Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis

Abstract

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent a rare diagnosis of the gastro-entero-pancreatic tract. Evidence from the current literature regarding their epidemiology, biology, and management is of variable quality and conflicting. Based on available data, the MiNEN has an aggressive biological behaviour, mostly driven by its (often high-grade) neuroendocrine component, and a dismal prognosis. In most cases, the non-neuroendocrine component is of adenocarcinoma histology. Due to limitations in diagnostic methods and poor awareness within the scientific community, the incidence of MiNENs may be underestimated. In the absence of data from clinical trials, MiNENs are commonly treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from the same sites of origin, based on the assumption of a biological similarity to their pure counterparts. However, little is known about the molecular aberrations of MiNENs, and their pathogenesis remains controversial; molecular/genetic studies conducted so far point towards a common monoclonal origin of the two components. In addition, mutations in tumour-associated genes, including TP53, BRAF, and KRAS, and microsatellite instability have emerged as potential drivers of MiNENs. This systematic review (91 full manuscripts or abstracts in English language) summarises the current reported literature on clinical, pathological, survival, and molecular/genetic data on MiNENs.

Keywords: 2017 WHO classification; 2019 WHO classification; MANEC; MiNENs; mixed adeno-neuroendocrine carcinoma; mixed non-neuroendocrine neuroendocrine neoplasms.

Figure 1

PRISMA flow diagram of study selection. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; n = number of studies; MiNEN = mixed neuroendocrine non-neuroendocrine neoplasm; MANEC = mixed adenoneuroendocrine carcinoma; * follow-up time ≥ 6 months for patients who were alive at the time of publication; ** Immunohistochemical data were not included, except when used to assess DNA mismatch repair protein status.

Figure 2

Treatment modalities of MiNEN in retrospective studies. MiNEN = mixed neuroendocrine non-neuroendocrine neoplasm; n = number of patients; CT = chemotherapy; RT = radiotherapy; BSC = best supportive care; peri operative = pre surgical and/or post-surgical; ADC-like = in keeping with standard of care for pure adenocarcinomas from the same sites of origin; NEC-like = in keeping with standard of care for pure neuroendocrine carcinomas.