BASICS
DESCRIPTION
- Renal cell carcinoma (RCC; also called hypernephroma or Grawitz tumor) accounts for 3 " 4% of all adult cancers and 2.3% of all cancer deaths " seventh most common malignant tumor in men and ninth in women.
- Characterized by obscure and varied presentations, including paraneoplastic syndromes, vascular findings, and uncommon metastatic sites
- Approximately 1/3 of patients present with metastatic disease at diagnosis.
- Early, aggressive surgical management provides the best opportunity for cure.
- System(s) affected: renal/urologic
EPIDEMIOLOGY
Incidence
- Predominant age: Patients in 5th to 7th decades; median age at diagnosis is 66 years.
- Predominant sex: male > female (1.6:1)
- Age-adjusted incidence is increasing 3% per year, likely due in part to increased detection as an incidental finding on imaging studies.
- In males, 10.7 new cases of RCC per 100,000 population per year versus 6.5 in females
ETIOLOGY AND PATHOPHYSIOLOGY
Unknown
Genetics
- 2 " 3% of cases are familial, with several autosomal dominant syndromes described.
- Oncogenes localized to the short arm of chromosome 3 may have etiologic implications. Chromosome 3p12 " p26 is specific for clear cell RCC.
- People with HLA types Bw44 and DR8 are prone to develop RCC. These are rare familial RCCs.
- Hereditary papillary RCC is an autosomal dominant form of disease associated with multifocal papillary renal tumors and a 5:1 male predominance.
RISK FACTORS
- Smoking, active and passive (increases relative risk by 2 to 3)
- Obesity (linear relationship in women)
- Hypertension (antihypertensive medications are not independently associated with RCC)
- End-stage renal failure
- Acquired renal cystic disease
- Tuberous sclerosis
- HIV infection
- Urban environment
- Heavy metal exposure (cadmium, lead)
- Environmental toxin exposure (asbestos, petroleum by-products, chlorinated solvents)
GENERAL PREVENTION
Smoking may contribute to 1/3 of all cases.
COMMONLY ASSOCIATED CONDITIONS
- Von Hippel " Lindau disease: 30 " 45% of these patients develop clear cell tumors.
- Tuberous sclerosis: associated primarily with angiomyolipoma and clear cell tumors
- Sickle cell trait: With few exceptions, renal medullary tumor is seen in young African American males with sickle cell trait.
- Adult polycystic kidney disease
- Horseshoe kidney
- Acquired renal cystic disease from chronic renal failure
DIAGNOSIS
HISTORY
>70% of RCCs are incidentally discovered in asymptomatic patients due to increased use of ultrasound, CT scan, and MRI.
PHYSICAL EXAM
- Classic triad of hematuria, abdominal mass, and flank pain in <10%
- Hematuria: 50 " 60%
- Flank pain: 35 " 40%
- Palpable mass: 25%
- Hypertension: 22 " 38%
- Weight loss: 28 " 36%
- Pyrexia: 7 " 17%
- Nonmetastatic hepatic dysfunction (Stauffer syndrome): 10 " 15%
- Neuromyopathy: 3%
- Scrotal varicoceles: 2 " 11% (most are left sided)
- Patients with vena cava thrombus present with lower extremity edema, new varicocele, dilated superficial abdominal veins, albuminuria, pulmonary emboli, right atrial mass, or nonfunction of the involved kidney
DIFFERENTIAL DIAGNOSIS
- Benign renal masses (e.g., renal hamartomas)
- Hydronephrosis
- Pyelonephritis
- Renal abscess
- Polycystic kidneys
- Renal tuberculosis
- Renal calculi
- Renal infarction
- Benign renal cyst
- Transitional cell carcinoma of the renal pelvis
- Wilms tumor
- Metastatic disease, especially melanoma
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Increased ESR: 50 " 60%
- Anemia: 21 " 41%
- Hypercalcemia: 3 " 6%
- Erythrocytosis: 3 " 4%
- Hematuria
- Urinary neoplastic cells
- Alkaline phosphate may be elevated.
- Increased renin
- Increased plasma fibrinogen
- Ultrasonography: Determine if mass is solid or cystic; simple cystic may be observed or subjected to percutaneous aspiration; solid lesions require further imaging.
- Abdominal/pelvic CT, using three-phase imaging, with and without IV contrast, is the optimal imaging modality to evaluate the kidneys; it is nearly 100% sensitive for detecting a renal mass >15 mm in diameter. A solid renal mass with >15 to 20 Hounsfield units change on multiphase CT has an 80% likelihood of being an RCC. A predominantly cystic mass with an irregular, nodular, or enhancing wall; calcifications; and/or septa >2-mm thick has a >70% likelihood of being a cystic RCC.
Follow-Up Tests & Special Considerations
- MRI with pre- and postgadolinium phases is superior to ultrasound in evaluating adenopathy, diagnosing intracaval and renal venous thrombus, and demonstrating bony metastases.
- Chest CT scan if initial chest x-ray suggests metastatic disease; brain CT scan if the patient has neurologic symptoms.
- Bone scan is indicated if the alkaline phosphatase level is elevated, or the patient has bone pain.
