Appendiceal Mucinous Neoplasms: From Clinic to Pathology and Prognosis

Abstract

Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing a prognosis of the disease. A historical perspective of the different classification systems of these tumors is essential for the understanding of the evolution of concepts and histopathological definitions that have led up to the present moment. We carried out a systematic review of the pathological classifications of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging have made a great effort to incorporate the new pathological descriptions and develop prognostic groups. The introduction of these new classification systems has posed the challenge of verifying how they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria and concluded that both classifications correspond well with the OS and DFS of these patients, with some advantage relative to the PSOGI classification due to a better histopathological description of the different groups.

Full text

Citation: González Bayón, L.; Martín
Román, L.; Lominchar, P.L.
Appendiceal Mucinous Neoplasms:
From Clinic to Pathology and
Prognosis. Cancers 2023,15, 3426.
https://doi.org/10.3390/
cancers15133426
Academic Editor: Marc Pocard
Received: 19 April 2023
Revised: 20 June 2023
Accepted: 26 June 2023
Published: 30 June 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cancers
Review
Appendiceal Mucinous Neoplasms: From Clinic to Pathology
and Prognosis
Luis González Bayón1, 2, *,† , Lorena Martín Román1 ,2 ,*, † and Pablo Lozano Lominchar 1,2
1Peritoneal Carcinomatosis Unit, Department of General Surgery, Hospital General Universitario Gregorio
Marañón, 28007 Madrid, Spain; pablo.lozano@salud.madrid.org
2Faculty of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
*Correspondence: lgbayon@salud.madrid.org (L.G.B.); lore_metro@hotmail.com (L.M.R.);
Tel.: +34-6-3061-2308 (L.G.B.)
† These authors contributed equally to this work and are co-first authors.
Simple Summary:
The cecal appendix is known to the general population because it is where acute
appendicitis develops and it usually needs a surgical intervention for treatment. However, it is also
the place of origin of tumors with special behavior. Those tumors are uncommon and generate
specific clinical situations, such as the mucocele or the pseudomyxoma peritonei syndrome, which
are the subject of much debate regarding definitions and pathologic classification. There is great
interest in achieving a common language for these tumors that will allow the sharing of research and
treatment results which will improve the existing information and management of our patients.
Abstract:
Appendiceal mucinous neoplasms have been classified differently over time causing
confusion when comparing results between working groups in this field and establishing a prognosis
of the disease. A historical perspective of the different classification systems of these tumors is
essential for the understanding of the evolution of concepts and histopathological definitions that have
led up to the present moment. We carried out a systematic review of the pathological classifications
of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical
and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging
have made a great effort to incorporate the new pathological descriptions and develop prognostic
groups. The introduction of these new classification systems has posed the challenge of verifying how
they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified
our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria
and concluded that both classifications correspond well with the OS and DFS of these patients, with
some advantage relative to the PSOGI classification due to a better histopathological description of
the different groups.
Keywords:
mucocele; pseudomyxoma peritoneal; mucinous appendiceal neoplasm; cytoreductive
surgery; HIPEC; acellular mucina
1. Introduction
The cecal appendix is a remnant organ with an unknown function in humans. It does
not exist in carnivorous or herbivorous animals but it does in omnivores. The mucosa of
the appendix has a colonic-type columnar epithelium with neuroendocrine cells and mucin-
producing goblet cells. The submucosa is rich in lymphatic tissue, which suggests that it
may play a part in the immune system. Another functional hypothesis of the appendix is
that it is a reservoir of good intestinal bacteria contributing to the maintenance of normal
intestinal flora [
1
]. It is such that a relationship has been found between appendectomy
and the development of colorectal carcinoma based on the alteration of the microbiome [
2
].
Cancers 2023,15, 3426. https://doi.org/10.3390/cancers15133426 https://www.mdpi.com/journal/cancers

Cancers 2023,15, 3426 2 of 24
Acute appendicitis is the most frequent pathology that develops in the cecal appendix.
However, the appendix is also the origin of tumors that display special behavior. The
most frequent tumors that develop in the appendix are mucinous tumors. These tumors
have been associated with specific clinical conditions such as mucocele or pseudomyxoma
peritonei syndrome (PMP). However, both of these terms are subject to much debate since
they have been widely used as pathological terms throughout the literature, resulting in
confusion and overlapping terminology surrounding the pathological classification of these
tumors. Currently, the term mucocele of the appendix can be used to describe the radiologi-
cal or clinical finding of a dilated appendix. It results from the intraluminal accumulation of
mucin secondary to either a mucinous tumor, or less commonly, an inflammatory obstruc-
tion. Mucoceles of the appendix represent a common way of presenting mucinous tumors
of the appendix. Secondly, the term PMP is used to describe the clinical entity characterized
by the accumulation of mucin within the peritoneal cavity. The most common origin of
PMP has been established to be mucinous tumors of the appendix, however, PMP can also
be the result of peritoneal dissemination (PD) from a mucinous tumor of the ovary or other
organs in the abdominal cavity (pancreas, gallbladder, colon, urachus
. . .
). Therefore, the
term PMP is no longer accepted as a pathological diagnosis.
The gold standard treatment for mucinous appendiceal neoplasms with PD is cy-
toreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC),
which has substantially changed the prognosis of these patients but must be performed in
specialized centers [3,4].
Despite optimal treatment with CRS + HIPEC, there is a wide range of clinical out-
comes; some patients achieve excellent outcomes (i.e., high cure rates and low recurrence
rates) while others show very aggressive behavior with early recurrences and limited
survival. Prognosis is mainly determined by the histopathological features of the primary
tumor and peritoneal deposits. However, determining prognosis has been complicated
by the several classification systems available since the 1990s as a result of the constant
evolution of pathological definitions. These have generated confusion amongst treating
physicians and made the comparison of treatment results difficult. In addition, the corre-
lation between prognosis and histology is not always accurate; this has encouraged the
search for new indicators of biological aggressiveness.
In this article, we want to review clinical aspects and management guidelines of
mucinous neoplasms of the appendix and PMP, and to expose the investigations carried
out by our group on the mucinous neoplasm of the appendix:
–
A systematic review providing a historical perspective on the evolution of the differ-
ent classification systems of these tumors published since the 1990s up to the 2016
Peritoneal Surface Oncology Group International (PSOGI) consensus, the 2017 AJCC
8th edition, and the 2019 WHO classification.
–
A pathological review of our series to the adoption of the PSOGI and AJCC 8th edition
classification criteria in order to evaluate which classification system best reflects the
prognosis of our cohort of patients.
2. Review Sections
2.1. Clinical Aspects
The conflict with mucinous lesions of the appendix starts in the clinic with the finding
of an appendiceal mucocele. Rokitansky described, for the first time, the appendiceal
mucocele [
5
], which is a clinical (currently radiological), surgical, or autopsy description
of a dilated appendix by mucinous secretions retained due to an obstructed lumen. The
cause of the obstruction is key. If secondary to chronic inflammation (fecalith, parasites,
lymphoid hyperplasia,
. . .
) without signs of epithelial hyperplasia or neoplasia, it is a
simple retention cyst (non-neoplastic mucinous appendiceal lesion) that can rupture and
release mucin into the peritoneal cavity without developing PMP [
6
]. If, however, the
obstruction is caused by an epithelial hyperplasia or neoplasia, with/without an associated

