Microsatellite Instability in Gallbladder Carcinoma
Andrea Primiani, Mohammad Shahid, Omer Yilmaz, Cristina R Ferrone, Darrell R Borger, A John Iafrate, Andrew X Zhu, Vikram Deshpande. Massachusetts General Hospital, Boston, MA
Background: Gallbladder carcinoma (GBC) is a rare neoplasm in the United States. However, the genetic abnormalities involved in the pathogenesis of GBC remain unclear. Microsatellite instability (MSI) has been described in many carcinomas, including colorectal, but little is known about the role and significance of mismatch repair (MMR) genes in gallbladder carcinogenesis.
Design: Using tissue microarrays, 69 primary GBCs and 16 metastatic GBCs from 84 patients were evaluated for MSI by analyzing protein expression of MSH2, MSH6, MLH1, and PMS2 with immunohistochemistry (IHC). MSI was defined as loss of expression of any of the MMR proteins. Histologic features of the specimens [i.e. tumor grade, extracellular mucin, and tumor infiltrating lymphocytes (TILs)] and patient survival were compared between cases with and without MSI. The presence of TILs was defined as ≥5 intraepithelial lymphocytes per 10 high power fields (HPF). MSI was also evaluated by IHC in 9 gallbladders with high-grade dysplasia (HGD) and in 7 with pyloric gland adenomas (PGA). Fluorescence in-situ hybridization (FISH) was performed to evaluate amplification of human epidermal growth factor receptor 2 (Her2). Genotyping for selected genes was performed using a multiplex PCR platform. Survival was compared with the Kaplan-Meier analysis.
Results: By IHC, MSI was present in specimens from 10 (12%) patients, none of which had a history of malignancies typically associated with Lynch syndrome. Concurrent loss of MSH2 and MSH6 or of MLH1 and PMS2 was seen in 5 cases and 2 cases, respectively. Isolated loss of MSH2 or PMS2 was seen in 3 cases and 1 case, respectively. The presence of TILs was the only histologic feature significantly associated with tumors with MSI (p=0.06). The median survival of patients with tumors with and without MSI was 24 and 28 months, respectively (p=NS). Of note, MSI was not present within areas of flat dysplasia or PGA. Her2 amplification was detected in 4 cases without MSI. Among the 18 cases evaluated by genetic sequencing, 4 mutations (PI3K, KRAS, NRAS, and TP53) were identified in cases, all without MSI.