January 17, 2007

Renal Cell Carcinoma

Synonyms and related keywords: renal cell adenocarcinoma, hypernephroma, hypernephroid tumor, Grawitz tumor, von Hippel-Lindau syndrome, VHL syndrome, VHL disease, hereditary papillary renal carcinoma, HPRC, familial renal oncocytoma, FRO, Birt-Hogg-Dube syndrome, BHDS, hereditary renal carcinoma, HRC, Stauffer syndrome, renal cancer, pheochromocytoma, pancreatic cysts, epididymal cystadenomas, endolymphatic sac tumors, central nervous system hemangioblastomas, retinal angiomas, islet cell tumors, fibrofolliculomas, colonic polyps, colonic tumors, pulmonary cysts, paraneoplastic syndromes, hypercalcemia, nonmetastatic hepatic dysfunction, polyneuromyopathy, amyloidosis, anemia, dermatomyositis, hypertension, varicocele, cigarette smoking, obesity, unopposed estrogen therapy, asbestos exposure, cystic kidney disease, renal dialysis, tuberous sclerosis, renal cell carcinoma


Background: 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).

VHL 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 develops in nearly 40% of patients with VHL 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.

HPRC 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 FRO can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. BHDS is a hereditary cutaneous syndrome. Patients with BHDS 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.


Mortality/Morbidity: Renal cell carcinoma is the sixth leading cause of cancer death. 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. 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 is twice as common in men as in women. The male-to-female ratio is 2:1.

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.


History: Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease. Twenty-five to thirty percent of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study.

    • Cytokine release by tumor (eg, IL-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions.
    • Resolution of symptoms or biochemical abnormalities frequently follows successful treatment of the primary tumor or metastatic foci.


  • Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
  • Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with bruit.
  • Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease. Organs involved include:
    • Lung (75%)
    • Soft tissues (36%)
    • Bone (20%)
    • Liver (18%)
    • Cutaneous sites (8%)
    • Central nervous system (8%)
  • Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.

Causes: A number of cellular, environmental, genetic, and hormonal factors have been studied as possible causal factors for renal cell carcinoma.


Lymphoma, Non-Hodgkin
Pyelonephritis, Acute
Pyelonephritis, Chronic
Wilms Tumor

Other Problems to be Considered:

Angiomyolipoma (benign neoplasm)
Oncocytoma (benign neoplasm)
Metastasis from distant primary
Metastatic melanoma
Renal adenoma (benign neoplasm)
Renal cyst
Renal infarct
Transitional cell carcinoma of renal pelvis


Lab Studies:

Imaging Studies:


Histologic Findings: Renal cell carcinoma has 5 histologic subtypes, as follows: clear cell (75%), chromophilic (15%), chromophobic (5%), oncocytoma (3%), and collecting duct (2%).

Table 1. Pathologic Classification of Renal Cell Carcinoma

Cell Type


Growth Pattern

Cell of Origin


Clear cell

Most common

Acinar or sarcomatoid

Proximal tubule



Bilateral and multifocal

Papillary or sarcomatoid

Proximal tubule

+7, +17, -Y


Indolent course

Solid, tubular, or sarcomatoid

Cortical collecting duct



Rarely metastasize

Tumor nests

Cortical collecting duct


Collecting duct

Very aggressive

Papillary or sarcomatoid

Medullary collecting duct




Medical Care: More than 50% of patients with renal cell carcinoma are cured in early stages, but outcome for stage IV disease is poor. The probability of cure is related directly to the stage or degree of tumor dissemination, so the approach is curative for early stage disease. Selected patients with metastatic disease respond to immunotherapy, but many patients can be offered only palliative therapy for advanced disease.

Surgical Care: Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease.



