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 1/14 CC 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.

FIGURE 1

In normal pancreas, MUC6 was expressed in the intercalated ducts and in the small tributary ducts, but not in the intralobular and interlobular ducts, nor in the islets.

FIGURE 2

MUC6 was expressed in only a minority of PanINs, mostly in areas with pyloric gland type features (A&B). It was not detected in higher-grade PanINs (C&D).

FIGURE 3

In intraductal papillary mucinous neoplasms (IPMNs), MUC6 was commonly expressed in the cystic (nonpapillary) areas with pyloric gland-like appearance. It was also detected at the base of the papilla forming regions (A), but the expression in the papillae themselves (transformed areas) seemed to be lineage dependent, was negative in most gastric/foveolar (A) and villous/intestinal-types papillae (B) but was positive in oncocytic (C) and, to a lesser degree of intensity, in pancreatobiliary-types (D). The only gastric/foveolar-type IPMN that was positive for MUC6 displayed labeling only in the areas with high-grade dysplastic changes (E&F), which acquired pancreatobiliary type features but not in lesser grade areas. In the majority of mucinous cystic neoplasm (MCNs), MUC6 was negative in the papillary component. Even if it was positive, the positivity was confined to the base of the papillae (G). Only 1/3 of ductal adenocarcinomas (DAs) studied (35%) labeled with MUC6, mostly focal and weak. There was a trend with higher MUC6 expression and higher grade (H).

FIGURE 4

It is difficult to classify mucinous cystic neoplasm (MCN) papillae either as villous/intestinal (columnar-cell) or pancreatobiliary (cuboidal-cell) owing to their chimeric morphology.

FIGURE 5

It is difficult to classify mucinous cystic neoplasm (MCN) papillae either as villous/intestinal (columnar-cell) or pancreatobiliary (cuboidal-cell) owing to their chimeric morphology.