Mixed Endocrine-Exocrine Carcinoma of Gallbladder Derived from Dysplasia

Mixed endocrine-exocrine carcinoma (MEEC) of gastrointestinal tract has been known to be rare but in fact, a significant number of cases reported in older literature as carcinoids were MEECs. These tumors may display variable proportions of two components, with variable structural patterns, ranging from individually scattered neuroendocrine cells to well-formed neuroendocrine tumor with organoid nesting, trabecular, or solid growth patterns, and variable grades of neuroendocrine component from carcinoid to well differentiated or poorly differentiated neuroendocrine carcinoma (NEC). Although these variations show organ dependent pattern in general, clear definitions and diagnostic features are still missing, as well as a definite knowledge of their biological properties and histogenesis. In gastrointestinal tract, MEEC was defined as epithelial malignant tumors characterized by a combination of a predominant exocrine component and a neuroendocrine cell subpopulation more than one third of total tumor volume. In the pancreas, MEEC includes mixed ductal-endocrine and mixed acinarendocrine carcinoma. However, MEEC of gallbladder is very rare and only a few cases have been reported so far as adenoendocrine cell carcinoma of gallbladder. It has been well established that invasive gallbladder carcinoma is preceded by preneoplastic lesions, including dysplasia and carcinoma in situ (CIS). In addition, metaplasia of intestinal or pyloric type is frequently observed near carcinomas, but its malignant potential is unknown. The genetic alterations commonly observed in sporadic biliary tract cancers include mutations of the K-ras, p16, adenomatosis polyposis coli, β-catenin, and p53 genes, p53 overexpression, and loss of heterozygosity (LOH) of chromosomal arms. Microsatellite instability (MSI) status in gallbladder cancer is different according to the histologic subtype and geographical and racial variants. MEEC of gallbladder with dominant NEC with the remaining mucosa showing various spectrum of mucosal change from low grade dysplasia (LGD) to high grade dysplasia (HGD) is described in the article. The results of the immunohistochemical and genetic analysis including MSI, LOH, and K-ras mutation suggest that NEC might be derived from dysplasia-adenocarcinoma (AC) sequence.