Kidney Cancer

Epidemiology and Pathogenesis

Renal cell carcinoma is the most lethal of the genitourinary cancers, though most tumours are now found incidentally as small, localised masses. Most cases are sporadic and linked to obesity, smoking, and hypertension, but ~4–6% arise from autosomal dominant familial syndromes — most importantly von Hippel-Lindau, which defines the VHL–HIF–VEGF pathway central to RCC biology and therapy.

Epidemiology

• Incidence is rising (wider imaging use and rising obesity), with the greatest increase in small, localised masses (now >40% of new tumours). US incidence ~81,800 (2023, includes renal pelvis); Canada ~7,500 (2020, 10th most common).
• Mortality — US ~13,920 (2022); the most lethal GU malignancy, though 5-year survival is improving ~1%/year.
• 5-year relative survival by stage: localised 93%, regional 70%, distant 13%, all stages 75%.
• Demographics — M:F 1.75:1 (worse mortality in men); typical age 50–70 (median 64); more common in Black, American Indian, and Alaska Native populations. RCC in children and young adults is more often symptomatic, locally advanced, high-grade, and of unfavourable histology.

Risk Factors

Most RCC is sporadic. Four established risk factors: obesity (~30% of cases, tending to lower-grade/stage tumours), smoking (~20%), hypertension, and chronic renal failure / dialysis (controversial — consider delaying screening until the 3rd dialysis year). Others include a family history without a defined syndrome, chlorinated-solvent exposure, retroperitoneal radiation, and acquired cystic renal disease. Moderate alcohol, fruit/cruciferous-vegetable, and fatty-fish intake may be protective. ADPKD does not increase RCC risk.

Familial Syndromes

All are autosomal dominant and together account for ~4–6% of cases:

Syndrome	Gene	Renal tumour	Key extra-renal features
Von Hippel-Lindau	VHL (3p25–26)	Clear cell RCC (bilateral, multifocal) + cysts	CNS/retinal haemangioblastomas, phaeochromocytoma, paraganglioma, pancreatic NETs/cysts, epididymal cystadenoma, endolymphatic sac tumour
Hereditary Papillary RCC	c-MET	Type 1 papillary (less aggressive)	—
Hereditary Leiomyomatosis & RCC*	Fumarate hydratase	Type 2 papillary or collecting duct	Cutaneous and uterine leiomyomas
Birt-Hogg-Dubé	Folliculin	Chromophobe, oncocytoma, hybrid tumours	Skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax
Succinate Dehydrogenase RCC*	SDHB/C/D	Clear cell, chromophobe, type 2 papillary, oncocytoma	Phaeochromocytoma / paraganglioma
Tuberous Sclerosis Complex	TSC1/2	AML, ccRCC, oncocytoma, cysts	Adenoma sebaceum, shagreen patches, seizures, intellectual disability, retinal/CNS/cardiac lesions, pulmonary LAM
Cowden / PTEN	PTEN	ccRCC, papillary, chromophobe	Trichilemmomas, breast and thyroid malignancy
BAP1 tumour predisposition*	BAP1	ccRCC	Uveal and cutaneous melanoma, mesothelioma, BCC

*Renal cancers in these syndromes tend to be more aggressive.

Von Hippel-Lindau (1:30,000–40,000) — RCC develops in 35–70%, with early onset (median 40) and bilateral/multifocal disease; RCC is the leading cause of death in VHL. The VHL gene at 3p25–26 is the most common mutation in sporadic clear cell RCC. Normally the VHL complex degrades hypoxia-inducible factors (HIF); without VHL, HIF accumulates → VEGF overexpression → the neovascularity of ccRCC (and EPO-driven polycythaemia). Phaeochromocytoma occurs only in certain (type 2 VHL) families; offer affected patients genetic evaluation and presymptomatic screening.

Belzutifan (Welireg) — an oral HIF-2α inhibitor, the first drug approved specifically for VHL disease (2021); it blocks HIF-2α from binding ARNT, shutting off VEGF/EPO transcription. It is indicated for VHL-associated RCC, CNS haemangioblastomas, and pancreatic NETs not needing immediate surgery (Study 004 objective response ~36% RCC, ~30% haemangioblastoma, ~83% pNET). Key toxicity: anaemia (EPO suppression).

