Distinction of High-Grade Neuroendocrine Carcinoma/Small Cell Carcinoma From Conventional Urothelial Carcinoma of Urinary Bladder: An Immunohistochemical Approach

Context: High-grade neuroendocrine carcinomas and small cell carcinomas (HGNEC/SmCC) of the urinary bladder are uncommon but aggressive neoplasms. Differentiation of HGNEC/SmCC from high-grade urothelial carcinoma (UC) is based on histomorphologic features, but can be difficult in small biopsies and cases with mixed morphology. Objective: We attempt to identify a limited immunohistochemical panel that aids in this distinction. Design: We selected 39 cases of bladder carcinoma with small cell morphology: 7 HGNEC/SmCC, 21 high-grade UC with neuroendocrine-like pattern, and 11 mixed neoplasms. Immunohistochemistry for pan-cytokeratin, synaptophysin, chromogranin, p63, and thyroid transcription factor-1 was performed. Results: Pan-cytokeratin was positive in 6 of 7 cases (86%) of the HGNEC/SmCC group. All 7 tumors were positive for synaptophysin, 6 of them were negative for p63 and chromogranin, and 1 was positive for p63 and chromogranin. All 21 high-grade UC with neuroendocrine-like pattern of growth showed positive staining for pan-cytokeratin, and were all negative for synaptophysin and chromogranin. Sixteen (76%) of high-grade UC were also positive for p63. All 11 mixed tumors were positive for pan-cytokeratin. In 10 of the 11 mixed tumors (91%), synaptophysin was positive in the neuroendocrine differentiated areas and it was negative in the urothelial component. In 2 of the 11 mixed tumors (18%) chromogranin was also positive. Three (27%) of the 11 mixed cases were positive for p63 in the UC foci. Chromogranin was negative in 6 of the pure HGNEC/SmCC and in 8 of the mixed tumors. None of the 39 samples were reactive for thyroid transcription factor-1. Conclusions: A limited immunohistochemical panel including pan-cytokeratin, synaptophysin, and p63 discriminates HGNEC/SmCC from high-grade UC.