Cancers 2023,15, 3426 3 of 24
epithelial degeneration process (adenomas, serrated lesions or mucinous neoplasm), then
it is considered a neoplastic mucinous appendiceal lesion [7].
The other clinical debate surrounds PMP. PMP is a rare clinical entity characterized
by the progressive accumulation of mucin throughout the peritoneal cavity, most likely
resulting from a perforated mucinous neoplasm of the appendix [
8
]. Classically, it was
diagnosed by the finding of a “jelly belly” at laparotomy (abdomen filled with mucinous
ascites). The term PMP was initially introduced by Wert [
9
] in 1884 describing a case
of mucinous ascites in the setting of a mucinous ovarian neoplasm. In 1901, Frankel
described a similar case arising from a cyst or mucocele from the appendix [
10
]. PMP
progresses in an indolent manner, being asymptomatic to mildly symptomatic with diffuse
unspecific abdominal pain. Due to this, it is often found incidentally in patients undergoing
radiological investigations or surgery for other reasons. Localized disease is frequently
found in the setting of acute appendicitis, or investigations for right iliac fossa pain that
may reveal a pelvic mass secondary to a dilated appendix or localized mucinous deposits.
In cases of advanced disease, the classical clinical picture of a “jelly belly” can be observed.
In these cases, patients have an increase in abdominal girth caused by the accumulation of
mucinous ascites. Often, this is accompanied by the onset inguinal and umbilical hernias
that appear as a consequence of increased intraabdominal pressure. Episodes of bowel
obstruction may occur as a result of small bowel involvement representing the final stages
of the disease. Disease progression leads to gradual abdominal distension and intestinal
sub-occlusion, emaciation, and the impossibility of nutrition by mouth [
11
]. The surgical
treatment used to be indicated late and generally consisted of an evacuation of mucin with
the usual macroscopic tumor residue. Some patients had to undergo surgery every year
to evacuate mucus, reaching a deadly situation of the impossibility of more mucinous
evacuation due to visceral impregnation (solid tumors surrounding intestines, stomach,
liver, spleen, bladder...etc.).
In 2000, Esquivel and Sugarbaker [
12
] evaluated the most common presentations
of PMP in their series of 217 patients: acute appendicitis (27%), followed by abdominal
distension (23%), vague abdominal pain (17%), or diagnosis of new onset hernia (14%).
A large population-based study from the Netherlands’ nationwide pathology database
(Pathologic Anatomic National Automatic Archive, PALGA) found the incidence of PMP
to be estimated at 2 per million inhabitants per year, with a certain predominance of
women [
13
]. The incidence of appendiceal mucinous tumors (LAMN and HAMN) may
be higher in interval appendectomy specimens from adults [
14
]. Alarming rates have
been described in a recent randomized clinical trial performed in the Netherlands where
an appendiceal mucinous neoplasm was found in 20% of cases above the age of 40 with
a previous periappendiceal abscess [
15
]. A meta-analysis found a pooled prevalence of
appendiceal neoplasms at interval appendectomy after an episode of complicated appen-
dicitis of 11% (95% CI 7–15%) [
16
]. In this setting, the most frequent type of appendiceal
primary tumor found was mucinous neoplasm (43%). A recent population-based study
from the SEER database identified that the risk of appendiceal adenocarcinoma or PMP
was significantly higher in patients with a periappendiceal abscess (OR 15.05, p< 0.0001,
perforated appendicitis (OR 4.09, p= 0.0018), and patients above the age of 40 (OR 26.46,
p< 0.0001) [17].
2.2. Endoscopy and Imaging Modalities
Many patients end up having an endoscopic evaluation of the digestive track as
part of the investigations carried out for vague abdominal symptoms. Endoscopies are
inevitably normal though the presence of seeping mucin through the appendix orifice can
be pathognomonic but infrequently seen. In the setting of PMP or an incidental finding of
a mucinous neoplasm, the European and American guidelines recommend an endoscopic
evaluation in order to rule out the presence of synchronous colorectal neoplasia [
3
,
4
]. A
German multicenter study described rates of synchronous colorectal neoplasia in 8.9% of
patients with a mucinous neoplasm of the appendix [18].

Cancers 2023,15, 3426 4 of 24
The most commonly used diagnostic modality for PMP is the computed tomography
scan (CT) of the chest, abdomen, and pelvis with an intra-venous and oral contrast. The
PMP expert panel agreed with a 96,4% consensus that CT imaging is the preferred preoper-
ative imaging modality [
3
]. The benefits of CT imaging include its accessibility, low cost,
and easier interpretation by radiologists not experienced in peritoneal malignancies.
The classical radiologic features of PMP include omental caking, mucinous ascites,
and scalloping of the liver [
19
]. These features, however, are only present in the setting
of an advanced disease. CT imaging can also reveal a mucocele of the appendix, which
refers to the radiological image of a mucin-filled and distended appendix that may be
accompanied by peripheral calcification. In the setting of acute appendicitis, a retrospective
study including 65 patients reported a sensitivity of 95% in the detection of appendiceal
tumors using CT imaging when taking morphologic criteria (i.e., cystic dilation or presence
of a soft tissue mass) or an appendiceal diameter greater than 15 mm [20].
On the other hand, the detection of peritoneal disease represents an ongoing challenge
with current imaging techniques. The detection of peritoneal deposits is determined by
their size and location. The sensitivity of CT to detect lesions greater than 5 cm ranges
from 59–94% but drops to 19–28% in lesions smaller than 1 cm and to 11–28% in lesions
smaller than 0.5 cm [
3
,
21
]. Sensitivity also depends on the involved area. To elaborate, one
retrospective study found that lesions in the ileocecal area had the lowest sensitivity for
detection (11–28%), followed by lesions in the right subdiaphragmatic area (11–22%) and
the omentum and transverse colon (25%). The detection rate of lesions in the small bowel
and/or its mesentery ranges from 18 to 55% [22].
Recently, the use of diffusion-weighted magnetic resonance imaging (DW-MRI) has
been shown to improve both sensitivity and specificity in the detection of peritoneal
metastasis with a sensitivity of 85–90% in cases of peritoneal deposits smaller than
1 cm [23]
.
A study published by Low et al. comparing preoperative MRI with CT reported that
MRI predicted tumor volume accurately in 91% of the patients and CT only in 50% [
24
].
Additionally, MRI was able to detect diseases in the small bowel in 92% of the cases whereas
CT did so in only 48%. These findings were backed up by the results from a larger study that
also highlighted that MRI requires experienced radiologists for its accurate interpretation,
especially when evaluating the small bowel [25].
The presence of disease in certain locations is associated with a worse prognosis due
to the reduced likelihood of achieving optimal CRS. These locations are the small bowel
and/or its mesentery, the porta hepatis and hepatoduodenal ligament, ureteric encasement,
and biliary obstruction [
26
]. Such observations led to the study and development of
radiologic scores to predict the resectability of the disease. One example of these scores is
the simplified preoperative assessment for appendix tumors (SPAAT) score [
27
]. This score
was developed to predict the ability of complete CRS in patients with low-grade peritoneal
disease originating from the appendix based on the following findings on preoperative
CT imaging: scalloping of the liver, pancreas, spleen, or portal vein (1 point each) and the
presence or absence of mesenteric foreshortening of the small bowel (from 0 to 3 points).
The score was externally validated on a larger cohort with a score of <3 accurately predicting
a complete CRS in 97.1% of the cases. Another example is the simplified radiographic score
(SRS) [
28
]. This score takes into consideration the thickness of the disease (measured in
millimeters) in five regions of the upper abdomen (inferior vena cava to the portal vein,
right hepatic lobe to left hepatic lobe, left hepatic lobe to lesser sac, Spiegel lobe to left
hepatic lobe, and Spiegel lobe to right crus). A sum greater than 28 mm predicts incomplete
CRS with a positive predictive value of 85% and a negative predictive value of 59% in their
validation cohort. The discriminative capacity of these scores has been further investigated
by other study groups. The usefulness of the SPAAT score was questioned after observing
a positive predictive value of 50% with a sensitivity of 40%, even though the cut-off of
three was associated with optimal CRS in the binary regression model [
21
]. A second study
group aimed to evaluate the utility of both scores and observed positive predictive values
of the SPAAT and SRS scores of 67% and 75%, respectively [29].

Cancers 2023,15, 3426 5 of 24
These scoring systems, however, have not been widely adopted and there still exists a
lot of variability in the reporting of radiologic imaging of patients with peritoneal disease.
With the aim of standardizing reporting, the Peritoneal Malignancy Institute in Basingstoke
proposed the PAUSE method [
30
]. This acronym stands for P: PCI score; A: abdominal
wall and ascites; U: unfavorable sites of disease (periportal, the root of mesentery, ligament
of Treitz, pelvic side wall disease, and disease involving the sacrum); S: small bowel and
mesenteric disease; and E: extraperitoneal disease. Following this method, the radiology
report will contain information that will aid in the selection of patients who will benefit
from CRS + HIPEC at the MDT as well as facilitating research across different centers.
2.3. Tumor Markers
The prognostic implication of tumor markers in PMP has been broadly studied by
different study groups over the course of time. The tumor markers associated with PMP
are the carcinoembryonic antigen (CEA), cancer antigen 19-9 (Ca19-9), and cancer antigen
125 (Ca-125). The results obtained have not been homogeneous across the different study
groups. However, current guidelines [
3
,
4
] recommend tumor markers to be included as
part of the preoperative work-up for these patients.
The elevation of all three tumor markers has been associated with a higher volume of
disease [
31
] and with a reduced probability of achieving optimal CRS [
32
,
33
]. The study
group from the peritoneal malignancy unit in Milan concluded that preoperative CEA,
Ca19-9, and Ca-125 could be used as predictors of optimal CRS [
33
] and reported that
Ca19-9 and Ca-125 were more powerful predictors of prognosis than histology. Similar
findings were observed by the study group in Sydney [
34
]. The elevation of tumor markers
preoperatively has also been associated with shorter OS and DFS outcomes [
32
,
35
]. CEA
elevation has been associated with shorter DFS [
36
], whereas other study groups found
Ca19-9 to be a predictor of shorter DFS [34,37].
2.4. Preoperatory Hystology
Increased awareness of appendiceal PMP and developments in cross-sectional imaging
has increased the detection capacity of appendiceal lesions. Therefore, it is currently under
debate whether histological confirmation is necessary in the setting of typical radiological
findings [
3
,
4
,
38
]. In case of diagnostic doubt, histological confirmation is recommended,
preferably by means of diagnostic laparoscopy or core needle biopsy. Fine needle aspiration
usually fails to sample representative tissue and frequently results in acellular mucin.
Exploratory laparoscopy should be carried out in a referral center and by placing the
ports in a midline position [
38
]. The advantages of laparoscopy include the possibility
of taking a proper biopsy under direct vision, assessment of small bowel and mesenteric
involvement, and an estimation of the PCI score. European guidelines do highlight that
staging with a proper evaluation of the small bowel and its mesentery plays an important
role in patients with a high-grade disease where initial treatment with systemic chemother-
apy (SCT) might be indicated [3].
2.5. Peritoneal Dissemination
Primary mucinous appendiceal neoplasms have a tendency to disseminate to the
peritoneum. PMP is characterized by the “redistribution phenomenon”, a term introduced
by Sugarbaker to explain the accumulation of mucin at predetermined anatomical sites and
its absence at others [
39
]. The most widespread model of how PMP develops is through the
rupture of an appendiceal mucinous neoplasm allowing mucinous material with or without
neoplastic cells to access the peritoneal cavity (transcoelomic spread). Consequently, the
mucin and cells enter the peritoneal fluid circulation in a clockwise direction as dictated by
the peristaltic movement of the gastrointestinal tract, the effects of gravity, and the suction
effect of the movement of the diaphragms [
40
]. Mucus accumulation occurs in sloping areas
of the abdominal cavity (Douglas pouch) and in areas of intraperitoneal fluid reabsorption
(diaphragms and greater omentum).