Other syndromes: HPRCC (c-MET tyrosine-kinase activation → less aggressive type 1 papillary); HLRCC (cutaneous leiomyomas and uterine fibroids in nearly all, RCC in only ~20% but unilateral, solitary, and aggressive — prompt surgery); and TSC (chromosomes 9 & 16, mTOR activation; classic triad of seizures, adenoma sebaceum, and intellectual disability; further features include ash leaf spots, shagreen patch, retinal hamartomas, and cardiac rhabdomyoma; 50% develop AMLs and ~2% develop RCC).

Pathology and Staging

Over 90% of malignant kidney tumours are renal cell carcinoma — all adenocarcinomas, most arising from the proximal tubule (chromophobe, collecting duct, and medullary types are the exceptions). Subtype and grade drive prognosis, and the AJCC 8th-edition TNM system hinges on tumour size and venous/perinephric extension. The commonest benign renal tumours are oncocytoma and angiomyolipoma; RCC is also the most common renal tumour in pregnancy.

RCC Subtypes

Subtype	Frequency	Origin / behaviour	Hallmark
Clear cell (ccRCC)	70–80%	Proximal tubule; worst prognosis of the common types but most responsive to systemic therapy	VHL / 3p loss (VHL inactivated in 70–90%)
Papillary	10–15%	Proximal tubule; often multifocal; common in ESRD/acquired cystic disease; type 1 better than type 2; systemic therapy ineffective	Trisomy 7/17, loss of Y; HPRCC (type 1), HLRCC (type 2)
Chromophobe	3–5%	Distal tubule / collecting duct; generally good prognosis	Hale colloidal iron positive; Birt-Hogg-Dubé
Collecting duct	<1%	Collecting duct; poor prognosis; may respond to cisplatin/gemcitabine	Ulex europaeus lectin positive
Renal medullary	Rare	Collecting duct; dismal, often metastatic at diagnosis	Sickle cell trait (not disease); young African-Americans
Unclassified	1–3%	Poorly differentiated, aggressive	—
Xp11.2 translocation / TFE3	Rare	Children/young adults (40% of paediatric RCC); prognosis ≈ ccRCC	TFE3 gene fusion

Multilocular cystic ccRCC behaves almost uniformly benignly, and papillary adenomas (≤5 mm) are benign look-alikes.

Other Histologic Features

• Sarcomatoid differentiation (1–5%) is not a subtype but an aggressive feature, most often seen with ccRCC or chromophobe — consider multimodal therapy.
• Cystic degeneration (10–25%) carries a better prognosis than purely solid RCC.
• Laterality/focality — most sporadic RCC is unilateral and unifocal; bilateral disease (2–4%) and multifocality (10–20%) are commoner with papillary histology and familial syndromes. Synchronous bilateral lesions are usually independent primaries, whereas asynchronous ones are usually metastases.

Grading

The Fuhrman grade (1–4) applies to clear cell and papillary RCC, while chromophobe, collecting duct, and medullary RCC are graded high vs. low only. Fuhrman (1982) has been superseded by the ISUP/WHO grade (2012/2016), which uses more objective nuclear criteria. Grade 4 includes sarcomatoid/rhabdoid change, giant cells, and extreme pleomorphism. Chromophobe RCC is no longer graded. Higher grade tracks with larger, more aggressive tumours.

TNM Staging (AJCC 8th Edition)

T stage	Definition
T1a / T1b	≤4 cm / >4–7 cm, confined to the kidney
T2a / T2b	>7–10 cm / >10 cm, confined to the kidney
T3a	Renal vein or segmental branches, pelvicalyceal system, or perirenal/sinus fat (not beyond Gerota) — medial perisinus-fat invasion is worse than lateral perirenal
T3b	IVC below the diaphragm
T3c	IVC above the diaphragm, or invading the IVC wall
T4	Beyond Gerota's fascia, including contiguous ipsilateral adrenal involvement

N1 (regional nodes) carries a 5-year survival of 0–20%, and M1 (distant metastasis) 0–10%. Ipsilateral adrenal involvement is pT4 if by direct extension, otherwise pM1.

Diagnosis and Evaluation

Most renal masses are now found incidentally on cross-sectional imaging. Contrast-enhanced CT (or MRI) characterises the mass, and the central question is whether a solid, enhancing mass is malignant — which, apart from fat-containing AML, imaging cannot reliably answer, so renal mass biopsy is used when the result will change management.

