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PROCEEDINGS

of the
XXXIII National Continuing
Medical Education Programme
in Surgery

SURGERY UPDATE 2015


Compiled by:

Dir. Prof. A.K.Sarda


MS, FAIS, FACS, FICS

Prof. Rajdeep Singh


MBBS, MS

On behalf of the
Department of Surgery
Maulana Azad Medical College
& associated
Lok Nayak Hospital
New Delhi
Year of publication: 2015

Price of extra copy of Proceedings: Rs.750/-

NOTE: The Organizing Committee of SURGERY UPDATE 2015 takes no


responsibility for the contents of the lectures which are the sole
responsibility of the concerned authors. None of the lectures has been
edited in part or in whole. A part or whole of the lecture may be reproduced
with the prior permission of the concerned author.
FOREWORD
The National Continuing Medical Education Programme in Surgery organized by the
department of Surgery, Maulana Azad Medical College, New Delhi is in its twenty
ninth year of existence. During this period has blossomed into a six day academic
exercise eagerly looked forward to by the surgeons all over the country and has
established itself as the gold standard for Continuing Medical Education
Programmes. One of its endearing features is the CME lectures brought out in a
bound format simply named the PROCEEDINGS, introduced and published in 1998
The PROCEEDINGS have become an integral part of the update since then. It is
satisfying to note that the bound lectures are carried by postgraduates all over the
country preparing for examinations or for interviews. Those who miss out on
attending the CME programme, still manage to procure copies of the
PROCEEDINGS in its photocopied form. This year also it gives us great pleasure to
present a book on the PROCEEDINGS OF THE XXXIII NATIONAL CONTINUING
MEDICAL EDUCATION PROGRAMME IN SURGERY, similar to previous years.

Every surgical disorder in the scientific programme has been chosen carefully in the
context of its importance to the attending delegates. All the authors are well-
recognized authorities with a vast personal clinical experience on the particular
subject they were chosen to elaborate. As will be evident from the written texts, they
have contributed a very comprehensive account of the respective topics and are also
to be commended for submitting the latest references at the end of each chapter for
ready referral. The quality of their text reflects their involvement in our programme. A
sincere effort has been made to format the book in a uniform manner without any
effort to edit the text provided by the contributors.

This years programme is a full day comprehensive CME on selected topics of


particular interest to the postgraduate. Emphasis is on subjects with more bearing on
their clinical application. Every years Proceedings can be considered one part of the
trilogy of books which will cover nearly the whole course for the postgraduate student
over a three year period.

We sincerely thank the contributors for their effort. We also wish to thank all the
colleagues in the department for their encouragement and guidance in making this
project possible. Especial thanks are to Prof. Rajdeep Singh, who has been
instrumental in collecting the articles and majorly formatting the text to its final form.
Our sincere thanks are also due to the resident staff who worked for procuring, proof
reading and formatting the text. Finally, we must emphasize the contribution of the
authors who have always given an overwhelming response to our endeavor of
bringing out the written text of our CME programme over the years. We sincerely
hope that the Proceedings will meet the stiff demands of the delegates and serve as
a nodal point of learning for the postgraduates.

Prof. Sanjeev Kumar Tudu Dir. Prof. Anil Kumar Sarda


HOD, Surgery, MAMC & LNH Hospital Organizing Secretary
& Organizing Chairman SURGERY UPDATE 2015
SURGERY UPDATE 2015
CONTRIBUTORS
Metastatic Carcinoma Breast Troubleshooting equipment and procedural
Dr. Ajit Sinha difficulties
Consultant, Department of Surgery Dr. Deborshi Sharma
VardhmanMahavir Medical College, Professor of Surgery,
New Delhi Lady Hardinge Medical College, New Delhi

MEN Syndrome Short bowel Syndrome


Dr. Amit Agarwal Dr. Deepak Ghuliani
Professor of Endocrine Surgery, Associate Professor, Surgery,
Sanjay Gandhi Postgraduate Institute of Medical Maulana Azad Medical College &
Education and Research, Lucknow assoc. Lok Nayak Hospital, Delhi

Approach to a patient with thyroid disease Robotic prostatectomy


Dr. Anjali Mishra Dr. Gagan Gautam
Additional Professor Endocrine Surgery, Head of Urologic Oncology & Robotic Surgery,
Sanjay Gandhi Postgraduate Institute of Medical Medanta The Medicity,
Education and Research, Lucknow Gurgaon

Investigations for peripheral vascular disease Management of the Axilla in Carcinoma Breast
Dr. Anjali Prakash Dr. Gaurav Agarwal
Professor of Surgery, Professor Endocrine Surgery,
Maulana Azad Medical College &assoc. Lok Sanjay Gandhi Postgraduate Institute of Medical
Nayak Hospital, New Delhi Education and Research, Lucknow

Motility disorders of oesophagus Approach to a patient with breast disease


Dr. Anubhav Vindal Dr. Geeta Kadayaprath
Associate Professor of Surgery, Head, Breast Surgical Oncology
Maulana Azad Medical College & Max Cancer Centre
assoc. Lok Nayak Hospital, Delhi New Delhi

Diagnostic Laparoscopy Early breast Cancer


Dr Anurag Mishra Dr. Harit Chaturvedi
Assistant Professor Surgery, Chief Consultant & Director Surgical Oncology,
Maulana Azad Medical College & Max Healthcare Hospitals,
assoc. Lok Nayak Hospital, Delhi New Delhi

Endourologic procedures for stones Urethral Injuries


Dr. Atul Goswami Dr. Iqbal Singh
Senior Consultant & Coordinator Urology Professor of Surgery,
Max Superspeciality Hospital, University College of Medical Sciences &
New Delhi assoc. Guru Teg Bahadur Hospital, Delhi

Subdiaphragmatic Abscess Hand Infection


Dr. Chandra B. Singh Dr. Jainendra K. Arora
Professor of Surgery, Associate Professor Surgery,
Maulana Azad Medical College & Vardhman Mahavir Medical College and
assoc. Lok Nayak Hospital, Delhi assoc. Safdarjung hospital, Delhi
Paraneoplastic Syndromes Locally advanced Carcinoma breast
Dr. Jitendra Kumar Dr. P. N. Agarwal
Asstt. Professor of Surgery, Director Professor of Surgery,
Lady Hardinge Medical College & assoc. Smt. Maulana Azad Medical College &
SuchetaKriplani Hospital, New Delhi assoc. Lok Nayak Hospital, Delhi

Management of Renal Malignancies Urinary Diversion


Dr. Kim Mammen Dr. Pawan Lal
Professor & Head of Urology, Professor of Surgery,
Christian Medical College Maulana Azad Medical College &
Ludhiana, Punjab assoc. Lok Nayak Hospital, Delhi

Radiotherapy in Carcinoma breast Approach to a patient with Obstructive Jaundice


Dr. Kishore Singh Dr. Pramod K. Mishra
Director Professor of Radiotherapy, Consultant GI Surgeon,
Maulana Azad Medical College & assoc. Govind Ballabh Pant Hospital,
LokNayak Hospital, New Delhi Delhi

Gastrointestinal polyps Cleft lip & Palate


Dr. Lalit Agarwal Dr. R.B. Ahuja
Associate Professor of Surgery, Professor of Plastic Surgery
Lady Hardinge Medical College & assoc. Smt. Maulana Azad Medical College &
SuchetaKriplani Hospital, New Delhi assoc. Lok Nayak Hospital, Delhi

Cholecystectomy Blood Component Therapy


Dr. Lovenish Kumar Dr. R.N. Makroo
Asstt. Prof. of Surgery, Consultant Transfusion Medicine, Molecular
Dr. BSAmbedkar Medical College, Biology & Immunology,
New Delhi Indraprashtha Apollo Hospital, New Delhi

Carcinoids Energy Source in surgery


Dr. Manoj Andley Dr. Rajdeep Singh
Professor of Surgery, Professor of Surgery,
Lady Hardinge Medical College & Maulana Azad Medical College &
assoc. Smt. Sucheta Kriplani Hospital, Delhi assoc. Lok Nayak Hospital, Delhi

Gastrointestinal stromal tumours Fundoplication


Dr. Nikhil Talwar Dr. Randeep Wadhawan
Assistant Professor, Surgery Director & Head, Minimal Access Surgery,
Lady Hardinge Medical College &assoc. Smt. Bariatric Surgery & Gastrointestinal Surgery,
Sucheta Kriplani Hospital, New Delhi Fortis Hospital, VasantKunj, Delhi

Operative Procedure for Breast Cancer Carcinoma tongue


Dr Nikhil Talwar Dr. Ravi Kannan
Assistant Professor, Surgery Director & Consultant Surgical Oncologist,
Lady Hardinge Medical College &assoc. Smt. Cachar Cancer Hospital and Research Centre,
Sucheta Kriplani Hospital, New Delhi Silchar, Assam

Stapled heamorrhoidopexy Ergonomics in Lap Surgeries


Dr. P. N. Agarwal Dr. Ravindra S. Mohil
Director Professor of Surgery, Consultant Surgeon & Professor Surgery,
Maulana Azad Medical College & Vardhman Mahavir Medical College and assoc.
assoc. Lok Nayak Hospital, Delhi Safdarjung hospital, Delhi
Radiology in Breast Disease Abdominal Compartment Syndrome
Dr. Richa Bansal Dr. Shaji Thomas
Consultant, Radiology Director Professor, Surgery,
Max Healthcare Hospitals, Lady Hardinge Medical College &
New Delhi assoc. Smt. Sucheta Kriplani Hospital, Delhi

Management of BPH Ischaemic bowel disease


Dr Rishi Nayyar Dr. Sundeep Saluja
Assistant Professor of Urology, Professor of Gastrointestinal Surgery,
All India Institute of Medical Sciences, GovindBallabh Pant Hospital,
New Delhi New Delhi

Undescended Testis Primary hyperparathyroidism


Dr. S.K. Jain Dr. Sunil Chumber
Professor of Surgery Professor of Surgery,
Maulana Azad Medical College & All India Institute of Medical Sciences,
assoc. Lok Nayak Hospital, Delhi New Delhi

Role/Impact of telemedicine in surgery Parasitic Infestations of Liver


Dr. S.K.Mishra Dr. Sushanto Neogi
Professor & Head of Endocrine Surgery, Professor of Surgery,
Sanjay Gandhi Postgraduate Institute of Medical Maulana Azad Medical College &
Education and Research, Lucknow assoc. Lok Nayak Hospital, Delhi

Tumour Markers in management of breast disease Sentinel Lymph node biopsy


Dr. S.V.S. Deo Dr. V. Seenu
Professor of Surgical Oncology, BRA-IRCH, Professor of Surgery,
All India Institute of Medical Sciences, N. Delhi All India Institute of Medical Sciences,
New Delhi

Thoracic Outlet Syndrome Venous Ulcer


Dr Sabyasachi Bal Dr. Vivek Agrawal
Director & Head Professor of Surgery,
Thoracic Surgery & Thoracic Oncology University College of Medical Sciences & assoc.
Fortis Escorts Hospitals, Delhi Guru TegBahadur Hospital, New Delhi

Anorectal malformations
Dr Satish K Aggarwal
Director Professor of Paediatric Surgery,
Maulana Azad Medical College &
assoc. Lok Nayak Hospital, Delhi
INDEX

1. Undescended Testis 1
Dr. S.K. Jain, Dr. Amit Gupta

2. Anorectal malformations 5
Dr. S.K. Aggarwal

3. Cleft lip & Palate 11


Dr. R.B. Ahuja, Dr.Vybhav Deraje

4. Urethral Injuries 18
Dr. Iqbal Singh

5. Urinary Diversion 23
Dr.Pawan Lal, DrSanjeev K. Tudu

6. Management of BPH 30
Dr. Rishi Nayyar, Dr.Ashish Kumar

7. Management of Renal Malignancies 39


Dr. Kim Mammen, Dr.Abhinav Jaiswal

8. Approach to a patient with renal disease 55

9. Benign Diseases of Breast 65

10. Sentinel Lymph node biopsy 74


Dr. V. Seenu, Dr. Piyush Ranjan Mishra

11. Tumour Markers in management of breast disease 77


Dr. S.V.S. Deo, Dr.Ashish Jakhetiya

12. Early breast Cancer 80


Dr. Harit Chaturvedi

13. Locally advanced Carcinoma breast 92


Dr. P.N. Agarwal, Dr.Vivek Wadhawa

14. Management of the Axilla in Carcinoma Breast 97


Dr. Gaurav Agarwal, Dr. Sendhil Rajan

15. Operative Procedure for Breast Cancer 103


Dr. Nikhil Talwar

16. Metastatic Carcinoma Breast 117


Dr. Ajit Sinha

17. Radiotherapy in Carcinoma breast 123


Dr. Kishore Singh

18. Approach to a patient with breast disease 125


Dr. Geeta K.

19. Radiology in Breast Disease 128


Dr.Richa Bansal

20. Hand Infection 139


Dr. Jainendra Arora

21. Venous Ulcer 145


Dr. Vivek Agrawal
22. Thoracic Outlet Syndrome 155
Dr. S. Bal

23. Primary hyperparathyroidism 160


Dr. Sunil Chumber, Dr. Pratyusha Priyadarshini

24. Surgery for Hereditary MEN-related tumors 162


Dr. Amit Agarwal, Dr.Navneet Tripathi, Dr.Roma Pradhan

25. Carcinoids 167


Dr. Manoj Andley

26. Paraneoplastic Syndromes 173


Dr. Jitendra Kumar

27. Approach to a patient with thyroid disease 181


Dr. Anjali Mishra, Dr.Chandan K.Jha, Dr.Niraj Kumari, Dr.Zafar Neyaz

28. Cystic Lesions of pancreas 186

29. Gastrointestinal stromal tumours 192


Dr. Nikhil Talwar, DrRigved Gupta

30. Motility disorders of oesophagus 196


Dr. Anubhav Vindal, Dr.Sachin Mittal

31. Short bowel Syndrome 201


Dr. Deepak Ghuliani, Dr.Abhinav Agrihari

32. Parasitic Infestations of Liver 209


Dr. Sushanto Neogi

33. Subdiaphragmatic Abscess 218


Dr. C.B. Singh, Dr Suresh R.

34. Ischaemic bowel disease 222


Dr. Sundeep Saluja, Dr.Harsh Shah

35. Abdominal Compartment Syndrome 229


Dr. Shaji Thomas

36. Approach to a patient with Obstructive Jaundice 234


Dr. P.K. Mishra, Dr.Arvind P.S., Dr.P. Narang

37. Diagnostic Laparoscopy 238


Dr. Anurag Mishra

38. Ergonomics in Lap Surgeries 247


Dr. R.S. Mohil, Dr.Sharmistha Bhattacharyya

39. Troubleshooting equipment and procedural difficulties 253


Dr. Deborshi Sharma, Dr.Swati Sattawan

40. Current status of laparoscopy for abdominal malignancies 259

41. Robotic prostatectomy 265


Dr. Gagan Gautam, Dr.K. Rupala, Dr.V. Mittal

42. Retrograde Intrarenal Surgery 271


Dr. Atul Goswami

43. Gastroesophageal Reflux Disease 271


Dr. Randeep Wadhawan
44. Stapled heamorrhoidopexy 275
Dr. P. N. Agarwal, Dr. Anurag Mishra

45. Cholecystectomy 277


Dr. Lovenish Kumar, Dr.A.K. Sarda

46. Carcinoma tongue 283


Dr. Ravi Kannan

47. Gastrointestinal polyps 299


Dr. Lalit Agarwal

48. Regional Anaesthesia 246

49. Blood Component Therapy 310


Dr. R.N. Makroo

50. Energy Source in surgery 317


Dr. Rajdeep Singh

51. Functional imaging 322

52. Role/Impact of telemedicine in surgery 331


Dr. S.K. Mishra

53. Investigation for peripheral vascular disease 336


Dr. Anjali Prakash
Undescended Testes

Sudhir Kumar Jain, Amit Gupta

Cryptorchidism (from the Greek KRYPTOS meaning hidden, and ORCHIS meaning testis) refers to absence
of a testis from the scrotum. During embryonic life, the testes form beside the mesonephric kidneys and descend
via the inguinal canal to the scrotum. If this process is faulty, a cryptorchid testis may halt along the normal path
of descent (undescended or retractile testis), may travel off the normal path of decent (ectopic testis), or may die
or never develop (absent testis). Therefore, the terms cryptorchid and undescended are not synonymous.
Isolated cryptorchidism is the most common congenital anomaly of the male genitalia, affecting almost 1% of
fullterm infants at the age of 1 year. Despite intense study both experimentally and clinically for the last century,
the cause of this condition remains poorly understood. Although there have been surgical advances in the
techniques of orchiopexy, areas of clinical controversy remain.

TESTICULAR DESCENT
Testicular descent is necessary for normal spermatogenesis, which requires the 2 F to 3 F cooler scrotal
environment. Embryonic testicular descent can be divided into three phases:
1. Transabdominal migration of the testis to the internal inguinal ring
2. Development of the processus vaginalis and the inguinal canal
3. Transinguinal descent of the testis to the scrotum

FACTORS IN TESTICULAR DESCENT


Hormonal Factors
Key hormonal factors implicated in testicular descent include the androgens, INSL3, estrogens, and AMH.
Androgens and the Androgen Receptor
Insulin-like Factor 3 and Its Receptor
Estrogens
Anti-mllerian-Inhibiting Substance
Calcitonin Gene-Related Peptide
Epidermal Growth Factor

Mechanical Factors
Perhaps the most important mechanical factor, the gubernaculum begins as a mesenchymal band that originates
on the lower pole of the testis/mesonephric duct and inserts in the scrotum. The exact mechanism through which
the gubernaculum mediates testicular descent is debated and may involve traction, muscular contraction, or
differential growth around a fixed point.

Males with prune-belly syndrome or other abdominal wall defects such as gastroschisis, omphalocele, or
umbilical hernia frequently have cryptorchidism.

Epididymal anomalies are seen adjacent to undescended testes in 33% of cases, but they are five times more
common in patients with an inguinal hernia than in patients with cryptorchidism, suggesting that other factors may
be involved.

DEFINITIONS AND CLASSIFICATION


Cryptorchidism is classified as palpable testes in 80% of the cases, and as nonpalpable testes in 20%. Palpable
testes include true undescended testes and ectopic testes and retractile testes as they are often misdiagnosed
as palpable undescended testes. Nonpalpable testes include intra-abdominal, inguinal, and absent testes.

VANISHING TESTIS
The term vanishing testis indicates that the testicular vessels and a vas deferens are found on surgical
exploration, but a testis is absent. In utero infarction of a normal testis by gonadal vessel torsion after gestational
weeks 12 to 14 is hypothesized, because ipsilateral wolffian duct differentiation and mllerian duct regression,
both of which require ipsilateral testicular hormones, occur normally. Supporting evidence for testicular infarction
includes the common finding of hemosiderin and calcium deposits in testicular remnants (nubbins) found on
exploration.

TESTICULAR AGENESIS
Testicular agenesis may result from failure of the testicular blood supply to develop or from abnormal gonadal
ridge differentiation. An example of the latter is 46,XY complete gonadal dysgenesis.

INCIDENCE AND NATURAL HISTORY


Isolated cryptorchidism is one of the most common congenital anomalies found at birth and affects upward of 3%
of full-term male newborns. Unilateral cryptorchidism is more common than bilateral cryptorchidism, which occurs
in 1.6% to 1.9% of boys. Approximately 33% of premature male infants are cryptorchid. The incidence in full-term

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males at birth is 2% to 4%, and at age 1 year it is 1%. Approximately 70% to 77% of cryptorchid testes will
spontaneously descend, usually by 3 months of age.

RISK FACTORS
Maternal, Paternal, and Gestational Factors
Maternal obesity, cesarean section, low birth weight, and prematurity have been associated with cryptorchidism,
each independently doubling the relative risk over that of the general population.

Genetic Factors
The familial cluster (risk for an undescended testis in a newborn male if a family member is already affected) is
3.6-fold overall, 6.9-fold if a brother is affected, and 4.6-fold if the father is affected.

Environmental Factors
Prenatal environmental exposure to a growing group of compounds termed endocrine disruptors. Such
compounds include DES (synthetic estrogen), DDT (pesticide), nonylphenol (industrial surfactant), bisphenol-A
and certain phthalates (plastics additives), and natural phytoestrogens (common in soy products).

ASSOCIATED ANOMALIES
Multiple factors are involved in normal testicular descent. As a result, many clinical syndromes that affect genetic
integrity or the endocrine, musculoskeletal, and nervous systems can be associated with this condition. For
example, abnormalities in chromosome number, such as autosomal trisomy, triploidy, and Klinefelters syndrome
(XXY), are commonly associated with cryptorchidism. Deficiencies in pituitary function, testosterone production,
5-reductase activity, and androgen receptor sensitivity effectively interrupt androgen activity and can result in
cryptorchidism.

CLASSIFICATION
Cryptorchid testicular position is most simply described as intra-abdominal, intracanalicular, extracanalicular
(suprapubic or infrapubic), or ectopic.

HISTOPATHOLOGY
The histopathologic hallmarks associated with cryptorchidism are evident between 1 and 2 years of age and
include decreased numbers of Leydig cells, degeneration of Sertoli cells, delayed disappearance of gonocytes,
delayed appearance of adult dark (Ad) spermatogonia, failure of primary spermatocytes to develop, and reduced
total germ cell counts.

WORK UP
If a testis is not in the scrotum, the cryptorchid testis is sought by gently advancing the examining fingers along
the inguinal canal toward the pubic tubercle. This examination is best facilitated by applying lubricant to the groin.
The overall accuracy of radiologic testing for an undescended testis is 44%. The workup for bilateral nonpalpable
testes merits special consideration because it may represent a life-threatening situation if it is associated with
either hypospadias or ambiguous genitalia.

CONSEQUENCES OF CRYPTORCHIDISM

Infertility
Impairment of germ cell maturation is a well-recognized consequence of cryptorchidism.

Neoplasia
It is a well-established fact that children born with undescended testes are at increased risk for testicular
malignancy. The most common tumor that develops from a cryptorchid testis is seminoma. The prevalence of
carcinoma in situ is 1.7% in patients with cryptorchidism.

2
Hernia
A patent processus vaginalis is found in more than 90% of patients with an undescended testis.

Testicular Torsion
The increased susceptibility of the testis to undergo torsion is the result of a developmental anatomic abnormality
between the testis and its mesentery. The mechanism is believed to be related to a greater relative broadness of
the testicle than its mesentery. Although torsion of an undescended testis is rare, it should be considered in any
child with abdominal or groin pain and an empty ipsilateral hemiscrotum.

MANAGEMENT OF CRYPTORCHIDISM
Important principles for the treatment of a child with an undescended testis include the following:
Proper identification of the anatomy, position, and viability of the undescended testis
Identification of any potential coexisting syndromic abnormalities
Placement of the testis within the scrotum in timely fashion to prevent further testicular impairment in
either fertility potential or endocrinologic function
Attainment of permanent fixation of the testis with a normal scrotal position that allows for easy palpation
No further testicular damage resulting from the treatment.

Definitive treatment of an undescended testis should take place between 6 and 12 months of age.Orchiectomy is
typically reserved for postpubescent males with a contralateral normally descended testis when the cryptorchid
testis is either anatomically or morphologically abnormal or too far from the scrotum to allow for tension-free
placement without compromising the vascular integrity of the testis.

Hormonal Therapy
Two types of medical treatment of an undescended testis can be provided: exogenous hCG and exogenous
GnRH or LHRH. The mechanism of action in both cases increases serum testosterone production by stimulation
at different levels of the hypothalamic-pituitary-gonadal cascade. The overall efficacy of hormonal treatment is
less than 20% for cryptorchid testes and is significantly dependent on pretreatment testicular location. Therefore,
surgery remains the gold standard for the management of undescended testes.

Surgical Treatment
It is very useful to examine the child after induction of general and regional anesthesia to reaffirm testicular
position or attempt to establish testicular position in the case of a previously nonpalpable testis.

Standard Orchiopexy
The key steps in this procedure are
(1) complete mobilization of the testis and spermatic cord
(2) repair of the patent processus vaginalis by high ligation of the hernia sac
(3) skeletonization of the spermatic cord without sacrificing vascular integrity to achieve tension-free placement of
the testis within the dependent position of the scrotum.
(4) creation of a superficial pouch within the hemiscrotum to receive the testis.

Techniques for High Undescended Testes


Occasionally, greater mobilization of the proximal spermatic cord structures does not provide adequate length to
allow for tension-free placement of the testis within the scrotum. Greater cord length can be obtained by
mobilizing the spermatic vessels medially. The spermatic vessels are usually the limiting factor in these
circumstances. The Prentiss maneuver was described in 1960 and is occasionally helpful in adding length to the
spermatic vessels by positioning the spermatic vessels medially and thereby choosing the hypotenuse of the
triangle, or the most direct course to the scrotum, created by the natural course of the vessels laterally through
the internal ring.

Fowler-Stephens Orchiopexy
Fowler and Stephens studied the vascular anatomy of the testis and devised a means to repair a high
undescended testis and preserve its blood supply via collateral circulation. The anticipated advantage of a two-
stage orchiopexy with spermatic vessel ligation is twofold: (1) to allow for development of collateral blood supply

3
to compensate for division of the main blood supply to the testis and (2) to allow for greater mobility of the testis
to place it within the scrotum.

Laparoscopic Management of an Undescended Testis


The advantages of laparoscopy over a conventional open surgical approach to a nonpalpable testis include
accurate anatomic assessment of testicular position and viability and, when necessary, optimal accessibility to
the crux of the surgical problem.

Diagnostic Laparoscopy for a Nonpalpable Testis


A nonpalpable testis accounts for approximately one fifth of children with an undescended testis. Diagnostic
laparoscopy is commonly used for the assessment of a nonpalpable testis, with the accuracy of testicular
localization reported to be greater than 95%.By using an already existing port site, diagnostic laparoscopy can
naturally transition to extend the operative procedure from diagnostic to therapeutic.
Laparoscopic Assessment
There are three distinct possible findingsand courses of actionwhen laparoscopy is used to assess a
nonpalpable testis. Findings include
Blind-ending vessels above the internal ring (vanishing testis)
Cord structures entering the internal ring (viable intracanalicular testis versus an intracanalicular or
scrotal atrophic testis)
Intra-abdominal testis

Inguinal versus Laparoscopic Exploration


The choice of traditional surgical exploration versus primary laparoscopy for assessment of a nonpalpable testis
is a matter of debate. Open surgical exploration via an inguinal incision was the procedure most commonly used
before the era of laparoscopy for the management of a nonpalpable testis. It is difficult to criticize traditional
nonlaparoscopic techniques of exploration; however, laparoscopy, whether primary or adjunctive to an open
exploration, offers a logical extension of surgical principles, especially if conversion to a therapeutic laparoscopic
procedure is anticipated.

Laparoscopic Orchidopexy
Laparoscopic orchidopexy is now standard in the urologists' armamentarium of management for an intra-
abdominal testis. A laparoscopic approach in the management of an intra-abdominal undescended testis has
advantages over standard orchidopexy performed through either an extended inguinal incision or a high inguinal
incision (Jones incision). Laparoscopy accurately assesses the presence, absence, viability, and entire anatomy
of an intra-abdominal testis. The age at which laparoscopic orchidopexy should be performed is the same as for
standard orchidopexy, usually between 6 and 8 months and certainly before 1 year of age.

Microvascular Autotransplantation
The indications for performing autotransplantation of an intra-abdominal testis must be weighed in light of the
circumstances of the clinical findings; the indications are similar to those for a Fowler-Stephens orchiopexy. An
important consideration that weighs in favor of this procedure is the variability of collateral blood supply in
patients with a high undescended testis, which may potentially compromise the Fowler-Stephens procedure.

Reoperative Orchiopexy
Reoperative orchiopexy is performed in cases of secondary cryptorchism after orchiopexy or inguinal hernia
repair.

Complications of Orchiopexy
Complications of orchiopexy include testicular retraction, hematoma formation, ilioinguinal nerve injury,
postoperative torsion (either iatrogenic or spontaneous), damage to the vas deferens, and testicular atrophy.
Atrophy of the testis is the most devastating complication, but it is seldom seen with standard orchiopexy.

References

1. Abratt et al., 1992. Abratt RP, Reddi VB, Saremboch LA: Testicular cancer and cryptorchidism. Br J
Urol 1992; 70:656-659.
2. Backhouse, 1982a. Backhouse KM: Development and descent of the testis. Eur J Pediatr 1982; 139:249-252.
3. Backhouse, 1982b. Backhouse KM: Embryology of testicular descent and maldescent. Urol Clin North
Am 1982; 9:315-325.
4. Berkowitz et al., 1993. Berkowitz GS, Lapinski RH, Dolgin SE, et al: Prevalence and natural history of
cryptorchidism. Pediatrics 1993; 92:44-49.
5. Wein: Campbell-Walsh Urology, 9th ed.
6. Bianchi, 1984. Bianchi A: Microvascular orchiopexy for high undescended testes. Br J Urol 1984; 56:521-524.
7. Jordan and Winslow, 1994. Jordan GH, Winslow BH: Laparoscopic single stage and staged orchiopexy. J
Urol 1994; 152:1249-1252.
8. Parkinson et al., 1994. Parkinson MC, Swerdlow AJ, Pike MC: Carcinoma in situ in boys with cryptorchidism: When
can it be detected?. Br J Urol 1994; 73:431-435.
9. Whitaker, 1970. Whitaker RH: Management of the undescended testis. Br J Hosp Med 1970; 4:25.

4
Anorectal malformations (Imperforate anus)

Satish Aggarwal

Anorectal malformations comprise a SPECTRUM of congenital malformations in which the anus fails to open
normally on to the perineum. At one end are low malformations where the anal canal is present but covered by
perineal skin or there is a perineal opening discharging meconium (perineal fistula). These are easy to treat by a
single perineal operation without the need for a colostomy. At the other end of the spectrum are severe (or high)
malformations where the rectum ends at or above the pelvic floor muscle and communicates with the genitor-
urinary tract; associated malformations are frequent and treatment is more complex- a colostomy is usually
needed at birth as initial management.

The malformations occur with a multifactorial aetiology. The embryological basis for high malformations is the
failure of the urorectal septum to develop resulting in a recto-urinary fistula in males and recto vaginal fistula in
girls. Mesodermal failure at the perineal mound is responsible for low lesions.

Classification

Anatomical Classification is based on the level of termination of the rectum in relation to the levator ani (pelvic
floor), and the part of urethras into which the bowel terminates as fistula. Following malformation types can occur:

High: Rectum ends above the levator. (Supralevator)


Intermediate: Rectum ends within the funnel of the levator.
Low: Rectum ends below the levator. (Translevator)

The typical malformations in males are:

High: Recto vesical fistula. Recto prostatic fistula


Intermediate: Recto-bulbar fistula
Low: perineal fistula, covered anus, anal stenosis, bucket handle anomaly

Typical female defects are:

High: recto vaginal fistula


Intermediate: Recto-low vaginal fistula, Recto-vestibular fistula
Low: Ano vestibular fistula, anterior ectopic anus.

Normal female anatomy Ano-vestibular fistula Recto-vaginal fistula Cloaca

5
Functional classification:
Alberto Pena proposed a functional classification that is much simpler and is aimed at decision making in
management. According to this the anomalies are divided into two groups:
1. Rectum ending within 1 cm of the skin: Suitable for primary perineal operation to create neo anus.
No colostomy needed.
2. Rectum ending more than 1 cm from the skin: Initial colostomy followed by definitive pull through at
6-8 weeks

According to Pena, in 80% patients the decision for colostomy or primary perineal operation can be taken on the
basis of clinical features and the appearance of the perineum. In the rest a prone cross table lateral film is
required to determine the distance of the rectal pouch from the skin. In these cases the above classification
comes handy to take a decision.

Krickenbeck classification
In 2005 a group of surgeons met at Krickenberg, Germany to simplify the classification. The new classification is
as follows:

Major clinical groups:


Perineal (cutaneous) fistula
Rectourethral fistula
o Bulbar
o Prostatic
Rectovesical fistula
Vestibular fistula
Cloaca
No fistula
Anal stenosis

Rare/ regional variants


Pouch colon
Rectal atresia/stenosis
Rectovaginal fistula
H type fistula
Others

Anatomy of sphincters in anorectal malformations:

The muscular component of continence is formed by levator ani, specially the lower most fibres (also called as
pubo-rectalis sling). Further there are the so called subcutaneous and superficial external sphincters that
surround the rectum and the anal canal. During an operation however, it is not possible to identify the different
components of the external sphincter. Surgically, there is a continuum of vertically oriented striated muscle fibres
from the skin at the anal dimple to the lowermost fibres of levator ani. A mid sagittal incision would bisect these
fibres into right and left halves. This is referred to as striated muscle complex. Aim of surgery is to bring the
rectum through the centre of muscle complex in order to restore the sphincter mechanism. Surrounding the
vertical fibres on either side are para-saggital fibres that lie horizontally and run from the perineal body in front to
the skin behind the anal dimple. The sphincters are well developed in low malformations but are poor in high
malformations.

Incidence: 1 in 5000 (similar incidence for TOF and HD)


Male: female :: 3: 2

Associated malformations:
Incidence: 50-60%
60% are genitor-urinary, 25% vertebral, 20% cardiac, 10% GI
15% have VACTERL / CHARGE association.
Severer the anorectal malformation the higher the incidence of associated malformations

Two most important aspects in the initial management are:

1. Is the case suitable for a primary perineal anoplasty without a colostomy or an initial colostomy followed
by delayed repair is more appropriate? (Best decided at 24 hours of age)

2. Is there any other life threatening association that needs more urgent attention e.g. tracheo-
esophageal fistula, severe cardiac malformation? Therefore, always pass a naso- gastric to rule out
oesophageal atresia and leave it for gastric decompression.

6
Clinical features and pathological anatomy

The topic is discussed separately in boys and girls.

Males:
Absent anal opening at birth.

Examine perineum: look for gluteal fold, natal cleft, and palpate spine/sacrum. Is it a flat bottom? Is there a
dimple at the anal site with pigmentation? Is ano-cutaneous reflex present? Is there a fold of skin under which
you can pass a probe (Bucket handle deformity), is there any mass?, can you see a thin white epithelial
thickening in the median raphe suggests anocutaneous fistula, is there any speck of meconium in the perineum
perineal fistula.

Is there any abnormality of the external genitalia bifid scrotum, hypospadias, and undescended testes? Look for
evidence of meconuria gas or meconium discharge per urethra.

Important: The exact level of anomaly may not be evident at birth because it takes time for the ingested air to
reach the rectum. Sufficient intra abdominal pressure builds up in about 24 hours to overcome the resistance of
the pelvic floor, so that meconium or air could force through a fistula.

If within 24 hours you can see meconium on the perineum low anomaly. Go for perineal anoplasty. No need for
colostomy.

If meconium or gas passed per urethra at any stage indicates high anomaly. Go for colostomy.

Prone Cross table lateral shoot abdominal film (If clinical information at 24 hrs insufficient to decide if a
colostomy is needed).

Technique:
Place a radio-opaque marker at the anal site.
Prone position with pelvis elevated leave in this position for 5 minutes before taking the x-ray (to allow
gas to layer on the meconium)
Dead lateral view centring over the greater trochanter.

Interpretation:
See distance of rectal gas from the marker (take care of magnification).
< 1cm: Suitable for primary repair
> 1cm: Colostomy needed.
.
Indicators of high anomaly (colostomy indicated):
No meconium in the perineum
Flat bottom, absent anal dimple/pigmentation, absent anocutaneous reflex,
Sacral abnormality (or on X-ray)
Meconium in urine (or gas in bladder on x ray)
Suggestion of a pouch colon on X ray (>50% of transverse span)
Associated bifid scrotum, proximal hypospadias, bilateral undescended testes

Indications of low anomaly (suitable for primary anoplasty):


Good perineum, pigmented dimple, anocutaneous reflex
Visible fistula in the perineum
Bucket handle deformity a bridge of skin over the anal site under which an instrument can be passed
and meconium can be seen under the skin.

Final decision will depend on many other factors: birth weight, maturity, and other malformations. It is safer to
open a colostomy in doubtful cases.
Although a prone cross table lateral shoot film is not required in majority, a plain abdominal film should be
obtained in all cases to exclude pouch colon, which is common in northern India. A bowel pouch spanning more
than 50% of transverse span of the abdomen suggests pouch colon. If so diagnosed, the child needs a
laparotomy rather than a simple colostomy.

Females:

Most anomalies are low. Look for the number of openings in the vulva/ perineum

3 openings: Ano-vestibular fistula (Commonest), recto-vestibular fistula, perineal fistula, anterior ectopic
anus
2 openings: Recto-vaginal fistula. (Rarely vestibular fistula with vaginal atresia).

7
1 opening: Common Cloaca

Examine in good light keeping the legs apart. The vestibular opening is usually very small and may be hidden
within the posterior fourchette. When probed the catheter may go posteriorly (ano-vestibular fistula) or superiorly
(rectovestibular fistula). This differentiation may be very subtle but is important in that rectovestibular fistula will
almost certainly require a colostomy while ano-vestibular fistula could be repaired primarily.

Colostomy or primary Mini PSARP?

Common cloaca and rectovaginal fistula always require a colostomy. Claoca will also need emergency evaluation
(US) for obstructive uropathy and distended vagina and often needs vesicostomy / vaginostomy in the same
sitting.

When there are three openings in the vulva the decision is more of individual surgeons choice. The safest option
would be to do a colostomy. However, it is not a dire emergency as the gut is getting decompressed, which may
be aided by calibration of the opening or gentle dilatation with Hegar dilators. The options should be discussed
with parents. While primary repair is definitive, saves the child from a stoma, there is a higher risk of wound
breakdown / infection leading to impaired continence, anal stenosis and need for redo surgery. The authors
current approach for ano-vestibular fistula is a primary PSARP at few weeks of age.

Surgery (colostomy or primary repair) may be carried out as a planned acute within the first few days. If the child
develops abdominal distension or decompression is not adequate, early colostomy is indicated.

Remember: if in doubt do a colostomy.

Colostomy:

High divided sigmoid / descending colostomy is performed through an oblique incision in the left iliac fossa.
Leave good skin bridge between the active stoma and the mucus fistula to facilitate application of stoma bag. .

For cloaca Transverse divided colostomy (distal colon may be needed for vaginal reconstruction)

Sigmoid/descending colostomy is easy to manage as the effluent is well formed, fluid loss and skin excoriation is
less, and it is easy to do a distal washout. The incidence of prolapse is low. Patients with large recto urinary
fistula may leak urine into the distal colon. With sigmoid colostomy there is less chance of hyperchloremic
acidosis as the urine comes out through the mucus fistula without getting absorbed significantly. Moreover,
performing a distal cologram is easier and more informative.

Pitfalls in colostomy

Transverse sigmoidostomy: While intending to perform a right transverse colostomy, a distended sigmoid loop
reaching the right hypochondrium is mistaken fro transverse colon and a stoma is created. This puts the distal
limb on traction and does not leave scope for mobilisation during definitive pull through operation. Distal cologram
will diagnose this accurately. Colostomy transplant at left iliac site is needed before considering a pull through.

Too low colostomy: This is the commonest mistake. The apex of the sigmoid loop is brought out as a stoma
leaving small length distally. The best way to prevent this is to identify the fixed portion of colon i.e. distal
descending colon and then come down along the sigmoid colon and form a stoma at a level that comes on the
surface without tension. This will leave most of sigmoid distal to the stoma, which can be used fro mobilisation
during pull through operation.

Loop colostomy: A loop colostomy is less likely to divert completely. Faecal contamination of the distal limb may
cause repeated urinary infections through a fistula, can cause feculomas, and jeopardise the pull though by
infective complications.

Twisted colostomy: The distally situated stoma brings out faeces while the proximally situated stoma acts as a
mucus fistula. This is a technical mistake during surgery and is of no major consequences provided the mother
gives pre-operative washouts through the mucus fistula only. The author has seen distal washouts being given
through the active stoma because the active stoma was the distally located stoma.

Further investigations during initial admission:

Renal and Spinal Ultrasound: to look for renal malformations, tethered cord
Echocardiography

8
Chest and spine Xray
Sacral Pena ratio
Chromosomal analysis
US spine MRI if US abnormal

Post op after colostomy


Distal loop washout with saline from day 5. Daily until clear, then weekly
Measure stoma output (if >20ml/kg/day start loperamide)
Monitor urinary sodium (if <10mmol/l add supplement to maintain at >10-40 mmol/l)
Prophylactic trimethoprim 2 mg/kg nocte
MCUG / distal loopogram at 4-6 weeks (cover with antibiotics; no cardiac anomaly: iv gentamycin 2
mg/kg; cardiac anomaly: iv gent + iv amoxicillin (250 mg) followed by oral amoxyl 125 mg 6 hrs later. (If
allergic to Penicillin- iv clindamycin (75mg) followed by oral clindamycin (37.5 mg) six hours later.

Post Discharge pre PSARP

Weekly distal washout, monitor weight, urinary sodium, increase trimethoprim as per weight, parental
support for stoma care.

Definitive Repair (PSARP Posterior Sagittal Ano Recto Plasty) is performed at 8-12 weeks.

Pre-op Distal washouts a day before or until clear


Check distal loopogram available.
Antibiotic on induction.
Consent

Operation in boys:
Under general endotracheal anaesthesia, bladder is catheterised. The patient is placed in prone jack knife
position. Buttocks are spread apart with elastic adhesive tape on each side. A mid sagittal incision is placed from
mid sacrum to just anterior to the anal dimple. Keeping in midline the incision is deepened. The muscle complex
and the parasagittal fibres are identified and confirmed with muscle stimulator. The coccyx may need bisection or
division to access the rectal pouch... The levator ani is divided in midline. Endopelvic fascia is divided to identify
the rectal pouch. The pouch is opened in midline between stay sutures and the fistula identified at the lower end
of the pouch. The fistula is closed from within with a purse string fine vicryl or PDS suture. The anterior dissection
immediately above the fistula is performed in the submucosal plane to prevent damage to the urethra. At about 2
cm from the fistula, the rectum can be mobilised full thickness all around. It is mobilised as much as is needed to
bring it down to the site of neo anus, which should be marked in the beginning of the operation at the anterior and
the posterior limit of the striated muscle complex. The levator is closed behind the rectum. The rectum is then
brought in the centre of the muscle complex and anoplasty is performed by muco cutaneous anastomosis at the
marked site of anus.

If the anomaly is very high and the rectal pouch can not be reached from below, a 28 size chest tube is placed in
the centre of muscle complex and the muscle closure is done around the tube as if the tube is the rectum. The
patient is then turned and a laparotomy performed to identify the rectal pouch and rectovesical fistula. After the
fistula is taken down, the rectum is tacked to the tube passed from below. The tube is then gently pulled in the
perineum bringing the rectal pouch at the skin where a muco cutaneous anastomosis is performed.

Operation for ano vestibular fistula in girls:


The position and anaesthesia are the same. Bladder is catheterised after positioning the patient. Incision is from
mid sacrum to the posterior fourchette. Muscle complex is divided in the midline. The vestibular fistula is held in
multiple stay sutures and a circumferential incision is made around it separating it from vagina in front. The key
step is separating the rectum from vagina. They are intimately adherent and share a common wall for varying
lengths, less in ano vestibular and more in recto vestibular fistula. Once sufficiently mobilised, the perineal body
is reconstructed, location of neo anus is decide as in boys. Anoplasty is performed and wound closed.

Post-op If no laparotomy feed 6-12 hrs later


Urinary catheter for 5 days.
Triple antibiotics for 48 hrs, then treatment dose Cephalexin/ trimethoprim until catheter comes out, then
prophylactic until VUR ruled out.
Nil PR for 14 days.
Dilatation to start at 14 days.

Closure of colostomy:
Performed once anal dilatation to adequate size achieved.
Continue dilatations until closure.
Skin preparation dermagard wipes 3/day. May use barrier applications {Adapt (Hollister), stomahesive
(Squibb)}

9
Continue dilatation post op for 4-6 weeks.

Regimen for anal dilatation post anoplasty


Use Hegar dilators.
First dilatation at 14 days (10 for low malformations)
First begin with size 8, and increase by one size every week to reach 16-18.

Normal size for age:


1-4 months Hegar 12
5-8 months Hegar 13
9-12 months Hegar 14
13 months + Hegar 16
(be wary of poor standardisation in India. Size 16 of one company may be equal to size 10 of another.)

Post colostomy closure:


Restart dilatations BD at the size stated in op notes
Decrease to daily after one month
Decrease to twice weekly after one month
Decrease to weekly after one month
Stop after a month

CONTROVERSIAL ISSUES

Primary PSARP for high malformations in males:


Some surgeons favour primary PSARP without a covering colostomy in selected cases of recto bulbar fistula. It is
a shade better than the standard approach of colostomy followed by PSARP in that the sensory stimulation for
maturation of anorectal continence mechanism is established immediately after birth, which should lead to better
continence mechanism. The tissue planes are easy to define. The child is saved from a colostomy. However, the
downside is that the anatomy is uncertain because the level of fistula has not been ascertained pre-operatively.
Consequently the blind perineal exploration increases the risk of damage to urethra, seminal vesicles, and
ureters. Also the operation is technically demanding. Careful patient selection is important for anaesthetic safety.

Laparoscopic repair of ARM

Laparoscopic approach has been successfully used to perform / aid repair. Colostomy is opened at birth.
Laparoscopic assisted pull through can be performed at about three months age. The colorectum in the pelvis is
mobilised laparoscopically and the fistula taken down. The urethral end of the fistula is closed with an endo-loop.
Many surgeons even leave the fistula open. The site of anus is decided by identifying the stratified muscle
complex by using a muscle stimulator. A small midline incision is made in the centre of this site and a 10 mm
trocar introduced in the pelvis. The mobilised rectum is pulled down through the port and anastomosed to the
skin.

The advantages of laparoscopic approach are clear visualisation of fistula in the deep pelvis, magnification and
accuracy. There is, however, limited experience and long term data is lacking.
The authors personal opinion favours laparoscopic pull through in a case where a laparotomy is necessary in
addition to posterior sagittal approach cases of rectovesical fistula, recto-bladder neck fistula. For rectobulbar
fistula (the commonest anomaly), the author favours a PSARP.

Anterior Sagittal Anorectoplasty (ASARP) in females

Some surgeons perform the pull through operation in females in lithotomy position using the anterior approach.
The operation is essentially the same as the more frequently used posterior approach. Similar outcomes are
reported. Advantage is that cumbersome posterior position is not required, the dissection is limited to anterior
aspect of the muscle complex, and the abdomen can be opened (if necessary) without a change in the position.
The author has no experience with this approach.

References

1. deVries PA, Pena A. Posterior sagittal anorectoplasty. J Pediatr Surg. Oct 1982;17(5):638-43.
2. Hong AR, Acuna MF, Pena A, et al. Urologic injuries associated with repair of anorectal malformations in male
patients. J Pediatr Surg. Mar 2002;37(3):339-44.
3. Parrott TS. Urologic implications of anorectal malformations. Urol Clin North Am. Feb 1985;12(1):13-21.
4. Pena A. Anorectal malformations. Semin Pediatr Surg. Feb 1995;4(1):35-47.
5. Pena A. Current management of anorectal anomalies. Surg Clin North Am. Dec 1992;72(6):1393-416.
6. Pena A. Management of anorectal malformations during the newborn period. World J Surg. May-
Jun 1993;17(3):385-92.
7. Pena A. Posterior sagittal approach for the correction of anorectal malformations. Adv Surg. 1986;19:69-100.

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8. Pena A, Devries PA. Posterior sagittal anorectoplasty: important technical considerations and new applications. J
Pediatr Surg. Dec 1982;17(6):796-811.
9. Pena A, Hong A. Advances in the management of anorectal malformations. Am J Surg. Nov 2000;180(5):370-6.
10. Pena A, Migotto-Krieger M, Levitt MA. Colostomy in anorectal malformations: a procedure with serious but
preventable complications. J Pediatr Surg. Apr 2006;41(4):748-56; discussion 748-56.
11. Shaul DB, Harrison EA. Classification of anorectal malformations--initial approach, diagnostic tests, and
colostomy. Semin Pediatr Surg. Nov 1997;6(4):187-95.

Cleft Lip and Cleft Palate

Rajeev B. Ahuja, Vybhav Deraje

EPIDEMIOLOGY

Oro-facial-clefting is the most common congenital anomaly of the head & neck and is known to occur in 1 in 500
live births. The incidence is highest in Asians and lowest in Africans and African Americans. Clefts of the lip (CL)
may be unilateral or bilateral, complete or incomplete, left or right sided and may occur with or without cleft palate
(CP). They frequently occur as isolated anomalies but maybe associated with syndromes such as Treacher
Collins syndrome, Apert syndrome, Pierre Robin sequence etcd. The reported distribution according to the type
of cleft is 25% CL alone, 50% CL/P and 25% isolated CP.There is a left sided preponderance in CL. For reasons
unknown there is male preponderance in CL/P whereas isolated CP is more common in females.

ETIOLOGY

The etiology remains unknown, but a multifactorial combination of heredity and environmental factors seems
most plausible. When one sibling has a CL/P, the probability of the next child being affected is 4%. When both a
parent and child are affected, the likelihood of the next child having a CL/P increases to 17%. Other factors
implicated to cause clefting are increased parental age, drug use(phenytoin, steroids) and infections during
pregnancy, smoking during pregnancy or folate deficiency.

Three theories exist which describe how embryological failure or errors result in cleft formation. The Fusion
failure theory suggests that clefts are formed when fusion of facial processes fail. The Mesodermal
penetration theory implicates the lack of neuroectoderm and mesoderm penetration into the bilaminar
ectodermal sheets as a result of which they give way. Newer understanding of the neuroembryology underlines
the Neuromeric theory,according to which, the face can be mapped into genetically determined developmental
zones with defined cellular contents and distinct spatial origins in their precursor tissue units. The occurrence of
clefts is nothing more than an orderly progression of deficiency states in the precursor fields resulting in varying
degrees of absence of soft tissue matrix or bone.

EMBRYOLOGY
th th
Facial development takes place between 4 -10 week of intrauterine life. The boundaries of the primitive mouth
(stomodeum) are the paired mandibular prominences inferiorly, paired maxillary prominences (MxPs) laterally
and the frontonasal prominence (FNP) cranially. These five facial prominences in a human embryo form the adult
facial features. Elevation of the margins of the FNP leads to development of median nasal prominence (MNP)
and the lateral nasal prominence (LNP) on each side. The depressed central region of the nasal placode is called
the nasal pit which forms the external nares.

Development of Upper lip: The MxPs migrate medially and fuse first with the LNP and then with the MNP. The
LNP and the MNP also fuse with each other. The lateral portions of the upper lip are formed from the maxillary
prominences from each side.

Cleft Lip: A unilateral CL results from failure of fusion of the MNP and the MxP on one side. A bilateral CL occurs
due to failure of fusion of the MxP on either side with the globular process (merged MNPs). The initial MxP-MNP
fusion remains intact during the early stages of cleft formation, but the MxP becomes somewhat disconnected
with MNP during its later forward growth resulting in an incomplete cleft.

Development of the Palate: From each MxP, a plate like lateral palatine process grows medially.
Simultaneously, a median palatine process forms from the posterior aspect of the merged MNPs. The fusion of
these three elements begins at the junction of the lateral palatine processes with the median palatine process in
the midline (from the point of the incisive foramen) and proceeds both posteriorly towards uvula and anteriorly
towards alveolus. The portion derived from the median palatine process forms the premaxilla which carries the
four incisors, and is called the primary palate; the lateral palatine processes form the secondary palate.

11
Ossification occurs in the primary palate and the anterior portion of the secondary palate to form the hard palate.
The posterior portion of the secondary palate does not undergo ossification and forms the soft palate.

Cleft palate: Clefts of the primary palate occur anterior to the incisive foramen and result from the failure of
fusion of the lateral palatine process(es) with the median palatine process. Clefts of the secondary palate occur
posterior to the incisive foramen and result from the failure of the lateral palatine processes to fuse with each
other and with the nasal septum. Anomalies of the mesenchymal merging of the palatal shelves can result in
submucous cleft palate (SMCP). There occurs imperfect muscle union (muscular diastasis) across the soft palate
with an intact mucosal surface (zonapellucida), bifid uvula and a notched posterior hard palate.

ANATOMY

Upper lip: The upper lip has a centrally placed Cupids bow with philtral tubercle in midline and two peaks-one on
each side at equal distance from philtral tubercle. There are two symmetrical philtral ridges extending from the
each peak of the Cupids bow to the corresponding base of columella. The philtral groove lies in between the two
philtral ridges. Two equal lateral lip elements extend from philtral ridges to the angle of mouth on each side. The
lip has a pinkish wet vermilion, a relatively darker dry vermilion and a white roll of Gillies at the skin-mucosal
junction. The lip has an outer skin, an inner mucosa and the orbicularis oris muscle in between.

The abnormalities seen in cleft lip are the direct consequences of disruption of the orbicularis oris muscle.

Unilateral Cleft Lip: On the affected side, there is a complete diastasis of the orbicularis muscle. The cleft
orbicularis is abnormally inserted to the columellar base medially and alar base and maxilla laterally, pulling them
apart.

Bilateral Cleft Lip: There is bilateral interruption in continuity of the lip white line, vermilion and orbicularis oris
muscle. The muscle gets aberrant insertion to the alar bases bilaterally, pulling them apart laterally. The
premaxilla is attached only to the nasal septum and the vomer.

Cleft lip nasal deformity: The cleft side alar cartilage is splayed out & flared. The angle between the medial and
lateral crus thus becomes obtuse. Caudal edge of nasal septum is deviated towards the normal side. Columella
on the cleft side appears shorter as it extends laterally to a dipped area in the rim of the nostril. The alar base is
usually pulled downward, backward and laterally. The nostril sill on the cleft side is thus larger and the alar-facial
angle is obtuse.

Palate: The palate is divided into hard palate (anterior 2/3rd) and soft palate (posterior 1/3rd). The premaxilla is
situated anterior to the incisive foramen. The anterior portion of the hard palate is formed by the palatine process
of maxilla while the posterior portion is formed by the horizontal plate of the palatine bone. The greater & lesser
palatine neurovascular bundles pass through the greater & lesser palatine foramina respectively which are
located in the posterolateral portion of the palatine bone. Both the palatine process of maxilla and the palatine
bones join the vomer.

12
The muscles in the velopharyngeal region play a role in swallowing, speech production and auditory tube
function. Muscles that insert into the palate are tensor velipalatini, the levatorvelipalatini, the
platoglossus,palatopharyngeus and musculus uvulae. These muscles form the opposing slings that meet in the
midline in the soft palate raphe. The muscle fibres in the soft palate are oriented transversely with no significant
attachment to the hard palate. The levator muscle is the critical muscle involved in the velopharyngeal closure. Its
sling suspends the soft palate from the cranial base and the contraction causes elevation &retrodisplacement of
the velum during speech and swallowing. The tendon of tensor hooks around the hamulus forming a 90 degree
turn as it enters the soft palate. Its fibres are attached to the eustachian tube. Besides tensing the velum, its
contraction dilates the eustachian tube and helping in the middle ear drainage.

Cleft Palate: Clefts of the hard and the soft palate vary in degree from bifid uvula at the posterior end of the soft
palate to a complete cleft in the roof of the oral cavity. Instead of the muscle fibres being transverse in orientation,
they become oriented in an anteroposterior direction converging along the medial border of the cleft. They get
abnormally inserted into the posterior and medial edge of the hard palate.

CLASSIFICATION
Several classification systems have been proposed over the years arranged along morphologic, anatomic, and
embryonic guidelines. In the Indian subcontinent, the Nagpur modification of Davis and Ritchies classification is
commonly used:
Group I: Cleft lip only (Pre alveolar clefts)
Group Ia: Cleft of lip and alveolus
Group II: Cleft palate only (Post alveolar clefts)
Group III: Cleft of lip, alveolus and palate (continuous pre alveolar + post alveolar)
Group I and III clefts are subdivided into unilateral / bilateral, and Group II is subdivided into clefts of hard and
soft palate.

FUNCTIONAL DEFICITS

Although CL/P may not be life threatening, many functions such as feeding, speech, middle ear ventilation,
hearing, maxillofacial growth, dentition, and occlusion can be grossly disturbed due to structures involved. With a
cleft in the alveolus and palate, the infant is unable to press the nipple and suckle the breast properly because of
inability to generate negative pressure in the mouth due to escape of the air through the cleft. Nasal escape of
the air contributes to gross distortions in speech.There may be nasal regurgitation of food due to common nasal-
oral chamber. Many cleft palate patients develop otitis media because of abnormal functioning of the Eustachian
tubes. This may grossly affect the normal hearing which can have grave impact on learning speech as well. A
cleft of the lip alone is operated for cosmetic reasons only.

TEAM APPROACH

The complexities of cleft lip and palate therapy make it necessary for a variety of clinicians to collaborate on the
planning and the delivery of the treatment. A multidisciplinary team approach is ideal where the plastic surgeon is
the main cog responsible for surgical repair and the overall management of the deformity. The orthodontist takes
care of maxillary arch collapse, misalignment of dental arches, malocclusion and dental problems. The speech
therapist is a vital member of the cleft team who assesses and trains these children for development of good
comprehensible speech. ENT surgeon takes steps to prevent any hearing problems. Pathologist, pediatrician,
radiologist, prosthodontist, psychologist, cleft nurse, social worker as well as a photographer complete the cleft
team. All contribute to the care of the cleft individual from infancy to adulthood.

13
TIMING OF SURGERY

There is no agreement on the ideal timing and the ideal technique of repair. More than one treatment plan is
acceptable. The plan usually followed is shown in Table 1.

BIRTH

PRESURGICAL NASOALVEOLAR MOULDING (1-6 weeks)

DEFINITIVE LIP REPAIR,GINGIVOPERIOSTEOPLASTY & PRIMARY RHINOPLASTY (3-6


months)

PALATE REPAIR( 12-18 months)

ALVEOLAR BONE GRAFT (7-11 years)

DEFINITIVE RHINOPLASTY & ORTHOGNATHIC SURGERY (after 17 years)

Table 1.
st
Presurgical orthodontic treatment is begun in the 1 week after birth with the maximum response occurring during
the first six weeks. Whenever presurgical orthopedics is not available and if the child is older than 3 months, a
definitive lip repair with nasal correction(limited open rhinoplasty) is done because presurgical orthopedics is
usually not effective after 3 months.Alveolar closure is also accomplished along with the lip repair by using the
local mucoperiosteal flaps from the alveolar segments (gingivoperiosteoplasty). Palatoplasty is done at the age of
12-18 months (before the baby begins to speak). Timing of alveolar bone grafting relates to the eruption of the
central incisor and canine. It is determined by the orthodontist. This is usually at the age of 711 years. Teeth
are brought into final alignment by orthodontist in tandem with a prosthodontist who replaces the missing teeth.
Definitive rhinoplasty and /or orthognathic surgery, if required, are carried out upon skeletal maturity (after 17
years of age).

PRE-OPERATIVE PARENTAL COUNSELING

Feeding Advice: Babies with only CL can usually suckle well by latching on with the alveolus and palate to suck
rather than using the orbicularis muscle as in the normal infant. They can be breast fed. Expressed breast milk
can also be fed to the baby with a spoon, which is mandatory in patients with cleft lip and palate. The hole in the
nipple can be increased in size by making a cross cut so that the milk flows out easily on its own rather than the
child requiring to press and suckle it. The simple and best method is spoon feeding. The mother should to be
taught that feeding needs to be done with babys head kept up (minimum 45 degrees) and the milk should be
poured from the spoon to the back of the tongue so that it flows easily down the pharynx without escaping
through the nasal passage. This prevents aspiration /coughing/choking. Such children also swallow a lot of air
while being fed. Frequent burping is required after every feed.

ENT checkup has to be done routinely as children with cleft palate are likely to develop recurrent middle ear
problems. If required, a small tube (Grommet) would be placed in the tympanic membraneto prevent damage to
the eardrum.

Speech development: Parents should be well informed that the children with cleft palate may speak differently
from other children. Speech problems occur because of incorrect speech patterns learned before palate repair
and /or the repaired soft palate is short and not mobile enough to achieve velopharyngeal closure. Nasal escape
of the air and the sound occurs producing an incomprehensible speech. Such children would require prolonged
speech therapy after the palate repair is accomplished. Few children may need further surgical interventions for
improvement in their speech (pharyngoplasty operation), aesthetics and alignment of dental arches.

Immunization and weight record: The child must be immunized as per the age schedule. The monthly weight
record needs to be maintained.
The prognosis regarding the number of stages / sequence of proposed surgical interventions as per the deformity
/ time duration involved / need for frequent hospital visits / possibility of surgical interventions till adulthood / final
cosmetic and functional outcome etc. should be clearly explained to parents. Monthly follow up is advised to
confirm that the baby is thriving well.

14
PRESURGICAL ORTHODONTICS
Presurgical maxillary orthopedics attempts to bring the maxillary cleft arches and the protruding premaxilla in
alignment before a definitive lip and anterior repair is accomplished. The simplest technique to achieve this is by
gentle pressure on the protruding premaxilla by the mother. External taping (nonsurgical lip adhesion) by a strip
of micropore tape placed across the cleft is another simple procedure. Nasoalveolar molding also accomplishes
the retraction of premaxilla. It takes advantage of the high degree of plasticity of the nasal cartilages during the
first six weeks after birth. A combined technique for simultaneous nasal and alveolar molding is employed. Acrylic
intraoral molding plate is constructed and modified at weekly intervals to gradually align the alveolar segments
and achieve narrowing of the alveolar gap. The nasal stent arising from the intraoral molding plate is also
modified as it lifts the nasal tip.

GOALS OF SURGERY
Four major goals of surgery on an infant with CL/P are: a) to reconstruct the features of the lip and nose for
maximum aesthetics, b) to separate the oral and the nasal cavities, c) to reconstruct the functional speech
mechanism and d) to encourage adequate normal growth of the facial skeleton. Aim should be to obtain an
anatomical as well as functional repair.

TECHNIQUES OF REPAIR
Unilateral cleft lip: Many normal anatomical landmarks and clues are present on the medial and lateral cleft lip
segments which aid in surgery (Fig.4). The principle is to lengthen the cleft side so that it equals the vertical
dimensions of the non-cleft side. A tissue rearrangement is designed to borrow tissue from the lateral element of
the cleft and introduce it into the medial element.
The most commonly used flap designs can be categorized as a) triangular flap technique and b) rotation
advancement flap technique.

(Fig.4)
Point 1: Lowest point in the arch of Cupids bow, midline of lip /
philtral tubercle
Point 2: Peak of Cupids bow on the non-cleft side. Point 3:
Proposed peak of Cupids bow on the cleft side (distance from 1 to
2)
Point 4: Midpoint of the columella
Point 5: Base of the columella on the non-cleft side.Point 6: Base
of the columella on the cleft side.
Point 7: Alar base on the cleft side
Point 8: Alar base on the non-cleft side
Point 9: Point of disappearance of white roll on the vermilion
cutaneous junction on the cleft side.

Rotation advancement technique

Originally described, and later modified by Millard himself, this technique is popularly known as a cut as you
go technique (Fig.5). The incisions are so designed that the flap on the medial lip segment rotates inferiorly
and a triangular flap designed on the lateral lip segment is advanced under the columella into the defect
created by the movement of the rotation flap. The technique introduces tissues in the upper third of the lip.
The scars are placed in the more anatomically correct position along the philtral column on the cleft side.
Nasal deformity can be corrected simultaneously. It is not an easy method for a beginner to master. Wide
clefts present the greatest challenge to the rotation advancement repair. Insufficient lengthening on the cleft
side is sometimes a problem especially when there is marked discrepancy in height between the cleft and
the non-cleft sides.

(Fig.5)

15
Triangular flap technique
It introduces tissue in the lower third of the medial segment and has the advantage of producing a pouting
tubercle (Fig.6). It is suitable for all kinds of incomplete and complete clefts (both narrow and wide). It is
comparatively easy to learn and teach as it is based on definite geometrical markings, and permits relatively
inexperienced cleft lip surgeon to obtain acceptable result. Simultaneous nasal correction is possible. The
disadvantages are that the philtral ridge on the cleft side is crossed by the final scar and no changes /
alterations are possible once the incisions have been made in the lip segments. Repaired lips may become
slightly longer than the cleft side which would require secondary surgical correction.

(Fig.6)

Bilateral cleft lip: More than a dozen techniques and their modifications have been described for complete
bilateral lip repair. The technique most commonly used previously wasVeau III straight line repair or its minor
variations. The major drawback of this procedure was lack of muscle to muscle approximation. With increasing
attention to muscular closure in the unilateral deformity, reports began to underscore the importance of
orbicularis oris repair in bilateral clefts.

After elevation of the prolabial flapthe lateral white-roll-vermilion-mucosal flaps are incised and orbicularis muscle
bundles are dissected bilaterally to be approximated in the midline behind the flap (Fig.7). The white roll could be
created using the native prolabial white roll or from the lateral segments.This is followed by alveolar
gingivoperiosteoplasty. Nasal deformity is also corrected primarily by semi open rhinoplasty through bilateral rim
incisions.

(Fig.7)

Cleft lip type nasal deformity


The major corrections required are alar cartilage repositioning and septal deviation. Primary rhinoplasty by a
Limited Open approach addresses both these issues where bilateral rim incisions are given, both the alar
cartilages are dissected free from the overlying skin and along pyriform aperture andstitches are applied to bring
the dome of alar cartilages closer to each other (Fig.8). Anatomic repositioning of the orbicularis muscle and the
alar cartilages helps to reorient the septum.

(Fig.8)

16
Cleft palate:
Veau-Wardill-Kilner operation (V-Y Pushback repair)(Fig.9)
The essence of the pushback repair is V to Y closure on the hard palate to achieve an increase in the
anteroposterior length of the palate at the time of primary palatoplasty. Tendon of tensor palatini is unhooked /
freed from around the hamulus. The greater palatine neurovascular bundle which emerges through the
posterolateral hard palate forms the pedicle of the mucoperiosteal flaps on either side. The levator muscles are
detached, reoriented and sutured either end-on or in an overlapped position. The nasal tissue is released and left
open. Although V-Y lengthening gains length, large open areas are left anteriorly and on the nasal surface. As
these raw areas close by contraction, a good deal of the length gained at surgery is lost by secondary
contraction. These shortcomings have been dealt with by the two flap palatoplaty technique described by
Bardach.

(Fig.9)

BardachsTwo flap palatoplasty(Fig.10)


The relaxing incisions are given along the alveolar margins to the edge of the cleft. It is often possible to close
much of the lateral incision and minimize raw areas. Muscle is completely freed from both the nasal and oral
mucosa followed by midline repair of the nasal layer followed by intra-velar-veloplasty and closure of oral
mucosal layer.

(Fig.10)

Intra-velar-veloplasty
Abnormal insertion of levatorvelipalatini muscles on the posterior border of the hard palate is detached, the
muscle bundles are dissected free from the oral and the nasal mucosa, reoriented in the transverse direction and
overlapped to reconstruct the levator sling. Release of tensor tendon just medial to the hamulus facilitates this
midline overlap to provide appropriate tension on the repair. Excellent speech outcomes have been reported with
this technique.

POST-OPERATIVE CARE
Cleft lip surgery: Spoon feeding can be resumed 4-5 hours after the surgery. Infants can resume breast feeding
after wound healing. Elbow restraints/splints (started preoperatively) are continued post-op for 3-4 weeks. The
arms are splinted with elbows extended to prevent the child from rubbing, scratching or manipulating the wound
causing accidental disruption of the repair. Parents should be informed that the lip scars would feel firm for 5-6
weeks after the repair. Gentle massaging of the scar facilitates its softening.

Cleft Palate Surgery: Palatoplasty patients must be monitored in the recovery for few hours to watch for any
respiratory difficulty, adequate oxygenation and bleeding. Palate repair acutely reorganizes the childs airway.
Sudden narrowing coupled with soft palate oedema and bleeding may partially obstruct the airway causing
respiratory insufficiency in acute postoperative period especially with push-back techniques. A silk stitch through
the tongue which is loosely taped to the cheek postoperatively can be lifesaving in emergency. Traction on this
stitch allows the tongue to be pulled forward without use of nasal or oral airway. Spoon feeds of clear liquids are
usually allowed 6-8 hours after surgery.Feedings are followed by water to clear the food particles. Liquid diet is

17
continued for two weeks after which semisolids are allowed. Arm restraints are removed after 3-4 weeks and a
normal diet is resumed. The patients are sent to speech therapist after four weeks of repair. Several sucking and
blowing exercises, speech stimulation and training is imparted which would require active cooperation from
parents. If the childs speech does not progress satisfactorily, active steps would need to be taken.

COMPLICATIONS
Complications after lip repair could be bleeding, wound infection and dehiscence. The wound may disrupt due to
excessive tension on the suture line or trauma. Infection could initiate or complicate the problem. This may heal
secondarily giving a bad stretched scar or may necessitate a redo which should not be attempted till entire
induration has subsided.
Complications after palate repair include respiratory problems / airway maintenance, bleeding, infection,
dehiscence and oronasal fistula. Airway problem (see above) with bleeding can be life threatening. Bleeding at
the conclusion of surgery must be controlled as it would become worse as the child awakens and the effect of
adrenaline weans off. Bipolar cautery, suture ligatures, adrenaline soaked gauze packs and sustained pressure
on the hard palate all can be employed to achieve haemostatsis. Dehiscence due to injury in first 2-3 weeks can
be repaired immediately. Immediate repair for gradual breakdowns due to inflammation and infection is not
advisable. Tissues should be allowed to settle for 6 months before repair is contemplated. Oronasal fistulas
become a source of persistent nasal air loss, nasal regurgitation, distorted articulation and malodorous breath.
Healing process is often accompanied with diminution in the size of the fistula. Soft palate fistula can be excised
and the defect closed primarily in 2 layers. Persistent hard palate fistulas require double layer closure with large
oral mucoperiosteal flaps 6 months after palatoplasty.

Bibliography

1. McCarthy. Joseph G. Plastic Surgery.1st edn. Philadelphia: W. B. Saunders Co; 1990: Vol 4;2451-2921.
2. Mathes Stephen J.Plastic Surgery.2ndedn. Philadelphia: Elsevier Inc;2006: Vol 4;1-364.
3. Neligan Peter C.Plastic Surgery.3rd edn. London: Elsevier Inc;2013: Vol 3;503-670.
4. Hopper Richard A. Cleft lip and palate: embryology, principles, and treatment. Charles HThorne,K. C. Chung, A
Gosain, G. C. Gurtner, B. J.Mehrara et al. (Eds.), Grabb and Smiths Plastic Surgery, 7th Ed. Philadelphia:
Lippincott-Williams,2014:173-199.
5. Sawhney C.P.Geometry of Single Cleft Lip Repair.Plastic & Reconstructive Surgery,1972;49(5):518-521.
6. Ahuja R.B. Primary Rhinoplasty in Unilateral Cleft Patients: The Limited Open Approach and Other Technical
Considerations.The Cleft Palate-Craniofacial Journal,2006; 43(4):492-8.

Urethral Injuries

Iqbal Singh

SURGICAL ANATOMY: The male urethra is a tubular structure extending from the bladder neck to the external
urinary meatus at the tip of the glans penis. It has four components which are named (from proximal to distal), the
prostatic, membranous, bulbar and penile urethra. The male urethra is divided into the anterior and posterior
urethra. Posterior urethra consists of prostatic urethra and the membranous urethra while
anterior urethra includes bulbar and penile urethra.The prostatic urethra extends from the bladder neck to the
verumontanum and is compressed on either side by the lateral lobes of the prostate, giving it a slit-like
configuration. The verumontanum is a small hillock of tissue indented at its crown by a pit called the utriculus
masculinus which marks the proximal extent of the external urethral sphincter and is an important landmark for
urologists performing transurethral resection of the prostate. The membranous urethra lies just distal to the
verumontanum and is located where the urethra penetrates the pelvic floor and it is the usual site of urethral
rupture at the time of a pelvic fracture, its course runs from the apex of the prostate to the perineal membrane,
spanning an average length of 2-2.5 cm. It is the primary location of continence as a consequence of the
surrounding pelvic floor musculature and external urethral sphincter. The bulbar urethra extends from the
membranous urethra to the penoscrotal junction and is located anteriorly within the corpus spongiosum. The
penile urethra is stretches alomg the length of the penis, lies flattened anteroposteriorly, but distends when filled
with fluid distally it becomes dilated within the glans penis where it is called navicular fossa.

The female urethra is around 23 cm long, extending from the bladder neck to the external urethral meatus.
Continence is maintained by the external striated urethral sphincter, which in women extends for almost the
whole length of the urethra. There is extra support from the surrounding pelvic floor musculature. In contrast to
men, the female bladder neck has little role in the maintenance of continence. The mid urethral region in the
females is urodynamically the zone of maximal urethral closing pressure (MUCP).

INTRODUCTION
Pelvic fractures causing disruption at the bulbomembranous junction is by far the main etiology of strictures in the
1
posterior urethra. Stein et al looked retrospectively at 2,589 patients who underwent urethroplasty procedures
from 2000 to 2011 in the USA, Italy, and India. They reported vehicular accidents as a cause for nearly 36% of

18
2
urethral strictures in India, vs. 15% in a cohort from the USA and Italy. Singh et al reported that traumatic
etiology was present in 11.9% of total stricture cases, pelvic fracture was the most common cause, and posterior
urethra was the most common site of involvement (60% of traumatic cases).

AETIOLOGY OF URETHRAL INJURIES


Blunt trauma (Vehicular accidents, Fall astride (straddle) e.g. on bicycle, fences, inspection covers and kicks in
the perineum. Sexual intercourse (Penile fractures and Urethral intraluminal stimulation); Penetrating trauma (
Gunshot wounds, Stab wounds, Dog bites, External impalement, Penile amputations); Constriction bands
(Paraplegia) and Iatrogenic injuries (Endoscopic instruments, Urethral catheters/dilators).

