Classification of mucinous appendiceal neoplasm and pseudomyoxma peritonei

Mucinous appendiceal tumors are uncommon and include a wide spectrum of tumors whose classification remained controversial. Some of these mucin producing appendiceal tumors can disseminate to the peritoneal cavity leading to pseudomyxoma peritonei (PMP). Despite several attempts to classify mucinous tumors of appendix and PMP by different authors in the past, no universally accepted classification system was present. The controversial issues were discussed at the 2012 World Congress of the Peritoneal Surface Oncology Group International (PSOGI) in Berlin. A panel of 71 experts from 13 different countries was formed under the lead co-ordinator Norman J. Carr. A total of 4 rounds of questionnaires and one meeting were held. The opinion of the majority was taken into account. Importance of intactness of muscularis mucosae, pushing invasion and infiltrative invasion were emphasized. The entities Low grade appendiceal mucinous neoplasm (LAMN) and High grade appendiceal mucinous neoplasm (HAMN) were defined.. The terminologies suggested for Goblet cell carcinoid and adenoneuroendocrine carcinoma were goblet cell tumor and adenocarcinoma ex goblet cell carcinoid. Acellular mucin in peritoneum was not classified under PMP which was classified into 3 categories depending upon low grade , high grade cytologic features and presence of signet ring cells. It was suggested to report the extent of mucin and cells separately. A reporting format solely for mucinous appendiceal tumors was formulated by the panel. However, there are some grey areas which may have to be addressed in future. ABSTRACT Ghosh Arnab1


INTRODUCTION
Primary appendiceal tumors are found in less than 2% of surgically removed appendix and include a wide spectrum of mucinous tumors which pose problems to both pathologist and clinicians `as their nature and classification remained controversial. 1  These tumors often cause accumulation of mucin in the appendiceal lumen leading to cystic dilation of appendix.Some of these mucin producing appendiceal tumors can disseminate to the peritoneal cavity leading to pseudomyxoma peritonei (PMP) despite the lack of classic infiltrative pattern of invasion and cellular atypia.And in most PMPs, the cells found in the peritoneal mucin pool are bland in appearance. 1,2hough since 1960s, these seemingly non-invasive and innocuous tumors were suspected as malignant, most reports before 2000 were of not much value in assessing the biological nature of different types of mucinous appendiceal tumors. 1,2

HISTORICAL ASPECT
Several attempts towards classifying mucinous tumors of appendix and PMP have been made in the past.Woodruff R  et al. in 1940 classified 146 cystic tumors of the appendix into mucocele and Adenocarcinoma Grade I. 3 However with time, various opinions, proposals and terminologies came up by different authors.Disputes continued about the nature and nomenclature of these tumors, classification of degree of dysplasia, if present and in case mucin is seen in the appendiceal wall, whether to call the lesion malignant or not.The term appendiceal muocele and cystadenoma was frequently used by many pathologists though the exact definition of the conditions were uncertain. 4][9][10][11] However the term PMP is included in 2010 WHO classification of tumors of the digestive system. 11[11][12][13]

PERITONEAL SURFACE ONCOLOGY GROUP INTERNATIONAL
The controversial issues were discussed at the 2012 World Congress of the Peritoneal Surface Oncology Group International (PSOGI) in Berlin.There it was proposed that a consensus method should be developed by a panel of experts.In that process, 71 international experts comprising 34 pathologists along with surgeons and medical oncologists from 13 different countries were included and invited to join the panel.The aim of the process was to develop a consensus on the terminology of PMP and appendiceal neoplasms including goblet cell carcinoid but excluding other tumors with neuroendocrine differentiation.The lead co-ordinator was Norman J. Carr and a modified Delphi approach was adopted for the study.The whole process included round 1 questionnaires to each participating panel expert.At the end of round 1, it was found that 6 different classifications of PMP and 12 distinct classifications for appendiceal lesions were in use by panel members.Furthermore it was noted that the same lesion may have been interpreted by different panel member in different way.n the above conference.This was followed by further round 3 and round 4 questions to minimize the differences in opinion and to come to a conclusion.For contentious issues, a two third majority was taken as consensus and for non-contentious issues, a simple majority was accepted. 14,15ithelial Appendiceal Neoplasms PSOGI panel classified non-carcinoid epithelial neoplasia of the appendix into following subtypes.(Table 2) • Adenoma (with low grade / high grade dysplasia) • Serrated polyp (with low grade / high grade dysplasia) • Low grade appendiceal mucinous neoplasm (LAMN) • High grade appendiceal mucinous neoplasm (HAMN)