Clinical Presentation

Over 50% of masses are incidental, and many stay asymptomatic until locally advanced. The classic triad (haematuria, flank pain, palpable mass) now appears in <5% and signals advanced disease. Features suggesting advanced disease: a palpable abdominal mass, a non-reducing or right-sided varicocele, bilateral lower-limb oedema (venous involvement), and cervical/supraclavicular lymphadenopathy. Spontaneous perirenal haemorrhage can obscure an underlying RCC — repeat CT a few months later.

Paraneoplastic Syndromes

Present in 10–20% of metastatic RCC (mnemonic NEW-HALF-CAP): Neuropathy (3%), ESR elevated (most common, 56%), Weight loss (34%), Hypertension (renin, 38%), Anaemia (36%), LFTs elevated (Stauffer syndrome — non-metastatic hepatic dysfunction, 14%), Fever (17%), hyperCalcaemia (5%; PTH-rP or osteolytic), Amyloidosis (2%), and Polycythaemia (EPO, 4%). Apart from hypercalcaemia, they resolve only with excision or systemic therapy. Hypercalcaemia management ladder: hydration → frusemide (furosemide) → steroids → bisphosphonates.

Laboratory Workup

CBC, urinalysis (including proteinuria), and a comprehensive metabolic panel (electrolytes, LFTs, GFR); the CUA adds ALP and corrected calcium for bone dysfunction. GFR and proteinuria assign a CKD stage that influences management. Refer to nephrology for eGFR <45, confirmed proteinuria, diabetic CKD, or an expected post-operative eGFR <30.

Imaging

Any solid mass enhancing >15 HU without fat is RCC until proven otherwise; ccRCC enhances more than papillary or chromophobe. Macroscopic fat (<−20 HU) is diagnostic of AML (5–10% are fat-poor), but calcification with fat is almost always RCC (calcification is virtually never seen in AML).

Non-contrast HU (homogeneous)	Interpretation
<20	Simple cyst
20–70	Indeterminate — needs further evaluation
>70	Haemorrhagic / proteinaceous cyst

On contrast-enhanced CT, a HU rise >20 is enhancing, <10 is non-enhancing, and 10–20 is indeterminate. The differential for a solid mass includes RCC, oncocytoma, AML, urothelial carcinoma, metastasis, abscess, infarct, and pseudotumour; an infiltrative pattern suggests lymphoma, high-grade urothelial carcinoma, collecting-duct or medullary RCC, sarcomatoid change, or XGP. Tumour size is inversely related to malignancy (≈19–25% of masses <4 cm are benign), and nodes ≥2 cm usually harbour malignancy.

• Modalities — contrast-enhanced CT is the modality of choice; MRI (comparable accuracy) is used when iodinated contrast is contraindicated and is best for adjacent-organ invasion and fat detection (T2 fat-suppression). On ultrasound, simple cysts are anechoic with posterior acoustic enhancement, AMLs are echogenic with a speed-propagation artifact, and anything not meeting strict simple-cyst criteria needs CT. PET has no role in routine RCC staging.
• Contrast safety — group II gadolinium agents are safe at any eGFR (nephrogenic systemic fibrosis is rare, mostly with group I); iodinated contrast needs caution at GFR <45 and saline prophylaxis at GFR <30, and metformin is held with renal insufficiency (risk of biguanide lactic acidosis).
• RENAL nephrometry score grades surgical complexity from five features — Radius, Exophytic/endophytic, Nearness to the collecting system, Anterior/posterior, and Location relative to the polar line (range 4–12; lower scores are more amenable to partial nephrectomy).
• Metastatic staging — chest is the commonest visceral site; obtain a CXR (CT chest for pulmonary symptoms, an abnormal CXR, or high-risk features: thrombus, adenopathy, large size, infiltrative appearance, extensive necrosis). Bone scan only for bone pain or raised ALP; brain imaging only for neurological symptoms.

Renal Mass Biopsy

About 20–30% of clinical T1 solid enhancing masses are benign (up to 40% in younger women; mostly oncocytoma or atypical AML). Biopsy is highly reliable for malignancy (diagnostic rate ~92%, sensitivity ~97%, specificity ~94%, non-diagnostic rate ~14%, histologic concordance 90% but grade concordance only 62%); note that ~20% of benign biopsies may still harbour cancer. It is offered when the result will change management (e.g. suspected metastatic, haematologic, inflammatory, or infectious disease) — not for a young, healthy patient unwilling to accept its uncertainty, nor an older/frail patient who will be managed conservatively regardless. Use core biopsy (2–3 cores, 16–18 G) over FNA; avoid biopsy of purely cystic masses (spillage, sampling error). Overall complications are ~8% — haematoma 4.9%, pain 1.2%, haematuria 1%, pneumothorax 0.6%, transfusion 0.4% — with no tumour seeding using modern technique.

