Sarcomatoid renal cell carcinoma: MRI features and their association with survival.

OBJECTIVE: To evaluate MRI features of sarcomatoid renal cell carcinoma (RCC) and their association with survival. METHODS: This retrospective single-center study included 59 patients with sarcomatoid RCC who underwent MRI before nephrectomy during July 2003-December 2019. Three radiologists reviewed MRI findings of tumor size, non-enhancing areas, lymphadenopathy, and volume (and percentage) of T2 low signal intensity areas (T2LIA). Clinicopathological factors of age, gender, ethnicity, baseline metastatic status, pathological details (subtype and extent of sarcomatoid differentiation), treatment type, and follow-up were extracted. Survival was estimated using Kaplan-Meier method and Cox proportional-hazards regression model was used to identify factors associated with survival. RESULTS: Forty-one males and eighteen females (median age 62 years; interquartile range 51-68) were included. T2LIAs were present in 43 (72.9%) patients. At univariate analysis, clinicopathological factors associated with shorter survival were: greater tumor size (> 10 cm; HR [hazard ratio] = 2.44, 95% CI 1.15-5.21; p = 0.02), metastatic lymph nodes (present; HR = 2.10, 95% CI 1.01-4.37; p = 0.04), extent of sarcomatoid differentiation (non-focal; HR = 3.30, 95% CI 1.55-7.01; p < 0.01), subtypes other than clear cell, papillary, or chromophobe (HR = 3.25, 95% CI 1.28-8.20; p = 0.01), and metastasis at baseline (HR = 5.04, 95% CI 2.40-10.59; p < 0.01). MRI features associated with shorter survival were: lymphadenopathy (HR = 2.24, 95% CI 1.16-4.71; p = 0.01) and volume of T2LIA (> 3.2 mL, HR = 4.22, 95% CI 1.92-9.29); p < 0.01). At multivariate analysis, metastatic disease (HR = 6.89, 95% CI 2.79-16.97; p < 0.01), other subtypes (HR = 9.50, 95% CI 2.81-32.13; p < 0.01), and greater volume of T2LIA (HR = 2.51, 95% CI 1.04-6.05; p = 0.04) remained independently associated with worse survival. CONCLUSION: T2LIAs were present in approximately two thirds of sarcomatoid RCCs. Volume of T2LIA along with clinicopathological factors were associated with survival.

OncoTree: A Cancer Classification System for Precision Oncology.

PURPOSE: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research. METHODS: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface. RESULTS: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics. CONCLUSION: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.

Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers.

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.

The Genomic Landscape of Renal Oncocytoma Identifies a Metabolic Barrier to Tumorigenesis.

Oncocytomas are predominantly benign neoplasms possessing pathogenic mitochondrial mutations and accumulation of respiration-defective mitochondria, characteristics of unknown significance. Using exome and transcriptome sequencing, we identified two main subtypes of renal oncocytoma. Type 1 is diploid with CCND1 rearrangements, whereas type 2 is aneuploid with recurrent loss of chromosome 1, X or Y, and/or 14 and 21, which may proceed to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5' adenosine monophosphate-activated protein kinase (AMPK) and Tp53 (p53) and display disruption of Golgi and autophagy/lysosome trafficking, events attributed to defective mitochondrial function. This suggests that the genetic defects in mitochondria activate a metabolic checkpoint, producing autophagy impairment and mitochondrial accumulation that limit tumor progression, revealing a novel tumor-suppressive mechanism for mitochondrial inhibition with metformin. Alleviation of this metabolic checkpoint in type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk.

The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling.

Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0-5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior.