The
new england journal
of
medicine
review article
medical progress
Renal-Cell Carcinoma Herbert T. Cohen, M.D., and Francis J. McGovern, M.D.
i
n the united states, renal cancer is the 7th leading malignant condition among men and the 12th among women, accounting for 2.6 percent of all cancers.1 About 2 percent of cases of renal cancer are associated with inherited syndromes. In the United States, 36,160 new cases of renal cancer are predicted to occur in 2005, many of which are being discovered earlier because of the widespread availability of radiographic testing. Nevertheless, 12,660 deaths from the disease are predicted to occur in 2005.1 Renal-cell carcinomas arise from the renal epithelium and account for about 85 percent of renal cancers. A quarter of the patients present with advanced disease, including locally invasive or metastatic renal-cell carcinoma. Moreover, a third of the patients who undergo resection of localized disease will have a recurrence. Median survival for patients with metastatic disease is about 13 months. Thus, there is a great need for more effective surgical and medical therapies.
From the Renal and Hematology–Oncology Sections, Departments of Medicine and Pathology, Boston University School of Medicine (H.T.C.); and the Department of Urology, Massachusetts General Hospital and Harvard Medical School (F.J.M.) — all in Boston. Address reprint requests to Dr. Cohen at the Department of Medicine, Renal Section, Boston University School of Medicine, Evans Biomedical Research Center, 650 Albany St., Rm. X-535, Boston, MA 02118, or at
[email protected]. N Engl J Med 2005;353:2477-90. Copyright © 2005 Massachusetts Medical Society.
overview The classic presentation of renal-cell carcinoma includes the triad of flank pain, hematuria, and a palpable abdominal mass. Few patients now present in this manner. Roughly half the cases are now detected because a renal mass is incidentally identified on radiographic examination. Other common presenting features may be nonspecific, such as fatigue, weight loss, or anemia. Risk factors for renal-cell carcinoma include smoking, obesity, and hypertension,2 as well as acquired cystic kidney disease associated with end-stage renal disease. A 1.6:1.0 male predominance exists,1 and the peak incidence is in the sixth and seventh decades. Gross or microscopic hematuria is an important clinical clue to the diagnosis of renal-cell carcinoma; thus, hematuria should be evaluated promptly by a computed tomographic (CT) scan of the genitourinary tract and, in patients older than 40 years of age, by cystoscopy to rule out bladder cancer. Prognosis is closely related to the stage of disease (Fig. 1). The Heidelberg classification of renal tumors was introduced in 19976 as a means of more completely correlating the histopathological features with the identified genetic defects (Table 1).
tumor types and molecular pathogenesis conventional or clear-cell renal-cell carcinoma
Von Hippel–Lindau disease (number 193300 in Mendelian Inheritance in Man [MIM]) is a rare, autosomal dominant, familial cancer syndrome consisting chiefly of retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytomas, and renal-cell carcinoma of the clear-cell type (Fig. 2). The von Hippel–Lindau tumorsuppressor gene (VHL) was identified in 1993.7 In this disease, one VHL allele is inherited with a mutation. Associated focal lesions, such as renal-cell carcinoma, arise from the inactivation or silencing of the remaining normal (wild-type) VHL allele (Fig. 3). Remarkably, defects in the VHL gene also appear to be responsible for about 60 percent of
n engl j med 353;23
www.nejm.org
december 8, 2005
Downloaded from www.nejm.org by ADITI SINGH MD on January 14, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.
2477
The
new england journal
of
medicine
Figure 1. Staging Overview and Five-Year Survival Rates for Renal Cancer. Survival data3 are based on the 1997 tumor–node–metastasis (TNM) staging guidelines.4 More recent renal-cancer staging is described elsewhere.5
the cases of sporadic clear-cell renal-cell carcinoma,8 which represents a major portion of all cases of renal-cell carcinoma. VHL protein, the product of the VHL gene, functions as a tumor suppressor, inhibiting growth when reintroduced into cultures of renal-cell carcinoma.9,10 Hypoxia-inducible genes are normally inhibited by VHL protein,11 including several encoding proteins involved in angiogenesis (e.g., vascular endothelial growth factor [VEGF]), cell growth (e.g., transforming growth factor a [TGF-a]), glucose uptake (e.g., the GLUT-1 glucose transporter), and acid–base balance (e.g., carbonic anhydrase IX [CA9]). When VHL protein is lost, these proteins are overexpressed, creating a microenvironment favorable for epithelial-cell proliferation (Fig. 4A). Thus, cells deficient in VHL protein behave as if they are hypoxic, even in conditions of normoxia. VHL protein, with elongin proteins C and B, binds cul2 protein (a member of the cullin family of ubiquitin ligase proteins), indicating that some VHL protein serves as the receptor subunit of a ubiquitin ligase complex
2478
n engl j med 353;23
that promotes the ubiquitination and destruction of proteins (Fig. 4B).12,13 VHL protein binds the transcriptional activators hypoxia-inducible factor 1a (HIF-1a) and 2a (HIF-2a) directly and destabilizes them.14 Furthermore, VHL protein promotes the ubiquitination and destruction of HIF-a.15-17 These VHL-regulated pathways are being studied as potential targets of therapies for clear-cell renal-cell carcinoma. HIF is the key regulator of the hypoxic response in multicellular organisms. Thus, VHL protein has a central role in oxygen sensing. For HIF-a to bind VHL protein, a proline residue must undergo hydroxylation, which is an unusual protein modification18,19 (Fig. 4B). A family of proline hydroxylases operates on HIF-a in a graded fashion, so that the extent of hydroxylation depends on oxygen tension.20,21 Hydroxylation of an asparagine residue blocks the interaction of HIF-a with the transcriptional coactivator p300.22 Thus, multiple hydroxylation steps cooperate to inhibit HIF-a activity. To correlate the genotype with the disease phe-
www.nejm.org
december 8 , 2005
Downloaded from www.nejm.org by ADITI SINGH MD on January 14, 2009 . Copyright © 2005 Massachusetts Medical Society. All rights reserved.
medical progress
Table 1. Sporadic and Hereditary Renal-Cell Carcinomas and Genetic Defects According to Histologic Appearance.* Sporadic Renal-Cell Carcinomas
Renal-Cell Carcinomas in an Inherited Syndrome
Histologic Appearance Incidence Gene and Frequency
Rare Syndrome†
Gene
percent Conventional
75
VHL, 60
VHL disease FCRC Hereditary paraganglioma
VHL Chromosome 3p translocation SDHB
Papillary
12
MET, 13 TFE3,
