Renal cell carcinoma (RCC)

Overview

• Epidemiology (US 2025): ~82,000 cases, ~14,500 deaths. RCC accounts for ~90% of malignant kidney neoplasms. Increasing incidental diagnoses on imaging; stage I dx has risen and stage IV fallen over time.
• Risk factors: smoking (longer duration/exposure → advanced RCC), obesity, hypertension, ESRD/acquired cystic kidney disease on dialysis, environmental toxins (cadmium, asbestos). ~5 to 8% associated with inherited syndromes.
• Historically the "internist's tumor" (protean presentations: fatigue, weight loss, anemia). The classic triad (hematuria, flank pain, palpable mass) is seen in ~10% today.

Histology subtypes

• Clear cell (ccRCC) ~75%: VHL inactivation → HIF accumulation → ↑ VEGF/PDGF → angiogenesis. Most chemo-resistant; treated with TKI/IO. Typically aggressive but can be indolent.
• Papillary ~10% to 15%: WHO 2022 treats papillary RCC as one entity (type 1/type 2 subdivision retired; former type 2 includes distinct entities such as FH-deficient RCC). Type 1 historically MET-driven, often multifocal (HPRC).
• Chromophobe ≤ 5%: BHD syndrome (FLCN). Usually indolent; best prognosis unless necrosis/sarcomatoid.
• Collecting duct and renal medullary (each ≤ 1%): aggressive; collecting duct often presents metastatic with median survival of only a few months.
• MiT family translocation RCC (TFE3-rearranged, usually Xp11.2; or TFEB-altered), unclassified: rare.
• Oncocytoma: benign, but its presence should prompt evaluation for coexisting RCC and ongoing surveillance.
• Sarcomatoid or rhabdoid differentiation can occur in any subtype and portends a worse prognosis (but responds well to IO).

Hereditary RCC Syndromes

• Suspect hereditary kidney cancer in a patient <45 to 47 y/o, with multifocal or bilateral tumors, or with a supportive personal/family history. Refer for genetic testing. Most listed syndromes are autosomal dominant; renal medullary carcinoma is the exception: SMARCB1 loss is somatic and the inherited factor is sickle cell trait/hemoglobinopathy, not an AD SMARCB1 predisposition syndrome.

Clinical and Workup

• Classic triad (flank pain + hematuria + palpable mass) in only ~10%, usually advanced.
• Most found incidentally on imaging.
• Paraneoplastic: erythrocytosis (EPO), hypercalcemia (PTHrP), hypertension (renin), Stauffer syndrome (paraneoplastic cholestasis/hepatic dysfunction without liver mets, reverses after resection), polymyalgia rheumatica.
• Imaging: CT with contrast for detection/staging; MRI if poor renal function, to assess local invasion, or to evaluate renal vein/IVC thrombus and to distinguish angiomyolipoma (fat). FDG PET does not reliably exclude RCC but may help for recurrence/distant mets.
• Biopsy for small renal masses (to decide AS vs surgery), or with suspicion of hematologic, metastatic, inflammatory, or infectious etiology; not required for a solid mass consistent with RCC if surgery is planned.

Staging (T)

• T1a ≤ 4 cm, limited to kidney → partial nephrectomy (preferred) or ablation (RFA).
• T1b >4 to 7 cm → partial nephrectomy (preferred when feasible) or radical nephrectomy.
• T2 >7 cm.
• T3 extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.
• T4 invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

Localized Disease

• Surgery is curative-intent: partial nephrectomy preferred for T1; radical nephrectomy for larger or complex masses (with some increased risk of CKD). Lymphadenectomy is controversial and does not clearly improve OS; there is no benefit to postoperative RT.
• Renal vein or IVC extension (stage III) does not preclude resection; ~50% have prolonged survival with successful resection (cardiopulmonary bypass may be needed).
• Ablation (RFA, cryotherapy): option for cT1a masses <3 cm; may have ↑ local recurrence vs surgery.
• Active surveillance for small renal masses (<3 to 4 cm, high rate of benign tumors, low metastatic potential), especially elderly or with competing comorbidities. Serial imaging every 3 to 6 months for 2 years, then every 6 to 12 months. Triggers for intervention: size >3 cm, growth >5 mm/yr, or infiltrative pattern.
• Adjuvant pembrolizumab (KEYNOTE-564): intermediate-high or high-risk resected ccRCC (T2 with nuclear grade 4 or sarcomatoid, ≥ T3, regional LN mets, or M1 NED after resection of all sites). DFS HR 0.68 initially, 0.72 at 57 mo; OS HR 0.62 (Choueiri NEJM 2024). FDA Nov 2021.
• Adjuvant belzutifan + pembrolizumab (LITESPARK-022): same risk population, vs pembrolizumab alone, DFS HR 0.72 (OS immature; more grade ≥ 3 AEs). FDA Jun 12, 2026.
• Adjuvant TKIs mostly negative: ASSURE (sunitinib or sorafenib, no DFS/OS benefit); PROTECT (pazopanib, no benefit); S-TRAC (sunitinib, DFS 6.8 vs 5.6 yrs, led to FDA approval, but ↑ toxicity and no OS benefit). Adjuvant IO otherwise negative: CheckMate-914 (nivolumab + ipilimumab, or nivolumab), IMmotion010 (atezolizumab), PROSPER (perioperative nivolumab). RAMPART: durvalumab + tremelimumab improved DFS vs active monitoring (HR 0.65; OS immature), durvalumab alone did not.

