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What can molecular pathology contribute to the management of renal cell carcinoma?

Nature Reviews Urology volume 8, pages 255–265 (2011)Cite this article

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Abstract

The incidence of renal cell carcinoma (RCC) is increasing and outcomes remain poor. One-third of patients with localized disease will relapse, and 5-year survival for patients with metastatic disease is less than 10%. No molecular test is currently available to identify which patients who have undergone 'curative' surgery will relapse, and which patients will respond to targeted therapy. Some well characterized biochemical pathways, such as those associated with von Hippel–Lindau disease, are aberrantly regulated in RCC and are associated with histological subtype, but the understanding of these pathways contributes little to the clinical management of patients with RCC. Gene expression and sequencing studies have increased our understanding of the genetic basis of the disease but have failed to establish any unified classification to improve molecular stratification or to predict which patients are likely to relapse or respond to targeted therapy. Instead, they have served to highlight that RCC is heterogeneous at histological, morphological, and molecular levels, and that novel approaches are required to resolve the complexity of RCC prognostication and prediction of treatment response.

Key Points

  • Despite the prominence of molecular-targeted therapy in renal cell carcinoma (RCC), and the wealth of information on pathobiology, there are no molecular pathology tests to guide disease prognosis or predict treatment response

  • Both candidate and systematic approaches to selecting potential prognostic and predictive biomarkers in RCC from genetic and proteomic studies have failed

  • Generic and RCC-specific methodological, biological and pathological factors can account for the failure of previous studies to identify robust biomarkers in RCC

  • There is a high level of molecular and pathological heterogeneity in RCC, which has not been taken into account by existing genetic and proteomic approaches

  • More-detailed heterogeneity mapping is required to establish the importance of heterogeneity in prognosis and prediction of therapeutic response

  • Future predictive assays in RCC will need to be multiparametric, and incorporate novel, high-throughput, highly quantifiable technologies to account for the complexity of the pathway networks involved

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Figure 1: Intratumoral heterogeneity of carbonic anhydrase IX (CAIX) expression (red signal) in renal cell carcinoma, by automated quantitative analysis.
Figure 2: Hematoxylin and eosin staining of a ccRCC nephrectomy sample illustrating intratumoral heterogeneity.
Figure 3: Development of the next generation of diagnostic test.

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Acknowledgements

The work of authors G. D. Stewart, F. C. O'Mahony, A. C. P. Riddick, D. J. Harrison and D. Faratian is funded by the Chief Scientist Office, grant number ETM37. The authors would like to thank SCOTRRCC coapplicants and collaborators for their useful discussions on some of the topics discussed in this Review. The authors would also like to acknowledge Dr. Gordon Mills for his helpful discussion developing the ideas behind biomarker properties and robustness. C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. Division of Pathology, Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK

    Grant D. Stewart, Fiach C. O'Mahony, Antony C. P. Riddick, David J. Harrison & Dana Faratian

  2. Department of Medical Oncology, St. Bartholomew's Hospital, West Smithfield, EC1A 7BE, London, UK

    Thomas Powles

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Contributions

G. D. Stewart, F. C. O'Mahony and D. Faratian researched data for, and wrote, the article. All authors made a substantial contribution to discussions of content and were involved in the review and editing of the article before submission.

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Correspondence to Grant D. Stewart.

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Competing interests

G. D. Stewart declares an association with Pfizer (speakers bureau/honoraria).

T. Powles declares associations with Astra Zeneca (grant/research support), GlaxoSmithKline (grant/research support) and Pfizer (speakers bureau/honoraria and grant/research support).

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Stewart, G., O'Mahony, F., Powles, T. et al. What can molecular pathology contribute to the management of renal cell carcinoma?. Nat Rev Urol 8, 255–265 (2011). https://doi.org/10.1038/nrurol.2011.43

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