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Review
. 2017 Mar 9:3:17009.
doi: 10.1038/nrdp.2017.9.

Renal cell carcinoma

James J Hsieh  1 , Mark P Purdue  2 , Sabina Signoretti  3 , Charles Swanton  4 , Laurence Albiges  5 , Manuela Schmidinger  6 , Daniel Y Heng  7 , James Larkin  8 , Vincenzo Ficarra  9
Affiliations
Review

Renal cell carcinoma

James J Hsieh et al. Nat Rev Dis Primers. .

Abstract

Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance. Localized RCC can be successfully managed with surgery, whereas metastatic RCC is refractory to conventional chemotherapy. However, over the past decade, marked advances in the treatment of metastatic RCC have been made, with targeted agents including sorafenib, sunitinib, bevacizumab, pazopanib and axitinib, which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGFR), and everolimus and temsirolimus, which inhibit mechanistic target of rapamycin complex 1 (mTORC1), being approved. Since 2015, agents with additional targets aside from VEGFR have been approved, such as cabozantinib and lenvatinib; immunotherapies, such as nivolumab, have also been added to the armamentarium for metastatic RCC. Here, we provide an overview of the biology of RCC, with a focus on ccRCC, as well as updates to complement the current clinical guidelines and an outline of potential future directions for RCC research and therapy.

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Conflict of interest statement

COMPETING INTERESTS

J.J.H. is a consultant for Novartis, Eisai and Chugai and received research funding from Pfizer, Novartis, Eisai and Cancer Genomics Inc. C.S. is a consultant for Roche, Pfizer, Boehringer Ingelheim, Novartis, Celgene, Servler, Eli Lilly, and Glaxo Smithkline, and owns stock options from Achilles Therapeutics, Epic Biosciences, Grail, and Apogen Biotech. L.A. is a consultant for Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer and Cerulean, and received research funding from Pfizer and Novartis. M.S. is a consultant for Pfizer, Bristol-Myers Squibb, Ipsen, Exelixis, Eisai, Roche, Novartis and Astellas. D.Y.H. is a consultant for Pfizer, Novartis and Bristol-Myers Squibb. J.L. received research funding from Novartis, Pfizer, Bristol-Myers Squibb, and Merck Sharp & Dohme. M.P.P., S.S. and V.F. declare no competing interests.

