Recommendations in the management

of epithelial appendiceal neoplasms and

peritoneal dissemination from mucinous
tumours (pseudomyxoma peritonei)

P. Barrios, F. Losa, S. Gonzalez-Moreno,

A. Rojo, A. Gómez-Portilla, P. Bretcha-
Boix, I. Ramos, J. Torres-Melero,
R. Salazar, et al.
Clinical and Translational Oncology

ISSN 1699-048X
Volume 18
Number 5

Clin Transl Oncol (2016) 18:437-448

DOI 10.1007/s12094-015-1413-9

1 23
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 Author's personal copy
Clin Transl Oncol (2016) 18:437–448
DOI 10.1007/s12094-015-1413-9

SPECIAL ARTICLE

Recommendations in the management of epithelial appendiceal

neoplasms and peritoneal dissemination from mucinous tumours
(pseudomyxoma peritonei)
P. Barrios1,11 • F. Losa1 • S. Gonzalez-Moreno2 • A. Rojo2 •
A. Gómez-Portilla3 • P. Bretcha-Boix4 • I. Ramos1 • J. Torres-Melero5 •

R. Salazar6 • M. Benavides7 • T. Massuti8 • E. Aranda9,10

Received: 30 June 2015 / Accepted: 17 August 2015 / Published online: 21 October 2015
Ó Federación de Sociedades Españolas de Oncologı́a (FESEO) 2015

Abstract The epithelial appendiceal neoplasms are
uncommon and are usually detected as an unexpected
surgical finding. The general surgeon should be aware of
the diversity of its clinical manifestations and biological
behaviors along with the significance of the surgical
treatment on the progression of the illness and the prog-
nosis of the patients. The operative findings and, especially,
tumor histology, determine the type of surgery. Intestinal
histologic subtype behaves and should be treated similarly
to the right colon neoplasms; while mucinous tumors, often
discordant between histology and its aggressiveness, can be
treated with a simple appendectomy or require complex
oncological surgeries. Mucinous tumors are often associ-
ated with the presence of mucin or tumor implants in the
abdominal cavity, being the clinical syndrome known as
& P. Barrios
pedro.barrios@sanitatintegral.org
1
Consorci Sanitari Integral (H. Sant Joan Despı́. Moisès
Broggi), Universidad de Barcelona, Barcelona, Spain
2
Anderson Cancer Center, Madrid, Spain
3
Hospital San José, Vitoria, Spain
4
Hospital Quirón-Salud Torrevieja, Alicante, Spain
5
Hospital de Torrecardenas, Almeria, Spain
6
Institut Català d’Oncologia (ICO-L’Hospitalet), Barcelona,
Spain
7
Hospital Regional Universitario, Málaga, Spain
8
Hospital General de Alicante, Alicante, Spain
9
Reina Sofı́a Hospital, University of Córdoba, Maimonides
Institute of Biomedical Research (IMIBIC), Córdoba, Spain
10
Spanish Cancer Network (RTICC), Instituto de Salud Carlos
III, Córdoba, Spain
11
Universidad de Barcelona, Barcelona, Spain
pseudomyxoma peritonei (PMP). PMP tends to present an
indolent but deadly evolution and requires a multimodal
approach as a single treatment with curative potential:
complete cytoreductive surgery plus hyperthermic Intra-
peritoneal chemotherapy (CCRS ? HIPEC) now consid-
ered the standard of care in this pathology. The general
surgeon should be aware of the governing principles of the
treatment of appendiceal neoplasms with or without peri-
toneal dissemination, know the therapeutic frontiers in
every situation (avoiding unnecessary or counterproductive
surgeries) and sending early these patients to specialised
centres in the radical management of malignant diseases of
the peritoneum in the conditions and with the necessary
information to facilitate a possible radical treatment.
Keywords Epithelial tumours of the appendix

Mucinous appendiceal tumours
Mucinous dissemination
from appendiceal neoplasm
Pseudomyxoma peritonei
(PMP)
Multimodality radical treatment of peritoneal
carcinomatosis
Complete cytoreductive surgery (CCRS)

Hyperthermic intra-peritoneal chemotheray (HIPEC)

Sugarbakeŕs technique
Introduction
Epithelial tumours of the appendix are quite infrequent.
They are usually detected during emergency surgeries,
representing a diagnostic and therapeutic challenge for
health care professionals [1–5]. The initial surgical treat-
ment has a direct effect on tumour progression and on
patient overall prognosis.
Epithelial tumours of the appendix can be divided into two
histological subtypes, intestinal and mucinous tumours [6],
with different clinical and biological behaviours. Intestinal

