The incidence of renal cell carcinoma (RCC) in the United States has been rising steadily, with an estimated 65,150 cases and 13,680 deaths in 2013 (1). RCC is the 6th most common malignancy in men and the 8th in women with a male-to-female ratio of 1.6:1. The majority of patients are now identified through incidental findings on imaging studies. Fortunately, the prognosis of early stage disease is excellent. However, 25% of patients have advanced disease at initial presentation, and metastatic disease is generally considered incurable. The median survival for patients with metastatic disease historically was 12–15 months, with 5-year survival of 10% (2). However, this appears to have changed over the past decade, as advances in the understanding of RCC biology combined with the development of novel targeted therapies have improved and redefined management of advanced RCC.
ETIOLOGY AND PATHOGENESIS
Numerous environmental, lifestyle, and genetic factors have been linked to the development of RCC, including cigarette smoking and obesity. Different pathologic types of RCC have been identified including clear cell, papillary, chromophobe, collecting duct, medullary, and unclassified RCC (Table 39-1) (2). High-grade variants with spindle cell differentiation are described as having sarcomatoid growth patterns and typically confer a poor prognosis (3). There are important biologic, prognostic, and therapeutic distinctions between these different diseases.
TABLE 39-1HISTOLOGIC CHARACTERIZATION ||Download (.pdf) TABLE 39-1 HISTOLOGIC CHARACTERIZATION
|Histologic Cell Type Survival ||Frequency (%) ||Syndrome ||Gene ||5 Years |
|Clear cell ||60–75 ||VHL disease/HP ||VHL/SDHB ||~60% |
| || ||FCRC ||3p del || |
|Papillary ||12 ||HPRC HLRCC ||MET FH ||~80% |
|Chromophobe ||4 ||BHD syndrome ||BHD ||~90% |
|Oncocytoma ||4 ||BHD syndrome ||BHD ||Benign |
|Collecting Duct ||<1 ||– ||– ||<5% |
|Medullary ||<1 ||– ||Sickle trait ||Rare |
Several hereditary syndromes predispose patients to RCC (4). Insight into Von Hippel Lindau (VHL) disease has formed the foundation of our understanding of clear cell RCC, which accounts for 75% of renal cancer and >90% of metastatic RCC. The VHL tumor suppressor gene is located on chromosome 3, and in the hereditary form of clear cell RCC, one allele is inherited as an abnormal gene. Development of RCC occurs when the second allele is altered by deletion, hypermethylation, or mutational inactivation. Biallelic gene alteration leads to loss of function of the tumor suppressor protein and is observed in nearly 100% of the hereditary cases as well as >75% of sporadic cases of clear cell renal carcinoma. The VHL protein normally functions to inhibit cellular growth and is involved in regulating the expression of several proangiogenic genes. Under normal oxygen conditions, the VHL protein targets the hypoxia-inducible factor (HIF) family of transcription factors for ...