Renal Cell Carcinoma

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Renal cell carcinoma (see the image below) is the most common type of kidney cancer in adults.^[1]It accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney.

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

Renal cell carcinoma may remain clinically occult for most of its course. Only 10% of patients present with the classic triad of flank pain, hematuria, and flank mass.

Other signs and symptoms include the following:

Weight loss

Fever

Hypertension

Hypercalcemia

Night sweats

Malaise

A varicocele, usually left sided, due to obstruction of the testicular vein

See Clinical Presentation for more detail.

Lab studies used for diagnosis of renal cell carcinoma include the following:

Urinalysis (UA)

Complete blood cell (CBC) count with differential

Electrolytes

Renal profile

Liver function tests (LFTs; aspartate aminotransferase [AST] and alanine aminotransferase [ALT])

Serum calcium

Imaging studies used to evaluate and stage renal masses include the following:

Excretory urography

CT scanning

PET scanning

Ultrasonography

Arteriography

Venography

MRI

See Workup for more detail.

The principal treatment options for renal cell cancer are as follows:

Surgery

Molecular-targeted therapy

Immunotherapy

Radiation therapy

Surgical resection remains the only known curative treatment for localized renal cell carcinoma, and it is also used improve outcome or for palliation in metastatic disease. Targeted therapy and immunomodulatory agents are considered standard of care in patients with metastatic disease. Chemotherapy is used only occasionally, in certain tumor types. Experimental treatment approaches include vaccines and nonmyeloablative allogeneic peripheral blood stem cell transplantation.

See Treatment and Medication for more detail.

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 (see Presentation), and resistance to radiation and chemotherapy.^{[2, 3, 4]}

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. (See Treatment.)

In recent years, clinical trials have established targeted therapy as the most common first-line treatment in patients with metastatic disease. Although the optimal treatment strategy continues to evolve, three 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. High-dose interleukin-2 (IL-2) and axitinib can be used in selected patients.

A number of agents are available to be used in second and subsequent lines of therapy, these include anti-angiogenic therapy (if not already used in first-line treatment), nivolumab, cabozantinib, and mTOR inhibitors. Recommendations regarding how to sequence approved agents during subsequent therapy are evolving; more work is needed. Clinical trials are currently exploring future directions, including 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 four hereditary syndromes associated with renal cell carcinoma are recognized, as follows:

von Hippel-Lindau (VHL) syndrome

Hereditary papillary renal carcinoma (HPRC)

Familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS)

Hereditary renal carcinoma (HRC)

von Hippel-Lindau syndrome, or 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 in these patients. Deletions of chromosome 3p occur commonly in renal cell carcinoma associated with von Hippel-Lindau disease. Chromosome 3p contains several of the genes associated with kidney cancer, including BAP-1 and PBRM-1, among others.

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

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). 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. Smoking has also been associated with advanced disease at presentation.

Obesity is a risk factor, particularly in women. Increasing body weight has a linear relationship with increasing risk. Hypertension is a possible risk factor.

Occupational exposure to certain chemicals, such as trichloroethylene, has been linked to increased risk for renal cell carcinoma.^[1]In addition, the risk of renal cell carcinoma increases with duration of exposure to benzene, benzidine, cadmium, herbicides and vinyl chloride.^[5]

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.^[6]Phenacetin-containing analgesics taken in large amounts may be associated with increased incidence of renal cell carcinoma; this agent is no longer approved for use in the United States.

Patients undergoing long-term renal dialysis have an increased incidence of acquired cystic disease of the kidney, which predisposes to renal cell cancer. In renal transplant recipients, acquired renal cystic disease also predisposes to renal cell cancer. Chronic hepatitis C infection^[7] and, according to meta-analysis of pooled data, kidney stones in males^[8]are associated with higher incidences of kidney cancer.

