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.

Survival Profile and Prognostic Factors for Appendiceal Mixed Neuroendocrine Non-neuroendocrine Neoplasms: A SEER Population-Based Study

“…Based on published literature, MiNENs have been reported in almost all digestive tracts including the esophagus, stomach, small bowel, colon, appendix, and rectum as well as other organs (5). Recently, Frizziero et al (6) found that the majority of the gastro-entero-pancreatic MiNENs occurred in the appendix (60.3%). However, most published studies are case reports and retrospective series with limited sample sizes.…”

Looking into digestive mixed neuroendocrine – nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors

“…This latter problem has been creating confusion in the literature, and inconsistent terminology has been used. 11 The last WHO classifications of tumours of endocrine and digestive organs have clearly stated that, to define a MiNEN, the two components, neuroendocrine and non-neuroendocrine, are to be 'morphologically recognizable'. 8,9 This evolution in the definition reflects the need to clarify the clinicopathological implications of diagnosing a mixed neoplasm, the behaviour of which can ultimately be predicted according to the available knowledge on the outcomes of its two components.…”

“…Indeed, from a biological and clinical point of view, the natural history and behaviour of MiNEN is the sum, and not the mean, of the NEN and the non-NEN components, in that they may both progress and metastasise independently, and both deserve to be considered in terms of treatment. 10,11 Regarding prognosis, it is, rather, driven by the most aggressive of the two components, and that is why each of them must be characterised, quantified and graded separately. The identification of the neuroendocrine component on H&E-stained slides implies the recognition of its welldifferentiated or poorly differentiated morphology, as we discussed elsewhere.…”

“…[17][18][19][20][21] In this context, it is worth noting that MSI-driven NECs and MiNENs seem to have a better prognosis than homologous neoplasms following an adenomatous polyposis coli (APC)-driven mechanism. 19,20 Independently from the pathogenetic pathway, the NEC component in these MiNENs shows a higher burden of genetic aberrations than the adenocarcinoma component, 11 although the specific genes involved in the acquisition of the neuroendocrine phenotype have not yet been identified. In particular, the loss of function of TP53 and RB seems to represent the most recurrent molecular lesion in the NEC component.…”

“…23 MiNENs of the oesophagus and of the gastro-oesophageal junction represent approximately 6-16% of all digestive MiNENs and 24% of oesophageal NENs. 11,24,25 They are more frequently diagnosed in males in the sixth decade of life. In most cases, oesophageal MiNENs are composed of NEC and squamous cell carcinoma.…”