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438
tumours resemble ascending colon adenocarcinomas and
should be treated correspondingly [7]. Mucinous tumours are
characterized by a wide spectrum of biological aggressive-
ness, requiring different surgical approaches, which will
depend on the natural history of each tumour, the surgical
findings and, over all, the surgical pathology results. The
recommended surgical strategy consists of a ‘‘radical’’
appendectomy, maintaining the integrity of the tumour, and
including the base of the appendix and its mesoappendix, for
perioperative histological node assessment [7, 8]. A right
colectomy associated with ileo-colonic lymphadenectomy is
an approach not justified in this type of tumours [9]; in fact, it
may be counterproductive [10].
The surgical management of mucinous tumours requires
a careful examination of the entire abdominal cavity, since
often there is peritoneal dissemination [11] even without
evidence of perforation or ruptured appendix [12]. The
features and extent of peritoneal disease and the associated
tumour histology will determine the treatment and prog-
nosis of these patients. The presence of diffusely dis-
tributed mucin within the abdominal cavity, with or
without abdominal tumour masses, enables the diagnosis of
pseudomyxoma peritonei (PMP) [13], a disease associated
with an indolent yet lethal behaviour, candidate to receive a
multimodality radical approach [14]. Presence of mucin
exclusively in the periappendiceal area is associated with
an uncertain biological behaviour, which depends largely
on the coexistence of neoplastic epithelial cells; acellular
mucin might require regular clinical follow-up, unlike
cellular mucin, which requires radical treatment [15].
Historically, peritoneal dissemination has been consid-
ered advanced systemic disease, prone to palliative mea-
sures. Recent knowledge regarding tumour growth and
peritoneal surface cell implantation allowed a shift of this
paradigm towards classifying it as a locoregional disease
[16]. This change, together with the low biological aggres-
siveness of PMP, encouraged the development of a radical
treatment for this condition, which combines complete
cytoreductive surgery with hyperthermic intra-peritoneal
chemotherapy (CCRS ? HIPEC) [17]. This multimodality
approach has been used for over 30 years in PMP [18],
achieving survivals lengths of 15, 20 and even 30 years. In
addition, complication rates are comparable to those
described in other complex oncological surgeries [19],
without negative impact on the patient’s quality of life [20].
Currently, CCRS ? HIPEC is considered the standard
treatment for mucinous appendiceal tumours with peri-
toneal dissemination [21–23]. Best clinical outcomes are
achieved with strict patient selection and early treatment
delivery [18]. Surgeons and oncologists should be familiar
with the indications and results of this technique and offer
it to their patients, avoiding the ‘‘wait and see’’ approach or
the application of other, less effective, treatments. Again,
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Clin Transl Oncol (2016) 18:437–448
early referral to specialized centres is crucial. Outstanding
oncologic centres have adopted CCRS ? HIPEC in their
regular practice. Furthermore, some countries have inclu-
ded in their national health plans the development of highly
specialized centers in this type of treatment.
In this paper, based upon the authors clinical experience
and the current literature review, we aim to address the
importance of the histopathological classification of
appendiceal mucinous tumours and the peritoneal dissem-
ination patterns. This should help the general surgeon in
choosing the most appropriate surgical procedure when
facing different manifestations of these complex and
infrequent tumours. We provide the clinical results of the
most referenced series in the literature and the most rele-
vant prognostic indicators, necessary in selecting the best
candidates for this treatment while maximising clinical
benefits. Lastly, we analyse the current role of systemic
chemotherapy in the treatment of PMP.
Classification of primary appendiceal neoplasms
and their peritoneal dissemination
The vermiform appendix differs histologically from the
colon because it presents larger proportion of mucus pro-
ducing cells, as well as a wall more prone to infectious or
tumoral rupture [24]. These characteristics influence in the
behaviour of some appendicular tumours. Between 0.7 and
1.7 % of appendectomy specimens have some type of
neoplasm [1, 4, 25], representing 0.4–1 % of all gastroin-
testinal tumours [2, 26]. More than 50 % of all appendiceal
tumours are neuroendocrine type, followed by non-neu-
roendocrine epithelial neoplasms (or simply called ‘‘ep-
ithelial tumours’’). There is an infrequent mixed tumour
subtype called mixed adenoneuroendocrine carcinoma
(MANEC). Other extremely rare types include mesenchy-
mal, lymphoid and neural tumours. The group of epithelial
neoplasms are further classified according to the percent-
age of extracellular mucus into two categories: intestinal
and mucinous [6]. These subtypes present different clinical
behaviour and aggressiveness.
Mucinous tumours represent approximately 90 % of the
epithelial tumours and up to 30 % of all appendiceal
tumours. Two thirds of mucinous tumours are benign, one
third are malignant. All of them often manifest a great
discordance between histological features and their bio-
logical behaviour, responsible for the wide terminology
used in these singular disease, some terms being confusing
and controversial [27]. Mucinous tumours have even been
labelled as ‘‘enigmatic’’ tumors [15].
Up to 20 % of appendiceal mucinous tumours (1–4
cases per million population per year) are associated to free
mucus accumulation within the peritoneal cavity, a clinical
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Clin Transl Oncol (2016) 18:437–448
Fig. 1 Pseudomyxoma peritonei syndrome. Histological type: dis-
seminated peritoneal adenomucinosis (DPAM)
manifestation known as PMP [3, 28] (Fig. 1). The term
PMP was keyed by Werth [29] in an attempt to describe the
presence of a ‘‘false mucinous tumour in the peritoneum’’,
secondary to a ruptured cystic ovarian tumour. Many years
later, Young et al. [30] questioned the ovarian origin of
PMP. They proposed an appendiceal origin and established
criteria for differentiating both origins. Currently, in the
presence of PMP, any mucinous ovarian tumour should be
considered of an appendicular origin, unless proven
otherwise [31]. PMP is frequently diagnosed late; in a
patient with progressive increased abdominal distension
(presence of mucinous ascites or ‘‘jelly belly’’), during the
study of ovarian tumours (most frequent presentation form
among women), or in patients with abdominal wall hernias
and/or abdominal discomfort [32].
No single or universally accepted histological nomen-
clature exists for PMP. Ronnett et al. [27] described the first
histopathological classification into two initial diagnostic
categories: disseminated peritoneal adenomucinosis
(DPAM) and peritoneal mucinous carcinomatosis (PMCA).
DPAM includes peritoneal lesions composed of abundant
extracellular mucin with little mucinous epithelium, low
cytologic atypia and limited mitotic activity, with or without
associated appendiceal mucinous adenoma. PMCA corre-
sponds to an appendiceal carcinoma and peritoneal implants
with abundant atypical proliferative epithelium. Further-
more, she introduced an unspecific ‘‘intermediate or dis-
cordant’’ category, represented by a predominantly
adenomucinous pattern with a minor component of adeno-
carcinoma (in some cases even with ‘‘signet ring’’ cells).
Ronnett found that most PMP are of appendiceal origin
(87 % of the cases) and determined the histologic classifi-
cation of PMP as an important independent prognostic factor
in patient survival. Ronnett’s work has been questioned
