MUC2 Is a Molecular Marker for Pseudomyxoma Peritonei

Abstract

Pseudomyxoma peritonei, a syndrome first described by Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although much past interest in the syndrome has focused on the question of whether the disease arises from primary appendiceal or ovarian mucinous tumors of varying malignant potential, the accumulation of extracellular mucin with its resulting obstruction of abdominal viscera and adhesion formation is one major cause of this disease's morbidity and mortality irrespective of the origin or transformed status of the epithelium secreting it. Because of this and because of the recent discovery and cloning of a series of specific mucin genes responsible for mucin secretion and extracellular deposition, we decided to analyze cases of pseudomyxoma peritonei with specific mucin cDNAs and corresponding antibodies to identify a characteristic marker for this disease which ultimately might be targeted therapeutically. Our study specifically investigated MUC2 and MUC5AC because these two mucins possessed the physicochemical property of being gel-forming, a property exhibited by pseudomyxoma peritonei grossly. Expression of MUC2 and MUC5AC in pseudomyxoma peritonei and in accompanying and nonaccompanying appendiceal and ovarian mucinous neoplasms were analyzed by in situ hybridization, immunocytochemistry and digital image analysis. A striking overexpression of both MUC2 and MUC5AC was observed in nearly all cases of pseudomyxoma peritonei of unknown and appendiceal origin. In these cases, however, MUC2 gene expression was more prominent. The mucin:cell ratio averaged 10 to 1 in these cases. The primary ovarian mucinous tumors, some of which exhibited pseudomyxoma ovarii and/or peritoneal implants but not classic pseudomyxoma peritonei, in contrast, expressed only MUC5AC and gave rise to implants where the mucin:cell ratio averaged only 1 to 1. MUC2 overexpression then supported an intestinal rather than ovarian origin for true pseudomyxoma peritonei, irrespective of whether an appendiceal primary was documented. In all cases studied, the fidelity of MUC2 and MUC5AC expression held irrespective of the degree of malignant transformation which was present. MUC2 is therefore a reliable molecular marker for pseudomyxoma peritonei.

Pathophysiology and biology of peritoneal carcinomatosis

“…Interestingly, cases of classic pseudomyxoma peritonei show the intestinal⁄appendiceal pattern (MUC-2+ and MUC-5AC+), as do appendiceal mucinous neoplasms, whereas cases of peritoneal implants or pseudomyxoma ovarii associated with primary ovarian mucinous neoplasms show the ovarian pattern (MUC-2-and MUC-5AC+), just as ovarian mucinous neoplasms do [36] . These findings support the notion that pseudomyxoma peritonei is a disease resulting from the accumulation of extracellular secretory-type mucin, particularly related to MUC-2 overexpression by neoplastic cells, thereby rendering MUC-2 expression a potential molecular target to inhibit the progression of the disease [35,37] .…”

“…MUC-2 is specifically expressed in goblet cells of the small bowel and colon, while MUC-5AC is generally expressed in the stomach and respiratory tracts. The vast majority of mucinous epithelial neoplasms of the appendix coexpress both MUC-2 and MUC-5AC, while mucinous neoplasms of the ovary express only MUC-5AC but not MUC-2 [35] . Interestingly, cases of classic pseudomyxoma peritonei show the intestinal⁄appendiceal pattern (MUC-2+ and MUC-5AC+), as do appendiceal mucinous neoplasms, whereas cases of peritoneal implants or pseudomyxoma ovarii associated with primary ovarian mucinous neoplasms show the ovarian pattern (MUC-2-and MUC-5AC+), just as ovarian mucinous neoplasms do [36] .…”

A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxoma peritonei

“…The reporting of CK20 positivity is variable in normal colonic epithelium as it is necessary (as in the current study) to have well-orientated mucosal sections to demonstrate staining in cells in the outer differentiated zone of the intestinal crypt (Hernandez et al, 2005). As in other studies (O'Connell et al, 2002;Mohamed et al, 2004), we demonstrated increased expression of MUC-2 in PMP tissue compared with normal mucosa and adenocarcinoma. Interleukin-9, which induces MUC-2 and MUC-5AC gene expression in the lung, and its receptor, IL-9Ra, were expressed at variable levels in all cases of PMP with increased IL-9 expression in the epithelial PMP cells compared with adenocarcinoma.…”

Borderline epithelial tumors of the ovary

“…Mucin gene overexpression studies, cytokeratin profiles and molecular genetic studies support the conclusion that the appendiceal tumor is the source of pseudomyxoma peritonei and the synchronous ovarian tumors. 85 Rarely, origin of pseudomyxoma peritonei is attributable to an ovarian borderline mucinous tumor associated with a mature teratoma. 25,86,87 Tumors with Noninvasive Carcinoma…”