Immunohistochemical Pattern of MLH1/MSH2 Expression Is Related to Clinical and Pathological Features in Colorectal Adenocarcinomas with Microsatellite Instability

Lanza, Giovanni; Gafà, Roberta; Maestri, Iva; Santini, Alessandra; Matteuzzi, Maurizio; Cavazzini, Luigi

doi:10.1097/01.mp.0000018979.68686.b2

Cited by 112 publications

(94 citation statements)

References 33 publications

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“…MSI analysis was conducted through the use of sequence analyzers (Beckman or ABI PRISM377, Applied Biosystems). In most MSI-H cases, immunohistochemical expression of MMR proteins (MLH1, MSH2, and MSH6) was analyzed as previously reported (25,28). Constitutional mutations in MMR genes were searched through direct sequencing on DNA extracted from blood lymphocytes (25).…”

Section: Methodsmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer Prognosis

Benatti

Gafà

Barana

et al. 2005

Clinical Cancer Research

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Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions,1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results:Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year^specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non^polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients.The survival benefit for patients with hereditary non^polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

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Section: Methodsmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer Prognosis

Benatti

Gafà

Barana

et al. 2005

Clinical Cancer Research

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332

233

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“…Immunohistochemical analysis of MLH1 protein expression is a simple and easy way to detect MMR deficiency, and its reliability has been investigated previously (24). In the present study, immunohistochemistry of MLH1 was performed as a reliable method to detect MMR deficiency.…”

Section: Histological Response To -----------------------------------mentioning

confidence: 99%

MLH1 expression predicts the response to preoperative therapy and is associated with PD-L1 expression in esophageal cancer

et al. 2017

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Abstract. Programmed death-ligand 1 (PD-1/PD-L1) inhibition therapy demonstrates potential as a future treatment for esophageal cancer. Mismatch repair status and tumor PD-L1 expression are the candidate predictive biomarkers for response to this therapy. In colorectal cancer, mismatch repair-deficient tumors are associated with improved survival, although they are not sensitive to 5-fluorouracil-based chemotherapy. The purpose of the present study was to investigate the association between MutL homolog 1 (MLH1) expression and prognosis, response to therapy and PD-L1 expression in esophageal cancer. Immunohistochemistry was used to evaluate MLH1 and PD-L1 expression in 251 resected specimens. Of the specimens, 30.3% exhibited low MLH1 expression and 15.5% exhibited high PD-L1 expression. The 5-year overall survival rates for the high MLH1 expression group and the low MLH1 expression group were 51.3 and 55.6%, respectively (P=0.5260). The responder ratio was 45.7% in the high MLH1 expression group and 15.4% in the low MLH1 expression group (P<0.0001). The frequency of high PD-L1 expression was 11.4% in the high MLH1 expression group (P=0.0064) and 25.0% in the low MLH1 expression group. MLH1 expression may be a predictive factor for the response to preoperative therapy in esophageal cancer, and esophageal cancer with low MLH1 expression may have a mechanism that assists in promoting tumor PD-L1 expression.

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“…Numerous studies have shown that immunohistochemistry for MMR protein expression is highly sensitive and specific for MSI, 8,10,11,[24][25][26][27][28][29][30][31] including 100% sensitivity in sporadic microsatellite instable colorectal carcinoma and approximately 90% sensitivity in familial cases, with 100% specificity in all cases when appropriate internal and external controls are employed.…”

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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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Immunohistochemical Pattern of MLH1/MSH2 Expression Is Related to Clinical and Pathological Features in Colorectal Adenocarcinomas with Microsatellite Instability

Abstract: Detection of colorectal carcinomas with highfrequency microsatellite instability (MSI-H

Cited by 112 publications

References 33 publications

Microsatellite Instability and Colorectal Cancer Prognosis

Microsatellite Instability and Colorectal Cancer Prognosis

MLH1 expression predicts the response to preoperative therapy and is associated with PD-L1 expression in esophageal cancer

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

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