We report the case of a high-grade carcinoma involving the kidney in a young male with renal vein thrombosis and review the differential diagnosis and immunohistochemical workup. High-grade neoplasms involving the renal sinus include collecting duct carcinomas (CDCs), renal medullary carcinomas (RMCs), invasive high-grade urothelial carcinoma (UC) of the upper urinary tract, clear cell renal cell carcinoma, and type 2 papillary renal cell carcinoma. Distinguishing UC from CDC and RMC is problematic in small biopsy samples. The diagnosis of CDC (a rare, aggressive subtype of renal cell carcinoma) is challenging and requires the exclusion of UC. Renal medullary carcinoma is characterized by an appropriate clinical setting and consistent loss of nuclear expression of integrase interactor 1 (INI-1). A panel consisting of p63, paired box gene 8 (PAX8), and INI-1 is most optimal in distinguishing UC from CDC and RMC. A subset of urothelial carcinoma of upper urinary tract may be positive with PAX8.