- CT or MR angiography for staging evaluation; vascular information helpful in planning resection
- PET is of limited use because of RCC 's inconsistent uptake of fluorodeoxyglucose, the most commonly used radiotracer, although this variable uptake may be an asset in predicting response to some targeted agents.
Diagnostic Procedures/Other
- No need to aspirate simple cyst unless symptomatic.
- Calcified cysts may contain RCC, requiring open renal biopsy of the cyst wall or partial nephrectomy.
- Hemorrhagic cyst: Aspiration cytology may be helpful, but needle biopsy of solid masses is discouraged, particularly if the patient has a normal contralateral kidney.
- Doppler-flow ultrasound of the renal veins or CT scan that shows the renal vein entering the vena cava can be used to rule out tumor thrombus.
Test Interpretation
- RCC tends to bulge out from the cortex, producing a mass effect.
- 48% of RCCs measure <5 cm, are grossly yellow to yellow-orange due to high lipid content in the clear cell variety. Average size has been decreasing due to incidental discovery and is now ~3.6 cm.
- Small tumors are typically homogeneous.
- Large tumors may have areas of necrosis and hemorrhage.
- About 5 " 10% of RCCs extend into the venous system as tumor thrombi.
- Five distinct subtypes:
- Clear cell: 70 " 80%; proximal tubule, typically solitary
- Papillary renal cell (previously termed chromophilic): 10 " 15%; proximal tubule; tumors tend to be bilateral and multifocal; type 1 and more aggressive type 2 variant
- Chromophobic: 3 " 5%; intercalated cells; tend to have a less aggressive course
- Medullary: <1%; typically affect younger patients; most are at an advanced stage with metastases at time of diagnosis; occur almost exclusively in patients with sickle cell trait
- Collecting duct: <1%
TREATMENT
Among small (<4 cm) renal masses, approximately 20% are benign, 60% represent indolent variants of RCC, and only 20% are potentially aggressive tumors.
MEDICATION
First Line
- Antiangiogenic agents (AAs) " agents that target neoplastic neoangiogenesis by directly blocking the vascular endothelial growth factor (VEGF), or its receptor (e.g., tyrosine kinase inhibitors; TKSs) offer greater efficacy compared to interferon, however radiologic complete response to therapy is rare (1)[A].
- Sunitinib represents front-line standard treatment for the good and intermediate prognosis groups of patients with clear cell RCC (2)[C].
- Sunitinib, sorafenib, pazopanib, and axitinib are all inhibitors of the tyrosine kinase portion of the VEGF family of receptors. Sunitinib is considered first-line treatment in advanced RCC and in patients refractory or intolerant to cytokine therapy. Sunitinib demonstrated improved response (31% vs. 6%; number needed to treat = 4) and longer median progression-free survival (11 vs. 5 months) over interferon-alfa in a randomized study of 750 patients (3)[B].
- Bevacizumab is a monoclonal antibody that binds and neutralizes circulating VEGF protein. Combined with interferon-alfa, bevacizumab offers patients with metastatic RCC a hazard ratio for progression-free survival of 0.63 (95% confidence interval 0.52 to 0.75; p = .0001) compared with interferon alone (4)[B].
- Sunitinib, sorafenib, and bevacizumab have demonstrated superior progression-free survival in patients with metastatic RCC when compared to interferon or placebo (5)[B].
- Resistance develops in nearly all patients treated with one or more of these drugs.
Second Line
- In the second-line setting or later, everolimus, an mTOR inhibitor, was associated with longer progression-free survival compared with placebo in a phase III trial of patients with RCC that had progressed despite treatment with sunitinib, sorafenib, or both (6)[B].
- Cabozantinib is a tyrosine kinase inhibitor poised for fast-track FDA approval for treatment of metastatic medullary thyroid carcinoma. In a 2015 phase III trial, cabozantinib demonstrated a 42% lower rate of disease progression or death (resulting in a 7.4 vs. 3.8 month survival) compared to everolimus in patients with RCC that had progressed after VEGF receptor " targeted therapy (7)[B].
- Response rates with traditional chemotherapeutic agents are typically <15%.
- Despite occasional reports of responses, a review of medroxyprogesterone, the most widely studied progestational agent, concluded that RCCs are neither hormone-dependent nor hormone-responsive.
ADDITIONAL THERAPIES
RCC is considered radioresistant, but radiation therapy may be useful to treat a single or limited number of metastases, particularly brain or bone metastases or painful recurrences in the renal bed.
SURGERY/OTHER PROCEDURES
- Surgery is curative in most patients with nonmetastatic RCC and is the preferred treatment for all but the most extensive disease.
- There is no current role for adjuvant therapy after nephrectomy for clinically localized disease.
- Assuming a normal contralateral kidney, radical nephrectomy, which can be done laparoscopically and involves node dissection and complete removal of the kidney and Gerota fascia, is the typical preferred approach.
- Partial nephrectomy has shown equal long-term, cancer-specific survival for small to medium (<7 cm) tumors when compared with radical nephrectomy. Partial nephrectomy, however, is a more technically challenging procedure.
