 104 management of, 265 pathology of, 264265 Hepatocellular adenomatosis management of, 266267 pathology of, 265266 Hepatocellular carcinoma advanced stage, 195 diagnosis, 192 early stages chemical ablation, 195 liver resection, 193195 liver transplant, 195 thermal ablation, 195 intermediate stage, 195 liver and biliary tract lesions, 104 liver surgery, in elderly patients, 4850 liver transplantation in Asia, 208 pretransplant neoadjuvant therapy, 211212 recurrence treatment, 212213 selection criteria and outcomes, 209211 local regional therapies arterial embolization, 216 bland embolization, 216218 chemo-embolization, 216218 drug-eluting microspheres, 218 percutaneous chemical/thermal ablation, 218219 radio-embolization, 218 pediatric hepato-pancreato-biliary disorders clinical features, 482483 incidence, 481 outcomes, 483 pathology, 482 surgical treatment, 483 staging systems, 192 systemic therapies advanced cirrhosis treatment, 220 anti-angiogenic therapies, 219220 cisPlatin, interferon, adriamycin, and 5-fluorouracil, 219 future developments, 220221 historical background, 219 treatment options, 192193 ultrasound applications, 38 variceal bleeding, 281 Hepatocyte transplantation, 297 Hepatopancreatoduodenectomy, 340 Hepatopulmonary syndrome, 285 Hepatotomy, 275276 Hereditary chronic pancreatitis, 452 Hereditary hemorrhagic telangiectasia, 268 Hereditary pancreatitis, 380 Hereditary tumor syndromes, 380 Heterotopic auxiliary liver transplantation, 295
494
INDEX
Heterotopic tissue, 268 HHT. See Hereditary hemorrhagic telangiectasia 5-HIAA. See 5-Hydroxyindoleacetic acid High-affinity somatostatin receptors, 424 High-grade pancreatic injuries, 466 HIHE. See Hepatic infantile hemangioendothelioma Hilar cholangiocarcinoma anatomic right trisectionectomy, 339 intrahepatic cholangiojejunostomy, 339 left trisectionectomy, 338 left-sided hepatectomy, 337 liver transplantation neoadjuvant chemoradiotherapy, 229231 organ allocation, 231 right hepatectomy, 338339 right trisectionectomy, 338 Hilar strictures, malignant biliary obstruction disease modifying treatment, 349 unilateral vs. bilateral, 349 HistidineTryptophanKetoglutarate, 471 Hockey stick incision, 25 HPD. See Hepatopancreatoduodenectomy HPE. See Hepatic portoenterostomy HPS. See Hepatopulmonary syndrome HT. See Hepatocyte transplantation HTK. See HistidineTryptophan Ketoglutarate 5-HTP. See 5-Hydroxytryptophan Human error, psychology of, 366 Hydatid cyst, 102 biological basis of surgery, 308 complications infection, 313 rupture, 313314 conservative procedures, 316317 diagnostic imaging angiography, 313 computed tomography, 311 magnetic resonance imaging, 311 radioisotope imaging, 313 ultrasonography, 311 intraoperative approach, 315316 laparoscopy, 320 medical therapy, 321 pathological basis of surgery, 308 puncture aspiration injection reaspiration, 320321 radical procedures, 317320 serology of, 313 structure of, 308310 topography, 314315 treatment, 315 5-Hydroxyindoleacetic acid, 154 5-Hydroxytryptophan, 424 Hyperglycemia, 471 Hypersplenism, 280 Hypervascular metastases, 113 Hypoechoic halo, 38 Hypoechoic liver, 39 Iatrogenic biliary injuries, 360 ICC. See Intrahepatic cholangiocarcinoma IG-ICC. See Intraductal growth type of intrahepatic cholangiocarcinoma Immune tolerance, 297 Immunosuppression, 475 Indocyanine green (ICG) test, 67, 334 Infants, gallstones, 480 Inferior pancreaticoduodenal artery, 19 Inflammatory pseudotumor, 268 Infundibular technique, 364 Injury grading, 463 Institutional factors, 85 Insulinoma biochemical diagnosis of, 415 ectopic, 414 endoscopic ultrasound, 415416 intraoperative ultrasonography, 416 laparoscopic enucleation, 93 localization modalities for, 415416 symptoms, 415 Interferon, 161 International Pancreas Transplant Registry, 470 International Registry of Hepatic Metastases of Colorectal Cancer, 123 International Union against Cancer, 21 Intraabdominal abscesses, 390 Intra-abdominal infection, hepatectomy abdominal drainage, 68 factors affecting, 68 Intra-arterial chemotherapy, 125126 Intra-arterial infusion therapies bland embolization, 216218 chemo-embolization, 216218 radio-embolization, 218 Intrabiliary metastases, 113 Intraductal growth type of intrahepatic cholangiocarcinoma, 223 Intraductal papillary mucinous neoplasm, 385, 409410, 412 Intrahepatic biliary anatomy, 78 Intrahepatic cholangiocarcinoma, resection of adjuvant therapy, 226 classification and terminology, 223 epidemiology, 223 pre-operative diagnosis, 223224 prognosis factors, 225226 risk factors, 223 surgical strategy, 