Renal Cell Carcinoma (RCC)

Overview

Renal cell carcinoma is the most common malignant neoplasm of the kidney, accounting for 80-85% of all primary renal malignancies and roughly 2-3% of all adult cancers, about 65,000-80,000 new cases annually in the US, with roughly 14,000-14,500 deaths per year - Robbins & Kumar Basic Pathology, p. 531; Goldman-Cecil Medicine, p. 2070. It is derived from renal tubular epithelium and therefore arises predominantly in the cortex. It is the sixth most common cancer in men and ninth in women, with a male-to-female ratio of roughly 2-3:1 and peak incidence in the sixth to seventh decade of life - Goldman-Cecil Medicine, p. 2070.

Risk factors

Cigarette smoking, obesity, hypertension, and diuretic use
Occupational exposure to cadmium
Acquired (dialysis-associated) polycystic kidney disease - risk increased roughly 30-fold
Pre-existing renal injury: polycystic kidney disease, horseshoe kidney, chronic renal failure on hemodialysis
Genetic predisposition, most notably von Hippel-Lindau (VHL) disease

(Robbins & Kumar Basic Pathology, p. 531; Goldman-Cecil Medicine, p. 2070)

Histologic subtypes

RCC is not a single disease but a group of distinct entities defined by morphology and genetics:

Clear cell carcinoma - most common (about 65% of cases), accounts for roughly 90% of metastatic RCC because of its aggressive behavior. Grossly golden-yellow due to abundant cytoplasmic lipid; histologically composed of cells with clear cytoplasm. Molecular hallmark is loss/inactivation of both copies of the VHL tumor suppressor gene (chromosome 3p25), leading to stabilization of hypoxia-inducible factors (HIFs) even under normoxia. HIFs upregulate VEGF, driving tumor angiogenesis, and cooperate with MYC to alter tumor metabolism. Occurs sporadically or as part of VHL disease (autosomal dominant, also predisposing to cerebellar/retinal hemangioblastomas); bilateral/multiple tumors develop in 40-60% of VHL patients. Frequently invades the renal vein.
Papillary renal cell carcinoma - about 25% of tumors combined with chromophobe type but accounting for only about 10% of metastases; associated with increased expression and activating mutations of the MET oncogene; tends to be bilateral and multifocal, with variable papilla formation.
Chromophobe renal cell carcinoma - less common, more indolent; tumor cells have eosinophilic cytoplasm.
Oncocytoma - benign, accounts for about 10% of renal tumors (not a carcinoma but included in differential).

(Robbins & Kumar Basic Pathology, p. 531; Goldman-Cecil Medicine, p. 2070)

Clinical presentation

Classic triad of flank pain, hematuria, and a palpable abdominal mass is now uncommon; more tumors are detected incidentally on CT/MRI performed for unrelated indications. RCC is also known for paraneoplastic syndromes (e.g., erythrocytosis, hypercalcemia, hypertension, Stauffer syndrome).

Staging and prognosis

Staging follows TNM criteria and is the principal determinant of prognosis. Metastatic potential varies strongly by subtype: clear cell (most aggressive, ~90% of metastatic disease) vs. papillary/chromophobe (more indolent, ~10% of metastases combined). Overall, roughly 40% of patients with RCC eventually die of the disease - Robbins & Kumar Basic Pathology, p. 531.

Management

Localized disease: Surgery remains central - radical or partial nephrectomy (nephron-sparing surgery preferred when feasible), increasingly performed laparoscopically or robot-assisted. Renal biopsy is now more widely used pre-treatment to guide decisions, and active surveillance has become an established option for small renal masses (including select complex cystic lesions) with oncologic outcomes comparable to immediate intervention, per the 2025 update to French RCC guidelines.
Adjuvant therapy: Adjuvant pembrolizumab is now used in high-risk resected disease; multiple trials of adjuvant immunotherapy (e.g., atezolizumab in IMmotion010) have been studied - Campbell-Walsh Urology.
Metastatic/advanced disease: First-line treatment is now dominated by combination regimens - immune checkpoint inhibitor doublets (e.g., nivolumab plus ipilimumab) or checkpoint inhibitor plus VEGF-targeted tyrosine kinase inhibitor (e.g., pembrolizumab plus axitinib, lenvatinib plus pembrolizumab) - largely supplanting older single-agent TKI or mTOR inhibitor (everolimus) approaches. For relapse after adjuvant immunotherapy, TKI monotherapy is generally prioritized for early relapse, while clinical trial enrollment is preferred for progression during/after adjuvant pembrolizumab.
Non-clear cell RCC subtypes are managed somewhat differently, given lower response rates to standard clear-cell-directed regimens, an area of active systematic review.

Recent evidence note

A few recent systematic reviews/meta-analyses are relevant and may refine or update details above:

PMID 41555735 (2026, NICE Pilot Treatment Pathways network meta-analysis) - cost-effectiveness and comparative evidence across systemic RCC treatments.
PMID 39529367 (2025) - systematic review of systemic therapy specifically for non-clear cell RCC.
PMID 39743997 (2024) - systematic review/meta-analysis of systemic treatments for advanced non-clear cell RCC.

These suggest the non-clear-cell RCC treatment landscape is still evolving and less standardized than clear cell RCC; if you need specific regimen recommendations for a non-clear-cell case, these papers would be worth pulling in full.

Let me know if you want me to go deeper into any specific aspect - staging system details, imaging findings, a particular subtype, or current systemic therapy sequencing.

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