THE AMERICAN ASSOCIATION FOR SURGERY AND TRAUMA (AAST) GRADING: The AAST grading
emphasizes the degree of disruption and the degree of urethral separation. It divides urethral injuries into the
following five types:

AAST-URETHRA INJURY SCALE


Table adapted from http://www.aast.org/library/traumatools/injuryscoringscales.aspx#urethra
Grade* Injury type Description of injury
I Contusion Blood at urethral meatus; RGU normal
II Stretch injury Elongation of urethra without contrast extravasation on RGU
III Partial disruption Contrast extravasation on RGU at injury site with visualization in the bladder
IV Complete disruption Extravasation of contrast on RGU at injury site without visualization in the
bladder; <2cm of urethra separation
V Complete disruption Complete transaction with >2 cm urethral separation, or extension into the
prostate or vagina
*Advance one grade for bilateral injuries up to grade III.

3
Goldman classification of urethral injuries is a more widely accepted classification than the one proposed by
the American Association for the Surgery of Trauma (AAST). The Goldman classification is based on anatomical
location of the urethral injury and was initially proposed by Colapinto and McCallum but later modified to include
4,5
type IV, IVa and V injuries.
3
Classification
Type I: Stretching of posterior urethra due to disruption of puboprostatic ligaments, with intact urethra.
Type II: Posterior urethral injury above urogenital diaphragm
Type III: Injury to membranous urethra, extending into proximal bulbous urethra (i.e. with laceration of
urogenital diaphragm)
Type IV: Bladder base injury involving bladder neck extending into the proximal urethra internal sphincter is
injured, hence potential for incontinence
Type IVa: Bladder base injury, not involving bladder neck (cannot be differentiated from type IV radiologically)
Type V: anterior urethral injury (isolated).

POSTERIOR URETHRAL INJURIES

Etiopathogenesis: Urethral disruption injuries typically occur in conjunction with multisystem trauma from
vehicular accidents, falls, or industrial accidents. Urethral injuries may be partial or complete disruption of the
urethra. Posterior urethral injuries are almost exclusively associated with pelvic fractures and occur between 1.5
6,7
and 10% of pelvic fractures; concomitant bladder injuries are present in 15% of such urethral injuries. Fractures
of the anterior pelvic ring or pubic diastasis are almost always present when urethral disruption is encountered.
The highest risk of urethral injury is in straddle fractures with a concomitant diastasis of the sacroiliac joint,
8
followed by straddle fracture alone, and a Malgaigne fracture. Because the posterior urethra is densely adherent
to the pubis via both the urogenital diaphragm and the puboprostatic ligaments, the bulbo-membranous junction
is more vulnerable to injury during pelvic fracture than is the prostate-membranous junction. In children, injuries
are more likelyto extend proximally to the bladder neck because of the rudimentarynature of the prostate.

Diagnosis: Blood at the urethral meatus is the most common finding, although highly variable, present in 37-
9
93%. Other findings include inability to urinate, perineal/genital ecchymosis, palpably full bladderand/or a high-
riding prostate. Meatal blood loss is present in 98% of posterior injuries and in 75% of anterior injuries. Due to the
findings of high-riding prostate or a butterfly perineal hematoma may be absent, urethral disruption is detected
when a urethral catheter cannot be placed or when it is misplaced into a pelvic hematoma.

Females may also develop proximal urethral avulsion injuries, although much more rarely than males; A female
urethral injury should be suspected from the combination of a pelvic fracture with blood at the vaginal introitus,

19
vaginal laceration, haematuria, urethrorrhagia, labial swelling and/or urinary retention. Vaginal examination is
indicated in all female patients with pelvic fracture to assess vaginal lacerations. Direct urethroscopy over
urethrography may be more useful in the initial evaluation of females with suspected urethral injury.

Initial Management:
When blood at the urethral meatus following pelvic trauma merits an urgent retrograde urethrogram to rule out
urethral injury. Blind catheter passage prior to retrograde urethrogram should be discouraged however in the
acute setting of a partial urethral disruption, a single gentle attempt with a well-lubricated catheter may be
attempted by an experienced surgeon/urologist if successful and if blood is present a pericatheter retrograde
urethrogram can be performed to identify any potential missed urethral injury.
Suprapubic Cystostomy.Immediate suprapubic tube placement remains the standard of care in men with
posterior urethral injuries.

Definitive Management:

Immediate Open Reconstruction: Immediate anastomotic reconstruction of posterior urethral disruption injuries
in men is discouraged due to poor outcomes in terms of higher rates of impotence and incontinence, stricture
formation, and blood loss (Webster et al, 1983; Koraitim, 1996). However in female urethral disruption with pelvic
fracture, immediate primary repair, or urethral realignment over a catheter can be attempted so as to minimise
urethrovaginal fistulas or urethral obliteration. Concomitant vaginal lacerations should be repaired to prevent
vaginal stenosis. Delayed reconstruction is challenging in women due to a shorter female urethra (about 4 cm)
less amenable for mobilization during an anastomotic repair when embedded in scar.(Podesta, 2001) however,
these authors found that a suprapubic approach with partial pubectomy provides excellent exposure enabling
female bladder neck reconstruction.

Primary Realignment (PR) & Cystoscopy:. Flexible cystoscopy is an option to diagnose (and manage) an
acute urethral injury. Cystoscopy can also distinguish between incomplete and complete rupture as it is easy and
quick to perform and can be done in a supine position and it may allow a guidewire to be passed into the bladder
for facilitating early catheterization. An attempt at primary realignment of the distraction with a urethral catheter
may be attempted in hemodynamically stable patients, either acutely or within several days of injury. Simple
passage of a coud catheter antegrade from an anterior cystotomy to the urethral meatus, then tying it to another
catheter that is drawn back into the bladder is feasible. I should avoid prolonged attempts at endoscopic
realignment in patients with pelvic fracture associated urethral injury (PFUI). Patients undergoing PR of PFUI
may be benefitted in a subsequent urethroplasty if necessary, which may be more amenable as compared to
patients undergoing SPC diversion alone.

Some Techniques used for primary realignment:


Simple passage of a catheter across the defect. This is feasible only in few cases and in partial ruptures
only.
Endoscopically assisted catheter realignment using flexible, rigid endoscopes, and biplanar fluoroscopy.
Use of interlocking sounds (''railroading'' or magnetic catheters to place the catheter. This is an open surgical
technique used for posterior urethral injury, where the sound is passed per urethra from below as well as
through the bladder urethra is aligned and repaired over a catheter.
Pelvic hematoma evacuation and dissection of the prostatic apex (with or without suture anastomosis) over a
catheter.
Catheter traction or perineal traction sutures to pull the prostate back to its normal location.
Traumatic posterior urethral injury and early realignment using magnetic urethral catheters.
Retrograde and anterograde flexible cystoscopy may be used, although prolonged endoscopic realignment
attempts risk infection of the pelvic hematoma and thus is not routinely recommended. The urethral catheter
is generally removed after 4 to 6 weeks while retaining a suprapubic catheter.Many patients despite
adequate urethral realignment, develop posterior urethral stenosis. In case patients void satisfactorily
through the urethra, the suprapubic catheter may be removed 7-14 days later. Primary realignment may
allow healing without stricture. If realignment is unsuccessful and SPC has been placed, both EAU (2014)
and AUA (2014) guidelines state that delayed primary urethroplasty can be performed up to 14 days after
the injury (as the fibrotic process has not yet begun so as to avoid extended duration of SPC), provided
10
thepatient has a short defect and can lie in the lithotomy position.

The EAU recommends treating posterior urethral distraction defects via a deferred urethral repair at a minimum
of 3 months after trauma. This delay allows time for the healing of orthopaedic injuries, absorption of pelvic
haematoma, descent of the bladder and prostate to more anatomical positions, stabilisation of the scar tissue,
and for the patient to be able to be placed into the lithotomy position

Incomplete urethral tears are best treated by stenting with a urethral catheter.Agentle attempt to place a urethral
catheter should be done, radiographic confirmation of adequate positioning is imperative. Open exploration with
realignment incases of high-riding or pie-in-the-sky bladder or associated bladder neck tear in males can be
done. Associated rectal injuries require open exploration, repair, irrigation, and placement of drains. Thus the

20
timing of the intervention may be : Immediate: < 48 hours after injury; Delayed primary: 2 days to 2 weeks after
injury and Deferred: > 3 months after injury

DELAYED RECONSTRUCTION (CONVENTIONAL URETHROPLASTY):


In posterior urethral disruption the rupture defect between the two severed ends fills with scar tissue, resulting in
a complete lack of urethral continuity. This separation is really not a stricture as it is a true urethral rupture defect
filled with fibrosis. At 3 months, scar tissue at the urethral disruption site is stable enough to allow posterior
urethroplasty to be undertaken safely, provided that associated injuries are stabilized. SPC drainage should be
maintained until the associated injuries have healed and patient can be appropriately positioned for the
reconstructive procedure.

Preoperative Evaluation: Before the reconstructive procedure is planned, imaging studies are necessary to
delineate the characteristics of the urethral rupture defect. A cystogram and retrograde urethrogram should be
obtained simultaneously (up-and-down-o- gram). MRI may be useful to estimate the exact length of the urethral
gap, the degree and direction of prostatic displacement, the degree and extent of fibrotic tissue and to reveal
false paraurethral tracks.

Endoscopic Treatments: Endoscopic treatments like optical/direct-vision internal urethrotomy ( cutting through
the pelvic scar to provide a channel between the two ends of the avulsed urethra cut-to-the-light procedure)
should bereserved for selected short urethral stenoses and partial distraction injuries for which early
catheterization can achieve urethral continuity. If preoperative evaluation indicates defects >1 cm endoscopic
procedures may be ineffective and have no advantage.

Surgical Reconstruction: Open posterior urethroplasty through a perineal anastomotic approach is the
treatment of choice for vast majority of urethral distraction injuries because it definitively cures the patient without
the needfor multiple procedures.

SOME TROUBLE SHOOTING POINTS:


1. Care must be taken to carefully and meticulously excise all fibrotic tissue from the proximal urethral margin
until at least a 28-Fr bougie passes without resistance.
2. The bulbar urethra should be anastomosed in a tension-free manner to the prostatic/membranous urethra.
3. In most patients, posterior urethral anastomosis can be successfully achieved through a perineal approach
alone. Adjunctive manoeuvres such as corporeal separation, inferior pubectomy, corporeal rerouting, may
beimplemented if direct anastomosis proves difficult.
4. In cases with (extensive gaps/severe fibrosis/fistula/prior failed anastomotic urethroplasty/ associated
bladder neck injury)an alternative combined progressive abdomino-perineal approach or PAPA (with or
without total/partial removal of the symphysis pubis) or a staged procedure may be helpful.
5. Staged procedure- marsupialisation/lay opening of urethra with perineal urethrostomy, and delayed repair
with a graft or flap 3 months after the injury if adequate mobilization is not feasible during the initial
surgery. Second stage closure of the laid open marsupialised urethra can be done using the modified
Johansons repair by using the buried skin principle around the urethral plate.

COMPLICATIONS OF URETHROPLASTY
1. Erectile Dysfunction. Some degree of impotence is often noted in up to 82% of patients with pelvic fracture
and urethral distraction injury.(Flynn et al, 2003)The etiology is multifactorial and variably attributed to
cavernous nerve injury, arterial insufficiency, venous leak, and direct corporeal injury. (Narumi et al, 1993;
Munarriz et al, 1995; Shenfeld et al, 2003). At-risk patients undergo preoperative penile arterial duplex
Doppler studies to identify candidates suitable for initial penile revascularization.
2. Recurrent Stenosis. After posterior urethroplasty, 5-15% of patients may have recurrent stenosis at the
anastomosis. (Mundy, 1996; Flynn et al, 2003; Koraitim 2005; Cooperberg et al, 2007). Endoscopic treatment
(e.g., with direct vision internal urethrotomy) is often successful in this setting because the majority of fibrotic
tissue has been eliminated.
3. Incontinence. Incontinence rates after reconstruction are low <4%, (Koraitim, 2005).Urinary continence after
urethral distraction is the rule rather than the exception, despite destruction of the external sphincter from
either the injury itself or repair.

Thus clinicians should monitor patients for complications (e.g., recurrent stricture, erectile dysfunction and
incontinence) for at least one year following urethral injury.

ANTERIOR URETHRAL INJURIES


Etiopathogenesis: Anterior urethral injures may be blunt (e.g., straddle injuries, where the urethra is crushed
between the pubic bones and a fixed object) or penetrating where the urethra may be lacerated, crushed, or
disrupted. In contrast to posterior urethral distraction, anterior injuries are most often isolated. The majority occur
after straddle injury and involve the bulbar urethra, which is susceptible to compressive injury because of its fixed
location beneath the pubis. As with posterior urethral injury, a high index of suspicion must be maintained in all
patients with blunt or penetrating trauma in the urogenital region, and urethrography should be performed in any
case of suspected urethral injury. Clinical signs of anterior urethral injuries include blood at the meatus, perineal

21
hematoma, gross hematuria, and urinary retention. In severe trauma the Buck fascia may be disrupted, resulting
in blood and urinary extravasation into the scrotum. The primary morbidity of straddle injury is urethral stricture,
which may become symptomatic even years later.

Initial Management: Armenakas and McAninch (1996) proposed a simple, practical classification scheme
dividing anterior urethral injuries on the basis of radiographic findings into (i) Contusion, (ii) Incomplete
disruption, and (iii) Complete disruption. Contusions and incomplete injuries can be treated with urethral catheter
diversion alone.

For penetrating injuries to the anterior urethra, both the EAU and AUA recommend open surgical repair,
except when there are other life-threatening injuries. The urethral ends are spatulated and an end-to-end
anastomosis is made. If an anastomotic urethroplasty cannot be performed, typically if the disruption is >23 cm
long in the bulbar urethra and >1.5 cm in the penile urethra, then the urethra should be marsupialised/lay open,
and delayed repair with a graft or flap can occur at 3 months after the injury.

For blunt trauma to anterior urethra, both the EAU (2014) and AUA (2014) recommend suprapubic or urethral
catheter placement and delayed treatment, as the extent of injury is not easy to document. Initial SPC continues
to be the accepted standard of care for major straddle injuries involving the urethra (Park and McAninch, 2004);
however, primary anterior urethral realignment has shown promising results with respect to stricture rate and
erectile dysfunction in patients with straddle injuries of lesser magnitude (Ying-Hao et al, 2000; Yu et al, 2007).
Primary repair should not be undertaken if the patient is unstable, the surgeon lacks expertise in urethral surgery
or in the setting of extensive tissue destruction or loss. Debridement of the corpus spongiosum after trauma
should be limited because corporeal blood supply is usually robust, enabling spontaneous healing of most
contused areas. Urinary diversion is maintained for 2 and 3 weeks for partial and complete ruptures, respectively.
Delayed Reconstruction: Before any planned procedure, a retrograde urethrogram and voiding cystourethrogram
should be obtained to define the site and length of the obliterated urethra clearly. Urethral ultrasound examination
may help delineate the length and severity of stricture.

Anastomotic urethroplasty is the procedure of choice for totally obliterated bulbar urethra after a
straddle injury. The typical scar is 1.5-2 cm long and can be completely excised. The proximal and distal urethra
can be mobilized for a tension-free, end-to-end anastomosis. This is a highly successful procedure in more than
95% of cases (Santucci et al, 2002). Endoscopic incision through the scar tissue of a totally obliterated urethra is
contraindicated. Partial urethral narrowing can be initially treated by endoscopic incision or dilation with a higher
success rate. Open repair should be delayed for several weeks after instrumentation to allow the urethra to
stabilize, and a 2-month period of suprapubic urinary diversion may be prudent preoperatively to optimize
conditions for repair of complex or recurrent strictures that have been catheter dependent.

IATROGENIC URETHRAL TRAUMA


Catheter placement is the most common cause of iatrogenic urethral trauma. Iatrogenic urethral injuries also
occur after radical prostatectomy, pelvic radiotherapy, and other abdominopelvic surgery. The main consequence
of iatrogenic trauma is urethral stricture. False passages should be treated with urethral catheter placement if
possible, while strictures should be managed endoscopically with incision or resection initially, followed by
urethral reconstruction if endoscopic management fails. The most common iatrogenic urethral trauma after
radical prostatectomy is anastomotic stricture. The EAU recommends dilation or endoscopic incision as the first
step in its treatment.

PAEDIATRIC URETHRAL TRAUMA


The recommended radiographic method for diagnostic evaluation of paediatric urethral trauma is RUG. As many
children with urethral trauma are unstable due other associated injuries, the first step in management according
to the Paediatric EAU guidelines is to provide urinary drainage. Transurethral catheterisation can be performed
only if the patient can still void and diagnostic evaluation is not suspicious for urethral rupture. A suprapubic
catheter should be placed, otherwise. According to the Paediatric EAU guidelines, there is no singular accepted
method to manage posterior urethral injuries; either immediate suprapubic drainage with late urethral
reconstruction or immediate primary re-alignment can be performed.

References

1. D.M. Stein, D.J. Thum, G. Barbagli, S. Kulkarni, S. Sansalone, A. Pardeshi, et al.A geographic analysis of male
urethral stricture aetiology and location.BJU Int, 112 (2013), pp. 830834
2. Singh J, Priyadarshi V, Pandey P, Vijay M, Bera M, Chakraborty S et al. Urethral Stricture Aetiology Revisited: An
Indian Scenario.UroToday Int J. 2013; 6(1):art 5. http://dx.doi.org/10.3834/uij.1944-5784.2013.02.05
3. Goldman SM, Sandler CM, Corriere JN et-al. Blunt urethral trauma: a unified, anatomical mechanical
classification. J. Urol. 1997;157 (1): 85-9.
4. Ingram MD, Watson SG, Skippage PL et-al. Urethral injuries after pelvic trauma: evaluation with urethrography.
Radiographics. 2008;28 (6): 1631-43.
5. Kawashima A, Sandler CM, Wasserman NF et-al. Imaging of urethral disease: a pictorial review. Radiographics.
2004;24 Suppl 1 (suppl 1): S195-216.
6. Brandes S and Borrelli J, Jr.: Pelvic fracture and associated urologic injuries. World J Surg 2001; 25: 1578.

22
7. Bjurlin MA, Fantus RJ, Mellett MM et al: Genitourinary injuries in pelvic fracture morbidity and mortality using
the National Trauma Data Bank. J Trauma 2009; 67: 1033.
8. Talan DA, Citron DM, Abrahamian FM, et al. Bacteriologic analysis of infected dog and cat bites.Emergency
Medicine Animal Bite Infection Study Group. N Engl J Med 1999;340(2):85-92.
9. Martinez-Pineiro L, Djakovic N, Plas E et al: EAU Guidelines on Urethral Trauma. Eur Urol 2010; 57: 791.
10. Ysebaert B, Oosterlinck W. Perineal anastomotic urethroplasty for posttraumatic urethral stricture with or
without previous urethral manipulations: a review of 61 cases with long term followup. J Urol 2009; 181: 1196
200

Urinary Diversion

Pawan Lal, Sanjeev K. Tudu

Advancements in bladder replacement construction and continent urinary diversion have reduced
treatment morbidity for patients facing cystectomy.

Historical Review
The quest for an ideal technique for urinary tract reconstruction following cystectomy dates back to 1852 when
15
Simon first reported diversion of urine to a segment of bowel by creating fistulas between the ureters and the
rectum in a patient with bladder exstrophy. Initially, efforts were aimed at either bringing the ureters to the skin or
diverting the urine to the sigmoid colon to benefit from continence provided by the anal sphincter. Prior to the
1950s, the use of the anal sphincter for continence established ureterosigmoidostomy as the urinary diversion of
choice. During this era, techniques of nonrefluxing ureteral anastomoses were improved. However, the risk of
long-term complications with ureterosigmoidostomy was significant (hydronephrosis: 32%; pyelonephritis: 57%;
2
metabolic derangements: 47%). In 1950, Bricker popularized the use of the ileum as a urinary conduit, which
constituted the gold standard for patients who underwent urinary diversion until the 1980s. The need for
improvements in the quality of life of patients led to the era of continent urinary diversion and bladder
replacement. By applying the concepts of a cutaneous catheterizable ileocecal reservoir developed in 1950,
6
several investigators reported encouraging initial results with colonic reservoirs in the mid 1980s, and Kock et al
24
concurrently developed a catheterizable ileal pouch. Camey and LeDuc reintroduced the concept of the
neobladder in 1979, and other investigators improved the technique by applying the experiences of the early
11
continent urinary diversion .

Selection of Type of Urinary Diversion


The goal of surgery in the management of infiltrating bladder cancer is either curative or palliative. If the intent is
palliative, then the simplest and most expeditious type of urinary diversion is best. If the goal is curative, then the
patient is apprised of reconstruction options for the urinary tract and undergoes preoperative evaluation. Although
the psychological impact of surgery and diversion is significant, any type of urinary reconstruction should be
acceptable with good preoperative assessment and education. Factors that affect the choice of urinary diversion
include patient age, manual dexterity, body habitus, physical and mental status, renal function, prognosis of the
primary disease, existing bowel pathology, prior radiation or chemotherapy, the presence of urethral disease, the
expectations, preferences, and fears of the patient, the experience and preference of the surgeon, and cost.
Since there is no unanimous choice for the best method of urinary diversion, all options should be considered.

Indications for an external collecting device diversion (bowel conduit) are either absolute or relative. Absolute
indications include impaired renal function, impaired physical ability to perform self-catheterization, and inability to
understand the significance and possible complications of a continent diversion. Relative indications include
advanced age, need for postoperative chemotherapy, previous pelvic irradiation, bowel disease (Crohn's
disease, colitis, cancer), body habitus, diseased urethra, and impaired functional status.Patient choice also is a
key factor in selection.

Options in Continent Urinary Diversion - the main categories are listed and explained below:

Non-continent cutaneous conduit A conduit from a part of the intestines (normally ileum or colon) is
constructed. It is non-continent, i.e. acts simply as a passage allowing urine to leak into an external collection
device outside of the body.

Continent cutaneous diversion A new bladder is constructed from a segment of the bowel (ileum or colon),
with a passage from the new bladder to an outlet at the body surface. The outlet includes a construction, i.e.
a tissue flap or equivalent, that makes it continent and it requires catheterization to be emptied.

Continent orthotopic diversion (Neobladder) A new bladder is constructed from a segment of the bowel
and connected to the intact urethra, using the urethral sphincter to gain continence after the surgery.

23
Non-continent cutaneous conduits

Ureterosigmoidostomy

One of the first urinary diversions using bowel included the use of ureterosigmoidostomy, where the ureters were
anastomosed to the sigmoid. Its major advantage is the potential for spontaneous emptying of urine with stool,
i.e. continence is maintained by the anal sphincter. However, ureterosigmoidostomy is prone to detrimental upper
tract changes in patients over time, e.g._10 years . Very high intrarectal pressures (up to 200 cm water ) led to
persistent pyelonephritis and incontinence. In addition, the mixture of faecal and urinary streams predisposed
patients to a higher risk of bowel adenocarcinoma. Several modifications of the ureterosigmoidostomy were
developed to decrease the significant complication rate associated with the procedure. The sigma rectum, or
Mainz II pouch, consists of a detubularised colon 6 cm both proximal and distal to the, rectosigmoid junction,
where the ureters are then implanted in a non-refluxing fashion. The objective of this pouch was to create a low-
pressure reservoir to protect the upper tracts, although the risk of adenocarcinoma still remained. Due to
increased complications both metabolic and risk of malignancy, the ureterosigmoidostomy should be avoided as
a urinary diversion approach unless absolutely necessary.

Continent Cutaneous Urinary Reservoir


6
In 1982, Kock et al described a technique for construction of an internal ileal
reservoir that consists of a 80-cm segment of terminal ileum isolated on its
mesentery at approximately 50 cm proximal to the ileocecal valve. Proximal and
distal 17-cm sections are used to construct the afferent and efferent limbs to the
pouch, and two medial 23-cm segments are detubularized, approximated, and
remodeled to form the reservoir. Afferent and efferent continent nipple valves are
then created by intussuscepting sections of bowel 5- to 6-cm in length with strips
of Marlex or polyglycolic acid mesh around the bases of the intussusceptions.
The ureters are anastomosed to the afferent limb using a mucosa-to-mucosa
anastomosis, the pouch is closed, and the efferent limb is brought through the
abdominal wall and fixed to the rectus fascia using a Dexon collar to form a
stoma through which urine can pass.

31
In 1992, Fisch et al described a form of continent urinary diversion termed the Mainz pouch (mixed
augmentation ileum and cecum pouch), which utilized cecum and ileum. To create the reservoir, 10 to 15 cm of
cecum and ascending colon, as well as terminal ileal segments of equal length, are isolated and detubularized.
The posterior wall of the pouch is completed by anastomosis of the ascending colon with the ileal loop, starting at

24
the inferior aspect. The latter is then anastomosed with the next proximal ileal segment. The ureters are
implanted in an antirefluxing manner in an open-end technique through a submucosal tunnel of 4 cm to 5 cm in
length. To create the continence mechanism, an additional 8 to 12 cm of ileum is isolated to form an ileal
intussuscepted valve by invaginating and fixing 6 cm of this latter segment with metal staples. Alternatively,
continence can be achieved by submucosal embedding of the appendix.

Mainz pouch
32
In 1985, Rowland et al described the cecoileal continent urinary reservoir, in which approximately 8 to 10 cm of
terminal ileum and 25 to 30 cm of cecum and ascending colon are isolated. The colonic segment is detubularized
either by incising along its antimesenteric surface with scissors or cautery or by placing a 60- to 75-mm
gastrointestinal anastomosis (GIA) stapler between the two more lateral tenia. The continence mechanism is then
created by tapering the efferent limb (terminal ileum) over a 12F red rubber catheter resting against the
antimesenteric surface of the ileum. A 60-mm GIA metal staple is applied to excise the redundant antimesenteric
portion of the ileum and to create a smooth tube for catheterization using 16F to 18F catheters. The ureters are
tunneled into the tenia of the colonic segment through an inverted "T" incision. A mucosal incision is then made
for the orifice, the ureter is cut either obliquely or spatulated, and a ureter-to-mucosa anastomosis is performed
over a 5F to 8F stent using interrupted 5-0 absorbable, synthetic, monofilament sutures. The cephalad end of the
pouch is folded to the caudal end, and the reservoir is closed with a single layer of running 3-0 braided synthetic
absorbable suture.
34
In 1986, Light et al described Le Bag, in which 20 cm of cecum and ascending colon are isolated with a
corresponding length of terminal ileum. Following detubularization, the free ileal and colonic borders are sutured
together, and the pouch is folded as described in the Kock procedure. The ureters are reimplanted on the colonic
portion of the pouch according to the preference of the surgeon. After tapering and reinforcing the ileocecal valve,
the ileal tail is brought through the
abdominal wall as the continent segment.

Orthotopic Bladder

Orthotopic neobladders represent internal reservoirs connected to the native urethra that rely upon the external
striated sphincter for continence. Reservoirs are typically constructed from detubularised small bowel and then
anastomosed to the native urinary outflow tract. Orthotopic neobladders were initially limited to men, as
women were thought to have an increased risk of local recurrence and voiding dysfunction with orthotopic
diversion. However, with experience and improved understanding of the female rhabdoid sphincteric mechanism,
orthotopic diversion has become more common in women, becoming the procedure of choice for most patients
after cystectomy. However, appropriate patient selection is critical to the success of orthotopic diversions. It
should not compromise the cancer control of a potentially curative surgery, and it is contraindicated if the urethra
is non-functional or involved with tumour. Like continent cutaneous diversions, orthotopic neobladders require
active patient participation to ensure proper maintenance of the reservoir. If medical or psychosocial issues
preclude this level of cooperation, the patient may be better served by an incontinent ileal loop diversion.

Camey and LeDuc,[24] Hautmann et al,[11] and Studer and Turner[37] described the creation of a bladder from
different bowel segments as an alternative for handling continuity of the urinary tract after cystectomy.

25
Studer Ileal Neobladder
Ileal Neobladder with W-shaped pouch (Hautmann)

Stomach as conduit / pouch


Advantages of gastric pouch
Less metabolic abnormality
Less stone formation
Less infection
No risk of tissue exposed to radiation
Easy to perform anti-reflux mechanism

Disadvantages of gastric pouch


Gastric atony , small stomach syndrome
Dumping syndrome
Hematuria-dysuria syndrome
Severe metabolic alkalosis ( in poor renal function)

Complications Relating to Techniques


Complications from earlier techniques affect 2% of patients with continent urinary diversion and 4.5% of patients
with neoplasms. Complications include infection, wound dehiscence, urinary fistulas, prolonged ileus (longer than
seven days), small bowel obstruction, respiratory distress (atelectasis, pneumonia, pulmonary embolus),
myocardial infarction, deep venous thrombosis, and bleeding.

Metabolic and Nutritional Effects


Possible metabolic and nutritional consequences associated with small and large intestinal segments for
continent diversion of the urinary tract include disturbances of electrolyte metabolism, abnormal drug metabolism,
calculus formation, altered hepatic metabolism, nutritional disturbances, osteomalacia, impaired sensorium,
growth
retardation, infection, and cancer development.

Electrolyte Abnormalities
Hyperchloremic metabolic acidosis develops as a result of sodium secretion (in exchange for hydrogen) and
bicarbonate (in exchange of chloride), as well as re-absorption of ammonia, ammonium, hydrogen ions, and
chloride when these segments are exposed to urine. The mechanism that appears to be most responsible for
hyperchloremic metabolic acidosis is excess absorption of chloride and ammonia, which maintains a chronic
endogenous acid load. Since chloride seems to be more readily absorbed from colonic than from ileal reservoirs
and since electrolytic derangements predominate when longer colonic segments are used for reservoir
construction, the use of an ileal segment may be preferable in patients with impaired renal function.
Hypokalemia and total body depletion of potassium may occur in patients with urinary intestinal diversion.
Potassium depletion is probably the result of renal potassium wasting as a consequence of renal damage,
osmotic diuresis, and gut loss through intestinal secretion.

Hypocalcemia is a consequence of depleted body calcium stores and excessive renal wasting. The chronic
acidosis is buffered by carbonate from the bone with subsequent release of calcium into the circulation, which is

26
then cleared by the kidney and results in a gradual decrease in body calcium stores. An impairment of renal
tubule calcium re-absorption also occurs. Normal bone mineral metabolism requires the interaction of calcium,
magnesium, and phosphate, which are influenced by parathormone, calcitonin, and vitamin D. Osteomalacia in
adults and rickets in children -- essentially the same condition -- are characterized by chronic loss of bone buffers
and calcium and lead to hyper-calciuria and bone demineralization. Mineral losses are eventually replaced by
osteoid with a resultant decrease in bone strength.

Alterations in bone mineral content occur in most patients who have had a urinary intestinal diversion for
extended periods of time.

Stomach : hypochloremic, hypokalemic, metabolic alkalosis

Jejunum : hyponatremia, hyperkalemia, metabolic acidosis

Ileum/colon : hyperchloremic, hypokalemic metabolic acidosis

Calculus Formation
The incidence of renal stone formation increases in patients with intestinal urinary reconstruction. The increases
range between 16.7% and 26.5% with the Kock pouch, 5.4% with the Indiana pouch, and 9.8% with the Mainz
pouch. Generally, the stones are comprised of struvite, calcium oxalate, calcium phosphate, or uric acid, and
mixtures of these minerals often are present in the same stone. Most stones reported to be infectious are
comprised of struvite and/or carbonate apatite and are related to foreign materials and infection. A small but
significant portion of stones are metabolic and consist of calcium phosphate and/or calcium oxalate secondary to
hyperchloremic metabolic acidosis.

Common risk factors for urolithiasis are chronic colonization of the reservoir with bacteria secondary to urine
alkalinity, renal infection with urease-producing bacteria, the presence of foreign materials (eg, sutures, metallic
staples, non-absorbable collars) in the reservoir, retained intestinal mucous, and increased urinary excretion of
phosphate, sulfate, and magnesium, and hypocitraturia.

Major risk for stone formation - hyperchloremic metabolic acidosis.


The incidence of stone formations in different types of conduits are :
Colon conduits : 3% to 4%
Ileal conduits : 10% to 12%
Continent cecal reservoirs : 20%

Nutritional Disturbances
The liver synthesizes and conjugates bile salts that are necessary for proper fat digestion and for the uptake of
vitamins A and D. After fat stimulates their release into the duodenum, bile salts are actively reabsorbed by the
distal ileum and returned to the liver by the enterohepatic circulation to be used again. After ileal resection,
length-dependent alterations in bile metabolism can lead to a multitude of intestinal events that may result in
diarrhea. Even though considerable amounts of bile salts are lost in the colon, the liver can synthesize and
maintain the salt pool after resection of up to 100 cm of ileum. If ileal resection is greater than 100 cm, hepatic
bile salt synthesis cannot match the losses. In this case, micelle formation in the jejunum decreases, and fat
malabsorption leads to steatorrhea (fecal fat of more than 20 g per day) and diarrhea. Hydroxylated fatty acids
directly decrease colonic absorptive capacity, cause active secretion of electrolytes and water, and form soaps,
which are cathartic.

Vitamin B12 is excreted exclusively into the bile. It is highly conserved by active uptake at the terminal ileum and
is returned to the liver by the enterohepatic circulation. Body stores of vitamin B12 may last three to six years in
complete malabsorption and six to 30 years in partial malabsorption. Loss of the distal ileum can impair vitamin
B12 absorption. A loss of 50 cm of terminal ileum appears to be the critical margin for sufficient vitamin B12
absorption. Substitution of vitamin B12 should be prescribed to patients who lose more than 50 cm of terminal
ileum after surgery.

Following removal of the ileocecal valve, the absorptive processes in some patients may be affected due to the
development of high concentrations of bacteria in the ileum. Severe diarrhea may occur as a result of fat
malabsorption or irritation of unreabsorbed bile salts on the colonic mucosa. Diarrhea also may occur when major
portions of the large bowel are removed. In this case, a significant amount bicarbonate can be found in the fecal
fluid, since alkaline ileal contents drain into a shortened large bowel segment, which may result in acidosis and
dehydration.

Infection
Approximately 80% of patients with continent intestinal diversion are bacteriuric with diverse bacterial flora. In the
first year of reconstruction, the incidence of septic episodes varies from 5% to 20%. The frequency of bacteriuria,
pyelonephritis, and sepsis is higher in patients with continent intestinal diversion than in those with an intact
bladder that is subjected to daily instrumentation by intermittent catheterization.

27
Carcinogenesis
The incidence of malignancy in intestinal segments used for urinary reconstruction is currently unknown. If cancer
develops, the most common site is the ureterointestinal anastomosis. The most common types of tumor are
adenocarcinoma (85%) and transitional cell carcinoma (10%), with the remaining 5% consisting of signet ring cell
carcinoma, adenomatous polyps, sarcoma, and undifferentiated carcinoma.[49] A possible mechanism is an
increase in exposure to carcinogens such as N-nitroso compounds, which are highly mutagenic and induce
tumors in many animal species. Nitrate is normally excreted by the kidney into the urine, and many species of
Gram-negative bacteria (Escherichia coli, Proteus, Klebsiella, Pseudomonas) can reduce nitrate and catalyze
the conversion of nitrite and secondary amines present in the urine into N-nitroso compounds. Fecal bacteria are
presumably responsible for the formation of these substances, although the admixture of urine and feces is not
considered an absolute requirement for this production. Long-term surveillance is mandatory for patients who
have undergone urinary reconstruction with intestinal segments.

Complications Related to the Reconstructed System

Obstruction
Ureterointestinal anastomosis obstruction is a serious complication, and surgical intervention is usually required
to preserve the upper urinary tract. Common factors predisposing to anastomotic structure formation are
inadequate ureteral length, poor vascular supply, poor surgical technique with ureteral twisting, and possibly an
increased angulation with chronic reservoir distension. The mean incidence for this complication is 7.5% with
continent reservoirs; with neobladders, the incidence is higher. When the ureters are reimplanted, the incidence
of obstruction is even higher (28%). Ureterointestinal anastomosis obstruction may be managed either by balloon
dilatation and stenting or by an open surgical procedure through a transreservoir approach. The incidence of
acute pyelonephritis ranges up to 5.8% with continent diversions and up to 8.0% with neobladders. In most
cases, its onset is related to obstruction of the ureterointestinal anastomosis.

Reflux
The estimated incidence of intestinoureteral reflux is 2.6% with continent reservoirs and 0.4% with neobladders.
Despite the controversy regarding the optimal type of ureterointestinal reimplantation (tunneled vs nontunneled),
the incidence of reflux is low regardless of which reimplantation technique is used.

Reservoir Complications
Hypertonicity of the bowel reservoir with associated episodes of urine leakage has been noted in 5.6% of
pouches and in 4.2% of neobladders. Whether the bowel is detubularized or left in its original tubular form, bowel
motility resumes in some segments across anastomotic lines. Pressure spikes may be noticed in both
detubularized and tubularized segments of bowel. Spontaneous perforation of the urinary reservoir is a rare
complication. The incidence with continent reservoirs is 4.8%, and no cases have been reported with
neobladders.

Efferent Limb Complications


Dysfunction of the continence segment occurs in 6% of patients with continent reservoirs, and dysfunction of the
intestinourethral anastomosis with neobladders occurs in 2.75% of patients.[46] Dysfunction of the continence
segment (ileocecal valve) may be due to intrinsic factors (eg, a dysfunctional plicated bowel limb) or extrinsic
factors (eg, a parastomal hernia). Multiple abdominal wall scars, weight gain, and a chronic increase in intra-
abdominal pressure due to constipation or chronic obstructive pulmonary disease may favor hernia development.
Difficulty with emptying the reservoir is encountered in 7% of patients with continent cutaneous reservoirs and in
12% of those with neobladders. In the former, the difficulty may be related to a long and tortuous efferent limb,
the creation of a false passage, or the development of a stricture along the efferent limb. For patients with
neobladders, the main causes of difficulty are intestinourethral strictures (6.26%) and urethral cancer recurrence
(3% to 18%). Protrusion of a ventral hernia through the incision line developed in one (1.7%) of our 60 patients.
Other series report an incidence rate of ventral hernia that ranges from 4.4% to 14%. Meticulous closure of the
abdominal wall with appropriate suture materials is the cornerstone in preventing this complication.

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1992;45:175-185.
32. Rowland RG, Mitchell ME, Bihrle R. The cecoileal continent urinary reservoir. World J Urol. 1985;3:185.
33. Rowland RG. Continent cutaneous urinary diversion: the Indiana pouch. In: Vogelzang NJ, Scardino PT, Shipley
WU, et al, eds. Comprehensive Textbook of Genitourinary Oncology. Baltimore, Md: Williams & Wilkins; 1996:479-
485.
34. Light JK, Engelmann UH. Le Bag: total replacement of the bladder using an ileocolonic pouch. J Urol. 1986;136:27-
31.
35. Lockhart JL. Remodeled right colon: an alternative urinary reservoir. J Urol. 1987;138:730-734.
36. Pow-Sang JM, Lockhart JL. Continent urinary diversion: the Florida pouch. Prob Urol. 1991;6:581-586.
37. Studer UE, Turner WH. Ileal low pressure bladder substitute with an afferent tubular isoperistaltic segment. In:
Vogelzang JN, Scardino PT, Shipley UW, et al, eds. Comprehensive Textbook of Genitourinary Oncology.
Baltimore, Md: Williams & Wilkins; 1996:495-508.
38. McDougal WS. Metabolic complications of urinary intestinal diversion. J Urol. 1992;147:1199-1208.
39. Davidsson T, Lindergard B, Mansson W. Long-term metabolic and nutritional effects of urinary diversion. Urology.
1995;46:804-809.
40. McDougal WS. Complications of urinary intestinal diversion. AUA Update Series, Lesson 37. 1992;11:290-294.
41. Davidsson T, Akerlund S, Forsell-Aronsson E, et al. Absorption of sodium and chloride in continent reservoirs for
urine: comparison of ileal and colonic reservoirs. J Urol. 1994;151:335-337.
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Clin North Am. 1991;18:725-735.
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1993;150:51-55.
44. Ginsberg D, Huffman JL, Lieskovsky G, et al. Urinary tract stones: a complication of the Kock pouch continent
urinary diversion. J Urol. 1991;145:956-959.
45. Mastandrea FD, Helal MA, Khan P, et al. The Florida pouch continent urinary diversion: long-term follow-up and
complications. In: Hohenfellner R, Fisch M, Wammack R, eds. Continent Urinary Reconstruction: Second
International Meeting. Abstract Book. Mainz Germany: Oswald OHG; 1995:39.
46. Rowland RG. Complications of continent cutaneous reservoirs and neobladders: series using contemporary
techniques. AUA Update Series, Lesson 25. 1995;14:202-207.
47. Terai A, Arai Y, Kawakita M, et al. Effect of urinary intestinal diversion on urinary risk factors for urolithiasis. J Urol.
1995;153:37-41.
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urinary tract. Urol Clin North Am. 1991;18:743-754.
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1991;18:737-742.

29
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or successful reality. J Urol. 1995;153:1363-1372.

Management of BPH

Rishi Nayyar, Ashish Kumar

Benign prostatic hyperplasia (BPH) also known as benign prostatic hypertrophy (technically a misnomer), benign
enlargement of the prostate (BEP or BPE), or adenofibromyomatous hyperplasia, clinically refers to the increase
in size of the prostate. As the terminology related to BPH can be very confusing, it is important to clear ambiguity
in the use of various common terms in practice as below:

1) LUTS (lower urinary tract Symptoms) Non specific term for symptoms which may be attributable to lower
urinary tract dysfunction. The two main groups of LUTS are storage LUTS (previously called irritative
symptoms) and Voiding LUTS (previously called obstructive symptoms). The term prostatism is no longer
used clinically because it is refers to non-specific symptom complex of LUTS which need not necessarily be
related to enlargement of prostate (Figure 1).
2) BPH (Benign prostatic hyperplasia) Histological basis for a diagnosis of BEP leading to BOO that results in
LUTS
3) BOO (Bladder outflow obstruction) Urodynamically proven obstruction to passage of urine
4) BPE (Benign prostatic enlargement) The clinical finding of an enlarged prostate, assumed to be due to BPH
5) BPO (Benign prostatic obstruction) BOO caused by BPE
6) OAB (Over active bladder) Symptom syndrome of urgency, with or without urge incontinence, usually
1
accompanied by urinary frequency and nocturia .

Lower urinary tract symptoms (LUTS) are a common complaint in adult men with a major impact on quality of life
(QoL), and substantial personal and societal expenditures. The present chapter offers practical evidence based
guidance on the assessment and treatment of men with various non-neurogenic benign forms of LUTS. The
understanding of the LUTS as a functional unit, and the multifactorial aetiology of these symptoms, means that
LUTS now constitute the main focus, rather than the former emphasis on Benign Prostatic Hyperplasia (BPH). In
this chapter we shall be discussing the clinical assessment of LUTS (not BPH) along with modalities for treatment
of BPH.

Figure 1: Multifactorial etiology of LUTS

Brief epidemiology
2
Worldwide, approximately 200 million men have symptoms related to BPH . The prostate gets larger in most men
as they get older, and, overall, 45% of men over the age of 46 can expect to suffer from the symptoms of BPH if
they survive 30 years. Incidence rates increase from 3 cases per 1000 man-years at age 4549 years, to 38
cases per 1000 man-years by the age of 7579 years. Whereas the prevalence rate is 2.7% for men aged 4549,
3
it increases to 24% by the age of 80 years .

30
CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

The clinical assessment of patients with LUTS has two main objectives:
To consider the differential diagnoses, since the origin of male LUTS is multifactorial.
To define the clinical profile of men with LUTS in order to provide appropriate care. The assessment
should ascertain treatment options and identify men at risk of disease progression.

Herein, various parameters important in the management of BPH are presented in accordance with the recent
most recommendations.

Medical History

The diagnosis of BPH can often be suggested on the basis of the history alone, with most patients presenting
with LUTS. Storage symptoms include urinary frequency, urgency (compelling need to void that cannot be
deferred), urgency incontinence, and voiding at night (nocturia). Voiding symptoms include poor urinary stream,
hesitancy (needing to wait for the stream to begin), intermittency (when the stream starts and stops
intermittently), straining to void, and dribbling. Pain and dysuria are usually not present.

The storage and voiding symptoms are evaluated using various available symptom and quality of life scoring
systems like the International Prostate Symptom Score (IPSS) questionnaire or Danish Prostate Symptom Score
(DAN-PSS). A validated symptom score questionnaire with QoL question(s) should be used for the routine
assessment of male LUTS in all patients and should be applied for re-evaluation of LUTS during treatment
4
(Grade of recommendation B, Level of evidence 3 as per EAU guideline 2015 ).

Besides progression of LUTS, BPH if left untreated may progress in the form of precipitation of complications.
Incomplete voiding results in stasis of bacteria in the bladder residue and an increased risk of urinary tract
infection. Urinary bladder stones may form from the crystallization of salts in the residual urine. Urinary retention,
termed acute or chronic, is another form of progression. Acute urinary retention (AUR) is the inability to void,
while in chronic urinary retention the residual urinary volume gradually increases, and the bladder distends.
Some patients that suffer from chronic urinary retention may eventually progress to renal failure, a condition
termed obstructive uropathy.

A sexual history is also important, as epidemiologic studies have identified LUTS as an independent risk factor
for erectile dysfunction and ejaculatory dysfunction in men.

Frequency volume charts and bladder diaries

The recording of volume and time of each void by the patient is referred to as a frequency volume chart. Inclusion
of additional information such as fluid intake, use of pads, activities during recording, or symptom scores is
termed a bladder diary. These should be used to assess male LUTS with a prominent storage component or
nocturia where it underpins the categorization of underlying mechanism(s) (Grade of recommendation B, Level of
4
evidence 3 as per EAU guideline 2015 ) and help in behavioural or medical management. Also they may cause a
bladder training effect, and influence the frequency of nocturnal voids.

Physical examination and digital rectal examination (DRE)

Physical examination to seek potential influences on LUTS, particularly focussing on the suprapubic area, the
external genitalia, the perineum, and lower limbs. Urethral discharge, meatal stenosis, phimosis and penile
cancer must be identified if present besides focused spinal and neurological examination. (Grade of
4
recommendation B, Level of evidence 3 as per EAU guideline 2015 )DRE is an integral part of the evaluation in
men with presumed BPH to evaluate for size, contour and palpable nodules if any. Decreased anal sphincter
tone or the lack of a bulbocavernosus muscle reflex may indicate an underlying neurological disorder.

Urinalysis

Urinalysis (dipstick or sediment) must be included in the primary evaluation of any patient presenting with LUTS
to determine conditions, such as UTI, microhaematuria and diabetes mellitus. (Grade of recommendation A,
4
Level of evidence 3 as per EAU guideline 2015 )

Prostate-specific antigen (PSA)

Probability of prostate cancer: The 2010 update of the American Cancer Society (ACS) guideline for early
5
detection of prostate cancer stresses the importance of involving men in the decision whether to test for prostate
cancer. The ACS recommends that men receive information about the uncertainties, risks, and potential benefits
associated with prostate cancer screening (ie, prostate-specific antigen [PSA] testing and digital rectal
examination [DRE] for prostate cancer).

31
Prediction of progression of BPH: Serum PSA is a stronger predictor of prostate growth than prostate volume and
is highly significant predictor of clinical progression.

Renal function measurement

Renal function assessment must be performed if renal impairment is suspected, based on history and clinical
examination or in the presence of hydronephrosis or when considering surgical treatment for male LUTS. (Grade
4
of recommendation A, Level of evidence 3 as per EAU guideline 2015 ).

Post void residual urine (PVR)

Measurement of PVR in male LUTS should be a routine part of the assessment. (Grade of recommendation A,
4
Level of evidence 3 as per EAU guideline 2015 ) PVR urine can be assessed by transabdominal US, bladder
scan or catheterisation. A large PVR measurement is not a contraindication to watchful waiting or medical
therapy, although large PVR may indicate a poor response to treatment and especially to watchful
waiting.Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR. This is of
particular importance for the treatment of patients using antimuscarinic medication.

Uroflowmetry

Uroflowmetry in the initial assessment of male LUTS may be performed and should be performed prior to any
4
treatment. (Grade of recommendation B, Level of evidence 2b as per EAU guideline 2015 ) Uroflowmetryis
limited as a diagnostic test because it is unable to discriminate between the underlying mechanisms for poor flow.

Imaging

Imaging of the upper urinary tract (with USG) in men with LUTS should be performed in patients with a large
PVR, haematuria or a history of urolithiasis. (Grade of recommendation B, Level of evidence 3 as per EAU
4
guideline 2015 )

When considering medical treatment for male LUTS, imaging of the prostate (either by TRUS or transabdominal
US) should be performed if it assists the choice of the appropriate drug.When considering surgical treatment,
imaging of the prostate (either by TRUS or transabdominal US) should be performed. (Grade of recommendation
4
B, Level of evidence 3 as per EAU guideline 2015 )Assessment of prostate size is important for the selection of
interventional treatment, i.e. open prostatectomy, enucleation techniques, transurethral resection, TUIP, or
minimally invasive therapies. It is also important prior to treatment with 5-ARIs. Prostate volume predicts the
development of progressive symptoms and complications.TRUS is superior to suprapubic (transabdominal)
volume measurement. The presence of a median lobe may guide treatment choice in patients scheduled for a
minimally invasive approach.

Urodynamics

When considering surgery pressure flow study may be used in patients where diagnosis of bladder outlet
obstruction is suspicious like large PVR (>300 ML), age > 80 or <50 yr, long standing diabetes mellitus or
4
neurological diseases. (Grade of recommendation C, Level of evidence 3 as per EAU guideline 2015 )

An algorithm devised by EAU for management of LUTS is given in Figure 2.

TREATMENT

A. Watchful waiting

Wasson et al, 1995 examined the impact of watchful waiting in 556 subjects with moderate symptoms of BPH
randomized to TURP (transurethral resection of prostate) versus watchful waiting. During 3 years of follow-up,
treatment failure was observed in 23 (8.2%) and 47 (17%) of subjects randomized to TURP and watchful waiting,
respectively. Men with mild symptoms are appropriate for watchful waiting. Men with LUTS should always be
offered lifestyle advice prior to or concurrent with treatment. (Grade of recommendation A, Level of evidence 1b
4
as per EAU guideline 2015 )

a. Indication
i. Patient driven as symptom is not bothersome
ii. Treatment complication and/or cost is perceived to be greater as compared with symptom bother

b. Use of simple measures


i. Decreasing total fluid intake especially before bedtime
ii. Moderating the intake of alcohol- and caffeine containing products
iii. Maintaining timed void schedule

32
B. Medical management

The ideal candidate for medical therapy should have symptoms that are bothersome and negatively affect quality
of life so that the patient is willing to make a lifetime commitment to medical therapy, provided the drug is
effective and adverse experiences are either nonexistent or minimal. Individuals presenting with recurrent
urinary retention, recurrent UTIs, renal insufficiency, bladder calculi, and recurrent gross hematuria may
develop life-threatening consequences from their BPH if it is not managed surgically.

a. Indication:
i. Symptoms bothersome and absence of absolute indications of surgery

b. Drugs
i. Alpha adrenergic blockers
ii. 5 alpha reductase inhibitor
iii. Anticholinergic agents
iv. Phosphodiesterase inhibitors
v. Combination therapy
vi. Phytotherapy

Figure 2: Assessment algorithm of LUTS in men aged 40 years or older

Alpha adrenergic blockers:


The 4 subtypes of the -1 receptor include 1a, 1b, 1c and 1d. Of these, the -1a receptor is most specifically
concentrated in the bladder neck and prostate. Provided that the -1a subtype is predominant in the prostate,
bladder neck, and urethra, but not in other tissues, drugs that are selective for this receptor (like tamsulosin) may
have a potential therapeutic advantage.

An approximately 4- to 6-point improvement is expected in IPSS/AUA-SI scores when -blockers are used.
Interestingly, -blocker therapy has not been shown to reduce the overall long-term risk for acute urinary
retention (AUR) or BPH-related surgery.

33
Common side effects of blockers include orthostatic hypotension, ejaculation changes, nasal congestion, and
weakness.

The -blocking agents for BPH can be subgrouped according to receptor subtype selectivity and the duration of
serum elimination half-lives, as follows:
Nonselective -blockers : Phenoxybenzamine
Selective short-acting -1 blockers : Prazosin, Alfuzosin, Indoramin
Selective long-acting -1 blockers : Terazosin, doxazosin, slow-release (SR) Alfuzosin.
Super selective -1a blockers : Tamsulosin, Silodosin
Super selective -1d blockers: Naftopidil

Terazosin: (1mg titrating to maximum of 10 mg) This is long acting titratable 1 selective blocking, single daily
dosing agent that was initially used in the treatment of hypertention. Maximum urine flow increase by 10% to
50%. Maximum tolerable doses have not been defined for any -blocker; however, the higher the dose, the more
likely the adverse events (orthostatic hypotension, dizziness, fatigue, ejaculatory disorder, nasal congestion).
Despite the requirement for dose titration and blood pressure monitoring, these older, often less costly, -
blockers appear to be equally effective to tamsulosin and alfuzosin, and the 2010 AUA guidelines state that they
remain reasonable choices for patients with moderate-to-severe LUTS due to BPH.

Tamsulosin:(0.4 mg) Tamsulosin is considered the most pharmacologically uroselective of the commercially
available agents because of its highest relative affinity for the -1a receptor subtype. This is long acting 1
selective, single daily agent. Thus reducing the incidence of adverse effects like dizziness, postural hypotension
and syncope. Arnold demonstrated a decrease in symptom score by upto 7 points. 25% to 70% improvement in
symptoms. Overall satisfaction was 87%. Ejaculatory dysfunction was also reported with tamsulosin, apart from
other adverse events of blocker.

Alfuzosin SR:(10 mg) Alfuzosin is selective 1 adrenoreceptor antagonist which is effective in the symptomatic
treatment of BPH. Buzelin et al reported peak urinary flow increased by 2.- 3.2 ml/sec and mean flow increase by
30%. Significant improvement was seen in obstructive and irritative symptoms.

Silodosin: In 2008, the US Food and Drug Administration (FDA) approved a new -1a receptor selective blocker,
silodosin for BPH. Since it is very highly selective inhibitor of the 1A adrenergic receptor, it causes practically no
orthostatic hypotension (in contrast to other 1 blockers). On the other side, the high selectivity seems to cause
more problems with ejaculation.

Naftopidil: This is a selctive 1d adrenoreceptor antagonist. Cochrene review suggests that treatment with
naftopidil provides short-term improvement in urinary symptom-scale scores (total IPSS/AUA), QoL (quality of
life) score, and urinary symptoms from baseline comparable to low-dose tamsulosin. Adverse effects due to
naftopidil were few and usually mild. Apart from IPSS naftopidil also improves symptoms of detrusor overactivity,
since 1d receptors are also located in the detrusor and are considered to be patho-physiologically involved in
the irritative symptoms associated with BPH.

Androgen manipulation (5 alpha reductase inhibitor):


The rationale for androgen suppression is based on the observation that the embryonic development of the
prostate is dependent on the androgen dihydrotestosterone (DHT). Reducing prostate volume is thought to
decrease the static component of BOO resulting from BPH. It acts better in prostate size > 40 cc and maximum
reduction in volume seen by 6 months (20%).The risk reduction in AUR and BPH related surgery was 57% and
55% respectively using finasteride as per the Proscar Long-Term Efficacy and Safety Study (PLESS). Side
effects include decreased libido and ejaculatory or erectile dysfunction.

Finasteride: a 4-aza-steroid, has demonstrated 5- reductase type 2blocking activity, resulting in the inhibition of
DHT-receptor complex formation. This effect causes a profound decrease in the concentration of DHT
intraprostatically, resulting in a consistent decrease in prostate size. One third of men treated with this agent
exhibit improvement in urine flow and symptoms.

Dutasteride: It has an affinity for both type 1 and type 2 5--reductase receptors. The significance of blockage of
type 1 receptors is currently unknown.

Both finasteride and dutasteride actively reduce DHT levels by more than 80%, improve symptoms, reduce the
incidence of urinary retention, and decrease the likelihood of surgery for BPH. Both finasteride and dutasteride
may reduce serum prostate-specific antigen (PSA) values by as much as 50%. The decrease in PSA is typically
maximally achieved when the maximal decrease in prostatic volume is noted (6 months). Thus, one must take
this into account when using PSA to screen for prostate cancer.

One prospective, randomized, double-blind study by the Enlarged Prostate International Comparator Study
(EPICS) was conducted to compare the efficacy of dutasteride to that of finasteride in men with symptomatic

34
BPH. While this study was conducted over the course of only one year, the data suggest that both of these drugs
were similarly effective in reducing prostate volume, improving Qmax, and LUTS for this population. Also prior to
initiating therapy with 5-ARIs, one should perform appropriate evaluations to rule out prostate cancer.

Combination therapy:
1. alpha blocker with 5 alpha reductase inhibitor
Medical Therapy of Prostatic Symptoms (MTOPS) Trial: This prospective, randomized, double-blind,
multicenter, placebo controlled trial revealed that patients receiving combination therapy were significantly
less likely to experience BPH progression than those receiving either monotherapy or placebo, with risk
reduction rates of 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with
placebo.

The Symptom Management After Reducing Therapy (SMART-1) trial demonstrated that after 6 months of
combination therapy, discontinuation of the -1-blocker is possible in men with moderate LUTS. However,
those with severe LUTS may require longer combination therapy16.

2. alpha blocker with anti-cholinergics


For a man with frequency, urgency and urge incontinencesymptoms suggestive of an overactive bladder
one can consider an anticholinergic such as oxybutynin or tolterodine.
There is minimal available evidence on the long-term outcome of medical therapy of mixed OAB and BOO
due to BPH. The short-term data suggest that combination of antimuscarinic and -adrenergic blocker
therapy is safe with minimal risk of retention or AUR in carefully selected men. It would seem advisable to
avoid treating men with a substantial residual urine (200 mL or more in the study), and men on this therapy
who are reporting increased hesitancy or showing signs of increasing PVR or clinical evidence of retention
should be warned to stop the anti-muscarinic element of the combination therapy immediately. Men with
significant obstruction and large, persistent residual urine volumes should be considered for surgical therapy
rather than the addition of antimuscarinic agents.

3. alpha blocker with Phosphodiesterase 5 Inhibitors (PDE5i)


The rationale for the use of PDEIs in the treatment of LUTS/BPH was initially based on demographic data
showing the frequent occurrence of both ED and LUTS in men as they age. This raised the possibility of a
common underlying mechanism at least contributing to both processes. This, in turn, raised the possibility of
new treatment options that might impact on both processes.

There is now good level 1 evidence of a beneficial effect of PDEIs on urinary symptoms. The mechanisms of
effect are still unclear. It is likely that PDEI treatment will be of value, especially for men with LUTS and
significant ED. Because recent U.S. data indicate the proportion of men reporting moderate to severe LUTS
ranges from 8% in those 30 to 39 years old to 26% in those 70 to 79 years old and the prevalence of ED is
also high and increases dramatically with age with 10% of 30- to 39-year-old and 59% of 70- to 79-yearold
men reporting mild to moderate or moderate to severe symptoms, this is clearly a substantial number of men
who may request treatment.

Tadalafil 5 mg od has been FDA approved as a standalone treatment of LUTS in BPH.

Phytotherapy
The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH is
common. Mechanism of action is unknown.The three plausible mechanisms that have received the greatest
attention are anti-inflammatory effects, 5-reductase inhibition, and growth factor alteration. Most of the studies
regarding phytotherapy have been plagued by weak design, definition, preparation of phytotherapy used.

Serenoa Repens (Saw Palmetto Berry): Also known as American saw palmetto, or dwarf palm plant, it is the
most popular phytotherapeutic agent available for the treatment of BPH. Overall, various studies has concluded
that S. repens was not more effective than placebo for treatment of urinary symptoms consistent with BPH.

Pygeum africanum (African Plum): Apart from the prosposed mechanism described, P. africanum (Tadenan) also
has a protective effect on the obstructed bladder. Thus none of those trials meets the guidelines recommended
by the International Consultation Conferences on BPH. Another meta-analysis for the Cochrane collaboration
(Wilt et al, 2002a) concluded that an effect was possible but not proven. Therefore the data concerning the
efficacy of P. africanum are not conclusive.

Hypoxis rooperi (South African Star Grass): Hypoxis rooperi (Harzol) has been studied in both a 6-month double-
blind, placebo controlled trial of 200 patients (Berges et al, 1995) and, subsequently, an open-label follow-up
(Berges et al, 2000). In the initial study, statistically significant improvements were documented for symptom
scores (IPSS), quality of life, PFRs, and PVRs (Berges et al, 1995). This magnitude of improvement has not been
observed with any other medical therapy previously evaluated for BPH.
-sitosterol: It does improve urologic symptoms and urinary flow rates, but its long-term effectiveness, safety, and
ability to prevent the complications of BPH are unknown.

35
Treatment algorithm of male LUTS (Figure 3).

Figure 3. Non-surgical treatment algorithm of male LUTS due to BPH.

C. SURGICAL MANAGEMENT

Open simple prostatectomy


a. Indications:
i. Large gland size (>80 cc)
ii. Sizable bladder diverticula which merits excision
iii. Large associated bladder calculus
iv. Associated conditions precluding lithotomy position e.g ankylosing spondylitis of hip

b. Approach:
i. Suprapubic (transvesical) approach (Freyers)
ii. Retropubic approach (Millins)

ADVANTAGES: When compared with TURP, open prostatectomy offers the advantages of lower re-treatment
rate and more complete removal of the prostatic adenoma under direct vision and avoids the risk of dilutional
hyponatremia (TUR syndrome) that occurs in approximately 2% of patients undergoing standard TURP.

DISAVANTAGES: As compared with TURP, include the need for a lower midline incision and a resultant longer
hospitalization and convalescence period. There also may be an increased potential for perioperative
hemorrhage.

Tolerability and safety: Mortality has decreased significantly during the past two decades (<0.25%). The
estimated transfusion rate is about 7-14%. Long-term complications include urinary incontinence (up to 10%),
bladder neck contracture (2-5%) and urethral stricture (about 6%). Erectile dysfunction occurs in 3% to 5% of
patients undergoing an open prostatectomy and is more common in older men than in younger men. Retrograde

36
ejaculation occurs in 80% to 90% of patients after surgery. The most common nonurologic adverse effects
include deep vein thrombosis, pulmonary embolus, myocardial infarction, and a cerebrovascular event. The
incidence of any one of these complications is less than 1% and the overall mortality rate resulting from this
operation should approach zero.

Practical considerations: Open prostatectomy is the most invasive but also the most effective and durable
procedure for the treatment of LUTS/BPO. In the absence of an endourological armamentarium and a holmium
laser, open prostatectomy is the surgical treatment of choice for men with prostates > 80 mL.

Minimally invasive surgery


Depending upon the level of energy used and temperature reached in the tissue where the energy source
(monopolar or bipolar electrocautery or laser energy) is applied and the type of electrode or laser fiber being
used, the prostate tissue may get ablated (coagulated and gradually shed away over time), incised or resected
into pieces or vaporized. Based upon this there are many types of procedures available, some of which are listed
below.
1. TURP (Transurethral resection of prostate)
2. TUIP (Transurethral incision of prostate)
3. TUVP (Transurethral vaporization of prostate)
4. TUMT (Transurethral microwave therapy)
5. TUNA (Transurethral needle ablation)
6. Laser
a. HoLEP (Holmium laser enucleation of prostate)
b. HoLAP (Holmium laser ablation of prostate)
c. Photoselective vaporization of prostate (KTP / green light laser)

TURP and TUIP

TURP is considered gold standard for the surgical management of BPH.TURP removes tissue from the transition
zone of the gland. TUIP involves incising the bladder outlet without tissue removal. This technique may replace
TURP in selected cases, especially in prostate sizes < 30 mL without a middle lobe.TURP results in a substantial
mean Qmax improvement (+162%), a significant reduction in IPSS (-70%), QoL score (-69%), and PVR (-77%).
TURP delivers durable outcomes as shown by studies with a follow-up of 8-22 years. There are no similar data
on durability for any other surgical treatment for BPO.

Tolerability and safety: Peri-operative mortality and morbidity have decreased over time, but the latter remains
considerable (0.1% and 11.1%, respectively). The risk of TUR-syndrome is low (< 1.1%). No case has been
recorded after TUIP. Bleeding requiring transfusion (2.9%). Acute urinary retention 4.5% (0-13.3%), clot retention
4.9% (0-39%), and urinary tract infection (UTI) 4.1% (0-22%) are other complications. Long-term complications
comprise urinary incontinence (1.8% after TUIP vs. 2.2% after TURP), bladder neck contracture (BNC) (4.7%
after TURP), urethral stricture (3.8% after TURP vs. 4.1% after TUIP), retrograde ejaculation (65.4% after TURP
vs. 18.2% after TUIP), and erectile dysfunction (6.5% after TURP).

Practical considerations: TURP and TUIP are effective treatments for moderate-to-severe LUTS secondary to
BPO. The choice should be based primarily on prostate volume (< 30 mL and 30-80 mL suitable for TUIP and
TURP, respectively). No studies on the optimal cut-off value exist but the complication rates increase with
prostate size. The upper limit for TURP is mostly suggested as 80 mL (based on Panel expert opinion, under the
assumption that this limit depends on the surgeons experience, resection speed, and choice of resectoscope
size). The size limit criteria are further blurred by the availability of Bipolar resection technique allowing resection
in saline (TURIS or bipolar TURP)

TUVP
Whereas TURP removes tissue by resection of prostatic tissue and causes hemostasis by fulguration,
transurethral vaporization of the prostate (TUVP) combines the concepts of vaporization and desiccation.For
TUVP, the cutting current power needs to be much higher than for a standard TURP. It is suggested that TURP
and TUVP provide comparable improvements in AUA score and peak flow rate for up to 1 year of follow-up.

TUNA
The aim is to increase prostatic temperature to in excess of 60 C using low-level radiofrequency (RF) energy
that is delivered by needles into the prostate and that produces localized necrotic lesions in the hyperplastic
tissue. The TUNA system (Medtronic, Inc, Minneapolis, MN) consists of a special catheter attached to a
generator. At the end of the catheter are two adjustable needles that are withdrawn into two adjustable shields
made from Teflon. The needles are advanced into the prostatic tissue and can be placed accurately into the
required position. The advantage of TUNA is that it can be delivered under topical anesthesia.The long-term
efficacy of the treatment has not been clearly evaluated, with no large series of patients having long-term follow-
up.

37
TUMT
The current transurethral method has developed from the early transrectal devices that supplied heat ranging
from 42 C to 44 C. The results with this early form of treatment were rather disappointing, and transurethral
catheters were developed that would allow higher temperatures to be used while cooling the urethral mucosa. In
one of these devices currently used, the Prostatron, the cooling fluid in the catheter maintains the urethral
temperature at about 44 C or lower while producing temperatures within the prostate of up to 70 C.

Lasers for BPH


Different types of lasers have been used for treatment of BPH. There are two ways in which lasers can have an
effect on the prostate, either by coagulation or by vaporization.

HoLEP and HoLRP (Holmium laser enucleation and holmium laser resection of the prostate)
Mechanism of action: The holmium:yttrium-aluminium garnet (Ho:YAG) laser (wavelength 2140 nm) is a pulsed
solid-state laser that is absorbed by water and water-containing tissues. Tissue coagulation and necrosis are
limited to 3-4 mm, which is enough to obtain adequate haemostasis.

Efficacy: Metaanalyses covering trials on HoLEP vs TURP found that symptom improvement was comparable or
superior with HoLEP. RCTs indicate that HoLEP is as effective as open prostatectomy for improving micturition in
large prostates, with similar re-operation rates after 5 years (5% vs. 6.7%, respectively).
Tolerability and safety: Dysuria is the most common post-operative complication. Compared to TURP, HoLRP or

HoLEP have shorter catheterisation and hospitalisation times. Potency, continence, and major morbidity at 48
months were identical. HoLEP has a shorter catheterisation time and hospital stay, reduced blood loss, and fewer
blood transfusions, but a longer operation time compared with TURP. HoLEP can be safely performed in patients
using anticoagulant medications. The impact on ED and retrograde ejaculation is comparable between HoLEP
and TURP/OP.

Practical considerations: Holmium laser operations are surgical procedures that require experience and relevant
endoscopic skills. The experience of the surgeon is the most important factor affecting the overall occurrence of
complications.

Greenlight laser or photoselective vaporisation of prostate (PVP) using Potassium-Titanyl-Phosphate (KTP)


Laser
Mechanism of action: The kalium-titanyl-phosphate (KTP) and the lithium triborate (LBO) lasers work at a
wavelength of 532 nm. Laser energy is absorbed by haemoglobin, but not by water. Vaporisation leads to
immediate removal of prostatic tissue, relief of BPO, and reduction of LUTS. There are three different Greenlight
lasers in use: the 80-W (KTP), 120-W HPS (LBO), and the 180-W XPS (LBO) laser systems. They differ in
maximum power output, fibre design, and maximum energy application.

Efficacy: Meta-analysis comparing PVP with TURP show equivalent short term results. Re-operation rates tend to
be higher with PVP (11% vs. 1.8%; p = 0.04).

Tolerability and safety: Significantly longer operating time but shorter catheterisation time and length of hospital
stay is seen with PVP. Blood transfusions and clot retention are also less. The Greenlight laser appears to be
safe in high-risk patients under anticoagulation treatment.

Practical considerations: The evolution of the Greenlight laser from 80-W to 120-W and then to 180-W resulted in
a wide variation in the degree of maturity of each laser therapy. Long-term results on 120-W and RCTs on 180-W
are still pending.

Diode Laser vaporization and Thulium laser enucleation


These are lasers available for clinical use using similar techniques as PVP or HoLEP, but make use of different
physical properties of the different laser type. Long term studies are still awaited for these lasers.

Intraprostatic stents
Their role is only in the management of patients who were unfit for surgery, in either the short or the long term, in
which the alternative would have been months or, indeed, a lifetime of indwelling urethral catheterization.In
general, stents are subject to misplacement, migration, and poor tolerability because of exacerbation of LUTS
and encrustation. The main immediate adverse events include perineal pain or bladder storage symptoms.
Treatment algorithm of bothersome LUTS refractory to conservative/medical therapy or with absolute surgical
indications is given in Figure 4.

38
Figure 4. Surgical treatment algorithm of male LUTS due to BPH

Emerging operations
Intraprostatic ethanol injections, Intra-prostatic botulinum toxin injections, minimally invasive (lap or robotic)
simple prostatectomy, prostatic urethral lift device etc are newer options on the horizon for management of BPH.

References

1. LUTS and BPH by Katie Moore and Jay Khastgir. In Medical Therapy in Urology , Ed. Iqbal shergill et al.
Springer-Verlag London Limited., page 73-87 Doi 10.1007/978-1-84882-702-2
2. http://www.nafc.org/index.php?page=facts-statistics
3. Verhamme, K; Dieleman, JP; Bleumink, GS; Van Der Lei, J; Sturkenboom, MC; Artibani, W; Begaud, B; Berges, R
et al. (2002). "Incidence and Prevalence of Lower Urinary Tract Symptoms Suggestive of Benign Prostatic
Hyperplasia in Primary CareThe Triumph Project". European Urology42 (4): 3238. doi:10.1016/S0302-
2838(02)00354-8
4. Gratzke C, Bachmann A, Descazeaud A, et al. EAU Guidelines on the Assessment of Non-neurogenic Male Lower
Urinary Tract Symptoms including Benign Prostatic Obstruction. Eur Urol. 2015 Jun;67(6):1099-109.
5. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Societyguideline for the early detection of prostate
cancer: update2010.American Cancer SocietyProstate Cancer Advisory Committee. CA Cancer J Clin. 2010 Mar-
Apr;60(2):70-98.

Management of Renal Malignancies

Kim Mammen, Abhinav Jaiswal

Classification
Many classifications for renal masses are present. One of the earlier classifications was given by Glenn in 1980.
Renal masses can be malignant, benign, or inflammatory as classified by Barbaric (1994) or they can be
classified based on radiographic appearance (simple cystic, complex cystic, fatty tumors, and others).

39
40
RADIOGRAPHIC EVALUATION OF RENAL MASSES

1) Intravenous Pyelography (IVP) - Although intravenous pyelography was often the first test that indicated a
renal mass in the past, it is now only occasionally used for the evaluation of hematuria. The lack of sensitivity
and specificity of intravenous pyelography for the detection of parenchyma tumors is well documented.
Features suggestive of malignancy on intravenous pyelography include calcification within the mass,
increased tissue density, irregularity of the margin, and distortion of the collecting system (Zagoria, 2000).

2) Ultrasonography - When a renal mass is identified by intravenous pyelography, unless the mass has
features suggestive of malignancy, ultrasonography should be the next study performed because it is
noninvasive, accurate, and relatively inexpensive (Davidson et al, 1997; Paspulati and Bhatt, 2006).
Ultrasonography is reliable for differentiation of solid tissue from fluid and can establish the diagnosis of a
simple renal cyst. Strict ultrasonographic criteria for simple cysts have been defined and include a smooth
cyst wall, a round or oval shape without internal echoes, and through transmission with strong acoustic
shadows posteriorly. If these criteria are met, observation is sufficient in an asymptomatic patient.

3) Computed tomography (CT) - A renal mass that is not clearly a simple cyst by strict ultrasound criteria
should be evaluated further with computed tomography (CT). A dedicated (thin-slice) renal CT scan remains
the single most important radiographic test for delineating the nature of a renal mass. In general, any renal
mass that enhances with intravenous administration of contrast material on CT by more than 15 Hounsfield
units (HU) should be considered an RCC until proved otherwise (Hartman et al, 2004). Solid masses that
also have substantial areas of negative CT attenuation numbers (below 20 HU) indicative of fat are
diagnostic of AMLs. On occasion, CT demonstrates an enhancing renal segment that is isodense with the
remainder of the kidney, suggestive of a renal pseudotumor.

