What is the diagnostic and prognostic role of neuron‑specific enolase (NSE), vimentin, and synaptophysin as immunohistochemical markers in sarcoma?

Role of NSE, Vimentin, and Synaptophysin in Sarcoma Diagnosis

These three markers have limited and inconsistent utility in sarcoma diagnosis, with vimentin being the only marker that is characteristically positive in sarcomas, while NSE and synaptophysin are typically negative and serve primarily to exclude other diagnoses.

Immunohistochemical Profile of Sarcomas

Vimentin

• Vimentin is the primary positive marker in sarcomas, showing characteristic positivity that helps distinguish sarcomas from carcinomas, lymphomas, and melanomas 1
• Vimentin positivity is a defining feature in the immunohistochemical work-up of cancers of unknown primary, where sarcomas are typically vimentin-positive but negative for cytokeratins and other epithelial markers 1
• However, vimentin lacks specificity as it can also be positive in some carcinomas (breast, renal cell) and other tumor types, making it insufficient as a sole diagnostic marker 1

Neuron-Specific Enolase (NSE)

• NSE is characteristically negative in sarcomas and serves primarily as a negative marker to exclude neuroendocrine tumors, neuroblastoma, and small cell carcinomas 1
• In the ESMO guidelines for cancers of unknown primary, sarcomas are listed as NSE-negative, distinguishing them from neuroendocrine tumors and germ-cell cancers which are NSE-positive 1
• Rare exceptions exist: isolated case reports document NSE-positive leiomyosarcoma, but this represents aberrant expression in abnormal cells rather than a diagnostic feature 2
• Critical pitfall: NSE positivity in a suspected sarcoma should prompt reconsideration of the diagnosis toward peripheral neuroepithelioma (Ewing's sarcoma family) or other small round cell tumors 3, 4

Synaptophysin

• Synaptophysin is typically negative in sarcomas and functions as a neuroendocrine marker to exclude neuroendocrine neoplasms 1
• Synaptophysin is a highly specific neuroendocrine marker, positive in 73.3% of peripheral neuroepitheliomas but not in conventional sarcomas 3
• The presence of synaptophysin in a suspected sarcoma strongly suggests an alternative diagnosis such as neuroendocrine carcinoma, peripheral neuroepithelioma, or poorly differentiated neuroendocrine tumor 1

Diagnostic Algorithm for Suspected Sarcoma

Initial Immunohistochemical Panel

1. Start with vimentin and cytokeratin (AE1-AE3) to establish mesenchymal versus epithelial lineage 1

   • Sarcoma: vimentin-positive, cytokeratin-negative
   • Carcinoma: cytokeratin-positive, vimentin variable

2. Add NSE and synaptophysin only if small round cell morphology is present to exclude Ewing's sarcoma family tumors and neuroendocrine neoplasms 1, 3

   • True sarcoma: NSE-negative, synaptophysin-negative
   • Peripheral neuroepithelioma: NSE-positive (95%), synaptophysin-positive (73.3%) 3

3. Include S-100 protein to evaluate for neural differentiation or melanoma 1, 3

   • Most sarcomas: S-100 variable or negative
   • Schwannoma/MPNST: S-100 positive
   • Melanoma: S-100 positive

Interpretation Caveats

When NSE is unexpectedly positive in a suspected sarcoma:

• Reconsider the diagnosis toward peripheral neuroepithelioma (Ewing's sarcoma family), which shows NSE positivity in 95% of cases 3
• Verify sample quality to exclude hemolysis, which can cause false NSE elevation 5, 6
• Consider chromosomal breakpoint analysis for Ewing's sarcoma (t(11;22) translocation) 4

When synaptophysin is positive:

• Exclude neuroendocrine carcinoma (small cell or large cell neuroendocrine carcinoma), which consistently expresses synaptophysin 1
• Consider poorly differentiated neuroendocrine tumor (NET G3) versus neuroendocrine carcinoma (NEC G3), which requires additional markers (chromogranin A, Ki-67) 1
• Evaluate for peripheral neuroepithelioma, which shows synaptophysin positivity in 73.3% of cases 3

When vimentin is negative:

• Question the diagnosis of sarcoma, as vimentin negativity is atypical 1
• Consider lymphoma (leukocyte common antigen positive) or undifferentiated carcinoma 1

Prognostic Role

• No established prognostic value for NSE, vimentin, or synaptophysin expression in sarcomas has been demonstrated in the literature reviewed 4
• In Ewing's sarcoma, neither NSE nor vimentin status showed prognostic significance in survival analysis (median disease-free survival 27.3 months) 4
• These markers function solely as diagnostic tools, not prognostic indicators in sarcoma management 4

Common Pitfalls to Avoid

1. Do not rely on NSE or synaptophysin alone to diagnose or exclude sarcoma, as aberrant expression can occur in rare cases 2, 7
2. Do not interpret vimentin positivity as specific for sarcoma, since some carcinomas (breast, renal cell) and melanomas can also express vimentin 1, 7
3. Verify that NSE measurements are not confounded by hemolysis, which releases NSE from erythrocytes and produces false elevations 5, 6
4. Recognize that NSE and synaptophysin lack specificity for neural differentiation in neoplastic cells, unlike their specificity in normal tissues 7