Discordance between Molecular and Immunohistochemical Analyses for Lynch Syndrome Assessment.
Angela N Bartley, Rajyalakshimi Luthra, Devki Saraiya, Russell R Broaddus. The University of Texas MD Anderson Cancer Center, Houston
Background: Microsatellite instability analysis (MSI) and immunohistochemistry (IHC) for DNA mismatch repair (MMR) proteins are well-accepted clinical approaches to evaluate cancer patients for the possibility of Lynch Syndrome (LS). Some investigators advocate for the use of only one testing method to screen for LS given that the concordance between PCR-based MSI analysis and IHC is typically high. While MSI and IHC discordances have been acknowledged, the prevalence and nature of these cases have not been well-described. We examined the outcomes of a large number of IHC/MSI analyses performed in our laboratory to document discordance and frequency.
Design: The clinical records of 736 cancer patients who underwent MSI and/or IHC testing from 2002 to 2010 were evaluated. Patients with both MSI and IHC analysis (n=628) were subsequently studied in detail. Based on microsatellite marker analysis, 478 were classified as microsatellite stable (MSS), 97 as MSI-high (MSI-H) and 53 as MSI-low. Discordance was defined as a discrepancy between the MSI and IHC results. All IHC and MSI results and pertinent clinical and family history on discordant cases were re-reviewed by two pathologists and one clinical geneticist.
Results: Discordances were identified in 13 of 628 evaluated cases (2.1%). Twelve of 97 MSI-high (MSI-H) cases (12%) were discordant, showing intact IHC expression of the MLH1, MSH2, MSH6, and PMS2 proteins. Nine of these carcinomas were colorectal, 2 endometrial, and 1 small intestinal. 7/12 patients were younger than 50 years at age of diagnosis. 8/12 patients had a first degree relative with an LS-associated cancer. Germline mutational analysis of six patients revealed mutations in four (all colorectal carcinomas; two in MLH1, one in MSH2, one in PMS2). Both patients with MLH1 mutations fulfilled Amsterdam II criteria, but the others did not. One of 478 MSS tumors showed loss of MLH1 and PMS2 on IHC. Methylation of MLH1 was not detected in this tumor. No mutations of MLH1or MSH2 were detected on subsequent sequencing or rearrangement analysis.
Conclusions: IHC/MSI discordance is surprisingly common, occurring in about 12% of MSI-H cancers. IHC testing alone would miss a significant number of informative cases given that MMR gene mutations were detected in 67% of the MSI-H patients with positive IHC staining for all markers. Therefore, the use of IHC by itself may yield misleading results that fail to identify potential LS patients.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 89, Monday Morning