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. 2025;115(8):632-647.
doi: 10.1159/000545979. Epub 2025 May 5.

Unveiling the Prognostic Role of Synaptophysin in Conventional Colorectal Carcinomas

Giovanna Sabella  1 , Giovanni Centonze  1 , Vincenzo Lagano  1 , Andrea Scardino  2 , Filiberto Belli  2 , Giovanna Garzone  1 , Carlotta Pardo  1 , Daniela Galbiati  1 , Sara Pusceddu  3 , Alessandro Mangogna  4   5 , Valentina Angerilli  6 , Matteo Fassan  6   7 , Andrea Vingiani  8 , Luca Agnelli  3   8 , Giancarlo Pruneri  8 , Stefania Gobba  9 , Silvia Uccella  10   11 , Stefano La Rosa  12   13 , Fausto Sessa  12 , Carlo Capella  12 , Massimo Milione  1 , Massimo Milione
Affiliations

Unveiling the Prognostic Role of Synaptophysin in Conventional Colorectal Carcinomas

Giovanna Sabella et al. Neuroendocrinology. 2025.

Abstract

Introduction: Although neuroendocrine differentiation in colorectal carcinomas (CRCs) has been extensively reported, the biological behavior of adenocarcinomas expressing synaptophysin (Syn) but lacking typical neuroendocrine morphology remains unclear.

Methods: We tested 663 conventional CRCs with non-neuroendocrine morphology for Syn expression and correlated the results with clinicopathological and molecular characteristics as well as patient survival (overall survival [OS] and disease-free survival [DFS]). The survival characteristics of Syn expression group were compared to those of conventional CRCs and subsequently to those of 14 minENs.

Results: Syn immunohistochemical expression ≥30% was confirmed in 27 (4.1%) patients and correlated with right colon site, grade 2, marked intratumoral lymphocyte infiltrate, and BRAF p.V600E mutation. At univariate analysis, variables associated with poor OS were 10-year increase in age (p = 0.001), stage III-IV (p = 0.001), Syn ≥30% (p = 0.001), infiltrative growth (p = 0.04), and residual tumor R1-2 (p = 0.03). At multivariable analysis, Syn expression in ≥30% of gland-forming tumor cells emerged as an independent negative prognostic factor for both OS and DFS. Moreover, 10-year increase in age, stage III-IV, and Syn ≥30% (p < 0.001) were associated with poor OS and marked peritumoral lymphocyte infiltrate with longer OS (p = 0.02). Comparable results were obtained according to DFS; in addition, right colon site (p = 0.04) was associated with longer DFS while KRAS mutation (p = 0.04) was associated with poor DFS at univariate analysis. MiNEN patients showed a shorter DFS than all conventional adenocarcinomas with or without Syn expression in univariate analyses (p < 0.001).

Conclusions: Among conventional CRCs, we provided evidence that Syn expression is associated with worse OS and DFS and contributes to predicting clinical outcome. Future studies should explore the molecular mechanisms underlying the acquisition of the neuroendocrine phenotype to identify new targeted treatment strategies.

Keywords: Amphicrine tumor; Colorectal carcinoma; Immunohistochemistry; Neuroendocrine tumor; Prognostic markers; Synaptophysin.

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Conflict of interest statement

Stefano La Rosa was a member of the journal’s Editorial Board at the time of submission. The other authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Figures

Fig. 1.
Fig. 1.
Scanning magnification of synaptophysin-expressing variable patterns in conventional colorectal cancers with a non-neuroendocrine morphology on hematoxylin and eosin (well-differentiated glandular pattern or cribriform with luminal comedonecrosis pattern). Synaptophysin-positive cells accounting for variable percentage of the whole tumor. a–c Hematoxylin and eosin (H&E). d–f Synaptophysin (Syn). Magnification, ×20.
Fig. 2.
Fig. 2.
Coexistence of synaptophysin immunoreactivity (brown) and AB staining (PAS and/or Alcian blue [AB] [pH 2.5], arrows) in the same neoplastic cells documented “amphicrine phenotype.” Magnification, ×20.
Fig. 3.
Fig. 3.
Overall survival (OS) in colorectal cancers (CRCs) according to synaptophysin (Syn) expression.
Fig. 4.
Fig. 4.
Disease-free survival (DFS) in colorectal cancers (CRCs) according to synaptophysin (Syn) expression.
Fig. 5.
Fig. 5.
Disease-free survival (DFS) in MiNEN group compared to conventional colorectal cancers (CRCs) and to “synaptophysin (Syn) positive group.”
See this image and copyright information in PMC

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