Unraveling Neuroendocrine Gallbladder Cancer: Comprehensive Clinicopathologic and Molecular Characterization

Abstract

PURPOSE Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions. PATIENTS AND METHODS We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes. RESULTS Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L, ATM, and BRCA2; amplifications of ERBB2 and MDM2; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of < 10 mutations/Mb. CONCLUSION Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer.

Comparative Survival Benefits of Surgery and Adjuvant Chemotherapy in Neuroendocrine Carcinoma of the Gallbladder: A Population-Based Study with Insight into Future Personalized Therapeutic Approach

“…The PI3K/AKT/mTOR pathway is involved in the progression of NENs [ 22 ]. Everolimus, a rapamycin inhibitor, has also shown improved progression-free survival and efficacy in patients with well-differentiated or moderately differentiated pancreatic NETs [ 27 ]. A study by Yao et al found that the median progression-free survival in patients with low- or intermediate-grade pancreatic NETs with radiological progression in the past 12 months receiving everolimus was 11.0 months compared to 4.5 months in the placebo group [ 28 ].…”

A rare occurrence of a poorly differentiated large cell neuroendocrine carcinoma of the gallbladder: A case report and review of the literature

“…Radiation can also be added; however, its benefits remain unclear due to the insensitivity of neuroendocrine tumors to radiotherapy [ 19 ]. There may also be a role for somatostatin analogs, targeted therapy, and immunotherapy [ 1 , 7 , 20 ].…”

“…Primary neuroendocrine neoplasms (NEN) are a rare malignancy with neuroendocrine tumors of the gallbladder comprising solely 0.5 % of cases of NENs and 5 % of all primary gallbladder carcinomas [ 1 , 2 ]. The World Health Organization (WHO) classification system subdivides NENs into well differentiated neuroendocrine tumors (NET), poorly differentiated NEC, and mixed endocrine non-endocrine neoplasms (MiNENs) [ 3 ].…”

Establishment and characterization of the first patient-derived radiation-induced angiosarcoma xenograft model (RT-AS5)

“…TSO500 panel-based sequencing was performed as described previously to analyze genomic aberrations that were present in the model 18 , 19 .…”