because includes a confusing ‘‘intermediate’’ category and
for the alleged lack of prognostic significance from the
presence or absence of epithelial cells within the mucus.
439
Misdraji et al. [33] exposed a major controversy
regarding this topic: if mucinous lesions confined to the
appendix are considered benign, is it the spread of a rup-
tured lesion equivalent to adenocarcinoma? He classified
mucinous tumours as low grade appendiceal mucinous
neoplasms (LAMN), mucinous adenocarcinoma (MACA),
and ‘‘discordant’’ category (low-grade appendiceal tumour
with high-grade peritoneal implants). Furthermore, he
explicitly excluded tumours with signet ring cells. Misdraji
concluded that LAMN confined to the appendix presented
no recurrence at 6-years follow-up. He found prognostic,
yet no histological differences, between intact wall ade-
nomas and those with perforation and dissemination into
the peritoneum.
A ruptured wall adenoma with adenomucinosis main-
tains histologic characteristics of an adenoma, despite the
cellularity of peritoneal lesions. However, it is not equiv-
alent to an intact adenoma with preserved wall and no
extra-appendicular lesions. Patients with LAMN with high
degree peritoneal implants have the same prognosis as
MACA patients. Misdraji recommends removing the ‘‘in-
termediate or discordant’’ category while maintaining the
terminology of mucinous ascites/cellular ascites given by
Scully (classifying the peritoneal disease in only two
prognostic categories). He emphasises the importance of
the peritoneal lesions histology, over the primary tumour
histology, regarding patient prognosis.
Bradley et al. [34], in a series of 101 patients with PMP,
exclusively of appendiceal origin, proposed DPAM,
PMCA, and PMCA-I categories, highlighting that ‘‘signet
ring’’ cells are considered PMCA. DPAM and PMCA-I,
with an equivalent survival at 1, 3, and 5 years, were
grouped together in a single, less aggressive, category. His
work also discourages the intermediate category (PMCA-I)
and proposes two categories based on peritoneal dissemi-
nation: mucinous carcinoma peritonei-low grade and
mucinous carcinoma peritonei-high grade. In his opinion,
by definition, ‘‘an adenoma is a tumour confined to the
appendiceal mucosa without evidence of invasion of the
muscularis mucosae.’’
Recommendations for appendiceal epithelial tumour
classification
The last edition of the WHO classification of tumours of
the digestive system [28] acknowledged the difficulty of
structuring a histological classification of epithelial
tumours, admitting various nomenclatures to describe the
same entity.
Currently recognised categories include adenoma (pre-
cursor lesion) and carcinoma. LAMN can be used to
encompass adenomas and ‘‘ruptured wall adenomas’’.
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Categories:
1. Mucinous tumour ([50 % of the lesion corresponding
to extracellular mucus)
1.1 Low grade appendiceal mucinous neoplasms
(LAMN).
1.2 Mucinous adenocarcinoma (MACA).
2. Non-mucinous or intestinal adenocarcinoma (\50 %
of the lesion corresponding to extracellular mucus).
These tumours present grades and other clinical
criteria similar to colorectal adenocarcinomas.
The TNM classification of malignant tumours (7a edi-
tion) separates appendiceal tumours from other colorectal
tumours, distinguishing between mucinous and non-muci-
nous versions. In the former, the grade and the T4 and M1
categories are further subdivided according to the presence
of mucus found exclusively in the right lower quadrant of
the abdomen (T4a) or beyond (M1).
The adenoma-carcinoma sequence is assumed for
appendiceal tumours, similarly to other colon tumours.
Most appendicular adenomas are considered low grade. In
the presence of high nuclear grade and architectural com-
plexity, a diagnosis of adenoma can only be made when the
lesion reminds a colon adenoma with intact muscularis
mucosae. The designation of adenoma implies that the
lesion can be cured with complete excision. When in doubt,
the alternative diagnosis (LAMN) is recommended. The
presence of any outbreak of mucin outside the appendix
(even with acellular mucin) is not compatible with the
diagnosis of adenoma. There is general consensus in using
‘‘LAMN versus MACA’’ for primary tumour classification,
as proposed by Misdraji, in view of the difficulties derived
from the classical terminology of ‘‘adenoma versus
adenocarcinoma’’.
Recommendations for peritoneal dissemination
classification
The WHO [28] subdivides peritoneal dissemination into
two categories: low and high grade PMP, which are
equivalent to Bardley’s mucinous carcinoma peritonei-low
grade and high grade categories. In general, low and high
grade PMP are associated with LAMN and MACA
respectively, although the existence of discordant cases is
acknowledged. Despite the simplicity and reproducibility
of this proposal, the term PMP should not be used as a
histological diagnosis. Therefore, the best terminology for
peritoneal lesions is still being discussed, although it is
accepted that a dichotomous classification seems more
acceptable than having three categories.
A double diagnosis must be made in every
anatomic/pathologic report of patients with appendiceal
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Clin Transl Oncol (2016) 18:437–448
mucinous neoplasms associated with peritoneal dissemi-
nation: one diagnosis for the primary appendiceal neo-
plasm (should it be available) and another one for the
peritoneal dissemination. Both diagnoses should consider a
binary classification, improving the reproducibility and
practicability. Thus it is possible to properly stratify
patients in a particular prognostic category and choose the
best treatment.
The used terminology between surgical oncologists,
medical oncologists, and pathologists is essential to ade-
quately address this complex disease. The Peritoneal Sur-
face Oncology Group International (PSOGI), with the joint
participation of international professionals with expertise
in this disease, is currently developing a single standardised
nomenclature.
Preliminary results were presented last October in
Amsterdam, at the PSOGI Congress, pending publication.
Meanwhile, all histological reports should follow and
specify the adopted classification system.
Surgical treatment of appendiceal epithelial
tumours
Surgical treatment depends on the natural history and
biological aggressiveness of appendiceal tumours, deter-
mined by the histological assessment conducted intraop-
erative or from samples obtained from previous surgeries
(Figs. 2, 3).
Mucinous tumours are usually located along the
appendix or on its tip. They are low grade tumours and
present expansive growth patterns, associated with low risk
for appendiceal base infiltration and infrequent nodal
invasion [9]. However, ‘‘signet ring’’ cells tumours are
considered high grade and aggressive in behaviour. Com-
plete surgical oncologic resection depends on the appen-
diceal base involvement and on the mesoappendix lymph
node status.
The use of right colectomy as the standard treatment for
appendiceal tumours comes from Hesketh’s work [35]
based on patients with intestinal type appendiceal tumours.
González-Moreno et al. [9] conducted a retrospective
multivariate analysis of 501 patients with appendiceal
mucinous tumours and peritoneal dissemination. They
found that lymph node involvement from mucinous
tumours only occured in 4.2 % of the patients and that
lymph node status did not influence overall survival of
patients with mucinous histology. In this cohort of patients,
right colectomy did not improve survival compared to
appendectomy [8]. Sugarbaker recommends an appendec-
tomy associated with histological study of the existing 4–7
nodes along the appendicular artery, and adjust surgery
accordantly, avoiding unnecessary colectomies (considered
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Clin Transl Oncol (2016) 18:437–448 441