224225 Intrahepatic cholangiojejunostomy, 339 Intrahepatic gallbladder, 363 Intrahepatic portal hypertension, 267, 280 Intraoperative cholangiography, 364365 Intraoperative pancreatography pancreatic injuries, 465466 Intraoperative ultrasonography, 416 Intraoperative ultrasound, 4243 colorectal liver metastases, 122 Intravenous erythromycin, 389 IOC. See Intraoperative cholangiography IOUS, Intraoperative ultrasound IPMN. See Intraductal papillary mucinous neoplasm Irinotecan, 135 Isolated liver metastases, 109 Isolated pancreatic metastases, 435 Isoperistaltic gastrojejunostomy, 403 Japan Integrated Staging score, 192 Jaundice, 367 Juxtahepatic injury, 276 Laparoscopic cholecystectomy, 89 common bile duct stones, 378 gallstone disease, 376 Laparoscopic common bile duct exploration choledochoduodenostomy, 91 choledochotomy, 9091 transcystic flushing, 89 transcystic stone extraction, 8990 Laparoscopic cystgastrostomy, 443 Laparoscopic distal pancreatectomy, 93 Laparoscopic enucleation, 93 Laparoscopic liver resection, 9395 Laparoscopic palliative bypass, 92 Laparoscopic pancreatectomy, 85, 9293 Laparoscopic pancreaticoduodenectomy, 93 Laparoscopic port sites, 204 Laparoscopic staging, 9192 Laparoscopically discovered gallbladder cancer adjuvant therapy, 204205 clinical presentation of, 199200 epidemiology of, 197198 palliative management, 205 pathology of, 198 patterns of spread, 198 radiologic workup, 200 staging systems, 198199 surgical management advanced tumors, 202 complications, 204 laparoscopic port sites, 204 liver resection, 203204 lymph node dissection, 204 re-resection after laparoscopic cholecystectomy, 202203 tumor invading into the subserosal layer, 201202 tumors confined to the muscular propria, 201 Laparotomy/Debridement with closed lavage, 443 closed packing, 441 with drainage, 441 laparostomy with open packing, 441, 443 minimally invasive approaches, 443 Laser lithotripsy, 377 Late stricture, of choledochojejunostomy, 468 LDLT. See Living donor liver transplantation l-DOPA. See l-Dihydroxyphenylalanine Learning curve effect, 366 Left hemihepatectomy, 32
495
INDEX
Left lateral sectionectomy, 3233 Left trisectionectomy hepatic resection, 32 hilar cholangiocarcinoma, 338 Left-sided hepatectomy, 337 Lexipafant, 440 LGSW. See Liver gunshot wounds Ligasure device, 94 Lipase, 483 Lipoma, 267 Lithotripsy, 377 Liver and bile ducts, surgical anatomy anatomical hepatectomies, 56 anatomy of biliary exposure, 1213 arterial blood supply of, 1112 biliary anatomy, 1011 biliary tract, 6 caudate lobe, surgical approach, 6 cystic duct, 910 early application of functional anatomy, 1 extrahepatic biliary anatomy, 89 falciform ligament, 14 gallbladder, 910, 14 hepatic veins, 13 intrahepatic biliary anatomy, 78 ligamentum venosum, 14 morphological anatomy, 1 portal system, 1314 radiological anatomy of, 13 segmental anatomy of, 15 and biliary tract lesions, CT and MRI imaging cholangiocarcinoma, 104 cross-sectional anatomy, 100 fibrolamellar carcinoma, 104 focal nodular hyperplasia, 102 gallbladder carcinoma, 104 hepatic hemangioma, 102 hepatocellular adenoma, 102, 104 hepatocellular carcinoma, 104 metastatic cancer to liver, 104 hydatid cyst biological basis of surgery, 308 complications, 313314 conservative procedures, 316317 diagnostic imaging, 311, 313 intraoperative approach, 315316 laparoscopy, 320 medical therapy, 321 pathological basis of surgery, 308 puncture aspiration injection reaspiration, 320321 radical procedures, 317320 serology of, 313 structure of, 308310 topography, 314315 treatment, 315 ultrasound applications diffuse liver disease, 36 focal hepatic lesions, 3639 Liver abscess, 356 amebic abscess diagnosis of, 253254 epidemiology of, 253 outcomes of, 255 pathogenesis of, 253 treatment of, 254255 fungal abscess, 258259 pyogenic abscess diagnosis of, 256257 epidemiology of, 255 microbiology of, 256 outcomes of, 258 pathogenesis of, 255256 treatment of, 257258 Liver biopsy, 478 Liver Cancer Study Group of Japan, 223 Liver failure, 48 Liver gunshot wounds, 274275 Liver metastases computed tomography, 109110 contrast-enhanced ultrasound, 109 detection, 114115 imaging findings cystic metastases, 113 hypervascular metastases, 113 intrabiliary metastases, 113 pitfalls and limitations, 113 magnetic resonance imaging, 110111 perfusion imaging, 112 positron emission tomography, 111112 preoperative staging, 115116 ultrasound techniques, 109 Liver resection laparoscopically discovered gallbladder cancer, 203204 stages of hepatocellular carcinoma, 193195 types of, 122 Liver