Renal Cell Carcinoma

Introduction

There are two major types of renal malignancies. Renal cell carcinoma (RCC) arises from the renal cortex and accounts for approximately 80-85% of all primary kidney cancers. Transitional cell carcinomas originate from the urothelial lining of the renal pelvis and represent the remainder of cases. The incidence of primary kidney cancers has increased over the past three decades, although they still only account for about 2% of all cancers.

Epidemiology and Etiology

• Incidence: Over 58,000 new cases of kidney cancer are diagnosed annually in the United States, and nearly 430,000 cases worldwide [1,2].
• Mortality is estimated at 13,000 deaths per year in the United States and 180,000 deaths worldwide.
• Four major variables affecting incidence rates are race, gender, age, and geography [3-6].
  • Incidence is higher in Hispanics and lower in Asians compared to white and Black individuals.
  • Renal malignancies are nearly twice as common in males as in females.
  • The average age at diagnosis is between 55 and 75 years.
• The etiology is not completely understood but may be related to chronic exposure of kidney parenchymal cells to mutagens.
• Hereditary: RCC is associated with several inherited conditions including von Hippel-Landau (VHL), an autosomal dominant disease associated with mutations of the VHL gene on the short arm of chromosome 3. VHL may cause visceral cysts, benign tumors, and RCC in approximately 40% of patients. Other associated conditions include horseshoe kidneys, autosomal dominant kidney disease and tuberous sclerosis.
  • Patients with hereditary renal malignancies are more likely to present at a younger age with bilateral or multifocal disease.
• Risk factors include cigarette smoking, which is responsible for about ~30% of cases; occupational exposure to petroleum, cadmium, asbestos, and arsenic; chronic analgesic use; hypertension; obesity; long-term dialysis; chronic hepatitis C; and acquired cystic disease of the kidney. A family history of first-degree relatives with RCC also increases risk [7, 8, 9, 10].

Screening Recommendations

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

Clinical Presentation

• History and Physical Exam: the most common presenting symptoms include hematuria (50-60%), abdominal pain (40%), and a palpable abdominal or flank mass (30-40%). These three findings constitute the classic triad of RCC, which is highly suggestive of locally advanced disease but is present in only ~10% of cases. Additional symptoms may include hypertension, fevers, night sweats, weight loss, malaise, and rarely, varicoceles in men (usually left-sided, from obstruction of the testicular vein) [8].
• Lab studies may be normal or reveal anemia. Lab abnormalities related to various paraneoplastic syndromes, (seen in up to 40% of patients) may include hypercalcemia, hypertension, erythrocytosis, hyperglycemia, cachexia, amyloidosis, and Stauffer's syndrome (nonmetastatic hepatic dysfunction) [11].
• Radiologic and Diagnostic Imaging: renal ultrasounds and contrast-enhanced CT scans are the most useful tests for distinguishing solid renal masses from benign cysts. They are used in both diagnosis and staging. MRI is useful for detecting local tumor invasion or venous involvement or if CT contrast is contraindicated due to renal function. 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 [12].
  • 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 [8].
• Definitive diagnosis is typically made by histologic evaluation of a surgical specimen.  Biopsy may be indicated in patients with unresectable tumors or those considered for non-surgical management.

Natural Course and Pathology

• Natural history: RCC often follows an indolent course, and many may be asymptomatic for years. Approximately 25-30% of patients present with metastatic disease at diagnosis.
  • Frequent sites of metastasis include the lung parenchyma (45-60%), bone (30-40%) and liver (20-40%) [13].
• Staging: the standard TNM system of the American Joint Committee on Cancer is used to stage renal malignancies and accurately defines tumor size, the extent of local invasion, vascular involvement, and the presence of lymph node metastases [6].
• Prognosis: the most significant prognostic factor is the pathologic stage at diagnosis. Other prognostic factors include nuclear grade, histologic subtype, and DNA ploidy and content.
  • RCC may remain localized or spread to the renal vein, perinephric fat, spread hematogenously or via lymphatics to distant sites. Five-year survival rates for localized, regional, and distant disease are 93%, 74%, and 17%, respectively [9,14].
  • Survival for patients with renal malignancies has improved over the past three decades owing to improvements in imaging and earlier detection. The overall five-year survival rates for patients diagnosed between 1974 and 1976 were 52%, significantly lower than the 62% for patients diagnosed between 1992 and 1998. Between 2013 and 2019, the five-year overall survival rate increased to 78% [14,15].
• 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 significance and divides carcinomas into the following five types: clear-cell (75-85% of carcinomas), chromophilic/papillary (10-15%), chromophobic (5-10%), oncocytic (3-7%), and collecting (Bellini's) duct (1%) [8, 16, 17].

Treatment

• Non-metastatic disease
  • Surgery remains the primary treatment for localized RCC. A radical nephrectomy involves the removal of the affected kidney, ipsilateral adrenal gland, proximal ureter, perirenal fat bound by Gerota's fascia, and, oftentimes, regional lymph nodes. A partial nephrectomy is preferred for select patients with early-stage disease and low tumor burden [18].
    • 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 [19].
    • 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 [20].
  • Radiation therapy has emerged as a promising treatment option for patients with localized disease who are not surgical candidates. Stereotactic body radiotherapy (SBRT) is the technique of choice, which delivers a high dose of radiation in 1 to 5 treatments (fractions). This is typically recommended for tumors < 7 cm in size.
  • Immunotherapy such as pembrolizumab is recommended in the adjuvant setting for select cases.
• Metastatic disease
  • Surgery can be used 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) [24].
  • 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 [25].
  • Systemic therapy is often selected depending on risk factors and histologic subtype. Treatment typically includes a combination of immunotherapy, such as pembrolizumab, nivolumab or ipilimumab and targeted therapies such as tyrosine kinase inhibitors.