Renal Cell Carcinoma 

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy.^{[1, 2, 3]}

Increasingly, renal cell cancers are diagnosed at an earlier stage, and nephron-sparing surgery and thermal ablation are gaining acceptance as a treatment of choice for smaller tumors. Radical nephrectomy is the standard for larger and central tumors.

In recent years, clinical trials have established the role of targeted therapy as the first line of therapy in patients with metastatic disease. Although the optimal treatment strategy continues to evolve, 3 agents that target angiogenesis (sunitinib, bevacizumab, and pazopanib) and a mammalian target of rapamycin (mTOR)–targeted therapy (temsirolimus) have been approved as front-line agents. These agents have largely replaced cytokines (immunotherapy) in treatment-naive patients. Newer clinical trials are testing newer agents, combinations of approved agents, and the optimal sequencing of these agents.

Go to Clear Cell Renal Cell Carcinoma and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics.

The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in 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: von Hippel-Lindau (VHL) syndrome, hereditary papillary renal carcinoma (HPRC), familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and hereditary renal carcinoma (HRC).

von Hippel-Lindau syndrome

von Hippel-Lindau disease is an autosomal dominant syndrome that 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 (CNS) 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 von Hippel-Lindau 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 (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

Hereditary papillary renal carcinoma

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.

Familial renal oncocytoma and Birt-Hogg-Dube syndrome

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 these individuals are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.

Hereditary renal carcinoma

Affected individuals with this inherited medical condition have an increased tendency to develop oncocytomas, benign kidney tumors that have a low malignant potential.

A number of environmental and genetic factors have been studied as possible causes for renal cell carcinoma (RCC), such as the following:

• Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-dependent fashion.
• Obesity is another risk factor, particularly in women; increasing body weight has a linear relationship with increasing risk.
• Hypertension may be associated with an increased incidence of renal cell carcinoma.
• Phenacetin-containing analgesia taken in large amounts may be associated with increased incidence of renal cell carcinoma.
• In patients undergoing long-term renal dialysis, there is an increased incidence of acquired cystic disease of the kidney, which predisposes to renal cell cancer.
• Tuberous sclerosis appears to be associated with renal cell carcinoma, although the exact nature of this is unclear.
• In renal transplant recipients, acquired renal cystic disease of the native kidney also predisposes to renal cell cancer.
• Von Hippel-Lindau disease is an inherited disease associated with renal cell carcinoma.
• A prospective evaluation by Cho et al concluded that longer duration of use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for renal cell cancer.^[4]

From 1975 to 2006, the incidence of kidney cancer rose 2% annually in the United States.^[5] The American Cancer Society estimated that in 2009 there would be 57,760 cases (35,430 in males and 22,330 in females) of malignant tumors of the kidney diagnosed, with 12,890 deaths (8,160 in males and 4,820 in females); renal cell cancer (RCC) accounted for 80% of this incidence and mortality.^[6]

In most of Europe, the incidence of kidney cancer has decreased or stabilized over the past decade, perhaps in part because of reduced tobacco smoking in men. Mortality from kidney cancer has also declined in most of Europe, principally in Scandinavia and other western European countries. In men, the mortality rate per 100,000 population fell from 4.8 in 1990-1994 to 4.1 in 2000-2004; in women, the rate fell from 2.1 to 1.8.^[7]

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 is slightly higher among black persons than among white individuals: 21.3 versus 19.2 per 100,000 population in men, and 10.3 versus 9.9 per 100,000 population in women.^[5] In addition, the incidence in men is greater than in women (1.6:1), and although the median age at diagnosis from 2002 to 2006 was 64 years,^[5] the disease has been reported in younger people who belong to family clusters.^[5]

Renal cell carcinoma (RCC) is the tenth leading cause of cancer deaths in males in the United States. In men, deaths from kidney cancer decreased 3.9% between 1990 and 2005; in women, deaths decreased by 7.8% during the same period. Overall, 5-year relative survival increased from 51% to 67% between 1975-1977 and 1996-2004.^[6] 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.^{[8, 9]} Except for stage I, these survival statistics have remained essentially unchanged for several decades.

A study by Abdollah et al found that the rate of complications, transfusions, and in-hospital mortality was higher among patients were treated with cytoreductive nephrectomy compared with nephrectomy. Risk is further increased among patients who are older, have higher comorbidity, or need secondary surgical procedures.^[10]

Five-year survival rates for renal cell carcinoma

After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%. Patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis.

A study by Heng et al found that progression-free survival at 3 and 6 months predicted overall survival among patients with metastatic renal cell carcinoma.^[11]

The 5-year disease-specific survival rate in patients with T1 renal carcinoma is 95% and in those with stage T2 disease, 88%. Patients with T3 renal carcinoma have a 5-year survival rate of 59%, and those with T4 disease had a 5-year disease-specific survival rate of 20%.

Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12-25%. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB renal cell carcinoma is 18%. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25-50%.

Unfortunately, 5-year survival rates for patients with stage IV disease are low (0-20%).

Survival prognostic factors

Motzer et al identified 5 prognostic factors for predicting survival in patients with metastatic renal cell carcinoma.^[12] These factors were used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months, and patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, whereas patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors are as follows:

• Low Karnofsky performance status (< 80%)
• High serum lactate dehydrogenase (LDH) level (>1.5 times upper limit of normal ULN])
• Low hemoglobin (below lower limit of normal [LLN])
• High "corrected" serum calcium (>10 mg/dL)
• No previous nephrectomy

Survival factors

The following are factors associated with increased survival in patients with metastatic disease:

• A long disease-free interval between initial nephrectomy and the appearance of metastases
• The presence of only pulmonary metastases
• Good performance status
• Removal of the primary tumor

Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau (VHL) disease and is a major cause of death in patients with von Hippel-Lindau disease. Because von Hippel-Lindau disease and other hereditary forms are transmitted in an autosomal dominant manner, family members of patients with these syndromes should be educated about familial multiple-cancer syndrome, and genetic counseling should be offered to the patients and family members.

Patients in the high-risk group should be made aware of the early signs and symptoms of the disease, and the need for early intervention for possible cure should be stressed. For patients with early stage disease who have undergone treatment, education about possible relapse should be provided.

For patient education information, see eMedicine's Kidneys and Urinary System Center and Cancer and Tumors Center, as well as Blood in the Urine and Renal Cell Cancer.