Managing the Complex Journey of Renal Cell Carcinoma

Renal Cell Carcinoma: Diagnosis and Evaluation
Steven C. Campbell, MD, PhD
Cleveland Clinic Foundation, Ohio

Considerable progress has been made in characterizing the etiology of kidney cancer. Most renal cell carcinomas (RCCs) arise from the renal tubular epithelium, particularly in the proximal portions of the nephron (Bukowski & Wood, 2007). One important discovery is that kidney cancer is not one but several types of cancer, each with a distinct histologic appearance, genetic basis, and clinical course. The most common subtype is clear cell RCC, which represents 75% of all kidney cancers (Linehan, Walther, & Zbar, 2003). The gene responsible for clear cell RCC is the von Hippel-Lindau (VHL) tumor suppressor gene that resides on the short arm of chromosome 3. When both alleles of this gene are mutated or silenced, there is dysregulated expression of hypoxiainducible factors and upregulation of their downstream effectors, such as vascular endothelial growth factor, which contribute to the profuse neovascularity associated with RCC. The other common subtypes of kidney cancer include papillary RCC and chromophobic RCC, which tend to be less aggressive than the clear cell variant. The gene responsible for most papillary RCCs is the c-Met proto-oncogene, a receptor for hepatocyte growth factor. When this receptor is mutated, it remains in the “on position” and is active on a constitutive basis. This leads to uncontrolled cellular proliferation and a predisposition to malignancy (Kaelin, 2004; Cohen & McGovern, 2005).

The only environmental factor that has been strongly linked to RCC is tobacco use (McLaughlin, Lipworth, & Tarone, 2006). A male predilection of 2:1 is observed for sporadic RCC, and most patients are diagnosed in the sixth through eighth decades of life (Campbell, Novick, & Bukowski, 2006). RCC is also more common in patients with end-stage renal failure and patients receiving renal replacement therapy, whether it is dialysis or renal transplantation (McLaughlin et al., 2006).

Familial Kidney Cancer
Approximately 96% to 97% of kidney cancers are sporadic; the remainder are familial, meaning the risk for developing RCC is inherited (Linehan et al., 2003; Cohen & McGovern, 2005). The most common familial form of kidney cancer is the VHL syndrome in which patients are born with a mutated allele of the VHL gene (Linehan et al., 2003; Cohen & McGovern, 2005; Campbell et al., 2006). Transmission is autosomal dominant, and the incidence is 1 per 30,000 births. Common manifestations include hemangioblastomas of the central nervous system, retinal angiomas, pancreatic cysts and tumors, pheochromocytomas, and RCC. RCC in VHL and other familial forms of kidney cancer tends to be early onset (typically in the third to fifth decades of life), bilateral, and multifocal. Presentation is thus distinctly different from sporadic RCC, which tends to be unilateral and unifocal and occurs later in life. Familial etiology should be considered in patients with early onset RCC, bilateral or multifocal disease, or a personal or family history of related tumor manifestations (Cohen & McGovern, 2005).

Clinical Presentation
The clinical presentation of RCC may vary greatly (Bukowski & Wood, 2007). The kidneys are sequestered within the retroperitoneum, surrounded by the body wall, so tumor growth to large size with local extension may occur in the absence of symptoms. The classic presentation with an abdominal mass, flank pain, and hematuria is often referred to as the “too late triad,” since many such patients are incurable. This symptom complex is now uncommon but unfortunately still occurs. Patients may also present with symptoms due to systemic metastases (e.g., bone pain) or paraneoplastic syndromes (Kim & Kaelin, 2004). The latter may include hypercalcemia, erythrocytosis, or cachexia and fatigue. These syndromes are due to dysregulated secretion of hormones or inflammatory mediators by the tumor. In these settings, the cancer may present in obscure ways, often mimicking other medical disorders. Accordingly, one of the common monikers for RCC is the “internist’s tumor.” In the modern era, RCC is most often diagnosed incidentally at the time of computed tomography (CT) or ultrasonography for unrelated complaints, and is now better termed the “radiologist’s tumor.” This is fortunate since most of these asymptomatic tumors are small, confined, and curable (Campbell et al., 2006).

Patient Evaluation
The initial evaluation of a patient with RCC should include a thorough history and physical examination, routine laboratory tests (comprehensive metabolic profile, complete blood count), CT scan of the abdomen and pelvis, and a chest radiograph (Campbell et al., 2006). Physical examination findings may include palpable lymphadenopathy, a discernable mass, or lower extremity edema, which suggests an obstructive inferior vena cava tumor thrombus. All of these finding are ominous. Fortunately, most patients will not present with any of these prognostic factors. The CT scan should be carefully reviewed for evidence of intra-abdominal metastases, regional lymphadenopathy, or venous involvement, and the status of the contralateral kidney should be evaluated. Magnetic resonance imaging should be considered if there is evidence of venous tumor thrombus, which occurs in approximately 5% to 10% of patients (Figure), or loss of tissue planes that may suggest invasion of adjacent organs. Chest CT and bone scans may be reserved for patients with an abnormal chest radiograph, bone pain, locally advanced disease, or a substantial decline in performance status (Cohen & McGovern, 2005). The utility of positron emission tomography scanning in the evaluation of patients with RCC remains controversial. Percutaneous biopsy of renal masses is associated with a high degree of inaccuracy and therefore rarely affects treatment decisions. It is only recommended when there is a clinical suspicion of lymphoma, renal abscess, or metastases to the kidney from another primary cancer (Cohen & McGovern, 2005).