Cancers 2023,15, 3426 6 of 24
Tumor implantation is the next step of the peritoneal metastatic cascade. For this,
tumor cells have to reach the submesothelial space to develop a tumor growth colony
(peritoneal implant). A total of two mechanisms have been described for this: the transme-
sothelial route and the translymphatic route. In the transmesothelial route, free cancer cells
attach to the mesothelium through adhesion molecules (CD44, integrins, selectins, etc.),
liberating cytokines (interleukins, EGF, HGF,
. . .
) that induce the contraction of mesothelial
cells exposing the submesothelial basement membrane [
41
,
42
]. This allows tumor cells
to adhere to the submesothelial plane through integrins and promote stromal invasion
by releasing metalloproteinases [
43
]. Jayne et al. suggested that tumor cells provoke the
apoptosis of mesothelial cells, which they confirmed with DNA fragmentation [44].
On the other hand, in the translymphatic route, free cancer cells gain access to the
subperitoneal lymphatic space through lymphatic stomata. Lymphatic stomata are open-
ings between mesothelial cells that are communicated with lymphatic capillaries where
peritoneal fluid reabsorption takes place. These areas contain many macula cribiformis
in the underlying connective tissue with a lot of oval foramina where the submesothelial
space is exposed [
45
]. Associated with lymphatic stomata are other structures named milky
spots which consist of macrophages, lymphocytes, and plasmatic cells supported by blood
and lymphatic vessels that surround stomata in specific places such as greater omentum,
appendices epiploic of the colon, diaphragm, falciform ligament, Douglas pouch, and the
interface of small bowel mesentery with the intestinal tube. These structures, lymphatic
stomata, macula cribiformis, and milky spots seem to play a role in the translymphatic
route that seems to be the main way of peritoneal implantation in PMP [
46
,
47
]. The other
main conditioning factor of the redistribution phenomenon is gravity, explaining why
tumor aggregates are commonly found in the pouch of Douglas, the paracolic gutters, and
the retrohepatic space [48].
2.6. CRS + HIPEC
In the past, peritoneal carcinomatosis was considered to be an incurable condition
identical to that of distant metastases. Lack of response to the systemic treatments available
at the time led to the development of aggressive locoregional treatments based on the
hypothesis that peritoneal carcinomatosis is a loco-regional disease. In 1979, the first CRS +
HIPEC procedure was performed by John Spratt on a PMP patient [
49
] at the University of
Louisville, Missouri. Spratt was working on dog models of peritoneal carcinomatosis and
had designed a hyperthermic chemotherapy peritoneal perfusion machine. The patient
was a 35-year-old man who had a 2-year history of abdominal distension and had been
diagnosed with PMP during a laparotomy. The histopathological study showed a mucin-
producing low-grade adenocarcinoma of unknown origin. The patient asked Spratt to
be the first case to undergo CRS + HIPEC. The procedure performed was an extensive
cytoreduction followed by the intraperitoneal perfusion with 105 mg of thiotepa at
42 ◦C
over 15 min with the abdomen closed. The intraperitoneal perfusion procedure was
repeated 5 days later with 75 mg methotrexate over 30 min. The postoperative period
was uneventful and the pathologist finally identified the PMP to be originating from the
pancreas. No subsequent follow-up is known.
The combination of CRS + HIPEC has been established to be the standard of care
for PMP patients as per the recently published European [
3
] and American treatment
guidelines [
4
]. Given the low incidence of PMP, randomized controlled trials evaluating
the benefit of CRS + HIPEC in this setting are missing. Therefore, evidence supporting
the use of CRS + HIPEC is mainly based on results from retrospective series. Concerns
regarding the use of CRS + HIPEC were raised after the results of the PRODIGE-7 trial were
published, where adding HIPEC with oxaliplatin to CRS of peritoneal metastases from
colorectal cancer did not provide any survival advantage but did increase postoperative
morbidity [
50
]. This triggered the need to investigate the efficacy of HIPEC treatment in
PMP patients. A large multicenter cohort study from the PSOGI registry included patients
with PMP treated with CRS alone (n= 376) or CRS + HIPEC (n= 1548) and concluded

Cancers 2023,15, 3426 7 of 24
that HIPEC was associated with better survival outcomes (hazard ratio (HR) 0.65 (95% CI
0.50–0.83), p= 0.001) without an increased risk of morbidity throughout the entire series
(HR 0.94 (95% CI 0.65–1.37), p= 0.76) [51].
Nonetheless, CRS + HIPEC is a complex procedure with associated morbidity and
mortality rates that cannot be overlooked. Performance status and the frailty of patients
have to be evaluated [
52
]. Recent prospective randomized trials have estimated severe
morbidity and mortality rates to stand between 25–27% and 0–2%, respectively [
50
,
53
].
In the setting of PMP, a recently published meta-analysis including 13 studies reported
a major complication rate (Clavien-Dindo
≥
3) for 1747 patients of 32.9% (95% CI 30.5
to 35.4%) [
54
]. Therefore, careful patient selection is vital. The decision to proceed with
CRS + HIPEC must take place at a multidisciplinary meeting with an expert radiologist,
pathologist, surgical oncologist, and medical oncologists in order to aid individualized
treatment strategies.
2.7. Systemic Chemotherapy (SCT)
The role of SCT in the treatment of patients with PMP is unknown. There exists an
overall lack of evidence regarding SCT treatment in terms of selecting which patients would
benefit from it and which regime. This task is made difficult by the overlapping and confus-
ing terminology that surrounded this pathological entity in the past, and its low incidence
that obstructs the possibility of conducting randomized clinical trials. Additionally, experts
recommend the use of the same treatment regimens approved for colorectal cancer [
55
],
even though the natural course, biological, and molecular profile are different [56,57].
Of note, one important contribution is the result of a large retrospective analysis
using the National Cancer Database (NCBD) including 5971 mucinous tumors of the
appendix [
58
]. Their relevant observation was that SCT benefited stage IV patients with
moderately (median OS 2.99 vs. 1.64 years, p= 0.0005) and poorly differentiated diseases
(1.57 vs. 1.02, p= 0.0007) but did not influence those with well-differentiated diseases [
58
].
Reinforcing this, a later publication using the NCDB including only patients with metastatic
low-grade mucinous appendiceal adenocarcinoma showed no survival advantage when
SCT was associated with the treatment of these patients [
59
]. These results have dictated
recommendations in treatment guidelines. Both the European [
3
] and North American
guidelines [
4
] do not recommend the use of SCT in low-grade diseases but contemplated the
use of SCT in high-grade diseases in the neoadjuvant and adjuvant settings, although, it is
specified that the level of evidence to support these recommendations is low. The guidelines
coincide in favoring neoadjuvant SCT in cases with initially unresectable diseases.
There have been few studies investigating whether neoadjuvant SCT provided any
survival benefit in the treatment of PMP with some disparity among the results. Optimistic
results were reported by Bijelic et al. [
60
]. The rate of histologic responses observed in
this retrospective series of high-grade PMP patients was 29%; this was associated with
improved OS (p= 0.003). Neoadjuvant SCT was also associated with lower PCIs (19 vs. 28,
p= 0.003). Additionally, Spiliotis et al. [
61
] published higher OS and DFS in high-grade
PMP patients following neoadjuvant SCT and CRS + HIPEC (median OS 19 vs. 10 months,
p= 0.042 and median DFS 10 vs. 0 months, p= 0.039). However, a similar study by Turner
et al. [
62
] reported a radiological response rate of 58% that did not translate into significant
changes in the PCI, CC score, or survival outcomes. Lieu et al. [
63
] analyzed the subgroup
of patients with poorly-differentiated PMP with SRC and observed improved DFS rates
with SCT. Milovanov et al. [
64
] described a 3-year OS of 22% with SCT vs. 14% without
SCT; p= 0.028.
On the other hand, the study by Votanopoulos et al. [
65
] found preoperative SCT
treatment to be a factor in a worse prognosis for both low-and high-grade PMP patients.
Recently, a report from the Aerospace Center Hospital, Beijing, China, on 750 patients
with PMP treated with CRS + HIPEC also concluded that preoperative SCT was associated
with worse survival outcomes in low-grade PMP patients, PCI < 20, and optimal CRS.

