Small cell carcinoma of urinary bladder is differentiated from urothelial carcinoma by chromogranin expression, absence of CD44 variant 6 expression, a unique pattern of cytokeratin expression, and more intense gamma-enolase expression

Histopathology. 1999 Aug;35(2):150-6. doi: 10.1046/j.1365-2559.1999.00715.x.


Aims: Small cell (neuroendocrine) carcinoma of the urinary bladder is clinically more aggressive than urothelial (transitional cell) carcinoma. We have investigated the immunohistochemical markers most useful in diagnosing small cell carcinoma in bladder.

Methods and results: We evaluated the expression of chromogranin A, CD44 variant 6 (CD44v6), cytokeratin (CAM 5.2), gamma-enolase, synaptophysin, and CD45 in 46 small cell carcinomas of the bladder. Small cell and urothelial carcinoma were mixed in 21 (46%) cases. The two immunohistochemical markers with best ability to discriminate between small cell and urothelial carcinoma were chromogranin A and CD44v6. Chromogranin A had 97% specificity for small cell carcinoma, staining 65% of cases with 2+/3+ mean intensity; only one case (5%) of urothelial carcinoma was weakly (1+/3+) positive. CD44v6 was 80% specific for urothelial carcinoma, with immunoreactivity in 60% of cases, compared with 7% of small cell carcinoma cases. In cases positive for CD44v6, the mean percentage of reactive urothelial carcinoma cells was 75% (range 10-100%), greater than the 12% of cells in three cases of small cell carcinoma (P = 0.31); further, the pattern of immunoreactivity was membranous vs. focal cytoplasmic, respectively. All small cell carcinomas stained with one of the three neuroendocrine markers tested; 76% of cases were reactive for synaptophysin and 93% for gamma-enolase, with specificities of 86% and 73% in comparison to urothelial carcinoma. gamma-enolase staining of small cell carcinoma was more intense (P = 0.01) than for urothelial carcinoma. Cytokeratin CAM 5.2 stained a mean 47% of cells in small cell carcinoma, always in a punctate perinuclear pattern, and 75% in urothelial carcinoma, in a membranous pattern.

Conclusions: CD44v6, chromogranin A, and possibly gamma-enolase and cytokeratin (CAM 5.2) help differentiate small cell carcinoma from urothelial carcinoma.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Small Cell / diagnosis*
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Transitional Cell / diagnosis*
  • Carcinoma, Transitional Cell / metabolism
  • Chromogranins / metabolism*
  • Diagnosis, Differential
  • Female
  • Glycoproteins / metabolism*
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Immunoenzyme Techniques
  • Keratins / metabolism*
  • Male
  • Middle Aged
  • Phosphopyruvate Hydratase / metabolism*
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / metabolism


  • Biomarkers, Tumor
  • CD44v6 antigen
  • Chromogranins
  • Glycoproteins
  • Hyaluronan Receptors
  • Keratins
  • Phosphopyruvate Hydratase