Six indications for renal mass biopsy: (1) metastatic disease prior to systemic therapy, (2) suspected lymphoma, (3) planned non-operative management, (4) bilateral tumours, (5) active surveillance, and (6) prior to systemic therapy.

Genetic Counselling

Refer for renal malignancy at age ≤46, multifocal/bilateral masses, a family history of renal malignancy, features suggesting a familial RCC syndrome, or syndromic histology (e.g. hybrid oncocytic/chromophobe tumours suggest Birt-Hogg-Dubé).

Localized and Locally Advanced Disease

Four options manage localized RCC — active surveillance, thermal ablation, partial nephrectomy, and radical nephrectomy — and the choice balances oncologic control against renal-function preservation, since many patients have baseline CKD. Locally advanced disease (venous tumour thrombus, T4) is managed surgically, and adjuvant pembrolizumab now has a role in high-risk resected clear-cell disease. See the Radical Nephrectomy and Robotic Partial Nephrectomy procedure pages for operative technique.

Treatment Options

For a small renal mass, partial nephrectomy is preferred for any cT1 mass when feasible; thermal ablation and active surveillance suit smaller masses in older/comorbid patients, and radical nephrectomy is reserved for high-complexity tumours. Counsel on CKD risk — predictors of post-operative CKD include older age, diabetes, hypertension, male sex, obesity, smoking, a larger tumour, and post-operative AKI.

Active Surveillance

Small renal masses grow slowly (median 0.12–0.34 cm/yr) with a low metastasis rate (1–2% over 2–4 years). It is the preferred strategy for masses <2 cm and an option for 2–4 cm, especially with advanced age, life expectancy <5 years, significant comorbidity, or CKD ≥3b. Triggers for intervention: size >3–4 cm, growth >5 mm/yr (AUA) or >0.5 cm/yr (CUA), stage progression, unfavourable biopsy, or patient choice. Surveillance imaging runs every 3–6 months initially, with annual chest imaging.

Thermal Ablation

Radiofrequency ablation (RFA, 50–105°C) and cryoablation (−40°C, 2 freeze-thaw cycles) are options for cT1a solid masses <3 cm (best <2.5–3 cm; unreliable >4 cm) in older/comorbid patients or hereditary multifocal disease. Avoid ablation near the hilum, proximal ureter, or collecting system. They have low morbidity and comparable cancer-specific survival to PN in selected patients, but a higher local recurrence (cryo 3–10%, RFA 5–20%) than PN (0–3%) or RN (0%) — recurrences are usually salvageable with repeat ablation. Bleeding is less with RFA (greater haemorrhage risk with cryoablation). Biopsy before or at the time of ablation. On follow-up, a successfully ablated tumour shows no contrast enhancement (RFA lesions don't shrink); residual enhancement signals recurrence — so ultrasound is not used for post-ablation surveillance.

Partial vs Radical Nephrectomy

Partial nephrectomy preserves renal function (median ~10% GFR loss vs ~35–40% for RN) at the cost of higher transfusion and urologic complications (urine leak) and a risk of hyperfiltration injury (proteinuria first; treat with an ACE inhibitor and low-protein diet). The number of preserved nephrons is the primary determinant of post-operative function; keep warm ischaemia <25 minutes, while hypothermia is tolerated up to 60–90 minutes. A negative margin is the goal — margin width does not matter. For a positive margin: no gross tumour → observe; aggressive features or gross tumour → reoperate.

Consider radical nephrectomy if: cold ischaemia >45 minutes, <20% functional nephron remaining (hyperfiltration-injury risk), high tumour complexity, or lymph-node involvement.

