Neuroendocrine Carcinoma of the Gallbladder

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 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.