Renal Cell Carcinoma

Introduction

There are two major kinds of renal malignancies: renal cell carcinoma arises in the renal cortex and comprises 80-85% of total kidney cancers, and transitional cell carcinomas, which arise in the renal pelvis and represent the remainder of cases. The incidence of kidney and renal pelvis malignancies has increased over the past three decades, although they still only account for about 2% of all cancers.

Epidemiology and Etiology

• Incidence is over 36,000 new cases annually in the United States and nearly 210,000 new cases worldwide.
• Mortality is approximated at 12,600 deaths each year in the United States and 102,000 deaths worldwide. Four major variables affecting incidence rates are race, gender, age and geography [1, 2, 3].
• • Incidence is higher in Hispanics and lower in Asians than in whites and African-Americans.
  • Renal malignancies are nearly two times more common amongst males as compared to females.
  • The average age at diagnosis is between 55 and 75 years of age.
  • Worldwide, rates of renal malignancies are highest in North America, Scandinavian countries, Australia, and several Western, Eastern, and Northern European countries. Incidence is lowest in Africa and Asia.
• Etiology is not completely understood but is possibly related to chronic exposure of kidney parenchymal cells to mutagens.
• Hereditary links are suggested by the occurrence of renal cell carcinomas in patients with genetic kidney conditions and diseases, including horseshoe kidneys, polycystic kidney disease, and von Hippel-Landau (VHL), an autosomal dominant disease associated with abnormalities of the VHL gene on the short arm of chromosome 3 and manifested by visceral cysts, benign masses, and the development of renal cell carcinomas in approximately 40% of patients.
• • Patients with hereditary renal malignancies are more likely to present at a younger age and w ith bilateral or multifocal disease.
• Risk factors include: cigarette smoking, which is estimated to be directly responsible for about one-third of these malignancies; exposure to petroleum, cadmium, asbestos, and arsenic; first degree affected relatives; heavy analgesic use; hypertension; obesity; tuberous sclerosis; renal dialysis; and acquired cystic disease of the kidney [4, 5, 6].

Screening Recommendations

• There is no current role for universal screening for renal malignancies.

Clinical Presentation

• History and Physical exam: the most common presentations are hematuria (50-60%), abdominal pain (40%), and a palpable abdominal or flank mass (30-40%). This "classic triad" is strongly suggestive of metastatic disease but is only present in about 10% of cases. Additional signs and symptoms may include hypertension, fevers, night sweats, weight loss, malaise, and rarely, varicoceles in men (usually left-sided, from obstruction of the testicular vein) [5].
• Lab studies: may be normal or reveal anemia or abnormalities related to various paraneoplastic syndromes, which are seen in up to 40% of patients and include hypercalcemia, hypertension, erythrocytosis, hyperglycemia, cachexia, amyloidosis, and Stauffer's syndrome (nonmetastatic hepatic dysfunction); experimental kidney tumor markers [7].
• Radiologic and Diagnostic studies: renal ultrasounds and dynamic intravenous contrast-enhanced CT scans are the m ost useful tests for distinguishing solid renal masses from benign renal cysts and are used in both diagnosing and staging these malignancies; MRI scans can be used to detect local tumor invasion and venous involvement; DNA flow cytometry can provide additional prognostic data; intravenous urography is typically used as an initial evaluation for hematuria; intravenous pyelogram or renal arteriography may be used to characterize suspicious renal masses or for preoperative mapping of the vasculature. A metastatic work-up with chest x-ray and bone scan is commonly conducted [8].
• • CT scans are the most sensitive diagnostic test and are greater than 90% accurate in determining tumor stage and resectability.
  • Approximately 25-40% of renal malignancies are detected incidentally on CT scans or ultrasounds obtained for unrelated medical issues. These asymptomatic tumors are often small at diagnosis and more amenable to treatment [5].
• Diagnostic studies : definitive diagnosis is achieved by the procurement of a tissue sample that is usually obtained at the time of surgery in patients with resectable tumors.