4) Magnetic Resonance Imaging (MRI) - Magnetic resonance imaging (MRI) is the alternate standard imaging
modality for the characterization of a renal mass (Pretorius et al, 2000; Zhang et al, 2004; Bassignani, 2006).
A basic consideration in the evaluation of a renal mass is that for such a mass to be considered malignant it
must enhance with the intravenous administration of contrast material. Such enhancement can now be
determined equally well by magnetic resonance angiography with intravenous gadolinium-labeled
diethylenetriaminepentaacetic acid, although the assessment is qualitative rather than quantitative. On T1-
weighted scans before and after administration of gadolinium, enhancement (vascularity) of the mass is
detected. This technique is most helpful in patients for whom iodinated contrast medium is contraindicated
because of severe allergy. One concern with MRI with gadolinium is the uncommon but potentially serious
complication of nephrogenic systemic fibrosis (NSF), which is more common in patients with renal
insufficiency.

5) Renal Angiography - Renal arteriography has a limited role in the diagnostic evaluation of renal masses
and is primarily reserved for patients with concomitant renal artery disease. In equivocal cases, the presence
or absence of neovascularity may help establish the diagnosis of RCC.

Simple renal cysts


1. They comprise of 70% of renal masses
2. They are most common benign lesion
3. Common after 50 yrs of age
4. Pathogenesis Renal vascular compromise or tubular obstruction
5. Investigations USG & CT Scan
6. Treat only if symptomatic - Pain, Bleeding or infection
7. Management
a. Percutaneous drainage & sclerosis-
i. With 95% alcohol
ii. Successful in 90% of cases
iii. Relative contraindication - peripelvic location adjacent to the renal vessels
iv. Laparoscopy preferable
v. Multiple treatment sessions may be required to achieve complete ablation
b. Open drainage
c. Laparoscopic drainage

41
Algorithm for renal masses

Renal Adenoma
1. Most common benign tumor
2. Discovered Incidentally or at post-mortem
3. Small, well-differentiated & typically asymptomatic
4. Radiologically - Very difficult to differentiate from RCC
5. Adenoma of any size should be treated Until proved otherwise
6. Treatment - Renal exploration and wedge resection

Metanephric Adenoma
1. Benign tumor
2. Most common incidental finding
3. Males affected more common than females (M:F:: 2:1)
th
4. Usually present in 5 decade of life
5. Features of polycythemia, hypercalcemia
6. Histologically related to epithelial Wilms' tumor
7. Wilms' tumor protein WT-1 + ve
8. Regression documented
9. Excision is done due to fear of malignancy

42
Cystic Nephroma (Multiloculated Cystic Nephroma
1. Well circumscribed and encapsulated tumor
2. Consists of multiple, non communicating, fluid-filled
spaces partitioned by septa - Hobnailed pattern
3. Unilateral and unifocal
th th
4. Bimodal peak 2-3 yrs of life & 4 5 decade
5. M>>F in Children F>>M in adults
6. Benign Course
7. Children Present as asymptomatic abdominal mass
8. Adults Present as abdominal pain, hematuria, urinary
tract infection, or hypertension
9. Children - TOC - Radical Nephrectomy
10. Adults - TOC Radical nephrectomy / NSS

Oncocytoma
1. Benign tumor
2. Origin Convoluted tubules
3. Asymptomatic
4. Pathology -Central stellate scar ( cut section ) Also seen on CT
5. Spoke wheel pattern on Angiogram
6. Sestamibi Scan Efficacy not proven
7. MRI - well-defined capsule, central stellate scar, and distinctive intensities on T1 and T2 images
8. Treatment - Nephrectomy

Angiomyolipoma
1. Benign neoplasm-characterized by 3 histological components - mature adipose tissue, smooth muscle
and blood vessels
2. Sporadic 80%
3. Associated with Tuberous sclerosis-20%
4. Clinical features - anemia, hypertension & massive retro
peritoneal hemorrhage (Wunderlich's syndrome)
5. 50% are Bilateral
6. Investigations
a. USG well defined, hyperechoic shadowing due to fat

b. CT scan - Presence of fat (confirmed by a value of -20


HU or lower)

c. MRI
i. High intensity signal in T 1 and T 2 (Blood
and protein containing fluid)
ii. Fat suppressed images

d. Renal Angio
i. Hypervascular
ii. Tortuous
iii. Pseudo aneurysms
iv. Onion skin
v. No AV shunting

7. Treatment
a. Observe - Asymptomatic & size < 4cm - imaging at 6- to 12-month intervals

43
b. > 4 cm active intervention
c. Nephron-sparing surgery - selective embolization
or partial nephrectomy
i. Symptomatic small AML with renal
insufficiency
ii. Bilateral tumors
iii. Solitary kidney
d. Total Nephrectomy - Large & Symptomatic tumor

Leiomyoma
1. Slow-growing, benign arises from capsule or peripelvic tissues
and less often, from the renal vein
2. Previously - large masses with pain, hematuria
3. Now - mostly small and asymptomatic
4. Can be purely cystic to complex cystic or purely solid, some
lesions enhance
5. Differentiation from RCC is not possible by clinical or
radiographic means
6. Large Radical Nephrectomy, NSS for peripheral tumours

Mixed Epithelial Stromal Tumor of the Kidney


1. Recently defined
2. Composed of a mixture of epithelial and stromal elements that
form solid and cystic growth patterns
3. Stain strongly for desmin and smooth muscle actin
4. Also seen in peri menopausal women on estrogen therapy
5. Age : 50 years
6. NSS can be offered but so far being managed by Radical
Nephrectomy

Reninoma
1. Specialized form of a hemangiopericytoma from juxtaglomerular cell.
2. Stain for factor VIII and factor VIIIrelated antigens.
3. Hypertension and hypokalemia and associated symptoms such as polydipsia, polyuria, myalgia, and
headaches
rd th
4. 3 or 4 decade, most commonly in females
5. All cured with excision
6. Consider in patients with severe hypertension and increased Renin ( First rule out RAS)

Renal Cell Carcinoma (RCC)


It is adenocarcinoma. Arises from renal tubular cells. It is the commonest renal tumor in adults (75%).

Aetiology - Smoking, Acquired renal cystic disease & Occupational exposure (e.g. Asbestos, cadmium, and
lead)

Associated with Inherited disorders - Von-Hippel Lindau disease & hereditary papillary renal cancer.

Pathology - Classification
1. Renal cell carcinoma
a) Clear cell (70-80%) Arise from proximal tubules. Tumor cells form small
nests, cytoplasm appears optically clear because glycogen and lipids are
removed by chemicals used in processing.
b) Papillary (10-15%) - Multi-focal and bilateral. Low columnar cells arranged in
papillary formations.
c) Chromophobic (3-5%)
d) Collecting duct (1%)
e) Unclassified (1%)

2. Sarcomatoid variants - No longer considered a distinct histologic subtype of RCC

44
Clinical presentation
50% of RCCs are detected incidentally. Also known as Internist tumor. Classic Triad of flank pain, abdominal
mass & hematuria is seen in 10 to 15% of patients.

Clinically may manifest as


1. Gross or microscopic hematuria 40%
2. Flank pain
3. Flank Mass
4. Left Varicocele
5. Anemia
6. Weight loss
7. Fever

Can also be associated with Paraneoplastic Syndromes.


1. Increased ESR 50%
2. Hypertension
3. Anemia
4. Weight loss
5. Fever
6. Abnormal liver function
7. Hypercalcemia
8. Polycythemia
9. Neuropathy/ myopathy

Investigations

Lab investigations Hb, ESR, Urine deposits for RBCs, renal parameters, Serum Calcium, LFT.

Ultrasound Abdomen - Exophytic, isoechoic, inhomogeneous, irregular mass with varying hypoechoic areas of
cystic degeneration.

Helical CT scan Abdomen - Most accurate imaging. Useful in Tumor staging & to find adjacent organ
involvement. Renal mass enhancement with contrast by more than 15 Hounsfield units.

MRI - On T1-weighted scans before and after administration of gadolinium, enhancement (vascularity) of the
mass is detected. On T2 weighted - hyper intense, compared with normal parenchyma. Indications - Contrast
sensitivity, Contraindication to the use of ionizing radiation e.g. pregnancy, IVC thrombus, Raised parameters.

45
PET (Positron Emission Tomography)
1. Uses radioactive glucose (18-fluorodeoxyglucose or FDG)
2. For staging & detecting tumor recurrence
3. Indication
Detection of small malignant nodes
Post Nephrectomy

Bone Scan Indication- High Serum Alkaline phosphatise, Bone pain

Chest CT Indication - Pulmonary symptoms, abnormal chest radiograph

Staging
Robsons staging
Stage I - Tumor within capsule

Stage II - Tumor invasion of perinephric fat (confined to Gerotas fascia)

46
Stage III -Tumor involvement of regional lymph nodes or renal vein and vena cava

Stage IV - Adjacent organs or distant metastasis

TNM Staging

47
Staging and Prognosis

TREATMENT
1. Radical nephrectomy
1. Principle - Early ligation of renal pedicle
2. Removal of tumor containing kidney & perirenal fat, adrenal gland regional hilar lymph nodes,
with Gerotas fascia

2. Nephron Sparing Surgery


1. Types Partial nephrectomy or Enucleation
2. Indication - Marginal renal function, Bilateral tumors & Solitary kidney

48
3. Other modalities
1. Radiotherapy
1. Radio resistant tumor
2. Palliative treatment of osseous or brain metastasis, hematuria
2. Chemotherapy - Poor response
3. Immunotherapy - Interferon alpha & Interleukin-2 ( for metastatic RCC )

Localized RCC Treatment


1. Surgery is the only curative therapy for stage I-III
- Radial nephrectomy is gold standard
- Partial nephrectomy in selected patients
2. No role for adjuvant therapy except under investigational protocol
3. 20-30% of patients relapse within 2-3 years
- Metastases to the lung most common 50%
- Local recurrence is rare 2-3%
4. Active Surveillance
5. Other Management Options

Advanced RCC Treatment


1. Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy
2. Surgery is palliative therapy for -
a. Solitary metastatic site
b. Solitary recurrence following nephrectomy
c. Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction

Targeted Therapy
Angiogenesis in RCC
Agents targeting VEGF (antibody): Bevacizumab
Agents targeting VEGF pathway:
- Sunitinib
- Sorafenib
Other VEGF pathway antagonists:
- Axitinib
- Pazopanib
- Tivozanib
Agents targeting PI3-K/Akt/mTOR pathway :
- mTOR inhibitors (Temsirolimus/ Everolimus)

49
Immunotherapy
1. Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-
20% with median duration of 19-91 months
2. Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary
edema, hepatic dysfunction, CNS dysfunction
3. Treatment requires ICU monitoring
4. Used for patients that can tolerate side effects.

UROTHELIAL TUMORS OF THE UPPER URINARY TRACT


1. Urothelial tumors involving the renal pelvis or ureter are uncommon
2. Multifocal
3. Etiology Smoking, Balkan Nephropathy, Analgesics, Occupation (petroleum and plastics) & Chronic
Inflammation
4. Risk of bladder cancer High

Clinical presentation
1. Hematuria, either gross or microscopic
2. Flank pain
3. Flank or abdominal mass
4. Weight loss
5. Anorexia

Investigations
1. Intravenous pyelography
a. Radiolucent filling defects
b. Obstruction or nonvisualization of the collecting system

2. CT Scan SOL in renal pelvis with or without involvement of parenchyma

Treatment
Nephroureterectomy with cuff of bladder Standard procedure for higher stage tumors

Alternatively Endoscopic resection for low stage tumors

50
WILMS TUMOR (NEPHROBLASTOMA)
1. Most common childhood renal tumor
2. 5% of childhood cancers
3. Peak First 4 yrs of life
4. Aetiology -
1. Mutations of WT1(11p13) or WT2 (11p15) gene
2. Associated syndromes - Beckwith -Wiedemann or WAGR
Pathology
1. 5% - Multicentric, Bilateral & IVC involvement
2. Histology - triphasic
1. Blastemal
2. Epithelial
3. Stromal
3. Prognostic groups Favorable & Unfavorable (anaplasia)

Clinical presentation
1. Abdominal mass -most common presentation
2. Hematuria in 1/4 of patients
3. Abdominal pain or fever
4. Features of renal vein & IVC involvement
5. Hypertension - 25%
6. Metastasis blood stream to lungs ,liver & bones

Investigations
1. Ultrasound
1. Initial study of choice
2. To differentiate from other masses

51
2. CT Scan tumor extension & status of opposite kidney

3. MRI - study of choice if extension of tumor into the inferior vena cava

Staging
The most important determinants of outcome- Histopathology and Stage
Children's Oncology Group staging- based primarily on imaging, surgical and histopathologic
findings.

Treatment
Radical nephrectomy- Transperitoneal approach
Accurate staging is essential for subsequent determination of the need for radiation therapy and the
appropriate chemotherapy regimen.
Exploration of the contralateral kidney is no longer indicated
Selective sampling of suspicious nodes.
Formal RPLND is not recommended
Gentle handling of the tumor throughout the procedure is mandatory to avoid tumor spillage- sixfold
increase in local abdominal relapse
Complications - hemorrhage and small bowel obstruction

National Wilms Tumor Study Group (NWTSG)


Formed in 1969 to study Wilms' tumor
NWTS-1 (1969 to 1973)

52
NWTS-2 (1974 to 1978)
NWTS-3 (1979 to 1986)
NWTS-4 (1987 to 1994)
NWTS-5 (1995 to 2003)

Treatment Protocol Used in the NWTSG-5 :-

Stage I & II- Favourable histology


Surgery
RT and CT- Not indicated

Stage III & IV- Favourable histology


Surgery
Chemotherapy- EEA4 regimen- 18 weeks
Dactinomycin- 75ugm/kg/dose
Vincristine - 0.05mg/kg/dose

Stage I Anaplasia
Surgery
Chemotherapy- EEA4 regimen- 18 weeks
Dactinomycin- 75ugm/kg/dose
Vincristine - 0.05mg/kg/dose

Stage II-IV Focal anaplasia


Surgery
Radiotherapy- 1080 cGy (abdominal and metastatic sites + lungs)
Chemotherapy- DD4A- 24 weeks regimen
Dactinomycin- 75ugm/kg/dose
Vincristine- - 0.05mg/kg/dose
2
Doxorubicin- 20 mg/m /dose

Stage II-IV diffuse anaplasia


Surgery
Radiotherapy- 1080 cGy (abdominal, metastastic sites and lungs)
Chemotherapy- Regimen I: 24 weeks
Dactinomycin- 75ugm/kg/dose
Vincristine- - 0.05mg/kg/dose
2
Doxorubicin- 20 mg/m /dose
Cyclophosphamide- 40-50 mg/kg /dose
Etoposide- 60 to 150 mg/m2/dose

Inoperable Tumors
This decision should not be based on preoperative imaging studies. Pretreatment with chemotherapy almost
always reduces the bulk of the tumor and renders it resectable. A patient determined to have an inoperable tumor
should be considered to have stage III and be treated accordingly. Repeat imaging is performed after 6 weeks of
chemotherapy. Majority of the reduction in tumor volume occurs in the first 4 weeks. After adequate shrinkage of
the tumor has occurred, definitive resection can be completed. Patients with progressive disease have a very
poor prognosis, and these patients will require treatment with a different chemotherapeutic regimen.

53
Bilateral Wilms Tumors
Occur in about 5% of children. Preferred approach- Initial biopsy, followed by preoperative chemotherapy. Renal
failure occurs in 9.1% and 18.8%, respectively, of patients with synchronous and metachronous bilateral Wilms'
tumor. Nephrectomy can be avoided entirely in almost 50% of patients who undergo initial biopsy followed by
chemotherapy. After 6 weeks of chemotherapy, repeat imaging is performed to assess response. Tumors not
responding to therapy require open biopsy to determine their histology. Patients with blastemal predominant or
anaplastic tumor should be changed to a different chemotherapeutic regimen. The patient should be reassessed
after an additional 12 weeks of chemotherapy to determine the feasibility of resection.

Options
Partial nephrectomy or wedge excision of the tumors
Radical nephrectomy on one side
Bilateral nephrectomy and dialysis - most common cause of renal failure
Transplantation- Waiting period of 2 years to ensure that metastatic disease does not develop

Partial Nephrectomy for Unilateral Tumors


Patients with the WAGR syndrome have an increased risk for renal failure, 38% at a median of 14 years from
diagnosis after radical nephrectomy. There is also an increased risk for renal failure in children with genitourinary
anomalies and Wilms' tumor. After preoperative chemotherapy, partial nephrectomy can be performed in 10% to
15% of patients. Increased risk for local recurrence after partial nephrectomy 8%.

Surgical protocol
The lesion should be completely excised with a margin of normal renal parenchyma
Frozen sections to confirm a negative margin and also to evaluate the histology
Patients with anaplasia or persistent blastemal predominant tumor after chemotherapy should be treated
by complete nephrectomy.

Outcome

LEIOMYOSARCOMA
1. MC subtype of sarcomas - 50-60 %
2. Cell of origin smooth muscle cell of the capsule or other perinephric structures
3. Female >> Males
th th
4. 4 6 Decade
5. Displaces rather than invading
6. Poor prognosis
7. Clinical features - Very large or rapidly growing renal mass, pain & hematuria
8. Investigation CT Scan or MRI
9. Nodal spread most common after lung involvement
10. Treatment- Radical Nephrectomy with good margins

CARCINOID TUMORS
1. Neuroendocrine cells - Primitive stem cells
2. Most asymptomatic
3. Minority will present with the carcinoid syndromeepisodic flushing, wheezing, and diarrhoea
4. Stain positive for neuron-specific enolase and chromogranin
5. Measurement of urinary or plasma serotonin or its metabolites can be diagnostic
6. CT findings are nonspecific, and most renal carcinoids are small and nonaggressive.
7. Surgical excision is the mainstay of treatment
8. Nephron-sparing surgery is preferred if the diagnosis is suspected preoperatively.
9. Prognosis is good, particularly when it is associated with a horseshoe kidney

LYMPHOMAS / LEUKEMIAS
1. Lymphomas
a. Bilateral
b. Non-Hodgkin's lymphoma - diffuse forms predominate
c. Risk Factors- Immune suppression, AIDS

54
2. Leukemias
a. Children- diffusely infiltrative
b. Commonly due to lymphocytic leukemia than the myelogenous forms
3. CT scan -Radiographic modality of choice
4. Treatment Chemotherapy (NHL-CHOP protocol), which includes cyclophosphamide, doxorubicin,
vincristine, and prednisolone.
5. Nephrectomy not indicated except in uncontrollable hemorrhage.

METASTATIC TUMORS
1. Most common sources - Lung, Breast & GIT
1. Mostly multifocal
2. Diagnosis - CT (isodense masses that enhance only moderately (5 to 30 HU) hypovascular pattern) or
ultrasound-guided percutaneous renal biopsy
3. Treatment- systemic therapy/palliative care
4. Nephrectomy if uncontrollable renal hemorrhage

References

1. Jonasch E, Matin S, Wood CG, Pagliaro LC. Renal cell carcinoma. In: Kantarjian HM, Wolff RA, Koller CA, eds. MD
Anderson Manual of Medical Oncology. New York, NY: McGraw-Hill; 2006. 757-84.
2. Linehan MW, Berton Z, Bates S. Cancer of kidney and ureter. In: Devita VT Jr, Hellman S, Rosenberg SA,
eds. Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. 1362-96.
3. Simon JW, Marshall FF. Kidney and ureter. In: Abeloff MD, Armitage J, Niederhuber J, Kastan M, McKenna W,
eds. Clinical Oncology. 2nd ed. New York, NY: Churchill Livingstone; 2000. 1784-99.
4. Cho E, Curhan G, Hankinson SE, et al. Prospective evaluation of analgesic use and risk of renal cell cancer. Arch
Intern Med. 2011 Sep 12. 171(16):1487-93.
5. Surveillance Epidemiology and End Results. SEER Stat Fact Sheets. National Cancer Institute. Available
at http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed: September 15, 2015.
6. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol. 1969
Mar. 101(3):297-301.
7. Robson JS. Advances in the treatment of renal disease. Practitioner. 1969 Oct. 203(216):483-93.
8. Cancer Facts & Figures 2014. American Cancer Society. Available at
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed:
September 15, 2015.
9. Abdollah F, Sun M, Thuret R, et al. Mortality and morbidity after cytoreductive nephrectomy for metastatic renal cell
carcinoma: a population-based study. Ann Surg Oncol. 2011 Oct. 18(10):2988-96.
10. Heng DY, Xie W, Bjarnason GA, et al. Progression-free survival as a predictor of overall survival in metastatic renal
cell carcinoma treated with contemporary targeted therapy. Cancer. 2010 Nov 18.
11. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670
patients with advanced renal cell carcinoma. J Clin Oncol. 1999 Aug. 17(8):2530-40.
12. Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural
history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002 Dec 1. 20(23):4559-66.
13. [Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.Kidney
Cancer. 2014. v.3:
14. [Guideline] Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J
Urol. 2009 Oct. 182(4):1271-9.
15. Sauk SC, Hsu MS, Margolis DJ, et al. Clear cell renal cell carcinoma: multiphasic multidetector CT imaging features
help predict genetic karyotypes. Radiology. 2011 Dec. 261(3):854-62

SUGGESTED READINGS
1. Campbell-Walsh Urology, 10th Edition By Alan J. Wein, Louis R. Kavoussi, Andrew C. Novick, Alan W. Partin, and
Craig A. Peters.
2. Smith and Tanagho's General Urology, Eighteenth Edition (Smith's General Urology) by Jack W. Mcaninch, Tom F.
Lue

Investigative workup of a patient with surgical disease of the kidney

An accurate history and careful examination will determine the sequence and spectrum of clinical investigations
required to make a diagnosis or decide on prognosis or treatment.

Description
The urinary tract consists of the kidneys, ureters, bladder, urethra and, in men, the prostate gland.
Imaging of the urinary tract can involve the following tests:
Plain kidney, ureters and bladder (KUB) testing.
Intravenous urogram.
Ultrasonography.
Nuclear medicine - including mercaptoacetyltriglycine (MAG3) and dimercaptosuccinic acid (DMSA)
scans.

55
Cystography.
Computed tomography (CT) scan.
Magnetic resonance imaging (MRI) scan.
More invasive tests.

Examination of the urine


Midstream urine (MSU) samplethis standard investigation requires consideration of: (1) macroscopic
appearancethis may be suggestive of a diagnosis, e.g. frothy urine suggests heavy proteinuria; (2) stick
testingincluding for pH (<5.3 in an early-morning specimen makes a renal acidification defect unlikely),
glycosuria, specific gravity (should be >1.024 in an early-morning or concentrated sample), nitrite (>90% of
common urinary pathogens produce nitrite) and leucocyte esterase; and (3) microscopyfor cellular elements (in
particular red cells, with the presence of dysmorphic red cells detected by experienced observers indicative of
glomerular bleeding), casts (cellular casts indicate renal inflammation), and crystals.
Quantification of proteinuriathis is important because the risk for progression of underlying kidney disease to
endstage renal failure is related to the amount of protein in the urine. Quantification by 24-h urinary collection is
cumbersome and unreliable in many patients, and has been replaced by estimation of the urinary
albumin:creatinine ratio (ACR; normal is <2.5mg/mmol for men and less than 3.5mg/mmol for women) or
protein:creatinine ratio (PCR; normal is <13mg/mmol) on a spot sample. An ACR of 100mg/mmol approximately
corresponds to proteinuria of 1.5g/day, and 350mg/mmol to nephrotic-range proteinuria.
Low-molecular-weight proteinuriais caused by proximal tubular injury and can be detected with markers
including -glutathione-S-transferase, 1-macroglobulin, and retinol-binding protein.

Estimation of glomerular filtration rate


Knowledge of the glomerular filtration rate (GFR) is of crucial importance in the management of patients, not only
for detecting the presence of renal impairment, but also in the monitoring of all patients with or at risk of renal
impairment, and in determining appropriate dosing of those drugs cleared by the kidney. Measurement of plasma
creatinine remains the standard biochemical test used to assess renal function.
Estimating the glomerular filtration rate (eGFR)from a measurement of plasma creatinine concentration, the
standard method uses the simplified Modification of Diet in Renal Disease (sMDRD) formula, which was based
on a predominantly Caucasoid North American cohort with chronic kidney disease, and requires knowledge of
the patients sex, age, and ethnicity (but not their weight or height). On the basis of the eGFR, stages of chronic
kidney disease (CKD) are classified as follows:
Limitations of the eGFRthis has not been validated in people below 18years of age, hospitalized patients, or
those with acute kidney injury, pregnancy, oedematous states, muscle-wasting disorders, amputations, or
malnourishment. Similarly, it has not been validated for extremes of age or body weight, or for ethnic groups
other than whites of northern European origin and African-Americans. Because of the inaccuracy of the MDRD
equation, particularly for those with eGFRs greater than 60 ml/min, a revised version (CKD-EPI) has been
introduced.
Other methods of measuring GFRisotopic methods can provide the most accurate determination of GFR, but
are not often required in routine clinical practice. Estimation of creatinine clearance with a 24-h urinary collection
remains a useful test, particularly when there is reason to doubt the validity of the eGFR.

Investigation of tubular function


Proximal tubuleanalysis of excretion of the following substances can assist in the diagnosis of proximal tubular
disorders: (1) glucosethe maximum reabsorption rate for glucose (TmG) in the proximal tubule can be
determined following infusion of 20% dextrose and is normally about 15mmol/litre (TmG/GFR); (2) phosphate
the theoretical maximum tubular threshold of phosphate (TMP/GFR) can be estimated by formula from the plasma
and urinary phosphate and creatinine concentrations, or can be measured directly following infusion of
phosphate; and (3) amino acidsfive types of renal aminoaciduria are distinguished: dibasic amino acids, neutral
amino acids (monoaminomonocarboxylic acids), glycine and imino acids, dicarboxylic amino acids, and
generalized amino aciduria (Fanconis syndrome).
Distal tubulea water-deprivation test can help to distinguish patients with primary or secondary nephrogenic or
cranial diabetes insipidus from those with primary polydipsia, who may all present with polyuria.
Renal-induced electrolyte and acidbase imbalances (1) estimation of urinary free-water clearance is useful in
the analysis of patients with hyponatraemia (see Chapter 21.2.1); (2) estimation of transtubular potassium
gradient (TTKG) is advocated by some as useful in analysis of disorders of potassium homeostasis (see Chapter
21.2.2); (3) tests of urinary acidification are discussed in Chapters 21.14 and 21.15.

Renal imaging
Ultrasonographythis noninvasive, safe, versatile and (relatively) inexpensive technique is the first-line method
for imaging the kidney and urinary tract in many clinical circumstances.

Ultrasonography
[3]
Generally ultrasonography is an excellent imaging modality as it is non-invasive, reliable and affordable. It can
be used to investigate the kidney, bladder, and prostate gland. It can also be combined with voiding, providing an
indication of the residual volume. This gives an indirect measure of bladder function.

56
Renal ultrasonography is useful for the following:
Acute kidney injury - mainly looking for post-renal obstruction.
Chronic kidney disease - the presence of small shrunken kidneys suggests irreversible damage. Normal
[3]
kidney size is approx 11 cm (varies with age, gender and race).
Detecting hydronephrosis and hydroureter.
Some children post following a urinary tract infection.[2]
Congenital anomalies - eg, hypoplasia, agenesis, duplex systems.
Renal cysts, abscesses and neoplasms can be detected - eg, simple cysts, polycystic kidneys.
Renal calculi can be detected but they can be mistaken for vessels or calcified tumours. [3]
Renal ultrasound can be combined with Doppler imaging to view the renal artery and vein, which may
help detect thrombosis, stenosis or aneurysms.
The kidneys are well shown by ultrasound which has the valuable property of distinguishing between
renal solid masses and renal cysts. Cysts can also be localised by ultrasound for percutaneous
puncture. Hydronephrosis is also well demonstrated by ultrasound as are polycystic kidneys. In the field
of renal transplantation ultrasound is valuable in showing perirenal fluid and lymph collections
(lymphoceles) and confirming swelling of the kidneys associated with rejection.
The distended bladder is also well shown by abdominal ultrasound and tumours including infiltration of
the wall can be assessed. The prostate can also be demonstrated, but is best examined by endoscopic
transrectal ultrasound. This is now widely used for ultrasound-guided biopsy of suspected prostatic
carcinoma and other prostatic lesions.
Most early carcinomas show as low density areas in the subcapsular zone but require biopsy for
confirmation since the appearance is non-specific. Patients with a raised prostatic serum antigen (PSA)
level or clinical suspicion of prostatic carcinoma may require multiple biopsy of the prostate under
ultrasound guidance.

Fig. Longitudinal ultrasound scan of normal kidney. The renal sinus is echogenic. The pyramids are relatively
hypoechoic compared with the remainder of the parenchyma. The dense echoes (arrows) at the bases of the
pyramids are due to the arcuate arteries.

Fig.Parasagittal section.Simple renal cyst.

57
RADIOLOGICAL EXAMINATION OF THE URINARY TRACT
The following radiological and imaging methods are available for the investigation of the urinary tract:
1. Simple radiology
2. Intravenous urography
3. Retrograde pyelography
4. Antegrade pyelography
5. Renal angiography
6. Cystography, cystourethrography and dynamic bladder studies
7. Urethrography
8. Cyst puncture
9. Ultrasound
10. Computed tomography
11. Isotope imaging and renography
12. MRI.

Plain X-rays
Plain X-rays of the renal tract are taken as a routine before most kidney investigations. Good quality
films will often show the renal outlines quite clearly, and gross enlargement of the kidney by
hydronephrosis or tumour may be readily recognised. Similarly, gross shrinkage of the kidney from
chronic pyelonephritis or from renal ischaemia may be diagnosed.
Calcification in the renal areas is most commonly due to renal calculi in the calyces or renal pelvis.
Nephrocalcinosis, or calcification within the renal substance, is much less common, and is seen in such
rare conditions as hyperparathyroidism, renal tubular acidosis, and medullary sponge kidney.
Calcification may also be observed in the kidney in renal tuberculosis, and occasionally in renal
tumours.
Plain X-rays will also demonstrate opaque calculi in the ureter and in the bladder. Calcification in the
bladder wall and ureter is seen in schistosomiasis. Very rarely calcification may be detected in bladder
tumours due to encrustations on the surface of a tumour.

Fig. Laminated bladder calculus shown by plain X-ray.

Plain kidney, ureters and bladder imaging


Plain x-rays can reveal opaque renal calculi. They may also be helpful in nephrocalcinosis where there is
increased uptake of calcium by the kidneys. CT scan of kidneys, ureter and bladder is the preferred imaging
modality looking for renal calculi. CT scanning has a higher radiation dose than plain x-ray but it has a much
better sensitivity for detecting a stone both directly and indirectly (eg, by detecting dilated ureter or
hydronephrosis). Spiral CT takes only five minutes and no preparation is required. Furthermore, CT scanning can
[1]
also detect lesions other than renal calculi - for example, perinephric abscesses and tumours.

Micturatingcystourethrogram - this involves instillation of contrast into the bladder following which x-rays are
[2]
taken whilst voiding. It is used in some children following a urinary tract infection.

Intravenous urogram
This is most useful when looking for obstruction in the urinary tract - for example, hydronephrosis due to the
presence of renal calculi. Other uses include diagnosis of medullary sponge kidney. However, it is time-
consuming and the use of contrast can lead to contrast nephropathy (good hydration is essential). Thus it is
important to have renal function tested beforehand and it should be used with caution in the elderly and in those
with renal impairment.

Provided that the kidney is functioning and the blood urea is not too high, intravenous urography will demonstrate
most lesions affecting the normal anatomy of the renal drainage system.

58
Congenital anomalies, such as double pelves and ureters, or duplex and horse-shoe kidneys, can be
diagnosed with certainty. Polycystic kidneys can also be identified unless renal failure has supervened.
In a typical case both kidneys are enlarged, and there are multiple calyceal deformities.

Local distortion of the renal calyces by a kidney mass is often seen on urography. In many of these
cases it is impossible to differentiate between hypernephromaand a simple cyst from the pyelogram. In
such cases imaging by ultrasound will provide a definitive answer and is the next investigation of choice.
CT will also differentiate renal tumour from cyst. If a cyst is demonstrated the diagnosis can be
confirmed by percutaneous cyst puncture, and the cyst can then be emptied by aspiration. If a tumour is
diagnosed or suggested by ultrasound the diagnosis can be confirmed by CT. This will also help staging
and show whether the renal vein is involved. Arteriography will also confirm the diagnosis of tumour, but
is now little used except where embolisation is being considered.

Fig.Polycystic kidneys. Note the bilateral splaying and deformity of the minor calyces and large size of the
kidneys.

Opaque or suspected non-opaque renal calculi may be further investigated by intravenous urography.
The relationship of an opaque renal calculus or of a suspected renal calculus to the ureter, pelvis or
calyces is clearly demonstrated. Non-opaque calculi are shown as filling defects which may be
obstructing the renal drainage system and causing hydroureter and hydronephrosis proximal to the level
of the obstruction.

Fig.Hydronephrosis with a calculus in the dilated lower calyx.

The bladder is also well shown at intravenous urography. Bladder tumourswhether papillomatous or
carcinomatous can be demonstrated though such tumours may be better visualised by cystography.
With carcinoma, assessment by ultrasound, CT or MRI may be required for staging.

59
Fig. MRI study of bladder carcinoma (arrow), b = bladder; r = rectum; n = nodal metastases on left side of
pelvis.

Prostatic lesions with bladder-neck obstruction are often assessed by intravenous urography. The
enlarged prostate may show as a large rounded filling defect at the neck of the bladder. The bladder
itself may show trabeculation and thickening of its wall and there may also be evidence of back pressure
on the kidneys. Diverticula of the bladder, which are more frequent in the elderly patient with bladder-
neck obstruction, can also be seen. In prostatic problems it is important to obtain a film or ultrasound
scan of the bladder after micturition, as the amount of residual urine gives a good index of the degree of
obstruction.

Hypertension of possible renal origin is investigated by intravenous urography in the first instance. This
will demonstrate unilateral or bilateral hydronephrosis and will direct attention to the unilateral
nonfunctioning kidney or to polycystic kidneys. Intravenous urography may also show a characteristic
pattern in hypertensive patients in whom the cause is unilateral ischaemia of a kidney. In these patients,
in whom the usual causative lesion is an atheromatous plaque stenosing the main renal artery the
ischaemic kidney is small and shows increased density of contrast in the pelvis and calyces as the
examination proceeds. This is because there is a greater percentage of water resorption on the affected
side than on the normal side.

Fig. Atheromatous renal artery stenosis shown by renal arteriography.

Retrograde pyelography
Retrograde pyelography is performed after cystoscopy and the insertion of a radiopaque ureteric
catheter by the surgeon. A small quantity of sterile contrast medium is injected up the catheter to outline
the renal tract and appropriate films are taken. The retrograde pyelogram was once used as a method of
clearly defining the anatomy of the renal drainage system in the patient with a non-functioning kidney or
with a poorly functioning kidney when intravenous pyelography had failed to provide adequate
visualisation. It is less widely practised today than in the past because the modern intravenous contrast
media with the use of high dosage and delayed films often provide diagnostic results where the older
contrast media might have been unsuccessful, and also because cases of suspected tumour or cyst are
now usually investigated by ultrasound or other methods mentioned above.
Retrograde pyelography is still sometimes used to confirm or disprove the relationship of a suspected
small calculus to the ureter. It is also sometimes used to help dislodge a ureteric calculus and 'oil' it
down the ureter.

60
Antegrade pyelography (percutaneous nephrostomy)
Percutaneous antegrade pyelography is a useful method of demonstrating the renal calyces, pelvis and
ureter in cases of suspected urinary tract obstruction where the intravenous method has been
unsuccessful or inconclusive. Unlike retrograde urography it does not require GA and it has a lower
incidence of urinary tract infection. It is also useful in infants and children where cystoscopy is difficult or
impossible.
A dilated renal calyx is punctured percutaneously from the lumbar region using a fine needle, and
contrast medium is injected. The technique can also be used to insert a catheter and provide temporary
drainage. The catheter tract can also be used for a percutaneous approach to renal calculi and for stent
insertions.

Renal angiography
An opaque catheter is passed percutaneously into the aorta and its preshaped tip is screened into the
renal artery origin with the aid of an image intensifier. The whole renal circulation can be beautifully
demonstrated using only a small quantity of low-concentration contrast medium.
The renal angiogram in the past provided a method of making a preoperative differential diagnosis in the
difficult cases in which a mass had been demonstrated in the kidney but it was uncertain whether this
was due to a tumour or cyst. The typical hypernephroma shows excessive vascularity with pathological
vessels throughout the tumour area. The typical cyst appears as a large rounded defect in the
angiogram. The method was highly accurate in differentiating between tumours and cysts though
occasionally a non-vascular tumour was encountered which gave rise to difficulty. As noted above
ultrasound or CT now provide simpler methods of confirming the diagnosis of renal cyst or tumour.
Renal angiography has also been widely used for the embolisation of vascular tumours and for the
investigation of renal hypertension. A small proportion of patients with hypertension are suffering from
renal ischaemia with secondary hypertension. The usual cause is an atheromatous narrowing of the
origin of a renal artery. Other less common causes of renal artery stenosis include a peculiar condition
occurring mainly in female patients and termed fibromuscular hyperplasia of the renal artery (Fig. 10.9).
Renal artery stenosis shown by angiography can now be treated by percutaneous dilatation with a
Gruntzig balloon catheter.

Fig.Atheromatous renal artery stenosis shown by renal arteriography.

Fig. Fibromuscular hyperplasia (1) shown by renal angiography.


Cystography
Cystography is performed after passage of a catheter into the bladder and injection of contrast medium.
The method is useful for outlining tumours of the bladder when intravenous urography has been
unsuccessful or equivocal. Ultrasound can also be used to demonstrate bladder tumours and CT or MRI

61
enables such tumours to be assessed and staged. The patient can then be asked to void and the extent
of vesicoureteral reflux and urinary stress incontinence can be assessed.
Attention has been drawn to the frequent occurrence of vesicoureteric reflux and to the importance of
this condition in the pathogenesis of chronic pyelonephritis. It is claimed that vesicoureteric reflux is
present in a high proportion of patients with chronic pyelonephritis, and that it may be an important
aetiological factor. Reflux is best demonstrated by performing a micturatingcystogram, though it may
occur spontaneously when the bladder is well filled. As the patient micturates, reflux up the ureters may
be seen as the bladder contracts.

Fig.Spontaneous vesicoureteric reflux after injection of the bladder through an indwelling catheter. There is
already gross hydroureter and hydronephrosis. (Urethral obstruction in a child due to congenital valves.)

Cystourethrography
This examination is used for the investigation of bladder-neck obstruction in males, the various forms of
bladder-neck disturbance seen in postpartum females, and other disorders of the peripheral control of
micturition. The technique is to fill the bladder via a catheter which is then removed. The act of
micturition is observed on the screen and films of the bladder-neck and urethra taken during micturition.
As already noted,vesicoureteric reflux may be observed during this procedure and is an important
finding. The procedure is performed with the aid of an image intensifier. This has the added advantage
that it is possible to take a video film or videorecord of the act of micturition. This can then be played
back and details observed at leisure.
Dynamic bladder studies are indicated in more complicated bladder problems with incontinence,
frequency, disorders of storage function and voiding, neuropathic bladder and postoperative disturbed
function. Various physiological measurements are superimposed upon a video image of the bladder and
urethra during filling and voiding. These measurements are the abdominal and bladder pressures
(recorded by rectal and bladder transducers respectively), the detrusor or intrinsic bladder pressure (the
recorded bladder pressure minus the abdominal pressure) and the urine flow rate. Analysis of these
synchronous recordings permits improved evaluation of the mechanisms of the bladder dysfunction.

Urethrography
Urethrography in the male is usually performed by injection of a viscous contrast medium which
provides excellent contrast throughout the urethra. The contrast medium is injected after insertion of a
tight-fitting nozzle into the meatus and the whole of the urethra is outlined. Obstruction by a stricture can
then be localised, and in the case of prostatic problems the prostatic urethra can be carefully studied.

Computed tomography scanning of the urinary tract


Again this involves a significant radiation dose, thus needs to be considered with care. It is useful in detecting the
following:
Renal calculi - as discussed under 'Plain kidney, ureters and bladder imaging', above.
Renal and bladder neoplasms - for detection and staging.
Renal trauma - detecting perinephric haematoma, for example.

Ultrafast multislice CT scanningthis allows resolution of 2 to 3mm or less and has become the mainstay of
renal imaging. CT urography can be performed with a combination of unenhanced, nephrogenic-phase, and
excretory-phase imaging: the unenhanced images are ideal for detecting urinary calculi; renal masses can be
detected and characterized with the combination of unenhanced, nephrogenic- and excretory-phase imaging; the
excretory phase provides imaging of the urothelium. CT angiography is the first-line investigation in the
evaluation of acute renal trauma, assessment of tumour blood supply in cases of nephron-sparing surgery, and
for the diagnosis of renal artery stenosis and/or aneurysms.

62
MRIthis is an alternative to CT scanning in patients who are allergic to conventional iodine-based radiocontrast
media and has particular value in the staging of renal carcinoma and assessment of complex renal cysts.
Magnetic resonance angiography (MRA) tends to overemphasize the significance of stenoses. Gadolinium
contrast scanning should be carefully considered in patients with eGFR below 30ml/min because of the risk of
nephrogenic systemic fibrosis, which limits the utility of magnetic resonance techniques for many renal patients.

Magnetic resonance imaging scanning of the urinary tract s is used in the following groups of patients:
Those who are at risk of contrast nephropathy.
Those who have an allergy to contrast agents.
Children. Magnetic resonance (MR) urography is being used in children and has the advantage that it
provides both functional and morphological imaging. However, this requires the use of complex
software.
Those with renal cell carcinoma.
Women with chronic urinary tract infections.

Enhanced MRI technology is also proving increasingly important in renal cell carcinoma but is still in an
experimental stage - eg, response to chemotherapy. MRI is also superior to CT scanning in detecting renal cell
carcinoma metastases into the renal vein. It may also be better when trying to determine whether renal lesions
are simply cysts, neoplastic or haematomas. It can also be used in the detection of renal artery stenosis -
magnetic renal angiography (MRA).

More invasive investigations

Ureteropyelography
Anterograde ureteropyelography - this requires puncture via the skin into the renal pelvis. Via the
puncture, contrast is injected and images obtained. This procedure can also be used to relieve
obstruction by insertion of a nephrostomy tube.
Retrograde ureteroscopy - this is performed by insertion of a cystoscope into the urethra and bladder.
This is followed by injection of contrast into the distal ureter, after which images are taken.

Angiography
This can be performed with the aid of CT or MRI. It is invasive and requires cannulation of the renal arteries. It
will provide a definite diagnosis of stenosis and allows angioplasty if necessary. There is also a risk of embolism
resulting from trauma to plaques.

Cyst puncture
Renal cysts can be punctured percutaneously from the lumbar region. This is best done under ultrasound control
when the point of puncture and the depth and size of the cyst can be assessed. The straw-coloured fluid they
contain is aspirated. Once the cyst is entered it can be outlined by injecting a small quantity of contrast medium.
This will show the size of the cyst and the contrast can be used to confirm that most or all of the fluid has been
aspirated.

ISOTOPE SCANNING
m
"Tc DMSA (dimercaptosuccinic acid) is widely used for renal imaging. This compound is fixed in the tubules with
a low extraction rate and good images may be obtained 1-2 hours after injection.
Lesions such as tumours show as filling defects as do benign lesions such as cysts (Fig. 10.14). In chronic
pyelonephritis uptake is often reduced and uneven as it is in other conditions with poor renal function, such as
obstructive uropathy and tuberculosis.

Renography.This method of scanning is widely used in renal' disease. It differs from normal scanning in that a
131 123
graph is obtained of the renal output of the isotope. The radioisotope used is usually I-hippuran or I-
hippuran. This is removed almost entirely from the kidney in one passage and is not reabsorbed. Scanning must
therefore take place immediately after a small intravenous injection of the radioactive isotope. A scintillator
counter is centred evenly over each kidney touching the skin. The normal renogram graph usually shows:
1. A sharp rise of activity within 30 seconds of the injection (A-B)
2. A slower rise during the next 3 to 5 minutes (B-C)
3. Falling off in the next 15 minutes (C-D).

This is the normal pattern but it will be changed in various ways depending on the type of disease from which the
kidney is suffering.

Comparison of the function of the two kidneys is also possible by comparing the results on the two sides.

63
99 m
Fig.Right renal cyst. Tc DMSA scan.Posterior projection. (A) Normal left image. (B) There is a non-specific
deficit in the upper half of the right kidney due to a cyst.

131
Fig. I-hippuran renogram. Normal. For explanation see text

Nuclear medicine involves low amounts of radiation and provides information regarding renal perfusion,
function and the contribution each kidney is making to total function. Renal nuclear medicine scanning(1)
dimercaptosuccinic acid (DMSA), used in estimation of differential renal function and detection of scarring
(usually associated with reflux); (2) mercaptoacetyltriglycine (MAG3), used in detection of functionally significant
obstruction, estimation of differential renal function, screening for renal artery stenosis, and monitoring of renal
transplants.

FDG-PET scanning combines the functional aspects of a nuclear medicine scan with the anatomical definition of
CT scanning and is used to investigate renal tumours and to diagnose and monitor large vessel vasculitis.

Invasive techniquesthese can allow therapeutic intervention as well as diagnosis, including antegrade or
retrograde ureteropyelography (insertion of stents to relieve urinary obstruction) and angiography (angioplasty or
stenting of the renal artery).
These procedures include 99m Tc-mercaptoacetyltriglycine scanning (MAG3) and 99m Tc-
diethylenetriamine-pentaacetate (DTPA) uptake scans.The latter is mostly being overtaken by the
former. These allow dynamic imaging, as both are filtered by the glomerulus and excreted by the kidney.
MAG3 scanning is useful in hypertension (looking to see whether those who have renovascular disease
will benefit from procedures to improve renal blood flow).MAG3 is also useful in delayed graft function
following renal transplant and discriminating between functional renal obstruction and simple dilatation
[4]
alone.
Scintigraphy can also be performed with DMSA. DMSA is given by intravenous injection and then static
imaging is performed 2-4 hours later. This provides information on the contribution each kidney is
making to total function. Thus it is useful in situations where there is bilateral scarring. It is also used in
some children following a urinary tract infection.

Renal biopsy
A renal biopsy should be considered in any patient with disease affecting the kidney when the clinical information
and other laboratory investigations have failed to establish a definitive diagnosis or prognosis, or when there is
doubt as to the optimal therapy. However, renal biopsy has the potential to cause morbidity and (on rare
occasions) mortality, hence its risk must be outweighed by the potential advantages of the result to the individual
patient. Biopsies which would be of interest but not in the patients interest should not be performed.

64
Benign Breast Diseases

The vast majority of the lesions that occur in the breast are benign. Much concern is given to malignant lesions of
the breast because breast cancer is the most common malignancy in women in Western countries; however,
benign lesions of the breast are far more frequent than malignant ones. With the use of mammography,
ultrasound, and magnetic resonance imaging of the breast and the extensive use of needle biopsies, the
diagnosis of a benign breast disease can be accomplished without surgery in the majority of patients. Because
the majority of benign lesions are not associated with an increased risk for subsequent breast cancer,
unnecessary surgical procedures should be avoided. It is important for pathologists, radiologists, and oncologists
to recognize benign lesions, both to distinguish them from in situ and invasive breast cancer and to assess a
patients risk of developing breast cancer, so that the most appropriate treatment modality for each case can be
established.

The term benign breast diseases encompasses a heterogeneous group of lesions that may present a wide
range of symptoms or may be detected as incidental microscopic findings. The incidence of benign breast lesions
begins to rise during the second decade of life and peaks in the fourth and fifth decades, as opposed to
malignant diseases, for which the incidence continues to increase after menopause, although at a less rapid
pace.

In this review, the most frequently seen benign lesions of the breast are summarized as developmental
abnormalities, inflammatory lesions, fibrocystic changes, stromal lesions, and neoplasms.

Developmental Abnormalities
Ectopic breast (mammary heterotopia), which has been described as both supernumerary and aberrant breast
tissue, is the most common congenital abnormality of the breast. Supernumerary breast tissue is seen mostly
along the milk line; the most frequent sites are the chest wall, vulva, and axilla. It may vary in its components of
nipple (polythelia), areola, and glandular tissue (polymastia). However, an anatomic location outside the milk line
should not preclude a diagnosis of ectopic breast tissue, because there are many well-documented, unusual sites
of such tissue, including the knee, lateral thigh, buttock, face, ear, and neck. Aberrant breast tissue is usually
located near the breast, most commonly in the axilla. They usually have a nipple and areola and a separate duct
system from that of the normal breast. When the nipple is absent, the presence of the accessory breast tissue is
difficult to identify. The accessory breast tissue responds in the same way as normal breast tissue to
physiological influences. The absence of a duct system may cause symptoms of obstruction during lactation and
may be mistaken clinically for a carcinoma. Accessory breast tissue and polymastia are more common among
Asians, especially Japanese, than whites. Recognition of ectopic breast tissue is important because it can serve
as a milieu for the development of a variety of benign and malignant lesions encountered in the normal breast. It
has been reported that ectopic breast tissue is more prone to malignant change and that ectopic breast cancer
occurs at an earlier age; however, malignancies in ectopic breasts are very rare. Excessive breast growth
(macromastia) can be seen in pregnancy as well as during adolescence.

Underdevelopment of the breast (hypoplasia), when congenital, is usually associated with genetic disorders, such
as ulnar-mammary syndrome, Polands syndrome, Turners syndrome, and congenital adrenal hyperplasia.
Among these disorders, Polands syndrome is the congenital anomaly that has been reported to be associated
with breast cancer most often. There are some recent studies suggesting the association of ulnar-mammary
syndrome and breast cancer; however, breast cancer has not been recorded in patients with Turners syndrome.
Acquired hypoplasia, on the other hand, is usually iatrogenic, most commonly subsequent to trauma or radio-
therapy. The complete absence of both breast and nipple (amastia) or presence of only nipple without breast
tissue (amazia) is rare.

Inflammatory and Related Lesions

Mastitis
A variety of inflammatory and reactive changes can be seen in the breast. While some of these changes are a
result of infectious agents, others do not have a well-understood etiology and may represent local reaction to a
systemic disease, or a localized antigen-antibody reaction, and are classified as idiopathic.
Inflammatory breast cancer, as the name suggests, mimics an infectious or inflammatory etiology. It often
develops without a palpable mass lesion and is often initially misdiagnosed. In fact, most patients with
inflammatory breast cancer are diagnosed after an initial treatment with antibiotics or anti-inflammatory therapies
failed to show clinical improvement. Mammographic and sonographic evaluation are helpful in establishing the
diagnosis. Image-guided biopsy of the abnormal breast parenchyma or skin biopsy confirms the diagnosis. A
negative skin biopsy should not be used to exclude the diagnosis.

Acute Mastitis
Acute mastitis usually occurs during the first 3 months postpartum as a result of breast feeding. Also known as
puerperal or lactation mastitis, this disorder is a cellulitis of the interlobular connective tissue within the mammary
gland, which can result in abscess formation and septicemia. It is diagnosed based on clinical symptoms and

65
signs indicating inflammation. Risk factors fall into two general categories: improper nursing technique, leading to
milk stasis and cracks or fissures of the nipple, which may facilitate entrance of microorganisms through the skin;
and stress and sleep deprivation, which both lower the mothers immune status and inhibit milk flow, thus causing
engorgement.

Because the duration of symptoms before starting treatment is found to be the only independent risk factor for
abscess development, early diagnosis and early management of mastitis is of value. However, there is little
consensus on the type or duration of antibiotic therapy and when to begin antibiotics. Because lactation mastitis
is a process of subcutaneous cellulitis, detection of pathogens in breast milk may not always be possible, so
breast emptying with frequent nursing or manual pumping and beginning empiric antibiotherapy seems to be the
most appropriate approach. When puerperal mastitis-associated abscess occurs, incision and drainage are
usually recommended; however, suitable patients assessed by ultrasonography can also be treated without
surgery by needle aspiration and antibiotics with excellent cosmesis.

Granulomatous Mastitis
Granulomatous reactions resulting from an infectious etiology, foreign material, or systemic autoimmune
diseases such as sarcoidosis and Wegeners granulomatosis can involve the breast. Identification of the etiology
requires microbiologic and immunologic testing in addition to histopathologic evaluation. Many different types of
organisms can cause granulomatous mastitis.

Tuberculosis of the breast is a very rare disease. However, both clinical and radiological features of tuberculous
mastitis are not diagnostic and easily can be confused with either breast cancer or pyogenic breast abscess by
clinicians. Remembering the fact that traveling from one place to another in the global world has been increasing
and that the prognosis for complete cure with appropriate antituberculous drug therapy is excellent, this entity
should also be taken into consideration. Definitive diagnosis of the disease is based on identification of typical
histological features under microscopy or detection of the tubercle bacilli with mycobacterial culture.

The term idiopathic granulomatous mastitis is used for granulomatous lesions without an identifiable cause.
This diagnosis can be made only by excluding other possible causes of granulomatous lesions. An autoimmune
localized response to retained and extravasated fat- and protein-rich secretions in the duct has been postulated,
but the etiology of the disease remains largely unknown. Histologically, chronic noncaseating granulomatous
inflammation is typically limited to lobuli. The recommended therapy of idiopathic granulomatous mastitis is
complete surgical excision whenever possible plus steroid therapy. Even when idiopathic granulomatous mastitis
is treated appropriately, in about 50% of the cases, persistence, recurrence, and complications such as abscess
formation, fistulae, and chronic suppuration are encountered, so long-term follow-up is necessary in these
patients.

Foreign Body Reactions


Foreign materials, such as silicone and paraffin, which are used for both breast augmentation and reconstruction
after cancer surgery, may cause a foreign body-type granulomatous reaction in the breast. Silicone granulomas
(siliconomas) usually occur after direct injection of silicone into the breast tissue or after extracapsular rupture of
an implant. Foreign body granulomatous response associated with multinucleated giant cells surround silicone.
Fibrosis and contractions may lead to clinically apparent firm nodules that may be tender.

Recurring Subareolar Abscess


Recurring subareolar abscess (Zuskas disease) is a rare bacterial infection of the breast that is characterized by
a triad of draining cutaneous fistula from the subareolar tissue; a chronic thick, pasty discharge from the nipple;
and a history of multiple, recurrent mammary abscesses. The disease is caused by squamous metaplasia of one
or more lactiferous ducts in their passage through the nipple, probably induced by smoking. Keratin plugs
obstruct and dilate the proximal duct, which then becomes infected and ruptures. The inflammation eventuates in
abscess formation beneath the nipple, which typically drains at the margin of the areola. Abscess drainage to
allow for resolution of the acute inflammation and then complete excision of the affected duct and sinus tract is
successful in most cases, but abscesses may recur when the process develops in another duct.

Mammary Duct Ectasia


Mammary duct ectasia, also called periductal mastitis is a distinctive clinical entity that can mimic invasive
carcinoma clinically. It is a disease of primarily middle-aged to elderly parous women, who usually present with
nipple discharge, a palpable subareolar mass, noncyclical mastalgia, or nipple inversion or retraction. The
pathogenesis and the etiology of the disease are still being debated. Smoking has been implicated as an
etiologic factor in mammary duct ectasia. This association appears to be more important in young women who
smoke. Mammary duct ectasia is usually an asymptomatic lesion and is detected mammographically because of
microcalcifications.

The most important histologic feature of this disorder is the dilatation of major ducts in the subareolar region.
These ducts contain eosinophilic, granular secretions and foamy histiocytes both within the duct epithelium and
the lumen. The inspissated luminal secretions may undergo calcifications that may be the presenting sign in
many patients.

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Mammary duct ectasia generally does not require surgery and should be managed conservatively. There is no
evidence in the literature indicating that mammary duct ectasia is associated with an increased risk for breast
cancer. In some patients, clinical presentation and mammographic findings may suggest malignancy, and biopsy
may be required to exclude malignancy.

Fat Necrosis
Fat necrosis of the breast is a benign nonsuppurative inflammatory process of adipose tissue. It can occur
secondary to accidental or surgical trauma, or it may be associated with carcinoma or any lesion that provokes
suppurative or necrotic degeneration, such as mammary duct ectasia and, to a lesser extent, fibrocystic disease
with large cyst formation.

Clinically, fat necrosis may mimic breast cancer if it appears as an ill-defined or spiculated dense mass,
associated with skin retraction, ecchymosis, erythema, and skin thickness. Mammographic, sonographic, and
magnetic resonance imaging findings may not always distinguish fat necrosis from a malignant lesion. Even the
macroscopic appearance of the benign lesion can suggest a malignant tumor. Histologically, however, the
diagnosis of fat necrosis presents no problem, as it is characterized by anuclear fat cells often surrounded by
histiocytic giant cells and foamy phagocytichistiocytes. Excisional biopsy is required if carcinoma cannot be
excluded preoperatively.

Fibrocystic Changes
Fibrocystic changes (FCCs) constitute the most frequent benign disorder of the breast. Such changes generally
affect premenopausal women between 20 and 50 years of age. Although many other names have been used to
describe this entity over the years, (including fibrocystic disease, cystic mastopathy, chronic cystic disease,
mazoplasia, Recluss disease), the term fibrocystic changes is now preferred, because this process is observed
clinically in up to 50% and histologically in 90% of women.

FCCs may be multifocal and bilateral. The most common presenting symptoms are breast pain and tender
nodularities in breasts. Although the exact pathogenesis of the entity is not clear, hormonal imbalance,
particularly estrogen predominance over progesterone, seems to play an important role in its development. FCCs
comprise both cysts (macro and micro) and solid lesions, including adenosis, epithelial hyperplasia with or
without atypia, apocrine metaplasia, radial scar, and papilloma. Over the years, it has been one of the major
issues to determine whether these lesions are a risk factor for the subsequent development of breast cancer. As
the use of mammography and the identification of benign breast diseases become more common, it is crucial to
identify women who are at an increased risk for breast cancer. Therefore, it is practical to evaluate FCCs under a
classification system first proposed by Dupont and Page as nonproliferative lesions, proliferative lesions without
atypia, and proliferative lesions with atypia (atypical hyperplasia). In various studies, it has been shown that the
great majority of breast biopsies (up to 70%) show nonproliferative lesions.

Nonproliferative lesions include cysts, papillary apocrine change, epithelial-related calcifications, mild epithelial
hyperplasia, as well as ductal ectasia, nonsclerosing adenosis, and periductal fibrosis. Proliferative lesions
without atypia include moderate or florid ductal hyperplasia of the usual type, sclerosing adenosis, radial scar,
and intraductal papilloma or papillomatosis. Proliferative lesions with atypia include atypical ductal and lobular
hyperplasia. In each of these lesions, the subsequent risk for breast cancer is associated with the histologic
appearance of the lesion=: compared with the general population, women with nonproliferative lesions on breast
biopsy have no elevation in breast cancer risk, whereas women with proliferative disease without atypia and
women with atypical ductal or lobular hyperplasia have a greater breast cancer risk, with relative risks ranging
from 1.31.9 and 3.913.0, respectively, according to various studies. Apart from the histologic features, the age
at biopsy and the degree of family history of breast cancer are reported to be the major determinants of breast
cancer risk after the diagnosis of benign breast disease. According to Hartmann et al., the risk for breast cancer
in young women with a diagnosis of atypical epithelial proliferation is twice the risk observed among women over
55 years with a diagnosis of atypical epithelial proliferation. It was also reported, in the same study, that family
history of breast cancer is an independent risk factor and that strong family history may increase breast cancer
risk even in patients with nonproliferative lesions. Absolute risk, however, for both atypical and nonatypical
epithelial proliferations is quite low. More than 80% of patients with a diagnosis of atypical hyperplasia do not
develop invasive cancer during their lifetimes.

Cysts
Cysts are fluid-filled, round or ovoid structures that are found in as many as one third of women between 35 and
50 years old. Although most are subclinical microcysts, in about 20%25% of cases, palpable (gross) cystic
change, which generally presents as a simple cyst, is encountered. Cysts cannot reliably be distinguished from
solid masses by clinical breast examination or mammography; in these cases, ultrasonography and fine needle
aspiration (FNA) cytology, which are highly accurate, are used.

Cysts are derived from the terminal duct lobular unit. In most cysts, the epithelial lining is either flattened or totally
absent. In only a small number of cysts, an apocrine epithelial lining is observed. Because gross cysts are not
associated with an increased risk of carcinoma development, the current consensus on the management of gross
cysts is routine follow-up of the patient, without further therapy.

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Complex (or complicated or atypical) cyst is a sonographic diagnosis that is characterized by internal echoes or
thin septations, thickened and/or irregular wall, and absent posterior enhancement. They are reported in
approximately 5%5.5% of all breast ultrasound examinations. The malignancy rate of complex cysts, which is
0.3% as described by Venta et al., is lower than that for lesions classified as probably benign. These patients
can be managed with follow-up imaging studies. However, if the lesion also includes an intracystic mass
(intracystic nodule), it should be regarded as suspicious for neoplasm and managed as solid lesions. Either a
core needle biopsy or surgical biopsy is indicated for these lesions.

Adenosis
Adenosis of the breast is a proliferative lesion that is characterized by an increased number or size of glandular
components, mostly involving the lobular units. Various types of adenosis have been described, of which
sclerosing adenosis and microglandular adenosis merit detailed description.
Sclerosing adenosis of the breast is defined as a benign lobulocentric lesion of disordered acinar, myoepithelial,
and connective tissue elements, which can mimic infiltrating carcinoma both grossly and microscopically.
Sclerosing adenosis can manifest as a palpable mass or as a suspicious finding at mammography. It is strongly
associated with various proliferative lesions, including epithelial hyperplasias, intraductal or sclerosing papilloma,
complex sclerosing lesion, calcification, and apocrine changes. It can coexist with both invasive and in situ
cancers. Studies found sclerosing adenosis to be a risk factor for invasive breast cancer apart from its
association with other proliferative lesions of the breast.

Sclerosing adenosis. Proliferation of small glands associated with microcalcifications. Low-power examination
demonstrates the lobulocentricity of the lesion.

Microglandular adenosis of the breast is characterized by a proliferation of round, small glands distributed
irregularly within dense fibrous and/or adipose tissue. Most of the glandular structures have open lumina in which
eosinophilic material is usually seen. The most important histological feature of microglandular adenosis is that it
may lack the outer myoepithelial layer seen in other types of adenosis. The lack of myoepithelial layer makes it
harder to differentiate microglandular adenosis from tubular carcinoma. However, the presence of basal lamina
encircling glandular structures, which can also be shown by laminin or type IV collagen immunohistochemical
stains, and the absence of epithelial membrane antigen staining in the luminal epithelial cells distinguish
microglandular adenosis from tubular carcinoma.

Although microglandular adenosis is considered benign, there is some evidence of the potential of this lesion to
become invasive carcinoma. Microglandular adenosis also has a tendency to recur if not completely excised.
Apocrine (adenomyoepithelial) adenosis, which seems to be a variant of microglandular adenosis, was first
described in association with adenomyoepithelioma. It is an apocrine change in deformed lobular units,
sclerosing adenosis, radial scars, and complex sclerosing lesions. The term apocrine adenosis is used to
describe a wide spectrum of apocrine lesions, and to prevent its inappropriate use, this term has been proposed
to describe apocrine changes in the specific underlying lesions.

Tubular adenosis of the breast is another and rare variant of microglandular adenosis that should be
distinguished from tubular carcinoma. The presence of an intact myoepithelial layer around the tubules is the
most helpful feature.

Metaplasia
Apocrine metaplasia is characterized by the presence of columnar cells with abundant granular, eosinophilic
cytoplasm and luminal cytoplasmic projections or apical snouts. These cells line dilated ducts or can be seen in
papillary proliferations. They are more frequently found in younger women. All normal and metaplastic apocrine
cells can be stained with gross cystic disease fluid protein 15.

Atypical apocrine metaplasia should be diagnosed only when the nuclei of the apocrine cells display significant
cytologic atypia.

Clear cell metaplasia of the breast is a rare lesion. Its significance comes from its morphologic similarity to clear
cell carcinoma. However, the similarity of its immunohistochemical staining profile with that of eccrine sweat
glands suggests that clear cell metaplasia may in fact represent eccrine metaplasia.

Epithelial Hyperplasia
Epithelial hyperplasia (ductal or lobular type) is one of the most challenging FCCs to diagnose properly. Epithelial
hyperplasia is the most common form of proliferative breast disease. It can be difficult to distinguish between
ductal and lobular hyperplasias. In addition, it can also be difficult to distinguish between usual ductal or lobular
hyperplasias and their atypical counterpartsatypical ductal hyperplasia and atypical lobular hyperplasia. Table
1 lists the various types of epithelial hyperplasia and associated risk of carcinoma.

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Histologic category of benign breast lesions associated with the relative risk for breast cancer for patients with no
family history

Ductal Lesions
Normally, breast ducts are lined by two layers of low cuboidal cells with specialized luminal borders and basal
contractile myoepithelial cells. Any increase in cell number within the ductal space is regarded as epithelial
hyperplasia. Further classification is based on the degree and architectural and cytologic features of the
proliferating cells. Usual ductal hyperplasia or simple hyperplasia denotes an increased number of cells without
architectural distortion or distention of the ductal contour. Usual ductal hyperplasia does not increase the risk for
breast cancer. In mild hyperplasia of the usual type, proliferating epithelial cells are a three- to four-cell layer,
whereas moderate hyperplasia describes epithelial proliferation more than four cells thick, often with
accompanying bridging of the luminal space. In florid hyperplasia, the lumen is distended and may be obliterated.
The most important cytologic features of mild, moderate, or florid epithelial hyperplasia are an admixture of cell
types (epithelial cells, myoepithelial cells, and metaplastic apocrine cells) and variation in the appearances of
epithelial cells and their nuclei.

Ductal epithelial hyperplasias.(A): Usual ductal hyperplasia. The epithelial proliferation is composed of
polymorphic cell types that partially occlude the lumen. (B): Florid epithelial hyperplasia. Proliferating solid
clusters of hyperplastic cells with the typical appearance of overlapped and uneven distribution of nuclei. The
epithelial proliferation obliterates and distends the ductal lumens. (C): Atypical ductal hyperplasia is characterized
by monotonous proliferation of regularly arranged cells; in this photograph, forming a cribriform pattern. Although
displaying features of low-grade intraductal carcinoma, quantitatively, being a single and small focus, this lesion
is interpreted as atypical ductal hyperplasia.

The term atypical ductal hyperplasia is defined as a type of a ductal hyperplasia that morphologically mimics low-
grade ductal carcinoma in situ (DCIS). Characteristically, it has a uniform population of cells. Most lesions of
atypical ductal hyperplasia are small and focal. They involve only a portion of a duct or only a few small ducts
measuring <2 mm. With the increasing use of mammography, and detection of calcifications, atypical ductal
hyperplasias are being diagnosed more frequently. Atypical ductal hyperplasia is a rare condition among patients
having biopsies for a palpable mass, seen in 4% of symptomatic benign biopsies. In contrast, 31% of biopsies
performed because of microcalcifications show atypical ductal hyperplasia. The significance of this lesion comes
from the fact that the patient has an increased risk for invasive breast cancer, which is about four to five times
that of the general population, and reaching nearly a tenfold risk if the patient has a first-degree relative with
breast cancer. The risk for breast cancer is higher in the ipsilateral breast, but the contralateral breast is also at
risk. Women with atypical ductal hyperplasia develop cancer usually within 1015 years of the diagnosis. The risk
for cancer declines after 15 years. The risk for breast cancer in women with atypical ductal hyperplasia is also
related to the patients menopausal status. Premenopausal women with atypical ductal hyperplasia have a
substantially higher risk than postmenopausal women with that diagnosis. Routine follow-up for both breasts is
recommended. Therapy options, such as chemoprevention, should be determined on the basis of other risk
factors for breast cancer.

Lobular Lesions
Lobular-type epithelial proliferations, both atypical lobular hyperplasia and lobular carcinoma in situ, are
collectively termed lobular neoplasia because, unlike ductal lesions, which exhibit heterogeneous morphologic
features, the histologic features of lobular type epithelial proliferations are very similar, and the only difference
between atypical lobular hyperplasia and lobular carcinoma in situ is the extent and degree of epithelial
proliferation. Because both lesions are regarded and managed as a risk factor rather than well-established
precursor lesions, lobular neoplasia terminology has gained general acceptance. Lobular neoplasia is a relatively

69
rare breast lesion. It rarely manifests itself clinically. Lobular neoplasia is identified as an incidental finding in
biopsies excised for other abnormalities. The frequency of detection depends on the volume of tissue removed
during surgery and extent of histological examination. Lobular neoplasia is most prevalent in perimenopausal
women. It is a multifocal lesion, and many patients have lesions involving multiple quadrants of the breast. Both
atypical lobular hyperplasia and lobular carcinoma in situ increase the risk for the subsequent development of
invasive carcinoma, by about fourfold for atypical lobular hyperplasia and tenfold for lobular carcinoma in situ.
Although subsequent carcinomas can occur in either breast without a direct relationship to the previous site of
biopsy, in a recent retrospective study, Page et al. reported that the development of invasive carcinoma after
atypical lobular hyperplasia was three times more likely to arise in the ipsilateral breast than in the opposite
breast. Invasive carcinomas may arise 1520 years after diagnosis. Systemic follow-up and appropriate risk
assessment is recommended for patients with lobular neoplasia.

Lobular carcinoma in situ is considered to be a risk marker rather than an obligatory precursor lesion of invasive
breast cancer; therefore, in general, it does not warrant surgical therapy. Most women with a diagnosis of lobular
carcinoma in situ do not develop invasive breast cancer within their natural lifetimes. The risk for developing
invasive cancer appears to be similar in both the ipsilateral and contralateral breasts. Therefore, if one has to
choose surgery for lobular carcinoma in situ, the only logical approach would be a bilateral total mastectomy.
Because this is an excessively morbid procedure for patients who have a moderate risk associated with the
diagnosis of lobular carcinoma in situ, chemoprevention is the preferred approach for these patients. However, if
the patient has other risk factors, such as a high-risk family history, prophylactic bilateral mastectomy with or
without reconstruction would be a consideration.

Columnar Cell Lesions


Columnar cell lesions of the breast represent a spectrum of lesions that have been encountered with increasing
frequency in needle core breast biopsies because these lesions are commonly associated with
microcalcifications and detected by mammographic screening. A working classification of these lesions has been
proposed by Schnitt and Vincent-Salomon as columnar cell change and columnar cell hyperplasia, each of which
may have atypia or not. Ongoing studies on the clinical significance of atypical columnar cell lesions, which are
also known as flat epithelial atypia, have shown that the likelihood of local recurrence or progression to invasive
breast cancer is exceedingly low. However, based on the foregoing observations, it has been suggested that at
least some lesions are probably neoplastic proliferations that may represent either a precursor of low-grade DCIS
or even invasive carcinoma, particularly tubular carcinoma.

When an atypical columnar lesion is encountered in a needle core biopsy, excision is suggested to exclude more
advanced lesions such as in situ or invasive cancer. On excisional biopsy specimen, a careful histologic search
for areas with diagnostic features of in situ or invasive cancer should be performed. Because this lesion has been
referred to by several different names in the literature, including blunt duct adenosis, columnar alteration of
lobules, hypersecretory hyperplasia with atypia, pretubular hyperplasia, and columnar alteration with prominent
snouts and secretions, it is difficult to assess its significance as a risk marker for development of invasive cancer.
Without having firm data, close follow-up of the patient with columnar cell changes is recommended at this point.

Radial Scar and Complex Sclerosing Lesion


Radial scars are benign pseudoinfiltrative lesions of uncertain significance. They are characterized by a
fibroelastotic core with entrapped ducts, surrounded by radiating ducts and lobules displaying variable epithelial
hyperplasia, adenosis, duct ectasia, and papillomatosis. Previously, radial scars were an incidental finding in
breast specimens excised for other diagnostic reasons, but their incidence has increased dramatically as a result
of population-based screening programs. Some authors have suggested using the term radial scar for lesions
measuring <1 cm, whereas the term complex sclerosing lesion was reserved for lesions measuring 1 cm or
larger.

Radial scars may serve as a milieu for the development of atypical epithelial proliferations, including atypical
intraductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, and DCIS. Over the years, many
authors have studied the biologic significance of radial scars. In a postmortem study by Nielsen et al. these
lesions were commonly associated with benign breast diseases, whereas Jacobs et al found that radial scars
were associated with a doubling of the risk for breast cancer, regardless of the type of primary breast disease,
and that the risk was even greater in women with larger or multiple radial scars.

The radiographic features of radial scars are nonspecific and may mimic carcinoma. The role of FNA cytology in
diagnosis is limited. Recent publications have shown the importance of core needle biopsy of these lesions for
diagnosis, but because malignancy cannot be reliably excluded with limited sampling, a spiculated lesion
suggestive of radial scar or complex sclerosing lesion at mammography may be excised on the basis of its size
and amount of sampling performed by core biopsy.

Radial scar.(A): The mammographic appearance of radial scar. Spiculated lesion with central radiolucency.
Radiating spicules frequently mislead the diagnosis of carcinoma. (B): Low-power view of radial scar shows
fibroelastotic core and radiating ducts exhibiting duct epithelial hyperplasia without atypia, cystic structures, and
microcalcifications.