Genetic disorders associated with renal cell carcinoma include von Hippel-Lindau syndrome, hereditary papillary renal carcinoma, Birt-Hogg-Dube syndrome, and hereditary renal carcinoma. The genetic disease tuberous sclerosis appears to be associated with renal cell carcinoma, although the exact nature of the association is unclear.

From 1975 to 2008, the incidence of kidney cancer rose fairly steadily in the United States, from 7 to 16 cases per 100,000 population.^[9] The increase appears to have been due in part to increased incidental detection because of the wider use of medical imaging. More recently, the increase has slowed, with incidence rates increasing by about 1% per year from 2006 to 2015.^[1]

Currently, cancers of the kidney and renal pelvis are the sixth most common cancer in US men, accounting for 5% of cases, and the eighth most common in US women, accounting for 3% of cases. The American Cancer Society estimates that in 2019 there will be 73,820 cases (44,120 in males and 29,700 in females) of malignant tumors of the kidney diagnosed, with 14,770 deaths (9820 in males and 4950 in females).^[1]Renal cell carcinoma is expected to account for 80% of this incidence and mortality.

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.^[10]

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, the incidence is slightly higher in blacks than in whites: 25.0 versus 21.9 per 100,000 population in men, and 12.6 versus 11.0 per 100,000 population in women.^[9]

The median age at diagnosis from 2010 to 2015 was 64 years. In familial clusters, however, the disease has been reported in younger people.^[9]

In the United States, death rates from kidney and renal pelvis cancer have been falling on average 0.7% annually over 2006-2015; these cancers currently constitute the twelfth leading cause of cancer death.^[9] 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.^{[11, 12]}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 in patients treated with cytoreductive nephrectomy than in those who underwent nephrectomy. Risk is further increased in patients who are older, have higher comorbidity, or need secondary surgical procedures.^[13]

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.^[14]

By T stage, the 5-year disease-specific survival rates in patients with renal carcinoma are as follows:

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%).

Motzer et al identified 5 prognostic factors for predicting survival in patients with metastatic renal cell carcinoma.^[15]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:

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

In addition, Albiges and colleagues identified obesity as a favorable prognostic factor in patients with metastatic renal cell carcinoma treated with targeted therapy. In a study of 1975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), median overall survival was 25.6 months in patients with a body mass index (BMI) of 25 kg/m² or higher, compared with 17.1 months in patients with a BMI of less than 25 kg/m². The adjusted hazard ratio (HR) for obesity was 0.84.^{[16, 17]}

Review of an external validation cohort of 4657 patients treated for kidney cancer in clinical trials from 2003 to 2013 also demonstrated longer overall survival in obese patients, with median overall survivals of 23.4 months versus 14.5 months for those with low BMI.^{[16, 17]}

The longer survival may relate to the fatty acid synthase (FASN) pathway. FASN acts as a metabolic oncogene and its overexpression has been associated with poor prognosis in renal cell carcinoma and other types of cancers. FASN was downregulated in overweight and obese patients in this study..^{[16, 17]}

Patients with a family history of genetic syndromes associated with increased risk for renal cell carcinoma should be educated about these syndromes, and genetic counseling should be offered to the patients and family members. For example, 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 that disorder/

Patients at high risk 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 the Cancer and Tumors Center, as well as Blood in the Urine and Renal Cell Cancer.

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Cell Type

Features

Growth Pattern

Cell of Origin

Cytogenetics

Clear cell

Most common

Acinar or sarcomatoid

Proximal tubule

3p-

Chromophilic

Bilateral and multifocal

Papillary or sarcomatoid

Proximal tubule

+7, +17, -Y

Chromophobic

Indolent course

Solid, tubular, or sarcomatoid

Cortical collecting duct

Hypodiploid

Oncocytic

Rarely metastasize

Tumor nests

Cortical collecting duct

Undetermined

Collecting duct

Very aggressive

Papillary or sarcomatoid

Medullary collecting duct

Undetermined

Kush Sachdeva, MD Southern Oncology and Hematology Associates, Inspira Health Network