Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Arai, Tomio; Esaki, Yukiyoshi; Sawabe, Motoji; Honma, Naoko; Nakamura, Kenichi; Takubo, Kaiyo

doi:10.1038/modpathol.3800018

Cited by 50 publications

(71 citation statements)

References 27 publications

(41 reference statements)

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“…Several reports, together with our results, have demonstrated that microsatellite-unstable gastric carcinomas are significantly associated with the elderly [2,[4][5][6], women [3,5], and antral location [2,4,5,9]. These characteristics are similar to those of medullary-type, poorly differentiated adenocarcinoma of the colorectum, which is a representative MSI-positive carcinoma showing predominant occurrence in older age, women, and the proximal colon [26]. Medullary-type colorectal carcinoma shows hypermethylation of the hMLH1 promoter with loss of hMLH1 expression [26].…”

Section: Discussionsupporting

confidence: 68%

“…These characteristics are similar to those of medullary-type, poorly differentiated adenocarcinoma of the colorectum, which is a representative MSI-positive carcinoma showing predominant occurrence in older age, women, and the proximal colon [26]. Medullary-type colorectal carcinoma shows hypermethylation of the hMLH1 promoter with loss of hMLH1 expression [26]. As already mentioned, papillary adenocarcinoma of the stomach has the same features [8].…”

Section: Discussionsupporting

confidence: 53%

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Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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Background Microsatellite instability (MSI) has been observed in 8-39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas. Methods Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings.Results MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51-64 years, 8.5 % at 65-74 years, 18.4 % at 75-84 years, 35.3 % at 85-96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage. Conclusions These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiatedtype carcinomas, indicating histological diversity during tumor growth.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 53%

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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“…4 An additional 10-20% of sporadic colorectal carcinomas are associated with MSI 4 and these are virtually all associated with loss of hMLH1 protein expression, primarily due to methylation of the hMLH1 promoter. [4][5][6] Conversely, defective hMSH2 or hMSH6 is almost always due to germline mutations. 7 Several investigators have reported that colorectal carcinomas with defective MMR often show distinctive clinicopathologic features including location in the proximal colon, younger patient age, mucinous differentiation, and a host-immune response characterized by a Crohn's-like lymphoid reaction or tumor infiltrating lymphocytes.…”

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confidence: 99%

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

2004

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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.

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“…[1][2][3][4][5][6] The World Health Organization recognizes MC as a separate entity of colorectal carcinoma in the 2010 edition of WHO Classification of Tumours of the Digestive System. 7 Medullary carcinoma typically presents as a large-sized tumor of the right side of the colon, especially in the cecum, in elderly patients, and is more frequently seen in women than in men, with a ratio of 2:1.…”

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Cadherin-17 and SATB2 Are Sensitive and Specific Immunomarkers for Medullary Carcinoma of the Large Intestine

Lin

Shi

Zhu

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

113

117

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Context.-Distinction of medullary carcinoma of the large intestine from other cytokeratin (CK) 7 À /CK20 À carcinomas can be challenging when working on a tumor of unknown primary because the majority of medullary carcinomas are negative for CK7, CK20, and CDX2.Objective.-To investigate the expression of cadherin-17 and SATB-2 and other markers in medullary carcinomas of the large intestine and cadherin-17 and SATB2 in a large number of carcinomas and normal tissues from various organs to further test their diagnostic specificity.Design.-This study evaluated cadherin-17 and SATB2 expression in 18 medullary carcinoma cases and 1941 tumors and 358 normal tissues from various organs. Other immunomarkers, including MLH1, PMS2, MSH2, MSH6, CDX2, CK7, CK20, TFF3, MUC4, calretinin, p504S, villin, and synaptophysin, were also tested on the 18 medullary carcinoma cases.Results.-The results demonstrated (1) loss of MLH1 and PMS2 in more than 80% of medullary carcinomas; (2) expression of cadherin-17 and SATB2 in 89% of medullary carcinomas; (3) focal expression of TFF3, MUC4, calretinin, CDX2, CK20, and synaptophysin in 72%, 72%, 67%, 67%, 28%, and 17% of 18 medullary carcinoma cases, respectively; and (4) expression of SATB2 and cadherin-17 in 97% and 98% of the colorectal adenocarcinomas, respectively, whereas their expression was seen in 3.6% and 3.3% of nongastrointestinal tumors, respectively.Conclusions.-We concluded that SATB2 and cadherin-17 were highly sensitive and specific markers for colorectal carcinomas and propose including MLH1, cadherin-17, and SATB2 in a routine immunostaining panel when working on a tumor of unknown primary, especially in an elderly patient with a CK7 À /CK20À carcinoma.

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Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Cited by 50 publications

References 27 publications

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

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

Cadherin-17 and SATB2 Are Sensitive and Specific Immunomarkers for Medullary Carcinoma of the Large Intestine

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