The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Antineoplastic agents -- Few options are available for the systemic therapy of renal cell carcinoma, and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat renal cell carcinoma. Objective response rates, either for single or combination chemotherapy, usually are lower than 15%. The recently approved multi-kinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease.
Drug Name
Aldesleukin (Proleukin) -- IL-2; T-cell growth factor and activator of T cells and natural killer cells. Affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly.
Adult Dose600,000-720,000 IU/kg q8h for as many as 5 d or per protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment
InteractionsCorticosteroids may decrease antitumor effect; NSAIDs increase capillary leak syndrome; potentiates effects of antihypertensive medications
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment
May cause sepsis-like syndrome due to "capillary leak"; other toxic effects are flu-like syndrome, fever, chills, fatigue, infection, myelosuppression, hepatic toxicity, neurological and neuropsychiatric findings, hypotension, erythema, rash, urticaria, and alteration in thyroid function (including hyperthyroidism and hypothyroidism); high-dose IL-2 has been associated with treatment-related deaths
Drug Name
Vinblastine (Velban, Alkaban-AQ) -- Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation.
Adult DosePer protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT use may result in death; severe bone marrow suppression; uncontrolled bacterial infection
InteractionsMay reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly
Pregnancy D - Unsafe in pregnancy
PrecautionsIT use may result in death
Dose-limiting toxicity is myelosuppression; other toxic effects include nausea, vomiting, alopecia, neurologic effects, local skin damage (if extravasated)
Drug Name
Gemcitabine (Gemzar) -- Cytidine analog. After intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.
Adult DosePer protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy D - Unsafe in pregnancy
PrecautionsMay cause myelosuppression (particularly thrombocytopenia); toxic effects include flu-like syndrome, LFT abnormalities, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic-uremic syndrome
Drug Name
5-fluorouracil (Adrucil) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. Has cell-cycle specificity with activity in S phase. Inhibits thymidylate synthase by 5-FU metabolite F-dUMP. Metabolite FUTMP incorporates into RNA and F-dUTP incorporates into DNA, resulting in alteration of RNA processing and inhibition of DNA synthesis.
Adult DosePer protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; poor nutritional status; myelosuppression
InteractionsIncreased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; other immunosuppressants exacerbate bone marrow toxicity; leucovorin enhances toxicity and antitumor activity when given before 5-FU; antifolate analogs (methotrexate and trimetrexate) increase formation of 5-FU metabolite; thymidine and uridine rescue host toxic effect
Pregnancy D - Unsafe in pregnancy
PrecautionsNausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (eg, bone marrow suppression) may occur; main toxic effects include myelosuppression, mucositis, diarrhea, metallic taste in mouth, hand-foot syndrome, alopecia, dermatitis, increased pigmentation, cerebellar ataxia, somnolence, confusion, seizure, rarely acute encephalopathy, chest pain syndrome, ECG changes, cardiac enzyme elevation, blepharitis, tear duct stenosis, and cholestatic jaundice with biliary stenosis
Drug Name
Sorafenib (Nexavar) -- First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced renal cell carcinoma.
Adult Dose400 mg PO bid 1 h ac or 2 h pc
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsCYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding
Pregnancy D - Unsafe in pregnancy
PrecautionsCommon adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C)
Drug Name
Sunitinib (Sutent) -- Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).
Indicated for advanced renal cell carcinoma. Reduces tumor size in patients with metastatic kidney cancer whose tumors have progressed following cytokine-based therapy.
Adult DoseStandard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle
Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle
Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; concurrent administration with St John's wort
InteractionsPotent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently)
Pregnancy D - Unsafe in pregnancy
PrecautionsCommon adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding
Drug Name
Interferon alfa 2a (Roferon A) and 2b (Intron A) -- Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties.
They have direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.
Adult Dose6 million IU/m2 SC in combination with low-dose IL-2 or per protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; vaccination with live vaccine during and for 3 mo after completion of therapy
InteractionsInhibits antitumor effects of cyclophosphamide; increases effects of phenytoin and phenobarbital; theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or compromised CNS; main toxic effects include flu-like syndrome, fatigue, anorexia, somnolence, confusion, depression, myelosuppression, mild and transient elevation in serum transaminases, mild proteinuria, hypocalcemia, acute renal failure, nephrotic syndrome, alopecia rashes, pruritus, irritation at injection site, chest pain, arrhythmias, congestive heart failure, impotence, decreased libido, menstrual irregularities, and increased incidence of spontaneous abortion


Further Outpatient Care:


  • Careful surveillance of patients with end-stage renal disease or VHL disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and CT scan is recommended.


  • Excruciating, sharp, bandlike back pain may be an early warning for cord compression due to metastatic renal cell carcinoma and should not be ignored. Urgent MRI should be performed to rule out cord compression, and high-dose dexamethasone therapy should be started.


  • Metastatic disease has increased survival with (1) a long disease-free interval between initial nephrectomy and the appearance of metastases, (2) the presence of only pulmonary metastases, (3) good performance status, and (4) removal of the primary tumor. Five-year survival rates are as follows:
    • After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%, and patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis.
    • The 5-year disease-specific survival rate associated with T1 renal carcinoma is 95% and with stage T2 disease, 88%. Patients with T3 renal carcinoma had 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%.
    • Five-year survival rates for patients with stage IV disease are low (0-20%).
  • A recent trial identified 5 prognostic factors for predicting survival in patients with metastatic renal-cell carcinoma. These factors are 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. Patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, while patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors were as follows:
    • Low Karnofsky performance status (less than 80%)
    • High serum lactate dehydrogenase level (>1.5 times upper limit of normal)
    • Low hemoglobin (below lower limit of normal)
    • High "corrected" serum calcium (>10 mg/dL)
    • No prior nephrectomy

Patient Education:

  • Patients in the high-risk group should be made aware of the early signs and symptoms, and the need for early intervention for possible cure should be stressed.
  • Patients in early stages who have undergone treatment should be educated about possible relapse.
  • For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Blood in the Urine and Renal Cell Cancer.


Medical/Legal Pitfalls:

Special Concerns:

1 comment:

coolfx89 said...

Renal cell cancer is one of the few tumors in which well-documented cases of spontaneous tumor regression in the absence of therapy exist, but this occurs very rarely and may not lead to long-term survival. The incidence of Renal cell cancer seems to be increasing, though it isn't clear why. The exact cause of renal cell cancer has not been determined but Smoking and misuse of certain pain medicines probably can affect the risk of developing renal cell cancer.

Renal Cell Carcinoma Metastais