Approach	Preferred for
Partial nephrectomy	Any cT1a (and feasible cT1b); absolute — solitary kidney, bilateral tumours, familial RCC; relative — CKD, proteinuria, young age, multifocal disease
Radical nephrectomy	High-complexity tumour with no CKD/proteinuria and a normal contralateral kidney (expected eGFR >45); standard for cT2 and most cT3

The randomized EORTC 30904 found RN gave better overall survival than PN (a much-criticised result, extinguished in the RCC-histology subgroup), with no cancer-specific difference and better renal function with PN — so PN is preferred for T1a (<4 cm), while T1b/T2 with a normal contralateral kidney is debatable.

Surgical approach	Indication
Flank (subcostal)	UPJ / radical nephrectomy (not feasible for PN)
Dorsal lumbotomy	Paediatric / bilateral
Thoracoabdominal	Large or upper-pole tumours
Anterior midline	Trauma / IVC involvement
Chevron	Bilateral or hepatic extension

Lymphadenectomy and Adrenalectomy

• Lymphadenectomy — landing zones are interaortocaval (right) and para-aortic (left). EORTC 30881 showed no survival benefit in cN0 disease (only 4% pN+), so it is not routine for cN0; it is recommended for cN+ (staging/prognosis) and considered with high-risk features (size >10 cm, grade 3–4, sarcomatoid, necrosis, extrarenal extension, thrombus).
• Adrenalectomy — preserve the ipsilateral adrenal unless imaging or exploration suggests involvement (adrenal metastasis <5%; CT has a 99.4% negative predictive value); removing an uninvolved gland does not improve survival.

Locally Advanced Disease and IVC Thrombus

RCC is the commonest cause of a secondary IVC tumour thrombus in adults; ~90% are clear cell, with ~15% nodal and ~20–25% metastatic disease. Distinguishing tumour thrombus from bland thrombus is critical for operative planning. Suspect a thrombus with lower-limb oedema, a non-collapsing or right-sided varicocele, dilated abdominal-wall veins, proteinuria, PE, a right-atrial mass, or a non-functioning kidney; MRI (or CT) defines the cranial extent and should be imaged close to surgery.

Level	Cranial extent
0	Confined to the renal vein
I	Within 2 cm of the renal-vein ostium
II	Subhepatic (below the hepatic veins)
III	Intrahepatic (hepatic veins to diaphragm)
IV	Suprahepatic (above the diaphragm)

45–70% are cured by radical nephrectomy with IVC thrombectomy — even level IV thrombi are curable. For cT4 disease, perform en-bloc resection of involved adjacent organs if feasible (debulking is rarely indicated); vaccinate (pneumococcus, H. influenzae B, meningococcus) before a likely splenectomy. By setting: N+ → RN + lymph-node dissection; T3 → RN + thrombectomy; T4 → RN + lymph-node dissection; unresectable → embolisation / neoadjuvant therapy.

Prognosis

Pathologic stage is the most important factor:

pT	5-year OS
T1a / T1b	90–100% / 80–90%
T2a / T2b	65–80% / 50–70%
T3a–c	20–70% (falling with level)
T4	0–30%

Nodal or distant metastasis is dismal (median CSS for pN1 ~2.8 years). Other factors: histologic subtype (collecting-duct, medullary, and sarcomatoid/rhabdoid worse; chromophobe and type 1 papillary better), Fuhrman grade, size, necrosis, and microvascular invasion. Prognostic nomograms include SSIGN, UISS, and Karakiewicz.

Adjuvant Therapy

The standard after resection is observation; high-risk features are grade 3–4, >T2b, unfavourable histology, and nodal involvement. KEYNOTE-564 established adjuvant pembrolizumab for high-risk resected clear-cell RCC (disease-free survival +9% at 24 months, overall survival +8% at 48 months). Eligibility: T3 or T4, N1, T2b with Fuhrman ≥3 and ECOG ≥1, or T2a with Fuhrman 4 or sarcomatoid differentiation. Adjuvant TKIs are mostly negative — S-TRAC (sunitinib) improved disease-free but not overall survival (FDA-approved), while ASSURE and PROTECT were negative. Neoadjuvant therapy has no role outside a trial.

Surveillance

Renal function dips post-operatively and reaches a new baseline by 3–6 months (monitor creatinine, eGFR, and proteinuria; refer to nephrology if eGFR <45 or CKD progresses). The commonest first-recurrence sites are lung (54%), lymph nodes (22%), bone (20%), and liver (15%). Surveillance intensity follows risk:

AUA risk group	Definition
Low	pT1, grade 1–2
Intermediate	pT1 grade 3–4, or pT2 any grade
High	pT3 any grade
Very high	pT4, pN1, sarcomatoid/rhabdoid, or positive margin

Image the abdomen and chest for at least 5 years, more frequently for higher risk (CT chest for high/very-high risk, CXR otherwise). A representative schedule:

• Low risk — PN: CT at 12 months → yearly ×3; RN: CT at 12 months; CXR yearly ×3.
• High risk — CT abdomen and CT chest every 6 months ×3 years → yearly to year 5.

