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Renal cancers are estimated to be diagnosed in 73,750 people in the USA in 2020, and to contribute to 14,830 deaths 1. The 2018 GLOBOCAN report on the global incidence of renal cancers has described 403,262 patients with renal cancer, and 175,098 deaths caused by renal cancers worldwide 2,3. Approximately 90% of all diagnosed renal parenchymal malignancies are renal cell carcinomas (RCCs) 4. A rare transformation called sarcomatoid dedifferentiation can occur in most RCC histological subtypes and portends an especially poor prognosis. RCCs in which sarcomatoid dedifferentiation has occurred are commonly referred to as sarcomatoid RCCs (sRCCs), and patients with sRCCs often present with advanced or metastatic disease and rarely survive >1 year 5-7. Sarcomatoid features are present in approximately 4-5% of all RCCs 8-11. However, this proportion can range from 1 to 29% depending on the primary histology and the reporting study 7,9-13. Although infrequently diagnosed in the localized setting (~20-40% of all sRCCs) 14,15 , approximately 20% of patients with metastatic RCC harbour sarcomatoid dedifferentiation 15. Patients commonly present with an sRCC at between 54 and 63 years of age 6,7,13,14,16,17 , and the male-to-female ratio ranges from 1.3:1 to 2:1 (refs 6,13,14,18,19). Similar to all other RCCs, the mechanisms underlying this gender difference remain unclear. However, possibilities include historical gender differences in occupational exposure or smoking habits, or the influence of sex hormones on tumour biology 20. The natural history and prognosis of sRCCs are poor, as approximately 60-80% of patients present with advanced or late-stage disease 14,15. Median survival is approximately 6-13 months and a higher percentage of sarcomatoid dedifferentiation on histology has been reported to confer a worse prognosis 6,7,11,21,22. Retrospective reports have shown reduced overall survival and cancer-specific survival in patients with increased sarcomatoid features 11,21. Compared with patients without sarcomatoid features, patients with ≥25% sarcomatoid features had ~30% increased overall risk of dying of any cause (HR 2.07, P = 0.048) 11 and those with ≥30% sarcomatoid features had a 52% increased risk of

is a cofounder of Gritstone Oncology and holds equity in An2H. Timothy A. Chan serves as an advisor for Bristol-Myers Squibb, Illumina and AstraZeneca. Timothy A. Chan receives research support from AstraZeneca and Illumina. Timothy A. Chan holds a patent for the use of TMB to predict immunotherapy response. This is licensed to PGDx and MSK and Timothy A. Chan are entitled to receive royalties. Vladimir Makarov holds patent rights.

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There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pancancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.

Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.