Renal Cell Carcinoma: A Review

Abstract

Importance: Renal cell carcinoma (RCC) is a common malignancy, with an estimated 434 840 incident cases worldwide in 2022. In the US, it is the sixth most common cancer among males and ninth among females.

Observations: Clear cell RCC is the most common histologic subtype (75%-80% of cases) and is characterized by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. Many patients (37%-61%) are diagnosed with RCC incidentally on an abdominal imaging study such as ultrasound or computed tomographic scan, and 70% of patients have stage I RCC at diagnosis. Although its incidence has increased approximately 1% per year from 2015 through 2019, the mortality rate of RCC has declined about 2% per year in the US from 2016 through 2020. Patients with a solid renal mass or complex cystic renal mass should be referred to urology. Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy, ablative techniques (eg, cryoablation, radiofrequency ablation, radiation), or active surveillance for some patients (especially those with renal masses <2 cm). For patients with renal masses less than 4 cm in size (48% of patients), partial nephrectomy can result in a 5-year cancer-specific survival of more than 94%. For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%, with a median overall survival of 46 to 56 months.

Conclusions and relevance: RCC is a common malignancy that is often diagnosed incidentally on an abdominal imaging study. Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV. First-line treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%, ablative techniques, or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors.

Figure 1.

Need title A, Chromosome 3p is a key genomic locus that is deleted in clear cell renal cell carcinoma (RCC) and contains key tumor suppressor genes. B, Regulation of the hypoxia response through the VHL-HIFα pathway. The biochemical interaction between the VHL protein (pVHL) complex and HIFα subunits are governed by the hydroxylation of HIFα subunits by a family of oxygen-dependent HIF prolyl hydroxylases (PHDs). In normoxic conditions, PHDs hydroxylate HIFα facilitate their binding to pVHL and target the HIFα subunits for degradation. In contrast, under hypoxia, or in the case of VHL inactivation, HIFα subunits stabilize and heterodimerize with the aryl hydrocarbon receptor nuclear translocator s protein (ARNT, also known as HIF1β) and act as a transcription factor for hypoxia-responsive genes, thereby increasing glycolysis-promoting angiogenesis via upregulation of vascular endothelial growth factor A (VEGFA), and increasing cellular growth through upregulation of platelet-derived growth factor (PDGF) and transforming growth factor (TGFα). C, Clear cell RCC therapeutic targets and mechanism of action. CCND1, cyclin D1; CTLA4, cytotoxic T-lymphocyte–protein 4; CUL2, Cullin 2; EPO, erythropoietin; rbx1, ring-box 1; mTORC1, mammalian target of rapamycin 1; PD-1, programmed cell death 1; PD-L1, PD ligand 1; TCR, T-cell receptor.

Figure 2.

Algorithm for Evaluation of a Renal Mass