Renal-Cell Carcinoma
InBrief
by Arno Housman, MD
Renal-cell carcinoma (RCC) refers specifically to primary, generally solid tumors arising from the renal cortex (as opposed to those arising from the urothelium of the collecting system). These tumors actually reflect a diverse collection of lesions of varying histologic origin and different biologic potential and represent 80%–85% of primary renal tumors. The most common solid tumor of the kidney is clear-cell carcinoma, representing ~75% of all RCCs. This type of tumor arises from proximal tubular cells and is most commonly associated with a chromosome-3p deletion. Other histological cell types of RCC include papillary tumors (~15%–20%) that may arise from the epithelium of the proximal tubule, and chromophobe tumors (~5%) that may arise from the distal nephron.
Further differentiation of cell types is determined by morphology and, possibly, immunohistochemical markers and cytogenetic and molecular genetic analysis. Some 3%–5% of RCCs may remain unclassified.
Staging
The American Joint Committee on Cancer (AJCC) TNM system is based on three important aspects of cancer assessment: size and extent of the main tumor (T); metastasis of cancer cells to adjacent lymph nodes (N), and metastasis of cancer to other organs (M). Higher numbers appearing after these letters refer to more advanced disease. Zeroes after these numbers refer to absence of involvement; N1 refers to regional node involvement, and M1 refers to distant metastasis.
Signs and Symptoms of Renal-cell Carcinoma
The classic triad of hematuria, palpable mass, and flank pain associated with renal-cell carcinoma is now only rarely encountered. Currently, the tumor often is found on radiographic imaging (computer tomography [CT], magnetic resonance imaging [MRI]) performed for other reasons. Despite earlier detection of the disease, the cancer still is confined to the kidney only 65% of the time when discovered.
Causes and Risk Factors
RCC is twice as common among men than women. The median age at diagnosis is 64 years, yet this cancer most commonly is seen among people 60–90 years of age.
Risk factors for RCC include smoking, hypertension, obesity, acquired cystic disease of the kidney as seen in chronic renal disease (especially that requiring dialysis), Von-Hippel Lindau disease, chronic hepatitis C, cytotoxic chemotherapy, and other genetic predispositions.
Genetic counseling is advised for individuals whose family history suggests a risk of RCC, all diagnosed persons < 46 years of age, and those with multifocal or bilateral disease. At this time, inherited genetics appears to play a role in 2%–4% of RCCs.
Treatment Options
Solid enhancing renal masses and complex cystic renal lesions (Bosniak 3 and 4) are considered cancers until proven otherwise. Cure requires surgical removal before cancer spread occurs. Controversies regarding evaluation and management of RCC reflect increasingly early detection and diagnosis, advances in surgical technique, development of biological therapies, and genetic testing. Long considered the "gold standard" to treat RCC, radical nephrectomy is now joined by partial nephrectomy and thermal ablation, when appropriate. Neither classic chemotherapeutic regimens nor radiation are effective against RCC.
Immunotherapy, novel targeted agents (vascular endothelial growth factor [VEGF] -receptor inhibitors and tyrosine-kinase inhibitors), and combination regimens offer optimism for the future. One combination regimen includes antiangiogenic VEGF-receptor/tyrosine-kinase inhibitors (sunitinib [Sutent], pazopanib [Votrient], or bevacizumab [Avastin]) with interferon-alpha. Another regimen includes a VEGF-receptor/tyrosine-kinase inhibitor, immunotherapy with nivolumab [Opdivo], and the immunosuppressant everolimus. The US Food and Drug Administration has recently approved the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) for advanced RCC. Other agents being studied include pembrolizumab (Keytruda), axitinib (Inlyta), ipilimumab (Yervoy), and atezolizumab (Tecentriq).
Large tumors (> 10 cm) warrant radical nephrectomy and local lymphadenectomy. Survival rates for smaller lesions seem to be the same whether radical or partial nephrectomy is performed, as long as there is no residual tumor. Current trends support nephron-sparing partial nephrectomy, when appropriate. Partial nephrectomy is used for primary lesions limited to the kidney and < 4 cm in size (T1a). It may also be used for bilateral tumors or other conditions (eg, solitary kidney or primary renal disease) that require nephron-sparing surgery. Use of thermal ablation (eg, cryoablation, radiofrequency ablation) is limited to elderly patients and those with small lesions who require intervention but have significant comorbidities. Long-term survival data is not yet available; short-term data supports use in appropriate candidates but requires long-term follow-up.
Prognosis
Following definitive surgery for RCC, overall 5-year survival is ~75%, mostly resulting from early, serendipitous tumor discovery. The 15-year, cancer-specific survival rates for kidney-confined RCC are 70% for clear-cell carcinoma, 90% for papillary carcinoma, and 88% for chromophobe carcinoma. In addition to histology, survival depends upon tumor size and tumor location within the kidney (with a subset involving tumor invasion into the renal collecting system) or extension beyond the kidney (eg, involving lymph nodes, major vascular structures, Gerota's fascia, or the ipsilateral adrenal gland). The prognosis for locally advanced or metastatic RCC remains poor.
Pearl to Know
Renal-cell carcinoma is now the seventh most common cancer type detected in men. The increasing incidence of RCC cannot be fully explained by the increase in incidental detection.
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