Gastric carcinoma in autoimmune gastritis: a histopathologic and molecular study

: Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathological and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from four Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, Mismatch Repair (MMR) proteins, and p53 and EBER in situ hybridization were performed. Histologic features and IHC were jointly reviewed by five expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%), were located in the corpus/fundus (58%) and were associated with OLGA stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia and ECL-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 Combined Positive Score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) MSI cases and 7 (37%) TMB-high. The most frequently altered genes were: TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [two amplified and five mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with long-standing misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB-high.