Metastatic RCC

IMDC risk model

• IMDC factors: Karnofsky <80%, time from dx to tx <1 yr, anemia (low Hb), hypercalcemia, neutrophilia, and thrombocytosis. Favorable (0), intermediate (1 to 2), poor (≥ 3).

Role of surgery

• Cytoreductive nephrectomy: CARMENA randomized de novo metastatic ccRCC (intermediate/poor risk) to nephrectomy then sunitinib vs sunitinib alone; sunitinib alone was noninferior. In the IO era, immediate systemic therapy is generally preferred, but nephrectomy may still benefit selected pts (good performance status, ECOG <2, no brain mets, minimal metastatic burden, resectable primary, or symptomatic primary with hematuria/pain).
• Metastasectomy for oligometastatic RCC: 5 yr OS ~45%; better with DFS >1 yr, age <60, single site, ECOG 0 to 1. Worse with DFS <1 yr, sarcomatoid features, ≥ T3, nonpulmonary or multiorgan mets, and >2 sites.

First-line and second-line systemic therapy (clear cell)

• TKI class AEs: HTN, fatigue, diarrhea, stomatitis, hand-foot syndrome, ↑ LFTs, cytopenias, cardiotoxicity.

First-line trials (all IMDC risk unless noted; CheckMate 214 and COSMIC-313 are intermediate/poor risk)

• Pembrolizumab + axitinib (KEYNOTE-426): mOS 47.2 vs 40.8 mo (HR 0.84, final 5-yr analysis, Rini Nat Med 2025; earlier analysis 45.7 vs 40.1 mo, HR 0.73).
• Nivolumab + cabozantinib (CheckMate 9ER): mOS 46.5 vs 35.5 mo (HR 0.79, final 5.6-yr analysis 2025; earlier analysis was 49.5 vs 35.5 mo, HR 0.70).
• Pembrolizumab + lenvatinib (CLEAR): mPFS 23.9 vs 9.2 mo (HR 0.47, final); final mOS HR 0.79 (53.7 vs 54.3 mo).
• Nivolumab + ipilimumab (CheckMate 214): intermediate/poor risk, mOS 46.7 vs 26.0 mo (HR 0.69 at 8 yr), durable responses (CR ~12%).
• COSMIC-313 (Choueiri NEJM 2023, mature 2025): triplet cabozantinib + nivolumab + ipilimumab vs nivo/ipi in 1L intermediate/poor-risk ccRCC. PFS benefit (HR 0.74) but OS not improved and grade 3 to 4 AEs 79% vs 56%. Triplet NOT adopted as SOC.

First-line (favorable risk)

• Pembrolizumab + axitinib, cabozantinib + nivolumab, OR pembrolizumab + lenvatinib. IO/TKI preferred over ipi/nivo (which underperformed in favorable risk in CheckMate 214).
• Sunitinib or pazopanib monotherapy: historic; reserve for IO-ineligible pts.

