Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma

Abstract

Small intestinal adenocarcinoma is an uncommon neoplasm morphologically similar to or indistinguishable from colorectal adenocarcinoma. Although much has been learned about genetic pathways critical to colorectal tumorigenesis, little is known about molecular alterations involved in the development of small intestinal adenocarcinoma. In this study, we immunohistochemically compared non-ampullary small intestinal adenocarcinomas with sporadic colorectal adenocarcinomas for the expression of several proteins known to serve pivotal roles in colorectal tumorigenesis. These included adenomatous polyposis coli and b-catenin involved in the Wnt signaling pathway, and DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 involved in the microsatellite instability pathway. The expression of two important tumor suppressors, p53 and RB, was also examined. The results show that complete loss of adenomatous polyposis coli immunoreactivity, presumably resulting from its gene mutations, was observed in eight of 26 (31%) small intestinal adenocarcinomas and 36 of 51 (71%) colorectal adenocarcinomas (P ¼ 0.0008). Nuclear localization of b-catenin, an indirect evidence of deregulated Wnt signaling pathway, was observed in 5 (19%) small intestinal adenocarcinomas and 36 (71%) colorectal adenocarcinomas (Po0.0001). Total lack of nuclear staining for one or more of the DNA mismatch repair enzymes occurred in a similar low frequency in both small intestinal and colorectal adenocarcinomas, seen in two of 25 (8%) and 10 of 47 (21%) cases, respectively (P ¼ 0.1958). The frequencies of aberrant p53 and RB expression were also similar between small intestinal and colorectal adenocarcinomas. These observations indicate that defects in the Wnt and microsatellite instability pathways occur in over 90% of colorectal adenocarcinomas, but in only 40% of small intestinal adenocarcinomas. Small intestinal tumorigenesis appears to follow a distinct, yet unidentified, molecular pathway(s) from its colorectal counterpart despite their morphologic similarity.

Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine

“…Colorectal cancer cases that are negative for CDX2 expression tend to be poorly differentiated tumours, and consistent with this finding, we observed that whereas 100% of well-differentiated tumours were % 70 57 31 43 15 28 13 Negative, % 30 43 69 57 85 72 CDX2 positive, only 58% of poorly differentiated tumours were CDX2 positive (Werling et al, 2003). The reported incidence of abnormalities in MMR genes in SBA patients has been variable, ranging from 5 to 45% by microsatellite testing and from 0 to 26% by immunohistochemical staining of tumour samples (Hibi et al, 1995;Rashid and Hamilton, 1997;Blaker et al, 2002;Planck et al, 2003;Brueckl et al, 2004;Zhang et al, 2006). In our study, we saw a higher rate of defective MMR, with 35% of patients showing loss of MMR protein expression.…”

Immunohistochemical expression of CDX2, β-catenin, and TP53 in inflammatory bowel disease-associated colorectal cancer

“…Therefore, at this time, final interpretation is not possible due to the absence of direct comparison using the same techniques between CD-associated SBA and sporadic SBA, the small size of our series, the fact that it is not possible to know if the tumors exhibiting b-catenin abnormalities in the previously published series are sporadic or CD-associated SBA. [55][56][57][58] In addition, the significance of isolated cytoplasmic b-catenin staining in the absence of nuclear expression, as a marker of b-catenin mutation, has been questioned. 56 Finally, as for i-CRC, we found high nuclear TP53 expression in the four CD-associated SBA tissue samples, a pattern suggesting that TP53 might be an actor of small intestinal carcinogenesis in CD patients, presumably as a result of chronic inflammation.…”

“…[55][56][57][58] In addition, the significance of isolated cytoplasmic b-catenin staining in the absence of nuclear expression, as a marker of b-catenin mutation, has been questioned. 56 Finally, as for i-CRC, we found high nuclear TP53 expression in the four CD-associated SBA tissue samples, a pattern suggesting that TP53 might be an actor of small intestinal carcinogenesis in CD patients, presumably as a result of chronic inflammation. Previous studies, mostly performed on sporadic SBA mucosal samples, showed variable TP53 expression, ranging from 24%-51.8%.…”

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas

“…57 Immunohistochemically, small intestinal adenocarcinomas more frequently express CK7, and less frequently express CK20, CDX2, and a-methylacyl coenzyme-A racemase, in comparison with CRCs. [58][59][60][61][62] Interestingly, a CK7 þ /CK20 À pattern is much more commonly seen in Crohn-associated small intestinal adenocarcinomas than in sporadic cases.…”