Urothelial carcinoma with osteoclast-like giant cells: An expanded immunohistochemical and molecular profile.

Osteoclast-rich undifferentiated carcinoma of the urinary tract, herein referred to as urothelial carcinoma with osteoclast-like giant cells (UCOGC), is a rare tumor currently classified under the "poorly differentiated urothelial carcinoma" subtype. This study aimed to evaluate the clinicopathologic, immunophenotypic, and molecular features of UCOGC to better characterize its origin and support its classification as a unique subtype. There were 14 UCOGCs studied with immunohistochemistry/in situ hybridization and compared to urothelial carcinomas with trophoblastic differentiation (n = 6) and giant cell urothelial carcinomas (n = 5). Markers were assessed in mononuclear (MN) and giant cell (GC) components. Next-generation sequencing was performed on 4 UCOGCs. The MN cells of UCOGC demonstrated high expression of CD68, CD163, SATB2, cathepsin K, and CSF1 in situ hybridization (ISH), with moderate staining for GATA3, p63, and PU.1 and low staining for pankeratin. The GCs showed high CD68, PU.1, and cathepsin K expression but low CD163, SATB2, and CSF1 ISH, with no staining for urothelial markers or pankeratin. Both MN and GC were negative for H3.G34W and HCG. Next-generation sequencing revealed mutations consistent with conventional urothelial carcinomas. The distinct biphasic morphology, characteristic immunophenotype, and molecular findings of UCOGC suggest it is of urothelial origin, and we believe it justifies its classification as a unique subtype rather than under "poorly differentiated urothelial carcinoma."