Description

• Renal cell carcinoma (RCC) arises from the parenchyma of the kidney (as opposed to urothelial cancer, which arises from the renal pelvis/calyces). According to SEER, there is estimated to be 65,340 new cases (including renal pelvis) in 2018 with 14,970 estimated deaths from kidney cancer.
• Common sites of metastases include lymph nodes, lungs, and bones.
• Early, aggressive surgical and/or systemic management provides the best opportunity for cure.
• System(s) affected: renal/urologic

Epidemiology

Incidence

• Predominant age: patients in 5th to 7th decades; median age at diagnosis is 64 years.
• Male to female 2:1
• >60% are detected as an incidental finding.
• The incidence of RCC is rising, whereas the death rate from RCC has concurrently decreased (SEER).
• The rate of metastatic disease increases with the size of the renal mass.
  • 1.1% (1 to 2 cm), 3.3% (2 to 3 cm), 6% (3 to 4 cm)

Etiology and Pathophysiology

• Most common site of metastatic disease is lung.
• Pathogenesis: loss of von Hippel-Lindau (VHL) gene resulting in decreased degradation of hypoxia-inducible factor (HIF), which in turn leads to increased expression of angiogenic growth factors (vascular endothelial growth factor [VEGF] and platelet-derived growth factor [PDGF])
• Five distinct subtypes
  • Clear cell: 70–80%; proximal tubule, solitary
  • Papillary renal cell (previously termed chromophilic): 10–15%; proximal tubule; tumors tend to be bilateral and multifocal; type 1 and more aggressive type 2 variant
  • Chromophobe: 3–5%; intercalated cells; tend to have a less aggressive course
  • Medullary: <1%; typically affects younger patients; most are at an advanced stage with metastases at time of diagnosis; occurs almost exclusively in patients with sickle cell trait
  • Collecting duct: <1%, aggressive disease with high mortality

Genetics

• 2–3% of cases are familial, with several autosomal dominant syndromes described.
• Oncogenes localized to the short arm of chromosome 3 may have etiologic implications. Chromosome 3p12–p26 is specific for clear cell RCC.
• Multiple hereditary types of RCC have been established, although VHL remains the most common, predisposing the clear cell RCC and vascular lesions.
• Hereditary papillary RCC is an autosomal dominant form of disease associated with multifocal papillary renal tumors and a 5:1 male predominance; no extrarenal manifestations
• Other familial RCCs include Birt-Hogg-Dubé (BHD) syndrome, hereditary leiomyomatosis and RCC (HLRCC), tuberous sclerosis.

Risk Factors

• Prior diagnosis of RCC—risk increases to 2–4% for a metachronous RCC in absence of familial disease
• Smoking, active and passive
• Obesity
• Hypertension (Antihypertensive medications are not independently associated with RCC.)
• End-stage renal failure: Patients on hemodialysis have an increased risk of RCC.
• Acquired renal cystic disease
• Tuberous sclerosis
• Family history of RCC
• Heavy-meat and high-fat dairy products
• Lower socioeconomic status
• Heavy metal exposure (cadmium, lead)
• Environmental toxin exposure (asbestos, petroleum by-products, chlorinated solvents)
• Complex renal cyst

General Prevention

Smoking may contribute to 1/3 of all cases.

Commonly Associated Conditions

• VHL disease: 30–45% of these patients develop clear cell tumors.
• Tuberous sclerosis: associated primarily with angiomyolipoma and clear cell tumors
• HLRCC: cutaneous and uterine leiomyomas; more aggressive type II papillary RCC. 15–30% develop RCC.
• BHD: associated with oncocytomas and chromophobe RCC, benign cutaneous lesions, lung cysts, and associated risk of pneumothorax
• Sickle cell trait: With few exceptions, renal medullary tumor is seen in young African American males with sickle cell trait.
• Adult polycystic kidney disease
• Renal cystic disease from chronic renal failure on dialysis