Synaptophysin and chromogranin A expression analysis in human tumors

Mol Cell Endocrinol. 2022 Sep 15:555:111726. doi: 10.1016/j.mce.2022.111726. Epub 2022 Jul 31.


The expression of the neuroendocrine markers synaptophysin and chromogranin A was analyzed by immunohistochemistry in 14,584 samples from 103 different tumor types and subtypes in a tissue microarray format. At least one of these markers was found to be positive in 96.7% of tumors from various subtypes of neuroendocrine neoplasms. In non-neuroendocrine tumors, synaptophysin and/or chromogranin A staining was seen in 6.3% (n = 584), specifically in 41 of 88 non-neuroendocrine tumor entities. Basal cell carcinomas of the skin (50% positive for chromogranin A alone) and adrenocortical carcinomas (91.7% positive for synaptophysin alone) stood out due to a frequent expression of only one specific marker. A subdivision of non-neuroendocrine neoplasms revealed "neuroendocrine differentiation" most commonly in adenocarcinomas from the female genital tract (18.9%), from pancreatico-/hepato-/biliary tract (15.8%) and the prostate (14.9%) while it was rare in urothelial (1.0%) and squamous cell carcinomas (0.6%). A comparison with clinico-pathological parameters of tumor aggressiveness did not suggest a clinical significance of neuroendocrine marker expression in 204 endometrium cancers, 249 pancreatic adenocarcinomas, 233 gastric adenocarcinomas and 1,182 colorectal adenocarcinomas. Within a cohort of 1,073 breast cancers of no special type, synaptophysin positivity was seen in 4.9% of cases and it was significantly linked to advanced tumor stage (p = 0.0427), high tumor grade (p = 0.0319) and loss of estrogen receptor expression (p = 0.0061) but unrelated to patient outcome. In conclusion, "neuroendocrine differentiation" can be observed in many different tumor types with non-neuroendocrine morphology. Evidence for a statistically significant association (p < 0.0001) between such a "neuroendocrine differentiation" and tumor aggressiveness could not be found.

Keywords: Chromogranin A; Immunohistochemistry; Synaptophysin; TMA; Tissue microarray.

MeSH terms

  • Adenocarcinoma*
  • Biomarkers, Tumor
  • Carcinoma, Neuroendocrine*
  • Chromogranin A
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Neuroendocrine Tumors*
  • Synaptophysin


  • Biomarkers, Tumor
  • Chromogranin A
  • Synaptophysin