Management of pseudomyxoma peritonei

JBUON 2015; 20 (Suppl. 1): S47-S55
ISSN: 1107-0625, online ISSN: 2241-6293 • www.jbuon.com
E-mail: [email protected]
REVIEW ARTICLE
Management of pseudomyxoma peritonei
Simon A. Fallis, Brendan J. Moran
Peritoneal Malignancy Institute, Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke, United Kingdom
Summary
Pseudomyxoma peritonei (PMP) is an uncommon clinical condition that typically originates from a perforated
epithelial neoplasm of the appendix. The clinical presentation is variable, often with non-specific symptoms and is
associated with abdominal distension in advanced cases.
Whilst traditionally considered benign, it is apparent that
PMP represents a spectrum of disease and, at best, should
be considered a “border-line” malignancy.
The condition is characterised by the development of
mucinous ascites. Tumour cells and mucin accumulate at
characteristic sites within the peritoneal cavity according to
the redistribution phenomenon, usually sparing the mobile
small bowel. In advanced cases, high volume disease and
mucinous ascites lead to compression of the gastrointestinal tract, bowel obstruction, and ultimately, starvation.
Controversy still exists over the pathological classification
of PMP and its prognostic value. Computed tomography
remains the optimal preoperative staging investigation. Elevation of serum tumour markers correlates with a worse
prognosis.
Optimal treatment involves cytoreductive surgery with
hyperthermic intraperitoneal chemotherapy (HIPEC). With
complete cytoreduction and HIPEC an 80% 5 year survival
can be achieved in patients with low grade disease. Maximal tumour debulking can produce good palliation and
long term survival in a small number of patients.
Initial high morbidity and mortality is seen to decrease
with increasing experience and this is likely to represent
improvement in patient selection and postoperative management as well as surgical expertise.
Key words: appendiceal mucinous tumour, cytoreductive
surgery, HIPEC, jelly belly, peritoneal malignancy, pseudomyxoma peritonei
Introduction
Pseudomyxoma peritonei (PMP) is an uncommon clinical condition characterized by mucinous ascites and predominantly originates from
a perforated epithelial neoplasm of the appendix
[1,2]. The clinical presentation is variable, often
with non-specific symptoms and is associated
with abdominal distension in advanced cases
[1,2]. Whilst traditionally considered benign, it is
apparent that there is a spectrum varying from
slowly progressive to aggressively malignant disease such that pseudomyxoma peritonei, at best,
should be considered a “border-line” malignancy
[2]. Similar clinical, radiological and pathological
features may originate from any abdominal mucinous tumour, in particular the ovary in females or
colorectal pathology in males or females. PMP of
non-appendiceal origin tends to be at the adverse
end of the spectrum. The primary tumour is more
likely to be a mucinous adenocarcinoma with a
worse prognosis than that in classical PMP of appendiceal origin.
The incidence of PMP is unknown as there is
no substantial information on the true incidence of
either appendiceal mucinous tumours or of PMP.
Estimates of an incidence of PMP of 1 per million
per year had been proposed [3], though this was
based on a figure with no scientific evidence. An
epidemiological analysis by Smeenk et al in 2008
of a population based study in the Netherlands [4]
reported an incidence of mucinous epithelial ne-
Correspondence to: Brendan J. Moran, MCh FRCS FRCSI. Peritoneal Malignancy Institute, Basingstoke and North Hampshire Hospital,
Aldermaston Road, Basingstoke, RG24 9NA, United Kingdom. E-mail: [email protected]
Received: 12/02/2015; Accepted: 02/03/2015
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Management of pseudomyxoma peritonei
oplasm of the appendix of 0.3% and progression
to PMP in 20%. Extrapolations from this paper
estimates the incidence of PMP as 2 per million
per year. However, experience in a high-volume
centralized treatment centre has suggested that
the incidence may be higher with 3 to 4 operable
cases per million per year [5].
