Mismatch repair protein loss and microsatellite instability in cholangiocarcinoma.

Abstract

237 Background: Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch Syndrome, is an autosomal dominant syndrome characterized by mutations in genes involved in DNA mismatch repair (MMR) and consequent microsatellite instability (MSI). These genetic aberrations lead to an increased incidence of multiple malignancies including colorectal and endometrial cancer, among others. While an association between biliary tumors and HNPCC has been proposed, no published studies have documented MMR protein loss and MSI in a series of biliary tumor samples. After diagnosing cholangiocarcinoma (CCA) in two clinic patients known to have HNPCC and incidentally noting MMR protein loss and MSI in their tumor, we conducted an exploratory study to evaluate the frequency of MMR protein loss and MSI in patients with CCA. Methods: Discarded tissue samples from patients with CCA treated at the Massachusetts General Hospital (n=44) were evaluated for the loss of MLH1, PMS2, MSH2, and MSH6 with immunohistochemical staining. The results were correlated with clinicopathologic features, and the MSI status was collected from the medical record. Results: Four (9.1%) of 44 patients were found to have loss of at least two MMR proteins: 2 pts had MSH2/MSH6 loss, 1 had MLH1/PMS2 loss, and 1 had loss of all 4 proteins. Two patients had previously been tested for microsatellite instability and both were MSI-high. The clinicopathologic features of the 4 patients included: median age 54.5 yo; M:F 1:3; diagnosed with ≥ 1 HNPCC-related malignancy 1/4; family history of ≥ 2 HNPCC-related tumors 2/4, intrahepatic:extrahepatic CCA 3:1; moderately-poorly:poorly differentiated 2:2; T1:T2 3:1; ≥1 positive lymph node 1/4; lymphovascular invasion 2/3; perineural invasion 2/4. Conclusions: MMR protein loss was discovered in 9.1% of patients with CCA in this initial cohort. A second validation cohort from a different institution is currently being tested, and the results will be presented at the meeting. CCA may be an underappreciated co-morbid neoplasm in the spectrum of tumors for HNPCC. MMR protein loss should be further explored as a mechanism of oncogenesis in CCA, and clinicians should be aware of this malignancy in surveillance of patients with HNPCC.