Cancers 2023,15, 3426 8 of 24
In addition, it did not provide any survival advantage in patients with high-grade PMP,
PCI > 20, or in cases of suboptimal CRS [66].
The results from studies evaluating the effect of adjuvant SCT are similarly inconclu-
sive. Blackham et al. [
67
] investigated the effect of perioperative SCT in the treatment of
low- and high-grade PMP patients. The results were that the SCT response rate observed
in low-grade PMP was 0%. In cases of high-grade PMP, the DFS was higher in patients
receiving adjuvant SCT (13.6 vs. 7.0 months, p= 0.03) but did not translate into an improve-
ment in OS (36.4 vs. 19.4 months, p= 0.14). Therefore, they concluded that high-grade PMP
patients could benefit from the use of adjuvant SCT and would recommend using SCT in
the neoadjuvant setting only in borderline resectable cases. These same recommendations
can be seen in the European and North American guidelines [4].
2.8. Pathology
The development of classification systems for PMP based on histopathological find-
ings and prognosis has been challenged by the existence of confusing and overlapping
terminology.
In 1995, Ronnet et al. [
68
] published their pivotal study where three different patho-
logical subgroups with their respective prognoses were defined. Disseminated peritoneal
adenomucinosis (DPAM) was used to refer to peritoneal lesions formed by abundant ex-
tracellular mucin and scant epithelial cells with little atypia or mitotic activity. Peritoneal
mucinous carcinomatosis (PMCA), on the other hand, was used to describe peritoneal
lesions composed of abundant mucinous epithelium, with high mitotic activity and cyto-
logical features of carcinoma. An intermediate category grouped lesions with discordant
characteristics (PMCA-I/D) with features of DPAM and PMCA. Patients with DPAM had a
significantly better prognosis than those with PMCA-I/D or PMCA (age-adjusted 5-year
OS rates were 84% versus 37.6% and 6.7% respectively; p< 0.0001).
In 2003, Misdraji et al. [
69
] introduced the term LAMN to describe primary muci-
nous lesions of the appendix with a pushing invasion that could perforate the wall of
the appendix and disseminate through the peritoneal cavity, unlike the adenocarcinoma
(MACAs) that presented an infiltrative invasion. LAMNs showed low-grade cytologic
atypia (rare mitotic figures, nucleomegaly, and scarce nuclear stratification) and minor
architecture complexity (flat epithelial proliferation and small papillary excrescences).
Conversely, mucinous adenocarcinomas of the appendix (MACA) were depicted by the
infiltrative invasion of the appendiceal wall with high cytologic atypia (full-thickness
nuclear stratification, vesicular nuclei, prominent nucleoli, nuclear membrane irregular-
ities, and brisk mitotic activity). When there was PD, they defined a two-tiered system:
LAMN involving the peritoneum with a better prognosis and MACA involving the peri-
toneum (
5-year OS 86 vs. 44%
;
p= 0.04
). The presence of SRCs was an exclusion criterion
from the study.
Subsequently, Bradley and colleagues [
70
] reviewed the histology of 101 cases of
PMP to assess the prognostic implications of Ronnet’s three-tiered classification. DPAMs,
previously attributed to adenomas in Ronnett’s classification, were credited with primary
LAMNs whereas PMCAs (high-grade atypia and/or SRC) were associated with moderate
or poorly differentiated appendiceal adenocarcinomas. They did not find differences
between the survival outcomes of the DPAM and PMCA-I groups. However, the PMCA
group did have a significantly worse 5-year OS. Therefore, they proposed a two-tiered
classification system whereby SRCs were included in the PMCA subgroup. The terminology
they advocated for was low-grade mucinous carcinoma peritonei (MCP-L) and high-grade
mucinous carcinoma peritonei (MCP-H).
Primary appendiceal tumors were classified into LAMN, MACA, SRC carcinoma, and
undifferentiated appendiceal carcinoma in the WHO 4th edition 2010 [
71
]. The two-level of
peritoneal lesions were defined as low-grade and high-grade diseases. Low-grade disease
entailed acellular content or few cells forming islands or strands, with light cytologic and
nuclear atypia, and scanty mitoses. The high-grade disease was characterized by a greater

Cancers 2023,15, 3426 9 of 24
number of cells, arranged in strands or islands, high-grade atypia, and frequent mitosis. The
existence of SRCs led directly to a high-grade lesion. However, at this time, PMP was still
recognized by the WHO as a pathological diagnosis and a borderline malignant entity. Carr
and co-workers [
72
] validated the prognostic power of the two-level staging system of the
WHO 4th edition classification and found significant differences in OS between low-grade
and high-grade PMP treated with CRS + HIPEC (5-year OS 84 and 48%; p< 0.001).
Additionally, in 2010, the AJCC 7th edition Cancer Staging Manual [
73
] separated
appendiceal carcinomas from colorectal carcinomas for the first time and distinguished
between mucinous and non-mucinous adenocarcinoma subtypes. For primary lesions, they
introduced a classification system similar to that of colorectal cancer: well-differentiated
(G1), moderately differentiated (G2), and poorly differentiated (G3) tumors. Histological
grade was included in the stage IV disease but only two histological prognostic groups
were recognized: stage IVA (G1, N0) low-grade mucinous adenocarcinomas and stage IVB
(G2-3, and any G with N positive) high-grade mucinous adenocarcinomas. Milovanov
et al. [
74
] endorsed the new AJCC 7th-edition staging classification, however, they defined
two prognostic groups into stage IVA (DPAM constituted a specific good prognostic group).
On the other hand, in a large retrospective database study by Overman et al. [
75
], the
outcomes for stage IVB were different between moderately differentiated and poorly
differentiated mucinous adenocarcinoma; hazard ratios (HRs) were 1.63 (95% CI: 1.14–2.34)
and 4.94 (95%CI: 3.32–7.35), respectively. Thus, the combination of moderate and poorly
differentiated diseases in the same prognostic group was not supported either.
Davison et al. [
76
] identified some pathological features of PMP that were correlated
with worse survival outcomes such as destructive invasion, high cytologic grade, high
tumor cellularity, angiolymphatic invasion, perineural invasion, and the presence of signet
ring cells (SRC). They gave a better pathologic description to the three-tiered classification
of the AJCC 7th edition staging classification: grade G1 included cases without adverse
features; G2, included at least one adverse feature except SRC; and G3 were those with the
presence of SRC. They found that G2 and G3 had a significantly worse prognosis than G1
(p< 0.0001). In the multivariate analysis, G2 presented a HR 2.7 (95% CI, 1.2–6.2) and G3
5.1 (95% CI, 1.7–14) relative to G1.
Significant progress in the pathological reporting of appendiceal mucinous neoplasms
and PMP took place after the PSOGI meeting in 2016. In this meeting, experts in PMP from
around the world voted on pathological terminology and its corresponding descriptions
following a Delphi process [
77
]. The Group supported the terms LAMN and high-grade
appendicular neoplasm (HAMN) for primary tumors with low or high cellular atypia, loss
of lamina propria and muscularis mucosae, fibrosis of submucosa, and pushing invasion
of the wall by acellular mucin or mucin with epithelial cells. The term cystadenoma
was discarded for the appendix, and the term adenoma was chosen to refer to those
colorectal type lesions confined to the mucosa and with intact muscularis mucosae, and
the term serrated polyp to describe a lesion with serrated features and intact muscularis
mucosae. They emphasized differentiating between pushing-invasion shown by LAMNs
and HAMNs, and infiltrative invasion which characterizes the adenocarcinoma. Mucinous
adenocarcinomas showed destructive invasion with tumor budding and/or small, irregular
glands within a desmoplastic stroma and they were classified into well, moderately, or
poorly differentiated types. The presence of SRC directly leads to the poorly differentiated
type and implies an aggressive disease with poor clinical results. The two types of primary
tumors with SRC were defined: mucinous adenocarcinoma with SRCs if less than 50 percent
of the tumor cells were SRCs and mucinous SRC carcinoma when SRCs account for more
than 50 percent of the tumor cells.
In the scenery of peritoneal dissemination, the grade of the peritoneal disease defined
the prognosis and four prognostic groups were identified: acellular mucin (AM), low-
grade mucinous carcinoma peritonei (LGMCP), high-grade mucinous carcinoma peritonei
(HGMCP), and high-grade mucinous carcinoma peritonei with signed ring cells (HGMCP-
SRC). AM is at the less aggressive extreme of the scale, whereas HGMCP-SRC is the most