Pathophysiology of PMP and the Concept of the “Redistribution Phenomenon”
PMP arises from mucin secreting peritoneal
and omental implants secondary to a perforated
mucinous neoplasm, typically originating in the
appendix. The initiating appendiceal neoplasm
progresses and gradually occludes the lumen,
causing the appendix to become distended with
sterile mucin, eventually perforating, and spilling
mucous and mucinous tumour cells into the peritoneal cavity. Following the initial rupture there
is often a continued slow leak of mucus.
Although some cases present as acute appendicitis, many occur without symptoms. It is hypothesized that the gradual occlusion of the lumen prevents significant bacterial contamination
of the mucin distended distal appendix.
Once free within the peritoneal cavity, epithelial cells continue to proliferate and can produce
significant volumes of mucus. This culminates
in the characteristic accumulation of gelatinous
mucus in the peritoneal cavity, also commonly referred to as “jelly belly” [6]. Whilst the classical
PMP appearances originate form an appendiceal
tumour, the clinical, radiological and indeed image guided biopsy appearances of “jelly belly”
may also originate from a true adenocarcinoma
of the appendix, of the colon or rectum, primary
peritoneal or ovarian malignancies, and there are
indeed case reports and small series of PMP cases originating from most intra-abdominal organs,
including the stomach, pancreas, liver, gallbladder, urinary bladder and urachus [2,7].
The distribution of mucinous tumour implants within the peritoneal cavity is determined
by what has been termed “the redistribution phenomenon” [2,8]. Rupture of the primary tumour
results in release of free floating cells and mucin
which disseminate throughout the abdominal
cavity. The epithelial tumour cells have either
none, or low, adhesion properties and consequently distribute within the peritoneal fluid [8]. Characteristically cellular deposits accumulate, and
proliferate, in predetermined sites by two main
mechanisms, absorption of peritoneal fluid and
JBUON 2015; 20 (Suppl. 1): S48
Figure 1. Omental cake and mucinous ascites with
relative sparing of the small bowel.
Figure 2. Disease on the under surface of the right
diaphragm.
gravity. The physiology of the peritoneal cavity
involves production, circulation and absorption of
peritoneal fluid. The main sites of fluid reabsorption are the greater and lesser omentum (accounting for the classical “omental cake”, Figure 1) and
the undersurface of the diaphragm, particularly
the right side, resulting in tumour accumulation
in the subdiaphragmatic and suprahepatic regions
(Figure 2).
The second main mechanism is by gravity
with cell accumulation in dependent sites, such
as the recto-vesical pouch, the right retro-hepatic
space and the paracolic gutters [2,8].
Mobile organs such as the small bowel and
its mesentery are usually spared, particularly early on in the course of the disease. In contrast the
less mobile, partially retroperitoneal, ascending
and sigmoid colon, as well as the fixed points of
Management of pseudomyxoma peritonei
the stomach in its distal portion and the duodeno- jejunal flexure at the ligament of Treitz can
be heavily involved by disease and may warrant
bowel resections such as colectomy and distal
gastrectomy to remove troublesome deposits
(Figure 3 and 4).
The relative sparing of the motile small bowel and its mesentery allows complete removal of
tumour in most patients without the need for substantial small bowel resection.
Extensive small bowel involvement can occur
at an early stage in more aggressive tumours and
even in less invasive tumours when the disease
is at an advanced stage. Prior attempts at tumour
removal, particularly where extensive abdominal
surgery has been performed, can lead to tumour
proliferation in scar tissue and may involve the
small bowel at the sites of adhesions. Extensive
small bowel involvement, particularly if the disease involves the serosa or infiltrates at the junction of the small bowel with its mesentery, may
prevent a complete tumour removal.
In advanced cases, high volume disease and
mucinous ascites lead to compression of the gastrointestinal tract, bowel obstruction, and ultimately, starvation. More aggressive tumours can
lead to the involvement of the bowel at an earlier
stage.
Clinical presentation
In the early stages of PMP, many patients
have no symptoms. Even when the disease burden
is marked, abdominal symptoms can be vague.
Some patients may have been investigated with
luminal endoscopy and labelled with irritable
bowel syndrome.