support devices, 295, 297 Liver surgery, elderly patients age-related liver changes, 4647 colorectal liver metastases, 4748 financial cost, 50 hepatocellular carcinoma, 4850 surgical risk evaluation, 47 Liver transplantation for acute and chronic liver failure auxiliary liver transplantation, 294295 donor selection, 289291 future perspectives, 295, 297 orthotopic liver transplantation, 292294 recipient selection, 288289 retrieval of deceased donor liver graft, 291292 splitting of deceased donor liver graft, 292 in Asia, 208209 hepatocellular carcinoma pretransplant neoadjuvant therapy, 211212 recurrence treatment, 212213 selection criteria and outcomes, 209211 hilar cholangiocarcinoma neoadjuvant chemoradiotherapy, 229231 organ allocation, 231 neuroendocrine tumors, 160161 stages of hepatocellular carcinoma, 195 variceal bleeding, 284 Liver trauma anatomical hepatic resection, 276277 classification of, 271 complications of non-operative management, 273274 definitive surgical procedures, 275 early decision making during laparotomy, 275 hepatotomy, 275276 liver gunshot wounds, 274275 liver injuries, 274 manouevres, 276 non-anatomic liver resection, 276 non-operative management of liver injury, 272273 perihepatic packing, 275 refractory bleeding, 275 selective vascular ligation, 275276 LiverMetSurvey, 123 Living donor liver transplantation, 208213 Living-donor pancreas procurement, 472 Local regional therapies arterial embolization, 216 bland embolization, 216218 chemo-embolization, 216218 drug-eluting microspheres, 218 percutaneous chemical/thermal ablation, 218219 radio-embolization, 218 Low-grade pancreatic injuries, 466 LPSP. See Lymphoplasmacytic sclerosing pancreatitis LT. See Liver transplantation lDihydroxyphenylalanine, 424 Lymph node dissection, 337 laparoscopically discovered gallbladder cancer, 204 Lymphadenopathy, 343 Lymphatic drainage of pancreas, 2122 Lymphoplasmacytic infiltration, 452 Lymphoplasmacytic sclerosing pancreatitis, 436 Macrocystic mucinous tumors, 41 Magnetic resonance cholangiography, 245 Magnetic resonance cholangiopancreaticography cystic tumors, 411 malignant biliary obstruction, 344 pancreatic ductal adenocarcinoma, 383 pancreatic injuries, 464 Magnetic resonance imaging colorectal liver metastases, 149 hydatid cyst, 311
496
INDEX
liver and biliary tract lesions cholangiocarcinoma, 104 cross-sectional anatomy, 100 fibrolamellar carcinoma, 104 focal nodular hyperplasia, 102 gallbladder carcinoma, 104 hepatic hemangioma, 102 hepatocellular adenoma, 102, 104 hepatocellular carcinoma, 104 metastatic cancer to liver, 104 liver metastases, 110111 neuroendocrine tumors, 155 pancreatic lesions acinar cell carcinoma, 107 cross-sectional anatomy, 100 metastatic cancer to pancreas, 107 pancreatic adenocarcinoma, 107 pancreatic neuroendocrine tumors, 106 solid pseudopapillary tumor, 106107 Malignant biliary obstruction causes of, 343 covered vs. uncovered stents, 349 CT scanning, 343 direct cholangioscopy, 346 endoscopic therapy, 347 methods of therapy, 347 percutaneous drainage of jaundice, 348 endoscopic intervention, 344 endoscopic retrograde cholangio-pancreatography, 344346 ERCP vs. PTC vs. surgery, 348 hilar strictures disease modifying treatment, 349 unilateral vs. bilateral, 349 MR scanning, 343344 operative vs. nonoperative palliation of, 404 plastic vs. metal, 348349 radiological diagnostic imaging, 343 radiotherapy brachytherapy, 349350 photodynamic therapy, 350 ultrasound, 343 Malignant disease, 24 Malignant gastroduodenal obstruction, 404 Malignant insulinomas, 416 MarseilleRome classification of chronic pancreatitis, 451 Mass-forming type of intrahepatic cholangiocarcinoma, 223 Mayo Clinic protocol, 230 MCN. See Mucinous cystic neoplasm MCT. See Microwave coagulation MdCT. See Multidetector computed tomography Mebendazol, 321 Medullary carcinoma, 436 Melanoma, 5455 noncolorectal, nonneuroendocrine metastases, 169 Memorial Sloan-Kettering Cancer Center, 201 MEN-1 syndrome, 423 Mercedes incision, 25 Mesenchymal hamartoma, 268, 305 Mesh hepatorrhaphy technique, 275 Metastasis resections, 7879 Metastatic cancer to liver, 104 to pancreas, 107 Metastatic colorectal cancer clinical risk scores, 120121 patient evaluation patient selection, 118 preoperative imaging, 118119 tumor resectability, 118 postoperative management adjuvant intra-arterial chemotherapy, 123 adjuvant systemic chemotherapy, 122 nonresectable metastatic disease, 124126 outcomes of resection, 123124 repeat liver resection, 129130 resectability techniques, 126129 prognostic factors, 