Adenoma
Adenomas typically occur in fifth decade and are more common in females. 4,16,17Grossly, mucin is absent on the external serosal surface.Appendix may or may not be dilated and on cut up, lumen may show presence of mucin.On microscopy, adenomatous hyperplasia is seen and, by definition, muscularis mucosae must be intact and there must not be any mucin and invasion in the appendicular wall or through the appendicular wall.Similar to the colorectal adenomas, it may be villous or tubular or tubulovillous and may show low grade or high grade dysplasia.Appendicular adenomas are more commonly of villous type in contrast to colonic adenomas and often show circumferential involvement.The main differentials include retention cyst and LAMN.Retention cysts usually show attenuation of epithelium while papillary architecture with tall mucinous cells indicates neoplastic epithelium of adenoma.The main differentiating point from LAMN is presence of an intact muscularis mucosae in adenomas. 1,4,14,19The terms "cystadenoma" of appendix should no longer be used. 14

Serrated polyps
It is similar to the colorectal counterpart with serrated features.Similar to the adenomas, the muscularis mucosae is intact.It may show low grade or high grade dysplasia.The term "serrated polyp" was preferred by the panel over other alternative terms as "sessile serrated adenoma". 14

Low Grade Appendiceal Mucinous Neoplasm (LAMN)
Usual age of presentation is sixth decade and is seen more in females. 7,12Approximately 25-30% LAMN are incidental finding and majority present as acute appendicitis. 15Grossly, mucin may or may not be seen on the serosal surface.On microscopy, the main feature is destruction of muscularis mucosae due to "pushing invasion" by the neoplastic epithelium and /or mucin.The epithelium show low grade dysplasia.Submucosa and muscularis propria may show fibrosis, hyalinisation or attenuation, but typical features of infiltrative invasion and desmoplasia (see below) are absent.
The fibrosis is typically characterized by small scattered bland fibroblasts in a dense collagenous, often hyalinised matrix.The neoplastic epithelium may push into or even through the wall as diverticulum. 14,19The differentials include adenoma, serrated polyps, HAMN (see below) and mucinous adenocarcinoma (see below).It is to be noted that any tumor with mucin and / or epithelium dissecting through the wall should not be called as adenoma.To differentiate LAMN from a ruptured adenoma may be difficult and may require several sections to find the pushing invasion by the neoplastic epithelium and low grade cytologic atypia. 14,19

High Grade Appendiceal Mucinous Neoplasm (HAMN)
In HAMN all the features are similar to LAMN except that the cytologic atypia is of high grade.HAMN is a rare entity.This terminology is not included in WHO classification 2010. 11Later, it was proposed by the PSOGI panel and was also included in American Joint Committee on Cancer (AJCC) Cancer staging manual 8th edition as well as in College of American Pathologists (CAP) protocol. 19,20It has to be differentiated from LAMN by the degree of cytological atypia and from mucinous adenocarcinoma by the absence of infiltrative invasion.

Mucinous adenocarcinoma (MA)
In MA, the main feature is infiltrative invasion and desmoplasia of the stroma.MA may be well, moderately or poorly differentiated depending on cytological atypia.
Infiltrative invasion has been defined as tumor budding (infiltration of single individual cells or clusters of up to 5 cells) and / or small irregular glands with frequent angulations.Desmoplastic stroma has been defined as proteoglycan rich extracellular matrix with activated fibro and myofibroblasts with vesicular nuclei.It has to be differentiated from the fibrosis and hyalinisation of submucosa and / or muscularis propria often seen in LAMN and High Grade Appendiceal Mucinous Neoplasm . 4,14,19cinous adenocarcinoma of appendix accounts for about 40% of all appendiceal adenocarcinomas.They can rupture and cause PMP, as well as, can also spread through hematogenous route.Histologically, they can be graded as well, moderately and poorly differentiated.The main differentials include LAMN, HAMN and Goblet cell carcinoma (discussed below).Patients with MA have a better prognosis than those with non-mucinous adenocarcinoma. 1,4,15

Mucinous adenocarcinoma with signet ring cells and Signet ring cell carcinoma
If signet ring cells are seen in the mucinous pool, the percentage of signet ring cells determines the diagnostic terminology.If signet ring cells are less than 50% of the cells, it is called as poorly differentiated mucinous adenocarcinoma with signet ring cells.And if they constitute more than 50% of the cells, it is termed as mucinous signet ring cell carcinoma. 14,19