Cancers 2023,15, 3426 10 of 24
aggressive. The remaining two intermediate categories are LGMCP (peritoneal implants
with <20% cellularity, little atypia, and few mitoses) and HGMCP (peritoneal implants
with >20% cellularity, marked proliferative activity, and atypia but without SRC). At least
>10% of the SRC component was required for a patient to be classified as HGMCP-SRC
(Table 1). Groups with epithelial cells are comparable to those established by Davison
et al. [
76
] G1, G2, and G3 and Shetty and colleagues [
78
] PMP 1, PMP 2, and PMP 3. Baratti
et al. [
79
] reclassified 265 PMP patients treated with CRS + HIPEC following the criteria
of the PSOGI classification but failed to validate its four prognostic groups. Instead, the
two-tiered classification of the WHO 4th edition was supported.
The AJCC 8th edition Cancer Staging Manual 2017 incorporated the advances in
terminology from the PSOGI consensus [
80
]. A great effort has been done to adapt TNM
to the definition of LAMN in the T category. Tis (LAMN) referred to low-grade mucinous
neoplasia with at least the loss of the muscularis mucosae; however, it could extend to the
submucosa and muscularis propria by pushing invasion without changing the prognosis,
making T1 and T2 categories not applicable. LAMN pT3 involves the subserosa and
LAMN pT4 implies involvement of the serosa as with other carcinomas. HAMNs were
classified using the same staging system as adenocarcinomas since they present a more
aggressive clinical course. Moreover, stage IV disease was classified by M and G categories.
The M category was divided into M1a, intraperitoneal dissemination of acellular mucin;
M1b, peritoneal implants with tumor cells; and M1c, non-peritoneal metastasis. The G
category was divided into three groups based on cytological features, tumor cellularity,
and the presence of SRCs. G1 presented low-grade cytological atypia, <20% cellularity,
without SRCs, and agreed to a well-differentiated adenocarcinoma. G2 corresponded to
a moderately differentiated mucinous adenocarcinoma with high cytological atypia, and
>20% cellularity without SRCs. Finally, G3 stated a poorly differentiated adenocarcinoma
defined by any component of SRCs. Finally, the peritoneal disease was staged into two
prognostic groups: stage IVA was defined by M1a (acellular mucin) or M1b G1 (low-grade
atypia); IVB by M1b G2 (high-grade atypia) or G3 (high-grade atypia with SRCs). Stage
IVC was M1c (non-peritoneum distant metastases).
The 2019 WHO 5th edition [
81
] classified appendiceal epithelial lesions into LAMN,
HAMN, and adenocarcinomas (mucinous adenocarcinoma, mucinous adenocarcinoma
with SRC, SRC carcinoma, and nonmucinous adenocarcinoma colorectal type). Goblet cell
adenocarcinomas and neuroendocrine neoplasias were also included within the epithelial
lesions, as well as two types of benign tumors: hyperplastic polyps and sessile serrated
lesions (with sparing of the muscularis mucosae) [
82
]. Peritoneal dissemination was classi-
fied into G1 for low-grade peritoneal mucinous neoplasia; G2 for high-grade peritoneal
mucinous neoplasia, and G3 for high-grade peritoneal mucinous neoplasia with SRC.
2.9. Other Histopathological Landmarks
2.9.1. Acellular Mucin
Pai and colleagues [
83
] observed that only one patient out of 14 with AM recurred
after 45 months. The existence of acellular or cellular mucin was associated with OS in the
multivariable analysis. Furthermore, Davison and co-workers [
76
] described that 7% of
patients with LAMN presented AM deposits and none of them recurred. Therefore, based
on these outcomes, patients with peritoneal dissemination of acellular mucin present a
lower risk of relapse with subsequently higher OS outcomes than those with low-grade
cellular diseases.
2.9.2. Signet Ring Cells
The presence of SRCs has also been a matter of much discussion. In 2014, Sirintrapum and
co-workers [
84
] studied the significance of SRCs in 55 patients with MACA and PD. None of the
11 patients with low-grade adenocarcinoma had SRCs, whereas 29 of the 44 in the high-grade
adenocarcinoma group presented SRCs. There were two types of SRC described: SRCs floating
in mucin pools or tissue-invading SRCs. The 5-year OS for patients with MACA with SRCs

Cancers 2023,15, 3426 11 of 24
in mucin pools was similar to that of patients with high-grade mucinous adenocarcinoma
without SRCs (36% versus 32%, respectively;
p= 0.58
). The presence of SRCs invading tissues
decreased OS to a median of 0.5 years, compared to 2.9 and
2.4 years
for high-grade mucinous
adenocarcinoma without SRCs
(p= 0.003)
and mucinous adenocarcinoma with floating SRCs
(
p= 0.004
). Moreover, mucinous adenocarcinoma with SRCs invading tissues was associated
with a higher rate of incomplete cytoreductions.
2.10. Prognostic Factors
As previously highlighted, the correlation between histology and prognosis has been
widely studied throughout the literature. However, several other prognostic factors have
been identified.
It is not surprising that the PCI and CC scores have been repeatedly associated with
survival outcomes by several study groups. At least four study groups found the PCI score to
correlate with OS in the multivariable analysis with cut-offs of PCI > 20 [
85
–
87
] and
PCI > 22 [79]
to be associated with worse OS. Similarly, the CC score of 2–3 was associated with worse survival
outcomes by several study groups [
79
,
85
,
86
,
88
–
90
]. LN status is another factor that has been
associated with OS in several studies [
85
,
86
,
90
]. Overall, these factors should be taken into
consideration when selecting patient candidates for CRS + HIPEC. Solomon et al. [
87
] in their
study on SRC cases with PD from the appendiceal, colorectal, and gastric origin, argued that
high PCI does not contraindicate CRS + HIPEC but MDT discussion is warranted in order to
evaluate whether optimal CRS is achievable. The study group of Levinsky et al. [
90
] came to a
similar conclusion; CRS + HIPEC can be considered in SRC patients given the absence of LN
metastasis and if CC0/1 can be achieved. However, the PCI, CC score, and LN status are factors
that are either determined intra- or postoperatively. Prognostic factors that are determined
preoperatively are needed in order to aid in the patient selection process [85].
Other factors that were found to be associated with prognosis by isolated study groups
were severe postoperative complications [
87
,
91
] preoperative SCT [
79
], elevated Ca19-9 [
92
],
and intraoperative transfusion [92].
Table 1.
Main histologic classification systems [
93
]. SRC—signet ring cells; DPAM—disseminated peri-
toneal adenomucinosis; PMCA—peritoneal mucinous carcinomatosis; PMCA-I/D—peritoneal mucinous
carcinomatosis with intermediate/disconcordant features; LAMN—low-grade appendiceal mucinous neo-
plasm; MACA—mucinous adenocarcinoma of the appendix, HAMN—high-grade appendiceal mucinous
neoplasms; LG-MCP—low-grade mucinous carcinomatosis peritonei; HG-MCP—high-grade mucinous
carcinomatosis peritonei.
Stage of Disease Type Histological Nomenclature Key Histologic Features
Ronnett et al.
[68]
Primary tumors
Benign
lesions.
Villous adenoma Adenomatous epithelium with villous architecture confined to the mucosa.
Cystadenoma Adenomatous epithelium without villous architecture confined to the
mucosa of a dilated appendix.
Dilated/ruptured adenoma.
Glands or strips of adenomatous epithelium within the wall or on the serosa
of a dilated or ruptured appendix without a stromal response. Dissecting
mucin or epithelium extending through the wall of the appendix.
Invasive
lesions
Adenocarcinoma Adenomatous epithelium invading the muscularis of the appendix
accompanied by a stromal response.
Mucinous adenocarcinoma
with SRC
Neoplasms with glandular and SRC differentiation, with or without
neuroendocrine features that showed marked cytologic atypia and
muscularis invasion.
Peritoneal implants
DPAM Scant strips of simple proliferative epithelium with minimal to moderate
cytologic atypia and no significant mitotic activity within abundant mucin.
PMCA I/D
Features of DPAM with focal areas of carcinoma +/−SRC.
I- Arising from a well-differentiated mucinous adenocarcinoma.
D- Arising from a villous adenoma with moderate to marked cytologic
atypia and areas of poorly differentiated carcinoma in the wall and serosa of
the appendix.
PMCA Abundant proliferative epithelium, glands, nests, or individual cells
including SRC, demonstrating marked cytologic atypia and mitotic activity.