119120 resectable management preoperative management, 121 surgery approaches, 121122 unresectable liver disease coverting to resection, 138140 regional chemotherapy, 136137 systemic chemobiologic therapy, 137138 systemic chemotherapy, 135136 systemic therapy, 140141 Metastatic disease, pancreas, 434435 Metronidazole, 246 MF-ICC. See Mass-forming type of intrahepatic cholangiocarcinoma MIBG. See Radiolabeled metaiodobenzylguanidine Microsatellite instability, 436 Microwave ablation, 183184 Microwave coagulation, 183184 Mild postpancreatectomy hemorrhage, 391 Mirrizis syndrome, 375 Misidentification injuries, 367 Mixed stones, 373 Monoclonal antibodies, 176 MRCP. See Magnetic resonance cholangiopancreaticography MRI. See Magnetic resonance imaging MSI. See Microsatellite instability MSKCC. See Memorial Sloan-Kettering Cancer Center Mucinous cystic neoplasm, 410412 Mucocele, 374 Multidetector computed tomography cystic tumors, 411 pancreatic ductal adenocarcinoma, 383 Multimodal strategies, colorectal liver metastases chemotherapy and surgery, 149150 computed tomography, 148149 magnetic resonance imaging, 149 management strategies, 150152 multidisciplinary team, 148 positron emission tomography, 149 preoperative staging, 148 resectability of, 149 resection margins, 149 strategies to improve respectability, 149 surgery, 149 tumor ablation, 150 Multiple single antibiotics, 257 Multivesicular cyst, 315 Multivisceral resections, 78 NAFLD. See Nonalcoholic fatty liver disease National Cancer Database, 198 National Cancer Institute of Canada, 137 National Pediatric Trauma Registry, 466 Natural orifice transabdominal endoscopic surgery, 91 NCIC. See National Cancer Institute of Canada Necrosis, acute pancreatitis, 441 Neoadjuvant chemoradiotherapy liver transplantation, hilar cholangiocarcinoma, 229231 Neoadjuvant chemotherapy, 121 Neoadjuvant systemic chemotherapy, 139 Neonatal cholestasis, 479 NETs. See Neuroendocrine tumors Neuroendocrine metastases, 53 Neuroendocrine tumor hepatic metastasis clinical features, 154 cryoablation, 160 diagnostic imaging, 155 hepatic artery embolization, 156158 hepatic resection, 156 laboratory investigation, 154 liver transplantation, 160161 medical treatment, 161 radiofrequency ablation, 158, 160 radionuclide therapy, 161 WHO Classification of, 155 Neuroendocrine tumors, 41, 56, 154 Nodular regenerative hyperplasia, 239, 266 NOMLI. See Non-operative management of liver injury Nonalcoholic fatty liver disease, 173 Non-anatomic liver resection, 276 Nonanatomical hepatectomies, 5 Noncolorectal metastases, 5455 Noncolorectal, nonneuroendocrine metastases breast cancer, 166 gastric cancer, 167168 gynecological tumors, 166 head and neck tumors, 168 melanoma, 169 pancreatic cancer, 167 predictive factors determining clinical outcome, 169170 renal cell cancer, 166167 respiratory tract, 168
497
INDEX
Noncolorectal, nonneuroendocrine metastases (Continued) sarcoma, 168169 Noncolorectal tumors, 56 Non-functional islet cell tumors, 421422 clinical presentation of, 422423 curative resection and survival, 426 curative surgery treatment for metastatic disease, 426427 for the primary tumor, 425426 extent of disease and localization, 423424 location of, 422 prognosis, 428 surgical palliation and survival, 427 treatment chemotherapy, 428 octreotide, 428 palliative surgery, 427 radiation therapy, 428 Non-functioning islet cell tumors, 414 Noniatrogenic bile duct strictures benign inflammatory pseudotumors, 370 biliary strictures secondary to pancreatitis, 369370 calculous disease, 370 sclerosing cholangitis, 370 Nonneuroendocrine metastases, 5455 Nonneuroendocrine tumors, 56 Non-operative management of liver injury, 272273 Nonparasitic simple hepatic cysts, 102 Nonresectable metastatic disease intra-arterial chemotherapy, 125126 management of, 124 systemic chemotherapy, 124125 NOTES. See Natural orifice transabdominal endoscopic surgery NRH. See Nodular regenerative hyperplasia Nutrition, 440 Obesity, 363 Obstructive chronic pancreatitis, 452 Obstructive jaundice, 334, 374, 401 Octreotide, 84 non-functional islet cell tumors, 428 Octreotide acetate, 420 Ocular melanoma, 55 OGTP. See osteoclast-like giant cell tumor of pancreas OIS-AAST. See Organ Injury Scaling Committee of the American Association for the Surgery of Trauma Okuda Classification, 192 OLT. See Orthotopic liver transplant Open cholecystectomy common bile duct stones, 377 gallstone disease, 375376 Organ Injury Scaling Committee of the American Association for the Surgery of Trauma, 463464 Oriental