Mixed adenoneuroendocrine carcinoma (MANEC) Appendiceal intesnal/mucinous "signet ring” cell tumor

Size < 2 cm Size > 2 cm

Right colectomy
No cecal infiltraon and/or Peritoneal carcinomatosis
+
Low histologic grade Cecal infiltraon present
Ileocolic lymphadenectomy
No peritoneal disseminaon High histologic grade

Without
Peritoneal
peritoneal
disseminaon
disseminaon
Appendectomy
(or minimal surgery)

PCI score
Peritoneal biopsies
Appendectomy
Right colectomy or
"radical" + minimal surgery
appendectomy ileocolic
lymphadenectomy PCI score
Peritoneal biopsies

Clinical follow-up Clinical follow-up

Peritoneal disseminaon Peritoneal disseminaon

during follow-up during follow-up

Refer paent to a peritoneal carcinomatosis specialized center

Fig. 2 Recomendations in the management of mixed adenoneuroendocrine carcinoma (MANEC) and appendiceal intestinal/mucinous ‘‘signet
ring’’ cell tumor

Appendiceal Mucinous Tumor

Intact mucocele Perforated tumor Associated to peritoneal disseminaon

“radical” appendectomy * Mucocele rupture

during surgery
Without
Bowel obstrucon
+ “radical” appendectomy bowel obstrucon
Abdominal exploraon +
(open laparotomy recommended) Abdominal exploraon and
“Radical” appendectomy descripon disease (Score PCI)
+ +
Meculous lavage ohe
enre peritoneal cavity and
Mucinous cytology study
Biopsies - the surgical wound
+/-
Appendiceal base biopses + +
Normal abdominal Appendiceal base biopsies + biopsies abdominal disease
+/-
exploraon Lymph node biopsies -
Lymph node biopsies + Mucinous cytology
Normal abdominal exploraon
Normal abdominal exploraon study By-pass or stoma formaon
Descripon of abdominal (minimal surgery)
disease (PCI) +
Periappendicular mucin + Descripon of abdominal
only Free abdominal mucin Abdominal disease biopsies disease (PCI)
and/or +/- +
Cecum resecon Right colectomy
Acellular Cellular (no other abdominal abdominal disease Appendectomy Abdominal disease biopsies
or +
mucin mucin disease)
Right colectomy Ileocolic lymphadenectomy