Cancers 2023,15, 3426 12 of 24
Table 1. Cont.
Stage of Disease Type Histological Nomenclature Key Histologic Features
Misdraji et al.
[69]
Primary mucinous
tumors
LAMN
Low-grade cytological atypia (nuclear enlargement, scarce nuclear
stratification, and rare mitotic figures) and minimal architectural
complexity (a uniform, flat, epithelial proliferation forming small
papillary excrescences). No infiltrative invasion of the
appendiceal wall.
MACA
High cytological atypia (full thickness nuclear stratification, vesicular
nuclei with prominent nucleoli and brisk mitotic figures) and
infiltrative invasion of the appendicular wall.
Peritoneal implants.
LAMN with peritoneal
dissemination.
Low-grade cytologic atypia with flat epithelium proliferation forming
papillary excrescences, low cellularity.
MACA with peritoneal
dissemination.
High-grade cytologic atypia, destructive invasion of the wall of the
appendix, high cellularity, and abundant mitotic figures.
PSOGI
classification
[77]
Primary mucinous
tumors.
Benign lesions. Serrated polyp with or
without dysplasia.
Tubular architecture with basal parts of the crypts showing serration,
and dilatation. Muscularis mucosae intact.
Mucinous
neoplasms.
LAMN
Pushing invasion with loss of the muscularis mucosae and fibrosis of
the submucosa. Filiform villi, undulating and flat. Basally orientated
nuclei with minimal atypia and rare mitotic figures.
HAMN
Pushing invasion with loss of the muscularis mucosae. Filiform villi,
undulating, flat with pseudopapillae. Loss of nuclear polarity and
frequent mitotic figures that may be atypical.
Mucinous adenocarcinoma
Infiltrating invasion (discohesive single cells or clusters of cells, small
irregular glands within desmoplastic stroma). Variably sized glands
and islands, and variable nuclear features and frequent mitotic
figures that may be atypical. Can be well-, moderately-, and
poorly differentiated.
Mucinous adenocarcinoma
with SRC. Infiltrating invasion. Poorly differentiated, with <50% of SRC.
SRC carcinoma. Infiltrating invasion. Poorly differentiated, with >50% of SRC.
Peritoneal implants
No epithelial
component.
Mucin without epithelial
cells.
Acellular mucin. Abundant mucin without evidence of neoplastic
epithelium. Extensive sampling required to discard presence of
neoplastic epithelium.
Epithelial
component
LG-MCP
Abundant mucin with low cellularity (<20% tumor volume
composed of neoplastic epithelium). Low-grade cytological features
with low proliferative activity.
HG-MCP
Abundant cellularity (>20% tumor volume composed of neoplastic
epithelium). High-grade cytological features with high proliferative
activity (can be mixed with areas of low-grade cytological features).
Infiltrative invasion into subjacent tissues. Must lack SRC.
HG-MCP with SRC
Abundant cellularity (>20% tumor volume composed of neoplastic
epithelium). High-grade cytological features with high proliferative
activity. Infiltrative invasion into subjacent tissues. SRC
component present.
AJCC 8th
edition [80]Primary lesions.
Benign lesions Adenoma LAMN confined to the mucosa with intact muscularis mucosae.
Premalignant
lesions
High-grade dysplasia Neoplastic cells confined to crypts that do not invade the
lamina propria.
Intramucosal
adenocarcinoma
Neoplastic cells invade the lamina propria with or without extension
into but not through the muscularis mucosae.
pTis.
Mucinous
appendiceal
neoplasms
LAMN
Neoplastic cells extend through the wall of the appendix with a
pushing front, without features of invasion.
Tis (LAMN)- LAMN confined by the muscularis propria, acellular
mucin, or mucinous epithelium may extend into de muscularis
propria.
pT3- involvement of the subserosa.
pT4a- involvement of the visceral peritoneum (with acellular mucin
or mucinous epithelium).
pT4b- direct involvement of adjacent organs or structures.
HAMN Tumors with architectural features of LAMN with areas of high-grade
dysplasia. pT staging follows that of mucinous adenocarcinoma.
Mucinous adenocarcinoma.
Neoplastic epithelium displays infiltrative and destructive growth
into the wall of the appendix, beyond the muscularis mucosae.
Associated with desmoplastic reaction.
pT1- involvement of the submucosa through the muscularis mucosa.
pT2- involvement of the muscularis propria.
pT3- involvement of the subserosa or mesoappendix.
pT4a- involvement of the visceral peritoneum (with acellular mucin
or mucinous epithelium)
pT4b- direct involvement of adjacent organs or structures.

Cancers 2023,15, 3426 13 of 24
Table 1. Cont.
Stage of Disease Type Histological Nomenclature Key Histologic Features
Peritoneal implants.
EIVA
M1a Intraperitoneal acellular mucin without neoplastic epithelium in the
disseminated peritoneal mucinous deposits.
M1bG1
Intraperitoneal dissemination containing tumor cells with low-grade
cytologic atypia without SRC. Low cellularity (<20%). No infiltrative
invasion of the peritoneum; may be involved with pushing front
without desmoplastic reaction. Perineural or lymphovascular
invasion rarely observed.
EIVB
M1bG2
Intraperitoneal dissemination containing tumor cells with mixture of
low- and high-grade cytologic atypia without SRC. High cellularity
(>20%). Infiltrative invasion of the peritoneum and into adjacent
organs. Perineural or lymphovascular invasion may be present.
M1bG3
Intraperitoneal dissemination with tumor cells displaying adverse
histological features. High cellularity (>20%). Infiltrative invasion of
the peritoneum, adjacent organs. Perineural or lymphovascular
invasion may be present.
3. Systematic Review on Mucinous Tumors of the Appendix with Peritoneal
Dissemination [93]
Our study group conducted a systematic review to gain sufficient historical back-
ground to understand the development of current classification systems and the basic
histopathological features which define each subcategory.
The PRISMA guidelines were implemented to carry out the systematic review, as
shown in Figure 1. MEDLINE and the Cochrane Library were consulted for publications
that assessed survival results across the different pathological categories in patients with
mucinous neoplasm of the appendix with PD treated with CRS + HIPEC.
Cancers 2023, 15, x FOR PEER REVIEW 14 of 26
M1bG3
Intraperitoneal dissemination with tumor cells displaying adverse histologi-
cal features. High cellularity (>20%). Infiltrative invasion of the peritoneum,
adjacent organs. Perineural or lymphovascular invasion may be present.
3. Systematic Review on Mucinous Tumors of the Appendix with Peritoneal
Dissemination [93]
Our study group conducted a systematic review to gain sufficient historical back-
ground to understand the development of current classification systems and the basic his-
topathological features which define each subcategory.
The PRISMA guidelines were implemented to carry out the systematic review, as
shown in Figure 1. MEDLINE and the Cochrane Library were consulted for publications
that assessed survival results across the different pathological categories in patients with
mucinous neoplasm of the appendix with PD treated with CRS + HIPEC.
Figure 1. Flow chart showing selection of studies for review.
The following criteria had to be met for a study to be considered for inclusion:
• Target population: patients with PD from a mucinous tumor of the appendix treated
with CRS + HIPEC.
• The studies had to report OS and DFS results based on any pathologic classification.
In addition, the results had to be shown as median and/or 5-year OS or DFS rate for
each histologic category of peritoneal implants. At the least, the survival results of
two different histological categories had to be compared in univariable or multivari-
able analysis.
3.1. Results
A total of thirty-eight studies were included. Ronne’s classification was the most
popular as nine studies utilized it. The PSOGI classification was used in six studies and
the AJCC 8th edition was used in seven studies.
Figure 1. Flow chart showing selection of studies for review.
The following criteria had to be met for a study to be considered for inclusion:
•
Target population: patients with PD from a mucinous tumor of the appendix treated
with CRS + HIPEC.

