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The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.

SUBMITTER: Naik P

PROVIDER: S-EPMC10906063 | biostudies-literature | 2024 Jan-Dec

REPOSITORIES: biostudies-literature

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The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Naik Priyanka P Dudipala Harshitha H Chen Yu-Wei YW Rose Brent B Bagrodia Aditya A McKay Rana R RR

Therapeutic advances in urology 20240101

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassi ...[more]

PMID: 38434237

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Project description:BackgroundRenal cell carcinoma (RCC) can exhibit a unique vascular tropism that enables tumor thrombus extension into the inferior vena cava (IVC). While most RCC subtypes that form tumor thrombi are of clear cell (cc) histology, non-clear cell (ncc) subtypes can also exhibit this unique growth pattern.ObjectiveTo characterize clinicopathologic differences and survival outcomes among patients with IVC tumor thrombus arising from ccRCC versus nccRCC.Design setting and participantsPatients diagnosed with IVC tumor thrombus secondary to RCC in our institutional experience from 2003 to 2021 were identified.Outcome measurements and statistical analysisClinicopathologic characteristics were compared by histology. Perioperative and oncologic outcomes including recurrence-free (RFS), overall (OS), and cancer-specific (CSS) survival were assessed using multivariable Cox regression analyses.Results and limitationsThe analyzed cohort included 103 patients (82 ccRCC and 21 nccRCC). There were no significant differences in baseline demographic parameters. Patients with nccRCC were more likely to have regional lymph node involvement (42.9% vs 20.7%, p = 0.037). No differences in perioperative outcomes, IVC resection, or IVC reconstruction were observed between groups. The median follow-up time was 30 mo. The median RFS was 30 (nccRCC) versus 53 (ccRCC) mo (p = 0.1). There was no significant difference in OS or CSS. This study was limited by its small sample size.ConclusionsPatients with IVC tumor thrombus arising from ccRCC and nccRCC exhibit similar perioperative and oncologic outcomes. While surgical appropriateness was not impacted by histologic subtype, multimodal strategies are needed to improve outcomes for patients with tumor thrombus.Patient summaryRenal cell carcinoma (RCC) can uniquely invade vasculature and form a tumor thrombus. This study examined the difference in outcomes of patients with tumor thrombus based on RCC subtype (clear cell vs non-clear cell). We found that patients exhibited similar surgical and survival outcomes regardless of RCC type.

Project description:Background and objectivePrevious germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.MethodsWe first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events.Key findings and limitationsClear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL.Conclusions and clinical implicationsThis analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants.Patient summaryIn this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

Dataset Information

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

Publications

The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma.

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