Follow-up:
CT Scan
Tumoral markers
(CEA, CA125, CA19.9)

- +

Considered cured Follow-up Follow-up

* ”radical” appendectomy: Refer paent to a peritoneal carcinomatosis specialized center

Appendectomy, with its base / biopsy
Complete meso-appendix resecon / lymph node biopsy

Fig. 3 Recomendations in appendiceal mucinous tumor management

exclusively prophylactic). When invasion of the appen- ileocecal valve. This surgical approach is also valid for the
diceal base is confirmed, a cecum resection can be per- treatment of low grade adenocarcinoid tumours smaller
formed, with negative margins, while preserving the than 2 cm in diameter without cecal extension, which often

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442
behaves as mucinous tumours [36]. Right colectomy is
only justified for mucinous tumours with ‘‘signet ring’’
cells, for those with nodal involvement of the mesoapen-
dicular area (regardless of tumour histology), or in the
context of a radical treatment when the colon is affected by
the tumour [37]. Outside these situations, right colectomy
is oncologically unnecessary and harmful. It might promote
retroperitoneal tumour dissemination [38] and may jeop-
ardise intestinal length in potential candidates to radical
treatments that may require further bowel resections [8,
10].
Mucinous tumours are often found as a dilation of the
appendix caused by intraluminal mucin retention or ‘‘ap-
pendiceal mucocele’’ (Figs. 4, 5). Other harmless lesions,
hard to categorize during surgery, might also occlude the
appendix [39]. However, the significance risk of mucinous
tumours requires that, a priori, all mucoceles should be
treated like tumour origin. Surgery will depend on muco-
cele size, integrity of appendiceal wall and on the operative
and surgical pathology analysis of the appendiceal base and
the mesoappendix lymph nodes. The integrity of the
mucocele wall must be maintained at all times, since sur-
gical rupture significantly aggravates prognosis [39, 40]. A
low grade mucinous tumour without ruptured wall repre-
sents a benign process, while tumour perforation is asso-
ciated with a 5-year mortality rate of 55 % [33].
Prognosis is worsened whenever mucinous material is
present out of the appendix. Therefore, a meticulous
exploration of the abdomen and pelvis (specifically the
ovaries) is mandatory [41]. When mucin is found diffusely
throughout the abdominal cavity, the diagnosis of PMP is
established [27], and patients should be referred to spe-
cialized centres with expertise in the treatment of malig-
nant diseases of the peritoneum.
A cytological study of mucin is necessary, whenever it
is found near the appendix and/or at the lower right
quadrant. When tumour cells are found in the mucin
material, (cellular mucin) PMP will develop in 33 % of the
Fig. 4 Appendiceal mucocele. ‘‘Radical’’ appendectomy: complete tumor resection with appendiceal base and mesoappendix
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Clin Transl Oncol (2016) 18:437–448
cases, compared to 4 % in the absence of tumour cells or
neoplastic epithelium (acellular mucin) [15]. Due to the
slow growing process, these patients can be followed
clinically, and a radical treatment prescribed only if peri-
toneal disease develops [42]. In non-specialised centres or
under unsuitable conditions for a radical approach, surgery
should be limited to an appendectomy (as indicated above),
cytological study of the abdominal fluid (or mucin), his-
tology of any abdominal biopsies and precise description of
abdominal findings reflected in the surgical operative note,
for future decisions. The abdomen and the surgical wound
must be thoroughly cleaned to prevent entrapment and
tumour growth [43]. Open laparotomy is preferred when
treating appendiceal mucocele. Even though laparoscopic
approach might be possible, it is considered risky when
handling big tumours, does not allow tumour palpation and
limits abdominal assessment [44–47].
Intestinal tumours of the appendix are usually found at
the base, behave as classic colorectal adenocarcinoma, with
lymph node disease present in 25 % of the cases, and
requires right colectomy with locoregional lymphadenec-
tomy [9].
Intestinal obstruction in the context of appendiceal
tumours is usually caused by the peritoneal disease. The
surgical treatment in these cases should be limited to
conducting a gastrointestinal by-pass or stoma and
description and biopsy of peritoneal lesions. It is important
to avoid aggressive surgical approaches and unnecessary
peritonectomies, preventing tumour extensions and hinder
subsequent potential radical treatments. Appendiceal
tumours can also be diagnosed by surgical pathology
studies of the appendices extracted from previous surg-
eries. In such cases, if the appendix presents perforation
and histological characteristics consistent with mucinous
adenocarcinoma, and/or evidence of peritoneal dissemina-
tion, a ‘‘second look’’ surgery is recommended, at a spe-
cialized centre, for radical treatment consideration. If the
appendix is perforated and the histological characteristics
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Clin Transl Oncol (2016) 18:437–448
Fig. 5 Malignant appendiceal mucocele
are consistent with adenomucinosis, a clinical follow-up
may be considered.
Clinical or radiological suspicion of peritoneal muci-
nous disease must be histologically confirmed by non-in-
vasive or laparoscopic biopsies. In order to correctly