The initial appendiceal tumour is commonly
asymptomatic, even when perforated, but suspected appendicitis is a common mode of presentation. Management of an unexpected appendiceal
neoplasm has been summarised elsewhere [9].
In 2000, Esquivel and Sugarbaker [10] looked
at 410 patients with appendiceal tumours. Overall
the most common presentations were suspected
appendicitis (27%), increasing abdominal distention (23%) and a new onset hernia (14%). In
women, the diagnosis was most commonly diagnosed after gynaecological investigation revealed
an ovarian mass. Computed tomography (CT) now
plays an increasingly important role in diagnosis.
We examined the mode of presentation of 222
patients undergoing surgery for PMP in Basingstoke in 2012 and 2013 [11]. Overall 36.5% of patients were diagnosed by preoperative CT alone
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Figure 3. Extensive disease encasing the stomach.
Figure 4. Following complete cytoreduction and partial gastrectomy prior to gastro-duodenal anastomosis.
Figure 5. CT image showing scalloping of the liver
from mucinous deposits..
JBUON 2015; 20 (Suppl. 1): S49
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Management of pseudomyxoma peritonei
and 14.4% by an abnormal CT that led to operative confirmation. 20.7% were diagnosed at laparoscopy or laparotomy with acute symptoms or
on histology after appendicectomy. An incidental
finding at surgery for a new onset hernia accounted for 5%.
Many reports suggest an increased incidence
in women but his may result from a lower threshold for abdominal imaging in women on suspicion of ovarian pathology resulting in both more
frequent and earlier diagnosis. In addition progressive ovarian involvement may lead to earlier
onset of symptoms.
In advanced cases, physical examination may
detect important clinical signs. Shifting dullness
of ascites suggest serous rather than mucinous
ascites. Mucinous ascites may be too dense to redistribute when the patient is repositioned. Large
ovarian masses and an omental cake are sometimes palpable. Disease in the rectovesical pouch
may be felt on digital rectal examination.
Investigations
A CT of the chest, abdomen and pelvis with
intra venous and oral contrast is the investigation
of choice [12]. Mucinous disease is typically represented by areas of low attenuation with islands
of high attenuation due to solid material within
the mucinous ascites. Tumour deposits on the visceral surfaces of the liver and spleen lead to the
classical appearances of “scalloping” on CT, distinguishing it from fluid ascites (Figure 5).
A striking feature of PMP is the relative sparing of the small bowel and its mesentery. In more
advanced cases this may lead to compartmentalisation of the small bowel in the central abdomen,
surrounded by a massive omental cake and mucinous ascites. Sparing of the small bowel and mesentery are essential for complete tumour removal.
Contrast enhanced CT can help predict the likelihood of successful cytoreductive surgery. Adverse
radiological features associated with small bowel
involvement include segmental obstruction and
tumour masses greater than 5cm on the small
bowel and its mesentery. When both features are
present there is an 88% probability of incomplete
resection compared with a 92% probability of
complete resection when both are absent [12].
Magnetic resonance imaging (MRI) in the
assessment of PMP has been proposed [13,14]
and appears promising but requires further evaluation. Positron emission tomography (PET) and
PET-CT have a limited role in the investigation of
low grade mucinous disease but may be of value
JBUON 2015; 20 (Suppl. 1): S50
in detecting extra-abdominal disease or liver metastases in patients with adenocarcinoma [15].
Serum tumour markers can provide useful
prognostic information in patients undergoing
surgery for PMP. CEA, Ca 125 and Ca 19.9 have
been found to have both diagnostic and predictive
value in some patients [16-18]. In a study of 519
patients who underwent complete tumour removal in Basingstoke, patients with normal tumour
markers had significantly higher disease free and
overall survival compared with patients with elevated tumour markers [19]. The number of elevated markers (0 –all three) correlated with a worse
outcome.
Tumour markers appear to provide prognostic information independent of histopathological
grading and may have a role in determining consideration of post-operative systemic chemotherapy and timing and frequency of follow-up.
