Synaptophysin expression in V600EBRAF-mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis

Eur J Cancer. 2021 Mar:146:145-154. doi: 10.1016/j.ejca.2021.01.016. Epub 2021 Feb 16.


Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.

Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).

Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.

Keywords: (V600E)BRAF; Colorectal cancer; Immunohistochemistry; Neuroendocrine; Prognostic markers; Synaptophysin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / immunology
  • Adenocarcinoma, Mucinous / pathology*
  • Adenocarcinoma, Mucinous / surgery
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / surgery
  • Female
  • Follow-Up Studies
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Synaptophysin / genetics*


  • Biomarkers, Tumor
  • SYP protein, human
  • Synaptophysin