classify mucinous peritoneal disease, multiple biopsies
may be necessary. Incomplete or conflicting pathology
reports must be reviewed by expert pathologists and
patients referred to specialized centers (avoid exhaustion of
other treatments modalities and the ‘‘wait and see’’
approach.
Surgical treatment of peritoneal dissemination
from appendiceal mucinous tumours
Perforation form appendiceal mucinous tumours is a quite
frequent condition, allowing flow of mucin and tumour
cells to the abdominal cavity [11, 12, 42] (Fig. 6). Peri-
toneal dissemination from these tumours might be present
without macroscopic or even microscopic evidence of
lesions of the appendiceal wall [12].
Mucin has a loosely adherent capacity, with a pre-
dictable distribution throughout the abdomen and pelvis; it
has special tropism to certain abdominal organs, such as
the ovaries (Krukenberg tumour), the greater/lesser
omentum (‘‘omental cake’’), the ligament of Treitz, the
ileo-cecal area and the sigmoid colon. Some anatomical
regions favour the accumulation of large volumes of
mucin, such as the pelvis, the sub-diaphragmatic area, the
area behind the liver and the paracolic gutters. This
abdomino-pelvic mucin and tumour masses distribution is
a characteristic feature of appendiceal mucinous neo-
plasms, both DPAM and PMCA [13].
In addition, PMP rarely presents liver and/or lymph
node metastases, and involvement of small intestine serosa
is limited (Fig. 7). PMP can thus be defined as a
443
locoregional neoplastic disease and, therefore, it can be
removed by a radical surgical treatment.
Most appendiceal tumours are low grade, and any
minimal tumour residue after surgery can be erradicated
using intraperitoneal chemotherapy administered immedi-
ately [18]. This multimodality treatment has being used for
more than three decades in appendiceal mucinous tumours
with peritoneal dissemination. First used by Spratt et al.
[17], most scientific and technical progress, as well as the
knowledge diffusion, is due to the work of Sugarbaker [14,
18, 37, 38]. Subsequent studies have helped to strengthen,
adapt and extend the clinical application of CCRS ? HI-
PEC in appendiceal and other tumour types associated with
peritoneal dissemination [21, 48, 49].
Complete cytoreductive surgery (CCRS): peritonectomies
procedures
The aim of CCRS is to eliminate any macroscopic tumour
manifestation. Any organ or tissue not grossly affected by
tumour, except for the omentum and the ovaries, should not
be removed in a systematic manner during this procedure.
Sugarbaker’s peritonectomy procedures constitute the rec-
ommended surgical strategy to achieve CCRS [19, 50, 51].
There are several classification systems in localising and
quantifying the volume of peritoneal disease [52]. The
most widely used is the peritoneal cancer index (PCI) [53],
it is determined at the time of surgical exploration of the
abdomen and pelvis. It serves as an estimate of probability
of complete cytoreduction and has been found to be an
accurate assessment of survival. The PCI quantitatively
combines the distribution of tumor throughout 13 abdo-
mino-pelvic regions, with a lesion size score quantifying its
volume from 0 to 39.
The quality of CCRS can be evaluated by the com-
pleteness of cytoreduction score (CC) [54] and it is to be
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444
Fig. 6 Appendiceal mucinous tumors. Spontaneous rupture, associated with peritoneal dissemination
Fig. 7 Pseudomyxoma peritonei. Histological type: peritoneal muci-
nous carcinomatosis (PMCA). ‘‘Omental cake’’ and absence of small
bowel tumoral implants
assessed after cytoreductive surgery is finalized. Complete
(CC-0 or CC-1) or incomplete cytoreduction (CC-2 or CC-
3) is determined. A CC-0 is apparent when there is no
peritoneal seeding visualized within the operative field
(absence of macroscopic tumour residue). CC-1 indicates
nodules persisting after cytoreduction less than 0.25 cm.
CC-2 has nodules between 0.25 and 2.5 cm, whereas a CC-
3 indicates nodules greater than 2.5 cm or a confluence of
unresectable tumor nodule. HIPEC is indicated only after
complete cytoreduction. Since CC-1 tumor nodule size is
thought to be penetrable by intracavitary chemotherapy, it
is designated as complete cytoreduction when periopera-
tive intraperitoneal chemotherapy is used [18].
CC-0 is associated to better prognostic results, and it is
mandatory for HIPEC eligibility when treating solid
tumours or tumours with fibrotic characteristics [55]. In
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Clin Transl Oncol (2016) 18:437–448
general, HIPEC does not offer any clinical benefits for
incomplete cytoreduction, although some studies with PMP
patients undergoing tumour debulking surgery presented
median survival rates of 3 years [56].
Formal contraindications for CCRS include extensive
involvement of the small bowel serosa and/or bowel
mesenteric peritoneum, tumour infiltration of the hepatic
hilum, presence of massive retroperitoneal nodal disease,
and unresectable liver metastases.
Hyperthermic intra-peritoneal chemotherapy (HIPEC)
Intraperitoneal chemotherapy must be administered
immediately after CCRS, before the formation of peri-
toneal adhesions and ‘‘tumour nests’’, in order to facilitate
an equal medication distribution throughout the abdomen,
bathing all peritoneal surfaces.
Heat (intra-abdominal temperature between 41 and
43 °C) enhances the effect of some chemotherapeutic
drugs [57]. Beyond 43 °C, however, the structure of the