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Intraductal Papilloma and Papillomatosis
Intraductal papilloma is a discrete benign tumor of the epithelium of mammary ducts. It can arise at any point in
the ductal system and shows a predilection for the extreme ends of the ductal system: the lactiferous sinuses and
the terminal ductules. The central papillomas tend to be solitary, whereas the peripheral ones are usually
multiple. Serous or serosanguinous nipple discharge is the presenting symptom in most women. Papillomas are
characterized by formation of epithelial fronds that have both the luminal epithelial and the outer myoepithelial
cell layers, supported by a fibrovascular stroma. The epithelial component can be subject to a spectrum of
morphologic changes ranging from metaplasia to hyperplasia, atypical intraductal hyperplasia, and in situ
carcinoma. The risk represented by the occurrence of such abnormalities in an otherwise benign papilloma is
currently debated. Central single papillomas have not been considered premalignant or markers of risk when they
are not associated with atypia. Two recent studies found significant correlation between the presence of atypical
ductal hyperplasia in papillary lesions on core biopsies and the presence of invasive or preinvasive carcinoma of
the breast in excisional biopsies. In another clinicopathologic study, MacGrogan and Tavassoli suggested that
the recurrence of papillomas is related to the presence of proliferative breast lesions (including usual ductal
hyperplasia, atypical ductal hyperplasia, and lobular neoplasia) in the surrounding breast tissue. Epithelial atypia,
even to the extent of low-grade DCIS has no known prognostic significance or impact on outcome when it is
confined to the central papilloma. Therefore, if atypia is encountered in a papilloma on an excisional biopsy, the
surrounding breast tissue should be carefully examined for further follow-up of the patient.

Papillomatosis (multiple papillomas) is defined as a minimum of five clearly separate papillomas within a localized
segment of breast tissue, usually in a peripheral or subareolar location. Multiple papillomas are more likely to
occur bilaterally, and their probability of having an in situ or invasive carcinoma is higher than with the central
papilloma. Therefore, in patients with multiple papillomas on excisional biopsy, thorough sampling of the
specimen, as well as diagnostic radiographic imaging of contralateral breast tissue is suggested to rule out
malignancy. All the available data suggest that the finding of a solitary, central, benign duct papilloma does not
carry any increased risk for subsequent breast cancer, while multiple papillomas may indicate a slightly elevated
risk for subsequent breast cancer.

Juvenile papillomatosis of the breast is defined as severe ductal papillomatosis occurring in young women of <30
years old. There are only eight male juvenile papillomatosis cases reported in the literature. This disease is
associated with a heightened risk for breast cancer. Because both a family history of breast cancer and an
increased risk for breast cancer are associated with the diagnosis of juvenile papillomatosis, long-term follow-up
is recommended both for the patient and the family.

Proliferative Stromal Lesions

Diabetic Fibrous Mastopathy


Diabetic fibrous mastopathy is an uncommon form of lymphocytic mastitis and stromal fibrosis. It occurs both in
premenopausal women and (rarely) in men with long-standing type 1 insulin-dependent diabetes mellitus, who
have severe diabetic microvascular complications. Clinically, diabetic fibrous mastopathy is characterized by
solitary or multiple ill-defined, painless, immobile, discrete lesions in one or both breasts that raise the suspicion
of carcinoma. The mammographic and sonographic findings of these lesions are also highly suspicious for breast
cancer, so a biopsy is always essential for definitive diagnosis. The characteristic pathologic findings of this entity
are dense keloid-like fibrosis; periductal, lobular, or perivascular lymphocytic infiltration with predominantly B
cells; lobular atrophy; and epithelioid fibroblasts embedded in dense fibrous stroma. The pathogenesis of diabetic
fibrous mastopathy is unknown. The disease probably represents an immune reaction to the abnormal
accumulation of altered extracellular matrix in the breast, which is a manifestation of the effects of hyperglycemia
on connective tissue.

Routine annual follow-up of patients with diabetic fibrous mastopathy is recommended. Core needle biopsy may
be useful in the diagnosis of recurrent lesions on follow-up.

Pseudoangiomatous Stromal Hyperplasia of the Breast


Pseudoangiomatous stromal hyperplasia (PASH) is a benign myofibroblastic proliferation of nonspecialized
mammary stroma. Its clinicopathologic spectrum ranges from incidental, microscopic foci to clinically and
mammographically evident breast masses. Originally, hormonal stimulation (particularly with progesterone) was
suggested in the etiology of PASH, on the basis of observations that this disease is most frequently seen in
premenopausal women or in elderly women taking hormone-replacement therapy, and because similar histologic
findings are seen in normal mammary stroma during the luteal phase of the menstrual cycle. However, the lesion
has since been found in men and in women not taking hormone therapy, and only a small percentage of PASH
cases are positive for estrogen receptors or for progesterone receptors.

Clinically, rare cases of PASH present as a well-circumscribed, dense, rubbery mass mimicking a fibroadenoma
or a phyllodes tumor. Both the mammographic and sonographic features in PASH are nonspecific, so biopsy of
these lesions is necessary to exclude a malignancy.

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On gross examination, PASH is usually a well-demarcated mass with a smooth external surface. The cut surface
consists of homogeneous white and rubbery tissue. Histologically, a complex network of anastomosing slit-like
spaces within a densely collagenous stroma characterizes PASH. The histologic appearance may cause
confusion with mammary angiosarcoma, so immunohistochemical vascular markers are used for distinction.
Immunohistochemically, the bland spindle cells that line these spaces are strongly positive for vimentin and CD34
and negative for cytokeratin and factor VIII.

The recommended treatment for PASH is wide local excision. Although PASH can recur, patient prognosis is
good.

Neoplasms

Fibroadenoma
Fibroadenoma is the most common lesion of the breast; it occurs in 25% of asymptomatic women. It is usually a
disease of early reproductive life; the peak incidence is between the ages of 15 and 35 years. Conventionally
regarded as a benign tumor of the breast, fibroadenoma is also thought to represent a group of hyperplastic
breast lobules called aberrations of normal development and involution. The lesion is a hormone-dependent
neoplasm that lactates during pregnancy and involutes along with the rest of the breast in perimenopause. A
direct association has been noted between oral contraceptive use before age 20 and the risk of fibroadenoma.
The Epstein-Barr virus might play a causative role in the development of this tumor in immunosuppressed
patients.

Fibroadenoma presents as a highly mobile, firm, non-tender, and often palpable breast mass. Although most
frequently unilateral, in 20% of cases, multiple lesions occur in the same breast or bilaterally. Fibroadenoma
develops from the special stroma of the lobule. It has been postulated that the tumor might arise from bcl-2-
positive mesenchymal cells in the breast, in a manner similar to that proposed for solitary fibrous
tumors.Macroscopically, the lesion is a well-circumscribed, firm mass, <3 cm in diameter, the cut surface of which
appears lobulated and bulging. If the tumor assumes massive proportions (>10 cm), more commonly observed in
female adolescents, it is called giant fibroadenoma. Microscopically, fibroadenoma consists of a proliferation of
epithelial and mesenchymal elements. The stroma proliferates around tubular glands (pericanalicular growth) or
compressed cleft-like ducts (intracanalicular growth). Often both types of growth are seen in the same lesion.
Fibroadenoma.(A): The cut surface of fibroadenoma is lobulated, solid, and gray-white, with a characteristic
bulging appearance. (B): Histologically the lesion consists of densely fibrotic stroma and compressed cleft-like
ducts.

Cytogenetic studies have reported chromosomal aberrations in both epithelial and stromal cells, suggesting that
the two components may involve neoplastic changes. Phyllodes tumor is a fibroepithelial tumor of the breast with
a spectrum of changes. Benign phyllodes tumor is usually difficult to differentiate from fibroadenoma.
Hypercellular stroma with cytologic atypia, increased mitoses, and infiltrative margins of the lesion are the most
reliable discriminators to separate lesions with recurrence and malignant behavior. In terms of surgical treatment
of these tumors, it is important to recognize phyllodes tumor because it should be excised completely with clear
margins to obviate any chance of local recurrence. In cases of recurrent disease, mastectomy is often performed.
Approximately 50% of fibroadenomas contain other proliferative changes of breast, such as sclerosing adenosis,
adenosis, and duct epithelial hyperplasia. Fibroadenomas that contain these elements are called complex
fibroadenomas. Simple fibroadenomas are not associated with any increased risk for subsequent breast cancer.
However, women with complex fibroadenomas may have a slightly higher risk for subsequent cancer. The
presence of atypia (either ductal or lobular) confined to a fibroadenoma does not lead to a greater risk for long-
term breast carcinoma compared with fibroadenomas in general.

Fibroadenomas in older women or in women with a family history of breast cancer have a higher incidence of
associated carcinoma. Two studies, which were considered to provide strong evidence of reliability according to
El-Wakeel et al., show that the relative risk of developing breast cancer in patients who had surgically excised
fibroadenomas increases in the presence of complex features within the fibroadenomas, ductal hyperplasias, or a
family history of breast carcinoma (in a first-degree relative). Progressive somatic genetic alterations that are
associated with the development of breast cancer have been studied in fibroadenomas. No genetic instabilities,
manifested as loss of heterozygosity or microsatellite instability, have been found in any fibroadenoma
components regardless of their association with breast cancer or their histologic complexity.

The current management of patients with clinically or radiologically suspected fibroadenoma varies. Some
physicians prefer excision for tissue diagnosis, but conservative management will likely replace surgical
treatment in the near future, on the basis of the young age of the patient, findings of benign imaging and clinical
characteristics, and benign findings on either FNA biopsy or needle core biopsy. Minimally invasive techniques,
such as ultrasound-guided cryoablation, seem to be an excellent treatment option for fibroadenoma in women
who wish to avoid surgery, or else the lesion may simply be treated with observation and followed up periodically.
Juvenile fibroadenoma is a variant of fibroadenoma that presents between 10 and 18 years of age, usually as a
painless, solitary, unilateral mass >5 cm. It can reach up to 15 or 20 cm in dimension, so although it is an entirely
benign lesion, surgical removal is recommended.

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Lipoma
Lipoma of the breast is a benign, usually solitary tumor composed of mature fat cells. It is occasionally difficult to
distinguish lipoma from other conditions clinically, thus causing diagnostic and therapeutic challenges.
Clinically, a lipoma presents as a well-circumscribed, smooth or lobulated mass that is soft and usually
nontender. FNA biopsy of these lesions reveals fat cells with or without normal epithelial cells. Usually both
mammography and ultrasound scanning give negative results, unless the tumor is large.

If the clinical diagnosis of lipoma is confirmed by either FNA biopsy or core biopsy, and the mammogram and the
ultrasonogram show nothing suspicious for malignancy at the site, the patient is normally followed through
palpation after 6 months. However, if the diagnosis is not certain or the lesion grows rapidly, the tumor should be
surgically removed.

Adenoma
An adenoma is pure epithelial neoplasm of the breast. This lesion is divided into tubular, lactating, apocrine,
ductal, and so-called pleomorphic (i.e., benign mixed tumor) adenoma. Except for lactating and tubular
adenomas, these lesions are uncommon. Both lactating and tubular adenomas occur during the reproductive
ages.

Lactating adenoma is the most prevalent breast mass during pregnancy and puerperium. It presents as a solitary
or multiple, discrete, palpable, freely movable breast mass that tends to be small (<3 cm). On gross examination,
the lesion is well circumscribed and lobulated. It is characterized by hyperplastic lobules in which proliferated
acini are lined by actively secreting cuboidal cells. Lactating adenoma may also develop in ectopic locations,
such as the axilla, chest wall, or vulva. Although the tumor may spontaneously involute, surgical removal may be
necessary because of the mass effect it produces, and in cases when lactation is not of concern, medical therapy
may be given to shrink the tumor. This tumor does not tend to recur locally, and there is no proven malignant
potential.

Tubular adenoma (also termed pure adenoma) of the breast presents as a solitary, well-circumscribed, firm
mass. It may resemble the appearance of noncalcified fibroadenoma radiographically. Histologically, tightly
packed tubular or acinar structures that are very regular in size and shape are seen in a sparsely cellular stroma.
Microcalcifications inside dilated acini have been described; numerous tiny, punctuate, and irregular
microcalcifications are prominent on mammography and ultrasonography.
Both lactating and tubular adenomas, (the true breast adenomas) can be distinguished from fibroadenoma and
nipple adenoma by the presence of scant stroma in the former.

Nipple Adenoma
Nipple adenoma, also known as florid papillomatosis of the nipple ducts or erosive adenomatosis, is a benign
tumor of the ductal epithelium that often clinically mimics Pagets disease and pathologically may be
misinterpreted as an adenocarcinoma. Typically, nipple adenoma presents as a discrete, palpable tumor of the
papilla of the nipple. Erosion of the nipple and nipple discharge are usually seen. Histologically, the tumor is
characterized by proliferating ductal structures that invade the surrounding stroma. A double layer of epithelium
lines these ductal structures. The presence of keratin cysts and tiny apical snouts are other distinguishing
features of the disease. Generally, a biopsy is necessary for diagnosis. Nipple adenoma can be successfully
treated by complete excision of the tumor with normal surgical margins. Recurrences of incompletely excised
lesions have been documented. Nipple adenoma is considered a benign lesion, but rarely malignant change
within or contiguous with nipple adenoma has been defined.

Hamartoma
Hamartoma of the breast is an uncommon benign tumor-like nodule, also known as fibroadenolipoma,
lipofibroadenoma, or adenolipoma, composed of varying amounts of glandular, adipose, and fibrous tissue.
Clinically, hamartoma presents as a discrete, encapsulated, painless mass. Although the pathogenesis of the
lesion is not clear, it is thought to result from a dysgenesis rather than a true tumorous process. Some cases
have been reported to be related to a genetic defect called Cowdens disease. The classic mammographic
appearance is a circumscribed area consisting of both soft tissue and lipomatous elements, surrounded by a thin
radiolucent zone.

On macroscopic examination, hamartomas are typically well-circumscribed lesions with smooth contours.
Histologically, the most characteristic appearance is otherwise normal breast and fat tissue distributed in a
nodular fashion within a fibrotic stroma that surrounds and extends to between individual lobules and obliterates
the usual interlobular specialized loose stroma.

There are some issues that should be taken into consideration when evaluating hamartomas. First, this lesion
can be very easily underestimated if the clinical finding of a distinct lump or breast asymmetry and the imaging
features are not interpreted thoroughly. Second, the pathologist should always be careful about a coincidental
epithelial malignancy occurring in the lesion, and the lesion has a potential problem of recurrence. Third, the
lesion should be placed in the differential diagnosis of biphasic breast tumors.
The current management of hamartomas is surgical removal.

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Granular Cell Tumor
Granular cell tumor is an uncommon, usually benign neoplasm that originates from Schwann cells of the
peripheral nervous system. It is most frequently found in the head and neck region, particularly in the oral cavity.
The tumor occurs in the breast in only 5%6% of cases.

Clinically, granular cell tumor can simulate carcinoma because of its fibrous consistency, fixation to the pectoral
fascia, skin retraction, and ulceration. Mammographic and ultrasonographic findings may further increase the
suspicion of a malignant lesion.

Grossly, granular cell tumor is generally 3 cm or smaller and appears almost well circumscribed when bisected;
in some tumors, however, infiltrative margins suggestive of a malignant lesion may be encountered.
Histologically, nests and sheets of polygonal cells with distinct cell borders and abundant granular eosinophilic
cytoplasm are characteristic. The S-100 protein immunoreactivity of these cells supports the hypothesis that
granular cell tumor derives from Schwann cells.

Granular cell tumor.Sheets or nests of large polygonal cells with abundant, coarsely granular, eosinophilic
cytoplasm and prominent, round to oval nucleus.

Although granular cell tumor is mostly benign, there are a few cases in the literature reported as malignant.
Features suggestive of malignancy are tumor size (>5 cm), cellular and nuclear pleomorphism, prominent
nucleoli, increased mitotic activity, presence of necrosis, and local recurrence .

Wide local excision is the treatment of choice for both benign and malignant granular cell tumors. Complete
removal may require inclusion of muscle and other adjacent structures, and histologically it is recommended that
the margins be completely free of tumor. Incomplete excision may result in local recurrences. Adjuvant therapy is
not given unless the tumor is malignant.

Sentinel lymph node biopsy in breast cancer

V. Seenu, Piyush Ranjan Mishra

Introduction

One of the most significant breakthroughs in breast cancer management in recent times has been in the area of
sentinel lymph node biopsy (SLNB), which is now an established staging technique for assessing regional lymph
node status while minimizing the morbidity associated with conventional axillary lymph node dissection (ALND).
Axillary lymph nodal (ALN) status remains the most important prognostic marker in the management of breast
cancer patients. Evaluation of axillary lymph nodes is critical for accurately staging patients and to decide
adjuvant chemotherapy . In a series of 27,420 pts with carcinoma breast overall incidence of metastasis to ALN
was 46%. The axillary lymph node involvement correlates with the size of the breast tumor ( tumor of size <1 cm,
incidence of axillary metastases is 3-22%; for tumor of 1-2 cm, it is around 36%). In the absence of local
treatment to axilla with either surgery or radiotherapy, the risk of axillary recurrence is high. While ALND provides
staging information and removes any disease in axilla providing regional disease control, there is no evidence
that removal of axillary lymph nodes provides a survival benefit. The 25-year follow up data from the landmark
National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 study clearly showed that there is no survival
advantage associated with ALND . ALND carries with it a significant morbidity in terms of lymphedema,
numbness in the distribution of intercostobrachial nerves, decreased range of motion in the shoulder, and overall
reduced quality of life.

Sentinel node concept


Through the significant efforts of David Krag & Armando Guiliano , SLN concept was introduced into breast
cancer and by late 1990s, it soon became evident that SLNB is a safe, reliable technique that accurately stages
the axilla, allowing the procedure to become accepted for widespread clinical use. The sentinel node concept is
based on the belief that lymphatics from primary tumor go to the first node in regional nodal basin (sentinel node/
hot node). Lymphatic mapping allows us to determine the number and location of these sentinel lymph nodes.
SN can be localized precisely for surgical excision and pathological examination by dye diverted technique (blue
node) or radio tracer guided technology (hot node) method or combination of both. As the sentinel node is most
likely to harbor a metastases, a focused histological analysis can be performed on this concentrated specimen.
The tumor status of this sentinel node will reflect the status of the rest of the regional nodal basin. Thus removal
of only the sentinel node/s can allow avoidance of many complications of ALND in breast cancer patients, while it
has the potential of providing all the staging information.

In validational studies (Table 1), SLNB has been shown to accurately predict the axillary status in early breast
cancer patients

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Validational Studies
Author Tech Success (%) Accuracy (%)
Krag (1993) Tracer 18/22 (82) 18/18
Giuliano (1994) Blue Dye 114/174 (66) 109/114 (96)
Giuliano (1997) Blue dye 100/107 (94) 100/100
Veronesi (1997) Tracer 160/163 (98) 156/160 (97)
Cox (1998) Comb 440/466 (94) 439/440 (99)
Albertini (1997) Comb 57/62 (92) 57/57 (100)
Our study (2010) Blue & Comb 385/423 (91) 378/385 (98)

Subsequently randiomized controlled trials, meta analysis and systematic reviews (Table 2) have shown that
sentinel node biopsy can be an alternative to conventional ALND in patients with clinically negative axilla.

Randomized trials of Sentinel Node Biopsy in Breast cancer


ACSOG Z 10 & 11
NASBP 32
ALMANAC
AMAROS
SNAC
IBCSG23-01
IEO
Veronesi

The primary outcomes measured in RCTs of SLND V/S ALND in breast cancer are axillary recurrence, over all
survival & disease free survival. The secondary outcomes measures are Operating time, morbidity &
complications & quality of life

Veronesi et al randomized patients with Tumors < 2 cm into ALND group (257 pts) v/s SN alone or followed by
ALND group if SN showed metastasis (259 pts). Of the 259 pts SLNB 92 (36%) had positive SN and ALND.
Of 167 who underwent SLNB alone, only 1 axillary recurrence was reported at 79 months. The 5 yr survival was
96.4% in ALND group and 98.4 % in SN group. At a median follow up of 79 mths (15-97) 18 events occurred in
ALND group and 16 in SN group. They concluded that SLNB can be offered as an alternative to ALND as
treatment for axilla in patients with breast cancer <2 cm in size.

Smidt et al reported successful identification of SN in 676 of 696 patients (97%). Sentinel did not reveal any
metastasis in 439 patients (65%) and did not undergo ALND. At a median follow up of 26 months axillary
recurrence occurred only in 2 patients ().46%). They concluded that axillary recurrence rates are low following
SLND alone in early breast cancer.

Bergikvist et al reported that Axillary recurrence following SN bx alone is very low. Out of 3534 pts of early breast
cancer who underwent SLND, 2246 patients did not have metastasis in SN. At median follow up of 37 months,
isolated axillary recurrence in 0.6%; local and axillary recurrence in 0.3%; axillary & distant metastasis in 0.3%.
the estimated 5 yr axillary recurrence following SLNB was 1.1%. The axillary recurrence rate following ALND in
pre Sentinel node era at their centre was was 1%-5 yrs & 1.6%-10 yrs.Van der Ploeg et al reported their results
on SLND in 1019 pts of which 755 paitnes were SLND negative for metastasis. At a median follow up of 46
months, axillary nodal recurrence was observed in 0.25% of patients and the predicted recurrence rate at 5
years was 0.4%. The over all and disease free surivial were 95.9 and 89.7% respectively. Van der Ploeg et al
also reported a systematic review of 14959 patients in 48 published reports. At a median follow up of 34
months, 67 axillary rec urrences were observed (0.3%). Recurrence was reported to be less with use of
radiotracer, superficial injection, performance of procedure at cancer centre and use of frozen section. The
authors also mention the possibiity of low recurrence to use of radiotherapy and use of systemic adjuvant
therapy.

NSABP-32 Trial randomized patients in to SLNB (2001 patients) and SLNB followed by ALND (1975 patients)
with the objective of knowing: whether SLNB alone results in same survival & regional control as SLNBALND.
The results of the study are given in table 4.
SLNB SLNBALND
OS 95% 96%
DFS 81.5% 82.4%
Shoulder dysfunction 13% 19%
Vol diff >5% 17% 28%
Arm numbness 8% 31%
Arm tingling 7% 13%

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The conclusions deduced from the study were
No significant diff. in OS, DFS and regional control between two groups
SLNB with out ALND is safe & effective regional nodal Rx in SN ve breast cancer

In the recently published results of ALMANAC Trial, a randomized study compared conventional axillary
dissection with Sentinel lymph node dissection. The relative risks of any lymphedema and sensory loss for the
SLNB group compared with the standard axillary treatment group at 12 months were 0.37. Drain usage, length of
hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly
lower in the SLNB group (all P <.001). Overall patient-recorded quality of life and arm functioning scores were
statistically significantly better in the SLNB group throughout ( P .003) (33).

In spite of the results of sentinel node biopsy in breast cancer demonstrating its important role in management of
breast cancer, there are still some lacunae in the available literature and limitations to perform sentinel node
biopsy in patients with breast cancer in Indian settings. These can be discussed under the following headings

Sentinel node identification


The currently recommended technique of sentinel node biopsy in breast cancer is the the combination of blue
dye (isosulfan blue or patent blue violet) and radiotracer guided technique. However, neither of the blue dyes are
currently marketed in India, are expensive and not easily available. In India some surgeons use Methylene Blue
for identificationof sentinel node in breast cancer with variable success rates. . However, there are nor
randomized trials comparing the efficacy of Methylene blue vis a vis isosulfan blue or patent blue violet in
identifying sentinel node in literature.

In older patients (>70 yrs) and in obese patients (BMI>30), the sentinel node identification rates reported in
literature are lower and hence these two parameters are considered as relative contraindication by some
investigators. SPECT scan as been shown to improve sentinel node identification rates in these patients.(Ref)
However, there is no randomized study comparing the efficacy of conventional lymphoscinitigraphy and SPECT
scan in identifying sentinel node in obese or polder patients.

False Negative Rate


Ultra sound (US) of axilla is an evolving method of evaluation of axilla in patients of breast cancer with clinically
negative axilla. US of the axilla may provide a significant improvement in the preoperative assessment of lymph
node status. In expert hands, axillary US almost always allows identification of the lymph nodes, assessment of
even the smallest nodes, and in-depth evaluation of node morphology. If US criteria to recognize metastatic
nodes can be consistently identified, axillary US, possibly in association with US-guided FNAC/ biopsy, may
significantly impact the choice of the surgical procedure and thus reduce the false negative rate of sentinel lymph
node biopsy in breast cancer. Obviously, patients with core biopsydocumented positive nodes or US highly
suspicious nodes might undergo straight to total axillary node dissection, saving financial resources and time.

Sentinel node evaluation


Conventioally the sentinel lympoh node biopsy specimen is subjected to conventional &E and lymph nodes that
are negative for metastases on conventional H&E are subjected to immunohistochemistry. However, in Indian
settings where patients present with larger operable breast cancer about 40% of patients with clinically negative
axilla will axillary lymph node metastasis,. In this set of patientst, accurate intraoperative evaluation of SLNs
permits an ALND to be performed during the initial operation if the node is positive, saving the patient both the
time, cost, and burden of a second operation. At present, there is no consensus on the utility of intraoperative
SLN analysis or the optimal method of evaluation. Two available procedures to determine the presence of nodal
metastasis are frozen section and imprint cytology. Table 3 shows the reported results of intraoperative imprint
cytology and frozen section

Imprint cytology Frozen section


sensitivity specificity sensitivity specificity
Miki Mori etal (2006) 47.1 98.3 88.2 100
Leidenius et al. (2003) 68 99 83 99
Beach et al. (2003) 69 100 54 100
Liang et al. (2003) 62.5 100 62.5 100
Nagashima et al. (2003) 70.3 99.6 83.8 100
Sauer et al. (2003) 58 100 77 100
Motomura et al. (2000) 96 90.8 52 100
van Diest et al. (1999) 62 100 87 100
Fisher et al. (1993) 98 100 90.2 100

Although a few studies have shown acceptable sensitivities for frozen section applied to intra-operative
diagnosis, many studies have claimed there are advantages to using imprint cytology in this setting. In 1999, the
College of American Pathologists recommended that SLNs be examined intraoperatively by cytologic methods. A

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key advantage of the imprint cytology over frozen sectioning is the avoidance of the loss of tissue attendant to the
use of a cryostat. Thus, imprint cytology preserves tissue for subsequent focused pathologic analysis of the
SLNs. Thus, it stands to logic that combination of FS & IC should be more accurate than either of the two and it
is relatively easy to perform both techniques on the eexcised sentinel node.Though there are studies in literature
comparing accuracy of FS vis a vis IC, there are no studies comparing combined accuracy of FS & IC vis a vis
conventional H&E. Though immunohistochemistry is the gold standard method of assessing the axilla, MR
spectrosocopy has been shown to identify biochemical markers in metstatic axillary and sentinel lymph nodes in
breast cancer. Howver, larger number of lymph nodes need to be evaluated to confirm the preliminary findings.
Vascular endothelial growth factor C (VEGF C) . It is a protein encoded by a gene which is a member of the
platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family, is active in angiogenesis,
lymphangiogenesis and endothelial cell growth and survival, and can also affect the permeability of blood
vessels. This secreted protein undergoes a complex proteolytic maturation, generating multiple processed forms
which bind and activate VEGFR-3 receptors. Only the fully processed form can bind and activate VEGFR-2
receptors. This protein is structurally and functionally similar to vascular endothelial growth factor D (VEGF-D).

Tumour markers in Breast Cancer

S.V.S. Deo, Ashish Jakhetiya

Introduction
A tumour marker is a molecular or tissue based process that provides future behaviour of a cancer but requires a
special assay that is beyond routine clinical, radiological or pathological examination. It can be any substance
found in blood, urine or body tissues that can be elevated or altered in cancer. The term tumour marker was
traditionally used to denote such a factor but with current explosive growth in cancer molecular biology and
genetics the term Bio-marker will be more appropriate . Biomarkers are synthesized and released by cancer
cells or produced by host in response to the presence of tumor. Elevated levels of biomarker can indicate
presence of cancer, however there are other causes also. Tumor markers can be measured at multiple levels:
DNA, RNA, protein, cell and tissue. For example, DNA based marker assays might detect gene mutations,
deletions, amplifications. RNA based marker assays which includes micro-RNA (miRNA) might detect over or
under expression of the message, splice differences in the message, or inhibitory miRNAs that prevent
translation of other transcripts. Protein based markers can include overexpression, under expression, or
qualitative abnormalities. One might detect cancer cells in tissues or fluid in which they do not belong, such as
regional lymph nodes, circulation or distant organs (like bone marrow). Biomarkers plays an important role in
management of various malignancies including Serum PSA for prostate cancer, CEA for colon cancer, CA-125
for ovarian cancer, AFP and HCG for germ cell tumours. However role of biomarkers in breast cancer
management is still evolving and few biomarkers are now gained widespread acceptance.

Potential uses of biomarkers


There are several possible clinical uses for a tumor marker. Tumor marker might be used for screening to detect
an established cancer earlier than it would have been using standard clinical signs and symptoms. Biomarkers
can also be used to establish diagnosis and staging of malignancy. The most frequent use of a biomarker is to
determine prognosis in a patient with established cancer. Biomarkers can be used to predict response to
particular therapy. Another important role of biomarkers is for post operative surveillance and monitoring
response to therapy in advanced disease.

Biomarker in breast cancer


Breast cancer is the most common cancer in women worldwide with significant morbidity, impact on health care
cost and mortality. As still there is no uniform adoption to policy of screening, advanced and metastatic
presentations are common, apart from that chemoresistence also contributes to poor outcomes. Breast cancer
treatment has experienced several changes in the past decades due to the discovery of specific prognostic and
predictive biomarkers that enable the application of more individualized therapies to different molecular
subgroups. Now apart for conventional prognostic factors (tumor size, grade, stage, lymph node status)
established molecular markers such as estrogen receptor (ER) and progesterone receptor (PR) plays significant
role in selection of patients benefiting from endocrine therapy. Still reliable biomarker for use in clinical practice
remains unavailable and it is crucial to identify new biomarker with the potential to enhance early diagnosis,
predict prognosis, drug resistance development and treatment choice in breast cancer. The American Society of
Clinical Oncology (ASCO) first published evidence-based clinical practice guidelines for the use of tumor markers
in breast cancer in 1996. ASCO guidelines are updated at intervals by an update committee of the original expert
panel and last updated guidelines were published in 2007.

Estrogen and Progesterone receptor (ER and PR)


ER is most important biomarker in breast cancer and expression of PR is strongly dependent on presence of ER.
Tumors expressing PR but not ER are less than 1%. ER and probably PR content are associated with a
favourable prognosis, and more importantly, highly predictive of benefit from endocrine treatment in both the

77
adjuvant and metastatic settings. ASCO guidelines recommend that ER and PR should be measured on every
primary invasive breast cancer and may be measured on metastatic lesions if the results would influence
treatment planning. In both pre- and postmenopausal patients, steroid hormone receptor status should be used to
identify patients most likely to benefit from endocrine forms of therapy in both the early breast cancer and
metastatic disease settings. From presence or absence of these receptors now quantitative assessments of
expression levels are available, still there are deficits in standardization for ER and PR assays (in particular,
immuno-histochemistry [IHC]), and further efforts at defining reproducibility and accuracy for particular reagents
are an important priority.

HER 2
HER2 is a member of the epidermal growth factor receptor (EGFR) family. It is amplified and over expressed in
15%to30% of newly diagnosed breast cancers and is associated with more aggressive behaviour. ASCO
recommends HER2 expression and/or amplification should be evaluated in every primary invasive breast cancer
either at the time of diagnosis or at the time of recurrence, principally to guide selection of trastuzumab in the
adjuvant and/or metastatic setting. Five prospective randomized clinical trials have now been reported in the
adjuvant setting, as well as a single, small, prospective, randomized neoadjuvant clinical trial. Each has shown a
remarkable beneficial effect of trastuzumab on pathologic complete response, disease-free survival, and overall
survival. Level II evidence suggests that overexpression of HER2 (3+by protein or> 2.0 FISH ratio by gene
amplification) identifies patients who have greater benefit from anthracycline-based adjuvant therapy. But at
present use of HER 2 is not recommended for adjuvant chemotherapy decision making. There are insufficient
data to support the use of HER2 as a predictor of response to endocrine therapy, although the evidence does
suggest that in patients with ER-positive tumours, the relative benefit from antiestrogens for those with HER2-
positive cancers is likely to be lower than for those with HER2-negative cancers. While the weight of evidence
suggests that HER2 amplification/over expression are associated with worse outcome, the role of this marker
purely to determine prognosis in clinical practice is unclear and it is not recommended for the sole purpose of
determining prognosis. Circulating HER2 extracellular domain (ECD) levels have been proposed as a surrogate
for tissue measures of HER2, to monitor patients for early relapse or to monitor response to standard therapies or
HER2-targeted therapies. The ECD of HER2 can be detected in serum or plasma, most commonly by a
commercially available enzyme-linked immunosorbent assay (ELISA), and is elevated in approximately 30% of
patients with metastatic breast cancer. It has been proposed to have same utility as of HER2, although
appealing; use of circulating HER2/ECD is hampered by a lack of high-quality studies and a lack of consistent
findings and is not currently recommended for any clinical setting.

CA 15-3 and CA 27.29


CA 15-3 and CA 27.29 are well-characterized assays that allow the detection of circulating MUC-1 antigen in
peripheral blood. Present data are insufficient to recommend CA15-3 orCA27.29 for screening, diagnosis, and
staging. Several well-designed studies have shown that an increase in CA 15-3 or CA 27.29 after primary and/or
adjuvant therapy can predict recurrence an average of 5 to 6 months before other symptoms or tests. Still there
are no prospective randomized clinical trials to demonstrate whether detection and treatment of occult or
asymptomatic metastases using tumor markers impact on the most significant outcomes (disease-free survival,
overall survival, quality of life, toxicity, or cost-effectiveness). For monitoring patients with metastatic disease
during active therapy, CA27.29 or CA 15-3 can be used in conjunction with diagnostic imaging, history, and
physical examination. Present data are insufficient to recommend use of CA 15-3 or CA 27.29 alone for
monitoring response to treatment. However, in the absence of readily measurable disease, an increasing CA 15-
3 or CA 27.29 may be used to indicate treatment failure. Caution should be used when interpreting a rising
CA27.29 or CA 15-3 level during the first 4 to 6 weeks of a new therapy, given that spurious early rises may
occur.

CEA
CEA levels are less commonly elevated than are levels of the MUC-1 assays, CA 27.29, or CA 15-3. Only
50%to60%of patients with metastatic disease will have elevated CEA levels; compared with 75%to90% who have
elevated levels of the MUC-1 antigen. CEA levels are minimally complementary with MUC-1levels and
recommendation for their use is similar as of CA 15-3 and CA 27.29. Available data suggest that it is reasonable
to evaluate one of the MUC-1 assays and CEA initially in a patient with metastatic disease. If the MUC-1 assay is
elevated, there appears to be no role for monitoring CEA, but if not, than CEA levels may provide supplementary
information to the clinician in addition to clinical and radiographic investigations.

Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor 1 (uPA and PAI 1)
uPA and PAI-1 are part of the plasminogen activating system, this system has been shown experimentally to be
associated with invasion, angiogenesis, and metastasis. uPA and PAI 1 levels can be used for the determination
of prognosis in patients with newly diagnosed, node-negative breast cancer patients. Adjuvant chemotherapy
provides substantial benefit in comparison to observation alone, in patients with high risk of recurrence as
determined by high levels of uPA and PAI-1.

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Markers of Proliferation

IHC based markers of proliferation which includes Ki67, Cyclin D, Cyclin E, p27, p21,Thymidine kinase,
Topoisomerase II and DNA flow-cytometry based markers of proliferation like DNA content, S phase ploidy are
presently not recommended for prognostication or any other purposes in breast cancer.

Bone marrow micrometastasis


Bone marrow micrometastasis in breast cancer patients are defined as epithelial cells found within a bone
marrow aspirate that may or may not be breast-derived, malignant, or viable. Only approximately 30% to 50% of
patients whose marrow contains micro metastases from breast cancer will develop clinically apparent breast
cancer metastasis during a 5- to 10-year period of follow-up. Given that 50% to 70% of the women with marrow
micrometastasis do not develop clinically metastatic breast cancer, it is clear that not all detectable breast cancer
cells in the bone marrow will have clinical relevance for a particular patient. ASCO do not recommend use of
bone marrow micro metastases for screening, diagnosis, staging, prognosis, surveillance, or monitoring
treatment of patients with breast cancer.

Circulating tumour cells (CTC)


CTCs are those cells present in the blood that possess antigenic or genetic characteristics of a specific tumour
type. The source of CTCs is unknown and the clinical significance of CTCs is not yet established. The presence
of CTCs in a breast cancer patient may predict for the presence of a micrometastasis or of an aggressive primary
tumor. One cell detection assay, the CellSearch Assay, has recently received US Food and Drug Administration
clearance for application to the metastatic breast cancer patient. At present ASCO do not recommend use of
CTC for diagnosis of breast cancer or to influence any treatment decision.

Multiparameter gene expression analysis


Studies suggest that assessing the expression of multiple genes in a tumor sample may provide useful
information about tumor behaviour. Now molecular subtypes are emerging as powerful predictive markers in
breast cancer depending upon the status of ER, PR and HER 2 receptors.

Oncotype DX: Oncotype DX is RT-PCR assay that measures the expression of 21 genes. This is used to
determine prognosis in newly diagnosed patients with node-negative, ER positive breast cancer who receive
tamoxifen. It has been suggested that tamoxifen-treated patients with an excellent estimated prognosis may be
spared adjuvant chemotherapy. In addition, patients with a high recurrence score (RS) appear to achieve a
higher proportional benefit from adjuvant CMF chemotherapy than those with low or intermediate RS.

Mammaprint (70 gene signature): MammaPrint is a gene expression profiling platform marketed by Agendia.
Appear to identify groups of patients with very good or very poor prognosis. Though FDA approved but ASCO still
do not recommend for clinical use.

Rotterdam (76 gene signature): Specifically studied in all lymph-node-negative breast cancer patients,
regardless of age, tumor size and grade, or ER/PR status. Not recommended for clinical use at present.

Beyond usual biomarkers


Various studies have shown prognostic values of P53, cathepsin D, cyclin E and proteomics in breast cancer,
however none of them is recommended by ASCO at present. Mammaglobin, osteopontin, snail, twist, Zeb-1,
fibroblast growth factor receptors (FGFR), phosphatase and tensin homolog (PTEN) and sirtuins (SIRT) are other
potential biomarkers for the prediction of metastatic disease. Some potential biomarkers for the prediction of
systemic chemotherapy resistance include Cytochrome P450 2D6 (CYP2D6), Phosphatidylinositol-4,5-
biphosphonate-3-kinase (PIK3CA), Retinoic acid receptor alpha (RARA), Signal transducer and activator of
transcription 3 (STAT3), Tissue inhibitor of metalloproteinase 1(TIMP-1) and Lin28. During the last years,
circulating noncoding molecules of RNA (miRNAs) are emerging as an innovative class of cancer biomarkers
since found aberrantly expressed in different human cancers (tissues and serum) and featured by unprecedented
levels of diagnostic specificity and sensitivity. Despite this exciting discovery, common BC specific miRNAs have
yet to emerge across studies, and it is too soon to interpret their functional role.

Conclusion
The current routinely used serum tumor markers have limited usefulness for diagnosis and/or screening of breast
cancer due to their very low sensitivity and specificity as well as to the fact that they can be raised also in case of
some benign conditions. As regards the usefulness of tumor markers for monitoring patients during follow up, the
debate is still open between scientific organizations. Role of tumor markers is emerging as an early warning able
to highlight those patients at risk to have a recurrence due to clusters of tumor cells undetectable by conventional
morphological imaging modalities. Molecular classification is now has good acceptance and prognostic value and
various treatment decisions are now taken by expression of hormonal receptors. The established
clinicopathologic markers, in particular ER and HER2, have clearly defined clinical applicability, but deficiencies
in the methodologies of assessment may still affect their use. Additional tools are required to facilitate clinical
decision-making processes especially for the optimal treatment of early hormone receptor-positive breast cancer.

79
Very few of the many individual prognostic markers evaluated are sufficiently powerful on their own to merit
clinical use.

Despite the significant increase in the amount of research conducted on breast cancer biomarkers in the last five
years, significant gaps remain that must be filled to translate this newly acquired knowledge into clinical practice.
Thus, there is a need to validate the expression of these potential biomarkers in large patient cohorts.

References

1. Harris L, Fritsche H, Mennel R, Norton L, et al. American Society of Clinical Oncology 2007 Update of
Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol 2007;25:5287-5312.
2. Michael J Duffy. Clinical Chemistry 2006;52(3):345351.
3. Weigel MT, Dowsett M. Current and emerging biomarkers in breast cancer: prognosis and prediction. Endocrine-
Related Cancer 2010;17: R245R262.
4. Mirabelli P and Incoronato M. Usefulness of Traditional Serum Biomarkers for Management of Breast Cancer
Patients. BioMed Research International Volume 2013, Article ID 685641, 9 pages
http://dx.doi.org/10.1155/2013/685641.
5. Pultz B, Luz F, Faria P, Oliveira A, Arajo R , Silva M. Far Beyond the Usual Biomarkers in Breast Cancer: A
Review. Journal of cancer 2014; 5(7): 559-571.
6. Daniel F Hayes. Biomarkers. Devita, Hellman and Rosenbergs cancer principles and practice of oncology. 9 th
edition. Page 694-701.
7. Hayes DF, Bast RC, Desch CE, et al. Tumor marker utility grading system: a framework to evaluate clinical utility
of tumor markers. J Natl Cancer Inst 1996;88:1456.

Breast Conservation Surgery

Harit Chaturvedi

Although radical and modified radical mastectomy (MRM) werethe historical mainstays of the treatment of Stage I
and IIbreast cancer for decades and MRM continues to be appropriatefor some patients, breast conservation
therapy (BCT) is now well established asoncologically safe treatment for primary breast cancer, andin fact has
1
been deemed the preferable surgical option in a1991 National Cancer Institute (NCI) position statement
onmanagement of early-stage disease. This consensus was reachedafter the completion of several prospective,
randomized clinicaltrials confirming survival equivalence in breast cancer patientsrandomly assigned to receive
BCT versus mastectomy. Follow-upas long as 20 years has been reported as well as ameta-analysis of all
trials2,with stability of the outcomeresults.. Local recurrence after breast preservation may be due to
inappropriatepatient selection, inadequate surgery or radiation therapy,or biologically aggressive disease.
Inadequate surgery may havecontributed to the increased risk of breast recurrence in theNCI and the EORTC
trials. Overall, the incidence of a recurrencein the treated breast ranges from 3 to 20 percent 2,3,4,5,6,7 .The
majority of failures in the treated breast can be salvagedwith mastectomy, and survival following such treatment
is approximately70 percent at five years. Primarymastectomy does not guarantee freedom from local
recurrencein Stage I and II breast cancer. The incidence of chest wallrecurrence ranges from 4 to 14 percent.

Four critical elements in patient selectionfor breast conservation treatment are:


History and physicalexamination.
Mammography and assessment techniques
Histological assessment of theresected breast specimen.
Assessment of the patientsneeds and expectations.

History and Physical Examination


Much of the information needed to determine a patientssuitability for breast conservation therapy can be
obtainedfrom a detailed history and physical examination. It is importantto note that age per se, whether young or
old, is not a contraindicationto breast conservation. In the elderly, physiologic age andthe presence of comorbid
conditions should be the primary determinantsof local therapy.

Mammographic Evaluation
Recent mammographic evaluation (usually within three months)prior to biopsy or definitive surgery plays an
important rolein establishing the appropriateness of breast conservation treatmentby defining the extent of a
patients disease, the presenceor absence of multicentricity, and other factors that mightinfluence the treatment
decision. It is important for evaluatingthe contralateral breast. Bilateral mammography is requiredfor palpable
lesions as well as nonpalpable lesions that canbe identified only radiographically. Nonpalpable masses
andmicrocalcifications comprise an increasing percentage of carcinomastreated with breast conservation.

The breast tumor should be measured in at least two dimensionson the mammographic views or from the
sonogram during ultrasonography,if it is performed. The size of the tumor should be includedin the
mammographic report. If the tumor is a poorly marginatedmass, approximate dimensions can be given from

80
either the mammogramor the sonogram. The skin of the breast in the area of a massshould be evaluated for
thickening that might signify tumorinvolvement. If the mass is associated with microcalcifications,an assessment
of the extent of the calcifications within andoutside of the mass should be made, including the dimensionsof the
area in which calcifications are located. If one or moreclusters of microcalcifications are the only markers of
thetumor, their location and distribution should be described.For evaluation of masses and microcalcifications,
specializedviews with positioning adapted to the location of the abnormalitymay be helpful. Magnification
mammography and spot compressionare important for characterizing microcalcifications and definingthe margins
of masses. Ipsilateral multifocality (in the samequadrant of the breast) or multicentricity (in different quadrantsof
the breast) may be present and influence the treatment selection.In every instance, when one abnormality is
seen, all areas ofeach breast should be fully evaluated for the presence of additionaldisease.

Using magnificationmammography and ultrasound, patients with tumors suitable forbreast conservation can be
8
identified with at least 95% certaintypreoperatively.

INTEGRATING MEDICAL ADVANCES INTO BCT PROGRAMS

Advanced Breast Imaging and BCT

Breast magnetic resonance imaging (MRI) is increasingly beingused, and has been reported to have
9
sensitivity approaching100% in detecting breast cancer. It is therefore potentiallyvaluable in ruling out
multicentric lesions, defining the extentof a primary breast tumor, and it is now standard-of-care managementin
screening patients with axillary metastases from an occultprimary for breast preservation.10-14 .MRI has also
been reported to be particularly useful in definingextent of invasive lobular cancers, and determining eligibilityof
15
these cases for breast-conserving surgery. Rodenko et al found that MRI-assessment of invasive lobular tumor
size correlatedwith pathology findings in 85% of 20 cases, compared to mammographycorrelation in only 32%;
16
Schelfout et al reported similarsuccess with MRI guidance in cases of invasive lobular carcinoma.

Specialized forms of computed tomography (CT) scanning havebeen developed for breast imaging and are
being used for distinguishingpatients with unicentric disease from those with multicentriclesions in hopes of
17
optimizing the selection of BCT candidates.Uematsu et al reported that use of three-dimensional helicalCT
images to plan lumpectomy volumes resulted in an approximatehalving of the positive margin rate. This
technique has alsobeen reported to improve success with lumpectomies performedfor invasive lobular cancer.

Breast ultrasonography has become a routine adjunct in preoperativebreast cancer imaging, and its
18
applications have been expandedto the intraoperative setting. Henry-Tillman et al reportedthat of 25 breast
19
cancers excised with intraoperative ultrasoundguidance, negative margins were obtained in 92%. Rahusen etal
reported similar success with intraoperative ultrasoundfacilitating lumpectomy performance, and demonstrated its
superiorityover standard wire localization for achieving margin controlin a prospective, randomized study of 49
breast cancer patientsrequiring image-guidance for lumpectomy. A major disadvantageof intraoperative
ultrasound is the requirement for either specializedsurgical training or the availability and flexibility of a
committedradiologist.

Whole-breast ultrasound, isnow being utilized for breast cancer screening in high-riskwomen because of its
advantages in imaging dense tissue. A naturalprogression was therefore to evaluate the known cancer-
containingbreast for multicentric disease. Similar to studies of MRI todetect multicentric disease, whole-breast
ultrasound has beenused to evaluate breast cancer patients prior to definitivesurgery, and reported findings have
influenced therapy in approximately15% of cases.20,21

Genetic Testing for Hereditary Breast Cancer Susceptibility

Approximately 5% to 10% of newly diagnosed breast cancers inthe United States are related to an inherited
germline mutation,most frequently in the BRCA1 and BRCA2 genes. BCT can safely be considered in selected
BRCA mutationcarriers, as long as the patient is counseled regarding theincreased risk of new primary tumors
bilaterally.

Studies have demonstratedsimilarly high rates of new contralateral breast cancers inpatients with BRCA
mutations, averaging four- to five-fold higherthan the rates of new contralateral breast cancer seen in
sporadicbreast cancer cases. This increased incidence of contralateraldisease represents further support for the
impression that thehigh rates of developing new ipsilateral breast tumors afterBCT are related to inherent risk in
the breast tissue as opposedto radiation-induced transformations.

Expanded BCT Eligibility

Neoadjuvant CTX and lumpectomy Preoperative chemotherapy (CTX) is standard management for
patientswith locally advanced breast cancer, resulting in primary tumorresponse rates of approximately 80%,
and progression of diseasein only 2% to 3%.22,23,24 This sequence allows for improvedoperability and provides
an in vivo assessment of chemosensitivity.

81
Several randomized, prospective studies have now been completed which prove the oncologic safety of
neoadjuvant CTXin early-stage as well as locally advanced breast cancer, withthe concurrent demonstration that
tumor downstaging does indeedimprove eligibility for BCT without increasing local recurrencerates.25-35 A
surgical component in the multidisciplinarycare of these patients is essential, as the clinical assessmentof
complete response overestimates the pathologic findings byapproximately three-fold, and local recurrence rates
tend tobe higher when radiation therapy is the only local therapy deliveredafter the neoadjuvant CTX.

Induction CTX is a reasonable and safe treatment approach forpatients with breast cancer of any stage if the
clinician iscertain that chemotherapy would be recommended in the postoperativesetting. The risk of
overtreatment can be minimized by obtainingmultiple diagnostic core biopsy specimens to confirm that alesion is
predominantly invasive, as CTX is clearly inappropriatetherapy for large-volume/palpable DCIS tumors or DCIS
with microinvasion.Patients presenting with multiple tumors or extensive calcificationson initial mammogram
should be counseled that preoperative CTXwill not convert them to BCT eligibility, regardless of theextent of
primary tumor shrinkage. Estimation of treatment responsetends to be more challenging with invasive lobular
cancers aswell.36-37 If the tumor is not associated with any microcalcifications,then a radio-opaque clip should
be inserted (preferably underultrasound guidance) either prior to delivery of the neoadjuvantCTX or within the first
couple of cycles. In the event thatthe patient has a complete clinical response to the preoperativeCTX, this clip
will serve as the target for subsequent mammography-assistedwire localization lumpectomy. Lesions associated
with microcalcificationshave an inherent localization target.
Imaging with ultrasound and/or mammogram can be repeated aftera couple of CTX cycles to evaluate tumor
response. Breast MRI may be a more accurate method ofassessing the extent of residual invasive tumor when
expertisewith this technique is available.

Plans for breast-preserving surgery may proceedif there was no evidence of multicentric disease at
presentationand if the tumor is resectable by lumpectomy after the neoadjuvanttreatment.

BCT for subareolar tumors and Paget's disease Tumors involving the subareolar tissue and/or nipple (eg,
Paget'sdisease of the nipple) have previously been considered relativecontraindications to BCT because of the
need for nipple removal.However, if disease appears to be confined to a central unifocalarea, without diffuse
microcalcifications, and if margin negativitycan be achieved, then performing a central segmentectomy isa
reasonable approach. The patient can undergo elective nipple-areolarreconstruction following completion of
breast irradiation, ifshe so desires.

Lumpectomy for multiple breast tumors Early studies of lumpectomy for patients with multiple tumorsrevealed
rates of local failure in excess of 20%, leading tothis feature being widely considered to represent a
contraindicationto BCT.38,39 The generally accepted approach is thatBCT can be attempted in these cases as
long as the tumors canbe encompassed within a single margin-negative lumpectomy specimen,and with a
cosmetically acceptable volume of residual breasttissue.

Pathological Features Influencing Treatment Choice

A number of pathologic factors have been assessed for theirability to predict an increased risk of recurrence in
the treatedbreast in patients undergoing conservative surgery and radiation.These factors include histologic type
and grade, the presenceor absence of tumor necrosis, vascular or lymphatic invasionor an inflammatory infiltrate,
the presence of DCIS in associationwith an invasive ductal carcinoma, margins of resection, andpathologic nodal
status.

Patients with invasive lobular cancers are candidates for conservativesurgery and radiation, provided that the
tumor is not diffusein the breast and that complete excision with negative marginscan be achieved. Under these
circumstances, there has been noincreased risk of breast recurrence in patients with invasivelobular carcinomas
treated with conservative surgery and radiation. Patients with positive axillary nodes do not have an increasedrisk
of breast recurrence when treated with conservative surgeryand radiation. This is in contrast to
patientsundergoing mastectomy where the number of positive axillarynodes correlates with the incidence of chest
wall recurrence.The diminished risk of breast recurrence in node-positive patientsmay be related to the combined
effects of chemotherapy and/ortamoxifen with radiation in these patients.

Pathologic Evaluation

The excised tissue should be submitted for pathology examinationwith appropriate clinical history and anatomic
site specificationsincluding laterality (right or left breast) and quadrant. Forwide excisions the surgeon
shouldorient the specimen (e.g., superior, medial, and lateral) forthe pathologist with sutures or other markers.
Gross examinationshould document the type of surgical specimen (e.g., excisionalbiopsy, ), the size of the
specimen, the measuredsize of the tumor, and the proximity of the tumor or biopsysite to the margins of excision.
The presence or absence oftumor at the margins of excision is determined by marking themwith India ink or
another suitable technique.

82
Frozen section preparation of tissue obtained from image-guidedneedle biopsies of nonpalpable lesions or
tumors less than 1cm is strongly discouraged. Small foci of invasive carcinomaor microinvasive disease may be
lost or rendered uninterpretableby freezing artifact. In general, frozen sections should beprepared only when
there is sufficient tissue that the finaldiagnosis will not be compromised and when the information isnecessary for
immediate therapeutic decisions.

The pathologist includes certain basic data in each surgicalpathology consultation report because they are of
prognosticimportance or are needed for staging or therapy.
Features that should be included in the surgical pathology consultationreport for invasive carcinoma include:
How the specimen wasreceived (e.g., number of pieces, fixative,orientation).
Thelaterality and quadrant of the excised tissue and the typeofprocedure as specified by the surgeon.
The measured size ofthe tumor (in three dimensions if possible),with verificationby microscopic
examination, particularly forpT1 lesions orthose associated with an EIC.
Histologic type and grade.
The presence or absence of coexistent DCIS or an EIC.
Thepresence or absence of peritumoral vascular or lymphaticinvasion.
The presence or absence of gross or microscopic carcinoma(eitherinvasive carcinoma or DCIS) at the
margins of excision.If tumoris not at the margin, the distance of the tumor orbiopsy sitefrom the margin
should be stated, and the locationof the positiveor close margin (superior, medial, etc.) identified.
The presence and location of micro-calcifications.
Lymphnode status. This should be recorded as the number oflymphnodes found in the specimen and
the number of involvednodes,the size of the largest involved node, and the presenceor absenceof
extension beyond the lymph node capsule.

The presence of a focus of tumor measuring two mm or less withina lymph node identified by routine histologic
examination isdefined as a micrometastasis and is classified as pN1a. Theclinical significance of multiple micro-
metastatic foci is unknown;however, it is recommended that they also be classified as pN1auntil further
information becomes available.

It is important to specify the presence of any special histologictypes of invasive breast cancer (e.g., tubular,
mucinous, papillary),most of which are considered low grade. All ordinary invasivecarcinomas (ductal, no special
type [NST]) should be assigneda histologic grade; some authors recommend grading invasivelobular carcinoma
as well.

The assessment of surgical margins is arguably the most importantaspect in the pathologic evaluation of breast
tumor excisionsin patients being considered for breast conservation. Althoughthe definitions of "positive" and
"negative" margins vary amonginstitutions, microscopic margin involvement appears to be associatedwith an
increased risk of local recurrence and, in most cases,indicates a need for further surgery, such as re-excision
ofthe tumor site.

Determination of estrogen and progesterone receptors is standardfor invasive breast carcinomas. . The results
of ancillary studies (such as steroidreceptor analysis, DNA ploidy, proliferative rate, etc.) areusually reported in
an addendum or supplement to the surgicalpathology report.

Patient Preferences

Perhaps the most difficult aspect of patient evaluation is theassessment of the patients needs and expectations
regardingbreast preservation. The patient and her physician must discussthe benefits and risks of mastectomy
compared with breast conservationtreatment in her individual case, with thoughtful considerationof each. Each
woman must evaluate how her choice of treatmentis likely to affect her sense of disease control, self-
esteem,sexuality, physical functioning, and overall quality of life.A number of factors should be considered:
1. Long-term survival.
2. The possibility and consequences of local recurrence.
3. Psychologicaladjustment (including the fear of cancer recurrence),cosmeticoutcome, sexual adaptation,
and functional competence.

Absolute and Relative Contraindications

In the selection of patients for breast conservation treatmentwith radiation, there are some absolute and relative
contra-indications.

Absolute Contraindications
1. Pregnancy is an absolute contraindication to the use of breastirradiation. However, in many cases, it
may be possible to performbreast-conserving surgery in the third trimester and treat thepatient with
irradiation after delivery.

83
2. Women with two ormore primary tumors in separate quadrantsof the breast or withdiffuse malignant-
appearing microcalci-ficationsare not consideredcandidates for breast conservation treatment.
3. A history ofprior therapeutic irradiation to the breast regionthat wouldrequire retreatment to an
excessively high total-radiationdoseto a significant volume is another absolute contraindication.
4. Persistent positive margins after reasonable surgical attempts.The importance of a single focally positive
microscopic marginneeds further study and may not be an absolute contraindication.

Relative Contraindications
1. A history of collagen vascular disease is a relative contraindicationto breast conser-vation treatment
because published reportsindicate that such patients tolerate irradiation poorly. Most radiation
oncologists will not treat patients with sclerodermaor active lupus erythematosus, considering it an
absolute contraindication.In contrast, rheumatoid arthritis is not a relative or an absolutecontraindication.
2. The presence of multiple gross tumors inthe same quadrant andindeterminate calcifications must be
carefullyassessed forsuitability because studies in this area are notdefinitive.
3. Tumor size is not an absolute contra-indicationto breast conservationtreatment, although there is little
publishedexperience intreating patients with tumor sizes greater thanfour to fivecm. However, a relative
contraindication is thepresence ofa large tumor in a small breast in which an adequateresectionwould
result in significant cosmetic alteration. Inthis circumstance,preoperative chemotherapy should be
considered.
4. Breast size can be a relative contra-indication. Treatmentbyirradiation of women with large or pendulous
breasts is feasibleif reproducibility of patient set-up can be assured and thetechnical capability exists for
greater than or equal to sixMV photon beam irradiation to obtain adequate dose homogeneity.

A family history of breast cancer is not a contraindicationto breast conservation

TECHNICAL ASPECTS OF SURGICAL TREATMENT

When breast conservation treatment is appropriate, the goalsof any surgical procedure on the breast are total
removal ofthe suspicious or known malignant tissue with minimal cosmeticdeformity. These goals apply to either
a diagnostic biopsy ordefinitive local excision prior to radiation therapy. Failureto consider them at all stages may
jeopardize conservation ofthe breast.

In most cases, local anesthesia can be utilized for the biopsy.Frequently, local anesthesia also can be used for
the definitivelocal excision, particularly when it is combined with intravenoussedation in selected patients.

Skin Incision

The placement and performance of the skin incision can be criticalto the quality of cosmesis. Curvilinear skin
incisions followingLangers lines (the natural lines of skin tension) generallyachieve the best cosmetic result .
However, at thethree oclock and nine oclock positions and inthe lower breast, a radial incision may provide a
better result,particularly if skin removal is necessary.

Recommended locations of incisions for performing


breast biopsy. For larger lesions in the lower breast,
particularly when skin must be excised, a radial
incision often results in better cosmesis.

The incision should be over or close to the tumor and of adequatesize to allow the tumor to be removed in one
piece. In the upperinner aspect of the breast, some retraction of the skin maybe necessary to avoid an incision
that may be visible with clothing.Periareolar incisions for lesions in the periphery of the breastare inappropriate.
Excision of a segment of skin rarely is necessary and is undesirablebecause it may alter the position of the nipple
or the inframammarycrease. Preservation of the subcutaneous tissue with separateclosure improves the
cosmetic result. The skin should be closedwith a subcuticular technique.

84
Techniques for Optimizing Success with Lumpectomy and Margin Control

Percutaneous diagnostic needle biopsy Percutaneous needlebiopsies are increasingly being used to
establish a diagnosisof breast cancer, and several studies have demonstratedthat lumpectomies are more likely
to be margin-negative whenthe breast cancer diagnosis has been established via percutaneousneedle biopsy as
opposed to open surgical diagnostic biopsy.Core needle biopsies are more accurate than fine needle
aspirates,and have the advantage of providing adequate tissue for determiningwhether or not the lesion has an
invasive histology. Core needlebiopsies can be done freehand for palpable lesions, or theycan be performed with
stereotactic mammography or ultrasoundguidance for nonpalpable lesions.

Specimen handling and intraoperative margin assessmentDirect communication between the surgeon and
pathologist isthe first step in optimizing margin control. At a minimum, thelumpectomy specimen should be
oriented by the surgeon (whenlogistically feasible, this should be done in the presence ofthe pathologist), and the
tissue margins should be inked (multiple-colorinks may facilitate the orientation of the specimen margins).While
frozen-section analysis of multiple margins is notoriouslytime consuming and inefficient, touch-prep evaluations
are beingincreasingly advocated as a rapid and reliable alternative.

The touch-prep method (also called imprint cytology) is relativelystraight forward, and is based on the premise
that cancer cellsare more adherent to a glass surface than benign cells. Thepathologist touches a microscope
slide against the lumpectomysurface, fixes, and then stains the slide with hematoxylin andeosin. Several surfaces
can be evaluated fairly quickly in thisfashion, and reported results have been very favorable. Coxet al found an
accuracy of 97.3% in use of touch-preps formargin analysis, and Klimberg et al estimated a margin
assessmentsensitivity at 100%.

Breast Tissue Management

The primary lesion should be excised with a rim of grossly normaltissue, avoiding excessive sacrifice of breast
tissue. Verysuperficial tumors in the subareolar area may require excisionof the nipple areolar complex to assure
adequate tumor marginsand to avoid devascularization. (Partial areolar excision withcareful approximation for
small lesions in the immediate subareolararea can provide adequate tissue removal and good cosmesis.)Closure
of the breast tissue may reduce the occurrence of asaucer-like defect, but the overall cosmetic result with
nippleareolar sacrifice will be less than optimal.

Lesions within the substance of the breast should be approachedby incising the overlying breast tissue. A
superior cosmeticeffect is usually achieved when the breast is not reapproximated.Reapproximation that appears
to be adequate with the patientrelaxed and supine often results in distortion of the breastwhen the patient is
upright and mobile.

Meticulous hemostasis is of critical importance. Hematoma formationproduces changes that are difficult to
interpret by physicalexamination. In addition, the evolving scar from a hematomamakes mammography
interpretation difficult. These changes maybe long lasting and lead to unnecessary biopsy because of thedifficulty
in evaluation. Drains in the breast should be avoided.

Specimen orientation by the surgeon with the use of sutures,clips, multicolored indelible ink, or another suitable
techniqueis important. The specimen should not be sectioned before itis submitted to the pathologist, because
this practice may compromiseaccurate evaluation of the surgical margins. The surgeon shouldexamine the
specimen for the determination of a grossly clearmargin. If a clear margin is not evident, re-excision shouldbe
performed at that time. Routine frozen section evaluationof margins is optional and does not guarantee negative
marginsafter a complete examination. Any uncertainty regarding orientationof the specimen should be clarified for
the pathologist by thesurgeon. In addition, clips outlining the breast defect mayaid the planning and execution of
radiation therapy and demarcatethe tumor bed for future imaging studies.

Image-directed Surgery

Nonpalpable carcinoma may be diagnosed by image-directed biopsyor needle localization and excision. If a
patient has a nonpalpablecarcinoma diagnosed by image-guided biopsy, then breast-conservingsurgery should
be conducted with presurgical localization witha guide such as guidewire. This will be facilitated by the
placementof a marker clip when image-guided biopsy is done for smalllesions, which are likely to be completely
removed by the procedure.

Suspicious lesions detected by mammography require presurgicallocalization in order to assure accurate removal
of the abnormalarea and avoid excess sacrifice of breast tissue. The methodsof localization may be by needle-
hookwire, blue dye injection,or a combination of both. The localization should be precise.Labeled craniocaudal
and lateral films that show the hookwireshould be sent to the operating room for the surgeonsorientation. The
surgeon usually should assess the exact locationby triangulation based on the position, depth of penetration,and
angle of the wire and place the incision closest to thetip of the wire in order to achieve the best cosmetic
result.Tunneling should be avoided, and attempts should be made tomake the skin incision as close to the lesion

85
as possible The same principles of skin incision and breast tissue managementused for palpable cancers
should be employed.

Incision placement for needle localization biopsy should be over the


lesion, not at the point of entry of the wire into the breast.

The breast tissue is dissected until the wire is identified within the
parenchyma, and then the wire is stabilized distally and brought into
the field. Traction on the wire should be avoided at all times.

Localization titanium clips may be left in the excision cavityto aid in placement of irradiation boost volume and to
ensureadequate coverage with tangential fields, especially for lateraland medial lesions.

Specimen Radiograph

A radiograph of the specimen should be obtained, preferablyin two dimensions (orthogonal projections).
Magnification andcompression of the specimen will increase the resolution ofthe radiograph. The specimen film
should be correlated witha preoperative mammogram and interpreted without delay. Theradiologists report
should indicate whether the mammographicabnormality (mass or calcifications) is seen in the specimenand if it
has been removed completely, as far as can be determined.

Re-excision of Biopsy Site

Re-excision of the previous biopsy site to assure negative marginsof resection must be carefully performed in
order to accomplishthis goal, to avoid excess breast tissue removal and to achievegood cosmesis. Proper
orientation of the original biopsy specimen(for example, short suture in the superior margin, long suturein the
lateral margin) will allow identification of the individualmargin surfaces involved with tumor. Re-excision can be
limitedto those areas. When the specimen has not been oriented, removalof a rim of tissue around the entire
previous biopsy is necessary.

For larger biopsy cavities, shaving of each individual margin,with marking of the new margin surface with sutures,
clips,or ink allows removal of residual tumor with preservation ofa maximum amount of breast tissue. For very
small cavities,removal of the entire biopsy site as an en bloc specimen isacceptable.

Management of the Axillary Nodes

Axillary dissection is the standard technique for managementof the axillary nodes. A Level I and II axillary
dissectionwill provide accurate staging information and maintain localcontrol in the axilla. In the patient
undergoing mastectomy,axillary dissection should be performed through the mastectomyellipse. In the patient
undergoing breast conservation, thebreast incision and the axillary incision should be separate.A continuous
incision from the breast to the axilla resultsin unnecessary deformity. Occasionally, a tumor in the axillarytail can

86
be removed through the same incision used to removethe axillary nodes. A transverse incision in the low
axillafrom just posterior to the border of the pectoralis major tonearly the anterior border of the latissimus dorsi
obtains anexcellent cosmetic result and excellent exposure. Some surgeonsprefer a vertical incision posterior
and parallel to the borderof the pectoralis major, which also provides good exposure andcosmetically good
results. During dissection, the long thoracicnerve, the thoracodorsal nerve, and the medial pectoral nerveshould
be preserved. Preservation of the intercostal brachiocutaneousnerve is desirable, as numbness of the posterior
upper arm isless likely to occur with nerve preservation. At times, preservationof this nerve should not be
performed because of grossly involvedlymph nodes. Stripping of the axillary vein is unnecessary andshould be
condemned because it increases the incidence of lymphedema.Usually, closed suction drainage is advisable.

Sentinel node biopsy :

Sentinel node dissection is indicated for small primary tumorswith clinically negative axillary lymph nodes and no
prior axillarysurgery. Pregnancy or multicentric carcinomas are contraindications.Experience with the technique
after neoadjuvant chemotherapyis limited and the available studies suggest a high false-negativerate. Sentinel
node dissection in this circumstance should beconsidered investigational and be performed only under
investigationalprotocols.
For patients who require preoperative chemotherapy, sentinelnode biopsy can be performed prior to the initiation
of chemotherapy.In general, patients with metastases in sentinel nodes detectedin hematoxylin and eosin-stained
sections should undergo completeLevel I and II axillary dissection. Immunohistochemistry shouldnot be routinely
performed, as the significance of metastasesin sentinel nodes detected only by immunohistochemistry remainsto
be determined. Therapeutic decisions should be made on thebasis of metastases identified by hematoxylin and
eosin staining.

In experienced hands, this sentinel node dissection has beenshown to be extremely accurate in predicting
axillary statusand is likely to replace axillary lymph node dissection forwomen with tumor-free sentinel nodes.
Experience with this techniqueprior to abandoning axillary lymph node dissection is essential.Surgeons should
perform both sentinel node biopsy and axillarylymph node dissection until they are confident that the
procedurecan be performed with identification of sentinel nodes in atleast 90 percent of patients with a false-
negative rate of 10percent or less. For most surgeons, this requires 20 to 30 sentinelnode biopsies followed by
axillary dissections to determinean individual surgeons technical accuracy.40,41 LevelI and II axillary lymph
node dissection should be performedas standard therapy.

Sentinel node biopsy usually results in minimal morbidity; however,rehabilitation after axillary lymph node
dissection or sentinelnode biopsy is essential. Usually, patients after sentinel nodebiopsy require no formal
exercise to return to full function.Patients after axillary dissection should be given formal exercisetraining to
prevent a frozen shoulder. Use of shoulder immobilizationand arm slings or wraps should be avoided, as these
contributeto a frozen shoulder. If a patient does not achieve early recoveryof full shoulder function (by six to eight
weeks), physicaltherapy should be instituted to avoid permanent dysfunction.

ONCOPLASTIC SURGERY

Oncoplastic procedures often permit wide resection of tissue which increases the chance of tumour-free margins.
Furthermore, positive margins under these circumstances usually reflect extensive disease for which mastectomy
(rather than re-excision) is indicated. It has been suggested that the chance of local relapse could be reduced by
more aggressive approaches to BCS but there are currently no data on longer-term follow-up of these
oncoplastic procedures. Moreover, there is no information from clinical trials on the safety of BCS for invasive
tumours in excess of 4 cm . Though margin status and the presence or absence of an extensive in
situ component are the principle determinants of local recurrence, consistent associations have been found for
tumours >2 cm . For node-positive patients, tumour size exceeding 5 cm was the only risk factor for local
recurrence on multivariate analysis .Therefore, it is likely that the risk of relapse would remain high for larger
tumours despite adequate surgical clearance. Nonetheless, it may be possible to excise large areas of non-high-
grade ductal carcinoma in situ (DCIS; >4 cm) with clear margins and partially reconstruct the breast with
autologous tissue replacement. Age less than 35 years and family history of breast cancer are additional factors
that must be considered when selecting patients for either oncoplastic surgery with a high EPBVE or skin-sparing
mastectomy with whole-breast reconstruction (higher risk of local recurrence or de novo cancer risk). Though it
may not be feasible in routine clinical practice to formally estimate the EPBVE from radiological measurements of
tumour and breast size, magnetic resonance imaging assessment of all patients is advisable. This can confirm
unifocality or exclude multifocal disease involving different quadrants. Where imaging is equivocal and tumour
parameters are borderline for BCS, it may be preferable to undertake a two-stage procedure; initial 'wide' local
excision of tumour permits full histopathological evaluation with assessment of margins. A definitive oncoplastic
procedure can subsequently be carried out either 2-3 weeks later or following radiotherapy to the breast. A one-
stage procedure is optimal and avoids any technical difficulties relating to the sequelae of previous surgery and
radiotherapy (scarring, fibrosis). There are less likely to be problems with skin viability when completion
mastectomy is undertaken after simple excision of tumour compared with a more complex oncoplastic procedure
with parenchymal undermining and transposition.

87
There is a higher chance of wound infection and fat necrosis in patients who smoke, are obese (body mass index
>30), have large breasts or are diabetic, and these potential complications and their effect on further oncological
treatment should be fully discussed with the patient.

Techniques of oncoplastic surgery

Oncoplastic surgery in the context of partial breast reconstruction encompasses both volume replacement and
volume displacement techniques. The former import additional tissue in the form of a flap and attempt to
compensate for loss of volume from surgical ablation. By contrast, the latter rearrange the remaining breast
tissue using methods of glandular advancement which serve to re-distribute the parenchyma and minimise the
impact of wide local excision. In effect, the volume loss is absorbed over a wider area with concomitant re-
shaping of the breast. Volume displacement surgery is less extensive than for autologous tissue transfer and
there is no donor site morbidity. However, the reconstructed breast is of smaller overall volume and a
symmetrisation procedure on the contralateral side is often required. This applies particularly to therapeutic
mammoplasty where tumour excision is incorporated into a standard or modified reductional procedure.

Volume displacement represents the simplest option for partial breast reconstruction and is usually preferred over
techniques for volume replacement which involve more extensive surgery with harvesting of a myocutaneous or
subcutaneous flap. These flaps cannot subsequently be used for whole-breast reconstruction should the patient
develop local recurrence and require mastectomy. Volume displacement techniques are only possible in patients
with medium to large breasts, whereas replacement techniques are suited to small breasted women. The choice
of method is determined by both the breast volume and the size of the surgical cavity for infill.

Volume replacement techniques

The majority of these techniques use the latissimus dorsi muscle which can be harvested as either a
myocutaneous or myosubcutaneous flap . . The former incorporates an island of overlying skin which can be
used to replace any excised breast cutis. The benefit of partial breast reconstruction with volume replacement
in terms of both cosmesis and patient satisfaction was most evident for patients with small breasts. Three-
quarters of these women were judged to have excellent cosmetic results on combined subjective and objective
assessment compared to none of those with large breasts who underwent a similar method of volume
replacement.

Rainsbury's group described a modified version of the latissimus dorsi (LD) musculosubcutaneous flap which is
popularly known as the 'LD mini-flap' .The LD muscle was harvested with a laterally placed lazy-S
incision through which resection of breast and axillary tissue was simultaneously performed. No skin overlying
the LD muscle was removed, though subcutaneous fat could be employed to enhance tissue bulk if necessary.
The technique is best suited to tumours in the superior and central (2 cm deep to nipple) aspects of the breast .
Tumour bed biopsies with frozen section can reduce the chance of positive margins and permit immediate
mastectomy if a second set of biopsies after routine cavity re-excision are also positive.

Dixon and colleagues incorporated the LD mini-flap into a two-stage procedure with a 'delayed-immediate'
axillary dissection and partial breast reconstruction 5-10 days after initial tumour excision. Where re-excision was
indicated, this was performed at the same time and the flap harvested through an extended axillary incision .