cholangiohepatitis, 370 Orthotopic liver transplantation, 192195 for acute and chronic liver failure immunosuppression, 292293 operative technique of, 292 outcomes in, 293294 post-operative management, 292293 Osteoclast-like giant cell tumor of pancreas, 435 Oxaliplatin, 135 Oxaliplatin-associated neurotoxicity, 140 Pain, 367 palliation of, 403405 Painless jaundice, 381 PAIR. See Puncture aspiration injection reaspiration PAK. See Pancreas after kidney transplant Palliation indications for, 401402 nonoperative techniques biliary decompression, 402 gastric decompression, 402403 operative techniques biliary decompression, 402 gastric decompression, 403 vs. nonoperative techniques, 404405 of pain, 403405 Palliative gastrojejunostomy, 403 Palliative surgery, non-functional islet cell tumors, 427 Palliative therapy, laparoscopically discovered disease, 205 Pancreas after kidney transplant, 470 Pancreas divisum, congenital anomalies, 483 Pancreas transplant alone, 470 Pancreas transplantation effects on secondary complications of diabetes, 474475 immunosuppression, 475 indications, 470471 outcomes, 474 pancreas donor, 471 pancreas recipient, 471 recipient categories pancreas after kidney transplant, 470 pancreas transplant alone, 470 simultaneous kidney and pancreas transplant, 470 recipient operations bladder drainage, 473474 enteric drainage, 474 portal venous drainage, 473 surgical complications, 474 systemic venous drainage, 472473 surgical techniques backtable preparation, 472 procurement, 471472 Pancreatectomy bile leak, 82 death, 83 delayed gastric emptying, 81 factors affecting complication rates extended lymphadenectomy, 8485 institutional factors, 85 laparoscopic pancreatectomy, 85 octreotide, 84 pancreatic duct management following resection, 8384 patient factors, 85 peritoneal drainage, 84 pylorus-preserving pancreaticoduodenectomy, 84 resection of contiguous structures, 8485 total and central pancreatectomy, 85 pancreatic anastomotic leak, 81 pancreatic fistula, 81 postpancreatectomy hemorrhage, 8182 Pancreatic abscess, congenital anomalies, 484 Pancreatic adenocarcinoma, 107 Pancreatic anastomotic leak, 81 Pancreatic cancer common symptoms, 401 diet as risk factor, 380 dietary factors, 381 noncolorectal, nonneuroendocrine metastases, 167 randomized controlled trials, 382383 Pancreatic duct, integrity of, 465466 Pancreatic duct management following resection, 8384 Pancreatic ductal adenocarcinoma adjuvant treatment, 391394 clinical presentation, 381 diagnosis and staging, 381385 epidemiology of, 380 etiology of, 380381 management of, 385 mortality and morbidity, 387399 delayed gastric emptying, 389 intraabdominal abscesses, 390 postoperative pancreatic fistula, 389390 postpancreatectomy hemorrhage, 390391 neoadjuvant treatment, 387 postoperative treatment, 391 preoperative biliary drainage, 385 prognosis, 394 risk factors, 380381 surgical resection extended lymphadenectomy, 387 extended resections, 387 pancreaticenteric anastomosis, 386387 standard vs. pylorus-preserving pancreatoduodenectomy, 385386 symptoms, 381 Pancreatic endocrine tumors classification, 414 functional islet cell tumors gastrinomas, 417419 glucagonomas, 419420 insulinoma, 414416
498
INDEX
somatostatinomas, 421 VIPomas, 420421 non-functioning islet cell tumors clinical presentation of, 422423 curative resection and survival, 426 curative surgery treatment, 425427 extent of disease and localization, 423424 location of, 422 prognosis, 428 surgical palliation and survival, 427 treatment, 427428 Pancreatic exocrine secretions, 474 Pancreatic fistula, 81 Pancreatic fluid, 389 Pancreatic inflammation, 439 Pancreatic injury diagnosis clinical presentation, 463 intraoperative exposure and evaluation, 464465 intraoperative pancreatography, 465466 laboratory investigations, 463 radiologic investigations, 463464 epidemiology of, 463 injury grading, 463 nonoperative management, 466 operative management distal ductal injuries, 466 high-grade injuries, 466 low-grade injuries, 466 proximal ductal injuries, 467 outcomes complications, 467 late stricture, 468 mortality, 467 pancreatic insufficiency, 468 pancreatic leaks and fistulae, 467 peripancreatic fluid collection, 467468 pseudocysts, 467468 Pancreatic ischemia, 453 Pancreatic leaks, 467 Pancreatic lesions, CT and MRI imaging acinar cell carcinoma, 107 cross-sectional anatomy, 100 metastatic cancer to pancreas, 107 pancreatic adenocarcinoma, 107 pancreatic neuroendocrine tumors, 106 solid pseudopapillary tumor, 106107 Pancreatic lymphoma, 434 Pancreatic main duct