Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: Non-clear cell renal cell carcinomas (ncRCC) make up a heterogeneous group subclassified into different subtypes that differ in genetic and biochemical characteristics from each other and from ccRCC. ncRCC are a rare finding in clinical practice, and no standard-of-care has yet been established. Treatment choices are in fact based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. The aim of this review is to supplyt precise recommendations for each histological type focusing on pathogenetic mechanisms of nc-RCC, summarizing the therapeutic strategies adopted over the last few decades, and exploring the emerging role of immunotherapy and new targeted drugs as future potential treatment options. ABSTRACT: Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.