Mixed adenoneuroendocrine carcinoma of the gallbladder: a case report and literature review.

Background: Primary neuroendocrine neoplasms (NENs) of the gallbladder are rare entities with a generally unfavorable prognosis. Among the subtypes of gallbladder neuroendocrine neoplasms (GB-NENs), gallbladder mixed adenoneuroendocrine carcinoma (GB-MANEC) is exceptionally rare and associated with a poor prognosis, representing a diagnostic and therapeutic challenge due to its dual differentiation. This article presents a rare case of GB-MANEC and reviews the pertinent literature on clinicopathological management in GB-MANEC. Case presentation: A 51-year-old female patient presented with non-specific abdominal complaints and unexplained anemia. Preoperative imaging with abdominal ultrasonography and contrast-enhanced computed tomography (CT) demonstrated an irregular mass within the gallbladder lumen accompanied by wall thickening. The level of carbohydrate antigen 125 (CA125) was mildly elevated (77.10 U/mL; normal level, 0.0-35.0 U/mL). A gallbladder mass measuring approximately 3.0 cm × 2.5 cm × 2.0 cm was identified during the cholecystectomy. Intraoperative frozen section revealed findings consistent with gallbladder adenocarcinoma (GB-AC) accompanied by a component of neuroendocrine carcinoma (NEC). Consequently, a radical surgery (cholecystectomy, partial liver resection, and regional lymphadenectomy) was undertaken. Postoperative histopathological examination confirmed the diagnosis of a GB-MANEC, specifically a tubular adenocarcinoma combined with a NEC, and each component accounted for more than 30%, which was confirmed by immunohistochemistry, represented as positive for synaptophysin (Syn), chromogranin A (CgA), and Ki-67 (90%). Critically, all surgical margins were free of tumor involvement. Postoperative high-throughput sequencing of the tumor identified a pathogenic amplification of the gene ERBB2 Human Epidermal Growth Factor Receptor 2 (HER2); gene mutations of TP53, NOTCH1, and KIT; and a gene fusion of SDHC. Based on these findings, adjuvant chemotherapy was initiated with a combination of cisplatin, gemcitabine, and etoposide, alongside the HER2-targeted monoclonal antibody trastuzumab. During 7 months of postoperative follow-up, imaging studies and blood biochemical assessments showed no evidence of recurrence or metastasis, and the patient has remained free of recurrence. Conclusion: This systematic review underscores the rarity and aggressive nature of GB-MANEC. A definitive diagnosis is primarily established through postoperative histopathology and immunohistochemistry. Surgical treatment remains the cornerstone of potentially curative treatment, while the dismal prognosis is often due to the high aggressiveness. Currently, the role of adjuvant chemotherapy remains undefined due to the extreme rarity of MANEC, thus highlighting the critical need for a multidisciplinary approach and further research to establish standardized postoperative management guidelines for the diagnosis and management of GB-MANEC.