Clinicopathologic and molecular characteristics of neuroendocrine carcinomas of the gallbladder

• Hui Tang ; Xiaojun Jiang ^[1] ; Lili Zhu ^[1] ; Liming Xu ^[1] ; Xiaoxi Wang ^[1] ; Hong Li ^[1] ; Feifei Gao ^[1] ; Xinxin Liu ^[1] ; Chuanli Ren ^[2] ; Yan Zhao ^[3]
  1. [1] Zhejiang University

     Zhejiang University

     China

     
  2. [2] Nanjing University of Chinese Medicine

     Nanjing University of Chinese Medicine

     China

     
  3. [3] Northern Jiangsu People's Hospital, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China

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• Localización: Histology and histopathology: cellular and molecular biology, ISSN-e 1699-5848, ISSN 0213-3911, Vol. 40, Nº. 3, 2025, págs. 389-400
• Idioma: inglés
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• Resumen

  • Gallbladder neuroendocrine carcinomas (GB-NECs) are a rare subtype of malignant gallbladder cancer (GBC). The genetic and molecular characteristics of GB-NECs are rarely reported. This study aims to assess the frequency of microsatellite instability (MSI) in GB-NECs and characterize their clinicopathologic and molecular features in comparison with gallbladder adenocarcinomas (GB-ADCs). Data from six patients with primary GB-NECs and 13 with GB-ADCs were collected and reevaluated. MSI assay, immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), comprehensive genomic profiling (CGP) via next-generation sequencing (NGS), and evaluation of tumor mutation burden (TMB) were conducted on these samples. The six GB-NEC cases were all female, with a mean age of 62.0±9.2 years. Of these, two cases were diagnosed as large cell neuroendocrine carcinomas (LCNECs), while the remaining four were small cell neuroendocrine carcinomas (SCNECs). Microsatellite states observed in both GB-NECs and GB-ADCs were consistently microsatellite stable (MSS). Notably, TP53 (100%, 6/6) and RB1 (100%, 6/6) exhibited the highest mutation frequency in GB-NECs, followed by SMAD4 (50%, 3/6), GNAS (50%, 3/6), and RICTOR (33%, 2/6), with RB1, GNAS, and RICTOR specifically present in GB-NECs.

    Immunohistochemical (IHC) assays of p53 and Rb in the six GB-NECs were highly consistent with genetic mutations detected by targeted NGS. Moreover, no statistical difference was observed in TMB between GBNECs and GB-ADCs (p=0.864). Although overall survival in GB-NEC patients tended to be worse than in GB-ADC patients, this difference did not reach statistical significance (p=0.119). This study has identified the microsatellite states and molecular mutation features of GB-NECs, suggesting that comutations in TP53 and RB1 may signify a neuroendocrine inclination in GB-NECs. The IHC assay provides an effective complement to targeted NGS for determining the functional status of p53 and Rb in clinical practice.