Second line and beyond (post IO/TKI)

• Cabozantinib (METEOR): workhorse, active post-VEGF TKI (targets MET and AXL; efficacy in bone mets).
• Lenvatinib + everolimus: mPFS ~14.6 mo.
• Tivozanib (TIVO-3): relapsed/refractory after ≥ 2 prior lines including a VEGF inhibitor.
• Nivolumab (post-VEGF): OS 25.0 vs 19.6 mo vs everolimus.
• Belzutifan (HIF-2alpha inhibitor) (LITESPARK-005, Choueiri NEJM 2024): vs everolimus after IO + TKI, mPFS 5.6 vs 5.6 mo, ORR 22% vs 4%, OS HR 0.88. FDA Dec 14, 2023 for advanced ccRCC after PD-1/PD-L1 + VEGF TKI.
• LITESPARK-011 (Motzer Lancet 2026): belzutifan + lenvatinib vs cabozantinib in 2L+ ccRCC post-IO, mPFS 14.8 vs 10.7 mo (HR 0.70), ORR 53% vs 40%, OS not significant (HR 0.85). LITESPARK-012 (1L belzutifan + pembrolizumab + lenvatinib, or pembrolizumab/quavonlimab + lenvatinib, vs pembrolizumab + lenvatinib) missed both PFS and OS at interim analysis (Apr 2026); belzutifan triplet not adopted in 1L.
• Re-IO: Do not routinely rechallenge with an ICI after progression on an ICI-containing regimen (CONTACT-03 and TiNivo-2 negative); an off-treatment interval alone is not an established indication.

Non-Clear Cell RCC

• For localized disease, nephrectomy remains standard. For advanced disease, targeted therapy or IO; chemotherapy is generally ineffective except for collecting-duct or renal medullary carcinoma (gemcitabine + platinum).
• Papillary: cabozantinib (PAPMET) preferred over sunitinib (crizotinib and savolitinib arms halted for futility). MET-driven disease defined by chromosome 7 gain, MET/HGF amplification, or MET kinase mutations.
• Bevacizumab + erlotinib (papillary, including HLRCC)
• Pembrolizumab monotherapy (KEYNOTE-427): non-clear cell ORR 26.7%, mPFS 4.2 mo, median DOR 29 mo.
• KEYNOTE-B61 (Albiges Lancet Oncol 2023): pembrolizumab + lenvatinib in advanced non-clear cell RCC (papillary, chromophobe, unclassified), ORR 49%, mPFS 17.9 mo; supports IO/TKI beyond monotherapy pembrolizumab.
• SAMETA (ongoing): savolitinib + durvalumab vs sunitinib in MET-driven papillary RCC.
• Chromophobe: sunitinib, mTOR inhibitors; emerging IO.
• Translocation RCC: cabozantinib, axitinib.
• Renal medullary ca (sickle trait): aggressive; platinum-based chemo.
• Collecting duct ca: platinum + gemcitabine.

VHL-Associated RCC

• Belzutifan (Welireg): HIF-2alpha inhibitor for VHL-associated RCC, hemangioblastomas, and pNET. FDA Aug 13, 2021 (LITESPARK-004). Allows management of symptomatic disease without surgery; first FDA-approved HIF-2alpha inhibitor.

Special Considerations

• Bone mets (~1/3 of advanced RCC, predominantly osteolytic): add zoledronic acid (renal dose adjustment) or denosumab to ↓ SREs.
• Brain mets are frequent in metastatic ccRCC; surgical resection or stereotactic radiosurgery are feasible alternatives to whole-brain RT; pts with treated brain mets can receive systemic therapy.
• Chemotherapy: RCC is highly chemo-resistant; collecting-duct and renal medullary carcinomas are the exception (platinum-based). Sarcomatoid differentiation is treated with ICI-containing therapy, not chemo.
• Elderly/survivorship: radical nephrectomy is a risk factor for CKD; favor nephron-sparing when appropriate. Monitor TKI/IO toxicities (HTN, immune-related AEs, thyroid dysfunction, hyperglycemia, cardiotoxicity), especially with pre-existing hypertension or coronary disease.

High-Yield RCC Pearls

• IMDC risk groups guide systemic therapy.
• 1L IO/TKI: pembro + axitinib, nivo + cabozantinib, pembro + lenvatinib; or ipi/nivo for intermediate/poor risk.
• Adjuvant pembrolizumab (KEYNOTE-564) for high-risk resected ccRCC; adjuvant TKIs are largely negative.
• Belzutifan for VHL-associated RCC, CNS hemangioblastoma, or pNET not requiring immediate surgery (may defer/reduce surgery, does not replace urgent surgery) and refractory ccRCC after IO + TKI.
• Cabozantinib is the workhorse 2L+ and 1L for non-clear cell (PAPMET).
• Cytoreductive nephrectomy is less common in the IO era (CARMENA); consider for good IMDC risk, oligometastatic, or symptomatic primary.
• Stauffer syndrome = paraneoplastic cholestasis without liver mets.
• VHL gene on 3p; drives ccRCC via HIF/VEGF.