intestine may be affected and toxicity occurs [58]. HIPEĆs
penetrating capacity into the tumour is 2–3 mm, depending
on tumour histology [59].
The most frequently used chemotherapy regimens in
HIPEC are mitomycin C/doxorubicin, during 90 min (Su-
garbaker’s protocol) [18] and oxaliplatin during 30 min
(Elias’ protocol) [60]. Both protocols use intravenously
administration of 5FU and folinic acid immediately before
HIPEC (bidirectional chemotherapy). Patients with DPAM
are candidates for CCRS ? HIPEC. Althought it has never
been formally demonstrated in PCMA patients consider a
short course of systemic chemotherapy beforehand, and
indicate CCRS ? HIPEC based on treatment response
(response or disease stability) [18]. HIPEC’s technical
feasibility and safety has been proven in numerous studies
(Fig. 8).
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Clin Transl Oncol (2016) 18:437–448
Fig. 8 Hyperthermic Intraperitoneal chemotherapy (HIPEC): open or ‘‘coliseum’’ modality
Results and prognostic indicators
of CCRS 1 HIPEC in the treatment of PMP
Debulking surgery has been the conventional treatment for
PMP [43]. Available literature regarding this approach
shows high recurrence rate and a reasonable 5-year overall
survival rate, but a dismal 10-year survival rate [61, 62].
Recurrences are treated with increasingly complex surg-
eries that offer little clinical benefit. The association of
other treatments, such as radiotherapy, intraperitoneal
radioisotopes, or systemic chemotherapy do not appear to
add any benefit to debulking surgery [42].
Upon the introduction of CCRS ? HIPEC, patients
have been classified according to the histological charac-
teristics of their condition, which has facilitated a better
assessment of the clinical benefits, as well as comparison of
results among different studies. Sugarbaker [18] classified
947 patients with PMP in DPAM, PCMA, and intermediate
variant. Overall survival rates at 20 years were 42 %,
which remained stable at 30 years follow up. Studies with a
comparable methodology and similar inclusion criteria
obtained similar results: overall survival rates of 87 and
74 % at 5 and 10 years, respectively, in a series of 456
patients from a specialized program in the UK [63] and
overall survival rates of 80, 74, 63, and 59 % at 3, 5, 10,
and 15 years at the Chua multi-institutional study, includ-
ing more than 2000 patients from 16 specialized centres.
This study also reports a progression-free survival of
8.2 years, with a median survival of 16.3 years [64].
The aforementioned results are influenced by different
patient-related factors and by the treatment administered.
Sugarbaker [18] identified tumour histology, PCI, CC, the
prior surgical score (PSS) [54], lymph node involvement
and extensiveness of small bowel involvement as factors
directly related to survival rates and adverse side effects.
445
These have become useful indicators in patient selection
for multimodality treatment.
Histology, PCI and CC are the most decisive prognostic
factors. The overall survival rate at 20 years in DPAM
patients is 68 %, versus 18 % in PCMA and intermediate
variant patients. DPMA patients with PCI equal or inferior
to 20, have a 20-year survival of 90 %, compared with
65 % survival among those with PCI over 20. Furthermore,
in PCMA patients, survival is assessed only at 10 years, at
which point it is 45 % in patients with PCI under 20,
compared to 28 % in those with PCI over 20.
Complete cytoreduction in DPAM patients is associated
with a 78 % 20-year survival rate, compared to 26 % for
incomplete cytoreduction. In PCMA, 10-year survival rate
is 54 % for complete cytoreduction and only 10 % for
incomplete cytoreduction. Complete cytoreduction barely
influences survival among PCMA patients with a PCI over
20.
The PSS determines the aggressiveness of surgeries
performed before radical treatment, and highlights the
importance of avoiding aggressive surgeries not associated
with HIPEC, since the peritoneum acts as a tumour con-
tainment barrier. PSS foretells the technical possibilities of
CRS and the post operative complications. Is a good pre-
dictor of survival among DPAM patients and, to less
extent, among PMCA patients.
Lymph node involvement is a prognostic factor for
patients with PMCA and with intestinal type tumours. 61 %
of patients with unaffected lymph nodes live at 10 years
compared with 38 % of those with nodal involvement.
Chua et al. [64] confirms the relevance of these indi-
cators and provides other factors that negatively affect
overall survival and progression-free survival. These
include age greater than 53 years, prior systemic
chemotherapy, postoperative major complications and
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446
prolonged time between diagnosis and radical treatment. In
this study HIPEC was not a significant independent factor
affecting overall survival, although it was associated with
better progression-free survival.
Complications from CCRS ? HIPEC do not exceed
those of other complex oncological surgeries [22] and are
associated especially with CCRS. Sugarbaker et al. [65]
reports a 30-day mortality of 2 %, 19 % grade 3–4 com-
plications and 11 % reoperations rates. Furthermore,
Chua’s findings are similar. High PSS, PCI over 20,
duration of surgery, number of intestinal anastomosis,
patient age and the clinical experience of the surgical team
are factors associated with morbidity and mortality results.
Quality of life in patients with PMP undergoing
