Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy agents such as interferon alpha and interleukin (IL)-2. New agents, such as sorafenib and sunitinib, having anti-angiogenic effects through targeting multiple receptor kinases, have activity in patients failing immunotherapy. In the past, these tumors were believed to derive from the adrenal gland; therefore, the term hypernephroma was used often.

Pathophysiology

The tissue of origin for renal cell carcinoma is the proximal renal tubular epithelium. Renal cancer occurs in both a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET).

At least 4 hereditary syndromes associated with renal cell carcinoma are recognized: (1) von Hippel-Lindau (VHL) syndrome, (2) hereditary papillary renal carcinoma (HPRC), (3) familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and (4) hereditary renal carcinoma (HRC).

von Hippel-Lindau disease is transmitted in an autosomal dominant familial multiple-cancer syndrome, which confers predisposition to a variety of neoplasms, including the following:

• Renal cell carcinoma with clear cell histologic features
• Pheochromocytoma
• Pancreatic cysts and islet cell tumors
• Retinal angiomas
• Central nervous system hemangioblastomas
• Endolymphatic sac tumors
• Epididymal cystadenomas

Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau disease and is a major cause of death among these patients. Deletions of 3p occur commonly in renal cell carcinoma associated with VHL disease. The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8. Mutations of the VHL gene result in the accumulation of hypoxia inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor and its receptor (VEGF and VEGFR, respectively). VEGF and VEGFR are important new therapeutic targets.

Hereditary papillary renal carcinoma is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma. Germline mutations in the tyrosine kinase domain of the MET gene have been identified.

Individuals affected with familial renal oncocytoma can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. Birt-Hogg-Dube syndrome is a hereditary cutaneous syndrome. Patients with Birt-Hogg-Dube syndrome have a dominantly inherited predisposition to develop benign tumors of the hair follicle (ie, fibrofolliculomas), predominantly on the face, neck, and upper trunk, and are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.

Frequency

United States

The age-adjusted incidence of renal cell carcinoma has been rising by 3% per year. According to the American Cancer Society, in 2007 there will be 51,590 cases (31,990 in males and 19,600 in females) of malignant tumors of the kidney diagnosed in the United States with 12,890 deaths (8,080 in males and 4,810 in females); renal cell cancer accounted for 80% of this incidence and mortality.¹ The greatest increase in incidence currently is observed in African Americans.

International

Number of deaths worldwide from kidney cancer exceeded 100,000 in 2001.

Mortality/Morbidity

Renal cell carcinoma is the eighth or ninth leading cause of cancer death in the United States. The 5-year survival rates initially reported by Robson in 1969 were 66% for stage I renal carcinoma, 64% for stage II, 42% for stage III, and only 11% for stage IV.² Except for stage I, these survival statistics have remained essentially unchanged for several decades.

Race

Renal cell carcinoma is more common in people of Northern European ancestry (Scandinavians) and North Americans than in those of Asian or African descent. In the United States, its incidence has been equivalent among whites and African Americans, but incidence among African Americans is increasing rapidly.

Sex

Renal cell carcinoma has a male-to-female preponderance of 1.6:1.

Age

This condition occurs most commonly in the fourth to sixth decades of life, but the disease has been reported in younger people who belong to family clusters.

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