Pyloric Gland Adenoma with Mismatch Repair Protein Loss and MSI-High Is a Precursor of Gastric Adenocarcinoma in Lynch Syndrome
Seung Eun Lee, Dong K Chang, Soyoung Kang, Cheol K Park, Kyoung-Mee Kim. Samsung Medical Center, Seoul, Korea
Background: Fundic gland polyposis is a gastric manifestation in patients with FAP. However, although gastric carcinoma is the second most common extra-colonic malignancy associated with Lynch syndrome, the detailed pathology or precursor lesions in the stomach are not described. In this study, we performed clinicopatholologic and molecular analyses using 13 gastric carcinomas from patients with Lynch syndrome.
Design: After computer search, 392 patients were identified to have both gastric and colonic adenocarcinomas. Additionally, 311 patients enrolled in familial cancer clinic suspected as Lynch syndrome were also retrieved. All the medical records of 703 patients in a single comprehensive cancer center from 1995 to 2011 were reviewed. Twenty patients met the Amsterdam II criteria and had been treated for gastric and colonic adenocarcinomas. Immunohistochemistry for mismatch repair (MMR) proteins, MSI tests, MLPA for hMLH1 and hMSH2 were performed to confirm Lynch syndrome.
Results: Thirteen patients were classified as Lynch syndrome and the average age of diagnosis of gastric carcinoma was 48 years. The location of tumor was antrum (n=8) followed by body (n=3) and cardia (n=2). Helicobacter pylori were demonstrated in 4 cases (30.8%) and background intestinal metaplasia and atrophy was identified in 11 cases (84.6%). The histology of gastric carcinoma included 10 tubular adenocarcinomas, 2 mucinous carcinomas, and a composite adenocarcinoma and endocrine carcinoma. In all cases, both gastric and colonic carcinomas were MSI-high and either hMLH1 or hMSH2 protein was lost in tumors.
Unexpectedly, pyloric gland adenoma (PGA) was identified in 4 cases around the carcinomas. PGAs mimicked fundic gland polyp except for the absence of oxyntic cells. Most tumor glands in PGAs were strongly positive for MUC6 and superficial layer was positive for MUC5AC, while MUC2 and CD10 were totally negative. In a PGA with germline hMLH1 mutation, hMLH1 protein expression was lost. Three PGAs with hMSH2 protein loss showed abnormalities in MLPA. The carcinomas around PGA were tubular adenocarcinoma of gastric mucin phenotype. In three cases, there was a direct transition from PGA to carcinoma and one PGA transformed to carcinoma over the follow up of 2 years.
Conclusions: We first identified that PGA may be a precursor lesion of gastric carcinoma in Lynch syndrome and accompanies MMR protein loss and MSI-high. Our findings suggest that MSI-phenotype is an early event and the MMR-deficient pathway also involves gastric carcinogenesis.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 117, Monday Morning