When cross sectional imaging is equivocal or
tissue is required for histological confirmation,
laparoscopy and biopsy can be useful. Wherever
possible, laparoscopic ports should be positioned
in the midline, such that these sites can be excised
by a midline laparotomy wound to reduce the risk
of tumour seeding. With advanced or recurrent
disease, laparoscopic access and visualisation of
the peritoneal cavity can be difficult and dangerous and for PMP adds little in most cases.
Treatment
The optimal management of pseudomyxoma
peritonei is complete cytoreductive surgery (CRS)
in combination with hyperthermic intraperitoneal
chemotherapy (HIPEC). The aim of this strategy
is to remove all visible disease within the peritoneal cavity. The intraoperative HIPEC then targets
any residual microscopic disease, or small volume
macroscopic tumour nodules (<2.5mm) [20-22].
Completeness of cytoreduction has been shown to
be the most important prognostic factor.
With an average operating time of 9 hours
[23], CRS and HIPEC is a major surgical intervention. Specialised anaesthetic and perioperative
management is required. Positioning of the patient on the operating table requires experience
in order to allow full access to the abdomen and
perineum whilst minimising the risk of neurological compression and compartment syndrome.
The operation starts with a midline incision
from xiphisternum to symphysis pubis, excising
the umbilicus and any previous midline scar.
Once the abdomen is open a full assessment of
the disease can be made. We usually commence
Management of pseudomyxoma peritonei
with a right parietal peritonectomy and mobilisation of the right colon identifying the right
ureter and gonadal vessels. Providing there is
widespread disease, peritonectomy is continued
to perform a right diaphragmatic peritonectomy
with full mobilisation of the liver. If required, a
liver capsulectomy is performed with the help
of a ball tipped diathermy at maximal setting. A
high power smoke extraction system is essential
to remove the resulting smoke. The same procedure is repeated on the left side with a left parietal
peritonectomy, identification of the left ureter and
gonadal vessels and left diaphragmatic peritonectomy if required.
A radical greater omentectomy is performed
inside the gastro-epiploic arcade and the spleen is
assessed. If the spleen is involved with disease a
splenectomy is performed after full mobilisation.
Care is taken not to damage the tail of the pancreas. Dissection into the pelvis starts with mobilisation of the rectum in the mesorectal plane posteriorly. Anteriorly the peritoneum is dissected off
the bladder. The rectum and sigmoid colon can
usually be spared but in advanced disease, and
following prior pelvic surgery, an anterior resection may be required. In the female, the ovaries
are routinely removed. A hysterectomy may also
be necessary. An appendicectomy may be all that
is required to remove the primary tumour. If there
is extensive disease around the caecum or terminal ileum or if there is a likelihood of adenocarcinoma then a right hemicolectomy is performed.
In the upper abdomen, the lesser omentum
is removed from the lesser curve of the stomach
preserving the left gastric vessels. The dissection
continues to the porta hepatis, taking care to take
only the peritoneum and preserve the common
bile duct, hepatic artery and portal vein. Identification of the portal anatomy is aided by retrograde cholecystectomy. After mobilisation of the
liver, disease in the aorto-caval grove is removed.
The peritoneum between the caudate lobe, right
crus of the diaphragm and inferior vena cava is
removed. When there is a high volume of upper
abdominal disease a distal gastrectomy may be
necessary. In the series from Basingstoke this was
necessary in almost 10% of patients with PMP
who had a complete cytoreduction [22].
Once all visible tumour has been removed,
HIPEC is administered by a continuous infusion
of Mitomycin C (10mg/m2, with dose adjustments
for patients with renal impairment, significant abdominal distention, recent chemotherapy and older age) heated to 42 degrees for one hour. We use
an open method to administer the chemotherapy
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utilising a “coliseum” technique.
After HIPEC the abdomen is washed out and
any gastrointestinal anastomoses are performed.
