Mixed adenoneuroendocrine carcinoma (MANEC) of the lower gastrointestinal tract: A systematic review with Bayesian hierarchical survival analysis

Background: Mixed adeno-neuroendocrine carcinomas (MANEC) are a subgroup of mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) described as mixed neoplasms containing dual neuroendocrine and non-neuroendocrine components. The aim of this study was to appraise the prevalence of MANEC in the lower gastrointestinal (GI) tract and provide reliable estimates of survival. Method: A systematic review was undertaken in accordance with PRISMA guidelines using PubMed, Embase, Cochrane Library of Systematic Review, Web of Science, and Scopus databases, and a Bayesian hierarchical survival pooled analysis was performed. Results: Of 182 unique records identified, 71 studies reporting on 752 patients met the inclusion criteria. Mean age was 64.2 ± 13.6, with a male-to-female ratio of 1.25. Overall, 60.3% of MANEC were located in the appendix, 29.3% in the colon, and 10.4% in the anorectum. More than a quarter (29%) of patients had stage IV disease at diagnosis, with higher prevalence in appendiceal than colonic and anorectal primaries. More than 80% had a high-grade (G3) endocrine component. Of the 152 patients followed up for a median of 20 months (interquartile range limits, 16.5–32), median overall survival was 12.3 months (95% credible interval [95%CrI], 11.3–13.7), with a 1.12 [95%CrI, 0.67–1.83] age-adjusted hazard ratio between metastatic and non-metastatic MANEC. Stage IV disease at diagnosis was more prognostically unfavorable in cases of colonic compared to anorectal origin. Conclusion: MANEC is a clinically aggressive pathological entity. The results of this study provide new insights for the understanding of tumor location within the lower GI tract and its prognosis in terms of overall survival.