Post-ablation follow-up uses contrast-enhanced CT/MRI, not ultrasound. Isolated local recurrence after RN/PN (2–4%, poor prognosis) can be cured in 30–40% with surgery or ablation.

Metastatic Disease

Treatment is guided by IMDC risk and centres on immune-checkpoint combinations, with cytoreductive nephrectomy now reserved for selected patients after the CARMENA era. Histology should be confirmed (by biopsy) before systemic therapy.

Prognostic Models

Model	Era	Factors	Risk groups (median OS)
MSKCC (Motzer)	Cytokine	KPS <80, diagnosis-to-treatment <1 yr, Hb below LLN, corrected Ca >10, LDH >1.5× ULN	0 favourable (30 mo), 1–2 intermediate (14 mo), ≥3 poor (5 mo)
IMDC (Heng)	Targeted	K-PINCH: KPS <80, Platelets >ULN, Interval <1 yr, Neutrophils >ULN, Calcium >10, Hb below LLN	0 favourable (not reached), 1–2 intermediate (27 mo), ≥3 poor (9 mo)

IMDC uses four Motzer factors (dropping LDH) plus neutrophils and platelets.

Cytoreductive Nephrectomy

In the cytokine era CN improved survival (SWOG 8949 + EORTC 30947). In the targeted era, CARMENA showed sunitinib alone was non-inferior to CN + sunitinib in intermediate/poor-risk disease (it does not apply to favourable-risk), and SURTIME favoured deferred CN (systemic therapy first). The 2019 CUA offers upfront CN to patients with good performance status (ECOG ≤1 / KPS ≥80; low IMDC risk, 0 risk factors), a resectable primary, limited metastatic burden — oligo-metastatic disease (<3 mets), no brain metastases (lung only) — minimal metastatic symptoms, and no active CNS metastases — and avoids it with rapidly progressing disease or limited life expectancy. CN may also be offered for palliative/symptomatic relief. Non-optimal candidates receive systemic therapy first, with CN if they respond well. Lymphadenectomy is not recommended for cN0 disease.

Metastasectomy and Local Therapy

About a third of metachronous metastases are resectable, and complete metastasectomy can give long-term survival in selected patients — best with isolated metastases, a >2-year interval from nephrectomy, and favourable sites (lung most common, thyroid, bone, pancreas, adrenal). SBRT can treat oligometastatic or oligoprogressive disease, and radiotherapy palliates a symptomatic primary or metastatic sites.

Systemic Therapy

First-line choice follows IMDC risk:

IMDC risk	Preferred first-line
Favourable	Axitinib + pembrolizumab (alternatives: avelumab/axitinib, sunitinib, pazopanib)
Intermediate / poor	Nivolumab + ipilimumab, or axitinib + pembrolizumab

The overall response rate to first-line systemic therapy is 30–40%. The key immunotherapy trials are CheckMate 214 (nivolumab + ipilimumab > sunitinib in intermediate/poor-risk), CheckMate 9ER (nivolumab + cabozantinib > sunitinib), and CLEAR (lenvatinib + pembrolizumab > sunitinib). Ipilimumab blocks CTLA-4 and nivolumab/pembrolizumab block PD-1; nivolumab + ipilimumab gives the highest complete-response rate (~9%).

• VEGF tyrosine-kinase inhibitors — sunitinib and pazopanib (equivalent in COMPARZ, but pazopanib causes more hepatotoxicity and sunitinib more fatigue, cytopenias, and hand-foot syndrome), plus sorafenib, axitinib (AXIS — second-line), and cabozantinib (VEGFR/MET/AXL). Class effects: hypertension, fatigue, diarrhoea, hand-foot syndrome, and — with sunitinib — hypothyroidism (monitor TSH). Bevacizumab is an anti-VEGF-A antibody.
• mTOR inhibitors — temsirolimus (first-line only in poor-risk, ARCC) and everolimus (later-line; first-line everolimus is inferior, RECORD-3). Sequence a VEGF-TKI first, then an mTOR inhibitor.
• Cytokines (historical) — high-dose IL-2 gives durable complete responses in 7–9% of ccRCC but with serious toxicity (vascular-leak syndrome; 2–5% mortality), so only high-dose regimens are used; IFN-α has been largely supplanted. Conventional chemotherapy is ineffective in ccRCC.

