Renal Cell Carcinoma (RCC)

Definition and Overview

• 6th most common cancer in men, 9th in women
• Male:female ratio of ~2:1 to 3:1
• Peak incidence in the 6th-7th decade
• Highest incidence in Black Americans; lowest in Asians/Pacific Islanders
• Only 4-6% of cases are familial; the vast majority are sporadic

Risk Factors

Classification and Pathology

1. Clear Cell Carcinoma (65% of RCC; 90% of metastases)

• Derived from the proximal convoluted tubule
• Grossly: solitary, well-circumscribed, golden yellow due to cytoplasmic lipid
• Histologically: cells with clear cytoplasm arranged in nests surrounded by delicate vasculature
• Molecular hallmark: loss/inactivation of both VHL alleles on chromosome 3p25
  • VHL normally causes oxygen-dependent degradation of HIFs (hypoxia-inducible factors)
  • Loss of VHL --> HIF stabilization even in normoxia --> upregulation of VEGF --> tumor vascularization
  • Also involves loss-of-function mutations in histone methylation regulators (epigenomic changes)
• Frequently invades the renal vein (and can extend into the inferior vena cava)
• Most virulent subtype

2. Papillary RCC (10-15%; largely indolent)

• Characteristic papillary growth pattern
• Frequently multifocal and bilateral
• Often presents as early-stage tumor
• Molecular hallmark: increased MET signaling (chromosome 7q)
  • Sporadic: increased MET copy number or somatic activating MET mutations
  • Familial: germline activating MET mutations
• Hypointense on T2-weighted MRI; hypoenhancing on all post-contrast phases
• Lower metastatic potential than clear cell

3. Chromophobe RCC (~5%; indolent)

• Neoplastic cells have eosinophilic cytoplasm with prominent cell membranes (like plant cells)
• Avid enhancement in corticomedullary phase on CT/MRI, but less than clear cell
• Better prognosis than clear cell or papillary
• Associated with Birt-Hogg-Dube (BHD) syndrome

Other Subtypes

• Collecting duct carcinoma: very rare, aggressive
• Oncocytoma: benign (10% of all renal tumors), mahogany-brown color, central stellate scar; cannot be reliably distinguished from RCC on imaging
• Sarcomatoid differentiation: can occur in any subtype; indicates aggressive biology and poor prognosis

Hereditary Syndromes

Clinical Presentation

• Hypercalcemia (~20%): from PTH-rP, IL-6-driven osteoclast activation, or bony mets
• Erythrocytosis: ectopic erythropoietin production
• Hypertension: excess renin secretion
• Stauffer syndrome: reversible hepatic dysfunction without hepatic metastases (resolves after nephrectomy)
• Fever of unknown origin: from cytokine (IL-6, IL-1) secretion

Imaging

• Category I/II: benign, no follow-up needed
• Category IIF: follow-up required
• Category III: surgical exploration (51% malignant)
• Category IV: surgical resection (>90% malignant)

Staging (AJCC 8th Edition)

• T3a: invasion of renal sinus fat or perinephric fat
• T3b: tumor thrombus in renal vein or IVC below diaphragm
• T3c: tumor thrombus in IVC above diaphragm or into right atrium
• ~30% of patients present with metastatic (Stage IV) disease

Treatment

Localized Disease (Stages I-III)

• Partial nephrectomy (nephron-sparing): preferred for T1 tumors (≤7 cm) and when kidney preservation is important (solitary kidney, bilateral tumors, impaired renal function)
• Radical nephrectomy: standard for larger or more locally advanced tumors; can be performed laparoscopically or open (flank, transperitoneal, or transthoracic approach); ipsilateral adrenal gland often removed; lymph node dissection is optional and controversial

• Sunitinib (VEGF-targeted TKI) - adjuvant use in high-risk patients
• Pembrolizumab (anti-PD-1 checkpoint inhibitor) - superior disease-free survival in high-risk patients after resection

Metastatic Disease (Stage IV)

• Cytoreductive nephrectomy: less commonly used in the current era of effective systemic therapy
• Metastasectomy: may extend survival and can cure selected patients (best candidates: disease-free interval >1 year, solitary metastatic site, lung metastases)

Prognosis

• Localized disease (Stage I-II): 5-year survival >80-90%
• Stage III: ~50-60%
• Metastatic (Stage IV): historically <10% at 5 years, but improving significantly with immunotherapy combinations
• Clear cell has the worst metastatic potential (90% of all RCC metastases)
• Chromophobe and papillary have lower metastatic rates but still require careful follow-up
• Sarcomatoid differentiation in any subtype is a poor prognostic indicator

Key High-Yield Points

1. VHL gene (3p25) is the molecular hallmark of clear cell RCC - loss leads to HIF accumulation --> VEGF overexpression --> angiogenesis
2. Clear cell RCC is prone to renal vein invasion and IVC thrombosis
3. RCC is one of the great mimics - causes fever of unknown origin, hypercalcemia, erythrocytosis, and Stauffer syndrome
4. Classic triad (hematuria + flank pain + mass) is now uncommon (<5-10%); most are found incidentally
5. RCC is resistant to chemotherapy and conventional radiation - surgery for localized disease, immunotherapy combinations for metastatic
6. Oncocytoma (benign) cannot be reliably distinguished from RCC on imaging - most are surgically resected
7. VHL disease: bilateral clear cell RCC in 40-60% of affected individuals; autosomal dominant, 3p25