Cancers 2023,15, 3426 14 of 24
•
The studies had to report OS and DFS results based on any pathologic classifica-
tion. In addition, the results had to be shown as median and/or 5-year OS or DFS
rate for each histologic category of peritoneal implants. At the least, the survival
results of two different histological categories had to be compared in univariable or
multivariable analysis.
3.1. Results
A total of thirty-eight studies were included. Ronnett’s classification was the most
popular as nine studies utilized it. The PSOGI classification was used in six studies and the
AJCC 8th edition was used in seven studies.
In the systematic review, nine studies supported a two-tiered classification system for
peritoneal dissemination, 12 studies supported a three-tiered system, and two supported a
four-tiered classification system.
Since the pioneer publication by Ronnet and Sugarbaker in 1995 to the present day,
the classification of mucinous neoplasms of the appendix has been the subject of extensive
research. The AJCC 8th edition has collected the descriptions made at PSOGI consensus
on both the primary and peritoneal lesions. However, the AJCC 8th edition recognizes
two prognostic groups in cases of peritoneal disease: stage IVA includes patients with
M1a (acellular mucin) and M1b G1 (low-grade atypia); whereas stage IVB groups together
patients with M1b G2 (high-grade atypia) and G3 (high-grade atypia with any component
of SRCs). Our study group endorses the division of patients with peritoneal disease into
four tiers as proposed by the PSOGI classification, based on the particularly good prognosis
of patients with AM in opposition to the particularly poor prognosis of patients with SRC.
In regard to Acellular mucin, several initial studies [
76
,
83
] have suggested that patients
with acellular mucin disease have a much lower risk of disease recurrence and improved
OS compared to those with a low-grade cellular disease. In AJCC terminology, M1a disease
seemed to have a lower risk of recurrence than M1bG1 [
94
]. The clarity gained in pathologi-
cal reporting as a result of the PSOGI consensus allowed further study groups to assess the
uniqueness of patients with acellular mucin. Reghunathan and colleagues [
95
] observed
only one recurrence out of 33 patients with acellular mucinous deposits, with 13 remaining
disease-free for more than 3 years (HR 9.8; p= 0.025). Furthermore,
Choudry et al. [96]
compared the risk of recurrence in patients with acellular mucin (19 patients) and scant
cellularity (30 patients), to those with moderate cellularity, defined by 2–19 percent of
epithelial cells (242 patients), and observed that the risk was higher in the latter with a HR
of 4.4 (p= 0.02).
There are three studies that applied the PSOGI terminology [
94
–
96
] that demonstrated
that acellular mucin was associated with improved DFS compared to LG-MCP; however, a
fourth study [97] found no significant differences.
In regard to signet ring cells, their presence has been traditionally associated with poor
outcomes. There were four studies [
74
,
86
,
88
,
89
] found to confirm this in the multivariate
analysis of OS of HGMCP compared to HGMCP-SRC in PSOGI terminology, or M1bG2
compared to M1bG3 in AJCC terminology. Ihemelandu and colleagues [
88
] observed that
median OS decreased from 45.4 months to 18.9 months in patients with moderate–high-
grade histology compared to those with SRCs (HR of 1.4, p< 0.001). Similarly, Munoz-
Zuluaga et al. [
86
] noted a 90 months median OS in patients with HGMCP that dropped to
26.4 months in those with HGMCP with SRC, with a HR of 2.9 (p< 0.001). Pathologists
are further challenged by the finding of SRC at the implants since they must distinguish
between floating SRCs in pools of mucin and tissue-invading SRCs. Sirintrapun [
84
]
described that the presence of tissue-invading SRC implies significantly worse OS and,
therefore, should be reported in the pathology report. However, SRCs floating in pools do
not impact the prognosis.

Cancers 2023,15, 3426 15 of 24
3.2. Conclusion
The AJCC 8th edition classification [
80
] has included many of the peculiarities of
appendiceal mucinous tumors that were described at the PSOGI consensus, as well as a
specific T staging for LAMN primary lesions. However, only two prognostic groups (stage
IVA and stage IVB) were recognized for patients with PD.
There are two study groups that have recently evaluated the prognostic impact of
the four-tiered PSOGI classification [
77
]. In 2017, Huang et al. [
92
] observed significant
differences in OS across the four subgroups with a HR of 3.13, p< 0.001. The median
OS in patients with AM and LGMCP was not reached; in patients with HGMCP, it was
58.2 months and 31.1 months in those with HGMCP-SRCs. However, in 2018, Baratti and
colleagues [
79
] were unable to reproduce similar results and concluded that the two-tiered
WHO classification (HR 1.48, 95% CI 1.04–2.10; p= 0.028) correlated better with OS than the
PSOGI classification (HR 1.22, 95% CI 0.93–1.59; p= 0.149). In their discussion, they argued
that having more subgroups reduces the number of patients in each, which decreases
statistical power.
CRS + HIPEC is the gold standard treatment for mucinous appendiceal tumors with
PD [
3
]. However, its major drawback lies in its high morbidity and mortality rates [
98
],
therefore adequate patient selection is paramount. For this, a universal language that
captures the prognostic implications behind specific pathologic features is urgently needed.
This will, in turn, aid the development of management protocols for this disease. The
existing scientific literature suggests that the best current classification system is the four-
tiered PSOGI classification system, however, it has not been established yet as such.
4. Which Classification System Defines the Best Prognosis of Mucinous Neoplasms of
the Appendix with Peritoneal Dissemination: TNM or PSOGI [99]?
The aim of this study was to evaluate the prognostic impact of PSOGI and AJCC 8th
edition classification systems of mucinous appendiceal neoplasms with PD. A retrospective
study was carried out using a prospective registry of consecutive patients treated by the
Peritoneal Carcinomatosis Unit at our center. Patients treated with CRS + HIPEC for a
disseminated appendiceal mucinous neoplasm between January 2009 and December 2019
were included. There were two expert pathologists in peritoneal surface malignancies
that reviewed the pathology slides obtained during the CRS + HIPEC procedure and
cases were reclassified adhering to the criteria set at the PSOGI consensus [
77
] and AJCC
8th edition classification. Survival analysis evaluated the impact of each classification
system (
PSOGI vs. TNM
) on OS and DFS while the concordance-index evaluated their
predictive power.
4.1. Pathological Evaluation
A microscopic assessment of the appendix differentiated between benign lesions,
LAMN, HAMN, and mucinous adenocarcinoma (MAC). Peritoneal implants were classified
into AM, LGMCP, HGMCP, and HGMCP-SRC. AM was defined by the absence of epithelial
cells and a granulation-like response of the peritoneum. Mucinous deposits where epithelial
cells showed low-grade atypia and constituted <20% of the tumor volume were graded as
LGMCP, whereas HGMCP when the cellular component was more abundant (>20%) and
displayed signs of high-grade atypia. At least >10% SRC component was required for a
patient to be classified as HGMCP-SRC. Careful examination was taken to discriminate
SRCs from degenerative SRC-like tumor cells, and their disposition was recorded (floating
within mucin deposits or invading tissue). Patients were also staged according to the AJCC
8th edition criteria as stages IVA or IVB [
80
,
100
]. Essentially, AM and LGMCP peritoneal
implants were graded as stage IVA, while HGMCP and HGMCP-SRC implants were graded
as stage IVB.

Cancers 2023,15, 3426 16 of 24
4.2. Results
The primary appendix tumor was available for histological examination in 66 cases.
Of these, 21 cases (31.8%) were classified as LAMN; 36 (54.5%) as MAC; 5 (7.6%) as MAC
with SRC; and 4 (6.1%) as signet ring cell carcinomas (SRCC). No cases matching the criteria
for HAMN were observed. The examination of the peritoneal implants reclassified patients
as AM in 20 cases (21.1%), LGMCP in 53 (55.8%), HGMCP in 8 (8.4%), and HGMCP-SRC in
14 (14.7%). There was a significant correlation between the grade of the primary appendix
tumor and the grade of the peritoneal disease (p< 0.001). There were seven LAMN cases
that developed AM implants (33.3%) and 14 developed LGMCP (66.7%); there were seven
MAC (six well-differentiated and one moderately differentiated) presented AM peritoneal
lesions (19.4%), 23 (17 well-differentiated and six moderately differentiated) presented
LGMCP (63.9%), five moderately differentiated developed HGMCP (13, 9%) and one poorly
differentiated presented HGMCP-SRC (2.8%). All MACs with SRC or SRCC developed
with HGMCP-SRC. The 30-day perioperative mortality rate was 2.1%. There was one
death on the eighth postoperative day due to massive pulmonary thromboembolism; the
second occurred on the thirteenth postoperative day due to mitral endocarditis and septic
shock. The Clavien–Dindo grade III/IV perioperative complication rate was 41.4%. The
histological subtype was not associated with postoperative morbidity and mortality.
The series median follow-up was 49.2 months. There were six patients lost to follow-
up and 11 out of 89 patients died. The median OS of the entire cohort was not achieved and
86.1% of patients were alive at 5 years. Disease relapse was detected in 39 out of
89 patients
.
The median DFS was 64.7 months (46.1–83.4) and 5-year and 10-year DFS rates were 51.5%
and 43.8%, respectively.
Factors that were significantly associated with survival on the univariate analysis were
preoperative and postoperative SCT, PCI, CC score, LN status, and PSOGI and AJCC classi-
fications. The survival results for each of the PSOGI and AJCC 8th edition subgroups are
shown in Figure 2. The median OS was not reached in AM or LGMCP and was
41.4 months
in HGMCP and 56.3 months in HGMCP-SRC (p= 0.002). Pairwise comparisons found
significant differences when comparing AM and HGMCP-SRC (
p= 0.006
) and LGMCP and
HGMCP (p= 0.001). Similarly, the median OS was not reached in stage IVA patients and
was 56.3 months in stage IVB (p< 0.001).
Once adjusted to other possible confounding factors, both classification systems PSOGI
and AJCC were significantly correlated with OS with similar HR; 10.2 (p= 0.039) and 7.7
(p= 0.002), respectively, and they had similar discriminative capacities (c-index values
of 0.685 and 0.669, respectively). Out of the previously mentioned factors, only PCI > 21
retained its significance in the multivariate analysis with a HR of 11.4, p= 0.022.
Factors that were found to be significantly associated with DFS on the univariate analy-
sis were preoperative SCT, PCI, CC score, preoperative elevated TM, LN status, and PSOGI
and AJCC classifications. The DFS results for each of the PSOGI and AJCC 8th edition
subgroups are shown in Figure 3. Once again, median DFS was not reached in patients
with AM but it was 60.9 months in LGMCP, 13.6 months in HGMCP, and
8.8 months
in
HGMCP-SRC (p< 0.001). A pairwise comparison method found significant differences in
the comparison of AM with LGMCP (p= 0.029), HGMCP (p< 0.001), and HGMCP-SRC
(p= 0.002); and LGMCP with HGMCP (p= 0.008) and HGMCP-SRC (p= 0.013). In the AJCC
classification, the median DFS of stage IVA patients was not reached and was
9.1 months
in
stage IVB patients (p< 0.001). Both classification systems were significantly associated with
DFS in the multivariate analysis with a respective HR of 12.7 (p= 0.001) and 3.7 (p< 0.001).
AM was found to have significantly lower recurrence rates than every other histological
subgroup (AM vs. LGMCP (HR 4.95, p= 0.03); AM vs. HGMCP (HR 17, p= 0.001) and
AM vs. HGMCP-SRC (HR 12.7, p= 0.001). However, analysis of the concordance index
suggested that both classifications had similar discriminative power (0.669 and 0.623 for
PSOGI and AJCC, respectively). The other risk factors associated with lower DFS in the
multivariate analysis were postoperative SCT, PCI > 21, and elevated TM.

