Abstract
Simple SummaryColorectal MANECs are highly aggressive carcinomas defined by a distinct neuroendocrine morphology and positivity for synaptophysin in the neuroendocrine component. It is unclear whether a neuroendocrine differentiation in conventional adenocarcinomas without a suggestive morphology is of clinical relevance. We tested 1002 conventional colorectal carcinomas with a non-neuroendocrine morphology for synaptophysin expression and correlated the results with clinicopathological characteristics as well as patient survival and compared the survival characteristics of synaptophysin expression groups to those of true MANECs. We found no survival differences between synaptophysin expression groups within conventional colorectal adenocarcinomas. MANECs, on the other hand, showed significantly worse survival characteristics. Our data suggest that synaptophysin expression in conventional colorectal adenocarcinomas is of minor prognostic relevance and that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs.Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear. Methods: We investigated synaptophysin expression in 1002 conventional colorectal adenocarcinomas and correlated the results with clinicopathological characteristics and patient survival and compared the survival characteristics of synaptophysin expression groups to MANECs. Results: Synaptophysin expression in conventional colorectal adenocarcinomas was associated with a shortened disease-free survival (p = 0.037), but not with overall survival or disease-specific survival (DSS) in univariate analyses and without any survival impact in multivariate analyses. Patients with “true” MANECs, on the other hand, showed a significantly shorter survival than all conventional adenocarcinomas with or without synaptophysin expression in uni- and multivariate analyses (e.g., multivariate DSS: p < 0.001, HR: 5.20). Conclusions: Our study demonstrates that synaptophysin expression in conventional colorectal adenocarcinomas, in contrast to MANECs, is not associated with a significantly poorer clinical outcome when compared to adenocarcinomas without synaptophysin expression. Furthermore, our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, also strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation.
Highlights
Epithelial tumors composed of a neuroendocrine and a non-neuroendocrine component are called mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) [1]
In a recent study of a large cohort of more than 1000 colorectal carcinomas, we found that mixed adenoneuroendocrine carcinomas (MANECs) patients have a significantly worse clinical outcome than all patients with the other colorectal adenocarcinoma subtypes that are listed in the 2019 WHO Classification of Tumors of the Digestive System (WHO) [4]
It can be difficult in conventional colorectal adenocarcinomas that only reveal their neuroendocrine differentiation when immunohistochemically stained for synaptophysin, the immunohistochemical gold standard for the detection of neuroendocrine differentiation [7,8], which represents an integral membrane glycoprotein that is found in presynaptic vesicles of neurons as well as normal neuroendocrine epithelial cells [9]
Summary
Epithelial tumors composed of a neuroendocrine and a non-neuroendocrine component are called mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) [1]. MANECs have to be correctly identified to be reliably distinguished from conventional colorectal adenocarcinomas This is usually easy, since the histological component suggestive of a neuroendocrine differentiation is recognizable in many cases on H&E-stained sections [1]. There are occasional cases in which the number of synaptophysin-expressing cells in the epithelium of the neoplastic glands is so high that it is close to or even exceeds the 30% threshold level Since such observations raise the question of the prognostic and clinical significance of neuroendocrine differentiation in these otherwise histologically inconspicuous conventional adenocarcinomas, a number of studies have dealt with this problem, but so far produced controversial results. Our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation
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