The volume of tissue within a typical latissimus dorsi musculosubcutaneous flap is usually sufficient for partial
breast reconstruction, but adequate mobilisation is required to ensure there is an optimal length of muscle. It is
generally difficult to use an LD flap for volume replacement within the inferior quadrants of the breast. There is no
evidence for any significant atrophy with time and these radiolucent flaps do not interfere with follow-up imaging
of the ipsilateral breast. Variants of this basic flap have been reported which aim to reduce muscle disruption and
hence donor site morbidity.
thoraco-dorsal artery perforator (TDAP) flap--this pedicled flap harvests only the skin or
subcutaneous fat overlying the LD muscle;
intercostals artery perforator (ICAP) flap--the skin or fat overlying the lateral chest wall can
alternatively be supported by the intercostals artery perforator vessels;
muscle-sparing latissimus dorsi flap--this is mainly composed of subcutaneous adipose tissue.

Volume displacement techniques

Several options are available for volume displacement which constitutes a spectrum of techniques of varying
complexity . The common aim of volume displacement is to utilise the remaining breast tissue to fill the defect
resulting from extirpation of the tumour. As previously discussed, resections which lead to loss of >10-20% of
breast volume are likely to incur significant cosmetic detriment and to demand some form of 'infill' to create an
acceptable cosmetic outcome in the longer term. Displacement techniques re-shape the breast through
advancement, rotation or transposition of existing parenchyma and skin with a resultant decrease in overall
breast volume.

88
Simple breast tissue mobilisation

The cosmetic outcome after removal of a relatively small volume of tissue can be enhanced by simple
mobilisation of breast tissue adjacent to the surgical cavity. The extent of this mobilisation depends on the size of
the defect and may involve undermining the whole breast plate . Extensive mobilisation of breast tissue can
sometimes threaten the blood supply to both glandular tissue and skin. This can lead to post-operative necrosis
and secondary sepsis or can compromise flap viability in the event of future mastectomy.

Local tissue flaps

Grisotti described an advancement rotation flap for filling a central defect after removal of the nipple-areola
complex .This is a dermatoglandula flap based on an inferior pedicle and has a skin paddle which replaces the
nipple-areola complex and can be used to fashion a new areola immediately.

Breast reduction techniques and therapeutic mammoplasty

Over the past decade, several reports have emerged describing integration of local tumour excision with a
classical reduction mammoplasty procedure. Most of these cases involve patients with relatively large breasts
and/or who desire smaller breasts and have a tumour located in the zone of resection for a conventional Wise
pattern reduction mammoplasty [27-29]. This includes inferior pole tumours from the 3 to 9 o'clock positions
together with tumours immediately above the nipple-areola complex in medium to large breasts.

Informed consent

Both volume displacement and replacement techniques represent more complex and challenging surgery than
standard wide local excision where a variable amount of breast tissue is removed, but no formal attempt is made
to reconstruct the breast. Patients must be aware of the pattern of scarring which may be more extensive than
anticipated for a reductional procedure. Moreover, patients must be informed of any need for surgery to the
contralateral breast to achieve symmetrisation and the possibility of completion mastectomy in the event of
incomplete tumour excision. The latter may be particularly traumatic after bilateral oncoplastic surgery and the
patient will be faced with the prospect of whole-breast reconstruction. A woman may chose to have a normal-
sized breast with a localised defect rather than a nicely shaped, but smaller breast with concomitant scarring and
a contralateral breast reduction. Conversely, she may opt for a mastectomy with immediate breast reconstruction
rather than an attempt at breast conservation with oncoplastic techniques in order to minimise any chances of
recurrence or to avoid radiotherapy. Patients should be warned of possible delays to adjuvant treatment in the
event of any complications and be made aware of fat necrosis which can give rise to a worrisome lump in the
breast. Where volume replacement techniques are employed, significant donor site morbidity can occur with
seroma formation and even wound dehiscence.

TECHNIQUES OF IRRADIATION

A multidisciplinary approach is necessary for optimal breastconservation treatment. Radiation therapy should be
deliveredonly after evaluation of the mammography findings, the pathologyfindings, and the surgical procedures
performed on the patient.The optimal combination of surgery and irradiation to achievethe dual objectives of local
tumor control and preservationof cosmetic appearance varies from patient to patient. The optimalcombination is
determined by the extent, nature, and locationof the tumor, the patients breast size, and the patientsrelative
concerns about local recurrence and preservation ofcosmetic appearance. Close cooperation between radiation
oncologistsand medical oncologists also is important because irradiationand adjuvant chemotherapy require
integration if both treatmentmodalities are used.
Although controversy has existed concerning the need for deliveringan additional boost dose to the primary site,
,
thereis growing consensus about its utility Most recently,the EORTC has reported the favorable impact of boost
on localfailure rates.

FOLLOW-UP CARE

Follow-up assessment of the results of breast conservation treatmentemphasizes the cosmetic outcome as well
as the detection oflocal recurrence. Regular follow-up examination includes thefollowing goals:
1. Early detection of recurrent or new cancer,allowing timelyintervention.
2. Identification of any treatmentsequelae and appropriate interventionswhere indicated.
3. Providingthe individual practice with the database necessaryto optimizetreatment and compare
outcomes against nationalstandards.

Regular history and physical examination in conjunction withbreast imaging are the cornerstones of effective
follow-up care.Unfortunately, many patients perceive history and physical examinationto be less important as
reliable follow-up measures than sophisticatedmedical testing. A public education effort is needed to addressthis
problem.

89
The following evaluations should be performed by the physicianat cited intervals following the completion of
treatment:

Examinations and Mammography

History and Physical Examination

Local failure occurs at a constant rate from years two througheight post-treatment; therefore, examination
frequency shouldbe based on risk factors for both local and distant recurrence.

EXAMINATION FREQUENCY
Every three to six months, years one to three. This will varyfor patients receiving adjuvant chemotherapy
who need more frequentassessment during the course of their active treatment.
Everysix months, years four and five. Some investigators prefertocontinue semiannual examinations
through year eight becausethe rate of local recurrence is constant through that time interval.
Annually after year five. More frequent follow-up for patientsat exceptionally high risk may be needed.

Mammography

A goal of follow-up imaging of the treated breast is the earlyrecognition of tumor recurrence. To prevent
unnecessary biopsy,it is important to know that postoperative and irradiation changesoverlap with signs of
malignancy on a mammogram. The changesinclude masses (postoperative fluid collections and
scarring),edema, skin thickening, and calcifications. At times, these changes may be impossible to
distinguish. Post-surgicaland radiation edema, skin thickening, and postoperative fluidcollections will be
most marked in the first six months. Afterthe first six to 12 months, radiographic changes will slowlyresolve
and demonstrate stability within two years for mostpatients.

In order to interpret mammograms accurately and assess the directionof change, the current mammogram
must be compared in sequencewith preceding studies. The diagnostic radiologist can tailormammographic
studies of the treated breast to the surgical siteby using special mammographic views in addition to routine
mediolateraloblique and craniocaudal views. Magnification and spot compressioncan be used with any view
to increase detailed visualizationof the site of tumor excision and other areas. Magnificationmammography
is useful to classify calcifications morphologicallyand quantitate them. In some cases, a view with the x-ray
beamtangential to the scar and various other additional obliquitieswill be helpful to differentiate recurrent
tumor from postproceduralchanges.

Ultrasonography can characterize a postoperative mass, suchas a seroma, as fluid-filled rather than solid.
As these massesresolve and scars form; a spiculated soft-tissue density thatmimics tumor may be seen on
the mammogram. Additional radiographicprojections of the site of tumor removal will facilitate moreconfident
radiographic interpretations.

SCHEDULE OF IMAGING OF THE TREATED BREAST

1. Postoperative, pre-radiation therapy mam-mography is particularlyimportant after malignant


microcalcifications have been removedor if the adequacy of the resection is questioned.
Magnificationmammography can be useful in identifying or verifying possibleresidual malignant
calcifications.
2. A baseline mammogram forcomparison should be performed sixto nine months after tumorexcision and
completion of all therapies.
3. At least annuallythereafter or at more frequent intervals aswarranted by clinicalor radiographic findings.

SCHEDULE OF IMAGING OF THE CONTRALATERAL BREAST

Mammography should be performed annually according to the guidelinesendorsed by both the AmericanCollege
of Radiology and the AmericanCancer Society and with synchronization of surveillance mammographyof the
treated breast. More frequent intervals may be warrantedby clinical or radiographic findings. (The risk of cancer
isapproximately the same for both the treated and untreated breast.)

Evaluation of Sequelae

At the time of the first follow-up examination and seriallythereafter, the physician should evaluate the patient for
anytreatment-related toxicities. This evaluation should include:
1. Assessment of the overall cosmetic result. A four-point scoringsystem is recom-mended for
assessing the cosmetic result .

90
2. Assessment of complications. Complications should be specifiedwith regard to symptomatology and
physical findings. The useof the Radiation Therapy Oncology Group (RTOG)/EORTC RadiationToxicity
Scoring Scheme is recommended for the grading of complications.
In addition, the simple measurement of arm circumference atfixed distances above and below the
olecranon is recommendedfor the evaluation and quantification of arm edema.
3. Patientevaluation of results. The patients evaluationof treatmentoutcomes in terms of psychological,
functional,and cosmeticconsequences should be taken into account in thefollow-up process.

Four-point Scoring System of Breast Cosmesis


Excellent
Treated breast almost identical to untreated breast.
Good
Minimaldifference between the treated and untreated breasts.
Fair
Obvious difference between the treated and untreated breasts.
Poor
Major functional and esthetic sequelae in the treated breast.

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17. Uematsu T, Sano M, Homma K, et al: Value of three-dimensional helical CT image-guided planning for made-to-
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surgical volume analysis. J Am Coll Surg 2001;193:593600

Locally Advanced Breast Cancer

P.N. Agarwal, Vivek Wadhawa

Locally advanced breast cancer (LABC) is defined by bulky primary breast tumors and/or extensive adenopathy.
This includes patients with T3 (>5 cm) or T4 tumors (chest wall fixation or skin ulceration and/or satellitosis) and
[1]
N2/N3 disease (matted axillary and/or internal mammary metastases) . Recent studies demonstrate that
prolonged survival can be achieved in patients with metastatic disease limited to the supraclavicular nodes after
[1], [2]
appropriate multimodality breast cancer treatment . As a result, American Joint Committee on Cancer
(AJCC) staging system now includes isolated supraclavicular metastases in the stage III/LABC disease category
[2]
. Five-year survival for stage III breast cancer is approximately 50%, compared with 87% for stage I. In India
60% of breast cancer present as LABC.

Diagnosis

Tissue Diagnosis

Establishing a tissue diagnosis is the initial priority on presentation of LABC. In many patients, core biopsy of the
tumor, either freehand or under ultrasound guidance, is diagnostic. Core needle is preferred over fine needle
aspiration, as cytology is insufficient to confirm lymphovascular invasion. Additionally, multiple cores should be
extracted both to confirm invasive cancer and to evaluate hormone receptor status and HER2/neu expression. A
negative or nondiagnostic needle biopsy with a clinically suspicious lesion is an indication to proceed to
diagnostic open biopsy; cases characterized by skin involvement may be amenable to punch biopsy. If matted,
fixed, axillary, or supraclavicular adenopathy is present, fine needle aspiration of the nodes should be performed
for staging.

92
Bilateral mammography

Prompt bilateral mammography in this setting is essential (except in known contraindications of BCT e.g.
inflammatory breast cancer, ulcerative lesions), regardless of patient age and date of her most recent study.
Diffuse, suspicious microcalcifications or multiple lesions in different quadrants indicate multicentric disease, and
[14]
are a contraindication to breast conservation therapy (BCT) . If BCT is a consideration, a microclip placed at the
primary tumor (biopsy site), under mammographic or ultrasound guidance, is essential before the initiation of
induction therapy, unless the primary tumor is associated with a cluster of microcalcifications. Up to 50% of
patients may have a complete clinical response, and an unmarked primary site eliminates the possibility of breast
preservation in these cases, as the lumpectomy site will no longer be adequately defined.

Breast and axillary ultrasound

Breast and axillary ultrasound frequently yield valuable information regarding the extent of disease. In particular,
[15], [16]
axillary ultrasound can be used for image-guided FNA ; ultrasound detection of apical axillary/infraclavicular
[17]
nodal metastases has been shown to provide important prognostic information . Unfortunately, ultrasound has
an approximately 20% false-negative rate, as metastases smaller than 5 mm in size are undetectable.

Metastatic Work up

A baseline bone scan, abdominal, pelvic and chest CT scans are recommended for detection of metastatic
disease. Directed radiographs to sites of new bone pain, or a head CT scan for new neurologic symptoms are
also appropriate in selected cases. The yield of a metastatic work-up in an asymptomatic, early breast cancer
[18]
patient is approximately 2% to 3%, but this risk rises to 30% in LABC . The most common sites of metastasis is
bones followed by lung, liver amd brain. The metastasis to bones may be osteoblastic or osteoclastic.

Therapeutic management

Neoadjuvant chemotherapy

Currently, optimal control is achieved with preoperative chemotherapy followed by surgery and radiation.
Preoperative versus postoperative chemotherapy have been directly compared in women with LABC and also in
women with early stage breast cancer. These prospective clinical trials have demonstrated overall survival
[6], [7], [8], [9], [10], [11],
equivalence for the two sequences, confirming the oncologic safety of the neoadjuvant approach
[12], [13]
. Since patients with LABC benefit from the tumor downstaging and improved resectability that can be
achieved with neoadjuvant chemotherapy, this sequence has become the preferred approach for patients with
bulky, locally advanced disease at time of diagnosis. Neoadjuvant chemotherapy offers several advantages
compared with traditional postoperative regimens. Invasive breast cancer patients have a significant risk of
harboring occult micrometastatic disease in distant organs.

Neoadjuvant chemotherapy allows for earlier exposure of these micrometastases to chemotherapeutic agents,
and an observed response to chemotherapy in the primary breast disease site indicates that the regimen has
effective antitumor activity.

Patients receiving preoperative chemotherapy should be reassessed after one or two cycles and again at the
completion of therapy to document response and explore surgical options. Repeat imaging may be useful at the
interim evaluation. If minimal or no response is observed after the initial cycles, a decision should be made to
either proceed with surgery or to cross over to a different systemic therapy. Surgery allows for a full pathologic
evaluation, facilitating decisions on adjuvant therapy. If an alternative regimen is selected, then reassessment
after two cycles of the crossover treatment is necessary. Follow-up imaging is essential after complete delivery of
neoadjuvant therapy for final preoperative surgical planning. Occasional patients that appeared to have a
unicentric cancer density at presentation will experience unmasking of extensive microcalcifications or
multicentric satellite tumors after chemotherapy response, and these findings may convert them to mandatory
mastectomy cases.

Subset analyses of the phase III studies reveal that patients who have a complete pathologic response (pCR)
have a statistically significant survival benefit, substantiating the concept that primary tumor response is a reliable
[4]
surrogate for chemotherapy effect on micrometastases. In the NSABP B-18 trial , patients with stage I to III
breast cancer randomized to receive preoperative doxorubicin and Cyclophosphamide and who experienced a
pCR had a 5-year overall survival of 86%, statistically superior to the outcome seen in all other study participants.
Predictors of a pCR include relatively smaller size primary breast tumors, estrogen receptor negativity, and high-
[5]
grade lesions .

Neoadjuvant chemotherapy regimen

Currently, doxorubicin-based chemotherapy is the most widely-studied induction regimen, and it results in at least
50% tumor shrinkage in more than 75% of cases. The NSABP B-27(1995-2000) protocol randomized patients

93
with resectable breast cancer to one of three neoadjuvant treatment arms: (1) doxorubicin and cyclophosphamide
alone; (2) doxorubicin, cyclophosphamide, and docetaxel; or (3) preoperative doxorubicin and cyclophosphamide
[23]
followed by postoperative docetaxel. Preliminary data reveal a pCR rate of 26% associated with the addition
of docetaxel to the preoperative regimen. Similarly, the University of Texas M.D. Anderson Cancer Center(2000)
[24]
has reported a pCR rate of nearly 30% in patients treated with preoperative doxorubicin, Cytoxan, 5-
fluorouracil, and weekly Taxol.

The Aberdeen trial(1996-1999) investigated whether the number of chemotherapy cycles is a stronger predictor
[25], [26]
of tumor response compared with chemotherapy type , demonstrating that the nature of the agent is more
important than the quantity. They also showed that poor responders may benefit from crossover to an alternative
regimen. Survival analyses at 3 years also suggest improved outcomes for patients on docetaxel plus
[26]
doxorubicin . Other neoadjuvant regimens currently being evaluated include trastuzumab, Navelbine,
capecitabine, and gemcitabine. Microarray technology and gene expression profiling are also being explored to
[29]
optimize selection of neoadjuvant therapy . In neoadjuvant chemotherapy all the cycles are given prior to
surgery but depending on the response surgery may be considered early and completion chemotherapy given
postoperatively There has been many combinations and schedule for chemotherapy a few recommended are
mentionedas follows.

FAC 5-FU 500mg/sqm IV day 1 and 8 Doxorubicin 50mg/sqm IV day Cyclophosphamide 500mg/sqm IV
day 1 Cycled every 21 days for 6 cycles
AC Doxorubicin 60mg/sqm IV day 1 Cyclophosphamide 600mg/sqm IV day 1 Cycled every 21 days for 4
cycles
AC followed by paclitaxel Doxorubicin 60mg/sqm IV day 1 Cyclophosphamide 600mg/sqm IV day 1
Cycled every 21 days for 4 cycles followed by paclitaxel 175mg/sqm 3hr IV infusion day 1 Cycled every
21 days for 4 cycles.

Neoadjuvant endocrine therapy

Neoadjuvant endocrine therapy for estrogen receptor-positive LABC also holds great promise. Three-to-four
months of therapy are preferred for an adequate response assessment, and preliminary studies suggest that
[27], [28]
aromatase inhibitors such as letrozole are more effective than tamoxifen . Presently it is always combined
with neoadjuvant chemotherapy

Monitoring response to neoadjuvant chemotherapy

A significant response to the primary chemotherapy regimen is observed in about 80% of cases; however,
accurate prediction of a pCR is challenging. Conventional modalities for assessing chemotherapy response,
including clinical examination, mammogram, and breast ultrasound, are incorrect in identifying pCR patients in
[3], [30]
nearly half of cases. The addition of imaging is clearly more useful than physical examination alone . Breast
[31], [32] [33] [34], [35]
MRI , positron emission tomography , and nuclear medicine sestamibi uptake scans have been
reported in small series as monitoring strategies with encouraging results but not yet routinely recommended.

Surgical : Breast conservation therapy and mastectomy

Treatment of the primary tumor is surgical. Treatment of the remainder of the breast tissue for control of occult
disease can be accomplished by either surgery or irradiation. The magnitude of the clinical response(i.e.
downstaging of tumour) to neoadjuvant chemotherapy in LABC prompted investigations of breast conservation
[19]
for selected patients. Singletary and colleagues conducted a feasibility study to evaluate the pathologic extent
of residual disease in 136 LABC patients treated with induction chemotherapy. Extensive scrutiny of the
postchemotherapy mastectomy specimens revealed that the residual tumor would have been amenable to
lumpectomy in approximately 25% of patients.
[11]
From this and other studies , several criteria for BCT in postneoadjuvant LABC have been adopted widely:
Patient desire for breast preservation
Absence of multicentric disease (tumors in different quadrants of the breast)
Absence of diffuse microcalcifications on mammogram
Absence of skin involvement consistent with inflammatory breast cancer
Residual tumor mass amenable to a margin-negative lumpectomy resection

Prospective, randomized controlled clinical trial data have confirmed acceptable rates of local control among
LABC patients undergoing breast-conserving surgery after neoadjuvant therapy. Several prospective,
randomized controlled trials of neoadjuvant versus adjuvant/postoperative chemotherapy have included cohorts
of patients with Stage III disease/LABC. Data from these studies have documented acceptably low rates of local
[20], [21]
recurrence in LABC patients undergoing breast-conserving surgery after neoadjuvant chemotherapy . The
NSABP B-18 investigators did note a trend toward higher local recurrence rates among patients requiring
preoperative downstaging in order to become lumpectomy eligible (15% versus 7% which is statistically
significant). This is not necessarily surprising, however, as postlumpectomy local recurrence is one manifestation

94
of aggressive tumor biology, and larger tumors are more likely to demonstrate aggressive behavior, even after
mastectomy. The margin for lumpectomy is kept at 1-1.5cmfrom postchemotherapy tumor edge. Postmastectomy
[22].
radiation (PMRT) is recommended for patients with T3 tumors because of this concept . Although women with
breast cancer are approached with the intention of offering breast-conserving therapy, there are situations in
which that is not possible. Contraindications to breast-conservation treatment include (1) presence of two or more
primary tumors in separate areas of the breast, (2) diffuse malignant-appearing microcalcifications, or (3) a
history of prior therapeutic irradiation to the breast that precludes full-breast irradiation for the present condition,
(4) Active collagen vascular disease. For women who are not well treated by breast-conserving therapy,
mastectomy is recommended.

Management of Regional Lymph Nodes

Today axillary lymph node metastases are considered a regional manifestation of metastatic breast cancer.
Axillary lymph nodes that are suspicious by palpation for tumor can be evaluated by FNA cytologic examination
when results will affect the order of therapeutic interventions. If axillary lymph nodes are matted or fixed (N2), the
disease has advanced beyond "early" breast cancer. When mobile axillary lymph nodes contain tumor, an axillary
dissection provides excellent local control of this axillary disease.This is only the surgical aspect of such control,
and there is a role for radiation and systemic therapy as well in controlling disease in the axilla. The primary
indication for axillary surgery today is the provision of pathologic staging. If the axillary lymph nodes are involved,
their removal accomplishes both goals: defining prognosis and diminishing the risk of subsequent axillary
recurrence. Presently, Axillary dissection is preferred modality for treatment of axillary lymph node in LABC.

Breast reconstruction

LABC traditionally has been perceived as a contraindication to immediate breast reconstruction (IBR), because of
concerns regarding adjuvant treatment delays and the cosmetic effects of PMRT to breast reconstruction.
[36]
Newman and colleagues noticed slightly prolonged interval for adjuvant chemotherapy among reconstructed
patients; this did not affect recurrence rates. IBR with implants, however, was associated with more radiation-
related complications; nearly half of the irradiated patients developed contractures or recurrent infections,
necessitating implant removal. Delayed reconstruction is therefore, usually preferred in LABC patients
undergoing mastectomy, because of the substantial likelihood that PMRT will be necessary, and the potential
damaging effects of radiating the reconstructed breast. Occasionally, LABC patients will require soft tissue
coverage of an extensive chest wall defect at mastectomy. In these cases, a latissimus dorsi flap is the most
common approach, as this flap is a technically straightforward and provides durable, radiation-tolerant coverage.
Breast reconstruction after local failure in the irradiated breast presents a unique challenge for the oncologic and
the reconstructive surgeon. The late effects of radiation are characterized clinically by a loss of skin elasticity,
fibrosis, and decreased blood supply. In a series of 680 consecutive patients who underwent TRAM flap breast
reconstruction, 108 had had previous irradiation, and no difference was found in flap survival in the two groups
[40]
.

Locoregional irradiation

The American Society of Clinical Oncology recommends PMRT for all patients who have four or more metastatic
axillary lymph nodes based upon axillary surgical findings at presentation (without neoadjuvant chemotherapy),
[37]
and that PMRT should be considered for all cases of LABC .

Patients who have at least four metastatic lymph nodes or 5 cm of residual disease in the breast after
chemotherapy clearly benefit from locoregional irradiation, and all lumpectomy patients require breast irradiation.
A conservative (and aggressive) approach would be to recommend radiation to all patients that present with
LABC, regardless of chemotherapy response. However, patients with little or no residual breast/axillary disease
after chemotherapy may not derive a significant benefit from regional nodal irradiation. Existing data are limited
regarding whether or not comprehensive irradiation is absolutely necessary to achieve optimal locoregional
control of disease in patients presenting with LABC, but in whom a substantial degree of downstaging occurred
with neoadjuvant chemotherapy.

The NSABP B-18 data suggest that surgical pathology indications for locoregional irradiation are the same for
patients that receive neoadjuvant chemotherapy and those that receive postoperative chemotherapy. In clinical
practice, the oncology team should review each patient in a multidisciplinary fashion, and discussions regarding
[38]
the complete multimodality management (including final radiation planning) should begin at presentation . For
whole breast irradiation IMRT is preffered with doses of 45-50 Gy in fraction of 1.8-2 Gy.all doses aregiven at
5doses per week regional irradiation of 50 Gy in fraction of 1.8-2 Gy.The ASCO guidelines for postmastectomy
radiation treatment state that postmastectomy radiation treatment is indicated when there are four or more
pathologically positive axillary lymph nodes and when the tumor is stage III (except for T3N0M0 lesions); the
need for postmastectomy radiation treatment is uncertain after neoadjuvant systemic chemotherapy, with one to
three pathologically positive axillary lymph nodes, for T3N0M0 tumors, for close or positive margins of resection,
or for positive lymph nodes associated with extracapsular extension.

95
Postoperative systemic therapy

Patients with hormone receptor-positive breast cancer should receive at least 5 years of either tamoxifen or an
aromatase inhibitor. Aromatase inhibitors should be given only to postmenopausal women, as these drugs do not
block estrogen production from functioning ovaries. Any woman of unknown menstrual status can have ovarian
function assessed by measurement of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and
estradiol levels. The role of ovarian ablation/suppression for premenopausal, hormone receptor-positive breast
cancer patients is not yet defined. Tumors overexpressing HER2/neu also require treatment with adjuvant
[39], [40]
trastuzamab .

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reconstruction. Plast Reconstr Surg 1997;100:1153.

Management of the Axilla in Carcinoma Breast

Gaurav Agarwal, Sendhil Rajan

The legendary American surgeon William Halstead, who propagated the radical mastectomy for treatment of
breast cancer hypothesized that the involvement of the axillary lymph nodes in breast cancer are due to spread
of the tumour in an step-wise manner, where the nodes of the axilla act as an anatomical barrier, thereby
limiting the spread of cancer cells. According to this hypothesis, metastatic spread of breast cancer happens
chiefly via the lymphatic system. This contiguous theory is applied in the operation room- en-bloc removal of all
the nodes and fibro-fatty tissue of the axilla along with the primary tumour is based on this. Halsteds theory
th
lasted from the 1890s to the mid part of the 20 century.

However, studies have shown that up to 30% of patients, despite being axillary node-negative; will ultimately
present with distant disease. Also, a considerable number of breast cancer patients are recognized to have
systemic disease at the time of presentation, due to entry of tumour cells into the bloodstream during initial
stages of the neoplastic process.The above data was put forth by Bernard Fisher in his 1980 paper where he
considered breast cancer to be a systemic disease from its very onset, thus advocating systemic therapy in
nearly all patients. Samuel Hellman in 1994 presented his Spectrum theory, which stated breast cancer
presentation to be a spectrum- as a disease that always remains local through its course to one that, at its very
clinical onset, may be systemic in nature.

Today, the regional axillary lymph nodes although thought to be ineffective barriers for spread of tumour cells,
are still considered to be of vital biological and prognostic importance, and are yet to be superseded by newer
molecular prognostic indices. Axillary lymph-node dissection (ALND) has been an important part of surgical
management of breast cancer over more than a century now, and, besides its therapeutic potential, also provides
key prognostic data for to select patients for further adjuvant systemic therapies. The main factor affecting node
positivity is tumour size, although other features, such as tumour grade, histological type and lympho-vascular
invasion also play a part. Axillary node metastases also have clinical relevance as they may represent either
loco-regional relapse or distant disease by acting as a source for tertiary spread.

In patients with invasive breast cancer, management of the axilla has two critical goals:
1. Prognostic and Staging Goal: Does the metastatic spread extend to the axillary nodes? If yes- what is the
extent of the spread and number of metastatic lymph nodes? Is there any extra-nodal infiltration?
2. Therapeutic Goal: When axillary lymph node metastases are present, ALND aims for surgical extirpation of
all remaining metastatic disease from the axilla. Also, radiation to the axilla after surgical intervention is also
widely followed. Studies have shown that ALND (without/before post-operative radiation to axilla) results in
enhanced relapse-free survival. However, its role on overall survival is little less established.

97
Management of the axilla in patients with breast cancer has improved significantly in the recent decades, chiefly
due to better understanding of the biological models of lymphatic networks within the breast and patterns of
tumour dissemination. The NCI consensus statement of the past recommends that treatment of potentially
curable breast cancer should include level I and II ALND (see below). The position of routinely performed ALND
for the treatment of breast cancer, in the last decade or so, has been more closely scrutinized due to various
reasons. These include an increase in the detection of small, non-palpable lesions detected mammographically
having a low risk of nodal metastases, a greater knowledge regarding the complications following ALND, and the
present treatment paradigm of providing adjuvant chemotherapy to the majority of patients with breast cancers
>1.0 cm, regardless of axillary lymph node status.

Breast cancer shows heterogeneous patho-biology, therefore making any blanket axillary treatment unsuitable for
disease management. The surgical management of axilla needs to be customized individually to each patients
requirement and preference, as well as to the characteristics of the tumour. It should be in concurrence with local
treatment protocols and available facilities. Sentinel lymph node biopsy (SLNB) is now recognised as the
standard of care in most centres the world over and has revolutionized axillary management through the last
decade and a half. Nevertheless, there is still limited information regarding long-term outcomes, and there are
multiple variations in practice and inconsistencies in methodology. Other procedures like the four node biopsy
and axillary sampling are limited to certain centres, and have not gained acceptance in routine clinical practice. In
patients undergoing breast conserving therapy (BCT), axillary irradiation (AI) has been studied as a substitute for
ALND. However, more conclusive studies need to be done for this to be a recommendation.

This review will seek to outline the scientific basis, technical aspects and outcomes of the current axillary lymph
node management strategies in patients with invasive breast cancers.

Surgical and Applied Anatomy of the Axilla

The lymphatic system of the breast is constituted of a large and complex network of peri-ductal and peri-lobular
lymph vessels, which drain principally to the axillary nodes. There is a connection between the dermis and the
intra-parenchymal lymphatics (via the sub-areolar plexus), which explains the spread of cutaneous malignancies
and drainage of tracer agents to axillary nodes. Sappey's plexus are specialized lymphatic channels that are
present under the nipple and areola. There is uni-directional flow of lymph from the superficial to deep plexus and
from the sub-areolar plexus through the lymph vessels of the lactiferous ducts to the peri-lobular and deep sub-
cutaneous plexus.

SLN biopsy can be accomplished only with knowledge of the intricate lymphatic anatomy of the breast. Lymphatic
anatomy also determines the preferred sites for loco-regional spread of malignancy. The vast majority of breast
tumours metastasise to the axilla regardless of the site of primary tumor within the breast. The internal mammary
nodes constitute an alternative path for drainage of lymph from the central zone and medial breast quadrants.
However, exclusive involvement of the internal mammary nodes is seen in <10% of node-positive tumours and
clinical signs are rare. Considerable morbidity can result from surgical removal of these nodes, with no advantage
in overall survival. Currently, the clinical and pathological significance of involvement of internal mammary nodes
is uncertain at best.

The axilla is a pyramidal shaped area, medially bounded by the chest wall, laterally by the latissimus dorsi,
posteriorly by the sub-scapularis, superiorly by the axillary vein and inferiorly by the inter-digitation of the
latissimus dorsi and serratus anterior muscles. About 50 lymph nodes are present within the loose areolar fat of
the axilla, although this number is variable. Arbitary division of the lymph nodes of the axilla is as follows: Level I
nodes are those found lateral to the lateral border of the pectoralis minor muscle; Level II nodes are those in the
central axillary group, found under the pectoralis minor muscle; Level III include the sub-clavicular nodes medial
to the medial border of the pectoralis minor muscle. (Figure-1) Expirtation of these nodes requires either division
or retraction of the pectoralis minor, although dissecting between the two heads of the pectoralis major can also
accomplish this. The pectoralis minor is enclosed in the clavi-pectoral fascia, which extends laterally to fuse with
the areolar tissue of the axilla. One can divide the axillary fascia and expose the contents of the axilla by
dissection along the lateral border of the pectoralis minor.

The axilla contains many clinically important structures, which require preservation during dissection and removal
of the lymph nodes with the fatty areolar tissue of the axilla. Rotters nodes are the inter-pectoral lymph nodes
present between the two pectoralis muscles. They are usually seen on the posterior surface of the pectoralis
major, in close relation to the lateral pectoral nerve, which if injured, results in atrophy of the muscle. The inferior
lateral aspect of the pectoralis major muscle is innervated by the medial pectoral nerve, which should also be
carefully preserved. The second cutaneous inter-costo-brachial nerve runs in a mediallateral direction
approximately a centimetre inferior to the axillary vein. Running just posterior to the inter-costo-brachial nerve in
the second inter-costal space is the long thoracic nerve (of Bell), which innervates the serratus anterior
muscle. It should always be identified before proceeding with axillary dissection, at a site just lateral to the
serratus anterior muscle. Any surgical dissection anterior to the inter-costal nerves will safely preserve the long
thoracic nerve as the latter runs in a superiorinferior direction, and is always posterior to the inter-costal nerves

98
(which run in a mediallateral direction). Division of the long thoracic nerve results in winging of the scapula.
The thoraco-dorsal nerve innervating the latissimus dorsi, is first seen posterior to the lateral thoracic vein. It
then travels infero-laterally, passing over the sub-scapular muscle, with the sub-scapular vessels, entering the
latissimus dorsi muscle in its medial aspect. Dissection therefore should be done along the lateral or anterior
aspects of the latissimus dorsi to prevent thoracodorsal nerve injury.

Management of Axilla in Invasive Breast Cancer Patients

The single most important prognostic factor in patients with invasive breast cancer is the presence of axillary
lymph node metastases, and therefore evaluation of the axilla is of paramount importance. Patients who have
axillary nodal metastases without systemic metastases exhibit 40% poorer overall survival at 5 years, when
compared to patients who do not have axillary metastases. Also, the number of positive lymph nodes (>3) and
presence of extra-nodal spread into axillary soft tissue are recognized high-risk factors for loco-regional
recurrence and overall survival. An ideal plan of management of the axilla remains a controversial topic, and it is
currently formulated based on the tumor characteristics, presence of clinically (including radiologically) detected
lymphadenopathy, patients desire, availability of local infrastructure and medical facilities and individual institute
protocols and acceptability of various choices. Table-1 provides a list of several options for management of the
axilla in invasive breast cancer patients.

Table 1: Options for management of axilla in patients with Invasive Breast Cancers
A. Established options backed by sufficiently high quality scientific evidence:
1. Axillary lymph-node dissection level I and II for
(a) patients with palpable axillary lymphadenopathy
(b) patients with metastatic sentinel lymph node

2. Axillary lymph node dissection levels I, II and III in patients with enlarged level III nodes or bulky level I and II
nodes.
3. Sentinel Lymph node biopsy for patients with clinically (including radiologically) impalpable/ non-enlarged
axillary lymph nodes:
(a) Sentinel-lymph-node biopsy with dye and isotope
(b) Sentinel-lymph-node biopsy with isotope only
(c) Sentinel-lymph-node biopsy with dye only
Further management of axilla based on SLN pathology:
(i) ALND if SLN has metastatic deposits (including micro-metastases)
(ii)Avoidance of ALND if SLN has no metastatic deposits or have isolated tumor cells (sub-
micro-metastases) evident on immuno-histochemical studies.

B. Other options- NOT backed by sufficient scientific evidence/ limited evidence:


May be practiced in clinical trial setting, not recommended for routine clinical use
(a) Axillary lymph node sampling
(i) Blue-dye-assisted node sampling
(ii) Blind sampling- such as four node sampling
(b) Observation only
(c) Avoidance of ALND in patients with metastatic SLN (except in highly selected very low-risk patients,
as per ACOSOG Z0011 criteria)
(d) ALND in patients with Sub-micro-metastases (isolated tumor cells) in SLN
* While only well established procedures namely ALND and SLNB are mostly practiced, in certain specific groups
e.g. small (<1 cm) low grade tumours with favourable risk profile- axillary surgical procedures may be avoided.

The foremost intention of axillary surgery in patients of operable breast cancer is to stage the axilla. Independent
predictors of survival include number of lymph nodes and the level of lymph node involvement.

Staging options
a) Sentinel lymph node biopsy
b) Axillary node sampling
c) Axillary dissection

Sentinel Lymph Node Biopsy (SLNB)

The aims of sentinel lymph node biopsy are axillary staging and avoidance of unnecessary axillary dissection
leading to significant morbidity. The principle behind SLNB is that the sentinel lymph node(s) is the first (group) of
node(s) to drain the tumour bed. If the SLN is free of the tumour then the nodes at the further station are also
tumour free and an axillary dissection can be avoided with oncological safety. Historically, Sappey in 1980
injected mercury in the lymphatic channels of the breast and concluded that drainage to the axilla occurs via a
sub-areolar plexus although recent studies have doubted this. The tracer can be injected via the intradermal,
sub-areolar or peritumoral route. Because the skin has richer lymphatics than the parenchyma, it is almost
always possible to differentiate the sentinel from the other higher level nodes when the tracer is injected in the

99
skin. In the case of non-palpable breast lumps, the dye or tracer needs to be injected under image guidance.
Chapgar et al, in a review of 3961 patients,concluded that the rate of identification by intra-dermal or sub-areolar
injection was 99.3% & 95.6% respectively compared to 91.1 % of peri-tumoral injection.

Indications of SLNB
a) Operable early breast cancer (T1, T2)
b) Clinically node negative

Under Trial/Partial evidence:


a) Locally advanced breast cancer with complete or good partial response after neo-adjuvant
chemotherapy and clinically N0 stage
b) Patients with extensive DCIS undergoing mastectomy.

A patient with clinically-N0 axilla is explained the procedure and consent is obtained to subject her to a SLNB
followed by a possible axillary dissection in case SLNB is reported metastatic. SLNB is performed using a colour
(blue) dye, radio-pharmaceutical or a combination of both, which is the preferred method, with highest SLN
detection rate and lowest false negative rates. The different agents used for SLNB are:
Isosulphan blue (Lymphazurin) or Patent blue dye V or Methylene blue

m
99 Technetium- labelled albumin/ antimony/goldor sulphur colloid

Although the volume of dye used has been different in various studies with similar results, when using a radio-
pharmaceutical, usually 0.5 -6 ml of Tc labelled dye in saline is injected at the periphery of the tumour or the
previous excisional biopsy site directed by manual palpation or USG guidance or injected around the areola. The
gamma probe is then employed to identify the site of maximum radioactivity in the axilla. A small skin crease
incision is made at the point of maximum intensity and the axillary fat is dissected to reach to the point of the
maximum radioactivity, highlighted by maximum sound emitted by the device. When blue dye is used, 2 - 7.5 ml
of sterile isosulphan blue or methylene blue (more cost effective) is taken and injected just prior to surgical skin
preparation. If no radioactivity is encountered/radiopharmaceutical not used, then the skin is incised between the
pectoralis major and the latissimus dorsi over the lower part of the axilla, axillary fat is dissected to visualise the
blue channels defined by the dye (SLNB is always done before the procedure for the breast tumour). These
channels are traced upto the first node/group of nodes which is/are biopsied and sent for histo-pathological
examination. For each patient, the average yield is found to be more than one in most studies, highlighting the
fact that SLN is not a single node but regularly a group of nodes. The node(s) is then subjected to frozen section
or imprint cytology and if the node is positive for malignant deposit, a complete axillary dissection is carried out.
As only one or two lymph nodes are submitted for histology, the SLN can be subjected to a more detailed
pathological examination than routine nodal tissue, with multiple-step sections and immuno-histochemical
staining - Cytokeratin (CK) staining is another method employed for intra-operative evaluation of sentinel lymph
nodes.

One-step nucleic acid amplification (OSNA) is a recently introduced method for intra-operative evaluation of
sentinel lymph node status in breast cancer The principle behind OSNA is measurement of mRNA copy
numbers of CK 19 (CytoKeratin19) in the SLN sample, giving a rapid report. (A vast majority of breast cancers
express CK19, therefore it is preferred). In recent times, researchers have also investigated the possibility of
using spectral imaging (which refers to the formation of a multi-planar image where each pixel in the spatial
plane records reflected intensities from a range of spectral bands) to assess the SLN(s) of breast cancer patients
with an idea to ultimately develop an optical system that can categorize spectra of normal and metastatic tissue
in the visible and near infrared region, providing a report quickly.

Reduction of morbidity, especially arm lymphedema, is a main objective of SLNB. Most studies show lower rates
of morbidity after SLNB compared with ALND.There is an increasing trend toward omitting ALND altogether in
patients with micrometastatic nodal disease identified by SLNB, as shown by recent studies. The IBCSG 23-01
trial randomized patients with SLN micromets (<2 mm) and T1/T2 tumours to either completion ALND or no
further intervention to the axilla. There was no significant difference in OS or DFS for patients of either arm at a
median follow-up of 49 months.The recent ACOSOG Z-0011 trial addressed the need for completion ALND for
patients with EBC that were clinically node negative and had less than three positive SLNs; all patients
underwent breast irradiation. At a median follow-up of 6.3 years, there were no significant differences in survival
or loco-regional recurrence between the SLND plus ALND group versus the SLND alone group. The five-year
overall survival, five-year disease-free survival and recurrence rates in the ipsilateral axilla were all similar
between the two arms.The National Comprehensive Cancer Network (NCCN), however, has not changed its
guidelines and continues to recommend completion ALND for all women with positive sentinel nodes until
additional randomized trial results are available.Other recent studies have shown that SLNB is as accurate in
patients presenting with a T3 tumour and clinically negative axilla as in patients with EBC. Thus, many clinicians
do not recognize large breast tumours as a contraindication to SLN dissection, as long as the axilla is clinically
negative.

At SGPGIMS, Lucknow, the SLNB protocol consists of a combination of 1% w/v methylene blue dye and 99mTc-
99m
Antimony colloid, both of which are produced in-house, therefore limiting their costs. A dose of 40MBq of Tc-

100
Antimony colloid is injected sub-areolarly 12-24 hours prior to surgery. Later, a few minutes before incising the
skin, 1-2 ml sterile methylene blue is injected in the sub-areolar region. The hand held gamma probe draped in a
sterile glove (Neo-probe 2000, Ethicon) is then employed trans-dermally to search for the hot SLN in the axilla,
surface marking of which is then done. A small 1-2 cm skin crease incision, placed posterior to the pectoral fold in
the upper axilla or exactly over the marked SLN is then made. Streaks of blue lymphatics are sought for, and
when found are followed in a supero-medial direction to a blue SLN. The hand held gamma probe is then used to
trace the areas/ SLN with radio-tracer concentration (hot area), once the SLN (blue, and /or hot) is identified, it is
removed intact. Other hot areas if found, are explored and further SLNs are thereby identified and removed. All
the SLNs removed are sent to the pathologist for frozen section histopathology and/or imprint cytology in cold
saline. If the frozen section histology shows metastasis in one or more of SLNs- a formal Level I+II axillary
dissection is performed, utilizing and extending the SLNB incision by an extra 3-4 centimeters.

A validation study conducted at SGPGIMS Lucknow, on 120 patients with early breast cancer, revealed a SLN
identification rate of 96% and false negative rate of <4%, thereby now establishing the oncological safety of this
procedure for patients with early breast cancer. Another validation study in patients with impalpable axillary lymph
nodes after undergoing neoadjuvant chemotherapy is currently nearing completion. Preliminary results for this
group show poorer SLN identification rates and higher false negative rates compared to EBC patients undergoing
primary surgery.

Axillary Node Sampling

When the radiotracer and/or blue dye fails in SLN identification, axillary node sampling is done. It may also be
combined with the SLNB to increase the overall sensitivity. The largest nodes (a minimum of 4) are excised. In
patients with non-palpable Level I nodes, level II or III nodes are sampled. This technique therefore permits
identification of skip metastases in the axilla although such cases are relatively rare (5%). Most of the
SLN/lymphatic mapping studies have recognized the first draining node in level I, therefore level I node is most
frequently sampled.

Avoidance of ALND and any axillary surgical procedure

Any of the staging procedures of the axilla can be safely omitted in selected clinically node-negative patients
having small (1.0 cm) non high- grade (I and II) tumours, in elderly patients associated with co-morbidities, and
also in cases of localised non-palpable DCIS amenable to wide excision. ALND, however, is no longer an
acceptable staging procedure for clinically node-negative patients. Studies are underway in clinically node-
negative patients undergoing preoperative ultrasound-guided biopsy to identify axillary metastases and,
therefore, allowing ALND at the without conventional SLNB.

Axillary Lymph Node Dissection (ALND)

A formal complete ALND is warranted in cases of histologically proven positive axilla by FNAC (palpation guided
or US guided) or cases in which SLN or axillary sampling specimen is positive for metastases (3). It may also be
required additionally in variety of other situations, as listed below.

Indications for ALND


a) Axillary node metastasis proven by fine needle aspiration (FNA), core biopsy, or SLN biopsy
b) Validation trials of SLN biopsy (in which a planned backup ALND is done to establish the proportion of
false-negative results).
c) Failed SLN biopsy (even in expert hands, SLN mapping fails in a few percent of cases).
d) Clinically suspicious nodes palpated at the time of an otherwise successful SLN biopsy procedure
e) Inflammatory breast cancer (following neo-adjuvant
chemotherapy, SLN biopsy appears accurate for non-
inflammatory disease, but remains investigational for
inflammatory breast cancer)
f) Unavailability of SLN biopsy
g) Isolated loco-regional recurrence, either in the ipsi-lateral
axilla after SLN biopsy or in the contra-lateral axilla, with
no evidence of a contra-lateral breast primary.

Though still regarded as a beneficial procedure by conferring


better regional disease control, the overall survival advantage with
ALND has always been in doubt, since the Halsted era.A large
meta-analysis of about 3000 patients has shown a survival benefit
of 5.4% from ALND. However, many other studies have shown no
survival benefit from ALND. The prevalence of node positivity in
patients undergoing ALND mainly depends on the tumour size, Fig 1: Levels of axillary lymph nodes: I, II and
although other factors, such as tumour grade and type, lympho- III in relation to the pectoralis minor muscle
vascular invasion, are also relevant. and tendon.

101
Technique of ALND

Classification of ALND isdone based on the extent dissected: level I, level I+II, or level I+II+III (complete ALND).
Axillary nodal Levels I & II are routinely dissected out along with all fibro-fatty and lymphatic tissue. A minimum of
10 nodes need to be histo-pathologically examined for optimal axillary staging. When level III nodes are found to
be enlarged, and also in patients exhibiting bulky level II nodes, a complete level III dissection is performed. Skip
metastases, refers to disease limited to levels II to III, sparing level I, or limited to level III, sparing levels I-II. As
most of these skip metastases were found at level II (isolated level III disease is rare), most recommendations
favour a level I+II ALND as the standard procedure.

Incisions utilized for ALND may be separate from or in-continuity


withthe incision used for the breast procedure. If a separate
incision is employed, it is best made transversely,about two finger-
breadths below the axillary skin crease, gently curved to follow a
skin-line. The length should be adequate for good exposure, but
must not extend beyond the anterior pectoral border, where it
would be visible the incision may be posteriorly extended if
required. A contiguous incision is perfectly rational in patients
undergoing mastectomy without reconstruction or BCS and for
tumours present high up in the axillary tail. In both cases, SLNB is
done through the axillary end of the incision before the breast
procedure. The procedure of ALND involves dissection and
removal of all fibro-fatty and lymphatic tissue including the lymph Fig 2: Completely dissected axilla, showing
nodes from whole of levels I and II, and if indicated level III. The intact and skeletonized long thoracic nerve
extent of dissection is from the axillary vein superiorly, to second and thoraco-dorsal neuro-vascular bundle.
digitations of the serratus anterior muscle inferiorly, and from the The axillary vein is not skeletonized, leaving a
layer of fascia with it, in an attempt to prevent
anterior border of latissimus dorsi muscle laterally to the rib-cage edema of the arm.
and intercostals muscles medially, with the nerve to serratus
anterior as a guide to the medial limit. The important structures
that are needed to be preserved include the axillary vein, the long
thoracic nerve and the thoraco-dorsal neuro-vascular bundle (Figure-2). The axilla is closed with a suction drain
in-situ using interrupted or sub-cuticular sutures, and a compression dressing applied.

Complications of Axillary Node Dissection

The axillary component of breast cancer surgery is responsible for the majority of post-operative complications,
and minor problems are frequent. Seromas are commonly seen (in up to 30% of patients), particularly if the
axillary drain was removed prematurely. These are managed by aspiration, performed in the outpatient clinic.
Long term complications include numbness over the medial part of the arm, occurring if the inter-costo-brachial
nerve was sacrificed.

The most feared and potentially disabling complications include upper limb lymphedema and recurrent cellulitis.
The incidence of lymphedemacontrasts between 7-60% according to the methods used to assess the arm and
the interval between surgery and follow-up. Most recent studies have reported that, after axillary dissection or
axillary irradiation, the incidence of lymphedema is 15-20%; and that this complication occurs more frequently if
the patient received both surgery and irradiation.A rare sequel of lymphedema is upper extremity angiosarcoma,
known as Stewart-Treves syndrome. The type of ALND and use of axillary irradiation are the prime factors
associated with the lymphedema formation. Other minor factors include obesity, older patient and infection.
Lymphedema may even manifest years after the operation. Patients should always be advised to avoid arm
swelling and infection by taking precautions not to suffer cuts and scrapes on the operated side, to avoid
injections, blood-pressure monitoring, and IV sampling/access, to avoid constricting clothing and jewellery, etc. In
a study conducted by Warmuth in 1998, of a survey of 330 patients who were disease-free 2-5 years after
surgery for early-stage breast cancer, 35% reported numbness, 30% reported pain, 15% reported arm swelling,
and 8% reported limitation of arm movement. However,most patients had mild symptoms, not interfering
significantly with daily activity.

Summary

Management of the axilla is a fundamental aspect of treating a patient with invasive breast cancer. Optimal
management of the axilla in breast cancer patients has evolved greatly during the last century and particularly the
last two decades, and is continuously undergoing refinement. Today, staging of the axilla is dominated by SLNB,
which is now practiced all across the developed world, usually with the dual localisation technique; and is rapidly
gaining prominence in developing nations such as India. Other procedures for axillary staging, as well as
therapeutic procedures need to be carefully assessed with respect to individual risk and tailored to patient
preference. A custom-made methodology integrating the variety of options on the basis of risk and cost-benefit
ratio, together with the choice of the patient, will undoubtedly prove to be the most ideal practice. In todays
practice, ALND is indicated in patients with clinically (including radiologically) enlarged axillary nodes, in those

102
with metastatic SLN or detection of metastatic nodes on lymph node sampling, and where ever SLN biopsy is not
available or a SLN study has failed to detect the SLN. However, there are currently ongoing studies that
challenge even these indications for ALND. Whenever required, levels I & II axillary nodes are routinely dissected
out along with all fibro-fatty and lymphatic tissue of the axilla. A minimum of 16 lymph nodes need to be
examined by the pathologist for optimal axillary staging. In presence of enlarged nodes in level III, and in patients
with bulky levels II nodes, a complete level III dissection is also performed. Various complications such as
seroma, lymphedema and cellulitis can occur post-operatively and patient education for their prevention and
treatment is paramount to their management.

References

1. Ciesl L et al, Alternative sites of injection for sentinel lymph node biopsy in breast cancer, ANZ J Surg 2003; 73:
6004.
2. Chagpar A, Martin RC 3rd, Chao C, Wong SL, Edwards MJ, Tuttle T, McMasters KM. Arch Surg. 2004
Jun;139(6):614-8; discussion 618-20.
3. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al: A nomogram for predicting the likelihood of additional nodal
metastases in breast cancer patients with a positive sentinel node biopsy. Ann SurgOncol 10:1140-1151, 2003
4. Giuliano AE: Z0011: A randomized trial of axillary node dissection in women with clinical T1 or T2 N0 M0 breast
cancer who have a positive sentinel node. 2003.
5. Warmuth MA, Bowen G, Prosnitz LR et al. Complications of axillary lymph node dissection for carcinoma of the
breast: a report based on a patient survey. Cancer 1998; 83:1362-8.
6. John R Benson, G QuercidellaRovere, and the Axilla Management Consensus Group,Lancet Oncol 2007; 8: 331
48
7. Giuliano AE, Morrow M, Duggal S, Julian TB. Should ACOSOG Z0011 change practice with respect to axillary
lymph node dissection for a positive sentinel lymph node biopsy in breast cancer? ClinExp Metastasis. 2012
Oct;29(7):687-92. Epub 2012 Aug 29.
8. Galimberti V, Cole BF, Zurrida S, et al. [S3-1] Update of International Breast Cancer Study Group Trial 23-01 To
Compare Axillary Dissection Versus No Axillary Dissection in Patients with Clinically Node Negative Breast
Cancer and Micrometastases in the Sentinel Node. Lancet Oncology 2013 Jun;14(7):e254.
9. Chung MH, Ye W, Giuliano AE, Role for sentinel lymph node dissection in the management of large (>or = 5 cm)
invasive breast cancer. Ann SurgOncol. 2001;8(9):688
10. Cody HS. Axillary Dissection for Breast Cancer. Operatice Tech in General Surg 2006;1524-1540
11. Newman LA, Mamounas EP. Review of breast cnacer trials conducted by the national surgical adjuvant breast
project. Surg Clin N Am. 2007;87:279-305.
12. Pegolo E, Puppin C, Gerometta A, Damante G, Puglisi F, Di Loreto C. One-step nucleic acid amplification (OSNA)
for intraoperative evaluation of sentinel lymph node status in breast cancer: a comparative study between CK19
protein expression and CK19 mRNA level in primary tumors and lymph node metastasis. Virchows Arch. 2013
Jul;463(1):7-15
13. Jack D. O'Sullivan ; Paul R. Hoy ; Harvey N. Rutt, Spectral imaging as a potential tool for optical sentinel lymph
node biopsies, Clinical and Biomedical Spectroscopy and Imaging II, 80872J (June 15, 2011)
14. Bensen JR et al, Management of the axilla in women with breast cancerThe Breast (2007) 16, 130136
15. Cserni G. What is a positive sentinel lymph node in a breast cancer patient? A practical approach. The Breast
(2007) 16, 152160.
16. J E A Somner, J M J Dixon, J S J Thomas, Node retrieval in axillary lymph node dissections: recommendations
for minimum numbers to be confident about node negative status; J ClinPathol. 2004 August; 57(8): 845848
17. Diseases of the Breast by Harris PJ, 4th edition 2009; Lippincott Williams & Wilkins
18. Sabiston textbook of Surgery, 19th Edition 2012, Saunders.

Operative Procedures for Breast Cancer

Nikhil Talwar

History and Terminology


1,2
Radical and extended radical mastectomy :Going back to the late 1800s, the treatment of breast cancer was
characterized by either wide excision or simple mastectomy. These resulted in extremely high rates of local
recurrence and poor survival. In 1894, William Halsted proposed that breast cancer was a local disease that
spread by contiguous extension, and that more extensive resection would provide a better chance of disease
control (Halsteds Theory).
1
The original radical operation of Halstead radical mastectomy consisted of en bloc removal of the breast, the
overlying skin, both the pectoralis major and minor muscles, in continuity with the regional lymph nodes along the
axillary vein to the costoclavicular ligament (level I, II, and III nodes). The long thoracic nerve and the
thoracodorsal neurovascular bundle with the axillary contents were routinely resected. This procedure often
required a skin graft to close the large skin defect created. Extended radical mastectomy was a logical
extension to a Halsted radical mastectomy, which achieved more radical lymphatic clearance by excision of the
internal thoracic and supraclavicular nodes. An even more radical mastectomy was the super-radical

103
mastectomy that also included four parts: Breast and axillary contents, Internal mammary artery and vein with
internal mammary lymph node chain, upper mediastinal nodes and low supraclavicular nodes.

Modified Radical Mastectomy: Unfortunately, a large number of women continued to die of metastatic breast
cancer after radical mastectomy. Moreover, morbidity was increased without significant advantages in survival or
local control. In 1948, Patey and Dyson of the Middlesex Hospital, London, advocated a modified radical
mastectomy for the management of advanced operable breast cancer, explaining, "Until an effective general
agent for treatment of carcinoma of the breast is developed, a high proportion of these cases are doomed to die."
They preserved the pectoralis major muscle and the lateral pectoral nerve and sacrificed the pectoralis minor
muscle and medial pectoral nerve the to allow clearance of axillary lymph node levels I to III. Subsequently,
Madden advocated a modified radical mastectomy (MRM) that preserved both the pectoralis major and minor
muscles even though this approach prevented complete dissection of the apical (level III) axillary lymph nodes.
Scanlon modified the Patey procedure by dividing but not removing the pectoralis minor muscle, allowing
removal of level III nodes and preservation of the lateral pectoral nerves to the major muscle.

The procedure described by Auschincloss differs from the Patey procedure by not removing or dividing the
pectoralis minor muscle. This modification limits the complete removal of high axillary nodes but is justified by
Auchincloss, who calculated that only 2% of patients will potentially benefit by removal of the highest level nodes.
The Auchincloss mastectomy is the most popular form of MRM in the present era.

Several prospective randomized trials documented equivalent survival rates with MRM as compared to radical
mastectomy, with less morbidity. As a result of these data, the radical mastectomy has become an historical
footnote in the treatment of breast cancer.

Breast conserving surgery: The fact that less radical surgery did not affect survival made people question
whether Halsteds theory was correct; that breast cancer was not a local disease that spread contiguously, but
instead, systemic disease was ultimately the main determinant of survival. The question arose as to whether the
breast needed to be removed or could be preserved without compromising survival. There had been several
reports of breast cancer being treated by radiation alone, and there was evidence that radiation could eliminate
subclinical foci of disease. This allowed for the combination of limited surgery and radiation therapy as a method
of adequately treating breast cancer while avoiding mastectomy. The use of radiation therapy in conjunction with
surgery has allowed dramatic reductions in the extent of surgery required for local control of breast cancer, with a
large number of patients now eligible for breast-conserving surgery.
3,4,5
Breast-Conserving Surgery
The aim of local treatment of breast cancer is to achieve long-term local disease control with the minimum of
local morbidity. The major advantages of breast-conserving treatment (BCT) are:

Box 1: Major advantages of BCT


1. An acceptable cosmetic appearance
2. Lower levels of psychological morbidity
3. Equivalence in terms of disease outcome for BCT and mastectomy in selected patients

Box 2: Four critical elements in patient selection for BCT


1. History and physical examination
2. Mammographic evaluation
3. Histologic assessment of the resected breast specimen
4. Assessment of the patient's needs and expectations

Recent (i.e., usually within 3 months) preoperative mammographic evaluation is necessary to determine a
patient's eligibility for BCT. Mammographic evaluation defines the extent of a patient's disease, the presence or
absence of multicentricity, and other factors that might influence the treatment decision, and evaluates the
contralateral breast.

Indications of BCT
Clinically, solitary cancers measuring 4 cm or less, without signs of involvement of skin or chest wall, can usually
be managed by BCT. Many units consider tumors measuring 3 cm or less clinically as the ultimate size of a
tumor for a patient to be able to undergo BCT. Patients with tumors measuring clinically larger than 4 cm can be
treated by BCT if the patient has large breasts. Conversely, in a patient with small breasts, excision of even a 1-
cm tumor may produce an unacceptable cosmetic result.

Box 3:Indications for breast conserving surgery:


1. T1, T2 (<4 cm), N0, N1, M0
2. T2 >4 cm in large breasts
3. Single clinical and mammographic lesion

104
Absolute and Relative Contraindications to Breast-Conserving Therapy
In the selection of patients for BCT, there are some absolute and relative contraindications.

Absolute Contraindications
1. Pregnancy: Pregnancy is an absolute contraindication to the use of breast irradiation. However, in
many cases, it may be possible to perform BCS in the third trimester and treat the patient with irradiation
after delivery.
2. Multifocal/multicentric disease: Women with two or more primary tumors in separate quadrants of
the breast or with diffuse malignant-appearing microcalcifications on mammography are not considered
candidates for breast conservation treatment.
3. A history of prior therapeutic irradiation to the breast region: Such patients would require
retreatment to an excessively high total radiation dose to a significant volume is another absolute
contraindication.
4. Persistent positive margins after reasonable surgical attempts: The importance of a single focally
positive microscopic margin needs further study and may not be an absolute contraindication.
5. T4, N2, or M1 lesions
6. Patients who prefer mastectomy.

Relative Contraindications
1. A history of collagen vascular disease: Such patients tolerate irradiation poorly.
2. Tumor size: It is not an absolute contraindication to breast conservation treatment, although there is
little published experience in treating patients with tumor sizes greater than 4 to 5 cm. However, a
relative contraindication is the presence of a large tumor in a small breast in which an adequate
resection would result in significant cosmetic alteration.
3. Breast size: Treatment by irradiation of women with large or pendulous breasts is feasible if
reproducibility of patient setup can be ensured and the technical capability exists for 6 MV or greater
photon beam irradiation to obtain adequate dose homogeneity.
4. Women with a strong family history of breast cancer or BRCA1 and BRCA2 mutation carriers: Such
patients are at higher risk of a recurrent cancer or a new cancer in the same or opposite breast.

Nonmitigating Factors
There are certain clinical and pathologic features that should not prevent patients from being candidates for
breast conservation treatment. These features include the presence of clinically suspicious and mobile axillary
lymph nodes or microscopic tumor involvement in axillary nodes. Tumor location is not a factor in treatment
choice. Tumors in a superficial subareolar location may occasionally require the resection of the nipple/areolar
complex to achieve negative margins, but this does not have an impact on outcome.

Technique of BCT
Two breast-conservation surgical procedures have been extensively studied and described: quadrantectomy
and wide local excision. Quadrantectomy is based on the belief that the breast is organized into segments, with
each segment draining into its own major duct, and that invasive cancer spreads down the duct system toward
the nipple. The evidence is that both of these premises are incorrect. Studies have shown similar rates of local
recurrence in both quadrantectomy and wide local excision, providing margins of excision are clear.
Quadrantectomy is no longer advocated because it produces a significantly poorer cosmetic outcome than wide
local excision. The consensus view is that the majority of patients having BCT can be adequately treated
by wide local excision.

The majority of wide excisions of palpable and impalpable cancers are performed under general anesthesia. The
patient is given a dose of intravenous antibiotics at induction (1.2 g of co-amoxiclav or a cephalosporin).

Incisions: The aim of wide local excision is to remove all invasive and
any ductal carcinoma in situ with a 1-cm macroscopic margin of
normal surrounding breast tissue. If a subsequent mastectomy is
likely, the scar should be within the ellipse of skin, which would be
excised at mastectomy. It is also important to place the incision in a
position that will obtain the optimal cosmetic result (Fig. 1A,B,C).
Langer described the predominant orientation of collagen fibers in the
skin and around the breast, and these lines are essentially circular
(Fig. 1A). Kraisl later demonstrated that lines of maximum resting skin
tension run in a more transverse orientation across the breast (Fig.
1B). In general, scars that are parallel to both the lines of maximum
resting skin tension and to the orientation of collagen fibers produce
the best cosmetic incisions with least hypertrophy and keloid Fig. 1.The direction of Langer's lines (A) and the
formation.An incision to excise a cancer should be placed directly over lines of maximum resting skin tension in the
the lesion. Excessive tunneling is not recommended because this may breast (the so-called dynamic lines of Kraisl) (B)
compromise margins and make a reexcision for positive margins
unnecessarily difficult. Excising skin directly overlying a cancer is only

105
necessary if the carcinoma is very superficial and/or Fig. 1 (C):Planning the
the skin is tethered. lumpectomy incision. Skin
incisions should be placed
within the Langers lines
Wide local excision: After making the skin incision,
when possible. Closer to the
the skin and subcutaneous fat are dissected off the
areola, circumareolar
breast tissue. The skin flaps should be elevated 1 to 2 incisions are appropriate, but
cm beyond the edge of the cancer (Fig. 2A). Normal excessive tunneling should be
breast tissue should be excised at least 1 cm beyond avoided. In the lower
the limit of the palpable mass. Having divided breast hemisphere of the breast,
tissue beyond the edge of the cancer, the deep aspect radial incisions can be
of the tumor can be palpated and dissection through considered, because these
the breast tissue is continued down to the pectoral result in less distortion of the
fascia and the breast tissue containing the cancer is nipple-areolar complex.
lifted off the fascia. It is not necessary to excise
pectoral fascia unless it is tethered to the tumor. Once
assured that an adequate biopsy has been performed,
a tissue-marking clip should be placed at the site of the biopsy so that the
area can be easily targeted in the future in case the lesion requires re-
excision.

Wound Closure: After excision, hemostasis should be achieved to avoid a


hematoma. Drains are not necessary after surgery. Once hemostasis is
achieved, surgical clips should be placed within the lumpectomy cavity in
the six anatomic locations (anterior, posterior, medial, lateral, superior,
inferior). This helps in the planning of the radiation therapy. The surgeon
should also never try to simply reapproximate the breast tissue. Sutures
should not be placed in the breast parenchyma to close the cavity. The
lumpectomy cavity will fill with seroma and fibrin, and ultimately fibrous
tissue, which maintains the normal, rounded contour of the breast. The
incision should be reapproximated with absorbable deep dermal sutures
followed by a subcuticular stitch or tissue adhesive. Fig. 2A: Finger of non-dominant
hand is placed over palpable cancer
Immediately after excision, the specimen is immediately orientated prior to and breast tissue is divided beyond
submission to the pathologist with sutures, ligaclips, or metal markers (Fig. the fingertips
2B).
6
Wire-Localized Lumpectomy
With the increased use of screening mammography, many cancers are
diagnosed by means of a stereotactic core biopsy of a mammographic
abnormality. In these cases, a wire-localized lumpectomy will be necessary.
Localization involves placing a rigid introducer needle with a flexible hooked
wire inside of it at the site of the abnormality using either biplanar
mammography or ultrasound.
3,4
Reexcision Lumpectomy
Reexcision lumpectomy should be performed in any patient with unknown or
positive margins. It is also strongly recommended in patients with close
margins, approximately 2 to 3 mm. Reexcision is necessary in one fourth to one
third of lumpectomies. Failure to reexcise close or positive margins stands a
high chance of leaving residual disease and increases local recurrence rates.
Fig. 2B: The lumpectomy specimen
The standard approach to a reexcision lumpectomy is to remove the entire should be oriented in three planes so
cavity. An ellipse of skin is drawn around the previous skin incision so that the that the pathologist can identify
previous scar is removed with the specimen. Skin flaps are then raised. The close or positive margins.
previous cavity is usually readily palpable, and the approach to the reexcision is
similar to that of a wide local excision. It is important not to violate the cavity
because this complicates the inking and evaluation of the new margins.
7,8
Axillary Surgery in Patients Undergoing Breast Conserving Surgery
The two main aims of axillary surgery in patients with operable breast cancer are to stage the axilla and to treat
any axillary disease. The presence or absence of axillary lymph node involvement is the single best predictor of
survival in patients with breast cancer, and important treatment decisions are based on it. The number of involved
lymph nodes and the level of lymph node involvement are independent predictors of survival of patients with
breast cancer.

Options for staging axillary disease include: (a) Sentinel lymph node biopsy, (b) Axillary node sampling, and (c)
Axillary dissection

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Box 4: Indications for sentinel lymph node biopsy (SNLB)or axillary node sampling
1. Operable breast cancer (T1, T2)
2. Clinically node-negative patients

Box 5: Contraindications for sentinel lymph node biopsy or axillary node sampling
1. Palpable lymphadenopathy
2. Prior axillary surgery
3. Chemotherapy or radiation therapy
4. Multifocal breast cancer

Box 6: Indications for axillary dissection


1. Preoperative diagnosis of axillary node metastasis
2. Positive SLN
3. Failed SLN biopsy or a recent inadequate ALND
4. Clinically suspicious nodes identified at surgery
5. Non availability of equipment for SLN biopsy

Technique of Sentinel lymph node biopsy


The combination of intraoperative gamma probe detection of radioactive colloid and intraoperative visualization of
isosulfan blue dye is more accurate than the use of either agent alone. On the day prior to surgery, or on the
morning of surgery, using a 25-gauge needle, 0.5 mCi of 0.2-micron technetium-99 sulfur colloid in a volume of
0.2 to 0.5 mL is injected (three to four separate injections) at the cancer site or subdermally. Subsequently, in the
operating room, 4 mL of isosulfan blue dye is injected in a similar fashion, but with an additional 1 mL injected
between the cancer site and the overlying skin. For nonpalpable cancers, the injection is guided by either
intraoperative ultrasound or by a localization wire that is placed preoperatively under ultrasound or stereotactic
guidance. Women are told preoperatively that the isosulfan blue dye injection will impart a change to the color of
their urine and that there is a very small risk of allergic reaction to the dye (1 in 10,000). The use of radioactive
colloid is safe and radiation exposure is very low.

A hand-held gamma counter is then employed transcutaneously to identify the location of the sentinel lymph
node. A 3- to 4-cm incision is made in line with that used for an axillary dissection, which is a curved transverse
incision in the lower axilla just below the hairline. After dissecting through the subcutaneous tissue and identifying
the lateral border of the pectoralis muscles, the clavipectoral fascia is divided to gain exposure to the axillary
contents. The gamma counter is employed to pinpoint the location of the sentinel lymph node. As the dissection
continues, the signal from the probe increases in intensity as the sentinel lymph node is approached. The
sentinel lymph node also is identified by visualization of isosulfan blue dye in the afferent lymph vessel and in the
lymph node itself. Before removing the sentinel lymph node, a 10-second in vivo radioactivity count is obtained.
After removal of the sentinel lymph node, a 10-second ex vivo radioactive count is obtained, and the lymph node
is then sent to pathology for either permanent or frozen section analysis. When necessary, a search is made for a
second sentinel lymph node. This procedure is repeated until residual radioactivity in the surgical bed is less that
10% of the 10-second ex vivo count of the most radioactive sentinel lymph node.

Complications associated with Sentinel Lymph Node Biopsy


Surgical Complications: As with any incision, the SLN biopsy can be associated with bleeding
(hematoma) and wound infection, although both of these are rare complications. Seroma formation after
SLN biopsy can occur and is readily treatable by needle aspiration. Other complications of SLN biopsy are
similar to those seen in ALND, including neurosensory disturbances, and lymphedema. Although it is
rare, and certainly less common than with ALND, it is a mistake to believe that SLN biopsy completely avoids
the risk of lymphedema. Lymphedema rates have been described in as many of 5% to 7% of SLN biopsy
procedures.
Technical Complications: Inability to find the sentinel node is a relatively rare occurrence. A meta-
analysis of data on SLN biopsy from 69 studies, reveals overall identification rate of 96% and overall false
negative rate of 8.4%. Given the importance of the axillary nodal status on guiding adjuvant therapy
decisions and the potential benefit of removing nodal disease early, if a SLN is not identified, a level I and II
axillary lymph node dissection should be performed. A rare, but serious, risk of sentinel node biopsy is the
potential allergic reaction to isosulfan blue or patent blue dye.

Technique of axillary lymph node dissection


A curvilinear incision is made just inferior to the hair-bearing area, extending from just posterior to the pectoralis
major muscle and just anterior to the latissimus dorsi muscle (Fig. 3A). A lazy S incision is an alternative, placed
between the pectoralis major and latissimusdorsi muscles (Fig. 3B). An anterior axillary fold incision can also be
used (Fig. 3C). The skin incision is deepened through the superficial fascia and skin flaps are developed deep to
this superficial fascia.

107
The medial dissection is begun by using skin hooks to
elevate the superior, medial, and inferior skin flaps and
dissecting in the plane between the subcutaneous fat and
axillary fat. Dissection continues with the aid of gentle
retraction with a swab. The lateral border of the pectoralis
major muscle is easily palpable and dissection should
continue to it.The first step is to raise superior and inferior
skin flaps. The incision should be carried straight down to
just above the axillary fascia and then flaps created. Once
the flaps are raised, the next step is to identify three
landmarks; the pectoralis major and minor muscles, the
axillary vein, and the latissimusdorsi muscle (Fig. 4B). With
the pectoralis major muscle retracted medially, the pectoralis
minor muscle is exposed, and the investing fascia can be
opened in a similar manner. During the exposure of the Fig. 3: Incisions for axillary dissection. A: Skin crease
muscles, it is important to identify and preserve the medial incision distal to the hair-bearing skin of the axilla. B:
pectoral neurovascular bundle. The latissimusdorsi muscle Lazy S incision placed between pectoralis major and
should be exposed to the point where the axillary vein latissimusdorsi muscles. C: Anterior axillary fold incision
crosses it. During this dissection, the lateral aspect of the (dashed line) placed parallel and posterior to lateral
intercostobrachial nerves will be encountered. Preserving border of the pectoralis major muscle.
these nerves, although adding time to the procedure, will
avoid numbness of the upper inner arm.Finally, the axillary
vein is exposed. The vein is often encountered during the exposure of the muscles. It is important not to dis- sect
superior to the level of the axillary vein because an injury to the brachial plexus can be one of the most
debilitating complications.

The dissection is greatly facilitated by retracting the axillary contents caudally. As the fat is dissected from the
vein, small superficial branches of the axillary vein are divided and ligated with 3-0 silk sutures. As the vein is
cleared laterally to medially, the next step is to identify the thoracodorsal bundle. (Fig. 4C). Once the entire
bundle is identified, the fibrofatty tissue can be cleared from the neurovascular structures so that they may be
seen entering the latissimusdorsi muscle.

As the thoracodorsal vein is cleared, a branch is noted heading toward the chest wall. This crossing branch can
often provide a clue to the location of the long thoracic nerve. Some surgeons will routinely follow this branch to
the serratus anterior at this point in the dissection to identify the long thoracic. Others identify the long thoracic
after the dissection of the level II nodes.

