The Dichotomy in the Preinvasive Neoplasia to Invasive Carcinoma Sequence in the Pancreas: Differential Expression of MUC1 and MUC2 Supports the Existence of Two Separate Pathways of Carcinogenesis

Abstract

Emerging evidence suggests a dichotomy in the dysplasia-CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of <15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of >55%). We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting "aggressive" and "indolent" phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n ‫؍‬ 43), intraductal papillary mucinous neoplasms (n ‫؍‬ 74), ductal adenocarcinomas (n ‫؍‬ 136), and colloid carcinomas (n ‫؍‬ 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2؉ (100%) and MUC1؊ (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1؉ and only 1% were MUC2؉. These results support a dichotomy in the dysplasia-CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the "indolent" pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell-cell and cell-stroma interactions as well as in immunoresistance of tumor cells) is a marker of the "aggressive" pathway (PanIN to ductal adenocarcinoma). The vast majority of pancreatic neoplasms are ductal adenocarcinomas, characterized morphologically by invasive tubular units that are often associated with a dense desmoplastic stroma. Ductal adenocarcinomas are among the most lethal cancers, with an overall 5-year patient survival rate of Ͻ5% (1-3). As is true for other epithelial malignancies, ductal adenocarcinomas are believed to arise from morphologically distinct precursor lesions (4 -12). A uniform nomenclature and standardized diagnostic criteria for these precursor lesions have recently been adopted, and the accepted terminology is now pancreatic intraepithelial neoplasia (PanIN; 13). KEY WORDS: Carcinogenesis

Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy

“…MUC4 is expressed by metasplastic ducts and its expression increases with a higher grade of PanINs (Swartz et al, 2002;Park et al, 2003). Similarly, MUC1 expression also increases with the progression of PanIN lesions ( Figure 1B), whereas MUC2 expression remains unchanged (Adsay et al, 2002).…”

“…The main mucin expressed by the normal pancreatic tissue is MUC6 . MUC6 and MUC1 are already expressed at an early stage of gestation in the fetal pancreas (Reid and Harris, 1998;Buisine et al, 2000;Adsay et al, 2002). MUC5B is moderately expressed, while MUC1 and MUC5AC are weakly detected in the adult pancreas (Yonezawa et al, 1997;Yonezawa et al, 1999;Andrianifahanana et al, 2001;Terris et al, 2002).…”

“…The main difference between adenocarcinoma of the pancreas and IPMT is an increased expression of MUC2 associated with a decreased expression of MUC1 in IPMT vs adenocarcinoma. (Adsay et al, 2002) In both cases, MUC4 is highly aberrantly expressed. While mucin gene profile is in general a good marker for PC, it also serves to distinguish IPMT from adenocarcinoma.…”

REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

“…Adsay et al suggested that the intestinal-type IPMN to colloid carcinoma sequence is a distinct pathway of carcinogenesis involving intestinal-related genes CDX2 and MUC2, and they described this pathway as the 'intestinal' pathway of carcinogenesis. 4,5,10 …”

Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade

“…Therefore, IPMN is gaining attention as a precursor of infiltrating adenocarcinoma in the pancreas as well as pancreatic intraepithelial neoplasia (PanIN). [4][5][6] Investigation of factors correlated with the progression of noninvasive and/or invasive IPMNs is important. …”