# Gallbladder Mixed Neuroendocrine–Non-Neuroendocrine Neoplasm Consisting of Adenocarcinoma and Neuroendocrine Tumor G2 Diagnosed after Surgery for Acute Cholecystitis: A Case Report and Exome Analysis

## TL;DR

A rare case of a gallbladder tumor with both adenocarcinoma and a neuroendocrine tumor was found to share genetic mutations, suggesting a common origin.

## Contribution

This is the first case report of whole-exome sequencing in a gallbladder mixed neuroendocrine–non-neuroendocrine neoplasm with a neuroendocrine tumor component.

## Key findings

- The tumor components shared TP53, ERBB3, and CDKN2A mutations, suggesting a common origin.
- Neuroendocrine tumor component was associated with a TP53 mutation despite its low frequency in typical neuroendocrine tumors.
- The patient remained recurrence-free for 36 months without adjuvant therapy.

## Abstract

Among neuroendocrine neoplasms (NENs), non-neuroendocrine and NEN components may rarely coexist, which are referred to as mixed neuroendocrine–non-NENs (MiNENs). Most gallbladder MiNENs are progressive and associated with neuroendocrine carcinoma (NEC), but rarely with neuroendocrine tumor (NET) as a component. To our knowledge, there are 4 reported cases of mixed gallbladder tumors with NET as a component. From the genetic analysis of MiNENs consisting of NEC, MiNEN is believed to have a common origin, as each tumor component shares a common TP53 mutation. Our case is an extremely rare reported case of a mixed gallbladder tumor with a NET component as a MiNEN, and the first reported case of whole-exome analysis performed on a resected specimen.

A 77-year-old woman presented to our hospital with epigastric pain. An emergency laparoscopic cholecystectomy was performed with a diagnosis of acute gallstone cholecystitis. Pathological examination revealed gallbladder MiNEN (adenocarcinoma + NET G2). Additional surgery was performed, but no residual tumor was found. The patient has been recurrence-free for 36 months after surgery without adjuvant therapy. The origin of the tumor was examined. Macroscopically, adenocarcinoma cells were present on both sides of the NET, while microscopically, some adenocarcinoma cells were positive for neuroendocrine markers (synaptophysin and chromogranin A). Staining for p53 showed wild-type staining with scattered, weakly expressing cells in both tumors. Subsequently, we performed whole-exome sequencing of each tumor component. The results showed that each tumor component shared TP53 c.1015G>T (p.Glu339Ter), ERBB3 c.889G>A (p.Asp297Asn), and CDKN2A c.416G>A (p.Gly139Asp) mutations, suggesting that the adenocarcinoma might have differentiated into NET G2.

In this case report, the tumors shared a common genetic mutation, suggesting that MiNENs with NET components may share a common origin. Furthermore, the NEN component of MiNEN occurring in the gallbladder was associated with a TP53 mutation, despite the low frequency of TP53 mutations in normal NETs.