Renal Cell Carcinoma (RCC)

Definition

Epidemiology

• Sixth most common cancer in men, ninth most common in women
• Male: Female ratio = 2:1 to 3:1
• Peak incidence in the 6th-7th decade of life
• Over 75,000 new cases diagnosed annually in the US; ~14,000 deaths/year
• Highest incidence in Black Americans; lowest in Asians/Pacific Islanders

• Cigarette smoking (most modifiable risk factor; risk decreases ~20 years after cessation)
• Obesity (risk rises with increasing BMI)
• Hypertension and diuretic use
• Acquired polycystic kidney disease (complication of chronic dialysis) - 30-fold increased risk
• Pre-existing renal disease: polycystic kidney disease, horseshoe kidney, chronic renal failure on hemodialysis
• Occupational exposure to cadmium
• Genetic predisposition (VHL disease, hereditary papillary RCC)

Classification and Pathogenesis

1. Clear Cell Carcinoma (65% of RCC)

• Most common subtype; derived from the proximal convoluted tubule
• Accounts for ~90% of all metastases from RCC
• Molecular hallmark: Loss/inactivation of both copies of the VHL (von Hippel-Lindau) gene on chromosome 3p25
• In VHL disease (autosomal dominant), germline mutation of VHL predisposes to bilateral, multifocal clear cell RCC in 40-60% of patients
• Without VHL protein, hypoxia-inducible factors (HIFs) are not degraded, remaining high even under normoxic conditions
• HIFs stimulate VEGF expression, driving angiogenesis and tumor vascularization
• HIF also collaborates with MYC to alter cellular metabolism and promote growth
• Recent genomic studies also show frequent loss-of-function mutations in genes regulating histone methylation (epigenomic changes)

2. Papillary Renal Cell Carcinoma (10-15% of RCC)

• Frequently multifocal and bilateral; tends to present at an early stage
• Unifying feature: Genetic abnormalities activating MET (tyrosine kinase receptor on chromosome 7q)
• Sporadic form: increased MET copy number or somatic activating mutations in MET
• Familial form: germline activating MET mutations
• Accounts for ~25% of total tumors but only 10% of metastases - more indolent than clear cell

3. Chromophobe Renal Cell Carcinoma (5% of RCC)

• Arises from intercalated cells of collecting ducts
• Characterized by multiple losses of entire chromosomes, leading to extreme hypoploidy
• Generally has a favorable prognosis
• Cells have eosinophilic (pale, chromophobe) cytoplasm with distinct cell membranes and perinuclear haloes

Morphology

• Clear cell carcinoma: Large, solitary, spherical mass (3-15 cm), arising in the cortex; cut surface is yellow to orange due to abundant cytoplasmic lipid and glycogen, with areas of hemorrhage and cystic change
• Tumor may fungate through the calyceal system into the ureter
• Classic feature: Invasion of the renal vein, with tumor growing as a solid column - may extend all the way into the inferior vena cava and even into the right heart
• Papillary RCC: Less vividly yellow (lower lipid content); shows necrosis, hemorrhage, cystic degeneration
• Chromophobe RCC: Tan-brown gross appearance

• Clear cell type (A): Cells with vacuolated, clear cytoplasm (lipid and glycogen dissolved out) and distinct cell membranes; arranged in nests separated by delicate fibrovascular stroma; small, round nuclei
• Papillary type (B): Cuboidal to low columnar cells lining papillae with fibrovascular cores; cuboidal cells with eosinophilic to clear cytoplasm
• Chromophobe type (C): Eosinophilic cytoplasm mixed with pale granular cells; very prominent distinct cell membranes, perinuclear haloes

Clinical Features

1. Painless hematuria (gross or microscopic)
2. Palpable flank/abdominal mass
3. Dull flank pain

Paraneoplastic Manifestations (important for exam!)

Diagnosis

• Ultrasound: Initial screening; can differentiate solid from cystic, but low sensitivity for small lesions
• Multiphasic contrast-enhanced CT (gold standard): Best for evaluating solid lesions; done in pre-contrast, arterial (~25 sec), nephrographic (~90 sec), and excretory phases. Key: enhancement on nephrographic phase differentiates malignant from benign
  • Clear cell RCC: Avid enhancement in corticomedullary phase; becomes hypoenhancing in nephrographic phase
  • Papillary RCC: Hypointense on T2-weighted MRI; hypoenhancing on all contrast phases
  • Chromophobe RCC: Avid corticomedullary enhancement, less than clear cell
• MRI: Preferred when contrast is contraindicated (poor renal function); excellent for delineating venous thrombus extension into renal vein/IVC; helpful for complex cysts

• CBC, chemistry profile (liver function, calcium, creatinine)
• CT chest, abdomen, pelvis
• Bone scan if: advanced disease, hypercalcemia, bone pain, elevated alkaline phosphatase
• Staging by TNM system (AJCC 8th edition)

TNM Staging

• T3a: Extends into renal vein/segmental branches, or perinephric fat
• T3b: Extends into vena cava below diaphragm
• T3c: Extends into vena cava above diaphragm or invades IVC wall

Treatment

Localized Disease (Stages I-III)

• Partial nephrectomy (nephron-sparing surgery): Preferred for tumors ≤7 cm; provides equivalent local control and survival to radical nephrectomy while preserving renal function; open or laparoscopic technique
• Radical nephrectomy: Preferred for large, centrally located tumors; tumors replacing most of the parenchyma; tumors with regional adenopathy; tumors extending into the IVC; can be open or laparoscopic
  • Ipsilateral adrenal gland removed; regional lymph node dissection is optional/controversial
• Adjuvant therapy: RCC is resistant to both radiation and cytotoxic chemotherapy
  • Sunitinib (VEGF tyrosine kinase inhibitor) or pembrolizumab (anti-PD-1) recommended for high-risk cases after nephrectomy

Metastatic Disease (Stage IV)

• ~30% of patients present with metastatic disease; another 20-30% relapse after surgery
• First-line systemic therapy: Anti-PD-1 checkpoint inhibitors + tyrosine kinase inhibitors (TKIs):
  • Nivolumab + cabozantinib or nivolumab + ipilimumab (anti-CTLA-4) - significantly superior to sunitinib monotherapy
  • Pembrolizumab + axitinib or pembrolizumab + lenvatinib - recommended in all risk groups
• mTOR inhibitors: Everolimus, temsirolimus - used for previously treated patients
• Belzutifan (HIF-2α inhibitor) - useful for VHL-mutation associated tumors
• Radiation therapy: Palliative role for bone and brain metastases
• Metastasectomy: May extend survival in selected patients (disease-free interval >1 year, solitary lung metastasis)

Prognosis

• Robbins & Kumar Basic Pathology, Chapter 12 (Kidney)
• Goldman-Cecil Medicine, Chapter 182 (Renal Cell Carcinoma)
• National Kidney Foundation Primer on Kidney Diseases, 8th ed., Chapter 6
• Campbell-Walsh-Wein Urology, Part XI