Fig. 4B: Superior and inferior flaps are raised, and the
pectoralis major, latissimusdorsi, and axillary vein are
Fig. 4A: Levels I to III of the axillary lymph identified.
nodes.

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For a level I and II dissection, the pectoralis minor muscle must be raised to allow access to the level II nodes.
This is greatly facilitated by rotation of the arm medially. The exposure of the axillary vein can then be continued
under the pectoralis minor muscle with inclusion of this fibrofatty tissue with the specimen. The axillary contents
are now dissected from medial to lateral off of the serratus anterior muscle. During this portion of the dissection,

Fig. 4D: After completion of the axillary dissection, the relationship of


Fig. 4C: The thoracodorsal neurovascular bundle is seen laterally. the nerves can be seen. The intercostobrachial nerve can be identified
Near the axillary vein, the thoraco- dorsal nerve is more medial and preserved. The long thoracic nerve is identified slightly lateral to
than the artery and vein. the serratus anterior, in the encapsulating fascia. The long thoracic
nerve is in the same anteroposterior plane as the thoracodorsal
nerve, so knowing where the thoracodorsal nerve is will help the
surgeon identify the long thoracic.

the medial aspect of the intercostobrachialnerve is identified, and the entire nerve can be freed from the
specimen if the decision was made to preserve it. The long thoracic nerve is also identified (Fig. 4D). Knowing
where the thoracodorsal nerve is will help the surgeon identify the long thoracic. The crossing branch of the
thoracodorsal vein will serve the same purpose. The most common mistake is to look for the nerve directly on the
serratus anterior, thus actually retracting the nerve into the specimen. Once identified, it is cleaned off along its
length. With both nerves visualized, the tissue between the nerves may be clamped at the inferior margin of the
vein and suture ligated. The tissue may now be dissected free from the muscle. The nerves should be visualized
throughout this portion of the dissection.

Once the specimen is removed, hemostasis is assured and a closed suction catheter is placed through a
separate incision lower on the chest wall. The drain is secured with a suture and attached to a suction reservoir.
The wound is closed with absorbable subcutaneous sutures and the skin reapproximated.

Complications after ALND are discussed under complications of modified radical mastectomy.
4,5,6,9
Modified Radical Mastectomy
A modified radical mastectomy removes all breast tissue, the nipple-areola complex, necessary skin, and the
level I and II axillary lymph nodes.

After the induction of general anesthesia, the patient is positioned supine with the arm abducted to 90 degrees on
an armboard. The arm is not secured to the armboard for the MRM so that it may be brought into the operative
field during surgery. The chest, axilla, and entire arm are prepared and draped in sterile fashion. The prepared
area should extend sufficiently beyond the breast so that the landmarks can be easily identified: across the
midline, to the costal margin, the base of the neck, and laterally to the operating room table, including around the
shoulder. The forearm and hand are draped in a towel secured with a bandage.

Incisions
The standard incision for a mastectomy is an elliptical skin incision including both the nipple-areolar complex and
the previous biopsy incision. The ellipse may be oriented either transversely or obliquely. The choice of incision
must be based on the size of the breast, body habitus of the patient, and size and location of the tumor (or biopsy
cavity). Care should be taken to make the ellipse wide enough that redundant skin is avoided, including dog-ears,
but not so wide that the closure is excessively tight. It is not necessary to extend the incisions further into the
axilla; a complete axillary dissection can be performed through the standard incisions. Undue tension may lead to
vascular compromise of the flaps.

There are several options for how this ellipse is oriented. The classic Stewart incision results in a transverse
scar (Fig. 5). It should begin at the lateral margin of the sternum and end at the anterior margin of the

109
latissimusdorsi. It is not necessary to extend the incisions further into the axilla; a complete axillary dissection can
be performed through the standard incisions. The Stewart incision may be modified to lie obliquely, so the final
incision extends superiorly at the lateral margin.

Fig. 5: The classic Stewart elliptical skin incision for central and Fig. 6:The modified Stewart oblique elliptical skin incision for
subareolar breast cancers. The medial extent of the incision is the inner quadrant breast cancers. The medial extent of the incision
ipsilateral margin of the sternum, while the lateral extent overlies often extends to the midsternum
the anterior margin of the latissimus dorsi muscle. The incision
incorporates the nipple-areola complex and skin overlying the
breast cancer en bloc with skin margins that lie 1 to 2 cm from the
cephalad and caudad extents of the cancer.

The other popular incision is the Orr oblique incision. As opposed to the modified Stewart incision, which
extends slightly superiorly in the lateral margin, the Orr incision is an oblique incision (Fig. 6). This approach is
ideal for upper, outer quadrant incisions but, as with the Stewart incision, can be used for most tumors. Incisions
appropriate for cancers occupying various locations in the breast are shown in Figures 5, 6, 7,8, 9, 10, 11. The
elliptical incision of the breast skin incorporates the nipple-areola complex and skin overlying the breast cancer
en bloc with skin margins that lie 1 to 2 cm from the cephalad and caudad extents of the cancer.

Raising of skin flaps


Skin flaps are developed using cautery or scalpel and extend to the boundaries of dissection for the modified
radical mastectomy, which are: (a) the anterior margin of the latissimus dorsi muscle laterally, (b) the lateral
border of the sternum medially, (c) the clavicle superiorly, and (d) the superior extent of rectus sheath inferiorly
(Fig. 11).

The skin incision is then made with a scalpel, dividing the skin and superficial fascia just until the breast tissue is
evident. Several superficial veins need to be cauterized. Once the skin incision is completed, the superior flap is
raised. The skin edges are elevated at a right angle to the chest wall to adequately expose the superficial fascia
(Fig. 12). The appropriate dissection plane for skin flap elevation is deep to the subcutaneous vasculature and
superficial to the vessels of the breast parenchyma. The surgeon elevates the skin flap with consistent thickness
to avoid creation of devascularized subcutaneous tissues. If cautery is used, it should not be maintained in one
position for too long a period of time to avoid thermal injury to the flap.

110
Fig 7: The classic Orr oblique elliptical skin incision for cancer of Fig. 8: Variation of the Orr oblique elliptical incision for
the upper outer quadrant of the breast. The incision, which is lower inner quadrant and lower midline (6 o'clock) breast
directed cephalad toward the ipsilateral axilla, incorporates the cancers.
nipple-areola complex and skin overlying the breast cancer en
bloc with skin margins that lie 1 to 2 cm from the cephalad and
caudad extents of the cancer.

Elevation of the breast parenchyma


Once the skin flaps are developed, the breast parenchyma and pectoralis major fascia are elevated from the
underlying pectoralis major muscle in a plane parallel with the muscle bundles as they course from their medial
origin (ribs 2 to 6) to their lateral insertion on the humerus (Fig. 13). Perforating vessels from the lateral thoracic
or anterior intercostal arteries, which are end arteries that supply the pectoralis major and minor muscles and
breast parenchyma, are regularly encountered and cauterized. Elevation of the breast parenchyma and pectoralis
major fascia is continued laterally until the lateral edge of the pectoralis major muscle and the underlying
pectoralis minor muscle are exposed.

The laterally placed neurovascular bundle in which the medial pectoral nerve innervates the pectoralis major and
minor muscles. If possible, this nerve is preserved to prevent atrophy of the lateral head of the pectoralis major, a
significant cosmetic and functional defect.

Axillary Dissection
As the breast is removed from the lateral border of the pectoralis major muscle, the space between the pectoralis
major and minor muscle can be developed so that palpation of the interpectoral (Rotters) nodes can be
undertaken (Fig. 14). Some surgeons only remove this tissue when palpable nodes are detected; other surgeons
routinely include the fibroareolar tissue in the interpectoral space, which can be swept laterally and included with
the specimen. However, excessive dissection in this area can lead to injury of the lateral pectoral nerve and is
unlikely to be of added benefit if grossly involved nodes are not present. The investing fascia of the axillary space
is sharply divided (Fig. 14), the pectoralis minor muscle is defined, and lymph nodes, which may lie between the
pectoralis muscles (Rotter nodes), are cleared. As the axillary lymph node dissection proceeds, the loose areolar
tissue of the lateral axillary space is elevated with identification of the lateral extent of the axillary vein in its
course anterior and caudad to the brachial plexus and axillary artery (the axillary contents can also be removed in
a medial to lateral direction). The investing layer of the axillary vein is dissected sharply, with dissection allowing
complete visualization of the anterior and ventral surfaces of the vein. Ligation and division of intervening venous
tributaries is performed. Dissection continues medially on the anteroventral surface of the axillary vein, and the
loose areolar tissue at the juncture of the axillary vein with the anterior margin of the latissimusdorsi muscle is
swept inferomedially to include the lateral group of axillary lymph nodes (level I, see Fig. 15). The
intercostobrachial nerves are visualized, and course through the level II axillary lymph nodes that lie below the
axillary vein. Generally, no attempt is made to salvage the superior trunk and branches of the intercostobrachial
nerve.

111
Fig. 9 (Left): Oblique elliptical skin incision for upper inner
quadrant breast cancers. The medial extent of the incision
often extends to the midsternum. The cephalad skin flap,
which is subsequently developed, must provide exposure to
the axilla for axillary lymph node dissection.

Fig. 10 (Above): Oblique elliptical skin incision for lower


outer quadrant breast cancers.

Fig. 11: Vertical elliptical skin incision for high-lying,


midline (12 o'clock), or infraclavicular breast cancers.
The lateral skin flap, which is subsequently developed,
must provide exposure to the axilla for axillary lymph
node dissection.

112
The thoracodorsal artery and vein are preserved- they are located deep in the axillary space and are invested
with loose areolar tissue and the axillary lymph nodes of the lateral and subscapular groups (Figs. 15, and 16).
The thoracodorsal nerve originates from the posterior cord medial to the thoracodorsal artery and vein and is
visualized and protected along its variable inferolateral course en route to its innervation of the latissimus dorsi
muscle.

The lateral axillary lymph node group (Fig. 15) is retracted inferomedially and anterior to the thoracodorsal
neurovascular bundle and dissected en bloc with the subscapular group of axillary lymph nodes (level I), which
are medially located between the thoracodorsal nerve and the lateral chest wall. Dissection of the posterior
contents of the axillary space exposes the posterior boundary of the axilla, allowing visualization of the heads of
the teres major muscle laterally and the subscapularis muscle medially.

Fig. 12: Initiation of the modified radical mastectomy. Fig. 13: Elevation of the breast and pectoralis major fascia off of
Development of skin flaps. the underlying muscle. Dissection should proceed superior to
inferior and medial to lateral.

Dissection then proceeds medially with extirpation of the central axillary lymph node groups (level II). A level III
dissection is generally considered unnecessary (unless there is grossly apparent disease present in the
axillary apex) because skip metastases to level III only occur in 2% to 3% of cases and due to increased
incidence of lymphedema. The surgeon continues the dissection en bloc to avoid separation of nodal groups
and disruption of lymphatic vessels in the axilla.

Fig. 14: Exposure of the pectoralis minor muscle and incision of the investing fascia of the axilla.

113
Fig. 15.Axillary lymph node dissection (Patey modification).

Fig. 16: The completed axillary lymph node dissection. In this illustration, the pectoralis minor muscle has been resected (Patey
modification).The medial and lateral pectoral nerves, the thoracodorsal neurovascular bundle, and the long thoracic nerve are preserved.

With medial dissection, the surgeon encounters the chest wall deep in the medial axillary space and is able to
identify and preserve the long thoracic nerve (of Bell), which is constant in its location, anterior to the
subscapularis muscle, and is closely applied to the investing fascial compartment of the chest wall. The long
thoracic nerve is dissected along its course to where it innervates the serratus anterior muscle (Figs. 14, 15, 16).

114
Damage to the nerve causes permanent disability with a winged scapula deformity. When level III
lymphadenopathy is present, a Patey modification of the modified radical mastectomy may be employed
(Figs. 15 and 16). As dissection proceeds medially along the lateral margin of the pectoralis major muscle,
abduction of the shoulder and extension of the arm along with finger dissection at the lateral margin of the
pectoralis major muscle allows visualization of the insertion of the pectoralis minor muscle on the coracoid
process of the scapula. The Patey modification involves division of the tendinous portion of the pectoralis minor
muscle near its insertion on the coracoid process with or without removal of the muscle, which permits access to
the apical axillary lymph nodes (level III).

Closure
Once the axillary lymph node dissection is complete, the resection specimen is sent for histologic examination
and for immunohistochemistry (ER, PR, Her2-neu). The surgical bed is irrigated with normal saline to evacuate
residual tissue, blood clots, and serum. Bleeding points are identified and cauterized or ligated. Just prior to
closure, two closed-suction drains are typically placed through two different stab incisions inferiorly (Fig. 16). The
laterally placed drain is positioned in the axillary space approximately 2 cm inferior to the axillary vein on the
ventral surface of the latissimus dorsi muscle to provide drainage of the axilla. The medially placed drain is
positioned under the skin flaps. Both drains are secured to the skin with a 2-0 silk suture and are connected to
the suction reservoir. The wound is closed with 3-0 or with 4-0 nylon suture.

Postoperative Care
Wound dressings are removed after 24 to 48 hours. The silastic catheters remain in place until drainage
becomes serous or serosanguineous in character and decreases to less than 30 mL per 24 hours for a 48-hour
period. Generally, the catheters are removed between postoperative days 5 and 7, but, when necessary for
continued high-volume drainage, can remain until postoperative day 10. Range-of-motion shoulder exercises
begin 24 hours after surgery.
2,10
Total Mastectomy and Prophylactic Mastectomy
The term total mastectomy refers to the removal of the entire breast, with the same limits of dissection as
described for the modified radical mastectomy. Care must be taken to remove the axillary tail of Spence, and
therefore identification of the latissimus dorsi muscle is important. Bot pectoral muscles and the axillary nodes
are preserved. The indications for total mastectomy include the patients with DCIS who elect mastectomy,
patients undergoing prophylactic mastectomy, patients in whom a recurrence develops in the breast after a BCS
that had included ALND, and patients with metastatic disease who are undergoing toilet mastectomy for local
control of the primary tumor.

Prophylactic mastectomy continues to be indicated as an option


for patients at high risk of developing breast cancer, including
known gene mutation carriers of BRCA1 or BRCA2, strong family
history of multiple first-degree relatives, or successive generation of
breast or ovarian cancer and high-risk lesions such as atypical
ductal hyperplasia and lobular carcinoma in situ. This decision
should be made with the assistance of a multidisciplinary team and
includes a thorough discussion of alternative such as close
surveillance and risk-reduction techniques.
10
Skin Sparing Mastectomy
This alternative to a simple total mastectomy for breast cancer can
be used when immediate reconstruction is planned, and usually
results in a better cosmetic appearance. A total mastectomy is
performed through a circumareolar incision. The nipple and areola
are excised with the rest of the breast, but the breast skin is Fig. 17: Skin sparing mastectomy incisions: varying
preserved as an envelope, which receives an immediate
incisions used in skin sparing mastectomy. The
reconstruction.
incision is in part determined by areas of previous
Complications of Breast Surgery biopsy. The goal is to minimize area of scar on the
Wound complications are typically minor and frequently managed skin envelope by incorporating biopsy incisions
on an outpatient basis, but can occur in up to 30% of cases. These
include flap necrosis, breast infections, seromas, and
hematomas. Very rarely, more serious complications can occur. Flap necrosis and epidermolysis occurs in 18-
30% of all mastectomies. Deep venous thrombosis and pulmonary embolism (PE) are potential complications of
any major surgery. Pneumothorax has been described as a result of wire localization or inadvertently deep
dissection. Brachial plexopathy may occur related to a stretch injury of a malpositioned patient.

Major Complications of Axillary Lymph Node Dissection


Seroma, Infection, Paresthesia, Chronic pain, Shoulder immobility, Axillary vein thrombosis, Thoracodorsal nerve
injury, Long thoracic nerve injury (winged scapula), Brachial plexopathy, Arm lymphedema, Breast lymphedema.

115
Box 7: Anatomic Complications of the Modified Radical Mastectomy
Vascular Injury
The first and second perforating vessels are too large for cautery. They are ligated.
The axillary vein, if torn, is repaired. Ligation may cause chronic edema.
Nerve Injury
Intercostobrachial nerve When cut, circumscribed numbness of the medial aspect of
the ipsilateral upper arm results.
Long thoracic nerve If cut, a winged scapuladeformity results
Medial and lateral thoracic nerves If cut, the pectoralis muscles atrophy.
Thoracodorsal nerve If cut, internal rotation and abduction of the shoulder are
weakened.

Lymphedema
The most significant complication of an ALND is lymphedema of the upper extremity. Approximately 10% to 30%
of patients who have an ALND will experience lymphedema.

Box 8: risk factors for lymphedema among patients undergoing axillary surgery
Extent of surgery: increased risk after level I,II,III dissection compared to level I,II dissection
Radiation
Infection
Regional recurrence
Inflammatory diseases (rheumatoid
arthritis, chronic dermatitis)
Venous obstruction
Obesity
Air travel

Box 9: Risk factors for lymphedema among patients undergoing axillary surgery
Use the opposite arm for intravenous catheters, blood draws, injections, or blood pressure
measurements.
Avoid cuts, scratches, or burns to the hand and arm by wearing long sleeves and/or gloves
when doing cooking, gardening, household projects, etc.
Do not wear tight or constricting jewelry or clothing.
Wear a compression sleeve on the arm when lymphedema manifests
Advice to maintain an ideal body weight.

Breast Reconstruction
Breast reconstruction may be performed as immediate reconstruction, that is, the same day as mastectomy, or
as delayed reconstruction, months or years later. Immediate reconstruction has the advantages of preserving the
maximum amount of breast skin for use in reconstruction, combining the recovery period for both procedures,
and avoiding a period of time without reconstruction. Immediate reconstruction does not have a detrimental effect
on long-term survival or local recurrence rates. Reconstruction may be delayed in patients who might require
postmastectomy radiation therapy and is usually delayed in patients with locally advanced cancer.
Reconstruction options include tissue expander and implant reconstructions and autologous tissue
reconstructions, most often with latissimusdorsi flaps, transverse rectus abdominis muscle (TRAM) flaps, and
more recently, muscle-preserving
perforator abdominal flaps.

Latissimus dorsi
musculocutaneous flap
This is the most widely used method
of breast reconstruction following
mastectomy. After completion of the
mastectomy and any axillary
clearance, the patient is turned on her
side and a suitably sized ellipse of
skin marked overlying the latissimus
dorsi muscle. The paddle is placed
sufficiently posteriorly to afford
adequate length to the flap (Fig. 18A).
The skin is incised, leaving it attached
to the underlying muscle. The skin and
fascia are dissected off the muscle
proximal and distal to the skin ellipse,
and the muscle freed on its deep
Fig. 18: The latissimus dorsi flap
116
surface, prior to dividing its posterior
attachment. It may then be elevated as a
flap based on the branches of the
subscapular vessels. Dissection is carried
along the flap pedicle until it can be rotated
and passed subcutaneously round to fill the
breast defect (Fig. 18B). The flap is then
rotated through the axilla to the anterior
defect. Ideally, the muscle should be
denervated to avoid future painful
contractions. The donor site is closed over
suction drains and the patient returned to
the supine position. The latissimus dorsi
muscle forms the tissue replacement for
the excised breast, and its overlying ellipse
of skin is sutured to the upper and lower
mastectomy flaps.

Alternative flaps
Although pedicled transverse rectus Fig. 19: The transverse rectus abdominis myocutaneous flap rotation. A,
abdominis myocutaneous (TRAM) flaps Contralateral technique. B, Ipsilateral technique.
based on the internal thoracic artery have a
somewhat perilous blood supply, free
TRAM flaps, or free deep inferior epigastric artery perforator (DIEP) flaps, based on the inferior epigastric artery
are increasingly employed where microsurgical skills are available. These are preferred by some surgeons to
latissimusdorsi flaps. A free superior gluteal artery perforator flap is another alternative.

References

1. Halstead WS. The results of operations for the cure of cancer of the breast performed at the John Hopkins
Hospital from June 1889 to January 1894. Ann Surg 1894; 20: 497555.
2. Haagenson CD. The history of surgical treatment of breast carcinoma from 1863 to 1921. In: Diseases of the
breast, 3rd ed. W.B. Saunders, Philadelphia 1986: 864-871
3. Dixon JM, Soon PSH. Breast-Conserving Surgery. In: Fischer, Josef E (eds): Mastery of Surgery. 5th ed.
Lippincott Williams & Wilkins; 2007:502-517.
4. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy,
lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med
2002;347:1233.
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7. Souba WW, Bland KI: Indications and techniques for biopsy. In Bland KI, Copeland EM III (eds) The Breast:
Comprehensive Management of Benign Malignant Diseases. Philadelphia: WB Saunders, 1998: 802-809
8. Allweis TM, Badriyyah M, Bar Ad V, et al. Current controversies in sentinel lymph node biopsy for breast cancer.
Breast 2003;12:163.
9. Bland KI, Beenken SW. Modified Radical Mastectomy with Immediate or Delayed Breast Reconstruction. In:
Fischer, Josef E (eds): Mastery of Surgery. 5th ed. Lippincott Williams & Wilkins; 2007:530-544.
10. Tuttle TM, HabermanEB, Grund EH et al. Increasing use of contralateral prophylactic mastectomy for breast
cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol 2007;25(33):5203309.

Growth for the sake of growth is the ideology of the cancer cells
~ Edward Abbey Comprehending Nature.

Metastatic breast cancer (A Surgeons approach)

Ajit Sinha

Introduction
Cancer incidence is generally expressed as age adjusted or age standardized rate according to the world
standard population per 100,000 persons.

In female, breast cancer continues to be the most frequent cause of cancer death (15% 40,290) preceded only
[1]
by lung cancer (26% 71,660) and the most frequently diagnosed cancer. This can be attributed to improvement
in imaging and diagnostics, coupled with advancement in treatment strategies over the recent years.

117
Among females, breast cancer and cervical cancer are the leading sites of cancer in 18 out of 25 population
2]
based cancer registry PBCR[

Metastatic breast cancer (MBC) ie; stage IV breast cancer is defined as the spread of tumor beyond the breast,
chest wall and regional lymph nodes to other sites of the body. So any T, Any N and M 1 constitute a metastatic
disease. Approximate 50% of patient with breast cancer develop distant metastasis. Tumor dissemination can
occur via-direct extension through chest wall, through blood and lymphatic. Common sites includes bone, lung,
[3]
liver, chest wall, brain and distant lymph nodes. Symptoms are related to the site and extend of the tumor.

While strategies for treatment of primary tumor has markedly improved, no significant cure is available for MBC
and current treatment strategies focus mainly on symptom control and minimization of adverse effects to improve
[4]
disease free survival (DFS) and good quality of life.

Systemic therapy is the treatment of choice and surgery in a breast cancer with distant metastasis is indicated
only to prevent local complications-ulceration and fungation. Though it is generally accepted that local therapy
provides no survival advantage once metastasis has occurred, infact tumor excision may further stimulate the
growth of metastasis, various RCTs however suggests that surgery of primary tumor can actually improve
[5]
survival in a patient with only bony metastasis.

Natural History of Breast Cancer


th
At approximately 20 cell doubling, breast cancer cells acquire their own blood supply (neovascularization),
thereafter may spread into systemic venous blood to seed into distant sites such as pulmonary circulation via
axillary and intercostal veins or via batson plexus into the vertebral column. Successful implantation of the
metastatic foci from breast cancer occurs after primary cancer exceeds 0.5 cm in diameter.

Management of the breast cancer is based on the understanding of the tumor natural history. Three viewpoints
have been proposed on the basis of various hypotheses concerning the tumor biology.
[6]
1. Contiguous Theory spread from one source by Dr. William Halsted.
Halsteadian theory proposed that breast cancer begins strictly as a local disease and that
tumor cells spread overtime in a contiguous manner through lymphatics and that even distant
metastasis are the result of direct extension of local involvement. This theory dictated on the
aggressive local therapy for control of disease on the breast chest wall and regional lymph
nodes and provided justification for radical breast surgery.

2. The Systemic Theory or Alternative Theory By Dr. Bernard Fisher.


Fisher postulated that breast cancer is a systemic disease and that operable breast cancer has
distant micro metastasis at its very early stage. Hence variation in local treatment would not
effect survival; since it is the presence of the micro metastasis that determines the final
outcome.
His theory had a therapeutic implication on the management of breast cancer by introduction of
[7]
adjuvant systemic treatment and part of surgery replaced radiation for locoregional control.

3. The Spectrum Theory-By Dr. Hellman.


This hypothesis synthesized the aspect of the previous two theories; that breast cancer is a
spectrum of proclivities ranging from a disease that remain localized throughout its course to
one that is systemic when it is first detectable. Dr. Hellman suggested that metastasis is a
function of the tumor growth and progression and lymph node involvement indicates more
malignant potential.

4. Recent Concepts
Metastatic potential is an inherent , genetically predetermined property that is expressed very early by
tumor cells
Tumor cells are programmed to metastasize to a certain site in the presence of a favourable
environment.
Surgical removal of a primary tumor may reverse tumor induced immunosuppressant and restores both
T and B cells immunity
Self seed theory self seeding of the tumor cells occur at the primary site or other distant sites;
[8]
which supports complete excision of the primary
Biologic hypothesis- surgical removal of the primary tumor in a woman with MBC may confer a growth
advantage on distant metastasis.

Clinical Presentation of a MBC

A patient may present as a MBC or develop a systemic recurrence after treatment of an apparently localized
breast cancer. Most common sites of metastasis in order of frequency are- bone, lung, pleura, soft tissue and
liver. Symptoms are related to the location and extend of the tumor.

118
Hormone receptor positive tumors are more likely to spread to bone as an initial site of metastasis; while
hormone receptor negative or HER 2 positive tumors are more likely to recur initially in viscera.

[10]
Lobular carcinoma more likely to metastasize to the pleura and abdomen compared to ductal carcinoma

Triple Negative breast cancer (TNBC)


Those patients whose tumor are negative for all the three biomarkers ER, PR, HER 2 are referred to as triple
negative and have increased risk of multiple visceral and brain metastasis and have poorer prognosis.
Chemotherapy is the mainstay of treatment for these patients
OMBC- Oligometastatic breast cancer is a subset of MBC with limited number and sites of metastasis and
constitutes as high as 20% of all MBC. There is increasing evidence that there is a potential advantage of
removing the primary tumor in OMBC by eliminating a potential source for further metastatic seeding,
restoration of immune competence and reduction in chemo resistance by reducing the number of clones.

Stage IV NED
Approx 1-10% of women with MBC have a metastatic of disease as an isolated lesion. These groups of patients
are known as Stage IV no evidence of disease (NED) and have relatively poorer prognosis due to early
metastasis at distant sites.

Diagnostic Approach for MBC

Staging evaluation includes:


Triple assessment ( thorough clinical examination , Imaging and histopathological examination)
Tissue diagnosis-
NCCN Panel recommends that metastatic disease at presentation or first recurrence of disease should be
biopsied for histological assessment of the biomarkers which will allow selection of appropriate treatment. As
discordance between the receptor status of primary and recurrent diseases has been reported in 7.2 % -
31% for ER and 0.7-11% for HER2, Reassessment is therefore mandatory. This discrepancy may be related
to change in the biology of the disease, differential effect of prior treatment on clonal subset, tumor
heterogeneity or imperfect accuracy of assay (NCCN guidelines 2015)
Metastatic work up and diagnostic radiographs of chest , CT of abdomen , bone scan and radiograph of the
long bones or weight bearing area that are painful or appear abnormal on bone scan
FDG-PET scan is helpful in situation where the standard imaging results are equivocal or suspicious.
Extensive evaluation to identify metastatic disease is not required in asymptomatic patients with Stage I and
II breast cancer because of low likelihood of metastasis. But in stage III breast cancer occult metastasis is
found in 20% of cases and staging studies are recommended.

Prognostic Factors in MBC-

The likelihood of response to therapy in a MBC is dependent on


Tumor biology (grade, ER/PR , HER 2 status)
Cancer related symptoms
Sites of recurrence
Number of the sites of recurrences
Performance status of the patient
Prior adjuvant therapy
Period of disease free interval

[10]
Prior therapy for metastatic disease

Patients who have received less therapy, experienced longer disease free interval since initial diagnosis, soft
tissue or bone metastasis, fewer symptoms, better performance status are more likely to experience longer
[10]
survival

Patients whose tumor is negative for ER/PR, HER receptors referred to as triple negative breast cancers have
relatively poorer prognoses.

Metachronous breast cancer have more frequent relapse rate and distant metastasis and better response to
chemotherapy in case of relapse as compared to synchronous breast cancer .

Management of MBC
MBC is considered as incurable disease and therefore treatment is mainly palliative. Systemic therapy is the
treatment of choice and removal of metastatic lesion is suggested only in selected patients .
A treatment goal in patients with MBC includes:
Prolongation of life
Control of tumor burden
Reduction in cancer related symptoms or complication
Improvement of quality of life and function

119
Various treatment options are:

1. Endocrine therapy
Patients with hormone receptor status positive tumors with minimal symptoms and limited visceral involvement
are candidates for initial treatment with endocrine therapy alone. ASCO guidelines suggest that Endocrine
therapy should be offered as the standard first line treatment for patients with hormone receptor positive MBC,
except in cases of immediate life threatening disease or when patient has developed resistance to endocrine
therapy. Sequential single agent chemotherapy rather than combination therapy is preferred, however
combination regimen must be considered for immediate life threatening disease as metastatic disease can
progress rapidly if there is no response to a single agent. No single agent has demonstrated superiority in
treatment of MBC and treatment selection must be based on previous therapy, differential toxicity, co- morbid
[12]
conditions and patients preference. First line Endocrine therapy is associated with 8-12 months of tumor
control. TAMOXIFEN is the standard endocrine therapy for hormone receptor positive tumors and causes
[10]
estrogen suppression and achieve response rate of 50% in ER positive MBC. Tamoxifen flare can occur in 5-
10% of the patients within days or weeks of therapy; characterized by intensification of bone pain, transient tumor
progression, hypocalcaemia, and must be distinguished from over tumor progression. It usually subsides in 4-6
weeks. Side effect of Tamoxifen includes hot flashes, increased risk of thrombosis , uterine bleeding,
endometrial cancer. For pre-menopausal women with metastatic disease, initial treatment is ovarian
suppression with selective ER modulator Tamoxifen.

Endocrine Therapy in Pre-Menopausal Women


1. Selective ER modulator : Tamoxifen
2. Ovarian ablation or suppression
LHRH agonist- Goserelin , Leuprolide
Progestin- Megestrol acetate
Androgen- Fluoxy mesterone
High dose estrogen Ethinyl estradiol
Surgical or Radio therapeutic Oophorectomy

Endocrine Therapy in Post-Menopausal Women


Options include-
1. Non steroidal Aromatase inhibitor- Anastrozole , Letrozole
2. Steroidal Aromatase inhibitor Exemestane
3. Selective ER modulator Tamoxifen
4. ER down Regulator Anti-Estrogen ; Fulvestrant
5. Progestin Megestrol acetate
6. High dose Estrogen Ethinyl estradiol

Post menopausal women with MBC , who are anti-estrogen nave OR who are on > 1 year of estrogen therapy,
options includes - Aromatase inhibitors , Selective ER modulators, ER down regulator (Fulvestrant ) . Whereas
post menopausal women with MBC , who have received prior Tamoxifen therapy in an adjuvant settings OR are
within 1 year of anti estrogen therapy , Aromatase inhibitors are the preferred options.

Resistance to endocrine therapy can develop in women with hormone receptor positive status. This is due to
activation of mammalian target of rapamycin ie; mTOR signal transduction pathway. In such cases Aromatase
Inhibitors AIs + inhibitors of mTOR (eg; Everolimus) are recommended.

Both pre and post menopausal women with hormone responsive breast cancer, benefit from sequential use of
endocrine therapy at disease progression.

2. Chemotherapy in MBC
Cytotoxic chemotherapy is the mainstay of treatment for MBC irrespective of hormone receptor status. It can
be used in women with hormone receptor status negative tumors, with symptomatic visceral metastasis or
hormone receptor status positive tumors refractory to endocrine therapy.
Due to its substantial side effects; the benefit must be weighed against the toxicities and treatment must be
interrupted in patients who shows significant response or palliation and reintroduced when there is tumor
progression or recrudescence of symptoms.

There is no optimal single first line Chemotherapy and treatment option must be based on efficacy of prior
treatment, risk of life threatening disease, relative toxicity, performance status co morbid conditions and patients
preference.

Recommendations by ASCO for Chemotherapy and Targeted therapy


Sequential single agent CT is preferred in a MBC, as it facilitates better understanding of the response and
less toxicity. However combination regimen is considered for patients with immediate life threatening disease
as the metastatic disease progresses rapidly if there is no response.

120
ERIBULIN a mitotic spindle inhibitor is used in MBC who have previously received at least 2
Chemotherapy regimen (Anthracyclines and taxanes)
In PHASE III RCT Addition of BEVACIZUMAB with PACLITAXEL with has demonstrated improved
[13]
response rate and progression free survival rate (PFS ) but not overall survival (O.S)
However the unique side effect of Bevacizumab is - increased risk of hypertension and thromboembolism
and there is no specific marker for tumors that are likely to benefit from antiangiogenic therapy

Single Agents
Anthracyclines Doxorubicin, Epirubicin
Taxanes Paclitaxel , Docetaxel
Anti-metabolites (5FU )- Capecitabine , Gemcitabine
Mitotic spindle inhibitors Eribulin , Vinorelbine
Platinum salts- Cisplatin, Carboplatin
Others Cyclophosphamide , Etoposide

Combination Regimen
CAF Cyclophosphamide ,Adriamycin, 5 FU
FEC- 5FU , Epirubicin, Cyclophosphamide
AC Adriamycin, Cyclophosphamide
EC- Epirubicin , Cyclophosphamide
CMF- Cyclophosphamide, Methotrexate , 5 FU
GT- Gemcitabine , Paclitaxel
Paxlitaxel, Bevacixumab.

3. Anti-HER2 therapy
It is a treatment targeted against Human epidermal growth factor 2 receptor, a protein that is over expressed by
certain type of aggressive breast tumors (20-25%).

The NCCN panel recommends selecting patients with HER -2 targeted therapies if the tumors are positive for
HER-2 by ISH (in situ hybridization) or 3+ve by ICH (immunohistochemistry)

TRASTUZUMAB is used as first line anti-HER2 therapy. When added to chemotherapy in HER2- positive
tumors, trastuzumab showed synergistic effect and improve response rate 7 times to progression as well as over
all survival rate.

Cardiomyopathy is a well known side effect of trastuzumab, hence concurrent administration with Anthracyclines
must be avoided.

LAPATINIB - second line anti-her 2 therapy for patient with tumor progressing despite Trastuzumab therapy. It is
a dual kinase inhibitor that targets both HER2 and EGFR tyrosine kinase.

PERTUZUMAB another humanized monoclonal antibody that binds to a domain of the HER2 saperately from
trastuzumab . it is assumed to overcome the limitations of trastuzumab

Preferred First Line Regimen for HER 2 positive tumors


Pertuzumab + Trastuzumab+ Docetaxel
Pertuzumab +Trastuzumab + Paclitaxel
Other regimen- Trastuzumab +Paclitaxel +Carboplatin
Trastuzumab +Docetaxel
Trastuzumab +Capecitabine

Regimen for Trastuzumab Exposed HER 2 Positive Diseases


Ado- Trastuzumab Emtansine (T-DM1 )
Lapatinib +Capecitabine
Lapatinib +Trastuzumab

Role of Surgery and Radiotherapy in MBC with Intact Primary


Role of surgery in MBC is very limited. Women with MBC with intact primary tumor are primarily treated with
systemic therapy and surgery is considered only for palliation of symptoms or complication such as ; fungation ,
skin ulceration, bleeding etc and done only when complete local clearance of the tumor may be obtained and
other sites of disease are not immediately life threatening. Radiation therapy is an alternative option.

Several studies suggested that surgical removal of primary breast cancer in MBC actually improves survival if
[14]
performed with negative surgical margins, esp. in patients with only bone metastasis. It was suggested that
the total tumor burden play a central role in survival and that the primary tumor can be considered as a another
metastatic site, therefore removal of the primary tumor could be considered as a part of multi modality strategy to

121
prevent further metastasizing of cancer cells. This is consistent with the recent studies that suggest a strong
correlation between the level of circulating tumor cells CTCs and prognosis of MBC.

However in a clinical trial presented at 2013 San Antonio Breast cancer Symposium, It was suggested that ,
patient with MBC may not benefit from surgery and radiation after chemotherapy ; as such treatment may
facilitate growth of metastatic disease and concluded that such treatment may be reserved only for palliation of
[15]
symptoms.

MANAGEMENT OF SITE SPECIFIC METASTASIS

Bone Metastasis
Skeletal related events like pathological fracture, bone pain, cord compression, hypercalcemia can occur in a
MBC with bone metastasis.

According to NCCN guidelines,


Iv BIPHOSPHONATE Pamidronate 90 mg or Zolidronic acid 4 mg can be given in combination with oral
Calcium and Vitamin D3 supplementation. If expected survival is 3 months or longer and Serum Creatinine is
below 3.0 mg/dl and can be given in lytic bone metastasis in addition to Chemotherapy OR Endocrine therapy
A monoclonal activity against RANK ligand of osteoclast; Denosumab -120 mg can also be given every 4 week.
While those with impending bone fracture or pathological fracture surgical stabilization or external beam RT
may be required

Brain Metastasis
nd
Breast cancer is the 2 most common source of brain metastasis being preceeded only by lung cancer with an
incidence of approx 10-15% among patients with MBC.
Data from a large population study shows that brain is most frequently the first site of relapse in patient treated
[16]
with Trastuzumab in HER2 receptor positive tumors, whether in adjuvant or metastatic settings. Assumed to
be due to the role of chemokines- CXCR4 , which is found to be up regulated in the HER2 receptor positive
tumors and have emerged as a main challenge affecting the morbidity and mortality of patient with HER2
receptor positive MBC.

WBRT remains the standard of care and is associated with short term tumor regression and clinical improvement
in MBC with brain metastasis with survival ranging from 3-6 months
Combining WBRT + Trastuzumab has a good response rate.
In patients refractory to WBRT + Trastuzumab, LAPATINIB + CAPECITABINE can be given; however, pulmonary
[17]
embolism could be a dose limiting toxicity
Stereotatic Radio surgery (SRS) - is a minimally invasive and well tolerated by patients who are not surgical
candidate. It is emerging as a new modality of management for brain metastasis so that patient can be spared
from upfront WBRT whenever feasible.

Breast cancer liver metastasis (BCLM)-


Radiofrequency ablation (RFA)
Hepatic resection , if Ro resection is feasible and no extra hepatic metastasis present
Regional Chemotherapy
Regional Radiotherapy

Pulmonary metastasis
VATS or conventional Resection

Malignant pleural effusion-


VATS and Talcum pleurodesis
Chemical pleurodesis- Talcum slurry, bleomycin, mitoxantrone, povidone iodine
Continuous pleural drainage
Local antibody therapy- Catumaxomab

Soft tissue metastasis


Local Radiotherapy

Lepto-meningeal disease
WBRT / Intrathecal chemotherapy with methotrexate or cytarabine.

MONITORING OF METASTATIC DISEASE

Monitoring the treatment of MBC involves a wide array of assessments. Determine the effectiveness of the
treatment and the acceptability of toxicity. It takes into account
complete clinical examination

122
laboratory tests
radiographic imaging
functional imaging
tumor biomarkers

Results of these assessments are classified as Response; continued response to treatment; stable disease;
uncertainty regarding disease status; or progression of disease.

The NCCN Panel recommends widely accepted criteria such as RECIST or WHO criteria for reporting response,
stability, and progression of disease. Frequency of monitoring can be reduced in patients who have long term
[18]
stable disease.

References

1. American Cancer Society; cancer facts and figures 2015 @ 2015 American Cancer Society.Inc
2. ICMR, National Cancer Registry Programme. Three year report of population based cancer registry PBCR; 2009-
2011
National cancer registry programme (ICMR 2013, Bangalore)
3. Principles and practice of Oncology; DaVita Hellman and Rosenbergs. Ninth edition
4. Bernard Marty C, Cardoso F, Piccart MJ. Facts and controversies in systemic treatment of MBC. Oncologist 2004;
9: 617-632.
5. Elisabetta Rapiti, Helena M, George V. Complete excision of primary tumor improves survival in patient with
Metastatic breast cancer at diagnosis. J.Clin Oncol 24; 2743-2749@ 2006 by American society of clin oncol.
6. Rinaa S.Punglia, M.P.H. Monica Morrow, Eric P. Winer. N.Engl Journal of medicine 2007; 356: 2399-2405.
7. J. Formos ; Med asso 2004;103(8): 579-598.
8. Frank et al. Int J.Radiation Oncology. Biol. phy 2008. Future oncology 2015; 11
9. ASCO post 2013. San Antonio Breast cancer symposium
10. Devita , Hellman and Rosenbergs . Principle and practice of oncology. Ninth edition
11. Clinicopathological features in bilateral breast cancer . Asian pac J Cancer prev 2012; 13: 4571-4575.
12. Chemotherapy and targeted therapy for women with HER2 negative metastatic breast cancer . American society
of clinical oncology. Ann H. Partridge, R Bryan Rumble; Lisa A Carey
13. Kathy muler; MD ; Mous Wang PhD, Julie Gralow ,MD. Paclitaxel plus Bevacizumab versus Paclitaxel alone for
MBC N.Eng J of Med. 2007; 357: 2666-2676.
14. Elisabetta Rapiti ,Helena M,George Vlastos. Complete excision of primary breast tumor improves survival in
patient with MBC at diagnosis. J Clin.Oncol.24;2743-2749@ 2006 ,ASCO
15. Surgical removal of primary tumor and axillary LN in women with MBC at firs presentation. A RCT. Rajendra
Badwe, MD. @2013 San Antonio Breast cancer syumposium.
16. Yin W, Jiang Y, Shen Z, Shaw Z. Trastuzumab in the adjuvant treatment of HER2 positive early breast cancer. A
meta analysis of RCT. 2011
17. Capecitabine therapy of CNS metastasis form breast cancer. J.Neurooncol. 2007; 85(2): 223-227.
18. NCCN Guidelines ; inc .2015.

Role of Radiotherapy in breast cancer

Kishore Singh

With advent of multidisciplinary approach for the management of breast cancer, the survival has gone up, the
local recurrence and distant metastasis gone down. Surgery, radiotherapy, chemotherapy, hormone therapy are
the different modalities used for treatment. In the past Keynes G practiced BCS in 1937. Mc Whirter changed it to
Total Mastectomy & RT in 1955. Now there is again trend of BCS & RT (NIH Consensus 1992). BCS & RT
together is called as Breast conservation therapy. Recent met analysis at 20 year with PORT for early stage
rd
disease showed 2/3 decrease in LR with clear effect on total mortality (all node positives, but degree of benefit
for 1-3 nodes positive is less clear).

Now the question arises, as the breast cancer is a systemic disease, what is the need for a local treatment
modality like RT after surgery? Answer given by a landmark EBCTCG trial 2000, initial local control obtained by
RT increase breast cancer specific and overall survival rates (Lancet 2005; 366:2087-2106). Among the 25 000
women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks
were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were
446% versus 495% (absolute reduction 50%, SE 08, 2p_000001). Surgery is good for removal of gross
disease but leaves behind subclinical disease, whereas radiotherapy is superior in controlling the subclinical
disease. Therefore combining two results in improved local control and reflected in better overall survival rates.

Now the next important question is who are the patient groups to be subjected to adjuvant radiotherapy? There is
consensus that PMRT should be considered when risk of LRF is greater than 20%, such as for patients with four

123
or more positive axillary lymph nodes, primary tumour size 5 cm or more (T3), T4 disease and positive/very close
margin. Some studies suggest other factors as risks of local recurrence such as age less than 40 years,
histological grade 3 tumours, presence of lymphovascular invasion, less than 6 nodes removed at axillary
dissection and significant nodal extracapsular spread (> 2 mm). The merit of PMRT, however, in this group of
patients is not known. When breast conservation therapy is planned, RT to tumour bed is mandatory irrespective
of tumour size.

RT is to be started within 8 months of surgery and within 6 weeks of last chemotherapy cycle. To be started early
if high risk of local recurrence or microscopic residual disease, or else it can be started after the completion of
adjuvant chemotherapy.

Table- 1: Classification of risk groups.


Low risk ER / PR ve
& N0
& T1
&G1
& Age >35 years
& LVI 0
& Her 2 neu Negative
Intermediate risk ER / PR + ve
& N0
& T >1
&G2-3
& Age <35 years
& N + (1-3 LN)
& Her 2 neu Negative
High risk 1. N + (>3 LN)
Or
2. N + (1-3 LN) & LVI +
Or
3. Her 2 neu Positive

It can be delivered using conventional or conformal (IMRT, 3D- CRT) techniques. RT is contraindicated if there is
past history of chest wall irradiation, collagen vascular disease and during pregnancy.

Newer technique of RT for early breast cancer


RT substantially reduces the risk of local recurrence following breast conserving surgery.

PARTIAL BREAST IRRADIATION (PBI) - 75% of recurrences appear in 1st 5 yrs at or near original tumor site
(represent original tumor). Usually done by shorter treatment time with high dose per fraction (Hypofractionation);
often called as Accelerated Partial Breast Irradiation (APBI)

Advantage Compared to Whole Breast Irradiation: Accelerated treatment (Shorter Single day to 1 week), better
combination with chemotherapy and decrease overall cost of therapy; reduced treatment volume might reduce
risk of long term complications.

ASTRO's Accelerated Partial-Breast Irradiation Consensus Statement was used to classify patients with invasive
breast cancer as suitable for brachytherapy (34.7%), cautionary (17.6%), or unsuitable (35.2%); 12.5% of
patients were unclassified.
Basis of APBI:
1. New disease development is not controlled by whole breast RT, PORT impact at the site of initial
disease only
2. Documented under utilization of BCT
3. Time, cost and convenience of BCT
4. Potentially Acute and Chronic Toxicity
5. QOL
6. Eliminate schedule problem with CT
7. Potential to outcome ( delays to local therapy)

Technique Aim of coverage tumor bed with 1cm margin


TM TM
- PBI (Brachytherapy) through SAVI , Contura
TM
- MammoSite Radiation therapy system (RTS)
TM
- TARGIT IORT
- Protons

124
Cosmetic: Good to excellent >80%; decline with time in first 3 yrs, then stable until 7 yrs. Outcome is related to
tumor size, location, breast size, body weight, dose and tech of RT and extent of resection. (Recht A. Oncology
1999; 4:23-30).

Poor Cosmetic outcome if :


Small breast and large tumor
Associated with nipple discharge or sub capsular location
Multi centric
Extensive micro calcification on mammography - LF
Coexisting medical condition Collagen vascular disease
Unterminated pregnancy
Extensive Intraductal component 35% failure, these patients have significant residual disease.
Age young (<35yrs), associated with recurrence 21% Vs 10%

ASTRO- Choosing wisely


Dont initiate whole breast radiotherapy as a part of breast conservation therapy in women age 50 with early-
stage invasive breast cancer without considering shorter treatment schedules.

Conclusion
Radiotherapy is an integral modality for treatment of breast cancer. May it be an adjuvant modality still its role
cant be underestimated. So it is necessary to understand the indication and timings of radiotherapy during the
course of breast cancer treatment.

Approach to a patient with breast disease

Geeta Kadayaprath

Clinical
The commonest presentation of a patient with breast disease, accounting for more than 50% of all complaints
pertaining to the breast, is a lump. While most of these lumps are likely to be benign, it is the responsibility of the
clinician to allay the fears of the patient and be certain that the lump is not malignant. The presence of a lump
should never be taken lightly if the patient is young or if the lump feels right or if there is no family history or is
found in a male patient.

The dictum should always be Triple Assessment. No effort should be spared to correlate clinical, radiological
and pathological findings to finally arrive at a diagnosis.

Besides a lump, the other complaints could be pain in the breast, nipple discharge, palpable lump in the armpit,
nipple retraction or changes in the skin of the breast etc.

One could also dwell upon the menstrual history, previous surgeries, hormonal use, family history, treatment
history etc. for additional clues

History
A detailed history followed by thorough examination is an important exercise and puts one on the right path to
establishing a diagnosis. One can use a template, such as shown below, to get a comprehensive history without
missing out on vital points

Physical Examination
A complete clinical breast examination (CBE) includes an assessment of both breasts and the chest, axillae, and
regional lymphatics. In premenopausal women, CBE is best done a week after menses, when breast tissue is
least engorged. With the patient in an upright position, the breasts are inspected, looking for asymmetry, nipple
discharge, obvious masses, and skin changes, such as dimpling, inflammation, rashes, and unilateral nipple
.
retraction or inversion

With the patient supine and one arm raised, palpate the breast tissue on the raised-arm side in the superficial,
intermediate, and deep tissue planes (i.e., the triple touch technique); axilla; supraclavicular area; neck; and
chest wall, assessing the size, texture, and location of any masses.It is important to note the size of the masses
for future reference. A pictoral record is always helpful.Now,inspect the areola-nipple complex for any discharge.
CBE sensitivity can be improved by longer duration (i.e., five to 10 minutes) and increased precision (i.e., using a
systematic pattern, varying palpation pressure, and using three finger pads and circular motions)
Benign masses generally cause no skin change and are smooth, soft to firm, and mobile, with well-defined
margins.

125
HISTORY AND EXAMINATION Performa

NAME: AGE/SEX: ID NO:

Lump in the breast Y/N Right/Left Duration- days/ weeks/ months/ years

Discharge from the nipple Y/N Spontaneous/ Expressed Colour- clear/ greenish/ milky/ bloody

Skin changes Y/N Discolouration /Dimpling/ Tethering/ Peau-de-orange/redness

Lump in the armpit Y/N Lump in the neck Y/N

Loss of appetite Y/N Loss of weight Y/N

Menarche - years

LMP - __/__/__ Premenopausal/ Perimenopausal /Postmenopausal

Married/ single

Age at first childbirth No. of children

Breast fed 1) Y/N Duration-


2) Y/N Duration-
3) Y/N Duration-

Use of oral contraceptives/ hormonal therapy Y/N

Previous surgery in breast Y/N Biopsy/ HPE- Y/N

Description-----------------------

Family history of breast or ovarian cancer or any other cancer Y/N If Y, then specify

H/O hypertension/ DM/ COPD/ Asthma/ thyroid disorder/CAD controlled/ uncontrolled

Treatment

Other significant history

Investigations done outside-

Diffuse, symmetric thickening, which is common in the upper outer quadrants, may indicate fibro-cystic changes.
Malignant masses generally are hard, immobile, and fixed to surrounding skin and soft tissue, with poorly defined
or irregular margins.However, mobile or nonfixed masses can be cancerous.

Infections such as mastitis and cellulitis tend to be erythematous, tender, and warm to the touch; they may be
more circumscribed if an abscess has formed. Similar symptoms may occur in patients with inflammatory breast
cancer. Therefore, caution should be used in assessing patients with suspected breast infections.
Digital palpation of the breast is effective in detecting masses and can help determine whether a mass is benign
or malignant.CBE can detect up to 44 percent of cancers, up to 29 percent of which would not have been
detected by mammography.Despite its accuracy, CBE alone is not adequate for definitive diagnosis of breast
cancer. Further evaluation, including follow-up examinations, imaging, and tissue sampling, is required in all
patients with breast masses

126
EXAMINATION

Right Breast Left Breast


Size of the lump-------------cms Size of the lump-------------cms

Distance from areolar margin-------------------cms Distance from areolar margin-------------------cms

Quadrant- UOQ/UIQ/LIQ/LOQ Quadrant- UOQ/UIQ/LIQ/LOQ

Skin-- dimpling/ tethering/ ulceration/ peau de orange/ Skin-- dimpling/ tethering/ ulceration/ peau de
redness orange/ redness

Fixity to muscle- Y/N Fixity to muscle- Y/N

Fixity to chest wall Y/N Fixity to chest wall Y/N

Nipple areola complex---Normal/ eczematous/ Nipple areola complex---Normal/ eczematous/


retracted/ ulcerated/ discharge retracted/ ulcerated/ discharge

Scar of previous surgery- Y/N Scar of previous surgery- Y/N

Axilla Lymph nodes present/ absent Axilla Lymph nodes present/ absent
Size- Size-
Number Number
Fixity Fixity

Supraclavicular lymphadenopathy-present/ absent Supraclavicular lymphadenopathy-present/ absent

Impression- Benign breast disease/ carcinoma Impression- Benign breast disease/ carcinoma
breast breast

Performance Score

GENERAL PHYSICAL EXAMINATION

SYSTEMIC EXAMINATION Respiratory System


CVS
CNS
Abdomen, P/V, P/R

In certain situations where there is no well- defined lump, only a vague nodularity or thickening of breast tissue,
one must compare it with the opposite side. If one is not happy with the findings and is unable to make much
headway after investigations, it may be worthwhile to do the next possible investigation or call the patient back for
an early follow up after 2-3 months.

Symptoms other than a lump

Mastalgia- Mastalgia is a very common presentation in the clinic. Premenstrual aggravation is usual. 70% of
mastalgias respond to reassurance alone while 10% of the remaining 30% require medical intervention.
Mastalgia as the first presenting symptom of cancer is rare with only 5-8% doing so.

Nipple Discharge- A single duct, spontaneous, serous or sanguineous, persistent discharge needs to be
investigated. In a young patient less than 30 years with no radiological or cytological proof, a period of
observation of 4-6 weeks may be undertaken. In women over the age the age of 45 years, it is best to go ahead
with surgery- microdochectomy or major duct excision.

Mastitis- Mastitis may present as a lump or diffuse area of erythema and edema and will have to be
differentiated from an inflammatory carcinoma. After thorough clinical examination, radiological investigations and
core biopsy, one will need to distinguish between acute mastitis, chronic granulomatous and non granulomatous
mastitis. The treatment for each situation is very different.

Special Situations- In patients presenting with repeated excoriation of unilateral nipple or areola with discharge
from the surface, healing and a repeat of such symptoms should be evaluated for Pagets Disease.

127
In young women with lumps, which have shown a significant increase in size, should be evaluated with a core
biopsy to rule out phyllodes tumour. Many a time, a core biopsy may also not be able to provide a definite
answer, wherein one should go ahead and excise the lump with adequate margins.

TRIPLE ASSESSMENT

Involves subjecting patient to clinical examination, radiological and pathology.


Radiology primarily involves mammograms, ultrasound of the breast and MR mammogram while pathology
involves cytopathology (FNAC) or histopathology (core biopsy or incisional biopsy or excisional biopsy).
.
The triple test is the combination of results from CBE, imaging, and tissue sampling When the three assessments
are performed adequately and produce concordant results, the triple test diagnostic accuracy approaches 100
.
percent Discordant results or results that cannot be evaluated may indicate the need for excisional biopsy.

The Triple Test Score (TTS) was developed to help physicians interpret discordant triple test results.A three-point
scale is used to score each component of the triple test (1 = benign, 2 = suspicious, 3 = malignant). A TTS of 3 or
4 is consistent with a benign lesion; a TTS of 6 or more indicates possible malignancy that may require surgical
intervention. Excisional biopsy is recommended in patients with a TTS of 5 to obtain a definitive diagnosis.

References
1. Campbell HS, Fletcher SW, Pilgrim CA, Morgan TM, Lin S. Improving physicians and nurses clinical breast
examination: a randomized controlled trial. Am J Prev Med. 1991;7:18.
2. Baines CJ, Miller AB. Mammography versus clinical examination of the breasts. J Natl Cancer Inst
Monogr.1997;(22):1259.
3. Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical
examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient
evaluations. Radiology. 2002;225:16575.

Radiology in Breast Disease

Richa Bansal

Mammography
All women 30 years old or older presenting with a breast mass should have mammography performed. Patients
who present with a palpable mass should undergo a diagnostic mammogram in which additional views of the
area in question are performed. Spot compression views and magnification views for concomitant calcifications
are recommended. The lump on the mammogram should be categorised as benign or suspicious of malignancy
according to the BIRADS descriptors and further imaging with ultrasound should be performed.

A BI-RADS designation of 4c or 5 should alert the pathologist that a malignant diagnosis is strongly suspected
and that further evaluation of the specimen (and possible rebiopsy) is needed if the biopsy is initially interpreted
as benign)

Mammographic features of breast cancer There are two general categories of mammographic findings
suggestive of a breast cancer: soft tissue masses and clustered microcalcifications.

Soft tissue mass/architectural distortion The most specific mammographic feature of malignancy is a
spiculated soft tissue mass; Approximately one-third of noncalcified cancers appear as spiculated masses, 25
percent as irregularly outlined masses, 25 percent as less specific round, oval or lobulated masses, less than 10
percent as well-defined round, oval, or lobulated masses, and 5 percent as areas of architectural distortion of
dense tissue without an obvious mass.

Clustered microcalcifications Clustered microcalcifications are calcium particles of various size and shape
measuring between 0.1 to 1 mm in diameter and numbering more than four to five per cubic centimeter.
Microcalcifications are seen in approximately 60 percent of cancers detected mammographically . Histologically,
these represent intraductal calcifications in areas of necrotic tumor or calcifications within mucin-secreting tumors
such as the cribriform or micropapillary subtype of intraductal cancer.

Calcifications that are not suspicious for malignancy and considered benign include vascular and skin
calcifications, rim-like calcifications, large coarse calcifications, and smooth round or oval calcifications.

Thus, mammographic findings such as masses and calcifications can be stratified by suspicion for malignancy,
and the BI-RADS 4a, 4b, and 4c categories are helpful in alerting the referring physicians, the pathologists, and
surgeons to the underlying risk of malignancy.

128
Typical BIRADs 5 lesion on
mammogram

Typical BIRADs 2 lesion on Benign calcifications


mammogram

Suspicious calcifications

129
In typically malignant lesions, attempt should be made to identify multi-focal or multi-centric disease although in
dense glandular breasts it may be a challenge. In such cases MRI helps in identifying the extent of the disease in
the same breast as well assessing the contralateral breast .

In the setting of a palpable breast mass, mammography is 82% to 94% sensitive and 55% to 84% specific for
detecting breast cancer. The sensitivity and specificity of diagnostic mammograms declined with breast density,
younger age, and mammographic examination. Dense breasts can limit the sensitivity of mammography both for
detection of breast cancers and for delineating disease extent. Younger women may present with large tumors
prior to the age at which screening is usually recommended. Accordingly, when women present with a suspicious
new mass, diagnostic mammograms should be part of the initial workup, despite young age or having had a
negative routine screening mammogram.

BIRADS Classification

Ultrasound of the Breast

Ultrasonography is often considered the diagnostic test of choice in patients <30 years old,because the density of
breast tissue in younger women limits the sensitivity of mammography.The false-negative rate for mammography
has been reported as high as 52% in patients <35 years old with a palpable malignant breast mass.In addition,
ultrasound is routinely available in the outpatient setting and is a ready extension of the physical exam.
Ultrasound helps in identifying whether the palpable lesion is cystic or solid. It can also distinguish between
simple or complex cyst architecture.Simple cysts are fluid-filled lesions that present as smooth, round, well-
demarcated, and anechoic and can be kept under follow up in an asymptomatic patient. Complex cysts and solid
lesions require further evaluation as in the algorithm below. Elastography has been proposed as a potential
adjunct to ultrasonography.

130
Complex cyst on Ultrasound

Elastography appearance of
Benign lesion

Elastography appearance of
malignant lesion

Ultrasound Algorithm

131
Ultrasonography of the axilla may also be performed to evaluate lymphadenopathy, and abnormal lymph nodes
biopsied.

MRI

Current National Comprehensive Cancer Network (NCCN) guidelines recommend MRI be 'considered' in patients
with newly diagnosed breast cancer to evaluate extent of disease and screen the contralateral breast, especially
in the setting of mammographically occult disease.

Indications of Breast MRI in Diagnosed Cases of Breast Cancer

In patients where the clinical extent of disease is larger than what is appreciated by mammography
(particularly in the setting of dense breasts which lower the sensitivity of mammography).
For invasive cancers that are contiguous to the chest wall and not completely included on mammographic
projections, MRI may be necessary to assess posterior tumor extension and pectoralis fascia or muscle
involvement if that will determine a change in surgical approach or the use of neoadjuvant therapy
For patients with axillary nodal metastases and a clinically occult primary tumor, breast MRI can facilitate the
identification of occult breast cancer
For women with Pagets disease of the breast who have a negative physical examination and mammogram,
breast MRI can define the extent of disease and aid in treatment planning
In women with locally advanced breast cancer who are being considered for upfront (neoadjuvant) systemic
therapy, breast MRI may be used to define the extent of disease, and potential for breast conserving
therapy.
For women with very high risk for contralateral disease (for example, because of an inherited predisposing
condition, or prior chest wall irradiation).
For women who are planning extensive reconstructive surgery, breast MRI may be used to identify occult
contralateral cancers.

Women should be informed of the risks and benefits of preoperative breast MRI. The limits of the accuracy of
MRI should be discussed with patients, so that they understand the need for biopsy of MRI detected lesions
before definitive surgery. Breast MRI should be performed with a dedicated breast coil by expert breast imaging
radiologists in institutions that have the capability to perform MRI guided needle biopsy and/or wire localization of
the findings.

Surgical decisions should not be based on MRI findings alone. MRI findings alone should not be used to change
surgical planning and conversion from breast conservation to mastectomy. All suspicious findings onMRI require
pathologic confirmation.

Newer Imaging Techniques in Breast

Digital mammography
Digital breast tomosynthesis
CAD
Contrast enhanced Mammography
Positron Emission mammography.

References

1. Silverstein MJ, Recht A, Lagios MD, et al. Special report: Consensus conference III. Image-detected breast
cancer: state-of-the-art diagnosis and treatment. J Am Coll Surg 2009; 209:504.
2. Lehman CD, DeMartini W, Anderson BO, Edge SB. Indications for breast MRI in the patient with newly diagnosed
breast cancer. J Natl Compr Canc Netw 2009; 7:193.
3. Warner E, Causer PA, Wong JW, et al. Improvement in DCIS detection rates by MRI over time in a high-risk breast
screening study. Breast J 2011; 17:9.
4. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology.
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on April 01, 2014).

132
Algorithm for Imaging of Breast Mass In Women <30 Yrs Age

133
Algorithm for Imaging of Breast Mass in Women > 30 Yrs Age

134
Biopsy Algorithm of Solid Lesions of Breast

Approach to breast disease: Pathologists Perspective

Anuj Khurana

Diseases of the mammary gland can be broadly classified as


Non neoplastic
Neoplastic (Tumor)

Non neoplastic: Includes


Inflammatory lesions:
Abscess (+/- lactational breast)
Mastitis (infective- bacterial), idiopathic granulomatous/lobular mastitis or secondary to mycobacterial
infection)

The nonneoplastic non-inflammatory lesions:


Fat necrosis
Duct ectasia
Spectrum of fibrocystic disease and fibroadenomatoid mastopathy.

Neoplastic conditions:
Benign clinical course
Fibroadenoma
Phyllodes (benign)

135
Nipple adenoma
Intraductal papilloma

Intermediate/Indeterminate
Borderline Phyllodes
Stromal sarcomas

Malignant
Carcinoma in situ (DCIS/LCIS)
Infiltrating Carcinoma (Most common) including the various subtypes
Pure /Primary sarcomas like malignant phyllodes, spindle sarcomas.

Based on clinical assessment and radiological evaluation patients with breast lump undergo various diagnostic
procedures, which are subsequently evaluated by a pathologist.

Pathological evaluation of a breast lump:

Cytological Diagnosis
Nipple fluid cytology: Presence / Absence of atypical cells
Fine Needle Aspiration (FNA)

Cytological classification of breast aspirates:


Categorised from C1 to C5
C1: Inadequate
C2: Benign
C3: Atypical; probably benign
C4: Suspicious for malignancy
C5: Malignant

Many a times, FNA cytology findings dictate the subsequent surgical procedure.

Intraoperative Evaluation by Frozen Section technique


Depending upon the degree of clinical suspicion, radiological findings and initial cytological or histopathological
results, the patient undergoes surgical procedure and specimen is sent for histopathogical examination; which
eventually decides the future management. In a clinically suspicious lesion with ambiguous patology, frozen
section technique may be adopted to provide intraoperative diagnosis and subsequent management

Histopathological Diagnosis
Most of the surgical specimens received for pathological evaluation:
I. Needle core biopsies

II. Excision specimens:


1) Unoriented (done for benign lesions like fibroadenoma/fibrocystic disease)

2) Oriented (marked with sutures/ink/J wire localised)


-Phyllodes
-Cytologically inconclusive but radiologically suspicious lesion (BIRAD III/IV)
-Suspicious micro calcification on routine mammography

III. Wide Local excision/ Breast Conservative Surgery


(Margin assessment +/- Primary diagnosis)- Intraoperative assessment

IV. Modified Radical Mastectomy


(+/- Sentinal node biopsy)

Specimen Handling and processing


Irrespective of nature of surgical specimen, adequate tissue fixation and proper tissue processing are imperative
for optimal pathological reporting

Importance of Tissue fixation.


Improper fixation can lead to:
- Suboptimal tissue details
- Erroneous interpretation of hormonal receptors.

136
Contents of the histopathology report:

Gross findings
Core needle biopsy:
Number and size of the submitted cores
Consideration of small size of the specimen: Inked by a special dye (So as to be identified throughout the journey
from fixation till sectioning

Unoriented specimens:
Three dimensional measurements
Comment on:
- Integrity (Single piece or multifragmented)
- Outer surface (Capsulated/Unencapsulated)

Oriented specimen: (Including WLE/ BCS)


Three dimensional measurements
Keeping in view of the Side (Left /Right): The prosector re-orients the specimen w.r.t sutures.
Comment on overlying skin (if present)
Protocol followed: Outer / Capsular surface is inked

The cut section findings are recorded:


- Presence of Lesion/ tumor
- Appearance
- Size
- Margins of lesion: Infiltrative/ Circumscribed
- Gross distances from margins are recorded.

Modified radical mastectomies:


- Three dimensional measurements
- Skin dimensions
- Axillary tissue: Size
- Appearance of skin: Any cutaneous changes like peau d orange, fungation or any previous scar/ suture.
- Nipple: Retracted/ Unremarkable
- The posterior surface/ base is inked ( formed by fascia or by pectoralis muscle)
- The inked surface is sliced serially at a gap of 1.0cm each.
Advantages of slicing:
- Adequate fixation of the tissue.
- Identification of multifocal lesions apart from the main tumor

Tumor is identified {Size ( pT size), lesional margins}


Distance from the inked base is noted.

Representative sections taken:


Tumor (Number of sections depending upon the size of tumor)
Surrounding breast
Nipple
Overlying skin
Base /Inked posterior surface
Axillary nodes:
Size of the largest lymphnode (Grossly involved/not involved)

Microscopic Findings:
Histological type:
Conventional IDC
Special histological subtypes
Lobular/ Mucinous/Tubular/ Medullary/ Metaplastic

Histological Grade:
Based on Nottingham histological grade (Based on modified Scarff Bloom Richardson grading) - I, II or
III
Three parameters
Tubule formation
Nuclear pleomorphism
Mitotic count

137
Other Parameters:
Presence or absence of DCIS
Grade/ Pattern of DCIS
Concept of EIC
Lymphovascular Invasion
Nipple Areola- Involvement by pagetoid spread or not
Overlying skin: Involved
Deep surgical margin: Status
If post therapy:
Presence or absence of residual tumor
Microscopic largest contiguous focus (determines ypT size)

Axillary Nodes:
Number
Number of positive nodes
Extracapsular extension: Present/ Absent
Largest involved node
Concept of isolated tumor cells/ micrometastases.

Final Report should include Pathological TNM stage

Immunohistochemistry (Theranostic tool)


-ER PR profiling (Allred scoring)
-Her 2 neu status (As per ASCO/CAP guidelines)
-Ki67 proliferation index

Other uses of IHC:


Identification of special histological subtypes (e.g lobular, metaplastic)
Detection of low volume disease /residual disease or isolated tumor cells.

Incorporate Her 2 neu by FISH ( if IHC for Her2 was borderline)

Summary and Recommendations

The majority of breast cancers are diagnosed as a result of an abnormal mammogram, but the majority of
mammographic findings represent benign tissue.
Triple assessment is the cornerstone to diagnosing breast disease especially malignancies
While FNAC can provide the diagnosis in a large majority, it is recommended to go for an ultrasound guided
core biopsy to improve the accuracy as well as distinguish between invasive carcinoma and DCIS as also for
receptor studies prior to neoadjuvant chemotherapy
Cystic lesions that resolve after aspiration do not need to be evaluated further unless they recur
A clinically suspicious mass should be biopsied, regardless of imaging findings.
Women who have an abnormal screening mammogram need further diagnostic evaluation with special views
and/or targeted ultrasonography to determine the need for tissue sampling or biopsy.
The American College of Radiology (ACR) BI-RADS (Breast Imaging Reporting and Data System) final
diagnostic assessment categories indicate the relative likelihood of a normal, benign, or malignant diagnosis
and standardize both the reporting of mammographic findings and the recommendations for further
management.
Ultrasound (US) examination of the breast is used to differentiate between solid and cystic masses and to
provide guidance for interventional procedures.
Breast MRI is highly sensitive, and can identify foci of cancer that are not evident on physical examination,
mammogram, or ultrasound. Although breast MRI is not recommended as a routine component of the
diagnostic evaluation of breast cancer but it should be considered in above mentioned circumstances.
Suspicious lesions seen on MRI must be biopsied to confirm diagnosis before planning definitive surgery.
Diagnostic algorithms can provide useful guidelines for the work up of a suspicious finding on breast imaging
or breast examination.
In the patient with a suspicious mammographic abnormality or palpable breast mass, the obligatory
diagnostic technique is biopsy which should preferably be image guided.
Excisional biopsies should be performed on lesions, which are clinically suspicious and ambiguous on
imaging, FNA or core biopsy

138
Hand Infections

Jainendra K. Arora

Introduction
Closed-space hand infections have been considered traditionally as an important concern and have been treated
as an emergency. Despite modern diagnostic methods, surgical treatment advances and the evolution of newer
antibiotics, hand infections remain a therapeutic challenge. Even those authors advocating an evident decrease
in the ratio of hand infections, underline the necessity of treatment of infected hands to be treated by experienced
staff.

Soft tissue anatomy of the hand: considerations relevant to infection


The differences between the palmar and dorsal structures may explain the different pathways of extension and
the different clinical signs of infection between the two sides of the hand. The palmar skin is thicker than the
dorsal and is anchored to the underlying structures. It contains many sweat glands but no hair follicles or
sebaceous glands, whereas the tough palmar fascia represents a thick and resistant fibrous tissue layer. Both
skin and fascia hinder the horizontal spread of pus and even edema to the palm. Pus is rather oriented to the
deeper palmar structures while edema is always more prominent at the dorsum of the hand. In the deeper
structures of the hand the anatomic relationships are established, but variations cannot be excluded.

Pathways of pus spread


The true anatomic communications represent pathways of decreased resistance for the spreading pus However,
in the late stages of purulent infections direct spread into the surrounding tissues through liquefactive necrosis is
anticipated.

Table 1: Pathways of pus spread.


From Through To
Index flexor tendon sheath 1. Proximal edge Thenar space (vice versa)
2. Lubrical channel
Middle and ring flexor tendon 1. Proximal edge Midpalmar space (vice versa)
sheath
2. Lubrical channel
Web space Lubrical channel Deep palmar spaces (vice versa)
Flexor policis longus tendon Proximal edge Radial bursa (vice versa)
sheath
Small finger flexor tendon sheath 1. Proximal edge 1. Ulnar bursa (vice vesa)
2. Lubrical channel 2. Midpalmar space
Ulnar bursa 1. Radial edge 1. Midpalmar space (vice versa)
2. Communication distal to the wrist 2. Radial bursa (viceversa)
3. Proximal edge 3. Parona's space of wrist
Radial bursa 1. Ulnar edge 1. Thenar space (vice versa)
2. Proximal edge 2. Parona's space of wrist
Hand dorsal subaponeurotic Narrow connection at MCP level Finger dorsal subaponeurotic spaces
space

Pathophysiology
In all closed spaces of the hand, accumulation of purulent material is raising the pressure, compromising the
blood flow, and causing ischemia and necrosis. These conditions are further aggravating the infection,
establishing a vicious circle. Direct inoculation (epithelium lysis), spread from the adjacent necrotic tissues or
through the lymphatic pathway, could result in the establishment of hand infections.

Pathogens
Gram positive cocci and especially S. aureus and -Hemolytic-Streptococcus group A (pyogenes) are usually
involved. This is the result of skin flora inoculation during injury.S. aureus is reported to range from 30 to 80% of
positive cultures although it has been shown that this percentage is decreasing while mixed gram positive and
gram negative hand infections are increasing. An emerging pathogen is the S. aureus that carries the PVL gene;
it is usually community-acquired and leads to necrotic lesions. At least 3 sets of cultures should be ordered, each
one including cultures for bacteria, mycobacteria and fungi. Gram stain provides important information. While
cultures are often negative, recent advances in the detection and identification of bacterial pathogens by
molecular methods greatly facilitate the diagnosis and expedite the initiation of treatment.

Empirical antibiotic treatment is mandatory, while waiting for the culture results, taking into consideration the
hospital flora and the local spread of community-acquired methicillin resistant S. aureus (CA-MRSA). The
introduction of antibiotics was a great progress in the early treatment of hand infections and led to the reduction
of devastating complications such as amputations.