- Better cancer-specific quality of life has been reported in patients who underwent radical versus partial nephrectomy and in those who underwent laparoscopic versus open surgery (8)[B].
- Surgical intervention in metastatic disease
- Metastasectomy in those with limited metastatic disease versus cytoreductive nephrectomy (debulking) prior to systemic therapy
- Transitional cell carcinoma of the renal pelvis or calyces: nephroureterectomy
- Wilms tumor in adults: radical nephrectomy for unilateral disease
- Cortical adenoma <3 cm (7 " 22% at autopsy): wedge resection
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- CT scan of the abdomen/renal fossa 3 to 6 months after surgery, to monitor recurrences
- For partial nephrectomy: renal ultrasound every 6 months for 3 years, then annually
- CXR or CT scan quarterly for 2 years, then periodically
- Skeletal x-rays and bone scan should be obtained only if patient complains of bone pain or if alkaline phosphatase is elevated.
- Postoperative follow-up with plasma transcobalamin II or serum haptoglobin level to detect or monitor recurrences
- Small (<3 cm), incidentally detected tumors may have an indolent behavior; immediate treatment in poor-risk patients may not be of benefit, and active surveillance may be a viable management strategy.
DIET
Red meat intake may increase the risk of RCC. Higher intakes of heterocyclic amines and polycyclic aromatic hydrocarbons generated in the processing and cooking of red meat have been associated with a 2-fold increase in the risk of papillary RCC and a 20 " 30% increase in the overall risk of RCC (9)[B].
PROGNOSIS
- Relapse occurs in approximately 1/3 of treated patients with localized disease.
- 5-year survival in the absence of metastases >50%; in the presence of distant metastases, 5-year survival decreases to 10%.
- Median survival for metastatic RCC is in the range of 10 to 12 months.
- Performance status at diagnosis and histologic grade of tumor also influence prognosis.
COMPLICATIONS
- Paraplegia can result with little warning from spinal vertebral metastasis.
- CNS metastases are not uncommon.
- ~30% of patients with RCC have metastatic disease when the diagnosis is established. Most common sites of metastasis are the lung (50 " 60%), bone (30 " 40%), regional nodes (15 " 30%), brain (10%), and adjacent organs (10%).
REFERENCES
11 Coppin C, Kollmannsberger C, Le L, et al. Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int. 2011;108(10):1556 " 1563.22 Di Lorenzo G, Buonerba C, Biglietto M, et al. The therapy of kidney cancer with biomolecular drugs. Cancer Treat Rev. 2010;36(Suppl 3):S16 " S20.33 Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115 " 124.44 Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144 " 2150.55 Heng DY, Bukowski RM. Anti-angiogenic targets in the treatment of advanced renal cell carcinoma. Curr Cancer Drug Targets. 2008;8(8):676 " 682.66 Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449 " 456.77 Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814 " 1823.88 Parker PA, Swartz R, Fellman B, et al. Comprehensive assessment of quality of life and psychosocial adjustment in patients with renal tumors undergoing open, laparoscopic and nephron sparing surgery. J Urol. 2012;187(3):822 " 826.99 Daniel CR, Cross AJ, Graubard BI, et al. Large prospective investigation of meat intake, related mutagens, and risk of renal cell carcinoma. Am J Clin Nutr. 2012;95(1):155 " 162.
ADDITIONAL READING
- Delahunt B, Srigley JR, Montironi R, et al. Advances in renal neoplasia: recommendations from the 2012 International Society of Urological Pathology Consensus Conference. Urology. 2014;83(5):969 " 974.
- Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol. 2012;23(Suppl 8):viii35 " viii40.
- Iacovelli R, Alesini D, Palazzo A, et al. Targeted therapies and complete responses in first line treatment of metastatic renal cell carcinoma. A meta-analysis of published trials. Cancer Treat Rev. 2014;40(2):271 " 275.
CODES
ICD10
- C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
- C64.1 Malignant neoplasm of right kidney, except renal pelvis
- C64.2 Malignant neoplasm of left kidney, except renal pelvis
- C64 Malignant neoplasm of kidney, except renal pelvis
ICD9
189.0 Malignant neoplasm of kidney, except pelvis
SNOMED
- Renal cell carcinoma (disorder)
- Hypernephroma (disorder)
- Renal cell carcinoma of bilateral kidneys (disorder)
- Clear cell carcinoma of kidney (disorder)
CLINICAL PEARLS
- RCC represents 3 " 4% of all cancers and 2% of all cancer deaths; most patients have clear cell histology and do not respond to standard chemotherapy.
- Diverse and obscure presentations are typical; most RCCs are found incidentally during radiologic studies.
- At presentation, up to 1/3 of patients with RCC have metastatic disease; recurrence develops in about 1/3 of those treated for localized disease.
- Only 20% of renal masses <4 cm represent potentially aggressive tumors.
- Surgery is curative in most patients with nonmetastatic RCC and is the preferred treatment for all but the most extensive disease.
- Multiple pharmacologic options are considered first-line for metastatic RCC; sequential treatments are likely to be pursued for most patients.