Natural Course and Pathology

• Natural course: often a long, indolent course of asymptomatic tumor growth, with 25-30% of patients presenting with metastasis at the time of diagnosis.
• • Frequent sites of metastasis: lung parenchyma (50-60%), bone (30-40%), liver (30-40%).
• Staging: the standard TNM system of the American Joint Committee on Cancer has replaced the Robson Modification of the Flocks and Kadesky Staging System as the most commonly used system to stage renal malignancies. The TNM system is thought to more accurately define tumor size, the extent of local invasion, vascular involvement, and the presence of lymph node metastases [3].
• Prognosis: is most significantly dependent on the pathologic stage of the disease. Other prognostic factors include nuclear grade, histologic pattern, and DNA content.
• • Tumors may be localized, spread directly to the renal vein or perinephric fat, or spread hematogenously or lymphatically to distant sites. Five-year survival rates for localized, regional, and distant disease are 90%, 60% and 9%, respectively [9].
  • Along with the increase in incidence, survival for patients with renal malignancies has improved over the past three decades. The overall five-year survival rates for patients diagnosed between 1974 and 1976 was 52%, significantly lower than the 62% for patients diagnosed between 1992 and 1998 [9, 10].
• Histologically: tumors were traditionally classified according to cell type (clear spindle, granular, oncocytic) and growth pattern (acinar, sarcomatoid, papillary). However, the revised classification scheme has more prognostic implications and divides carcinomas into the following five types: clear-cell (75-85% of carcinomas), chromophilic/papillary (12-14%), chromophobic (4-6%), oncocytic (2-4%), and collecting (Bellini's) duct (1%) [5].

Treatment

• Non-metastatic disease
• • Surgery is the most effective treatment modality used for patients with renal malignancies. A radical nephrectomy offers the best chance of a cure and involves the removal of the affected kidney, ipsilateral adrenal gland, proximal ureter, perirenal fat bound by Gerota's fascia and, often times, regional lymph nodes.
  • • Regional lymph node dissection is controversial, as its staging value is limited given the ability for venous spread of the cancer, thus bypassing the lymphatics [11].
    • Following nephrectomy, five-year survival for patients with disease confined to the renal parenchyma is 80-85%, but survival is ? 25% for patients with extracapsular spread or lymph node involvement [12].
  • Radiation therapy following surgery is controversial, with studies suggesting that adjuvant external beam radiation therapy can potentially improve local control in patients with adrenal invasion, positive surgical margins, or perinephric fat extension, but has no significant effect on overall survival [13].
  • Adjuvant chemotherapy has not been shown to improve overall survival or decrease relapse rates in patients with early or locally advanced renal malignancies [5].
• Metastatic disease
• • Surgery can be employed in metastatic disease as part of a multimodality treatment approach or for palliation of disease symptoms.
  • • Debulking or cytoreductive nephrectomy should be considered in patients with a good performance status and has been shown to significantly improve overall survival in patients with metastatic renal malignancies treated with immunotherapeutic agents postoperatively. A combined analysis showed a median survival of 7.8 months for patients treated with interferon alpha alone, as compared to 13.6 months for patients treated with nephrectomy and adjuvant interferon (p = 0.002) [14].
  • Radiation therapy given as a palliative modality, can improve patient quality of life. Up to 86% of patients with focal symptoms attributable to metastatic disease were shown to derive a palliative response to radiation treatments, with about half of the patients achieving a complete palliative response [15].
  • Chemotherapy either in single agent or combination, has historically not achieved consistent response rates to warrant their routine use in patients with metastatic disease. More recent studies have suggested that g emcitabine, in combination with 5-FU or capecitabine, may improve progression-free survival in these patients. Overall survival, however, remains very poor [16].
  • Immunotherapy with interferon alpha and interleukin-2, either alone or combined, has been reported to achieve response rates of 10-30% in patients with metastatic disease. Despite the significant side effects associated with both cytokines, these agents have been shown to modestly lengthen median survival in select patients [17, 18].
  • • Targeted and biologic therapies are currently being investigated in clinical trials for patients with renal malignancies. Recombinant humanized monoclonal antibodies to vascular endothelial growth factor ( bevacizumab [Avastin] ) are being studied as part of a multimodality treatment approach for patients with metastatic disease. Monoclonal antibodies that inhibit epidermal growth factor receptor (EGFR) ligand binding ( cetuximab [Erbitux]) and EGFR small-molecule tyrosine kinase inhibitors ( erlotinib [Tarceva] ) are also being investigated for patients with advanced disease. Additional novel therapies currently being examined include the use of dendritic cell-based vaccines and peripheral blood stem cell transplantations. Since metastatic renal cell carcinoma is one of the most treatment-resistant malignancies, patients should consider enrolling in ongoing clinical trials [19].