If an anterior resection has been required a stapled
colorectal anastomosis is performed and routinely defunctioned with a loop ileostomy. Up to four
abdominal drains are inserted. It is our routine
practice to place chest drains if the diaphragmatic
peritoneum has been removed. Patients are managed post-operatively on an intensive care unit. In
some units early post-operative intra-peritoneal
chemotherapy (EPIC) is used. In Basingstoke selected patients receive 5-fluorouracil at 15mg/kg
for up to 4 days post-operatively via a tenckhoff
catheter.
If complete cytoreduction is not possible,
maximal tumour debulking (MTD) is performed.
MTD usually involves a greater omentectomy and
either an ileocolic anastomosis or a total colectomy and ileostomy.
Histopathological classification
The classification of pseudomyxoma peritonei
has been confusing. There have been a number of
different terminologies and classification systems
used for epithelial appendiceal neoplasms. In addition, the clinical presentation of PMP can also
result from high grade colonic mucinous neoplasms, adenocarcinoma of the appendix and mucinous adenocarcinomas originating from other
intra-abdominal organs. PMP of appendiceal origin is a best a borderline malignant condition but
more accurately represents a spectrum of disease
from low to high grade.
Different pathological classifications of PMP
have led to difficulties in the interpretation of
treatment outcomes. Some series include all cases
including those originating from adenocarcinoma
while some report only those arising from lowgrade appendiceal tumours.
In 1995, Ronnet et al. [24] produced the first
internationally recognised classification system
based on patients who had undergone cytoreductive surgery in Washington by Sugarbaker’s group.
They divided PMP into three categories: Disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA) and an
intermediate group. Bradley et al. [25] proposed
classification into two distinct categories, mucinous carcinoma peritonei low grade and mucinous carcinoma peritonei high grade. The former
incorporating DPAM and the intermediate group,
the latter PMCA, including cases that are moderately to poorly differentiated and those with sigJBUON 2015; 20 (Suppl. 1): S51
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Management of pseudomyxoma peritonei
net ring cell morphology.
A classification by the WHO in 2010 [26] divided PMP of appendiceal origin into low and
high grade. A review of over 270 cases by Carr
et al. [27], correlating histology with clinical findings and survival data found that categorisation
as either low grade or high grade correlated well
with prognosis. The Peritoneal Surface Group International is working with the leading pathologists on appendiceal tumours to reach a consensus on this classification.
The pathological classification is important
as it provides an indication of prognosis following CRS and HIPEC. Patients with low grade PMP
appear to gain maximal benefit.
Outcomes of CRS and HIPEC
Surgery for pseudomyxoma peritonei traditionally involved repeated debulking for symptomatic relief with limited expectation of long
term survival and no prospect of cure. The lack
of a successful treatment strategy and the rarity
of PMP meant that historical series were small
and selective. In a series from the Mayo Clinic, between 1957 and 1983, Gough and colleagues [28]
reported a 32% 10-year survival in 56 patients
who underwent serial debulking and selective intraperitoneal radiotherapy or chemotherapy.
The modern management strategy of CRS and
HIPEC was developed and popularised by the work
of Paul Sugarbaker and colleagues at the Washington Cancer Institute [29]. In 1999 Sugarbaker
et al. [21] published as series of 385 patients, 205
of which received HIPEC. Complete cytoreduction
was associated with 5 year survival of 80% compared to 20% in whom macroscopic tumour removal could not be achieved. What has come to be
known as the “Sugarbaker procedure” is now the
accepted standard of care with subsequent series
confirming the efficacy of CRS and HIPEC. Disease
or progression free survival of 75%, 56-70% and
67% at 1 year, 5 years and 10 years respectively
and overall survival of 69-75% at 5 years, 57% at
10 years have been reported [22,30-33].
Completeness of cytoreductive surgery is a
major predictor of outcome independent of histological grade. The completeness of cytoreduction
is assessed after surgery with no visible tumour
is graded as CC-0 and residual disease and with
no nodule greater than 2.5mm as CC-1. Residual
disease nodules between 2.5mm and 2.5cm correspond to CC-2 and greater than 2.5cm CC-3 [34].
Scores of CC-0 and CC-1 are taken to represent
complete cytoreduction with significantly betJBUON 2015; 20 (Suppl. 1): S52
ter reported outcomes than seen in patients with
CC-2 or CC-3 residual disease.
