Redefining Renal Cell Carcinoma: A Molecular Perspective on Classification and Clinical Implications

Renal cell carcinoma (RCC) is the most common primary tumour of the kidney. RCC is a clinically and pathologically heterogenous entity, which has traditionally been classified under two broad categories: clear-cell and non-clear cell. With improved molecular diagnostic methodologies and genetic testing, the classification of RCC has shifted from a morphological basis to a molecular/genetic focus, and has been systematically updated to reflect these advancements. The new 2022 World Health Organization (WHO) classification of RCC is the most recent of these updates, and contains significant changes, as compared to the previous 2016 classification. The most substantial of these changes is the establishment of a new category of molecularly-defined RCC, including TFE3-rearranged RCC, TFEB-altered RCC, ELOC-mutated RCC, fumarate hydratase-deficient RCC, succinate dehydrogenase-deficient RCC, ALK-rearranged RCC, and SMARCB1-deficient renal medullary carcinoma. In this narrative review, the authors briefly summarise the histopathological characteristics, clinical course, current treatment standards, and future treatment directions of each of these molecularly-defined RCC subtypes.