139
Host type and infection
In immunocompromised patients (underlying malignancy and immunosuppressive disease) or patients receiving
steroids and anti-tumor necrosis factors, closed-space hand infections present subtly and a high rate of morbidity
must be expected if treatment is delayed. Temperature elevation, localized tenderness and erythema are
indications for hospitalization while broad spectrum antibiotics and debridement are needed. Discoloration,
fluctuation, drainage or, even worse, hypotension were found to be late signs.Polymicrobial infections and mixed
infections are likely to occur in these patients, including gram negative bacteria and/or anaerobes and
appropriate antibiotics must be administered. The same principles apply to patients with diabetes mellitus,
intravenous use of drugs and in human bite and crush injuries, as well as in injuries in highly contaminated
environments

Diagnosis
Because of the deep location of closed space accumulations the typical signs infection are often absent.
Throbbing pain, edema and restricted finger motion are the most common sings and symptoms, while specific
clinical signs such as Kanavel's signs (septic tenosyn-ovitis) may be obtained in cases of infections in closed
spaces. Finally, systemic signs of infection are usually absent. Apart of a complete laboratory testing (complete
blood count, ESR, CRP), imaging studies such as radiographs and ultrasound are helpful in the diagnosis of
concomitant skeletal involvement or deep space collections. Culture samples must be obtained before the
administration of antibiotics; Gram stain, antibiotic resistance phenotypes, detection of the mecA gene, and
molecular typing of the isolates must be requested from the microbiology departments.

Cellulitis
Cellulitis is characterized by a nonpurulent diffuse spreading of inflammation characterized by erythema, warmth,
pain, swelling, and induration. Skin breakdown is a frequent cause, but often no inciting factor is identified. Group
-hemolytic Streptococcus is the most common offending pathogen and causes a more diffuse spread of
infection. S. aureusis the second most common offending pathogen and will cause a more localized cellulitis. The
diagnosis of cellulitis is clinical. Septic arthritis, osteomyelitis, an abscess, a deep-space infection, and
necrotizing fasciitis are severe infectious processes that may initially mimic cellulitis. These must be ruled out
appropriately before initiating treatment, and serial exams should be conducted to ensure proper diagnosis.
Treatment of cellulitis consists of elevation, splint immobilization, and antibiotics that cover both Streptococcus
and Staphylococcus. Intravenous antibiotics are usually initiated for patients with severe comorbidities and those
who fail to improve on oral antibiotics after 24 to 48 hours. Failure to improve after 24 hours indicates a need to
search for an underlying abscess or other infectious cause.

Abscess
An abscess will present much like cellulitis, but they are two clinically separate entities. The defining difference is
an area of fluctuance. Skin-puncturing trauma is the most common cause. S. aureusis the most common
pathogen, followed by Streptococcus. Treatment consists of incision and drainage with appropriate dbridement,
wound cultures, wound packing, elevation, immobilization, and antibiotics. The packing should be removed in 12
to 24 hours or sooner if there is clinical concern, and warm soapy water soaks with fresh packing should be
initiated. Most should be allowed to heal second- arily. Delayed primary closure should only be performed after
repeat washouts for larger wounds where complete infection has been achieved.

Felon
Felon is an infection of the pulp of the distal phalanx , a subcutaneous abscess of the fingertip and is most
commonly caused by penetrating trauma It is usually a primary infection caused by an unnoticed injury in more
than 50% of cases . Many authors advocate secondary infection from the extension of a severe or neglected
infection around the nail as tissue liquefactive necrosis favors the spread to the surrounding tissues, although the
anatomical course of the lymphatics does not support this opinion.4

S. aureus is the most common pathogen. The fingertip contains multiple septa con- necting the distal phalanx to
the skin. These septa are poorly compliant, and presence of an abscess will increase pressure and lead to
severe pain and tissue death. The typical signs of acute inflammation are present. The initial sticking pain in the
distal phalanx transforms to throbbing severe pain, while the initial tenseness of the pulp is replaced by an
induration and later by a fluctuating boggy mass. Due to presence of septa, pus or edema have no means of free
egress and therefore occlude the blood supply and result in necrosis of the pulp and distal phalange. At the first
stage necrosis can spare the epiphysis and distal interphalangeal (DIP) joint, but in neglected cases spontaneous
expulsion of the necrotic tissue is expected. At this stage the finger pulp is a bluish insensitive pus bag with
asinus opening by the nail side. Usually there are no systemic signs of infection.

A lateral incision is preferable since the transverse dissection of the radiating columns of fat and connective
tissue results in more efficient drainage and wound closure is by secondary intention. A longitudinal incision over
the area of greatest fluctuance is the safest procedure when incision and drainage is required. Many other
procedures, including hockey-stick or fish-mouth shaped incisions, are no longer recommended because of injury
to neurovascular structure.

Attention should be drawn to avoid exposure of the healthy DIP joint or the flexor tendon sheath through a

140
proximally extended incision. The treatment of coexisting osteomyelitis of the distal phalanx depends on the
amount of bone involvement and includes resection of the involved bone or even amputation.

Surgical drainage of the finger pulp performed too early, at the stage of a more diffuse inflammation, that some
authors call an early felon, could be an unnecessary and even harmful procedure over a cellulitis, causing diffuse
pain and tenderness throughout the whole finger. Imaging modalities (e.g. ultrasound) can help the differential
diagnosis by detecting fluid accumulations. . The wound is irrigated and packed, with warm soapy water soaks
and packing changes initiated within 24 hours and performed two to three times daily until secondarily healed.
Antibiotic coverage should cover for Staphylococcus and Streptococcus species.

Decrease of pain sometimes signals an aggravation of the felon as the necrotic process destroys the septa and
therefore offers a temporary relief.

Paronychia
Paronychia is an infection beneath the nail fold. The nail plate can be viewed as an invagination into the dorsal
skin extending down to the distal phalanx periosteum. Predisposing factors include anything that causes nail
trauma, such as manicures, artificial nails, or nail biting. The infection may spread around the nail plate from one
side to the other, or it may extend into the pulp and result in a felon. An acute paronychia is usually caused by S.
aureus or Streptococcalspecies. Patients report pain, erythema, swelling, and possibly purulent drainage involv-
ing the periungual tissue. Treatment consists of warm water soaks and oral antibiotics if diagnosed early. If
purulence or fluctuance is present, then a freer elevator or 18-gauge needle can be passed along the involved
nail fold to decompress the collection (Fig. ). If the infection involves the eponychial fold, a small proximally based
flap of eponychium is created by using a scalpel, followed by irrigation and packing. The nail plate must be
removed if the infection extends beneath the nail plate. Packing is kept in place for 24 to 48 hours, followed by
warm water soaks and local wound care. Usually, the wound cannot be repacked once the dressing is removed.A
chronic paronychia is most commonly caused by Candida species and is most often found in patients who
perform jobs involving the submersion of their hands in water or other moist environments. These develop into
thickened nails with callus-like formation along the nail folds and may occasionally become red and inflamed.
They do not respond to antibiotic treatment, and nail plate removal with marsupializa- tion of the skin proximal to
the eponychial fold will allow the wound to heal secondarily. The environmental factors leading to the chronic
paronychia must also be corrected in order for treatment to be successful.All hand infections other than cellulitis
will require surgical management. Clinical examination, particularly noting the area of greatest tenderness and/or
inflammation, is the single most useful diagnostic tool to purulence requiring drainage.

Osteomyelitis
Osteomyelitis in the hand usually occurs due to an open fracture with significant soft tissue injury. The presence
of infected hardware, peripheral vascular disease, diabetes, and alcohol or drugabuse are also predisposing
factors. Presentation includes persistent or recurrent swelling with pain, erythema, and possible drainage. It will
take 2 to 3 weeks for periosteal reaction and osteopenia to be detected on radiographs. Bone scans and MRI are
useful modalities to aid in diagnosis. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have
low specificity but are useful for monitoring the progress of treatment, with CRP being more reliable. Treatment
consists of antibiotics alone in the early stage as long as there is favorable response. All necrotic bone and soft
tissue, if present, must be dbrided. Initial intravenous antibiotic therapy should cover S. aureus, the most
common pathogen, and should then be adjusted according to bone cultures. Antibiotic therapy is continued for 4
to 6 weeks once the patient clinically improves and there is no further need for dbridement. For osteomyelitis in
the setting of an acute fracture with internal fixation in place, the hardware should be left in place as long as it is
stable and the fracture has not yet healed. If the hardware is unstable, it must be replaced. An external fixation
device may be useful in this setting. If osteomyelitis occurs in a healed fracture, all hardware and necrotic bone
and soft tissue must be removed.

Pyogenic Arthritis
Infection of a joint will progress quickly to severe cartilage and bony destruction if not addressed quickly. Direct
trauma and local spread of an infection are the most common causes. Hematogenous spread occurs most
commonly in patients who are immunocompromised. S. aureusis the most common pathogen, followed by
Streptococcus species. Neisseria gonorrhoeaeis the most common cause of atraumatic septic arthritis in an adult
less than 30 years of age. Presentation includes exacerbation of pain with any joint movement, severe pain on
axial load, swelling,erythema, and tenderness. Radiographs may show a foreign body or fracture, with widened
joint space early in the process and decreased joint space late in the process due to destruction. Joint aspiration
with cell count, Gram stain, and culture is used to secure the diagnosis. Treatment of nongonococcal septic
arthritis includes open arthrotomy, irrigation, dbridement, and packing the joint or leaving a drain in place.
Intravenous antibi- otics are continued until there is clinical improvement, followed by 2 to 4 weeks of additional
oral or intravenous antibiotics. Gonococcal septic arthritis is usually treated nonoperatively. Intravenous
ceftriaxone is first-line therapy. Joint aspiration may be used to obtain cultures and decrease joint pressure .

Necrotizing Infections
Necrotizing soft tissue infections occur when the immune system is unable to contain an infection, leading to
extensive spread with death of all involved tissues. This is different from an abscess, which forms when a

141
functioning immune system is able to wall off the infectious focus. Necrotizing infections can result in loss of
limb or life, even with prompt medical care.

Bacteria spread along the fascial layer, resulting in the death of soft tissues, which is in part due to the extensive
blood vessel thrombosis that occurs. An inciting event is not always identified. Immunocompromised patients and
those who abuse drugs or alcohol are at greater risk, with intravenous drug users having the highest increased
risk. The infection can by mono- -hemolytic Streptococcus being the most
c -hemolytic Strep- tococcus, S. aureus, and anaerobes. Prompt clinical
diagnosis and treatment are the most important factors for salvaging limbs and saving life. Patients will present
with pain out of proportion with findings. Appearance of skin may range from normal to erythematous or maroon
with edema, induration, and blistering. Crepitus may occur if a gas-forming organism is involved. Dirty dishwater
fluid may be encountered as a scant grayish fluid, but often there is little to no discharge. There may be no
appreciable leukocytosis. The infection can progress rapidly and can lead to septic shock and disseminated
intravascular coagulation. Radiographs may reveal gas formation, but they must not delay emergent dbridement
once the diagnosis is suspected. Intravenous antibiotics should be started immediately to cover gram-positive,
gram-negative, and anaerobic bacteria. Patients will require multiple dbridements, and the spread of infection is
normally wider than expected based on initial assessment.

Necrotizing myositis, or myonecrosis, is usually caused by Clostridium perfringensdue to heavily contaminated


wounds. Unlike necrotizing fasciitis, muscle is universally involved and found to be necrotic. Treatment includes
emergent dbridement of all necrotic tissue along with empirical intravenous antibiotics.

Wet gangrene is most common in diabetics with renal failure and an arteriovenous shunt. It is usually
polymicrobial. Patients will present with a necrotic digit that is purulent and very malodorous, with rapidly evolving
pain, swelling, skin discoloration, and systemic collapse. Emergent treatment is the same as for other necrotizing
infections, and amputation of the involved digit or extremity must often be performed.

Tenosynovitis/bursitis
Flexor tenosynovitis (FTS) is a severe pathophysiologic state causing disruption of normal flexor tendon function
in the hand. A variety of etiologies are responsible for this process. Most acute cases of FTS are due to purulent
infection. FTS also can occur secondary to chronic inflammation as a result of diabetes, RA, crystalline
deposition, overuse syndromes, amyloidosis, psoriatic arthritis, systemic lupus erythematosus, and sarcoidosis.

The primary mechanism of infectious FTS usually is penetrating trauma. Most infections are caused by skin flora,
including both Staphylococcus and Streptococcus species. Bacteria involved vary by etiology of the infection: bite
wounds (Pasteurella multocidacat, E. corrodenshuman); diabetic patients (Bacteroides, Fusobacterium,
Haemophilus species, gram-negative organisms); hematogenous spread (Mycobacte- rium tuberculosis, N.
gonorrhoeae); or water-related punctures (Vibrio vulnificus, Mycobacterium marinum). Infection in any of the
fingers may spread proximally into the wrist, carpal tunnel, and forearm, also known as Paronas space.

Suppurative FTS has the ability to rapidly destroy a fingers functional capacity and is considered a surgical
emergency. Suppurative FTS results from bacteria multiplying in the closed space of the flexor tendon sheath
and culture-rich synovial fluid medium causing migration of inflammatory cells and subsequent swelling. The
inflammatory reaction within the closed tendon sheath quickly erodes the paratenon, leading to adhesions and
scarring, as well as increase in pressures within the tendon sheath that may lead to ischemia. The ultimate
consequences are tendon necrosis, disruption of the tendon sheath, and digital contracture.

Patients with infectious FTS present with pain, redness, and fever . Physical examination reveals Kanavels
cardinal signs of flexor tendon sheath infection: finger held in slight flexion, fusiform swelling, tenderness along
the flexor tendon sheath, and pain over the flexor sheath with passive extension of the digit.Kanavels signs may
be absent in patients who are immunocompromised, have early manifestations of infection, have recently
received antibiotics, or have a chronic, indolent infection.

If a patient presents with suspected infectious FTS, empiric intravenous antibiotics should be initiated. Prompt
medical therapy in early cases may prevent the need for surgical drainage. For healthy individuals, empiric
antibiotic therapy should cover Staphylococcus and Streptococcus. For immunocompromised patients (including
diabetics) or infections associated with bite wounds, empiric treatment should include coverage of gram- negative
organisms as well.

Adjuncts to antibiotics include splint immobilization (intrinsic plus position preferred) and elevation until infection
is under control. Hand rehabilitation (i.e., range-of-motion exercises and edema control) should be initiated once
pain and inflammation are under control.

If medical treatment alone is attempted, then initial inpatient observation is indicated. Surgical intervention is
necessary if no obvious improvement has occurred within 12 to 24 hours.

Several surgical approaches can be used to drain infectious FTS. The method used is based on the extent of the

142
infection. Michon developed a classification scheme that can be useful in guiding surgical treatment drainage of
a stage II FTS. A Brunner incision allows better initial exposure but may yield difficulties with tendon coverage if
skin necrosis occurs. A 16-gauge catheter or 5-French pediatric feeding tube then is inserted into the tendon
sheath through the proximal incision. The sheath is copiously irrigated with normal saline. Avoid excessive fluid
extravasation into the soft tissue, because the resulting increase in tissue pressure can lead to necrosis of the
digit. The catheter is removed after irrigation. The incisions are left open. Some surgeons prefer a continuous
irrigation technique for a period of 24 to 48 hours. The catheter is sewn in place, and a small drain is placed at
the distal incision site. Continuous or intermittent irrigation every 2 to 4 hours with sterile saline can then be
performed through the indwelling catheter.In severe or aggravating infections, drainage through a wide or limited
approach, in a bloodless field, is necessary. The wide approach is either lateral or palmar (zig-zag) whereas the
limited consists of two small incisions over the two edges (A1 and A5 pulleys) of the infected sheath. Surgeons
advocating the limited approach claim a better final range of motion, while others believe that a limited approach
should be used in less severe cases, although there are no level I studies comparing the type of incision. All
authors agree that intra-operative irrigation is useful or at least of no harm. In addition, many authors advocate
that post-operative sheath irrigation until the resolution of the acute inflammation. The irrigating solution consists
of normal saline without antibiotics.

After surgery, an intrinsic plus splint is applied, the hand is elevated, and the appropriate empiric antibiotic
coverage is instituted while awaiting culture results. The hand is reexamined the following day. Drains are
removed before discharge from the hospital. The wounds are left open to heal by secondary intention. In severe
cases, repeat irrigation and operative dbridement may be required.

Antibiotic therapy is guided by culture results as well as clinical improvement. Once there is no further need for
debridement, a 7- to 14-day course of oral antibiotics is generally prescribed

Ulnar bursitis is often difficult to be diagnosed due to its deep location. It is characterized by the development of
hand edema, especially upon the dorsum. A general fullness is seen in the palm, but the palmar concavity is not
lost at first. The wall of the bursa often becomes necrotic before the extensive formation of exudate, and this
permits the trespass of the accumulation to the surrounding closed spaces. There is exquisite tenderness and the
wrist becomes fixed, whereas the little finger and sometimes the ring finger show tenderness to palpation and
pain on passive extension. Extension to the radial bursa is observed up to 85% of cases.

Radial bursitis is diagnosed by the swelling and tenderness in the thenar eminence and along the radial bursa.
The treatment in cases of purulent accumulation consists of surgical drainage, debridement of abscesses through
a palmar incision over the infected area followed by intraoperative irrigation with normal saline. Care should be
taken not to injure the branch of the median nerve, which supplies the thenar muscles as it passes across the
radial bursa, approximately 1 cm distal to the transverse ligament of the wrist.

In both tenosynovitis and bursitis the surgical wounds can be closed by secondary intention unless there is
continuous postoperative irrigation.Passive assisted and active exercises to restore range of motion start with the
remission of acute inflammation and after the removal of postoperative irrigation system (after 2448 hours).
However Nemotoet al. in 1991 suggested mobilization to start even if the irrigation system is in place and
advocates the use of the system for a week postoperatively.

In the presence of multiple painful fingers, careful evaluation will reveal the infected one from its marked painful
rigidity.

Decrease of tenderness to a considerable degree does not necessarily mean a definite improvement; it may be
only a temporary relief due to the rupture of the infected sheath at its proximal edge and therefore of extension of
the pus to more proximal structures. Differential diagnosis should include acute bleeding into the tendon sheath
in patients under anticoagulation therapy and also tenosynovitis developing in 2/3 of patients with gonococcal
infection.

Michons stages of suppurative flexor tenosynovitis and appropriate treatment


Stage Findings Treatment
Increased fluid in sheath, mainly a serous
I Catheter irrigation
exudate
Minimal invasive drainage indwelling catheter
II Purulent fluid, granulomatous synovium
irrigation
Necrosis of the tendon, pulleys, or tendon
III Ext open debridement+/- amputation
sheath

Paron's Space potential space between FPL tendon, FDP tendons, & pronator quadratusis known as the
subtendinous space of the wrist or Parona's space;pus in FPL sheath can ascend in the radial bursa and
eventually rupture into this space; pus in little finger sheath can ascend in ulnar bursae & rupture into Paron's
space; pus from thenar abscess or midpalmar abscess may rupture into Parona's space; if pus from either the
radial or ulnar bursae ruptures into Parona's space, it can be drained by the same incision used for releasing pus

143
from the proximal end of the ulnar bursae

Deep space infections of the hand


These are infections of the midpalmar space, the thenar space and compartment, the hypothenar space and
compartment and the subaponeurotic space of the dorsum of the hand. They are either a primary infections via
direct bacterial inoculation or secondary infections through extension from adjacent tendon synovium/bursae or
fascial spaces. An aggressive treatment may prevent devastating complications from the adjacent sheaths,
nerves, bones and joints. Close observation and antibiotics are always necessary. Drainage, debrideament and
intraoperative irrigation are the subsequent steps, whereas the decision for continuous postoperative irrigation is
based on intraoperative findings. The wound can be closed later or by secondary intention if continuous
postoperative irrigation is not used. Rehabilitation with passive assisted or active range of motion exercises
begins after the remission of the acute inflammation.

In a mid-palmar infection the concavity of the palm is usually lost. There is an exquisite tenderness over the
infected area which is pallid and sometimes red. Fingers are held rigidly flexed, with decreasing rigidity from the
little to the index finger. However, finger rigidity in case of mid-palmar infections is less severe than the rigidity of
septic tenosynovitis. There is usually a pitting edema in the remaining palm (over the thenar) and at the dorsum
of the hand, while in the case of pus extension along the lubrical channel, swelling of the web space is also
observed. The midpalmar space is drained and debrided through a palmar incision (transverse, longitudinal or
along one of the lubrical channels) taking care to avoid injury of the neurovascular bundle or contamination of the
surrounding tissues (the ulnar bursa in particular).

In thenar compartment and thenar space infections a painful swelling of the thenar eminence is observed. The
concavity of the palm is lost and often soft edema on the dorsum of the hand is present. The 1st metacarpal and
the thumb are abducted and distal phalanx flexion becomes more marked. In extensive infections, a double
incision over the volar and dorsal side is necessary for drainage of the infected spaces/compartments.
In hypothenar compartment and space infections the abscess is more localized. There is often limited swelling in
the palm but always painful swelling of the hypothenar eminence. The incision is located over the hypothenar
with care to avoid injury to the neurovascular bundle.

In subaponeurotic space infections the dorsal edema is more soft and the ischemia of the skin less severe than in
cases of subcutaneous pus accumulation. Attempts of finger extension may be limited by pain. The dorsal
incisions for the drainage of the subaponeurotic space are longitudinal, over the 2nd and between 4th5th
metacarpals.

Because of the intimate relationship of the midpalmar and the thenar spaces, any infection persisting for more
than 48 hours extends in the majority of cases to the adjacent space. When both spaces are involved, a
considerable abscess is formed under the flexor tendons.

Web space infections


These are either primary infections from direct inoculation or secondary extending from the adjacent anatomical
structures. The diagnosis is clinical and based on an abscess forming at the distal edge of the palm separating
the adjacent fingers.

This is a subfascial infection of a web space and is usually caused by skin trauma that becomes infected; it often
occurs in laborers. The adherence of the palmar web space skin to the palmar fascia prevents lateral spread, so
the infection courses dorsally, resulting in both palmar web space tenderness and dorsal web space swelling and
tenderness. The attachment of the palmar fascia to the skin results to the spread of the pus into the dorsal
subcutaneous space with the typical picture of a collar-button abscessThe adjacent fingers will be held in
abduction with pain on adduction. Surgical treatment includes drainage of the often multi-loculated abscess,
through a palmar and/or a dorsal incision. The incision should never cross the edge of the web to avoid the
formation of dysfunctional scars.The web is a significant crossroad in hand infections.

Treatment
In deep space hand infections apart of antibiotic coverage and immobilization with hand elevation, the surgical
incision and drainage of all potentially communicating spaces and compartments is mandatory, along with
intraoperative irrigation and sometimes, continuous postoperative irrigation. Parameters such as the pathway of
inoculation, the environment where the initial injury occurred and above all the underlying condition of the host
must be taken into consideration for a radical and successful treatment. Finally, postoperative hand therapy must
be initiated as soon as the acute signs of infections subside.

Antibiotic treatment is usually initiated with penicillinase-resistant penicillin or cephalosporins. The oral empiric
antibiotic treatment expected to be effective against suspected CA-MRSA infections includes ciprofloxacin,
clindamycin, rifampin, tetracyclines, and TMP-trimethoprim/sulfamethoxazole. For more serious infections,
intravenous vancomycin is recommended. Alternative intravenous therapies include daptomycin, gentamicin, and
line-zolid. In crush injuries, injuries in highly contaminated environments or in immunocompromised hosts, gram
negative bacteria and/or anaerobes are suspected.

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Antibiotics are usually required for 7 to 10 days unless complications arise.The route of administration is
intravenous for all cases that require hospitalization, until the remission of the acute signs of infection.
Subsequently an oral regimen could be administered.

Specific approaches will be presented for the different types of closed-space infections. In all cases a bloodless
field is imperative for the evaluation of all potentially infected closed-spaces and for the drainage through safe
anatomical paths. Special attention must be given to the avoidance of use of Ershmarch bandage so as to limit
the spread of infection. Simple elevation of the hand and forearm is usually adequate for a bloodless field.

Venous ulcers

Vivek Agrawal, Ashesh Jha


1
Venous ulcer or stasis ulcer accounts for 80% of the lower extremity ulceration . Venous ulcers are difficult to
treat owing to its chronicity and high recurrence rate , which ranges from54% to 78% 2.Studies have shown that
an estimated 5% to 8% of the world population suffers from the venous disease and approximately 1% develops
3 4 5 6 7 8
venous ulcers . Venous ulcers most commonly occur in women & elderly persons . Advancing age ,
obesity , previous leg injuries, deep venous thrombosis & phlebitis are the risk factors that have been described
9
with venous ulceration . Nonhealing ulcers can be complicated by cellulitis, osteomyelitis, & malignant
transformation. Although the overall prevalence of venous ulcers are low but the refractory nature of these ulcers
& complications associated with these ulcers increases the morbidity & mortality of the patients and adversely
impact the quality of life 10 11 .

Pathophysiology
The pathophysiology of venous ulcer is not completely understood , however venous incompetence & associated
venous hypertension are thought to be the primary predisposing factors for ulcer formation. Therefore it is
imperative to know the venous anatomy of the lower limb to understand the overall effect of the venous
incompetence and venous hypertension on the development of chronic venous insufficiency and venous
ulceration. The venous system of the lower extremity comprises of three components: the superficial veins ,
perforator veins & deep veins . The deep veins lay within the muscle of the lower extremity , whereas the
superficial vein lie above the fascia overlying the muscles. The perforators or communicating veins connects the
superficial and the deep systems. The superficial veins are low pressure systems whereas the deep veins are
high-pressure systems. All three venous system have one way valve , which only open towards the deep venous
system and in normal circumstances, prevent reflux of blood .During ambulation, as the calf muscle contracts ,
the deep veins are compressed ,thus propelling blood proximally towards the heart. With brief rise in pressure ,
the valve of the all three system close preventing retrograde flow of blood 12 13 14 15 16 . As the calf muscle relaxes ,
the deep veins empty thus allowing a drop in pressure. The venous valve open during this phase, allowing the
blood to flow from the superficial veins through the communicating veins to the deep venous system 17 . In
17
patients with venous insufficiency, this series of events does not occur .

Venous hypertension , a sustained elevation of ambulatory pressure, is the hallmark of venous disease and may
be caused by an abnormal calf muscle pump. An abnormal calf muscle pump may occur due to incompetent
18
veins or valves of the lower extremities , muscular dysfunction , limited mobility or combination of the three
19
.Vein incompetence may be acquired or congenital often due to absence or dysfunction of valves . Contraction
of the calf muscle ,specifically the gastronemicus and the soleus muscle empty the intramuscular deep veins and
20
decrease the volume of venous blood present in the lower extremity . Anatomically, the plantar venous plexus
of the foot has a smaller vessel diameter than does the outflow tract of the posterior tibial deep veins, thus adding
the cephalad flow of venous blood. Compression of the plantar plexus is assisted by ambulation thereby
decreasing the strain on calf muscle pump. Venous ulcer may occur in some of these patient who lack the benefit
of the calf muscle pump and the plantar plexus that facilitate the movement of blood back to the heart.

Erect ambulatory patients who lack proper compensation of the venous system develop venous pooling near the
ankle. Increased venous pressure with concomitant reduced differential between the arteriolar and the venular
21
side of the capillary bed may trap leukocytes in post capillary venules . These leukocytes may activate and
release proteolytic enzymes , which leads to the formation of free radicals which may lead to local tissue damage
21 22
. Activated leukocytes also can release various cytokines such as tumor necrosis factor(TNF) & Interleukin
1(IL 1).In addition to leukocyte activation, margination of white cells can act as diffusion barrier to oxygen and
nutrients necessary for tissue survival 23 . Venous blood pooling in the lower limb increases the capillary
intraluminal pressure leading to stretching of the interendothelial pores with subsequent increase in the capillary
permeability and edema formation. Additionally macromolecules such as fibrinogen and alfa-macroglobulin may
leak into the dermis through the dilated capillary pores 23 . Alpha-macroglobulin may bind growth factors such as
24
TNF & transforming growth factor beta(TGFb),which are required for wound repair . Entrapment of these

145
growth factors may make them unavailable for the tissue repair. Fibrionogen leaking into the dermis leads to the
formation and deposition of fibrin cuff around the dermal blood vessels, which also may act as an additional
diffusion barrier to oxygen and nutrients 23 .

Recently, it also has been proposed that arterio-venous(AV) shunting may play a role in the pathogenesis of
venous ulcers 20 .This theory is supported by presence of elevated oxygen content of the venous blood,
premature venous filling, increased blood flow in the skin of legs on angiography,and decreased capillary density
in leg skin in patients with venous insufficiency possibly representing hypoperfusion of nutritive capillaries.

Clinical examination & Diagnosis

History
The patients history provides important information necessary for the differentiation of the types of ulcers that
develop in the lower extremity. The following symptoms are common to the most venous disorder & focused
question to elaborate these symptoms may provide the essential information for defining the etiology of ulcer
formation.
Aching
Swelling
Distended superficial veins
Bleeding
Skin discolouration
Ulceration
Restless leg syndrome
History of past DVT
History suggestive of Pelvic pathology
Family history

Most of the patients usually describe an increase in symptoms with prolonged standing. They deny pain but
acknowledge a more subtle dull ache or fatigue. Often these symptoms have been present for many years and
have been attributed to age or other factors. The symptoms are typically less noticeable in the morning but get
worse throughout the day are often exacerbated in women by menstrual cycle. Nighttime cramping and restless
legs also may be due to venous disease and often are noticeable after a particular long or active day. Patients
often experience itching in the lower leg which may be accompanied by stasis dermatitis or the other features of
chronic venous insufficiency. Many of these symptoms are significantly or completely relieved with treatment of
the superficial venous reflux.

Physical examination
A complete physical examination must always be performed . In addition attention should be directed towards the
involved extremitys circumference, edema, Skin changes, color , temperature, pulse as well as the location, size
and appearance of the ulcer.

Differential diagnosis of leg ulcer:


The differential diagnosis of leg ulcers are endless. Common causes of leg ulcers are as follows.
1) Vascular
- Arterial
- Venous
- Lymphatic
2) Vasculitis
- Periarteritisnodosa
- Rheumatoid arthritis
- Lupus erythematosus
- Hypertension
- Hematological Sickle cell anemia, Thalassemia , Polycythemia vera
3) Metabolic disorders :
- Diabetes mellitus
- Pyoderma gangrenosum
4) Tumors
- Squamous cell carcinoma
- Mycosis fungoides
5) Miscellaneous
- Drugs
- Factitial
Arterial ulcers
Arterial occlusive disease is a frequent cause of lower extremity ulcerations. These are located on the distal end
of the extremities. The ulcer appear as punched-out lesion. These ulcers are painful and the signs of chronic
ischemia are present in the involved extremity.

146
Venous ulcers
On physical examination, venous ulcers are commonly irregular in shape and shallow. Granulation tissue and
fibrin are often present in the ulcer base. These ulcers are commonly located above the medial malleolus Other
findings include lower extremity varicosities; edema; venous dermatitis associated with hyperpigmentation ,
hemosiderosis or hemoglobin deposition in the skin; and lipodermatosclerosis associated with thickening and
fibrosis of normal adipose tissue under skin. A clinical severity score based on the CEAP (clinical, etiology,
anatomy, and pathophysiology) classification system can guide the assessment of chronic venous disorders. The
highest CEAP severity score is applied to patients with ulcers that are active, chronic (greater than three months
duration, and especially greater than 12 months duration), and large (larger than 6 cm in diameter) . Poor
prognostic factors for venous ulcers include large size and prolonged duration .

Vasculitis ulcers
Ulcer formation secondary to vasculitis falls in broad category of diseases including polyarteritisnodusa,
hypersensitivity angitis ,Wegeners granulomatosis & necrotizing vasculitis*. The important points in making the
diagnosis are the history, laboratory testing and a biopsy to document the presence of vasculitis.These ulcer
appear primarily on the lower extremity from the midcalf to the dorsum of the foot.These lesion also have a
punched-out appearance with gangrenous central tissue. They can be unilateral or bilateral and are frequently
painful.

Hematologic ulcers

Sickle cell anemia : Ulceration occurs in approximately 75% of patients with sickle cell anemia. The
pathophysiology of this process involves a lowered oxygen tension and pH in areas of stasis in the distal portion
of lower extremities. The shape is usually round or oval and they are very refractory to healing.
Thalassemia : The presence of ulceration with thalassemia is not common. The mechanism for tissue damage is
probably inadequate tissue oxygenation.These ulcer appear similar to those of patients with sickle cell anemia.
Polycythemia Vera : Ulcer formation in this group of patients most likely has a dual origin. Either the increased
viscosity of the blood results in venous thrombosis ,valvular incompetence and venous ulceration,or local hypoxia
occurs at the capillary level and causes tissue damage.

Metabolic Leg ulcers

Diabetes Mellitus
The etiology of ulcer formation in patient with diabetes is multifactorial .Microangiopathy , sensory neuropathy &
infections predisposes these patients to ulcer formation. There are a number of rare cuases of ulcers in the lower
extremities of diabetes , including necrobiosis lipoidicadiabeticorum, diabetic dermopathy ,and bullae
diabeticorum.

Pyoderma Gangrenosum
It presents as an acute necrotizing ulcer predominantly on the lower extremities. Pyoderma gangrenosum
frequently produces an irregular ulcer with a necrotic base. This skin lesion begin as a deep-seated painful
nodule or as a superficial hemorrhagic pustule either de novo or after minimal trauma. This lesion was once
pathognomonic for ulcerative colitis but has been observed in many other conditions.

Tumors causing ulcers


Squamous cell carcinoma : These lesions occurs most commonly on sunexposed areas of the face neck and
extremities. The ulcers are shallow with a raised and everted border and never heals. When a chronic leg ulcers
of any etiology has been present for a long period and not healing,squamous cell carcinoma should be
considered.

Mycosis Fungoides : This is the most common type of lymphoma affecting the skin.There are three stages of
presentation: patch,plaque and tumor. Ulceration occurs secondary to necrosis of the tumor.

Miscellaneous causes of leg ulcer


Medications : Bromide and iodide compound can produce skin lesion.These ulcers usually occur on the anterior
surface of the tibia and are extremely painful.

Radiation : Ionizing radiation to the lower extremities in doses above 10 Gy may cause acute dermatitis which
can ulcerate 6 to 8 weeks following the acute reaction.

Decubitus ulcers: They are seen frequently in bedridden patients secondary to neurologic causes or general
debilitation.The lesion occur from prolonged pressure to a small surface area, on the lower extremity primarily the
malleoli and heels.

147
Diagnostic studies
The clinical diagnosis may be supported by further diagnostic testing as indicted, specially if other diagnoses are
being considered in differential.

Vascular studies
The initial evaluation of a venous ulcer should rule out concurrent arterial disease. Using a standard a
sphygmomanometer , the clinician can determine an ankle to brachial pressure index (ABPI).If the patient has an
ABPI between 0.5 to 0.8 ,it indicates that there may be concurrent arterial disease and venous disease. If the
26
ABPI is less than 0.5,the ulcer is more likely to be arterial in origin .

Duplex Ultrasound
It is often the initial choice for patient evaluation because it is widely available and easy to use. With this
technique one can delineate vascular architecture , site of venous reflux and status of deep venous system. For
venous evaluation patient is examined in the standing position , compression of the calf by manual pressure
produces a systolic flow of blood in the anterograde direction. After the release of the calf muscle, a patient with
valvular incompetence will demonstrate retrograde flow in the vein being evaluated.*Despite the widespread use
of this technique , considerable skill is necessary for a thorough evaluation of the deep veins.Functional testing
such as Plethysmography can be a complementary method alongside ultrasound to evaluate the calf muscle
27 28
dysfunction .

Invasive Techniques
The gold standard for defining the patients venous anatomy and demonstrating reflux is venography. In
ascending venography , the patient is upright while a tourniquet is applied above or below the knee. Contrast dye
is introduced,and if the dye is seen distal to the tourniquet , the patient is assumed to have venous reflux. In
descending venography ,the patient is placed in supine position and the contrast is injected into the common
femoral vein. The patient is then tilted downward , and the level to which the contrast dye leaks is observed.A
leak below the level of knee considered significant for reflux.

A comparison between various invasive and noninvasive techniques were performed by Mantonis group. They
found continuous wave Doppler and ambulatory strain guage plethysmography are of little value in the work up of
patients with deep venous insufficiency.They suggested colour duplex ultrasound should be used as a first line
29
diagnostic tool , with ascending phlebography used only when the triple ultrasound is inconclusive .

Radiological studies
Magnetic resonance imaging is becoming more popular as a diagnostic tool in the evaluation of these patients.
Magnetic resonance venography can show occluded vessels and alteration of blood flow, in addition they may
display subcutaneous fibrosis and infiltration of extrafascial spaces 30.

Biopsy & Tissue culture


These investigations are rarely warranted in the cases of classical venous ulcer. However in certain cases biopsy
can be performed to rule out malignant transformation. Although tissue culture has been considered as gold
standard in the assessment of wound infection, recent studies have shown a culture swab to be equivalent in the
31
initial evaluation of bacterial wound infection .

Therapy

General principles
The core principles for management of venous ulcerations are
1) Clean wound base
2) Compression
3) Surgical interventions/procedures
4) Medications

The clean ulcer


The aim of wound care is to provide an optimum environment for healing. A clean ulcer with healthy appearing
granulation tissue at its base is considered as the best environment for healing. It may be achieved by applying
the following methods
- Debridement :
- Treating infection:
- Wound care : Dressings,Topical agents

Compression
Compression is undoubtedly one of the most important factors in the healing of venous ulcer 32.Compression not
only supplements the pumping action of the calf muscle but also increases tissue pressure to reverse the
33
gradient between the capillaries and intravascular space , thus leading to reduction in tissue edema .It is
important to rule out concomitant arterial disease before initiating compression therapy.

148
Compression therapy should be performed in two consecutive phases. The first treatment phase is
decompression phase, which should take place at the time of active leg ulcer. The goal of this phase to reduce
edema and promote wound healing. For decompression phase three types of compression may be utilized : 1)
inelastic compression bandage ,2) multi-layered elastic bandage, 3) mechanical compression using intermittent
34
pneumatic compression boots .

Inelastic compression bandages provide limited pressure at rest, but high pressure with activity. The prototype of
inelastic bandage is the Unna boot, a moist, zinc oxide impregnated paste bandage that hardens to an inelastic
form. Unna boots require frequent reapplication because they do not accommodate for changes in leg volume as
edema subsides and they have limited absorptive capacity for highly exudative wounds. The multi-layered elastic
bandage system is comprised of a cotton or wool layer for absorption of exudates , one or two elastic wraps, and
self-adherent wrap that maintains the bandage in place. Multi-layered elastic bandage exert continuous pressure
(40-45 mmHg at the ankle) at rest and with activity. They require less frequent reapplication than inelastic
bandages because they have the ability to conform to the lower extremity better and have superior absorptive
capacity for highly exudative wounds. The disadvantage to multi-layered inelastic compression bandage is that
they require a certain degree of expertise for adequate application. Mechanical compression is reserved for
patient who are unable to ambulate and for those who fail to respond to standard compression therapy.

Pictures of Unna boot

Triple layer compression bandage

For the second phase or maintenance phase, which occurs after wound healing, elastic graduated compression
stockings are used to control venous HTN and prevent ulcer recurrence.
Surgical intervention/procedure

The main objective of surgical treatment in these patients are to achieve ablation of the hydrostatic forces of axial
reflux (i.e disconnection of SFJ , SPJ & stripping) and removal of hydrodynamic forces of perforator venous
reflux. Various studies have shown that no more than 15% of patient have isolated deep venous reflux , whereas
53% of patients have isolated superficial reflux35.Patients with reflux in the superficial and perforating veins are
more amenable to surgical treatment and may actually have clinical cure after surgery. The surgical intervention
may help to reduce venous reflux, hasten healing, and prevent ulcer recurrence. Venous insufficiency may be
taken care of surgically by saphenous vein ablation, subfascial endoscopic surgery for the interruption of the
perforating veins; stenting for treatment of iliac vein obstruction and removal of incompetent superficial veins with
36 37 38
phlebectomy, stripping, sclerotherapy, or laser therapy . Surgical management has been shown to achieve
an ulcer healing rate of 88 percent, with only a 13 percent recurrence rate over 10 months 39. There should be an
early evaluation for possible surgical intervention however the superiority of surgery over medical management
has never been proved 40.By repairing or eliminating or repairing venous incompetence one can reduce the risk of
recurrent venous ulceration 41. Subfascial endoscopic perforator vein surgery has been described for treatment of
42
venous ulceration with proven incompetent perforators .

149
Available surgical options are:
A. Saphenofemoral Junction Ligation

Saphenofemoral junction ligation alone, sometimes referred to as a Trendelenburgs procedure, is associated


with a high rate of recurrence of varices. Recent research has shown that it is necessary to remove the
saphenous vein to ensure that as much venous reflux as possible is eliminated.

A few sound principles:


1. In a patient of normal build the SFJ lies directly beneath the groin crease; in the obese it lies above. An incision
made below the crease is likely to be too low.
2. Do not divide any vein until the SFJ has been unequivocally identified.
3. Beware of the superficial external pudendal artery that usually passes between GSV and CFV but passes
superficial to the GSV in 5% of cases.
4. Follow and divide all tributaries (Superficial circumflex iliac, superficial inferior epigastric, superficial external
pudendal) beyond secondary branch points. Failure to do so leaves a network of superficial veins connecting the
veins of the thigh with those of the perineum, the lower abdominal wall and the iliac region. These cross-groin
connections are a frequent cause of recurrence.
5. Ligate the GSV deep to all tributaries flush with the CFV.
6. Divide the deep external pudendal vein as it comes off the CFV
7. Retract the lower margin of the wound to identify and ligate the posteromedial thigh branch that often joints the
GSV high in the thigh. Failure to do so increases the risk of haematoma formation after stripping above the
bandage, as well as medial thigh recurrence. A high anterolateral branch should be dealt with similarly.

B. Stripping

Several randomized trials have clearly shown that routinely stripping the GSV reduces the risk of recurrence
developing through the Hunterian perforating veins and to remove a vein in the thigh which is difficult to treat later
by sclerotherapy. Stripping markedly reduces the risk of recurrence by:

1. Disconnecting the thigh perforators and saphenous tributaries


2. Preventing any neovascularisation arising from the saphenous stump reconnecting with the GSV.

Perhaps the most common problem with conventional stripping of the GSV has been that of saphenous nerve
damage. Stripping the vein either to or from the ankle has long been recognized as carrying a significant risk of
this unpleasant complication. It is interesting to speculate on the mechanism of saphenous nerve damage when
the vein has been stripped only as far as the knee. Trauma within the femoral triangle is one possibility.
Inadvertent passage of the stripper out of the LSV and through the fascia lata is another. For this reason, and
because the main GSV below this level is rarely varicose, many now recommend stripping to the knee. The GSV
should be stripped to approximately one hands breadth below the knee. At this level the below knee perforator
(Boyd) would have been crossed but the saphenous nerve would not yet have joined the vein. Also, important
perforating veins below the knee are a part of the posterior arch circulation and not the great saphenous vein.

Alternatives to stripping
New venous surgical techniques have been developed in an effort to reduce the number and size of lower-
extremity incisions and hematomas, to eliminate postoperative discoloration, and to reduce the recuperation time.

Radio frequency (RF) ablation: The intervention employs radiofrequency (RF) energy mediated heating of the
vein wall to destroy the intima and denature collagen in the media with resulting fibrous occlusion of the vein.24
the Closure system (VNUS Medical Technologies Inc., San Jose, CA) consists of a bipolar heat generator and
collapsible catheter electrodes suitable for use in veins ranging from 2 to 12 mm in diameter. The procedure is
usually performed under conscious sedation and local anesthesia in an outpatient setting. The catheter is
preferably introduced into the saphenous vein at the knee percutneously under ultrasound (US) guidance or
through a small incision and direct exposure of the vein. The position of the catheter at the saphenofemoral
junction is confirmed by US. Local tumescent anesthetic is instilled in the subcutaneous tissues superficial to the
vein under US guidance. The vein wall temperature is allowed to equilibrate at 85Cafter turning on the circuit
and graduated withdrawal of the catheter is performed at a rate of 3 cm/min. The heating is controlled by
monitoring temperature and impedance of the vein wall via a feedback system. Veins up to 12 mm in diameter
are treated. The mechanics of the surgical procedure are relatively straight forward with a few caveats. The
treated vein should be relatively straight, free of severe tortuosity or thrombus and without aneurysm.
Contraindications include a post phlebitic vein that cannot be accessed, a mega saphenous vein (>12 mm), and
significant dilation of the proximal saphenous vein with an aneurysmal SFJ.

Endovenous laser therapy: Endovenous laser therapy (EVLT) is similar to RF ablation, but laser energy is used
for ablation of the saphenous vein.25 The procedure is faster and easier to perform than RF ablation and there is

150
no size limitation of the saphenous vein that can be treated. Both the 810-nm and the 940-nm diode lasers are
effective in inducing thrombotic vessel occlusion. Laser-induced indirect local heat injury of the inner vein wall by
steam bubbles originating from boiling blood is proposed as the pathophysiological mechanism of action of EVLT.
This causes collagen contraction and endothelial damage. The result is thickening of the vein wall and
contraction or thrombosis of the lumen.

The use of diode laser energy to ablate the saphenous vein is a method that obviates the need for general
anaesthesia and is associated with less pain than traditional surgical stripping of the great saphenous vein. This
procedure can be performed in an office based setting using local anaesthesia following preoperative
assessment with duplex ultrasound.

Foam Sclerotherapy: An increasing number of authors have recently reported successful injection of
incompetent GSV with 3% polidocanol in the form of foam.26 The foam is generated by mixing liquid and air in a
standardized procedure of forward and backward movements within a close double-syringe system. The GSV is
punctured directly under US guidance, and the foam injected. Results are verified by serial post treatment duplex
examinations

C. Saphenopopliteal Ligation

Some surgeons advocate routine stripping of the short saphenous vein should be disconnected and never
stripped. The short saphenous vein operation should be carried out first, if a long saphenous vein operation is to
be performed under the same anaesthetic.

Failure to mark the SPJ preoperatively will lead to a misplaced incision in a significant number of cases that will
necessitate further blind incisions or abandonment of the procedure. Clinical examination and hand held Doppler
are not reliable. Insist on a duplex ultrasound.

D. Ligation of the Lower Leg Perforating Veins

Surgery for these veins is usually required in patients with lipodermatosclerosis or ulceration. The presence of
incompetent perforators in patients with advanced CVI (clinical classes 4 to 6) is an indication for surgical
treatment in a fit patient. Whereas open perforator ligation is done only in those with healed ulceration, a clean,
granulating open ulcer is not a contraindication for subfascial endoscopic perforator vein surgery (SEPS).

Subfascial ligation of the medial communicating veins (Lintons operation): In view of considerable wound
complications associated with Lintons radical operation of subfascial ligation, which included long medial,
anterolateral, and posterolateral calf incisions, it was soon abandoned and he advocated only a long medial
incision from the ankle to the knee to interrupt all medial and posterior perforating veins53 A long vertical incision
is made through the skin and subcutaneous fat down to the deep fascia, approximately 1 cm behind the
subcutaneous posterior border of the tibia. Any subcutaneous veins that are divided are ligated. The deep fascia
is incised in the same line as the skin incision and is held open gently with a self-retaining retractor. As the
subfascial space is opened, leashes of communicating vessels can be seen passing from the posterior tibial
vessels between the muscles to the undersurface of the deep fascia. These vessels are isolated, divided and
ligated. When all the communicating veins have been ligated, the deep fascia and skin are carefully
approximately. The disadvantage of Linton procedure is that the lateral perforating veins can not be taken care by
this procedure.

Extrafascial ligation of perforators (Cocketts procedure): This operation is not commonly employed today.
The aim of surgery is to clear all the extrafascial enlarged veins and to divide perforating veins. However, the
perforating veins may be difficult to accurately locate in this plane and the dissection tends to be traumatic
because of adherence of subcutaneous fat and connective tissue to the fascia due venous ulcer and
lipodermatosclerosis and associated with a higher incidence of skin necrosis.

Posterior approach (Robs procedure): This is done if the perforators on the lateral side are also to be ligated.
The incision is a posterior subfascial one and the perforators on both the sides are ligated and divided. This
procedure offers advantage in the fact that the incision is away from the areas of ulceration and thus results in
good healing.

Subfascial endoscopic perforator surgery (SEPS): The major drawback of open procedure was a high
incidence of wound complications. Edwards in 1976 designed a device called the phlebotome to ablate the
incompetent perforators from sites remote from the diseased skin. The phlebotome is inserted through a medial
incision just distal to the knee, deep to the fascia, and advanced to the level of the medial malleolus. Resistance
is felt as perforators are engaged and subsequently disrupted with the leading edge. Hauer28 introduced the
endoscopic technique for division of perforating veins in 1985. His work was soon followed by other investigators
in Europe, who used different types of endoscopes or mediastinoscopes to perform the surgery with direct vision
through a single incision made in the proximal calf.

151
The use of laparoscopic instruments was described by ODonnell, who infused saline beneath the fascia to
facilitate the visualization and dissection of the subfascial plane. In Australia, Conrad29 began using carbon
dioxide insufflation in 1993 and published a report on his first seven patients in 1994. This technique, the two
port technique, employs one port for the camera and a separate port for instrumentation, thereby making it
easier to work in the limited subfascial space. All perforators encountered are divided either with the harmonic
scalpel or electrocautery or sharply between clips. The surgeons apply metal clips to the perforating vein before
the transection or simply use electrocautery to cauterize the veins. However, the use of metal clip in a potentially
infected wound with chronic unhealthy skin and ulcer may not be desirable. The repeated movement in and out of
the operative field to reload metal clips can be time consuming when multiple perforators are found. On the other
hand, the application of electrocautery in the limited subfascial space may cause inadvertent damage to the
surrounding soft tissue by the electrical currents. The production of smoke during dissection by electrocautery
may obscure the operative field, and intermittent evacuation of smoke is needed. The ultrasonic scalpel uses
precise ultrasonic vibration to coagulate and transect the vessels in a smoke-free environment.30,31 It has been
widely used in different areas, both in laparoscopic and open surgery. The scalpel vibrates at a rate of
55000times/sec. This mechanical action results in protein denaturation and the formation of coagulum, which
seals off blood vessels. The same action causes vaporization of cells resulting tissue fragmentation. This dual
action makes dissection quicker resulting in decreased operating time.

Complications
1. Major venous damage: Deep veins can be damaged during varicose veins surgery through attempts to control
bleeding and misidentification of anatomy. Complete division of the common femoral vein is estimated to occur
once in every 10,000 varicose veins operations.
2. Arterial damage.
3. Nerve damage. Popliteal dissection, stripping and distal avulsions may result in damage to the divisions of the
sciatic nerve (usually the common peroneal nerve), saphenous and sural nerve.
4. Haematoma. This is the commonest cause of discomfort after varicose veins and can be minimized by
operating the patient in the head-down position, careful hemostasis, and evacuation of all clots from the stripper
tunnel and use of a tourniquet.
5. Venous thromboembolism.
6. Necrosis of the wound edges: this is the most common and troublesome complication of both the subfascial
and extrafascial operations. It appears to occur more frequently after the extrafascial operation

E. Elimination of Residual Varicosities

Sclerotherapy: The aim of injection sclerotherapy is to place a small volume of sclerosant in the lumen of a vein
empty of blood, and then appose the walls of that vein with appropriate compression. The vein fibroses and gets
closed without the formation of clot. The sclerosant must remain localized within the segment of vein to be
treated. The vein must be kept empty of blood both during and after the injection. Patients should be mobilized
immediately afterwards and be encouraged to walk on a daily basis. This measure allows symptoms and signs of
allergic reactions to appear and be treated. The comfort of elastic compression can be evaluated, and the deep
venous circulation is stimulated and any sclerosant that has entered from the superficial injection is flushed.
Immobility is a relative contraindication to sclerotherapy.

Indications of sclerotherapy:
1. Telangiectasia
2. Reticular varicosities and reticular veins
3. Isolated varicosities
4. Below knee varicosities
5. Recurrent varicosities

Contraindications:
1. Presence of arterial occlusive disease
2. Patient immobility
3. Hypersensitivity to the drug
4. Acute thrombophlebitis
5. Huge varicosities with large communications to deep veins

Technique:
1. The patient is examined standing and varices are marked with an indelible pen.
2. A number of 2ml syringes fitted with 26 gauge needles are filled with 0.5 ml of sclerosant. Maximum volume
that can be given during one treatment is around 10 ml of sclerosant.
3. The skin is cleaned and venepunctures are made at 5 cm intervals along the course of each vein.
4. The patient lies down, veins are transfixed and the needle is slowly withdrawn. As soon as the blood appears
in the vein, the vein is emptied and the sclerosant is injected into the empty vein.
5. Cotton wool balls are placed and fixed with micropore tape.

152
6. When all injections have been completed, crepe bandages are applied and the patient is encouraged to
walk.
7. Compression bandages are worn for 3 weeks. After this period the legs are carefully inspected and
untreated varices or failed injection sites are re-injected.

Complications
The complications of injection sclerotherapy include:
1. Anaphylaxis.
2. Allergic reactions. Typically symptoms include urticaria, peri-orbital and oral swelling, bronchospasm and
migraine.
3. Ulceration. Ulceration follows extravascular injection. Commonly it is due to arterial occlusion caused by
sclerosant reaching a terminal arteriole. Another cause is reactive vasospasm because of a large volume of
injection. Treatment is symptomatic. Unless the ulcer is obviously infected (rare) antibiotics have no role.
4. Arterial injection. This is a serious complication that is accompanied by severe pain distal to the injection site.
The most vulnerable artery appears to be the posterior tibial artery at the ankle. Treatment includes
analgesia, cooling of the foot, and infusion of heparin and dextran.
5. Pigmentation. Pigmentation is due to the deposition of haemosiderin, often following superficial
thrombophlebitis. Most commonly seen in those treated with sodium tetradecylsulphate and hypertonic
saline and least common with polidocanol.
6. Superficial thrombophlebitis. This occurs when clot remains in the lumen of the sclerosed vein and is largely
due to inadequate compression. Localisedhaematoma is particularly painful and may be eased by aspiration
with a needle or scalpel under local anaesthesia.
7. Deep venous thrombosis. The risk is reduced by careful patient selection and by advising patients to walk
immediately after injection treatment and thereafter on a regular basis each day.
8. Nerve damage. Can occur due to approximate injection and/or pressure from bandaging.
9. Telangiectatic matting: or neoangiogenesis is the new appearance of red telangiectasias in a site of prior
sclerotherapy. It is believed to be a complex process in which new vessels grow in response to endothelial
growth factors or platelet-derived growth factors. Prevention is best achieved through use of dilute solutions
and in small volume

Skin Grafts and Flaps


Skin grafts and flaps have been used for the management of chronic ulcerations. They should only be applied to
a clean, uninfected ulceration with an adequate vascular supply. It has been suggested that the benefit of skin
grafts are the transplanted cells, which can secrete growth factors and other products that might enhance
healing. Full-thickness or split-thickness grafts can be used. Allogeneic (cultured) keratinocytes also may be used
but can be expensive. There is increasing interest in tissue-engineered skin. Graft skin (Apligraf) is a bilayered
skin equivalent that includes dermal and epidermal components and is manufactured by harvesting neonatal
foreskins and extracting both keratinocytes and fibroblasts that are then cultured separately to create the
epidermal and dermal components. Graftskin has been approved by the Food and Drug Administration (FDA) for
use in diabetic neuropathic ulcerations and venous ulcerations. Dermagraft is comprised of human fibroblasts on
a bioabsorbable scaffold; studies indicate that this product also may be useful for venous ulcerations.

Prevention of recurrence
The cornerstone of prevention of recurrence of venous ulceration is compression 38.A Cochrane review cited
circumstantial evidence for the benefit of compression as a whole ,and referred to evidence that high
compression is superior to moderate compression for the prevention of recurrence. Patient education is
important in the prevention of recurrences as well.

Oral agents for the treatment of venous ulcers


Pentoxifylline is xanthine derivative that is thought to treat occlusive disease by decreasing blood viscosity with
approval by the FDA for the treatment of claudication 39.In a systemic review of clinical trials , it has been found to
be helpful in treating venous ulcers and has been recommended as an adjunctive treatment 40.

Zinc was popularized as a topical treatment for leg ulcers during the past century , and one study found it helpful
for arterial and venous ulcers 41.Although it might have a mild antimicrobial effect , there is no evidence that zinc
can improve wound healing 41.It is argued that although Unna boots(made with zinc paste) are used in the
treatment of venous ulcers , they may be effective because of compressive effect and not because of the
42
composition of the plaster .A metaanalysis did not find sufficient evidence that oral zinc sulfate could improve
the wound healing of venous ulcers 43.

Diuretic treatment of peripheral edema caused by CVI is a temporizing measure that does not address the true
physiological problem 44.In the treatment of venous ulcers, however they may occasionally found to be useful to
acutely decrease the volume of leg edema.

Oral micronized purified flavonoid fraction modulates leukocytes adhesion and prevent endothelial damage and it
45
may also promote healing of venous ulcer .

153
Aspirin & Iloprost are also used as an adjunct to compression therapy, however there are insufficient data to
recommend their routine use.

Adjunctive management/ Advanced / Investigational Techniques


Several supplemental techniques have tried or are under investigation. The topical application of Simulium
vittatum erythema protein extracted from black flies may locally increase blood flow to aid in wound
46 47
healing .Topical autologous platelets have no significant adjuvant effect on healing of chronic venous ulcers
48
. Platelet derived growth factors , however have become popular in wound care centre,and have been shown to
49 50 51
be helpful in diabetic ,neuropathic ,decubitus ulcers. However the role of PGDF in chronic venous ulcer is
52
inconclusive .Recombinant PDGF.BB (Becaplermin) has been approved by the FDA for use in diabetic foot
ulcers.* and a recombinant GCSF product (Filgastrim) is proven to be effective as a subcutaneous injection for
the treatment of infected diabetic foot ulcers.*At this time,none of these treatments have been comprehensively
studied for the treatment of venous ulcers.
Further clinical studies are needed to elucidate the role growth factors may play in venous ulcers.*

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ulcer healing [see comment]. Angiology 54:S45-S50, 2003 (suppl 1)
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protein in saliva of a blood-feeding black fly, Simuliumvittatum. J ExpBiol 1998;201:1553-61.
52. Senet P, Bon FX, Benbunan M, et al: Randomized trial and local biological effect of autologous platelets used as
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growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four
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55. Wieman TJ, Smiell JM, Su Y: Efficacy and safety of a topical gel formulation of recombinant human platelet-
derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III
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DermatolSurg 2003;29: 863-6.

The Thoracic Outlet Syndrome

Sabyasachi Bal

Thoracic outlet syndrome is not the name of a single entity, but rather a collective title for a variety of conditions
attributed to compression of these neurovascular structures as they traverse the thoracic outlet.The thoracic
outlet is bordered by the scalene muscles, first rib, and clavicle. Neurovascular structures pass from the neck and
thorax into the axilla through this space. Thoracic outlet syndrome remains one of the most controversial clinical
entities in medicine.

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Epidemiology

The wide variability of symptoms and signs in patients with thoracic outlet syndrome and the lack of an objective
confirmatory test for the diagnosis makes correctly identifying patients with thoracic outlet syndrome difficult.
Therefore, determining its exact incidence remains elusive; estimates range from 3-80 cases per 1000
population. Thoracic outlet syndrome is more common in women, particularly those with poor muscular
development, poor posture, or both.

Functional anatomy

The neurovascular bundle courses through 3 spaces, or triangles, as it exits the neck to reach the axilla and
proximal arm. All 3 spaces can be the source of compression of the various components of the neurovascular
bundle, including the brachial plexus and the subclavian vessels. These spaces are small at rest and become
even smaller with certain arm maneuvers, such as abduction and external rotation. [13, 14] This can aid in the
diagnosis of thoracic outlet syndrome and forms the basis for provocative testing,

The first space is the interscalene triangle. It is bordered by the anterior scalene muscle, the middle scalene
muscle, and the upper border of the first rib. This space contains the trunks of the brachial plexus and subclavian
artery. The interscalene triangle is the most common site for neural compression, vascular compression, or both.

The second space is the costoclavicular triangle, which is bordered by the clavicle, first rib, and scapula and
contains the subclavian artery and vein and the brachial nerves.

The third and final space is beneath the coracoid process just deep to the pectoralis minor tendon; it is referred to
as the subcoracoid space.

Sport Specific Biomechanics

Thoracic outlet syndrome is most often seen in patients who engage in repetitive motions that place the shoulder
at the extreme of abduction and external rotation. An example of such activity is swimming, especially with the
freestyle stroke, butterfly stroke, and backstroke. When a swimmer reports tightness and pain around the
shoulder, neck, and clavicle as his or her hand enters the water, thoracic outlet syndrome should be suspected.

In addition to swimmers, other athletes affected by thoracic outlet syndrome include water polo, baseball, and
tennis players and athletes in any other activity that places repetitive stress on the shoulder at the extremes of
abduction and external rotation. These individuals may present with neurologic and arterial or venous symptoms.
Venous thoracic outlet syndrome most commonly develops in young male athletes in whom the upper extremity
musculature is overdeveloped as a result of work or physical conditioning. Baseball players, whose sport requires
repetitive throwing motions, are at increased risk for arterial thoracic outlet syndrome in their dominant arm.

Presentation

The initial presentation of thoracic outlet syndrome is dependent on whether the compression is primarily
vascular, neurogenic, or a combination of both. It is also dependent on the underlying continuum of
histopathologic changes noted with chronic nerve compression, ranging from intermittent to constant debilitating
symptoms. Three symptomatic patterns emerge; these are vascular, true neurogenic, and disputed or
nonspecific-type thoracic outlet syndrome.

Vascular thoracic outlet syndrome is rare and can involve the subclavian artery or vein. Both forms of vascular
thoracic outlet syndrome tend to occur in young patients who perform vigorous overhead arm activity such as
throwing. With venous obstruction (if secondary to thrombosis, Paget-von Schrtter syndrome), patients may
present with upper extremity swelling, venous distention, or diffuse arm or hand pain (including the forearm).

With arterial obstruction, patients may report color changes of their affected upper extremity, claudication, or
diffuse arm or hand pain (including the forearm). Because of arterial collateral blood flow, the iinitial symptoms
tend to be mild, with arm ache and fatigue, particularly after overhead activity. Patients typically seek medical
evaluation after ischemic events (eg, ulceration, gangrene, absent pulses) occur.
Neurogenic thoracic outlet syndrome involves compression of the brachial plexus. Similar to vascular thoracic
outlet syndrome, a pure neurogenic presentation is also rare. Patients present with painless atrophy of the
intrinsic muscles of the hand, and athletes may report difficulty grasping a racket or ball as a result of intrinsic
muscle weakness. They may also report sensory loss or paresthesias. Pain is often reported but is not as
dramatic as in the nonspecific-type thoracic outlet syndrome. Again, neurogenic thoracic outlet syndrome tends
to affect individuals who perform overhead arm activities.

The disputed or nonspecific-type thoracic outlet syndrome refers to a large group of patients with unexplained
pain in the arm, scapular region, and cervical region. Typically, their symptoms begin after a traumatic event (eg,

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motor vehicle accident). Much debate surrounds this diagnosis, with certain providers believing the disorder is
underdiagnosed and others believing it is overdiagnosed.

The clinical examination

The examination should begin with an assessment of the patients posture. A slumped posture of the shoulders
and upper back and a poked-forward position of the head and neck are comfortable but potentially damaging for
the scapular and neck muscles and are thought to contribute to the susceptibility for thoracic outlet syndrome.

The symmetry of both arms should be evaluated. Cervical active range-of-motion assessment and the Spurling
test (ie, patients head is placed in extension and lateral flexion, with axial compression applied by the examiner
to the patients head in an effort to recreate radicular pain) should be performed. Active and passive range of
motion of both shoulders should be examined. A careful neurovascular examination of both upper extremities is
needed, taking care to remember that the muscles and nerves supplied by the lower brachial plexus are most
commonly affected.

Vascular thoracic outlet syndrome has different examination signs depending on whether the venous or arterial
vessels are affected. With venous compression, patients often present with edema and cyanosis of the upper
extremity. They may also have distended veins in the shoulder or chest. With arterial compression, patients often
present with pallor, a weak or absent pulse, and coolness of the upper extremity. Decreased blood pressure
greater than 20 mm Hg in the affected arm compared with the contralateral arm is sometimes noted and is a
reliable indicator of arterial involvement. Rarely, small infarcts are noted in the hands and fingers, which are due
to embolization.

The classic finding in a person with neurogenic thoracic outlet syndrome is the Gilliatt-Sumner hand. This
physical examination finding includes atrophy of the abductor pollicis brevis with lesser involvement of the
interossei and hypothenar muscles. Patients may also have decreased sensation that follows the ulnar nerve
distribution because the lower trunks of the brachial plexus are usually more involved than the upper trunks.

Patients with disputed or nonspecific-type thoracic outlet syndrome tend to have diffuse upper extremity pain with
guarding. Examination tends to be difficult and findings nonfocal. Weakness and decreased sensation tend to be
unreliable signs that are difficult to quantify.

Because of the variability of the structures involved in thoracic outlet syndrome, many provocative maneuvers
have been described to aid in diagnosis. They include the Adson maneuver, Wright test, and Roos stress test.
Note, however, that these tests have high rates of false-positive and false-negative results.

The Adson maneuver is performed by positioning the tested shoulder in slight abduction and extension. Then, the
patient extends his or her neck and turns the head toward this affected shoulder. The patient inhales while the
examiner simultaneously palpates the ipsilateral radial pulse. If the pulse diminishes or the patient has
paresthesias, the test result is considered positive as long as this maneuver does not cause symptoms on the
asymptomatic contralateral side.

The Wright test is performed by progressively hyperabducting and externally rotating the patients affected arm
while assessing the ipsilateral radial pulse. Again, the test result is considered positive if the pulse diminishes or
paresthesias develop.

The Roos stress test is performed with the patient positioning both of his or her shoulders in abduction and
external rotation of 90 with elbow flexion at 90. The patient then opens and closes his or her hands for several
minutes. Reproduction of symptoms or a sensation of heaviness or fatigue is considered a positive test result.

Causes

Causes of thoracic outlet syndrome can be divided into bony and soft-tissue factors. Bony factors include
abnormalities such as anomalous cervical ribs, hypoplastic first thoracic ribs, and exostoses of the first rib or
clavicle.[17, 18] The rate of anomalous cervical ribs is considered to be 0.17-0.74% in the general population, and
the rate of rudimentary first ribs is 0.29-0.76%.

Soft-tissue factors include congenital anomalies such as anomalous fibrous muscular bands near the brachial
plexus and hypertrophic muscles in athletes and weight lifters. Space-occupying lesions (eg, tumors, cysts) and
inflammatory processes also occur in the soft tissues and can cause thoracic outlet syndrome.

Trauma or mechanical stress to the neck, shoulders, or upper extremities can lead to thoracic outlet syndrome. In
fact, a combination of neck trauma and anatomic predisposition (ie, cervical rib) is considered the main etiology
of thoracic outlet syndrome. Posttraumatic conditions such as hematoma, myositis ossificans, and scar formation
can be important variables, as can a droopy shoulder secondary to trapezius muscle weakness. Thoracic outlet
syndrome can be secondary to malunion of a clavicle fracture.

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Interestingly, multiple points of compression may be present as the peripheral nerves descend from the thoracic
outlet to the hand (simultaneous thoracic outlet syndrome and ulnar nerve compression at the elbow or carpal
tunnel syndrome in the wrist). This has been referred to as double-or multiple-crush syndrome.

Diagnosis

In thoracic outlet syndrome with vascular compromise or nerve compression, with resultant atrophy of the
intrinsic hand muscles, the diagnosis is not controversial and specific tests can confirm the diagnosis. However,
no infallible clinical tests, laboratory tests, radiographic tests, or electrical studies establish the diagnosis of
thoracic outlet syndrome syndrome in patients with disputed or nonspecific-type thoracic outlet syndrome. Many
tests are available to refine the differential diagnosis and confirm or exclude other potential conditions (see
Differentials and Other Problems to Be Considered).

To exclude systemic disease and inflammation, a few simple blood tests may refine the differential diagnosis for
thoracic outlet syndrome, including a blood glucose level, complete blood cell (CBC) count, erythrocyte
sedimentation rate (ESR), basic metabolic panel, thyrotropin level, and rheumatologic workup, if indicated.

Imaging

Radiography
Cervical spine and upper thoracic spine radiographs may demonstrate bony abnormalities. Chest, shoulder, and
clavicle radiographs may also identify bony abnormalities.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI)


CT scanning and MRI are more useful for identifying other conditions that might cause similar symptoms, rather
than for establishing the diagnosis of thoracic outlet syndrome.

Magnetic resonance angiography (MRA)


MRA can be useful for the diagnosis of arterial vascular thoracic outlet syndrome.

Venography and duplex scanning


Venography and duplex scanning (ie, ultrasonography combined with Doppler velocity waveforms) are used to
assist in the diagnosis of subclavian vein compression (thrombosis). These tests can be performed dynamically
with positions that recreate the tension placed on the thoracic outlet during certain motions such as abduction
and external rotation.

Other Tests
Electrodiagnostic studies can be helpful for classic cases of neurogenic thoracic outlet syndrome and therefore
can be useful when the results are positive. However, many symptoms are intermittent in neurogenic thoracic
outlet syndrome; therefore, negative test results do not rule out this diagnosis. Electrodiagnostic testing can also
be helpful in diagnosing other neuromuscular disorders.

Nerve conduction velocity has been used for the diagnosis of thoracic outlet syndrome as defined by a reduction
to less than 85 m/s of either the ulnar or median nerves across the thoracic outlet and was found to corroborate
the clinical diagnosis. A nerve conduction velocity of less than 60 m/s was considered an indication for surgery.
However, as with many aspects of thoracic outlet syndrome, this remains controversial and has not been
universally accepted.

Somatosensory evoked potentials are equally controversial, with some studies favoring their use and others not.

Electromyography may be helpful in confirming the presence or absence of a specific alternative diagnosis.

Management

Surgery in cases of thoracic outlet syndrome is indicated for acute vascular insufficiency and progressive
neurologic dysfunction. For subclavian venous thrombosis, treatment addresses 3 problems: the clot, the
extrinsic compression, and the intrinsic damage to the vein. Thrombolysis with urokinase is the most commonly
recommended treatment, with continued anticoagulation for several months. The timing of surgical
decompression is debated, but surgical decompression is needed for long-term improvement. Patients with acute
ischemia of the upper extremity require prompt diagnosis and surgical treatment.

All other patients should receive nonoperative treatment that includes relative rest, nonsteroidal anti-inflammatory
medications (NSAIDs), cervicoscapular strengthening exercises, and modalities such as
ultrasound, transcutaneous nerve stimulation, and biofeedback. Conservative care has been shown to be
successful in most patients. In those patients in whom pain is refractory to conservative care, surgery should be
considered.

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Physical Therapy
Physical therapy that addresses postural abnormalities and muscle imbalance relieves symptoms in most
patients with thoracic outlet syndrome by relieving pressure on the thoracic outlet. This is based on 3 potential
effects of abnormal static or repetitive postures and positions.

First, increased pressure directly around nerves at various entrapment points or increased tension on nerves
creates chronic nerve compression. Second, certain postures maintain muscles in abnormally shortened
positions, resulting in a new length. When these adapted muscles are stretched, pain occurs. Third, abnormal
posture results in some muscles being stretched and others being shortened to new lengths, resulting in both
being placed at a mechanical disadvantage and leading to muscle imbalance. This is the basis for physical
therapy.

Although, many conservative protocols for physical therapy are described, few outcome studies have been
published. The few studies available demonstrate positive outcomes for most patients.

Patient treatment includes several components that address the brachial plexus nerve compression and muscle
imbalance in the cervicoscapular region. Key points emphasized in treatment begin with education. Postural
correction focuses on positions of most risk and least risk for compression, with integration into the patient's
activities of daily living at work, home, and sleep. For example, patients should avoid overhead arm positions
while sleeping. Postural and position correction can be aided by wrist splints, elbow pads, soft neck rolls for
nighttime use, and lumbar supports for sitting. In addition, the impact of body habitus and general physical
conditioning should be evaluated and discussed (ie, obesity, breast hypertrophy).

Physiotherapy focuses on pain control and range of motion with specific stretching exercises. Stretching should
begin with short, tight muscles (ie, upper trapezius, levator scapulae, scalenes, sternocleidomastoid, pectoralis
major, pectoralis minor, suboccipitalis) and should not be aggressive. Once pain control and cervical motion are
regained, strengthening exercises of the lower scapular stabilizers are begun, as is an aerobic conditioning
program. The importance of patient compliance should not be overlooked.

Surgical Intervention

Little argument exists for the surgical treatment of a patient with severe compression or compromise of the
subclavian vein or artery. However, less severe cases are more controversial. Likewise, patients with atrophy of
the intrinsic muscles of the hand secondary to thoracic outlet syndrome with no distal sites of compression need
surgical intervention.

Because of the high prevalence of surgical complications and variable reports of success, many surgeons offer
surgery to patients with disputed or nonspecific-type thoracic outlet syndrome only as a last resort after prolonged
conservative management and a detailed discussion regarding the risks and complications of surgery. Potential
complications from surgery can include pneumothorax, injury to the subclavian artery or vein, injury to the
brachial plexus and long thoracic nerve, apical hematoma, intercostobrachial nerve injury, and injury to the
thoracic duct.

The surgical approach used varies and may be specialty dependent, with the transaxillary approach preferred by
many thoracic and vascular surgeons and the anterior supraclavicular approach favored by most neurosurgeons.
Both approaches allow for first rib removal and part or total scalene muscle removal.

Success rates for surgery vary dramatically in the literature. One review of 47 patients with thoracic outlet
syndrome revealed 75% lower plexus and 50% upper plexus compressions remained asymptomatic at 4.6 years.
Morbidity in this study involved 17% of patients and was most frequently the result of incisional pain. However,
not all studies have been so impressive. One retrospective analysis of patients with nonspecific neurogenic
thoracic outlet syndrome demonstrated work disability at 1 year after surgery in 60% of patients. At 4.8 years of
follow-up, 72.5% patients were limited in activities.

This has led many surgeons to agree with Wood et al, who empathically stated in 1988 that some errors always
occur in diagnosis, and, therefore, surgery should be advised "on a basis of exclusion and with great
reservation." This is especially true for disputed or nonspecific-type thoracic outlet syndrome.
Postoperative physical therapy is essential for strengthening and range of motion.