With an incomplete cytoreduction (CC-2 and
CC-3), or major tumour debulking, the 5 year
survival was 24%. This is compared with 85% in
patients with CC-0 and 80% with CC-1 complete
cytoreduction [23]. The ability to achieve a complete cytoreduction may depend upon the extent
of disease and histological grade. As previously
discussed, involvement of the small bowel and
mesentery remain the major limiting factors.
Previous surgery, particularly attempts at partial
debulking, can reduce the chances of complete cytoreduction with compromise of the natural peritoneal barrier and entrapment of tumour within
scar tissue and adhesions [35].
Although complete cytoreduction is the optimal treatment, where it is not possible, maximal
tumour debulking, usually involving a greater
omentectomy, colectomy and end ileostomy can
produce good palliative results and even long
term survival in a small number of patients. In a
recent series, Dayal et al. [5] reported 748 consecutive patients who underwent surgery for PMP in
Basingstoke, 205 of whom received maximal tumour debulking. Overall survival was 47%, 30%
and 22% at 3, 5 and 10 years compared with 90%,
82% and 64% in those who received complete cytoreduction.
Morbidity and mortality
CRS and HIPEC is a complex surgical intervention and carries a significant risk of complications including anastamotic leakage, intra-abdominal abscesses, small bowel and pancreatic
fistulae, respiratory infections and venous thromboembolism. Operating times are long, averaging
around 9 hours and can result in significant blood
loss. Neutropenia and associated sepsis are recognised complications of intraperitoneal chemotherapy.
Reoperation rates for post-operative complications have been reported to range from 11% [36[
to 21% [37] and 30 day mortality from 0% to 14%
[38].
It is now clear that the learning curve for surgical units performing complex procedures like
CRS and HIPEC can have a major impact on outcomes [39]. Initial high morbidity and mortality is
seen to decrease with increasing experience and
this is likely to represent improvement in patient
selection and postoperative management as well
as surgical expertise.
Management of pseudomyxoma peritonei
Follow-up
The rational for active follow-up is the ability to detect and treat recurrent disease. Elective
reoperation for recurrent disease is beneficial for
selected patients. Esquivel and Sugarbaker [40]
reported 5 year survival of 74% in selected patients with recurrent PMP of appendiceal origin
who underwent repeat CRS and HIPEC. Mohamed
et al. [41] reported 5 year survival of 70% from the
initial operation in selective patients who had 3 or
more attempts at CRS and HIPEC.
Our practice involves CT scanning and serum
tumour markers at one year post-operatively and
annually thereafter for 10 years. Earlier imaging
can be employed if symptoms develop or a high
suspicion of recurrence exists. This strategy has
developed due to the fact that early recurrence after complete cytoreduction is likely to represent
aggressive, rapidly progressive disease, unlikely
to be amenable to salvage surgery. In early recurrent disease and particularly in high grade PMP,
systemic chemotherapy is advocated by some although strong evidence is lacking.
Patients likely to benefit from further CRS
and HIPEC are those with slowly progressive disease. As such, a policy of watch and wait can be
S53
employed with low volume or stable recurrence
with the option of reoperation with evidence of
progression or development of symptoms.
The optimal strategy for follow-up has yet to
be defined and as the experience from large international units develops and the follow-up data
matures this will provide fertile ground for future
research.
Conclusions
Pseudomyxoma peritonei is an uncommon
condition that classically originates from a ruptured mucinous appendiceal neoplasm. It is, at
best a borderline malignancy and with a spectrum of disease from low grade to high grade and
adenocarcinoma. The optimal treatment for PMP
is complete cytoreduction combined with hyperthermic intra-peritoneal chemotherapy. This is a
major surgical intervention and requires careful
patient selection and perioperative management
to minimise morbidity and mortality and should
be performed in experienced centres.
The treatment PMP has become a model for
other peritoneal malignancies, particularly peritoneal mesothelioma and selected patients with
colorectal peritoneal metastases.
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