Non-clear cell renal cell carcinoma: unpacking a messy term

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous category comprising approximately 25% of epithelial renal tumors. Unlike their far more common clear cell counterpart, many nccRCC subtypes are rare, poorly understood, and often aggressive in nature. Treatment options are very limited and generally have been unsuccessfully extrapolated from ccRCC trials. Numerous subtypes also seem to emerge in the context of inherited conditions or syndromes affecting younger individuals. In recent years, the World Health Organization classification of renal tumors has been frequently updated with the recognition of novel entities beyond ccRCC. The recommendations currently demonstrate a shift from morphology-based to molecularly based classification. Thus, aberrations in genes such as TFE3, TFEB, FH, SDH, SMARCB1, ELOC, and ALK define separate entities that cannot be distinguished on the basis of microscopic appearance alone. This review aims to deconstruct the general and nondescriptive term of nccRCC to provide a comprehensive presentation of specific subtypes, highlighting their epidemiologic associations and distinctive biological and clinicopathologic features. Delineating these complexities reveals areas that warrant improvement, which will translate into optimal diagnosis, treatment, and overall patient care.