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Immunohistochemical Test for MLH1 and MSH2 Expression Predicts Clinical Outcome in Stage II and III Colorectal Cancer Patients

Giovanni Lanza, Roberta Gafà, Alessandra Santini, Iva Maestri, Laura Guerzoni, Luigi Cavazzini

From the Department of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara; and the Division of Clinical Oncology, St Anna Hospital, Ferrara, Italy

Address reprint requests to Giovanni Lanza, MD, Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Anatomia Istologia e Citologia Patologica, Università di Ferrara, Via Fossato di Mortara 64/b, 44100 Ferrara, Italy; e-mail: lng{at}unife.it

PURPOSE: To evaluate the prognostic significance of DNA mismatch repair (MMR) status in a large series of stage II and III colorectal cancer patients. The relationship among MMR status, adjuvant chemotherapy, and clinical outcome was also investigated.

PATIENTS AND METHODS: The study included 718 patients with colorectal adenocarcinoma (393 stage II and 325 stage III) who underwent curative surgical resection. MMR status was determined by immunohistochemical analysis of MLH1 and MSH2 expression. Microsatellite instability (MSI) was assessed in 363 patients using mononucleotide and dinucleotide markers.

RESULTS: One hundred fourteen (15.9%) carcinomas showed abnormal MMR protein (MMRP) expression (96 MLH1 negative and 18 MSH2 negative) and were classified as MMRP negative, whereas 604 tumors demonstrated normal MLH1/MSH2 immunoreactivity (MMRP positive). MLH1/MSH2 expression was closely related to MSI status (P < .001) and several clinicopathologic features. Patients with MMRP-negative carcinomas demonstrated a marked reduction in the risk of cancer-related death with respect to patients with MMRP-positive tumors (hazard ratio, 0.2579; 95% CI, 0.1289 to 0.5159). A better clinical outcome for patients with MMRP-negative tumors was observed in both stage II (P = .0006) and stage III (P = .0052) disease. In stage III disease, the survival advantage conferred by MMRP-negative tumors was more evident among patients treated with surgery alone than among patients who received adjuvant chemotherapy. A nonsignificant trend for survival benefit from adjuvant chemotherapy was observed among patients with MMRP-positive carcinomas but not among those with MMRP-negative carcinomas.

CONCLUSION: Immunohistochemical testing for MLH1/MSH2 expression provides useful prognostic information for the management of stage II and III colorectal cancer patients.

Supported by the Consiglio Nazionale delle Ricerche, "Progetto Strategico Oncologia," Grant No. CU03.00366, and by the Ministero dell'Istruzione, dell'Università e della Ricerca, and the Fondazione Cassa di Risparmio di Ferrara.

Presented in part at the 3rd European Organization for Research and Treatment of Cancer–National Cancer Institute International Meeting on Cancer Molecular Markers, Brussels, Belgium, April 18-20, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.