Cancers 2023,15, 3426 17 of 24
Cancers 2023, 15, x FOR PEER REVIEW 18 of 26
Figure 2. Overall survival according to Peritoneal Surface Oncology Group International classifica-
tion of peritoneal implants (A) and eighth edition of the American Joint Commiee on Cancer (B)
[99]. AM, acellular mucin; HGMCP, high-grade mucinous carcinoma peritonei; HGMCP-SRC,
HGMCP with signet ring cells; LGMCP, low-grade MCP.
Figure 2.
Overall survival according to Peritoneal Surface Oncology Group International classification
of peritoneal implants (
A
) and eighth edition of the American Joint Committee on Cancer (
B
) [
99
].
AM, acellular mucin; HGMCP, high-grade mucinous carcinoma peritonei; HGMCP-SRC, HGMCP
with signet ring cells; LGMCP, low-grade MCP.

Cancers 2023,15, 3426 18 of 24
Cancers 2023, 15, x FOR PEER REVIEW 19 of 26
Figure 3. Disease-free survival according to Peritoneal Surface Oncology Group International clas-
sification of peritoneal implants (A) and eighth edition of the American Joint Commiee on Cancer
(B) [99]. AM, acellular mucin; HGMCP, high-grade mucinous carcinoma peritonei; HGMCP-SRC,
HGMCP with signet ring cells; LGMCP, low-grade MCP.
4.3. Discussion
The clinical outcome of patients with mucinous neoplasms of the appendix with PD
treated with optimal CRS + HIPEC can vary greatly. Histology has an important role in
determining the clinical course of the disease [68–70,72,101,102]. The greatest achievement
of recent classification systems [77,80,100] has been to provide concrete pathological cri-
teria to define the different histological grades in an aempt to universalize the terminol-
ogy used and standardize treatment protocols.
The PSOGI classification system [77] supports the existence of four prognostic sub-
groups, whereas AJCC 8th edition [80,100] recognizes two tiers. The findings from our
series appear to agree with the two prognostic groups outlined by the AJCC 8th edition
[80,100]. The 5-year OS rates of AM and LGMCP (95% and 94%, respectively) were
Figure 3.
Disease-free survival according to Peritoneal Surface Oncology Group International classi-
fication of peritoneal implants (
A
) and eighth edition of the American Joint Committee on Cancer
(
B
) [
99
]. AM, acellular mucin; HGMCP, high-grade mucinous carcinoma peritonei; HGMCP-SRC,
HGMCP with signet ring cells; LGMCP, low-grade MCP.
4.3. Discussion
The clinical outcome of patients with mucinous neoplasms of the appendix with PD
treated with optimal CRS + HIPEC can vary greatly. Histology has an important role in
determining the clinical course of the disease [
68
–
70
,
72
,
101
,
102
]. The greatest achievement
of recent classification systems [
77
,
80
,
100
] has been to provide concrete pathological criteria
to define the different histological grades in an attempt to universalize the terminology
used and standardize treatment protocols.
The PSOGI classification system [
77
] supports the existence of four prognostic subgroups,
whereas AJCC
8th edition [80,100]
recognizes two tiers. The findings from our series appear
to agree with the two prognostic groups outlined by the AJCC
8th edition [80,100]
. The 5-year

Cancers 2023,15, 3426 19 of 24
OS rates of AM and LGMCP (95% and 94%, respectively) were excellent and comparable to
those of stage IVA (94.3%). Similarly, HGMCP and HGMCP-SRC subgroups had consider-
ably worse prognoses with 5-year OS rates of 50% and 30% (
p= 0.434
) comparable to stage
IVB (39.7%). However, the following points must be highlighted:
Firstly, the negative impact of the presence of SRC on survival could not be demon-
strated in our series. However, this has been repeatedly observed by many study groups
resulting in the criticism of the AJCC 7th edition [
73
] as patients with and without SRC
were grouped into the same prognostic group [
75
]. Ihemelandu and Sugarbaker [
88
] and
Munoz-Zuluaga et al. [
86
] noticed significantly lower median OS in patients with SRC
compared with those without SRC: 18.9 (HR 1.4, p< 0.001) and 26.4 (HR 2.9, p< 0.001)
months, respectively. The reduced number of patients with SRC in our series (n= 14) as
well as the unexpectedly high survival outcomes achieved (median OS 56.3 months) may
explain why our series could not verify the negative impact of SRC on survival. Secondly,
when recurrence is considered, the study we conducted emphasizes the higher recurrence
risk of high-grade tumors, as previously noted by many other study groups, [
94
–
96
] as
well as the exceptionally low propensity of AM to recur when compared with cellular
counterparts. This was clearly noted in our series as the 5-year DFS rates of patients with
AM were much higher than those with LGMCP (82.2% vs. 51.2% with a HR of 4.95, p= 0.03).
Although the AJCC 8th edition included a distinct category for this particularity (M1a),
patients were later grouped together with LGMCP (M1b G1) into stage IVA, therefore, the
lower risk of recurrence of AM disappears in the AJCC 8th edition.
Histology is currently still considered to be the main factor driving patient prognosis,
which, in turn, conditions treatment and follow-up schemes. For example, the use of SCT
which was previously administered more frequently as this disease was originally thought
to be incurable, has been found to be of benefit in high-grade histologies [
58
]. This has been
adapted by recent clinical guidelines [
3
,
4
] that contemplate the use of neoadjuvant SCT
to reduce tumor burden in high-grade tumors where optimal CRS (CC0-1) is not initially
feasible but not in low-grade cases. The Peritoneal Malignancy Institute (PMI) Basingstoke
has assessed the influence of histology on follow-up protocols recommending different
surveillance schemes based on a patient’s final histology [
103
]. Similarly, the Manchester
study group [
104
] advocated for a limited surveillance scheme of annual CT scans for up to
5 years in patients with AM arising from a primary LAMN after observing a 3% recurrence
rate (at 12 and 56 months). In general, we agree with this viewpoint, as long-term follow-up
protocols may be ineffective in AM and may result in unnecessary radiation exposure.
However, one key finding that we would like to emphasize from the results of our
study is that histology on its own has limited discriminative power as none of the classifica-
tion systems scored a c-index value higher than 0.7 predicting OS and DFS. Therefore, other
prognostic factors (serological TM [
105
], biological markers [
106
,
107
]
. . .
etc.) should be
taken into account to achieve better patient stratification. We would also like to highlight
that some histological landmarks still have to be properly defined such as the number of
slides that should be assessed to confidently categorize a patient as AM [
108
] and the clear
pathologic description of malignant SRC.
4.4. Conclusions
The AJCC 8th edition and the PSOGI classification systems have demonstrated a
similar capacity of stratifying patients into prognostic groups in our patient cohort. When
considering DFS, the PSOGI classification seems to provide a slightly better prognostic
stratification. However, histology’s discriminative capacity is insufficient on its own. Other
prognostic indicators must be identified in order to improve patient classification and
establish more efficient treatment and follow-up regimes.
Author Contributions:
All authors have contributed equally to each part of the manuscript. Writing—
original draft preparation, L.G.B.; writing—review and editing, L.G.B. and L.M.R. All authors have
read and agreed to the published version of the manuscript.

Cancers 2023,15, 3426 20 of 24
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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