Goblet cell carcinoid
Goblet cell carcinoids show poorer prognosis than pure appendiceal neuroendocrine tumors. 19The term Goblet cell carcinoid is well recognised and is present in AJCC 8th edition.However PSOGI panel considered it as misleading and suggested a new name "Goblet cell tumor" which is synonymous.It was further suggested that this entity should be subtyped as mucinous (>50% extracellular mucin) and non-mucinous (<50% extracellular mucin). 14me tumors show a combination of goblet cell carcinoids and adenocarcinoma and behave more aggressively than pure goblet cell carcinoid. 19These tumors have been named "adenoneuroendocrine carcinoma" in WHO 2010. 11However AJCC 8th edition and CAP protocol have mentioned that this term may cause a mistaken impression of a poorly differentiated neuroendocrine carcinoma.[21] Pseudomyxoma peritonei (PMP) As mentioned above, PMP refers to the accumulation of mucin within the peritoneal cavity secondary to mucinous DOI : 10.3126/jpn.v8i1.19458epithelial neoplasia mostly of appendiceal origin, namely LAMN and mucinous adenocarcinoma. 4The usual age of presentation is 6 th to 7 th decade and in some series it shows female predilection. 4It usually shows slow and continuous intra-peritoneal growth but distant metastasis is rare.Generally it originates from the mucinous tumor from the appendix but occasional cases of primary mucinous tumor of other organs including ovary, colon, urachus and pancreas were reported. 1,4OGI panel defined PMP as intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by redistribution phenomenon.It can include mucinous ascites, peritoneal implants, omental cake and ovarian involvement.It most commonly arises from the appendiceal neoplasia.It was noted that PMP is a clinical syndrome which should be considered malignant and appendiceal lesions with low grade or high grade features can present as PMP.
It was decided by the panel that the peritoneal component and the appendiceal tumor should be reported and termed separately. 14,19OGI panel classified peritoneal disease component into 4 diagnostic groups viz., 14,19 • "Acellular mucin only" is characterised by presence of mucin without epithelial cells.A comment should be added on whether the mucin is confined close to the organ of origin or distant from it.The word PMP should be avoided for this category unless clinically indicated.
• "High grade mucinous carcinoma peritonei" or "peritoneal mucinous carcinomatosis (PMCA)" is characterised by PMP with high grade histologic features.Even focal high grade atypia also should be considered under this category.
• "High grade mucinous carcinoma peritonei with signet ring cells" or "PMCA with signet ring cells (PMCA -S)" is characterised by PMP with signet ring cells.
So, the summary of the PSOGI diagnostic groups is that the term PMP should be used only if cells are present in the mucin and PMP is divided into 3 groups as low grade, high grade and signet ring.These grading schemes are not applicable to poorly differentiated neuroendocrine carcinoma and goblet cell carcinoid. 19,20porting Format The reporting format of CAP addresses all types of appendiceal tumors including mucinous and non-mucinous tumors.The PSOGI group formulated a separate reporting format meant only for appendiceal mucinous tumors and PMP.It has been provided above for the convenience of the readers.Majority suggested that in PMP, the spread of cells and mucin should be assessed and reported separately (fig.1). 14

CONCLUSION
PSOGI has put a great effort to standardize the terminologies related to appendiceal mucinous tumors and PMP.However, still there are several uncertain issues, discrepancies and grey zone areas, which can be addressed in future.There are differences between PSOGI guideline and AJCC 8th edition recommendations.Subjective variations regarding low and high grade dysplasia among different pathologists can occur and differentiating signet ring cells from degenerating tumor cells may become tricky especially if the cellularity is low.Furthermore, all these different conditions and terminologies should have proper therapeutic and prognostic significance, for which further studies with long term follow up are required.

Figure 1 :
Figure 1:Reporting format for mucinous tumors of appendix as recommended by the PSOGI group14

Figure 1 :
Figure 1: Reporting format (Continued) for mucinous tumors of appendix as recommended by the PSOGI group 14

Figure 1 :
Figure 1: Reporting format (Continued) for mucinous tumors of appendix as recommended by the PSOGI group 14

Figure 1 :
Figure 1: Reporting format (Continued) for mucinous tumors of appendix as recommended by the PSOGI group 14

Table 1 : Different terminologies used by different authors in the past 1 Comparisons Among Classification Schemes for Appendiceal Mucinous Neoplasms and Pseudomyxoma Peritonei
18 DOI :10.3126/jpn.v8i1.19458thecontext, it is noteworthy that these lesions have different mutations to their colonic counterparts, suggesting they are different type of neoplastic proliferation.18