stenosis, 452 Pancreatic neoplasms, 4142. See also Non-functioning islet cell tumors Pancreatic neuroendocrine tumors, 435 pancreatic lesions, 106 Pancreatic polypeptideoma, 423 Pancreatic pseudocyst, 407 congenital anomalies, 484 Pancreatic pseudocysts, 91 Pancreatic resections distal pancreatectomy, 7374 duodenum-preserving pancreatic head resection, 7576 enucleation, 7677 metastasis resections, 7879 multivisceral resections, 78 recurrence resections, 78 segmental resections, 76 total pancreatectomy, 7475 vessel resections, 7778 Whipple resection, 73 Pancreatic trauma, 463 Pancreaticopleural fistulas, 453 Pancreaticenteric anastomosis, 386387 Pancreatitis, choledochal cyst, 356 Pancreatoduodenectomy vs. pylorus-preserving pancreatoduodenectomy, 336337 Panitumumab, 137 Parasympathetic innervation, 22 Partial pancreaticoduodenectomy, 73 Partial surgical shunts, 283 Patient-related factors, bile duct injury acute cholecystitis, 360362 congenital abnormalities, 362363 Paucity, 478 PBD. See Preoperative biliary drainage PCLD. See Polycystic liver disease PDAC. See Pancreatic ductal adenocarcinoma PDT. See Photodynamic therapy Pediatric hepato-pancreato-biliary disorders biliary atresia, 478 choledochal cysts, 479480 congenital anomalies, 483484 gallbladder disease, 480481 hepatoblastoma, 481 hepatocellular carcinoma, 481483 PEI. See Percutaneous ethanol injection Peliosis hepatic, 267268 Percutaneous catheter drainage, 443444 Percutaneous chemical/thermal ablation, 218219 Percutaneous cholangio-drainage, 385 Percutaneous cholecystostomy, 375 Percutaneous drainage of jaundice, 348 Percutaneous ethanol injection, 184 Percutaneous necrosectomy, 443, 446 Percutaneous transhepatic biliary drainage, 247248 Percutaneous transhepatic cholangiography, 348, 367 Perfusion imaging, 112 Perihepatic packing, 275 Peripancreatic fluid collection, 467468 Peritoneal drainage, 84 Peroral cholangioscopy, 333 Persistent hyperinsulinemic hypoglycemia of infancy, 484 PET. See Positron emission tomography PET-CT. See Positron emission tomography with CT Pharmacologic therapy, 282283 PHHI. See Persistent hyperinsulinemic hypoglycemia of infancy Photodynamic therapy, 350 Photofrin, 350 PIAF. See cisPlatin, Interferon, Adriamycin, and 5-Fluorouracil Pleomorphic giant cell carcinoma, 435 PNET. See Pancreatic neuroendocrine tumors POC. See Peroral cholangioscopy Polycystic liver disease clinical presentation, 303304 Gigot classification of, 304 novel treatments, 305 surgical treatment, 304305 POPF. See Postoperative pancreatic fistula Portal hypertension causes of, 281 clinical manifestations ascites, 280 hepatocellular carcinoma, 281 hypersplenism, 280 pulmonary syndromes, 280281 variceal bleeding, 280 etiology of, 280 evaluation, 281 and general surgeon, 285286 pathophysiology of, 280 Portal vein embolization, 67, 334 tumor respectability, 126 Portal venous drainage, 473 Portopulmonary syndromes, 285 Positron emission tomography colorectal liver metastases multimodal approaches, 149 with computer tomography, 383 gallbladder cancer, 329 liver metastases, 111112 neuroendocrine tumors, 155 Posterior inferior pancreaticoduodenal artery, 19 Posterior superior pancreaticoduodenal artery, 1819 Posthepatectomy infections, 68 Postoperative bile leak consequences of, 66 management of, 66 presentation, 66 Postoperative pancreatic fistula definition, 390 grade A fistulas, 389 grade B fistulas, 389 grade C fistulas, 389390 pancreatic fluid, 389 Postoperative treatment, pancreatic ductal adenocarcinoma, 391 Postpancreatectomy hemorrhage, 8182 intraluminal and extraluminal, 390 mild, 391 severe, 391 PPH. See Portopulmonary syndromes; Postpancreatectomy hemorrhage PPL. See Primary pancreatic lymphoma PPoma. See Pancreatic polypeptideoma
499
INDEX
Ppower Doppler, 36 ppPD. See Pylorus-preserving pancreatoduodenectomy Preoperative biliary drainage, 385 Primary pancreatic lymphoma, 434 Primary prophylaxis, 281282 Primary resection therapy, 194 Primary sclerosing cholangitis cholangiocarcinoma, 324325 diagnosis of, 324 endoscopic treatment, 325 medical treatment, 325 natural history of, 324 surgical management, 325327 Procedure-related factors, bile duct injury critical view technique, 365 misidentification concepts, 363365 technical problems, 365 Procurement surgical technique, 471472 Prophylactic octreotide, 84 Proton pump inhibitors, 417 Proximal ductal pancreatic injuries, 467 PSC. See Primary sclerosing cholangitis Pseudocysts, 467468 Pseudolipoma hereditary hemorrhagic telangiectasia, 268 heterotopic tissue, 268 inflammatory