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-enolaseexpression

Aims: Small cell (neuroendocrine) carcinoma of the urinary bladder is clini cally more aggressive than urothelial (transitional cell) carcinoma. We hav e investigated the immunohistochemical markers most useful in diagnosing sm all cell carcinoma in bladder, Methods and results: We evaluated the expression of chromogranin A, CD44 va riant 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 carcin oma 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 fo r 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 ce ll carcinoma (P = 0.31); further, the pattern of immunoreactivity was membr anous vs. focal cytoplasmic, respectively. All small cell carcinomas staine d with one of the three neuroendocrine markers tested: 76% of cases were re active for synaptophysin and 93% for gamma-enolase, with specificities of 8 6% and 73% in comparison to urothelial carcinoma, gamma-enolase staining of small cell carcinoma was more intense (P=0.01) than for urothelial carcino ma. 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 cytoker atin (CAM 5.2) help differentiate small cell carcinoma from urothelial carc inoma.