Figures

Figure 1
Figure 1. Distinct subtypes of RCC
Approximately 75% of renal cell carcinomas (RCCs) are a | clear cell RCC (ccRCC). b | Papillary RCCs make up ~15% of all kidney cancers and are divided into two types based on staining features: b | type 1 (basophilic) and c | type 2 (eosinophilic). d | Chromophobe RCCs make up ~5% of kidney tumours. Other minor subtypes include e | MiT family translocation RCCs and f | collecting duct RCCs. Additional minor subtypes include medullary RCC, clear cell papillary RCC, acquired cystic disease-associated RCC, tubulocystic RCC, mucinous tubular and spindle RCC, succinate dehydrogenase-deficient RCC, hereditary leiomyomatosis, renal cell carcinoma-associated RCC and oncocytoma. Tumours not fitting into any of these categories are designated unclassified RCC. Scale bar = 200 μm.
Figure 2
Figure 2. Globalkidney cancer incidence
Estimated age-standardized rates (ASRs) of incidence for both sexes (per 100,000 persons) in 2012. Rates are generally higher in developed countries, with the highest incidence the Czech Republic (reasons unknown). Data from GLOBOCAN database; http://globocan.iarc.fr.
Figure 3
Figure 3. VHL inactivation in ccRCC and its implication in targeted therapy
Loss of VHL is the most frequent genetic feature of clear cell renal cell carcinoma (ccRCC). Its loss relieves the cell of negative regulation of the hypoxia inducible factors (HIFs), which results in increase HIF target gene expression and ensuing changes in cellular metabolism and signalling that enhances cell survival. For example, increased vascular endothelial growth factor (VEGF) expression increases angiogenesis in concert with increased signalling from growth factor receptors in endothelial cells in the tumour microenvironment (including fibroblast growth factor (FGF) and hepatocyte growth factor (HGF)). Collectively, these changes provide the targets for therapeutic agents to impede tumour growth, as indicated. FGFR, FGF receptor VEGFR, VEGF; TSC, tuberous sclerosis complex; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; AKT, RAC-α serine/threonine-protein kinase; Rheb, GTP-binding protein Rheb; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; S6K1, ribosomal protein S6 kinase; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; HRE, HIF response element; MET, hepatocyte growth factor receptor.
Figure 4
Figure 4. Cancer evolution and tumour heterogeneity in ccRCC
Although VHL mutation and 3p loss of heterozygosity are early events that are evident in all clear cell renal cell carcinoma (ccRCC) cells regardless of the region of the tumour sampled, common driver mutations (for example, SETD2, MTOR and KDM5C mutations) are present heterogeneously — suggestive of subclonal evolution of the tumour. a | Cancer subclones originate from the most recent common ancestor cell (MRCA) in which a normal cell acquires all functional capacities to become cancer cell. b | Genomic heterogeneity can result from the sequential, parallel accumulation of mutations, contributing to the heterogeneity and the evolution of ccRCC. In this example, ‘R’ represents the genomic characteristics of the primary tumour and ‘M’ represents the genomic characteristics of the metastatic sites, numbered accordingly. The major genetic lesions acquired after VHL mutation feature in different samples and are indicated on the branches. c | However, some evidence suggests that tumours can converge by way of parallel evolution. Here, a hypothetical beaded river model depicts the sequential convergence of SETD2 and KDM5C mutations through different spatiotemporally distinct genetic events.
Figure 5
Figure 5. Stages of kidney cancer and recommended treatments
Staging renal cell carcinoma (RCC) is based on size, position and lymph node involvement. For example, a stage I or II tumour is enclosed wholly in the kidney. Stage III tumours can extend into major veins or adrenal glands within Gerota’s fascia (the layer of connective tissue encapsulating the kidneys and adrenal glands) or can involve one regional lymph node involvement. Stage IV tumours can invade beyond Gerota’s fascia and/or have distant metastases. *Until the introduction of newer targeted therapies beginning in 2005, the 5-year survival of stage IV RCC was <10%. Treatment is largely guided by stage,. For example, those with stage I RCC who are fit for surgery are recommended partial nephrectomy. However, radical nephrectomy is also an option; for elderly patients or those who cannot undergo surgery owing to comorbidities, active surveillance or ablative therapies are recommended. In patients with stage III RCC, radical nephrectomy is recommended with lymph node dissection in those with clinical enlarged lymph nodes, but systemic therapies might be the only available option for those with extensive disease and poor performance status.
Figure 6
Figure 6. Indications for radical nephrectomy
a | Radical nephrectomy could be considered in cases with multiple small renal tumours (circled). b | Conversely, radical nephrectomy and contextual excision of neoplastic thrombus into renal vein or cava vein tumour thrombus is the gold standard treatment for patients with venous involvement.
Figure 7
Figure 7. Therapeutic evolution and survival outcome of metastatic ccRCC through the four different eras
a | Prior to 2004, two drugs were available to treat RCC (with a median survival of ~15 months). This so-called dark age of treatments was followed by the modern age (2005–2014), which saw seven additional regimens gain approval (increasing median survival to ~30 months). Currently, the golden age has already witnessed the introduction of three drugs, with more anticipated over the next decade. b | These advances promise to be translated to a significant number of patients (~50%) achieving durable remissions under active surveillance by 2025 with a median survival of ~5 years. The ultimate goal is the future diamond age of drug approvals is >80% of patients with metastatic ccRCC long-term survival. Dashed lines represent predicted survival.
Figure 8
Figure 8. Treatment algorithms for renal cell carcinoma
Given the advances in renal cell carcinoma (RCC) research, how patients are treated — based on their individual tumour characteristics — will likely change in the future.
See this image and copyright information in PMC

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