pseudotumor, 268 miscellaneous rare benign solid liver lesions, 268 peliosis hepatic, 267268 PTA. See Pancreas transplant alone PTC. See Percutaneous trans-hepatic cholangiography PTCD. See Percutaneous cholangio-drainage Pulmonary syndromes, 280281 Puncture aspiration injection reaspiration, 320321 PVE. See Portal vein embolization Pylorus-preserving pancreaticoduodenectomy, 84, 385386 Pyogenic liver abscess diagnosis of, 256257 epidemiology of, 255 microbiology of, 256 outcomes of, 258 pathogenesis of, 255256 treatment of, 257258 Pyrexia, 440 Radiation therapy, 428 Radiochemotherapy, 391 Radio-embolization, 218 Radiofrequency ablation, 126 thermal ablation, 181183 Radioisotope imaging, hydatid cyst, 313 Radiolabeled metaiodobenzylguanidine, 155 Radionuclide therapy, neuroendocrine tumors, 161 Randomized controlled trail operative vs. nonoperative palliation malignant biliary obstruction, 404 malignant gastroduodenal obstruction, 404 pancreatic ductal adenocarcinoma CONKO-1, 391392 ESPAC-1, 391393 Rapamycin, 235 Rare benign cystic lesions, 305 Rare benign solid liver lesions, 268 Rare tumors acinar cell carcinoma, 432 adenosquamous carcinoma, 432434 autoimmune pancreatitis, 436437 giant cell tumors, 435 medullary carcinoma, 436 metastatic disease, pancreas, 434435 pancreatic lymphoma, 434 renal cell carcinoma, 434 solid pseudopapillary neoplasm, 432 Von HippelLindau syndrome, 435 Rare vascular liver tumors hepatic epithelioid hemangioendothelioma, 233235 hepatic hemangiosarcoma, 237238 hepatic infantile hemangioendothelioma, 235237 nodular regenerative hyperplasia, 239 RCC. See Renal cell carcinoma Recurrence resections, 78 Recurrent metastatic disease, 129130 Recurrent pyogenic cholangitis acute management, 246247 clinical presentation, 244245 complications, 250 definitive management, 247 definitive surgery, 248250 hematological and biochemical investigations, 245246 minimal access approach, 247248 pathogenesis of, 242243 pathology of, 243244 Recurrent variceal bleeding, 282 Refractory bleeding, 275 Regenerative nodules, 266 Regional chemotherapy, 136137 Renal cell cancer, 166167, 434 Repeat liver resection, 129130 Resectable liver disease, systemic therapy, 140141 Resectable tumors, 385 Resection of contiguous structures, 8485 Respiratory tract, 168 Retroperitoneal laparostomy, 447 RFA. See Radiofrequency ablation Right hemihepatectomy, 3031 Right hepatectomy, 338 Right trisectionectomy hepatic resection, 31 hilar cholangiocarcinoma, 338339 Routine arteriography, 416 RPC. See Recurrent pyogenic cholangitis Sarcoma, 54 noncolorectal, nonneuroendocrine metastases, 168169 SCA. See Serous cystadenoma Sclerosing cholangitis, 370 Segmental resections, 57, 76 Selective surgical shunts, 283 Selective vascular ligation, 275276 Self-expanding metal stents, 349 SEMS. See Self-expanding metal stents Sepsis, 367 Serous cystadenoma, 407409, 412 Serum amylase, 463 Severe postpancreatectomy hemorrhage, 391 sFLR. See Standardized future liver remnant Short-term biliary stenting, 377 Simple biliary hepatic cysts, 301 Simple cystenterostomy, 357 Simultaneous kidney and pancreas transplant, 470 Sinusoidal obstruction syndrome, 174176 SLT. See Split-liver transplantation SMA. See Superior mesenteric artery Small duct disease, 458459 Small solitary hepatic metastases. See Hepatic metastasectomy SMV. See superior mesenteric vein Solid liver lesions, 3739 Solid pseudopapillary neoplasm, 432 Solid pseudopapillary tumor, 106107 Somatostatin analogs, 391 Somatostatin receptor scintigraphy, 424, 435 neuroendocrine tumors, 155 Somatostatinomas, 421 Sorafenib, 220 Special dedicated high-frequency transducers, 42 Spectral Doppler, 36 Spironolactone, 285 SPK. See Simultaneous kidney and pancreas transplant Split-liver transplantation, 290 SPPN. See Solid pseudopapillary neoplasm SPT. See Solid pseudopapillary tumor Spyglass, 347 SRS, Somatostatin receptor scintigraphy SSTR-targeted therapy, 161 Staging laparoscopy, 9192 Standard lymphadenectomy, 387 Standard vs. pylorus-preserving pancreatoduodenectomy, 385386 Standardized future liver remnant, 177 Stapling devices, 94 Steatohepatitis, 174 Steatorrhea, 421 Steatosis, 173174 Sterile cyst, 315 Streptozotocin, 420 Streptozotocin plus doxorubicin, 428 Streptozotocin plus fluorouracil, 428 Sunitinib, 220 Superior mesenteric artery, 381 Superior mesenteric vein, 381 Superior pancreaticoduodenal artery, 18 Surgeon/hospital-related factors laparoscopic equipment, 366
500
INDEX
