Clear cell carcinoma of the kidney, an adenocarcinoma arising from the proximal convoluted tubules (PCTs), accounts for 85% of primary renal neoplasms. The inactivation or deletion of the Von Hippel-Lindau (VHL) gene on chromosome 3p is associated with an enhanced production of vascular endothelial growth factor (VEGF), and is found in 50% to 60% of sporadic clear cell renal carcinomas. VEGF is believed to augment the growth of new blood vessels typically seen with clear cell kidney cancer and its metastases.

Papillary carcinomas account for 10% and also arise from the PCTs but are distinct from clear cell carcinomas, are often multifocal, and are often with multiple genetic abnormalities. Papillary carcinomas are further divided into two subtypes depending on pathology, gene expression, and prognosis. Type I tend to be a lower grade at diagnosis and carry a better prognosis, while Type II tend to be a higher grade with a poorer prognosis. The remaining 5% of renal carcinomas include oncocytomas (well-differentiated adenocarcinomas) and chromophobic and transitional carcinomas. Wilms tumor (nephroblastoma) is seen predominantly in childhood.

The most widely used and most predictive grading system for renal cell cancer is the Fuhrman Nuclear Grade.

Kidney cancer is listed among the world’s 10 most common cancers. More than 57,000 Americans were diagnosed with kidney cancer in 2009, an increase from approximately 36,000 in 2006. Males account for 60% of diagnoses and African-Americans have the
highest rate of any racial or ethnic group. Nearly 13,000 patients will die in 2010 from kidney cancer.

In general, cigarette smoking roughly doubles the risk of kidney cancer with an increased dose-dependent risk in heavy smokers. Approximately 30% of males and 25% of females with renal cancer have a history of tobacco use. Industrial exposure to cadmium, asbestos, petroleum byproducts, and ingestion of the drug phenacetin (analgesic nephropathy) has been associated with a higher risk. Lesser risk factors include acquired multicystic kidney disease, patients with end-stage renal disease who are on hemodialysis, obesity, and hypertension. Several hereditary conditions predispose patients to renal cell cancers. Notably, VHL disease, an autosomal dominant hereditary condition involving the inactivation of the tumor-suppressor VHL gene, predisposes patients to a variety of neoplasms including clear cell histology renal carcinoma. Inactivation of the VHL gene stimulates angiogenesis through VEGF and its receptor targets in new therapeutic agents. The VHL gene is also mutated in a high number of sporadic or non-hereditary RCCs.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder associated with fibrofolliculomas (benign hair follicle tumors), pulmonary cysts, and renal cancers most commonly of the chromophobe, oncocytoma histology, or a hybrid of the two subtypes. BHD syndrome is caused by a germline mutation in the tumor-suppressor BHD gene, which encodes a novel protein folliculin that has an unknown function.

The most common clinical signs and symptoms of renal cancer include hematuria (56% of patients), flank pain (38%), abdominal mass (36%), weight loss (27%), and fever (11%). However, the classic triad of hematuria, flank pain, and abdominal mass occurs in less than 20% of patients and many are asymptomatic until the disease is advanced. Twenty-five percent of renal cancers are found incidentally in radiographic imaging, and 30% of patients will have metastatic disease at diagnosis. Common metastatic sites are lung (75%), soft tissues (36%), bone (20%), and liver (18%); brain metastases are often a late manifestation. Hypercalcemia is present in up to 20% of patients despite the absence of bony metastases and is related to ectopic production of parathyroid hormone-related protein, osteoclast activating factor, or tumor necrosis factor. Erythrocytosis due to excess erythropoietin production has been described in 3% of patients. Ectopic production of other hormones including renin
and glucagon produce clinical manifestations of hypertension and hyperglycemia, respectively. Stauffer syndrome, identified in up to 20% of patients, is a hepatic dysfunction associated with elevated alkaline phosphatase, transaminases, activated partial thromboplastin time, and hepatomegaly in the absence of liver metastases.

RCCs are traditionally staged using the TNM staging system (Table 12.1). Newer prognostic systems include the University of California, Los Angeles, integrated staging system (UISS) and the Memorial Sloan-Kettering Cancer Center (MSKCC) system. The UISS (Table 12.2), more predictive for localized tumors, factors in TNM staging, Fuhrman grade, and Eastern Cooperative Oncology
Group performance status and stratifies patients into low-, intermediate-, or high-risk categories. The MSKCC system (Table 12.3) for advanced disease includes Karnofsky performance status, elevated lactate dehydrogenase levels, anemia, hypercalcemia, and the absence of prior nephrectomy, and predicts favorable, intermediate, or poor risk groups.