Management and outcomes of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: A systematic review and pooled analysis of 56 patients.

Background: Tumors of mixed neuroendocrine and nonneuroendocrine histology are classified as collision, combined, or amphicrine and can occur in most organs, including the hepato-pancreato-biliary tract. Given the rarity of mixed adenoneuroendocrine carcinoma (MANEC) of the ampulla of Vater, the patient characteristics, management, and outcomes remain unclear. We sought to systematically review the worldwide literature on ampullary MANECs.

Methods: Eligible studies were identified through a systematic search of the MEDLINE (via PubMed), Scopus, and Cochrane Library databases (end-of-search-date: January 5th, 2022), according to the PRISMA 2020 statement.

Results: A total of 39 studies reporting on 56 patients with ampullary MANEC were included. The median age was 63.0 (interquartile range [IQR]: 51.0-69.0) years and 55.6% were male (n = 25/45). Most had combined tumors (64.4%; n = 29/45), followed by collision (24.4%; n = 11/45), and amphicrine tumors (11.1%; n = 5/45). More than half had lymph node metastasis (56.8%; n = 25/44), yet only 7.9% had distant metastasis (n = 3/38). Tumor resection (i.e., mostly pancreaticoduodenectomy) was performed in 96.3% (n = 52/54), followed by adjuvant chemotherapy in 61.8% (n = 21/34). Nearly half experienced disease recurrence (47.2%; n = 17/36) over a median follow-up of 12.0 (IQR: 3.0-16.0) months, and 42.1% (n = 16/38) died over a median follow-up of 12.0 (IQR: 4.0-18.0) months. The most common cause of death was disease progression/recurrence in 81.3% (n = 13/16).

Conclusion: Early diagnosis and management of ampullary MANEC is challenging yet crucial to improve outcomes since many patients are diagnosed at an advanced disease stage and have unfavorable outcomes. Multicenter granular data are warranted to further understand and improve outcomes in these patients.