CCRS ? HIPEC immediately decreases after treatment,
with a recovery to pre-treatment levels within 1 year [66].
The Peritoneal Surface Oncology Congress (Milan
2006) [21] unanimously agreed that CCRS ? HIPEC is
considered the standard treatment for mucinous tumours
associated with peritoneal dissemination. Subsequent
studies support this recommendation [12, 14, 18, 48, 49,
63, 64, 67, 68]. The level of acceptance is growing among
the scientific community [69]. Several countries, supported
by national health care system, have promoted the creation
of specialized centers, working as referrals for the study
and treatment of peritoneal malignant diseases [70–73].
Patient follow-up after CCRS 1 HIPEC
Follow-up after CCRS ? HIPEC in PMP includes a
physical examination and measurement of the CEA, CA19-
9 and CA12.5 every 3 months, CT every 6 months during
5 years. Afterwards, a CT scan is performed every 2 years
up to 10 years [5, 20]. Despite PET́s poor value in these
patients because of its scarce diagnostic accuracy, it is
reserved for patients with elevated tumour markers and no
conclusive findings of disease on CT [69]. Appendiceal
tumours are associated to colorectal tumours, and vice
versa. It is recommended to perform colonoscopy in these
patients, and consider prophylactic appendectomy in
patients undergoing surgery for colorectal carcinoma.
Prescripcion of new radical treatment
(iCCRS 1 HIPEC)
Between 8 and 28 % of PMP patients who undergo
CCRS ? HIPEC present recurrence [74, 75]. Yan et al.
[76], in a multi-institutional series of 402 patients, found
that those who developed peritoneal recurrence and
underwent iterative radical treatment (iCCRS ? HIPEC)
had higher survival rates than untreated patients. The
specific aspects of the peritoneal recurrence must be taken
123
Clin Transl Oncol (2016) 18:437–448
into account when determining the reason for failure and
when planning iCCRS ? HIPEC [61]. Diffuse and/or
extended peritoneal recurrence must be attributed to
HIPEC failure, while isolated and/or localized peritoneal
recurrence must be attributed to CCRS failure. Recurrences
affecting the hepatic hilum and the precaval region are
difficult to approach surgically and are hard to access for
peritoneal chemotherapy. Therefore, iCCRS ? HIPEC
must be very selectively administered and requires CC-0
[55, 77–82].
Candidates for a new radical treatment must present
good general status, a healthy nutritional state, limited
tumour volume, and no systemic neoplastic disease. At
least, 1 year period must have passed since any previous
radical treatment. An incomplete CCRS during the initial
CCRS ? HIPEC is an absolute contraindication for
iCCRS ? HIPEC [68].
Role of systemic chemotherapy in the treatment
of PMP
Systemic chemotherapy has never been prospectively
evaluated in the treatment of PMP. This is due to its slow
growing capacity (associated with long periods of stabil-
ity), the heterogeneity of patients (different histologic
classifications and surgical treatments) and because surgi-
cal treatment alone provides long-term clinical benefits
[43, 83, 84]. All the available studies on systemic
chemotherapy are therefore retrospective, and mostly lim-
ited to unresectable disease. No study has shown a clear
survival benefit, presumably by the diversity of
chemotherapy agents used and the variety of histologies
found in this disease [83, 85, 86].
Lieu et al. [87] retrospectively analysed the impact of
systemic chemotherapy in 142 patients with poorly dif-
ferentiated adenocarcinomas and signet ring cell adeno-
carcinomas. Patients with unresectable or metastatic
disease had radiological response rates of 44 %, progres-
sion-free survival of 6.9 months, and overall survival of
1.7 years. His conclusion was that chemotherapy clearly
shows benefits in patients with aggressive histopathologic
variants.
Sugarbaker et al. [88] recently analysed the role of
FOLFOX4 neoadjuvant chemotherapy on a prospectively
consecutive series of 34 PCMA patients. He reported a
29 % objective response rate; however, there was also a
50 % of disease progression, confirmed by intraoperative
findings. According to Chua’s multicentre study,
chemotherapy regimes administered before CCRS ? HI-
PEC is a poor prognostic factor regarding progression-free
survival and overall survival. The results of both studies
require a prudent analysis of the role of systemic
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Clin Transl Oncol (2016) 18:437–448
chemotherapy. There is no prospective or retrospective
study justifying chemotherapy after CCRS ? HIPEC for
treating PMP, except for some isolated cases reported in
the literature, which usually correspond to patients with
aggressive histologic subtypes [89].
In conclusion, systemic chemotherapy should be
reserved for patients with unresectable disease from
aggressive histological subtypes. Survival rates of these
patients might improve compared to a purely palliative
approach, although the level of evidence is low (IV/V).
Systemic chemotherapy for DPMA patients is not recom-
mended, even when used only as palliative care, since there
is no clinical evidence justifying it.
Acknowledgments The authors are grateful to the members of
Grupo Español de Tratamiento de los Tumores Digestivos (TTD) and
Grupo Español de Cirugı́a Oncológica Peritoneal (GECOP) for their
review and valuable contributions.
Compliance with ethical standards
Conflict of interest None.
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