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Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors

From the Departments of Medical Genetics, Laboratory Medicine and Pathology, Oncology, Biostatistics, and Clinical Epidemiology, Mayo Foundation, Rochester, MN; Pathology Department, University of Queensland, Queensland; Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Brisbane; Department of General Practice and Public Health, University of Melbourne, Victoria, Australia; Departments of Surgery and Pathology, Mt Sinai Hospital, Toronto, Ontario, Canada; and Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Address reprints requests to Noralane M. Lindor, MD, E7B Medical Genetics, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email: nlindor{at}mayo.edu

PURPOSE: To compare microsatellite instability (MSI) testing with immunohistochemical (IHC) detection of hMLH1 and hMSH2 in colorectal cancer.

PATIENTS AND METHODS: Colorectal cancers from 1,144 patients were assessed for DNA mismatch repair deficiency by two methods: MSI testing and IHC detection of hMLH1 and hMSH2 gene products. High-frequency MSI (MSI-H) was defined as more than 30% instability of at least five markers; low-level MSI (MSI-L) was defined as 1% to 29% of loci unstable.

RESULTS: Of 1,144 tumors tested, 818 showed intact expression of hMLH1 and hMSH2. Of these, 680 were microsatellite stable (MSS), 27 were MSI-H, and 111 were MSI-L. In all, 228 tumors showed absence of hMLH1 expression and 98 showed absence of hMSH2 expression: all were MSI-H.

CONCLUSION: IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.

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