The American journal of surgical pathology
June 24, 2026 · via Europe PMC
Neuroendocrine Carcinoma of the Gallbladder: Clinicopathologic and Immunohistochemical Analysis of 31 Cases.
Reid MD, Pehlivanoglu B, Memis B, +11 more, Adsay V.
AI summary — for doctors, generated from the abstract only
In the largest series to date of gallbladder neuroendocrine carcinoma (31 cases out of 636 gallbladder cancers), these tumors were aggressive, often mixed with adenocarcinoma, nearly always presented at advanced stage, and had markedly shorter survival (median 6.1 months) than ordinary gallbladder cancer.
What was studied
A clinicopathologic and immunohistochemical analysis of 31 neuroendocrine carcinomas (NECs) identified among 636 gallbladder cancers, comparing their features and outcomes with ordinary gallbladder carcinomas (O-GBCs) in the same cohort.
Key findings
- Of 31 NECs, 7 were pure small cell, 2 pure large cell, and 22 had a mixed adenocarcinoma component; a fifth arose within intracholecystic neoplasms (high-grade glandular dysplasia seen in 15 cases, including 6 as intracholecystic neoplasms, versus only 6% in ordinary gallbladder cancer).
- NECs presented with more advanced disease: 72% were pT3/T4 compared with 26% of ordinary gallbladder cancers (P=0.001); lymph node metastasis occurred in 5 of 10 evaluable cases, and 5 patients had distant metastases.
- Markers of the pRB/p16 tumor suppressor pathway were frequently inactivated (83% overall, with 67% showing pRB loss), along with mutant p53 in 88.8% and SMAD4 loss in 24% of cases.
- Median survival was only 6.1 months, significantly shorter than ordinary gallbladder cancer, with shorter survival associated with higher (pT3 vs pT2) stage.
Clinical relevance
The findings suggest that gallbladder neuroendocrine carcinoma, though rare (under 5% of gallbladder cancers), behaves far more aggressively than ordinary gallbladder cancer and often presents at advanced stage, which may inform prognosis discussions and highlight the pRB/p16 pathway as a common feature of this tumor's biology.
Who should care
Limitations
This is a retrospective case series without a prospective treatment comparison; lymph node data were available for only 10 of 31 cases, limiting precision of the reported nodal metastasis rate.
Gallbladder neuroendocrine carcinoma is rare but highly aggressive, typically presenting at advanced stage with a median survival of only about 6 months, substantially worse than ordinary gallbladder cancer.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
Neuroendocrine carcinomas of the gallbladder (GBNECs) have been very poorly characterized. In this study, 31 NECs were identified through an analysis of 636 GB cancers and contrasted with the ordinary GBCs (O-GBCs) in the same cohort. Seven were pure small cell NECs, 2 pure large cell, and 22 had mixed adenocarcinoma component (with NEC component being small cell in 6 and large cell in 16). High-grade glandular dysplasia was evident in 15 (6 as intracholecystic neoplasms; vs. 6% in O-GBC), F:M ratio was 5.2:1, and median age was 58 (vs. 65 in O-GBC). The average neuroendocrine component constituted 80% of the tumor; the median Ki-67 was 70%; lymph-vascular invasion was seen in 74%, and perineural invasion in 56%. GBNECs presented with more advanced tumors; 72% were pT3/T4 (vs. 26% in O-GBC, P =0.001). Lymph node metastasis was in 5/10 (with lymph nodes available in the specimen), and 5 had distant metastases. Tumor cells were positive for neuroendocrine markers (synaptophysin 95%, chromogranin 75%, CD56 90%), keratins (AE1/3 90%, Cam5.2 88%), with upper-GI profile (CK7 65%; CK20 0%); TTF-1 expression in 25%. pRB loss was detected in 67%, positive p16 83%, mutant p53 88.8%, and SMAD4 loss in 24%. Overall, the pRB/p16 pathway was inactivated in 83% (12 [67%] as pRB loss/p16 + , and 3 [17%] as pRB + /p16 - ). DAXX was retained in all. Loss of pRB and p16 was also detected in about a third of the adenocarcinoma and preinvasive components. ATRX loss was noted in 1 large-cell NEC. The median survival was 6.1 months, significantly shorter than O-GBCs, although a few survived unexpectedly longer. Factors associated with shorter survival included pT3 versus pT2 stage, and a trend for lower synaptophysin and CD56 expression. In conclusion, NECs constitute <5% of GBCs, and two-thirds are admixed with an adenocarcinoma component. A fifth arises in intracholecystic neoplasms. Inactivation of the pRB/p16 pathway is common, with 2/3 showing pRB loss. They present as advanced tumors and behave aggressively.
DOI
10.1097/pas.0000000000002580
PMID
42333416
PMCID
PMC13429189
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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