Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Abstract

Defective DNA mismatch repair has been proposed as a second pathway for colonic carcinogenesis, particularly in tumors arising in the right colon. We investigated whether tumors arising in the appendix are associated with defective DNA mismatch repair using immunohistochemistry for mismatch repair enzymes hMLH-1, hMSH-2, hMSH-6, and hPMS-2. These immunoassays have been shown to be highly sensitive and specific for defective DNA mismatch repair in sporadic and familial adenocarcinomas. Sporadic adenocarcinomas with defective DNA mismatch repair essentially always show loss of hMLH-1, while loss of hMSH-2, hMSH-6, or hPMS-2 is almost always due to germline mutation. In all, 35 cases of appendiceal epithelial neoplasms were evaluated, comprising 18 low-grade appendiceal mucinous neoplasms confined to the appendix; eight low-grade appendiceal mucinous neoplasms with extra-appendiceal spread (five peritoneum and ovaries, two peritoneum, one ovaries only); and nine invasive adenocarcinomas (three with metastatic disease). All immunohistochemical slides were reviewed by two pathologists. One (11%) invasive adenocarcinoma showed absent expression of hMSH-2 and hMSH-6, but preserved hMLH-1 and hPMS-2 expression. This case was a 26-year-old female with a history of synovial sarcoma who presented with acute appendicitis and appendiceal perforation (median age for other invasive carcinomas, 62 years; range 38-76 years). The appendiceal tumor was a moderately differentiated, colonic-type adenocarcinoma without significant extracellular mucin or tumor-infiltrating lymphocytes. The remaining invasive carcinomas and low-grade appendiceal mucinous neoplasms demonstrated preserved expression of all mismatch repair enzymes, including the seven cases in which extra-appendiceal tumor was also evaluated. We conclude that defective DNA mismatch repair does not play a role in the pathogenesis of low-grade appendiceal mucinous neoplasms. Defective DNA mismatch was found in 11% of invasive carcinomas, likely due to a germline mutation. These findings suggest that sporadic appendiceal neoplasia rarely arises through the defective DNA mismatch repair (mutator) pathway.

High-level Microsatellite Instability in Appendiceal Carcinomas

“…These included: 1) pT1 N0 moderately differentiated adenocarcinoma with loss of MSH2/MSH6 expression and MSI-high by PCR, in a 29-year-old man with Lynch syndrome due to germline A636P MSH2 mutation, 25 2) moderately differentiated colonic-type adenocarcinoma with loss of MSH2/MSH6 expression, confined to the appendix, in a 26-year-old woman with a history of synovial sarcoma, 27 3) invasive adenocarcinoma arising from a sessile serrated polyp, with loss of MLH1 expression in both the adenocarcinoma and polyp but MSI-high by PCR only in the carcinoma component, 29 and 4) pT4a pN2a invasive mucinous carcinoma with MSI-high by PCR and loss of both MLH1 and MSH2 expression, in a 42-year-old man without a family history of cancer. 26 (The appendiceal serrated adenoma was MSI-high with allelic shifts in 3 of 5 microsatellite markers, but no immunohistochemistry or mutational testing of individual MMR genes was performed.…”

“…20, 22, 23, 24 To our knowledge, only four individual cases of MSI-high appendiceal carcinomas and one case of an appendiceal serrated adenoma with MSI have been previously reported. 25, 26, 27, 28, 29 Only one of these patients had documented Lynch syndrome. 25 …”

Immunohistochemical expressions of cytokeratins, mucin core proteins, p53, and neuroendocrine cell markers in epithelial neoplasm of appendix

“…In fact, immunophenotypic changes [9,10], genetic alterations of TP53, K-RAS, and DPC4, or loss of chromosome 18q [11][12][13] have been reported in appendiceal adenocarcinomas. However, the information is still fragmentary, and the results are still inconsistent in particular with p53 positivity or endocrine cell population.…”

Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma

“…28 Although one apparent case of clear cell sarcoma with MSI has been reported, the t(12;22) status of the case was not specified. 54 In keeping with the observation that loss of hMLH1 and hMSH2 is rare in most sporadic malignancies, 34,41,55 hMLH1 and hMSH2 expression was preserved in clear cell sarcoma. However, we did note absence of hMSH6 in two clear cell sarcomas (only one of which demonstrated MSI).…”