Surgeon/hospital-related factors (Continued) learning curve effect, 366 psychology of human error, 366 Surgical resection, pancreatic ductal adenocarcinoma, 385387 extended lymphadenectomy, 387 extended resections, 387 pancreaticenteric anastomosis, 386387 standard vs. pylorus-preserving pancreatoduodenectomy, 385386 Surgical shunts, 283284 Sympathetic innervation, 22 Symptom palliation, 401 Symptomatic hepatocellular carcinoma, 192 Synchronous liver metastases neoadjuvant chemotherapy, 130131 surgery, 131 Systemic chemobiologic therapy, 137138 Systemic chemotherapy nonresectable metastatic disease, 124125 unresectable liver disease, 135136 Systemic therapies advanced cirrhosis treatment, 220 anti-angiogenic therapies, 219220 cisPlatin, interferon, adriamycin, and 5-fluorouracil, 219 future developments, 220221 historical background, 219 unresectable liver disease, 140141 Systemic venous drainage, 472473 TACE. See Transarterial chemo-embolization; Trans-catheter arterial chemo-embolization TachoSil, 65 Telangiectatic focal nodular hyperplasia, 263 Tenting injuries, 366367 TFNH. See Telangiectatic focal nodular hyperplasia Therapeutic packing, 275 Thermal ablation CLOCC study, 184 cryotherapy, 180181 edge cryotherapy, 181 limitations of, 180 microwave ablation, 183184 percutaneous ethanol injection, 184 radiofrequency ablation, 181183 stages of hepatocellular carcinoma, 195 Thermal injuries, 366367 TIPS. See Transjugular intrahepatic portosystemic shunt Top-Down cholecystectomy, 365 Total cyst excision, 356 Total pancreatectomy, 7475, 85 Total surgical shunts, 283 Total vascular exclusion, 128129 TP. See Total pancreatectomy Trans-abdominal ultrasonography, 383 choledochal cyst, 355 Trans-abdominal ultrasound, 441 malignant biliary obstruction, 343 Transarterial chemo-embolization, 195 Trans-catheter arterial chemo-embolization, 216217 Transcystic flushing, 89 Transcystic stone extraction, 8990 Transjugular intrahepatic portosystemic shunt, 283 Tumor ablation multimodal approaches, 150 techniques, 126 Tumor respectability definition of, 118 portal vein embolization, 126 total vascular exclusion and cooling, 128129 tumor ablation techniques, 126 two-stage hepatectomy, 127128 TVE. See Total vascular exclusion Two-stage hepatectomy, 127128 Two-stage liver resection, 127 Type B juxtahepatic injuries, 276 UCDA. See Ursodeoxycholic acid UCSF. See University of California at San Francisco UICC. See International Union against Cancer Ultrasonography hydatid cyst, 311 transabdominal, 382383 Ultrasound gallbladder and bile ducts, 3941 intraoperative, 4243 liver diffuse liver disease, 36 focal hepatic lesions, 3639 liver metastases, 109 malignant biliary obstruction, 343 pancreas diffuse pancreatic diseases, 41 pancreatic neoplasms, 4142 radiological anatomy of liver, 13 University of California at San Francisco, 209210 Univesicular cyst, 315 Unresectable liver disease coverting to resection, 138140 regional chemotherapy, 136137 systemic chemobiologic therapy, 137138 systemic chemotherapy, 135136 systemic therapy, 140141 Unusual functional islet cell tumors, 421 Urine, 154 Ursodeoxycholic acid, 377 Vagotomy, 403 Variceal bleeding acute variceal hemorrhage, 282 clinical manifestations, 280 devascularization procedures, 284 endoscopic therapy, 282283 liver transplantation, 284 pharmacologic therapy, 282283 primary prophylaxis, 281282 recurrent, 282 surgical shunts, 283284 transjugular intrahepatic portosystemic shunt, 283 Variceal decompression, 283 Vascular endothelial growth factor, 137 Vascular injuries, 360 Vasoactive intestinal peptide, 420 VEGF. See Vascular endothelial growth factor Venous bleeding, 95 Venous drainage of pancreas, 2021 Vessel resections, 7778 VIPomas, 420421 Von HippelLindau (VHL) syndrome, 435 Watery diarrhea, hypokalemia, and achlorhydria, 420 WDHA. See Watery diarrhea, hypokalemia, and achlorhydria Wedge resections, 5657 Whipple resection, 73 Y-graft, pancreas transplants, 473 ZES. See ZollingerEllison syndrome ZollingerEllison syndrome, 416417
501
With a Foreword by Yuji Nimura, MD, President of the Aichi Cancer Center, Japan, and Past President of the IHPBA
This book demonstrates the wisdom of the new knowledge and technical skills of these diverse disciplines where cooperative efforts contribute toward the benefit of the patients with HPB disorders.
Also Available
Hepatocellular Carcinoma: A Practical Approach
Edited by Bandar Al Knawy, K. Rajendra Reddy and Luigi Bolondi ISBN: 9780415480802 e-ISBN: 9780203092880
Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK 52 Vanderbilt Avenue, New York, NY 10017, USA
www.informahealthcare.com