Preferential Expression of MUC6 in Oncocytic and Pancreatobiliary Types of Intraductal Papillary Neoplasms Highlights a Pyloropancreatic Pathway, Distinct From the Intestinal Pathway, in Pancreatic Carcinogenesis

Abstract

The expression of different MUC glycoproteins has helped define cellular lineage in variety of pancreatic neoplasms, and has helped identify distinct carcinogenic pathways such as the intestinal pathway characterized by diffuse/strong MUC2/CDX2 expression in intestinal-type intraductal papillary mucinous neoplasms (IPMNs) and their associated colloid carcinomas (CCs). In this study, the expression profile of MUC6, a pyloric-type mucin, was investigated in both preinvasive and invasive pancreatic neoplasia. Florid papillary (“in-situ”) components of 9 intraductal oncocytic papillary neoplasms (IOPNs), 24 IPMNs, and 7 mucinous cystic neoplasms (MCNs), were analyzed immunohistochemically for MUC6 expression, as were 15 PanINs, 112 usual invasive ductal adenocarcinomas (DAs), and 14 CCs. In PanINs, MUC6 expression was limited to the very early areas of PanIN-1A that typically have pyloric features. Expression was lost in later stages. Similarly, in IOPNs or IPMNs or MCNs, MUC6 expression was detectable in the cystic or flat areas that have pyloric-like histology. However, in the more advanced (papillary) components of these neoplasms, MUC6 expression was mostly limited to the “cuboidal-cell” but was not seen in the “columnar-cell” phenotype: there was diffuse or strong expression in 8/9 IOPN and, relatively weaker but consistent expression in all 6/6 pancreatobiliary-type IPMNs; whereas virtually no expression in villous or intestinal-type IPMNs. The 7/8 gastric or foveolar-type IPMNs were also negative; in the single case with positivity, the labeling was limited to high-grade dysplastic areas. Interestingly, the papillae in MCNs were also mostly negative. Among invasive carcinomas, 39/112 DAs and only 1/14CC expressed MUC6. In DA, the expression did not correlate with survival (P=0.94), or any of the markers of aggressiveness: more than 2-cm tumor size (P=0.76), positive surgical margins (P=0.27), lymph node metastasis (P=0.82), or high grade (P=0.08). In conclusion: (1) The expression of MUC6 in oncocytic and pancreatobiliary-type neoplasms but not in villous or intestinal-type neoplasms supports the presence of a pyloropancreatic pathway distinct from the MUC2/CDX2 expressing intestinal pathway in intraductal papillary neoplasia. (2) MUC6 expression is present in the earliest (nonpapillary) form of any type of preinvasive neoplasia regardless of whether it is PanIN or IOPN or IPMN or MCN suggesting that these entities may share some characteristics early on, but evolve along divergent pathways as they progress.

Pancreatic lymphoepithelial cysts express CEA and can contain mucous cells: potential pitfalls in the preoperative diagnosis

“…32 Interestingly, mucins are differentially expressed in mucinous cysts of the pancreas; MUC5AC is consistently expressed in the epithelial lining of pancreatic mucinous cysts; MUC2 is expressed in intestinal-type epithelial lining; and both MUC1 and MUC6 are expressed in pancreaticobiliary and oncocytic epithelial lining. 33,34 The mucin expression profile of lymphoepithelial cysts has not been described previously in the literature. In our study, MUC1 and MUC4 were positive in all cysts and MUC2 and MUC6 were negative in all cysts.…”

GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

“…19 These two pathways are clinically, pathologically and genetically distinct. Analogous to the pancreas, two precursor pathways have been pathologically identified in the biliary tree, comprising non-papillary biliary intra-epithelial neoplasia (bilIN) lesions, and IPBNs.…”

Interobserver variability in intraductal papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles

“…This however may reflect our low number of pancreatobiliary cases. 19 Previous studies have distinguished MUC1 as an aggressive marker in pancreatic neoplasms, positive in areas of invasive carcinoma and IPMN with high-grade dysplasia. [20][21][22] Though limited in the number of cases, the pancreatobiliary subtypes of IPMN in our study were the only ones with positivity for MUC1.…”