Rehabilitation

Physical Therapy
Continued regular stretching of the muscles around the cervical girdle (eg, scalene, pectoralis major and minor,
trapezius, levator scapulae, and sternocleidomastoid muscles) is essential.

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Recommended exercises for thoracic outlet syndrome include neck stretching, abdominal breathing, and postural
exercises. Ineffective therapies include shoulder shrugs (useful for prevention), weight lifting, and neck traction.
Exercises should be performed at home at least twice a day.

Medical Issues/Complications

Patients may require continued postoperative anticoagulation with warfarin.


To help prevent recurrence of thoracic outlet syndrome, the patient should avoid sleeping with his or her
arms in an overhead position.

Primary Hyperparathyroidism

Sunil Chumber, Pratyusha Priyadarshini

Introduction

Parathyroid gland was first identified by Sir Richard Owen during the autopsy of Indian Rhinoceros in 1850. In
1879, Ivar Viktor Sandstorm, named parathyroid glands in human as Glandulae Parathyroideae and he also
described tetany in post thyroidectomy patient. Felix Mandl performed first planned successful parathyroidectomy
for carcinoma of parathyroid in 1925.

Parathyroid glands are four in number and located on the posterosuperior surface of thyroid. However in 13%
they are supernumerary (more than or equal to five) and in 3% they are lesser in number. A normal parathyroid
gland measures 5-7 mm in size and weighs 15-40mg. Inferior parathyroid glands and the thymus are derived
embryologically from third branchial pouches, while superior parathyroid glands arise from third branchial pouch
along with the thyroid.

Hyperparathyroidism is the third most common endocrine disorder after diabetes mellitus and thyroid disease. It
is three times more prevalent in women and also its incidence increases with age. Primary hyperparathyroidism
(PHPT) is frankly elevated or inappropriately normal parathormone levels in the presence of hypercalcemia. It is
the most common cause of hypercalcemia. Most common cause of primary hyperparathyroidism is parathyroid
adenoma in 80-85% of cases. Remaining 15-20% of cases are due to multiglandular parathyroid hyperplasia
which are mostly associated with MEN1 or MEN2a. Parathyroid carcinoma is rare and accounts for <1% of cases
of primary hyperparathyroidism. Diagnosis and management of parathyroid disease has changed radically in the
past two decades.

Clinical presentation

Patients with hyperparathyroidism have been known to present with classic pentad of symptoms (kidney stones,
painful bones, abdominal groans, psychic moans and fatigue overtones). In western countries due to routine
screening of serum calcium, more and more patients are diagnosed in asymptomatic or pauci-symptomatic
stage. However, the clinical presentation in our country has not changed much over the decades. In our
experience of more than 300 primary hyperparathyroidism, 95% of patients were symptomatic at presentation
and multisystem involvement is rule rather than exception. Skeletal system is most common involved system in
approximately 70% of patients. Bone disease may present as osteopenia, osteoporosis, bone deformities, brown
tumors, increased fragility, delayed healing of fractures and multiple fractures. Next common organ to get
involved is kidney in approximately 30-40% of patients. Kidney involvement may present with nephrolithiasis,
nephrocalcinosis, hypercalciuria, chronic renal insufficiency,nephrogenic diabetes insipidus,thirst,polydipsia and
polyuria. Gastrointestinal involvement is present in 25-30% of patients, with peptic ulcer disease being most
common manifestation and pancreatitis present in 5% of our patients. Central nervous system involvement is
often underreported (10% in our series) because most of the symptoms are very subjective and can be elicited
only on detailed questioning. Myopathy is another common clinical manifestation and proximal muscle groups are
more frequently involved. Most of the patients have no palpable disease however, in patients with large adenoma
neck lump may become palpable.

Investigations

Biochemical Studies
The diagnosis of PHPT is established with the presence of an elevated serum calcium and intact PTH level.
Patients with PHPT also have decreased serum phosphate and elevated 24-hour urinary calcium concentrations.
Elevated levels of alkaline phosphatase are found in approximately 60-70 % of patients with PHPT and are
indicative of high-turnover bone disease. Alkaline phosphatase levels are markedly elevated in patients with

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severe bone disease; however in patients with isolated renal disease they may be normal. These patients are
prone to develop postoperative hypocalcemia due to bone hunger.

Few patients may present with normocalcemic PHPT due to vitamin D deficiency, a low serum albumin, or a low
normal blood calcium set point. Normocalcemic PHPT is more prevalent in our country (approximately 25% in our
series). These patients have increased total PTH levels with or without increased blood ionized calcium levels.

Radiologic Tests
In patients with PHPT, characteristic bone lesions are present on radiograph. Subperiosteal resorption is virtually
pathognomonic for hyperparathyroidism and is typically seen at the radial aspect of the middle phalanx of the
index and middle fingers.Bone mineral densitometry studies using dual-energy absorptiometry are being
increasingly used to assess the effects of PHPT on bone. Abdominal ultrasound examination is used selectively
to document renal stones.

Preoperative Localization Tests


It has become routine to localize hyperfunctioning parathyroid glands before parathyroidectomy. Localization
studies have permitted surgeons to perform more limited operation. The predominant imaging techniques for
preoperative localization of parathyroid adenomas are ultrasonography and 99mTc-sestamibi scintigraphy.
Numerous studies done to compare these techniques suggest similar sensitivities and specificities for detection
of solitary adenoma. Reported sensitivities for the detection of solitary parathyroid adenomas by ultrasonography
range from 72% to 89%. Sonography has the advantage of being more specific regarding the site of an adenoma
in relation to the thyroid gland. In our series ultrasonography was performed in 65% patients and its sensitivity
was 86% and it was accurate in localizing the culprit lesion in 77% of patients. Sestamibi with 99mTc is the most
commonly used radiotracer for imaging the hyperfunctioning parathyroid glands and has been extensively studied
in the setting of primary hyperparathyroidism . Sensitivity of parathyroid scintigraphy has been reported to range
from 80-100% and it clearly has an advantage in the detection of ectopic glands, particularly in the mediastinum .
Sensitivity of sestamibi scan in our series was 93% and it was more sensitive for ectopic lesions as compared to
ultrasonography (94% versus 44%). A preoperative approach combining both sonography and scintigraphy has
been shown to predict more accurately the presence and location of solitary adenomas than either technique
alone. At our centre combining both the modalities for localization increased the sensitivity to 97%.

Single-photon emission CT is now being used increasingly as it has been shown to be superior to other nuclear
medicinebased imaging. It is more sensitive than sestamibi scan and has got better image acquisition,
specifically it can indicate whether an adenoma is located in the anterior or posterior mediastinum
(aortopulmonary window), thus enabling the surgeon to modify the operative approach accordingly.

CT and MRI scans are less sensitive than sestamibi scans, but are helpful in localizing large paraesophageal and
mediastinal glands. More recently, four-dimensional CT (4D-CT) has shown utility in parathyroid localization. This
technique incorporates the perfusion of contrast in hyperfunctioning parathyroid tissue over time, thus providing
functional information in addition to the anatomic information provided by conventional three-dimensional CT
imaging.

Management

Surgery is the mainstay of treatment for PHPT and requires successful localization and excision of the abnormal
gland(s). The surgical approach to patients with primary hyperparathyroidism has evolved since the first
successful parathyroidectomy performed by Felix Mandl in 1925. Since then, bilateral neck exploration with
resection of enlarged parathyroid glands has been the gold standard operation performed for this disease.
Conventional neck exploration is conducted through a standard transverse skin crease neck incision. An attempt
is made to identify all the 4 glands and excision of abnormal gland is done with or without biopsy of normal gland.
It has more than 95% cure rate and minimal morbidity in the hands of an experienced endocrine surgeon.
However, since 80-90% of primary HPTH cases are due to a single parathyroid adenoma, the need for bilateral
neck explorations have been questioned and it lead to evolution of unilateral approaches termed minimally
invasive parathyroidectomies. Various types of minimally invasive procedures available are minimally invasive
radioguided parathyroidectomy (Norman et al), minimally invasive parathyroidectomy with intraoperative PTH
assay (Irvin et al), video-assisted and endoscopic parathyroidectomy. The prerequisite for all of them is
successful preoperative localization with nuclear scan and/or ultrasonogaphy of neck. Open minimally invasive/
focused parathyroidectomy comprises of reduced skin lesion placed on the side of localization, division of strap
muscles, identification of the abnormal parathyroid gland and ligation of its vascular supply and excision. In this
approach only abnormal gland is excised and no attempt is made to identify other glands. Bergenfelz et al
compared bilateral versus unilateral neck exploration for primary HPTH in the first prospective randomized trial
and reported that there was no difference in cure rates or complications between patients in the two groups.

In our series, minimally invasive parathyroid surgery was performed in overall 58% of our patients, however after
year 2000, 76% of surgeries were carried out by minimally invasive approach. At our centre, for all patients
diagnosed with primary hyperparathyroidism, two localizing investigations preferably USG and sestamibi scan
are ordered. In patients with no evidence of familial disease and concomitant thyroid pathology, if findings of both

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the investigations are concordant, an open minimally invasive parathyroidectomy without introperative PTH assay
or frozen section is performed. In remainder of our patients conventional neck exploration is the procedure of
choice. Cure rates for minimally invasive surgery and conventional neck exploration in our series were 97.7% and
98.5% respectively which includes the reoperative cases in both groups. There was no mortality in whole series
and only one patient had transient paresis of unilateral recurrent laryngeal nerve which recovered completely.

For patients undergoing reoperative parathyroid surgery a comprehensive preoperative work up is must before
venturing into the surgery. Operative records of previous surgery, localization studies and previous histopatholgy
should be reviewed extensively. For patients operated outside, the surgeon who had performed the initial surgery
preferably should be contacted. If needed fresh localization studies should be ordered. Intra operative infusion of
methylene blue dye has been found to be very useful in facilitating the localization of gland in reoperative
surgery.

Most of our patients will develop hypocalcemia after successful surgery due to hungry bone syndrome. All the
patients will require calcium and vitamin D supplementation for 3 to 6 months after surgery which can be
gradually tapered down. Patients are called for regular follow up at 6 monthly interval and serum calcium and
intact PTH level are monitored. Outcome after parathyroid surgery is excellent, most of the patients report
improvement in bone pain, elevation of mood and sense of well being immediately after surgery. In the long term,
the healing of fractures is accelerated and bone mineral density improves after surgery and most of the sequelae
of the disease are reversed.

Conclusion

The diagnosis of PHPT is based on the presence of elevated serum calcium and intact PTH level. Most of our
patients present with classical symptoms of PHPT. The most common pathology for PHPT is single adenoma
and surgery is the mainstay of treatment for PHPT. The surgical management of primary hyperparathyroidism
has evolved significantly over the past few decades mainly due to improved preoperative localization of
parathyroid adenomas. Ultrasonography and nuclear scintigraphy successfully localize the adenoma in 85-95%
of patients with PHPT. Minimally invasive parathyroidectomy has replaced conventional bilateral neck exploration
in patients with a localized adenoma on preoperative imaging. In carefully selected patients, the minimally
invasive technique provides cure rates comparable to the traditional bilateral approach. Conventional neck
exploration is reserved for patients who have familial disease, concomitant thyroid pathology, discordant or
nonlocalized lesion. Despite improvement in imaging modalities and surgical technique, a good parathyroid
surgeon is must to ensure successful parathyroid surgery. The old dictum that for parathyroid surgery the only
localization which is needed is to locate a good parathyroid surgeon will always remain relevant.

References

1. Textbook of Endocrine Surgery (eds Orlo H. Clark Quan-Yang Duh and Electron Kebebew) pp 365-371 Elsevier
Saunders, Philadelphia, PA.
2. Endocrine Surgery: Principles and Practice (eds Hubbard J, Inabnet WB, Lo C-Y) pp 267-278 Springer, London
3. The Parathyroids, Basic and Clinical Concepts (1994),pp. 531551. Raven,New York.

Surgery for Hereditary MEN-related tumors

Amit Agarwal, NavneetTripathi, Roma Pradhan

Introduction

MEN syndromes have been well characterized in the past 10 to 15 years following identification of their molecular
underpinnings. Genetic testing plays an indispensable role in clinical management of these tumours in children
and adults. MEN 1 probably has the widest pleiotropy of any hereditary cancer syndrome whereas MEN2 is
notable for remarkably precise genotype-phenotype correlations at the level of the codon that determines timing
of surgical intervention.Surgeons have to recognize these syndromes and use a multidisciplinary approach for
early and presymptomatic diagnosis, reduction of morbidity and mortality and avoidance of surgical
misadventures.

Multiple Endocrine Neoplasia (MEN) definition

These are familial conditions with tumors involving two or more endocrine glands in index case & family
members.Prevalence of MEN2 is 1 in 35000 and of MEN1- is 1 in 20-40,000. They follow autosomal dominant
inheritance with important implications for family members

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MEN1
st
In MEN 1 syndrome, proband is affected by at least 2 out of 3 major MEN 1 related tumors & 1 degree relative
with 1 major lesion.
Endocrine major lesions % Minor lesions associated %

Primary hyperparathyroidism 95 Foregut carcinoid 2


Thymic, bronchial 10
GIT

Entero-Pancreatic tumors 40-80 Adrenal cortex NF 25


Gastrinomas 50 Lipomas 30
Insulinomas 10 Facial angiofibromas 85
NF- PP 20 Thyroid tumors 25
Glucagonoma, VIPomas, Somatostatinoma 2 Pheochromocytoma <1
Ependymoma 1

Anterior Pituitary tumor 15-90


Prolactinoma 60
GH+PRL, GH,NF 20
ACTH, TSH 2-5

MEN 1 mutations, in about 50% cases cause truncation of meninresulting in loss of function. At least 10 % cases
have de novo mutations. There is no evident genotype - phenotype correlation in MEN1. MEN 1 has high
penetrance rates with more than 50 % expressing by 20 years and more than 95 % by 40 years

Clinical situations requiring consideration for MEN 1 are :


Hyperparathyroidism in young age (< 55 years)
Multiglandular / recurrent HPT in absence of renal disease
Any classic MEN 1 lesion and family h/o associated lesions
Any MEN 1 lesion & adrenal incidentaloma
All patients with pancreaticoduodenal tumors
All patients with bronchial/ thymic carcinoids

In the absence of treatment, endocrine tumors are associated with an earlier mortality in patients with MEN1.
Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by the age of 50
years and the cause of death in 50-70% of patients with MEN1 is usually a malignant tumor process or sequelae
of the disease.

Treatment of MEN1

Management is generally similar to that for the respective tumors occurring in non-MEN1 patients. However, the
treatment outcomes are not as successful as those in non-MEN1 patients. MEN1 associated tumors with
exception of pituitary tumors are usually multiple, thereby making it difficult to achieve a successful surgical cure.
Occult metastatic disease is more prevalent in MEN1 patient with metastasis in about 50% cases. MEN1
associated tumors may be larger, more aggressive and more resistant to treatment.

Hyperparathyroidism in MEN1
It is the most common endocrinopathy in MEN 1 with 100 % penetrance by age 50 years. MEN1 constitutes
about 2-4% of all cases of PHPT. MEN1 associated hypercalcaemia is usually mild and hypercalcemic crisis is
rare. Age of onset is earlier at 20-25 years with no sexual preponderance.

Surgery is the definitive treatment. All four glands are usually involved having asymmetrical hyperplasia.
Parathyroid carcinoma in MEN setting is rare. There is controversy regarding optimal surgery i.e sub-total versus
total parathyroidectomy with autotransplantation. After subtotal parathyroidectomy, problems of recurrent or
persistent hypercalcemia occur in 40%-60% of patients within 10 years. Permanent hypocalcemia occur in 10-
30% of patients. Patients who underwent Total parathyroidectomy with autotransplantation may also have
Persistent disease due to supernumerary parathyroid glands. In case of recurrence, transplanted parathyroid
tissue in forearm can be removed.

Open bilateral exploration is recommended in such patients and there is no role of minimally invasive
parathyroidectomy. Resections less than sub-total parathyroidectomy are associated with unacceptably high
frequency of persistent or recurrent disease.There is a trend toward using sub-total parathyroidectomy instead of
total because of concerns about a higher rate of post-operative hypoparathyroidsim. In addition, a thymectomy
should routinely be performed in these patients. Intraoperative parathormone assay is helpful in documenting

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curative PTH fall and completeness of surgery. Calcimimetics are indicated post failed surgery as well as in
patients in whom surgery is contra-indicated.

Pancreatic Islet tumors/Insulinoma


Pancreas of patients with MEN1 is characterized by the presence of multiple small endocrine tumors (upto 5 mm
in diameter), known as microadenomatosis distributed throughout the pancreas. These are often accompanied by
1 or more macrotumors (>5mm), some of which may be functionally active. If left behind, they could grow and
become symptomatic, explaining the relapse rate observed in MEN1. Pancreatic islet tumours can be associated
with gastrinoma in 10% cases and the two tumors may arise at different times. Furthermore, the question of
potential malignancy is also to be considered (8.55%). Localization of insulinomas is difficult on imaging and may
require regionalization with intra-arterial calcium stimulation test

Surgery is the optimal treatment for insulinomas. There is wide range of extent of surgery:
Enucleation of a single tumor
Distal/partial pancreatectomy
Sub-total pancreatectomy
Excision of all macroscopic pancreatic tumors with enucleation of nodules in the remaining pancreas

The best surgical approach for patients with insulinomas in the setting of MEN-1 is controversial . Because these
patients are more likely to have multiple and malignant neoplasms, some advocate subtotal pancreatectomy to
the level of the portal vein along with enucleation of lesions from the pancreatic head. However, whether more
extensive pancreatic resection has an impact on the overall survival of these patients is unknown. Not all patients
with MEN-1 have aggressive disease, and such an approach cannot be definitively advocated unless one can
identify the subset of patients with specific MEN-1 mutations or pathologic features that are most likely to benefit
from radical surgery. Given that redo pancreatic surgery in large volume centers has low morbidity, a reoperation
policy for patients with MEN-1 and recurrent insulinoma remains an alternative option to initial subtotal
pancreatectomy

Gastrinoma

Role of surgery in treating MEN1- associated gastrinomas is controversial. There is considerable debate
regarding the extent of surgery: aggressive resection versus conservative surgery. Surgical procedure depends
on the location of tumour in pancreas, duodenum, lymph nodes or liver. Long term prognosis is associated with
tumor size and presence of hepatic metastases ( 25-40% of patients with tumor more than 4 cm develop hepatic
metastasis). Overall survival in tumors less than 2cm is 100% at 15 years and 52% at 15 year in metastatic
disease. Goals of treatment is to control gastric acid hypersecretion, reduce the risk of distant metastatic disease
and improve survival. Some studies have shown that resection of localized gastrinomas often did not require
extended surgical resection and were associated with excellent long-term outcomes. Others have shown that
aggressive resection surgery based on accurate localization was useful for biochemical cure of gastrinoma in
patients with MEN 1.

Non-functioning pNETs

Identification of these tumours is important as malignant pNETs are now reported to be the commonest cause of
death in MEN1. These tumors are now the most common pNETs in MEN1 setting. Non functioningtumours are
associated with worse prognosis than functioning tumors. Treatment of these tumours is controversial. Surgical
resection can be offered for tumors more than 2 cm. For tumors less than 1cm, if there is significant growth or
doubling of tumor size over 3-6 month interval then surgical resection is indicated.

Carcinoid tumors

Carcinoids can be located in the bronchi, GIT, pancreas or thymus. Male patients with history of cigarette
smoking have a higher risk for development of thymic carcinoids. The course of thymic carcinoids in MEN1
appears to be particularly aggressive. The presence of thymic tumors is associated with a significantly increased
risk of death in patients with MEN1 (hazard ratio, 4.29, median survival is 9.5 years). Surgical removal of
carcinoids, if resectable, is the treatment of choice.

Adrenocortical tumors

Incidence of asymptomatic adrenocortical tumors is 20-73% in MEN patients. Primary hyperaldosteronism and
ACTH independent cushings syndrome are also common.
Surgery for non-functioning adrenal tumors is indicated in (i)Size > 4cm; (ii) have atypical or suspicious
radiological features; (iii) show significant measurable growth over a 6-month interval

Thyroid tumors

Thyroid tumors comprising adenomas, colloid goiters, and carcinomas have been reported to occur in more than

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25% of patients with MEN1 syndrome. Treatment is similar to that for non-MEN1 patients

MEN 2A

MEN 2A syndrome is defined as the presence of medullary thyroid cancer,pheochromocytoma and PHPT
associated with a germline RET mutation. In a patient with one or two of the clinical features of MEN 2A, the only
way to be certain of a diagnosis of MEN 2A is to identify a RET mutation or identify the clinical features of MEN
2A in other first-degree relatives. In the absence of an autosomal dominant familial inheritance pattern or RET
mutation, at least two of the classical clinical features of MEN 2A are required to make a clinical diagnosis of
MEN 2A. In the presence of a germline RET mutation and in the absence of any clinical features, that individual
is said to be at risk for the clinical features of MEN 2A, and appropriate management should ensue.

Medullary thyroid carcinoma in MEN 2A


Hereditary MTC occurs at younger age than sporadic MTC and associated with C cell hyperplasia, multifocal and
frequently bilateral tumours. About 50% of index patients with MEN2 present with locally advanced disease with
regional lymph node metastasis. Previous investigation for pheochromocytoma is mandatory to avoid the
potential risk of hypertensive crisis during surgery for MTC, since pheochromocytoma occurs in about 50% of
MEN patients. Also, hyperparathyroidism needs to be investigated, since it affects 20-30% of MEN2A.
MEN2 RET codon mutations Level of risk of Age before which
subtype development & prophylactic thyroidectomy
aggressiveness of MTC recommended

MEN2A/FMTC 768,790,791,804,891 1(lowest risk) 5-10 yrs

MEN2A/FMTC 609,611,618,620,630,634 2(intermediate risk) 5yrs

MEN2B 883,918,922 3(highest risk) 6 mo

MEN2 patients with clinically detected MTC should be subjected to total thyroidectomy with bilateral central
compartmental with or without lateral neck compartmental dissection. High priority must be given to preserving
parathyroid function during surgery for hereditary MTC. Normal parathyroid glands should be left in-situ with an
adequate vascular pedicle. Prophylactic treatment of HPT is not usually recommended. Accidentally resected or
devascularized glands must be immediately autografted to a heterotropic site in the neck or forearm in patients
with MEN2A, especially with 634 mutation.

Role of prophylactic thyroidectomy for carriers of MEN2


Bilateral and multicentric MTC is the most common cause of death in patients with MEN2A. MTC follows
anorderly pattern of development, from C-cell hyperplasia to microscopic MTC to a visible focus. Another
important finding was of an age-dependent progression of early MTC specific to the RET codon. This resulted in
codon directed prophylactic surgery. There is enough evidence now to show that total thyroidectomy that is
performed before MTC develops or spreads beyond the gland is currently the only curative treatment modality.

In older MEN 2A series, where treatment was initiated after the identification of a thyroid nodule, MTC progressed
and showed 15-20% of cancer mortality. Early prophylactic thyroidectomy may have lowered the mortality from
hereditary MTC to less than 5%, well below the cancer mortality in MEN1.A three level risk stratification has been
adopted for prophylactic thyroidectomy, generally as close as possible to earliest reported age of onset of each
genotype. For highest risk group ( codon 918,883 mutations) , including MEN2B carriers, prophylactic
thyroidectomy should be done within first year of life, preferably by age of 6 months.

Parathyroid surgery in MEN2A


HPT is generally diagnosed at or after thyroidectomy in MEN 2 kindreds. It tends to be milder, more often
asymptomatic and caused by a single enlarged parathyroid gland. A germline mutation at codon 634 has the
highest association with development of HPT in a given MEN2A family. There is a collective conclusion that a
less aggressive resection of only enlarged glands may be sufficient with fewer complications in terms of
hypoparathyroidism. Surgery has evolved from aggressive conventional exploration of all 4 glands to focused
MIP with low rates of persistent/recurrent disease and minimal complications.

Pheochromocytoma in MEN2A
Pheochromocytomas are most frequent with mutations in codons 634 and 918. MEN2 associated
pheochromocytomas are diagnosed at an early age. Screening for pheochromocytoma is recommended from
age of 5-7 years especially for codon 634 carriers. MEN2 pheochromocytomas are often bilateral and multifocal.
Pheochromocytomas in MEN2 are rarely extraadrenal (<1%) and malignant (3-4%). They may be accompanied
by diffuse and/or nodular hyperplasia of the surrounding and contralateral adrenal medulla. Surgical options
include unilateral / bilateral total adrenalectomy and partial/cortical sparing adrenalectomy. There is little

165
controversy whether to go for routine unilateral adrenalectomy versus bilateral adrenalectomy in apparent
unilateral pheochromocytoma in MEN2 setting.

B/L Pheochromocytoma develop in 35-50% of MEN2 patients. Risk of recurrent contralateral pheochromocytoma
is about 30% during 5 years and 50% during 11 years of follow up. 25% of patients following b/ladrenalectomy
require hospitalization for adrenal insufficiency. Bilateral resection reserved for patients with family history of
malignant PCC. For bilateral adrenalectomy or subsequent operation of the contralateral gland after prior
adrenalectomy, an adrenal cortical sparing adrenalectomy is generally recommended. Recurrence has been
reported in 10-20% of patients on long term follow up.

Indication for Extent of neck dissection Management of devascularized


surgery parathyroid glands

Prophylactic Central neck dissection(CCLND) RET mutation consistent with


thyroidectomy in based on RET mutation, age, serum, MEN2A:cryopreserve/ autograft in forearm
MEN2A / FMTC calcitonin, USG

Prophylactic CCLND routine, lateral based on age, Autograft in neck


thyroidectomy in calcitonin, USG
MEN2B

Therapeutic Level1 RET mutation: CCLND routine RET mutation consistent with
thyroidectomy in Level2 RET mutation: CCLND routine, MEN2A:cryopreserve/autograft in forearm
MEN2A/FMTC lateral based on age, calcitonin, USG RET mutation consistent with FMTC:
autograft in neck

Therapeutic CCLND+B/L MRND Autograft in neck


thyroidectomy in
MEN2B

Therapeutic CCLND+ I/L MRLND Autograft in neck


thyroidectomy in
Sporadic MTC

MEN2B

MTC in MEN2B
The most distinctive feature of MTC in the setting of MEN2B is the ominous potential for early metastases (50%).

In gene mutation carriers surgical recommendations


Prophylactic total thyroidectomy with CCLND by the age of 6 months
Homolateral LN exploration (2 compartments) in cases with macroscopic evidence of carcinoma at
surgery
Bilateral lymphadenectomy ( 3 compartments) in cases with evident LN metastasis
Mediastinal lymphadenectomy ( 4 compartments) is added in cases with imaging evidence of
mediastinal LN

Pheochromocytoma arises in 50% of individuals affected with MEN2B. 50% patients have bilateral involvement
as hyperplasia precedes development of PCC. Spectrum of adrenal involvement includes nodular/diffuse
hyperplasia, multiple small pheochromocytoma and thickening of entire adrenal medulla.

Treatment options
For unilateral disease:
Unilateral total adrenalectomy with close FUP
Bilateral total adrenalectomy

For Bilateral disease:


Bilateral total adrenalectomy
Unilateral total and C/L adrenal sparing surgery
Bilateral adrenal sparing surgery

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Carcinoid tumors

Manoj Andley

Introduction
Carcinoid tumors are rare, slow-growing neoplasms of neuroendocrine origin generally asymptomatic (incidental
finding) but minority develop metastatic disease. They cause carcinoid syndrome (flushing, diarrhea, valvular
heart disease) if they metastasise to liver or if primary tumor is not in gastrointestinal tract. Also called as
Neuroendocrine Tumor (NET), Gastroenteropancreatic NET, Malignant Carcinoid, Neuroendocrine Carcinoma,
Neoplasm of uncertain or unknown behavior of Oral cavity, Digestive organs, or Female genital organs.

DEFINITIONS

Carcinoid syndrome:
Clinical syndrome resulting from bioactive secretions of functional tumors. Less than 10% of carcinoid tumor
cases develop carcinoid syndrome.
Findings associated with carcinoid syndrome are:
Cutaneous flushing, mostly in face, neck, and upper chest
Watery & explosive diarrhea
Palpitations
Wheezing
Valvular heart disease

TYPES
Traditional classification by embryonic origins:
Foregut carcinoids (respiratory tract, stomach, duodenum, biliary system, pancreas)
Midgut carcinoids (jejunum, ileum, appendix, cecum, proximal colon)
Hindgut carcinoids (distal colon, rectum)

WHO classification of Gastroenteropancreatic neuroendocrine tumor (NET) based on malignant


potential:
Well-differentiated endocrine tumor (proliferation index [PI] < 2%)
Well-differentiated endocrine carcinoma (PI 2%-15%)
Poorly differentiated endocrine carcinoma (PI > 15%)
Mixed exocrine-endocrine tumors
Tumor-like lesions

Classification by presentation:
Nonfunctioning - presenting as tumor mass.
Functioning - presenting as carcinoid syndrome due to secretion of bioactive substances.
Features of carcinoid syndrome
o Characterized by flushing (pale, purplish, or red), diarrhea (watery and explosive),
bronchoconstriction, tachycardia or hypotension, telangiectasia, and right-sided heart disease
or failure.
o Bioactive secretions include Serotonin, Corticotrophin, Histamine, Dopamine, Substance P,
Neurotensin, Prostaglandins, Kallikrein, and Tachykinins.
o Symptoms can be precipitated by exertion, eating, or drinking (especially tyramine-containing
foods and ethanol).

Classification by site and subtype:


Lungs and Bronchi (Cell of origin: Epithelial Endocrine Cell)
1. Typical carcinoid (well-differentiated NET)
a. Histologic features - minor cellular atypia
b. Mitoses rare, usually indolent
c. May secrete corticotropin, rarely secretes serotonin

2. Atypical carcinoid (well-differentiated neuroendocrine carcinoma)


a. Histologic features - cellular atypia, increased mitoses, areas of necrosis
b. Usually aggressive
c. high incidence of metastases

Stomach (Cell of origin: Enterochromaffin-like cell)


1. Chronic atrophic gastritis type A-associated carcinoid tumor:
a. Well differentiated
b. Noninvasive

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c. Indolent
d. Often multiple
e. Not associated with carcinoid syndrome

2. Carcinoid tumor associated with Zollinger-Ellison syndrome or Multiple Endocrine Neoplasia 1:


a. Well differentiated
b. Noninvasive
c. Indolent
d. Often multiple
e. Not associated with carcinoid syndrome

3. Sporadic Carcinoid tumor:


a. Well differentiated
b. Often invasive
c. May be aggressive
d. High incidence of metastases
e. Associated with atypical carcinoid syndrome (flushing mediated by histamine)

Small Bowel (Cell of origin: Epithelial Endocrine Cell)


a. Usually well differentiated
b. Contains serotonin and substance P
c. Often multiple, usually in ileum
d. Associated with carcinoid syndrome

Appendix (Cell of origin: Subepithelial Endocrine Cell)


a. Usually well differentiated
b. Contains serotonin and substance P
c. Usually indolent

Colon (Cell of origin: Epithelial Endocrine Cell)


a. Usually well differentiated
b. Contains serotonin and substance P
c. Usually right-sided
d. Often presents at late stage

Rectum (Cell of origin: Epithelial Endocrine Cell)


a. Usually well differentiated
b. Contains serotonin and substance P
c. Carcinoid syndrome rare

Frequency of organs involved: 5,468 cases identified by National Cancer Institute (NCI) from 1973 to 1991 and
2,837 cases registered in prior NCI programs
a. 73.7% in gastrointestinal tract
18.9% appendix
15.4% ileum
11.4% rectum
4.2% cecum
3.2% stomach
2% duodenum
1.9% jejunum
1.2% rectosigmoid
1% ascending colon
Other sites with < 1% frequency - Meckel's diverticulum, ileocecum, hepatic flexure of colon,
transverse colon, splenic flexure of colon, descending colon, sigmoid colon, nonspecified colon,
nonspecified intestine, liver, gallbladder, nonspecified biliary tract, pancreas, nonspecified digestive
tract
b. 25.1% respiratory system (trachea, bronchi, lung)
c. 0.56% reproductive system
d. 0.52% ovary, 0.04% cervix, 0.6% unspecified site

EPIDEMIOLOGY
Approximate age at presentation dependent on tumor site:
a. Appendix - age 40-50 years
b. Lungs, bronchi, and trachea - age 50 years
c. Rectum - age 60 years
d. Small intestine - age 60-70 years

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e. Stomach - age 60-70 years
f. Colon - age 70 years

Possible risk factors:


Saturated fat intake may be associated with risk for carcinoid tumor of small intestine.
Gastric carcinoid reported in 1 patient who had used long-term omeprazole but causation not shown.

Associated conditions:
13% overall rate of associated noncarcinoid neoplasms (based on series of 8,305 carcinoid tumors).
Associated conditions reported in retrospective review of 36 patients with gastric carcinoid (11% of
whom had carcinoid syndrome)
67% had atrophic gastritis
58% had pernicious anemia
39% had hypothyroidism
19% had diabetes
6% had adrenocortical insufficiency
6% had hyperparathyroidism
Zollinger-Ellison syndrome also associated with gastric carcinoid tumors Multiple Endocrine Neoplasia I
Possible association with sarcoidosis (report of 7 cases and discussion can be found in Mayo Clinic Proc 1997

ETIOLOGY AND PATHOGENESIS


Causes
Carcinoid tumors originate in cells of neuroendocrine system.
Carcinoid syndrome caused by secretion of bioactive substances by tumors.
Metastases to lungs and liver

Pathogenesis:
Carcinoid syndrome occurs when neuroendocrine cells of carcinoid tumor secrete bioactive substances.
Most common substance is serotonin (5-hydroxytryptamine) degradation product of serotonin, 5-
hydroxyindoleacetic acid (5-HIAA), when released in circulation leads to:
o Increased gastric motility (by exciting smooth muscle) bronchoconstriction (by exciting smooth
muscle) platelet aggregation.
o Vasoconstriction or dilation.
o Increased production of serotonin and 5-HIAA may lead to tryptophan deficiency and
subsequent reduced niacin synthesis which may result in pellagra
Bioactive substances secreted may include many amines and peptides including serotonin, histamine,
dopamine, substance P, corticotrophin (ACTH), neurotensin, tachykinins, and kallikrein.

HISTORY AND PHYSICAL EXAMINATION


History:
Usually asymptomatic
If present, symptoms vary by tumor site:
Pulmonary carcinoids (well-differentiated pulmonary neuroendocrine tumors):
o Recurrent pneumonia, cough, hemoptysis, chest pain.
o Symptoms of Cushing syndrome with ectopic ACTH syndrome symptoms of acromegaly with
ectopic secretion of growth hormone- releasing factor
Gastric carcinoid tumors:
o Abdominal pain and symptoms of pernicious anemia in patients with chronic atrophic gastritis type A.
o Abdominal pain, diarrhea (gastric hypersecretion), and gastrointestinal bleeding in patients with
Zollinger-Ellison syndrome.
o Flushing in histamine-mediated atypical carcinoid syndrome, primarily in patients with sporadic
gastric carcinoids.
Tumors of small intestine:
o Abdominal pain
o Small bowel obstruction
Appendiceal tumors:
o < 10% patients symptomatic
o Carcinoid syndrome has been reported in patients with liver metastases
Tumors of colon:
o Pain
o Anorexia
o Weight loss
Rectal tumors:
o 50% patients asymptomatic
o rectal bleeding constipation
o pain

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Carcinoid Heart Disease may present with symptoms of right heart failure (possibly due to inactivation of
vasoactive substances by lungs)
Symptoms associated with carcinoid syndrome
o Classic syndrome occurs in < 10%
o Episodic cutaneous flushing, mostly in face, neck, and upper chest
o Watery, explosive diarrhea
o Palpitations

Physical examination
General physical: Carcinoid tumors usually found incidentally during surgeries for other conditions, so typically
not associated with physical findings.
Skin: cutaneous flushing, cyanosis, telangiectasia can be seen with carcinoid syndrome
Cardiac: findings with carcinoid heart disease may include(2) tachycardia, hypotension and murmurs
Lungs: wheeze may occur with pulmonary disease
Abdomen: hepatomegaly may be seen with liver metastases

DIAGNOSIS AND STAGING

Making the diagnosis


Nonfunctioning tumors often detected incidentally
Diagnosis of carcinoid syndrome based on consistent symptoms plus objective findings, such as
o elevated biologic markers: e.g. Urinary 5-hydroxyindoleacetic acid (5-HIAA) or Plasma
Chromogranin A
o neuroendocrine origin identified on histology

Biomarkers of carcinoid tumor


1. 24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA): 5-HIAA is a metabolite of 5-
hydroxytryptamine (serotonin). Normal range 3-15 mg/24 hours. Avoid serotonin-rich foods 48 hours
prior to urine collection (bananas, avocados, plums, eggplant, tomatoes, plantains, pineapples,
cantaloupe, hickory nuts/pecans, dates, grapefruit, honeydew, kiwis, walnuts).
a. urinary 5-HIAA levels may be falsely lowered by levodopa.
b. elevated 5-HIAA or serotonin levels in 24-hour urine collection reported in 75% of patients with
carcinoid tumors, 4% of 50 patients with solid noncarcinoid tumors, 0 of 55 patients with
suspected carcinoid syndrome (flushing but no carcinoid tumor).
2. Plasma Chromogranin A (CgA)
a. CgA levels > 130 mcg/L associated with 62.9% sensitivity and 98.4% specificity for
gastroenteropancreatic endocrine tumors.
b. Elevated CgA levels reported in 80% of carcinoid tumors and 7% non- neuroendocrine tumors.
c. CgA levels 100-1,000 times normal reported in classical midgutneuroendocrine tumors.

Imaging studies

Computed Tomography
Characteristic appearance of infiltrated carcinoids on CT
Spiculated with stellate pattern.
Mass lesions.
Evidence of calcification and fibrosis.
Can detect mucosal thickening, submucosal mass, and luminal narrowing.
76%-100% detection rates reported for carcinoid tumors with CT.

Magnetic resonance imaging (MRI)


Not routinely used for carcinoid tumors but may be useful if other imaging studies conflicting or
unhelpful.
67%-81% detection rates reported for carcinoid tumors with MRI.
May detect pulmonary lesions not seen well on CT
o Bronchial carcinoids have high T2-weighted signal intensity
o Short tau inversion recovery (STIR) (T2-weighted sequence with fat suppression) can
distinguish between small masses and vasculature.

Ultrasound
Endoscopic ultrasound sensitive for tumors in pancreatic head, duodenal wall, local lymph nodes. Can be used to
distinguish nonfunctioning NET from adenocarcinoma based on:
High vascularity
Abundant color Doppler signal
Pulsatile or wave pattern
Endoscopic ultrasound may detect and localize gastroenteropancreatic neuroendocrine tumors.

170
Small bowel enteroclysis
Used to diagnose small bowel midgut carcinoids.
Large volume of contrast introduced via tube in distal duodenum.
Provides luminal view of small bowel.
May not detect primary tumor, mesenteric nodes or masses, liver metastases.
Multidetector computed tomographic (CT) enteroclysis may have high sensitivity and specificity for small
bowel lesions.

Biopsy and pathology

Histologic pattern of typical carcinoid:


o Classified as well-differentiated neuroendocrine tumor
o Small cells with regular, well-rounded nuclei
o 5 generally accepted growth patterns
Insular
Trabecular
Glandular
Undifferentiated
Mixed

Histologic pattern of atypical carcinoid also called anaplastic carcinoid:


o Well-differentiated or poorly differentiated neuroendocrine tumor
o Increased nuclear atypia higher mitotic activity
o Areas of necrosis

STAGING

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MANAGEMENT

For non-metastatic disease

For jejunum/ilium/colon
Bowel resection with regional lymphadenectomy is recommended.
Perform examination of entire bowel as multiple lesions may be present.
Assess proximity to or involvement of superior mesenteric artery and superior mesenteric vein.
Consider prophylatic cholecystectomy if future treatment with octreotide is possible.

For duodenum, appropriate treatment options include


endoscopic resection
transduodenal local excision with or without lymph node sampling pancreatoduodenectomy (6)

For appendix
For nonmetastaticappendiceal carcinoids 2 cm, appendectomy recommended
For appendiceal carcinoids > 2 cm or incomplete resection, appropriate treatment options include re-
exploration or right hemicolectomy (6)

For rectal carcinoids


2 cm, transanal or endoscopic resection recommended
> 2 cm, low anterior resection or abdominoperineal resection are appropriate treatment options (6)

For stomach
If hypergastrinemic patient with solitary or multiple tumors 2 cm, appropriate treatment options include
expectant management
endoscopic resection with biopsy of tumor and adjacent mucosa
somatostatin analogues in patients with Zollinger-Ellison syndrome
octreotide LAR 20-30 mg monthly intramuscular
lanreotide 120 mg monthly subcutaneous
If hypergastrinemic patient with solitary or multiple tumors > 2 cm, endoscopic resection is recommended,
surgical resection in some cases (6)
If normal gastrin
Radical gastric resection with lymph node removal is recommended consider endoscopic or wedge resection for
tumors 2 cm (6).

For lung
Lobectomy or other anatomic resection plus mediastinal lymph node dissection or sampling
recommended (6)
Resection recommended if incomplete resection, consider radiation therapy with or without
chemotherapy (6)

Treatment of unresectable locoregional disease or distant metastatic disease

If asymptomatic with low tumor burden, appropriate treatment options include(6)


Observation by performing tumor marker analysis and imaging studies every 3-12 months
octreotide or lanreotide
If locally symptomatic, consider resection of primary tumor

If tumor burden is clinically significant, treat with octreotide or lanreotide

If carcinoid syndrome, appropriate treatment options include octreotide or lanreotide


Octreotide (short-acting form 100-500 mcg 3 times daily, or long- acting form 10-30 mg [up to 60 mg]
every 4 weeks) reported to relieve symptoms of carcinoid syndrome in patients with metastatic carcinoid
tumors
Lanreotide (60-120 mg every 4 weeks) and octreotide may be equally effective in reducing symptoms of
carcinoid syndrome
Echocardiogram if patient has signs or symptoms of heart disease or if planning surgery

Treatment of progressive locoregional unresectable or metastatic disease that fails to respond to above
treatment
Octreotide or lanreotide recommended (6)

Consider any of the following options hepatic regional therapy, including


Hepatic artery chemoembolization; reported to provide symptom palliation for median 13 months
Radiofrequency ablation for neuroendocrine liver metastases; reported to provide symptom palliation for
mean 11 months

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Cytoreductive hepatic resection for functioning metastatic neuroendocrine tumors reported to be safe
and effective in selected patients (6)
Everolimus 10 mg/day plus interferon alfa-2b.

Diet
Avoid identified precipitating factors for carcinoid syndrome(3) like alcohol
Catecholamines, chocolate coffee, cheese.

PROGNOSIS

References

1. van der Lely AJ, de Herder WW. Carcinoid syndrome: diagnosis and medical management. Arq Bras
EndocrinolMetabol. 2005;49(5):850-60.
2. Robertson RG, Geiger WJ, Davis NB.Carcinoid tumors. Am Fam Physician. 2006;74(3):429-34.
3. Maroun J, Kocha W, Kvols L, et al. Guidelines for the diagnosis and management of carcinoid tumours. Part 1:
The gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group.CurrOncol.
2006;13(2):67-76.
4. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999;340(11):858- 68.
5. Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB. Recent advances in radiological and radionuclide
imaging and therapy of neuroendocrine tumours. Eur J Endocrinol. 2004;151(1):15-27.
6. Kulke MH, Shah MH, Benson AB, et al. Neuroendocrine Tumors. Version 1.2015. In: National Comprehensive
Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

Paraneoplastic syndrome

Jitendra Kumar

In addition to local tissue invasion and metastasis, neoplastic cells can produce a variety of peptides (e.g.-
hormones or cytokines ) that that can stimulate hormonal, hematologic, dermatologic, or neurologic responses.
Even tumor tissue itself can induce immunologic responses. All these systemic response can produce wide
varieties of signs and symptoms and termed as paraneoplastic syndrome. However, almost every type of
malignancy has the potential to produce it but tumors of neuroendocrine origin, such as small cell lung carcinoma
(SCLC) and carcinoids, produce a wide array of peptide hormones and are common causes of paraneoplastic
syndromes.

Definition:
Paraneoplastic syndromes refer to the disorders that accompany benign or malignant tumors but are not directly
related to mass effects or invasion.(1)

or

Paraneoplastic syndromes are a group of clinical disorders associated with malignant diseases that are not
directly related to the physical effects of the primary or metastatic tumor.(2)

In nutshell the syndromes may be due to


1. tumor production of substances that directly or indirectly cause distant symptoms,
2. depletion of normal substances that leads to a paraneoplastic manifestation, or
3. host response to the tumor that results in the syndrome

173
The paraneoplastic syndrome may be the first sign of a malignancy, and its recognition may be critical for early
cancer detection. Careful studies of the prevalence of paraneoplastic syndromes indicate that they are more
common than is generally appreciated. Consequently, atypical clinical manifestations in a patient with cancer
should prompt consideration of a paraneoplastic syndrome.

Paraneoplastic syndromes may parallel the underlying malignancy, and successful treatment of the tumor leads
to disappearance of the syndrome. However, many paraneoplastic syndromes, especially those of an immune or
neurologic etiology, do not predictably resolve with treatment of the underlying malignancy. In some situations,
the underlying disease cannot be treated, but the symptoms and complications of the paraneoplastic syndrome
can be successfully managed. Proteins secreted in paraneoplastic syndromes may be used as tumor markers.

Paraneoplastic syndromes are usually divided in to the following categories:


Endocrine
Hematologic
Cutaneous
Neurologic/Neuromuscular
Rheumatologic
Renal
Gastrointestinal

Endocrine

Hormones can be produced from eutopic or ectopic sources. Eutopic refers to the expression of a hormone from
its normal tissue of origin, whereas ectopic refers to hormone production from an atypical tissue source. For
example, adrenocorticotropic hormone (ACTH) is expressed eutopically by the corticotrope cells of the anterior
pituitary but it can be expressed ectopically in SCLC.

Ectopic Adrenocorticotropic Hormone Syndrome


Ectopic ACTH production accounts for 1020% of Cushing's syndrome.
Tumors Associated with Ectopic Adrenocorticotropic Hormone (In order of frequency)
Small cell lung carcinoma (Most common cause >50%.
Thymic carcinomas (15%).
Bronchial carcinoid (10%).
Pancreas (islet cell tumors) (10%).
Other carcinoids (5%.)
Pheochromocytoma (2%).
Others:
Medullary cancer of the thyroid
Adenocarcinoma ,etc

The differential diagnosis of a patient with hypercortisolism includes Cushing's disease, adrenal dysfunction,
ectopic ACTH production, and corticotropin-releasing hormone (CRH) overproduction. Pituitary overproduction
(Cushing's disease) is the cause of disease in over 55% of patients, followed in frequency by adrenal
dysfunction, ectopic ACTH production (occurring in 11% to 25%), and CRH overproduction, which is quite rare.

Clinical Manifestations
Signs and symptoms of classic hypercortisolism include truncal obesity, purple striae, hypertension, fatigue,
moon facies, buffalo hump, weakness, depression, amenorrhea, hirsutism, decreased libido, osteopenia,
osteoporosis, impaired wound healing, impaired glucose tolerance diabetes, easy bruising, and edema. In
contrast, ectopic ACTH production from SCLC causes myopathy with weakness, muscle wasting, weight loss,
hyperpigmentation, and hypokalemia. Carcinoid tumors that secrete ectopic ACTH may cause signs and
symptoms that overlap those of pituitary-dependent Cushing's disease and paraneoplastic ACTH overproduction

Diagnosis
laboratory findings include a baseline serum cortisol level greater than 29 g/dL (to convert to nmol/L, multiply by
27.588), a urinary free cortisol level greater than 47 g/24 h, and a midnight adrenocorticotropic hormone level
greater than 100 ng/L.13

Failure to respond to high-dose dexamethasone suppression distinguishes ectopic (ie, paraneoplastic) Cushing
syndrome from a pituitary source. For the high-dose dexamethasone suppression test, 2 mg of dexamethasone
is given orally every 6 hours for 72 hours, and levels of urine 17-hydroxycorticosteroid (an inactive product
resulting from cortisol breakdown) are measured at 9 am and midnight of days 2 and 3 of the test. The
suppression test is considered positive if 17-hydroxycorticosteroid levels are reduced by 50% or more.

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Once the diagnosis of ectopic ACTH production has been established, localization is the most important aspect
of therapy. Imaging studies, including computed tomography (CT), magnetic resonance imaging, and
somatostatin receptor scintigraphy (ie, octreotide scan), are then used to locate the primary tumor.

Treatment
Surgery is the treatment of choice in patients with early stage tumors producing Cushing's syndrome because it
can completely alleviate symptoms. Although bilateral adrenal removal is effective in treating Cushing's
syndrome, the patient must have lifelong glucocorticoid and mineralocorticoid replacement.
Medical therapy with ketoconazole (200400 mg PO bid), metyrapone (250500 mg PO every 6 h), mitotane (3
6 g PO in four divided doses, tapered to maintain low cortisol production), or other agents that block steroid
synthesis or action is often the most practical strategy for Because of its rapid onset of action and favorable
toxicity profile, ketoconazole has evolved as the therapy of choice for ectopic ACTH. Primary suppression of
ACTH production can be accomplished by cytotoxic chemotherapy for the primary malignancy or octreotide
suppression of ACTH release.

Syndrome of Inappropriate Antidiuretic Hormone Production

Tumors with neuroendocrine features, such as SCLC and carcinoids, are the most common sources of ectopic
vasopressin production, but it also occurs in other forms of lung cancer and with central nervous system (CNS)
lesions, head and neck cancer, and genitourinary, gastrointestinal, and ovarian cancers.
Compensatory mechanisms, such as decreased thirst, suppression of aldosterone, and production of atrial
natriuretic peptide (ANP), may mitigate the development of hyponatremia in patients who produce excessive
vasopressin.

Clinical Manifestations
Most patients with ectopic vasopressin secretion are asymptomatic and are identified because of the presence of
hyponatremia on routine chemistry testing. Symptoms may include weakness, lethargy, nausea, confusion,
depressed mental status, and seizures. The severity of symptoms reflects the rapidity of onset as well as the
extent of hyponatremia. Hyponatremia usually develops slowly but may be exacerbated by the administration of
IV fluids or the institution of new medications. Thirst is typically suppressed.

Diagnosis
Hyponatremia and reduced serum osmolality occur in the setting of an inappropriately normal or increased urine
osmolality. Urine sodium excretion is normal or increased unless volume depletion is present. Other causes of
hyponatremia should be excluded, including renal, adrenal, or thyroid insufficiency. Physiologic sources of
vasopressin stimulation (CNS lesions, pulmonary disease, nausea), adaptive circulatory mechanisms
(hypotension, heart failure, hepatic cirrhosis), and medications, including many chemotherapeutic agents, should
also be considered as possible causes of hyponatremia. Vasopressin assay is not usually necessary to make the
diagnosis.

Treatment
As with any syndrome associated with ectopic hormone production, treating the underlying disease is the most
effective means of controlling SIADH. Chemotherapy treatment of the associated SCLC is generally associated
with improvement in the syndrome.

Fluid restriction to less than urine output, plus insensible losses, is often sufficient to partially correct
hyponatremia. Salt tablets or saline are not helpful unless volume depletion is also present. Demeclocycline
(150300 mg orally three to four times daily) can be used to inhibit vasopressin action on the renal distal tubule
but its onset of action is relatively slow (12 weeks). Conivaptan, a nonpeptide V2-receptor antagonist, can be
administered either PO (20120 mg bid) or IV (1040 mg), and is particularly effective when used in combination
with fluid restriction in euvolemic hyponatremia.

Severe hyponatremia (Na < 115 meq/L) or mental status changes may require treatment with hypertonic (3%) or
normal saline infusion together with furosemide, to enhance free water clearance. The rate of sodium correction
should be slow (0.51 meq/L per h) to prevent rapid fluid shifts and the possible development of central pontine
myelinolysis.

Hypercalcemia

There are 4 principal mechanisms of hypercalcemia in cancer patients. Secretion of parathyroid hormone (PTH)-
related protein (PTHrP) by tumor cellsknown as humoral hypercalcemia of malignancyaccounts for 80% of
cases and occurs most commonly with squamous cell tumors. Another 20% of cases arise directly from osteolytic
activity at sites of skeletal metastases. Breast cancer, multiple myeloma, and lymphomas commonly cause
hypercalcemia via this mechanism.9 Rarely, hypercalcemia may result from tumor secretion of vitamin D, which
has been described in association with certain lymphomas, or from ectopic tumor secretion of PTH.9

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Clinical Manifestations
The clinical features of hypercalcemia include nausea, vomiting, lethargy, nephrolithiasis, renal failure, and coma.

Diagnosis
In patients with malignancy-associated hypercalcemia, typical laboratory findings include an elevated calcium
level, a low-to-normal PTH level, and often a high PTHrP level.

Treatment
As with SIADH, the optimal approach to paraneoplastic hypercalcemia is treatment of the underlying tumor. Other
important measures are removal of excess calcium in the diet, medications, or IV solutions.

Oral phosphorus (e.g., 250 mg Neutra-Phos 34 times daily) should be given until serum phosphorus is >1.0
mmol/L (>3 mg/dL Bisphosphonates such as pamidronate (3090 mg IV), zolendronate (48 mg IV), or
etidronate (7.5 mg/kg per day PO for 37 consecutive days) can reduce serum calcium within 12 days and
suppress calcium release for several weeks. Bisphosphonate infusions can be repeated or oral bisphosphonates
can be used for chronic treatment. Dialysis should be considered in severe hypercalcemia when saline hydration
and bisphosphonate treatments are not possible or are too slow in onset.

Hypocalcemia
Tumors associated with bone metastases such as breast, prostate, and lung cancers can lead to hypocalcemia.
Patients with hypocalcemia and osteoblastic metastases have increased skeletal avidity for calcium, thus
implicating the rapid deposition of calcium in bone as the cause of hypocalcemia. Hypocalcemia can also occur in
patients whose tumors secrete calcitonin (i.e., medullary carcinoma of the thyroid and, rarely, breast cancer,
colorectal cancer, SCLC, and carcinoid).

Clinical manifestations
In many cases it is asymptomatic; however, it can occasionally lead to the development of significant symptoms
secondary to neuromuscular irritability and cardiovascular changes. These symptoms include peripheral and
perioral paraesthesia, cramps, tetany, seizures, bronchospasm, laryngospasm, anxiety, confusion, cardiac
arrhythmias, and congestive cardiac failure. In severe cases, hypocalcemia can be life threatening, especially if it
remains unrecognized and untreated.

Oncogenous Osteomalacia

Tumor-induced or oncogenousosteomalacia is a rare paraneoplastic syndrome characterized by osteomalacia


with hypophosphatemia, hyperphosphaturia, and undetectable or inappropriately low circulating concentrations of
1,25-dihydroxyvitamin D3.

Mean age at diagnosis is approximately 35 years. Patients typically present with bone pain, phosphaturia, renal
glycosuria, hypophosphatemia, normocalcemia with normal parathyroid hormone function, low levels of 1,25-
dihydroxyvitamin D3, and increased alkaline phosphatase levels. The majority of neoplasms causing this
syndrome are benign, but the syndrome has also been described with carcinoma of the lung, multiple myeloma,
and prostate cancer

The definitive therapy is removal of the tumor, if possible, which leads to clinical and biochemical cure.
Otherwise, treatment requires large doses of vitamin D and phosphate.

Hypoglycemia

Mesenchymal tumors, hemangiopericytomas, hepatocellular tumors, adrenal carcinomas, and a variety of other
large tumors have been reported to produce excessive amounts of insulin-like growth factor type II (IGF-II)
precursor, which binds weakly to insulin receptors and strongly to IGF-I receptors, leading to insulin-like actions.
The diagnosis is made by documenting low serum glucose and suppressed insulin levels in association with
symptoms of hypoglycemia.

Treatment of the underlying malignancy, if possible, may reduce the predisposition to hypoglycemia. Frequent
meals and IV glucose, especially during sleep or fasting, are often necessary to prevent hypoglycemia.
Glucagon, GH, and glucocorticoids have also been used to enhance glucose production.

HEMATOLOGIC

Erythrocytosis
The most common solid tumor leading to erythrocytosis is renal cell carcinoma then is hepatoma. Other tumors
leading to erythrocytosis include Wilms tumor, hemangiomas, cerebellar hemangioblastoma, sarcomas, uterine
fibroids, adrenal tumors, and pheochromocytomas. Ectopic production of erythropoietin by cancer cells causes
most paraneoplastic erythrocytosis.

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It is important to rule out other causes of erythrocytosis, even in the presence of a tumor. Erythropoietin can be
measured in the blood when it is suspected that it is overproduced secondary to a tumor.
Paraneoplastic erythrocytosis rarely requires specific therapy other than control of the underlying neoplasm and
occasional phlebotomy when required.

Anemia
Normochromic, normocytic anemia of cancer is a common paraneoplastic syndrome, characterized by low serum
iron levels, normal or increased ferritin levels, normal iron stores, and a low serum erythropoietin level.
Paraneoplastic pure red cell aplasia is most commonly associated with thymoma.

Granulocytosis
Neoplasms most commonly associated with granulocytosis include Hodgkin's lymphoma, lymphoma, and a
variety of solid tumors, including gastric, lung, pancreatic, and brain cancers and malignant melanoma.
Paraneoplastic granulocytosis does not require treatment. The granulocytosis resolves when the underlying
cancer is treated.

Granulocytopenia
Rarely, tumors may produce a factor that suppresses granulopoiesis by interfering with any number of growth
factors. The preferred therapy for severe granulocytopenia is direct stimulation with growth factors, including
granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor.

Eosinophilia
Eosinophilia is commonly associated with Hodgkin's lymphoma and mycosis fungoides and is rarely associated
with other lymphomas and solid tumors.
Definitive treatment is directed at the underlying malignancy. In most patients who develop shortness of breath
related to eosinophilia, symptoms resolve with the use of oral or inhaled glucocorticoids.

Thrombocytosis
Thrombocytosis is present in 40% of patients with lung and gastrointestinal cancers, 20% of patients with breast,
endometrial, and ovarian cancers, and 10% of patients with lymphoma. Patients with thrombocytosis are more
likely to have advanced-stage disease and have a poorer prognosis than patients without thrombocytosis.
Paraneoplastic thrombocytosis does not require treatment.
Thrombocytopenia
A syndrome similar to idiopathic thrombocytopenic purpura is commonly seen in lymphoid malignancies including
CLL and lymphomas, as well as Hodgkin's lymphoma. Rarely, solid tumors such as lung, breast, and GI cancers
have been associated with a similar syndrome. These patients may have bleeding, petechiae, and purpura and
may respond to high-dose prednisone, splenectomy, or both. As is typical of nonparaneoplastic idiopathic
thrombocytopenic purpura, patients have adequate or increased megakaryocytes in the bone marrow and do not
respond to transfusion of platelets.

Thrombophlebitis
Patients with cancer have a hypercoagulable state. Deep venous thrombosis and pulmonary embolism are the
most common thrombotic conditions in patients with cancer. Migratory or recurrent thrombophlebitis may be the
initial manifestation of cancer.
The most common cancers associated with thromboembolic episodes include lung, pancreatic, gastrointestinal,
breast, ovarian, and genitourinary cancers, lymphomas, and brain tumors.

Coagulopathies
Acquired von Willebrand factor is seen in plasma cell dyscrasias, gastric and adrenal carcinomas, leukemias, and
lymphomas.
When possible, successful treatment of the underlying malignancy associated with acquired von Willebrand
factor can lead to resolution of the bleeding diathesis.

CUTANEOUS MANIFESTATIONS OF CANCER


Paraneoplastic dermatoses are a heterogeneous group of clinical manifestations that may have a benign
appearance. They are the second most common paraneoplastic syndrome, only behind endocrine syndromes.

Curths criteria for the diagnosis of cutaneous paraneoplastic syndromes


1) Both conditions began simultaneously (neoplasia and paraneoplasia)
2) Development of a parallel course. ( Treatment of the neoplasia results in regression of the skin lesion;
recurrence of the neoplasia implies recurrence of the skin lesion.)
3) The skin lesion is not associated with a genetic syndrome.
4) There is a specific type of neoplasia that occurs with paraneoplasia.
5) The dermatosis is rare in the general population
6) There is a high frequency of association between both conditions

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Association of dermatoses with systemic neoplasias
Dermatosis Associated neoplasia
Acanthosis NigricansMaligna Abdominal adenocarcinomas (gastric neoplasia)
Acquired Pachydermatoglyphia Gastric and pulmonary carcinoma
Erythema gyratumrepens Pulmonary, esophageal and breast
Bazex paraneoplastic acrocheratosis Aerodigestive tract (oral cavity,
larynx, pharynx, trachea, esophagus and lung)
Acquired hypertrichosis lanuginose Colorectal, pulmonary and breast
Necrolytic migratory erythema Glucagonoma
Leser-Trlat Sign Gastric and colorectal
Paraneoplastic pemphigus Non-Hodgkin lymphoma, chronic lymphocytic
leukemia, Castlemans disease, thymoma
Pityriasis rotunda Hepatocellular carcinoma, gastric and esophageal
carcinoma, prostate cancer, chronic lymphocytic
leukemia and multiple myeloma
Dermatomyositis Ovarian carcinoma, bronchogenic adenocarcinoma
Palmoplantar keratoderma Esophageal Carcinoma
Pyoderma gangrenosum Myelodysplastic syndrome, myeloma, leukemia
Sweet syndrome Acutemyelogenous leukemia, myelodysplastic
syndrome

NEUROLOGIC MANIFESTATIONS OF CANCER


Neurologic diseases are defined as paraneoplastic when they occur in increased frequency in patients with
cancer and are not related to a direct effect of tumor, infection, metabolic abnormalities, or toxicity of therapy. In
response to a developing cancer, a patient produces tumor-directed antibodies known as onconeural antibodies.
Because of antigenic similarity, these onconeural antibodies and associated onconeural antigen-specific T
lymphocytes inadvertently attack components of the nervous system as well. In contrast to paraneoplastic
endocrine syndromes, PNS are detected before cancer is diagnosed in 80% of cases. Because tumor cells
themselves do not directly produce the causative agents of PNS, and because onconeural antibodies may cause
permanent damage, successful cancer treatment does not necessarily result in neurologic improvement.
Immunosuppressive therapy is a mainstay of PNS treatment, but success is variable.

Onconeural antibodies are classified according to 3 main categories:


(1) those that are molecularly well characterized with a strong cancer association (anti-amphiphysin, anti-CV2
[CRMP5], anti-Hu [ANNA-1], anti-Ma2, anti-recoverin, anti-Ri [ANNA-2], anti-Yo [PCA-1]);
(2) those that are partially characterized (ANNA-3, anti-mGluR1, anti-Tr, anti-Zic4, PCA-2); or
(3) those occurring in both cancer- and noncancer-associated syndromes (anti-acetylcholine receptor [AchR],
antinicotinic AchR, anti-VGCC, anti-VGKC) (27N)

Limbic encephalitis

Clinical feature
Mood changes, hallucinations, memory loss, seizures, and less commonly hypo- thalamic symptoms
(hyperthermia, somnolence, endo crine dysfunction); onset over days to months.
Associated antibodies: anti-Hu (typically with small cell lung cancer) ; anti-Ma2 (typically testicular cancer); anti-
CRMP5 (anti-CV2); anti-amphiphysin

Diagnosis
EEG: epileptic foci in temporal lobe(s); focal or generalized slow activity; FDG-PET: increased metabolism in
temporal lobe(ss); MRI: hyperintensity in medial temporal lobe(s); CSF analysis: pleocytosis elevated protein,
elevated IgG, oligoclonal band.
Associated cancers:SCLC (~40%-50% of LE patients.), testicular germ-cell (~20% of LE patients), breast (~8%
of LE patients),thymoma, teratoma, Hodgkin lymphoma .

Treatment options
IVIG, 400-1000 mg/d to total 2-3 g; Methylprednisolone, up to 1 g/d IV Prednisone, 1 mg/kg per day orally,
Plasma exchange, Cyclophosphamide, ~2 mg/kg/d orally, Rituximab, 375 mg/m2IV per dose.

Paraneoplastic cerebellar degeneration

Clinical feature
Ataxia, diplopia, cerebellar dysphagia, dysarthria; prodrome of dizziness, nausea, vomiting. Associated
antibodies:Anti-Yo antibodies in patients with breast and gynecologic cancers and anti-Tr antibodies in patients
with Hodgkin's lymphoma are the two paraneoplastic antibodies typically associated with prominent or pure
cerebellar degeneration.

178
Diagnosis
FDG-PET: Increase metabolism (early stage) and then decreased metabolism( late stage) in cerebellum.
MRI: cerebellar atrophy ( late stage).
Associated cancers:
SCLC, Gynecologic, Hodgkin lymphoma and Breast.

Treatment options
IVIG, 400-1000 mg/d to total 2-3 g; Methylprednisolone, up to 1 g/d IV Prednisone, 1 mg/kg per day orally,
Plasma exchange, Cyclophosphamide, ~2 mg/kg/d orally, Rituximab, 375 mg/m2IV per dose.

Lambert-eaton myasthenia syndrome (LEMS)


In approximately 60% of patients with Lambert-Eaton myasthenic syndrome, the disorder is associated with an
underlying cancer, usually SCLC.182,205(D) Proximal weakness is a common presenting complaint, but bulbar
symptoms are uncommon. In most patients, Lambert-Eaton myasthenic syndrome is not a pure motor syndrome.
Paresthesias are frequently reported206; and patients may report dry mouth or erectile dysfunction.
Characteristic electrophysiologic abnormalities include augmentation of the compound motor action potential with
repetitive stimulation. Most patients with Lambert-Eaton myasthenic syndrome benefit from plasmapheresis and
immunosuppressive therapy. Drugs that increase presynaptic acetylcholine release may also decrease
symptoms; for example, 3,4-diaminopyridine.

Subacute Sensory Neuronopathy and Encephalomyeloneuritis


This is most frequently associated with SCLC. Others are breast and hodgkins lymphoma. Diagnosis of SSN-
EMN and documentation of anti-Hu antibody should lead to the search for an SCLC. The disorder progresses
relentlessly over days to weeks, and sensory nerve action potentials are lost. The cerebrospinal fluid (CSF)
usually demonstrates increased protein concentration and a lymphocytic pleocytosis, and in SSN associated with
anti-Hu antibody, the dorsal root ganglia show lymphocytic infiltration and loss of neurons. Most cases of SSN
are associated with other autoimmune disorders rather than with cancer, and anti-Hu antibodies are absent.
Treatment of the underlying SCLC may ameliorate signs of neurological dysfunction, and treatment of Hodgkin's
lymphoma with chemotherapy was followed by clinical improvement in one patient. Immunosuppression may
produce at least transient disease stabilization even in patients who did not receive treatment for the underlying
tumor.

Autonomic Neuropathy
A pure paraneoplastic autonomic neuropathy is rare, but approximately 25% of patients with anti-Hu syndrome
and SSN-EMN have autonomic dysfunction.114 (DThe disorder is usually associated with SCLC and
autoantibodies that react with neurons in the myenteric plexus. GI dysmotility is usually a core complaint, with
orthostatic hypotension, hypoventilation, sleep apnea, and cardiac dysrhythmias being variably present.
Treatment of the underlying tumor and/or immunosuppression is usually unable to reverse neurologic
dysfunction, but may stabilize disease.

Paraneoplastic Visual Syndromes


This group of disorders involves the retina and, less frequently, the uvea and optic nerves.The most commonly
associated tumor is SCLC. Melanoma-associated retinopathy affects patients with metastatic cutaneous
melanoma. Patients develop the acute onset of night blindness and shimmering, flickering, or pulsating
photopsias that often progress to visual loss. The ERG demonstrates reduction in the b-wave amplitude.
Paraneoplastic optic neuritis and uveitis are very uncommon and can develop in association with
encephalomyelitis. Some patients with paraneoplastic uveitis harbor anti-CV2/CRMP5 antibodies.
Paraneoplastic retinopathies usually fail to improve with treatment, although rare responses to glucocorticoids,
plasma exchange, and IVIg have been reported.

Paraneoplastic Stiff-Person Syndrome


This disorder is characterized by progressive muscle rigidity, stiffness, and painful spasms triggered by auditory,
sensory, or emotional stimuli. Rigidity mainly involves the lower trunk and legs, but it can affect the upper
extremities and neck. Symptoms improve with sleep and general anesthetics. Electrophysiologic studies
demonstrate continuous motor unit activity. Antibodies associated with the stiff-person syndrome target proteins
[glutamic acid decarboxylase (GAD), amphiphysin] involved in the function of inhibitory synapses utilizing -
aminobutyric acid (GABA) or glycine as neurotransmitters. Paraneoplastic stiff-person syndrome and
amphiphysin antibodies are often related to breast cancer. Optimal treatment of stiff-person syndrome requires
therapy of the underlying tumor, glucocorticoids, and symptomatic use of drugs that enhance GABA-ergic
transmission (diazepam, baclofen, sodium valproate, tiagabine, vigabatrin).

RHEUMATOLOGIC MANIFESTATION
Paraneoplastic arthropathies arise as rheumatic polyarthritis or polymyalgia, particularly in patients with
myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the colon, pancreas, prostate, and
CNS. Hypertrophic osteoarthropathy may be observed in patients with lung cancers, pleural mesothelioma, or
phrenic neurilemmoma. Scleroderma may precede direct evidence of tumor. The widespread form is typical of

179
malignancies of the breast, uterus, and lung (both alveolar and bronchial forms). The localized form is
characteristic of carcinoids and lung tumors (bronchoalveolar forms). Systemic lupus erythematosus (SLE) may
develop in patients with lymphomas or cancers of the lung, breast, or gonads. Secondary amyloidosis of the
connective tissues is a rare presentation in patients with myeloma, renal carcinoma, and lymphomas.

Hypertrophic Osteoarthropathy
Hypertrophic osteoarthropathy is characterized by periostosis and subperiosteal new bone formation along the
shaft of long bones and the phalanges (digital clubbing), joint swelling, and pain.100,112(N) The symptoms of
paraneoplastic hypertrophic osteoarthropathy may resolve with successful cancer therapy. Other treatment
options include bisphosphonates, opiate analgesics, nonsteroidal anti-inflammatory drugs, and localized palliative
radiation.

RENAL SYNDROMES
Membranous nephropathy has been clearly associated with malignancy. Although the majority of cases are
idiopathic, in the elderly as many as 22% may be associated with cancer. Various forms of malignancy have
been described in patients with membranous nephropathy. The most common has been carcinomas of the lung,
colon, and stomach. Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more
than 20 mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone
(ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the lung (ie,
small cell lung cancer. Nephrotic syndrome is observed, although infrequently, in patients who have Hodgkin
lymphoma (HL); non-Hodgkin lymphoma (NHL); leukemias; melanomas; or malignancies of lung, thyroid, colon,
breast, ovary, or pancreatic head.

GASTROINTESTINAL SYNDROMES
Watery diarrhea accompanied by an electrolyte imbalance leads to asthenia, confusion, and exhaustion. These
problems are typical of patients with proctosigmoid tumors (both benign and malignant) and of medullary thyroid
carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2 and F2) that lead to
malabsorption and, consequently, unavailability of nutrients.

CONCLUSION
As the number of patients with cancer grows, and as these patients live longer, the incidence of paraneoplastic
syndromes will likely increase. These conditions affect the presentation, clinical course, and treatment of cancer.
As a result of recent diagnostic and therapeutic advances, many paraneoplastic syndromes are currently well
defined, have a clear pathogenesis, and have effective treatment options. The ability to recognize and treat
paraneoplastic syndromes may have a substantial effect on clinical outcomes, ranging from earlier cancer
diagnosis, to improved quality of life, to increased delivery of tumor-directed therapy. Furthermore, ongoing
research into these disorders may shed light on mechanisms of tumor development, maintenance, and
proliferation.

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Approach to a Patient with Thyroid swelling

Anjali Mishra, Chandan Kumar Jha, Niraj Kumari, Zafar Neyaz

I. Epidemiology

Thyroid nodules are discovered by palpation in 3%-7%, ultrasonography (USG) in 20%-76% and during autopsy
in 50-65% of the general population. The incidence of thyroid nodule has been correlated with various risk factors
mainly iodine nutrition of the population, age, gender, therapeutic and environmental radiation. According to the
available estimates, in India about 71 million people suffer from Goiter or other iodine deficiency disorders. The
incidence of goiter in sub- Himalayan region of India continues to be high despite an active National Goiter
control Programme (NGCP). According to conventional definition goiter is an enlarged thyroid but what the exact
cut off of enlargement is not well- defined. So far as thyroid nodule is concerned the American Thyroid
Association defines a thyroid nodule as a discrete lesion within the thyroid gland that is radiologically distinct
from the surrounding thyroid parenchyma.

Main Causes of Thyroid Swelling


1. Colloid Nodule
2. Follicular adenoma
3. Multinodular goiter
4. Graves disease
5. Thyroid Cyst
6. Primary thyroid malignancy: Papillary thyroid carcinoma (PTC), Follicular thyroid carcinoma (FTC),
Poorly differentiated thyroid carcinoma (PDTC), Medullary Thyroid Carcinoma (MTC), Anaplastic thyroid
carcinoma (ATC), Thyroid lymphoma
7. Metastases to thyroid from primary malignancy of bronchus, breast, and colon etc.
8. Thyroiditis
a. Immunologically mediated
b. Infective
9. Lymphangioma, Hemangioma or hamartoma
10. Physiological e.g. Puberty, pregnancy

II. Clinical Evaluation

There are many causes of thyroid swelling or enlargement. The evaluation of thyroid swelling is chiefly focused
on excluding presence of thyroid malignancy and dysfun