Second-line therapy depends on prior treatment (after immune-checkpoint therapy → cabozantinib or axitinib; after a VEGF-TKI → nivolumab or cabozantinib). Non-clear-cell RCC (~15–25%) has no standard therapy — enrol in a trial, otherwise treat as for clear-cell (IO combinations or sunitinib).

Bone-Modifying Agents

For bone metastases, zoledronic acid (avoid in renal dysfunction; monitor renal function) or denosumab (anti-RANK-ligand) reduce skeletal-related events. Give calcium and vitamin D (watch for hypocalcaemia, though paraneoplastic hypercalcaemia can coexist) and arrange a dental examination first (osteonecrosis-of-the-jaw risk).

Non-RCC Renal Malignancies

Beyond RCC, the kidney can be involved by sarcoma, haematologic malignancy, and — most commonly of all — metastases from other primaries. Distinguishing these from RCC matters because their management is often non-surgical.

Renal Sarcoma

Renal sarcoma is rare (1–2% of malignant renal tumours, peak in the 5th decade) but more lethal than sarcoma at any other genitourinary site; leiomyosarcoma is the commonest subtype in the kidney (whereas liposarcoma is the commonest in the retroperitoneum). It presents like a large, rapidly growing RCC (mass, pain, haematuria) and is hard to distinguish from sarcomatoid RCC. Management is surgical — wide excision with negative margins (often radical nephrectomy with en-bloc resection), as the initial resection is the best chance of cure. Chemotherapy responses are disappointing, and adjuvant chemoradiation (effective for extremity sarcoma) does not help renal or retroperitoneal sarcoma. The key prognostic factors are margin status and tumour grade.

Lymphoma and Leukaemia

The kidney is commonly involved by haematologic malignancy, and lymphoma is the most common. Suspect renal lymphoma with infiltrative lesions, splenomegaly, disproportionate lymphadenopathy, or nodes outside the usual renal landing zones; B symptoms (fever, weight loss, fatigue) are common. Because treatment is systemic chemotherapy ± radiotherapy, obtain a percutaneous biopsy and avoid nephrectomy (reserved for uncontrollable haemorrhage or the rare primary renal lymphoma). Leukaemic renal involvement is commoner in children.

Metastases to the Kidney

Metastases are the most common malignant neoplasm in the kidney, outnumbering primary tumours (found at autopsy in ~12% of cancer deaths). The commonest sources are lung, breast, and GI cancers, melanoma, and haematologic malignancy; lesions are typically multifocal, infiltrative, and poorly enhancing. Suspect metastasis with multiple renal lesions plus widespread disease or a known non-renal primary, and confirm with percutaneous biopsy.

Other Tumours

Carcinoid tumours arise from neuroendocrine cells (associated with horseshoe kidney; diagnosed by urine/plasma serotonin; carcinoid syndrome is uncommon) and have a generally good prognosis with surgical excision. Renal small-cell carcinoma, Ewing/round-cell tumours, and adult Wilms tumour warrant multimodal therapy.

Benign Tumours and Renal Cysts

Benign lesions account for ~20–30% of small renal masses. Simple cysts are ubiquitous and need no follow-up, complex cysts are stratified by the Bosniak system, and the two solid benign tumours that matter most are angiomyolipoma (the only one confidently diagnosed on imaging, by its fat) and oncocytoma (indistinguishable from RCC).

Renal Cysts and the Bosniak Classification

Simple cysts are the commonest benign renal lesion (a third of people >60), with risk factors of increasing age, male sex, hypertension, and renal insufficiency; acquired cystic disease (e.g. in ESRD) raises RCC risk. Anything that is not a simple cyst needs contrast-enhanced cross-sectional imaging and Bosniak (v2019) classification. Most cystic RCCs are multilocular cystic renal neoplasms of low malignant potential — a better prognosis than solid RCC, with no reported metastases.

Renal cysts may be sporadic, acquired (ACKD), or genetic (ADPKD, ARPKD):

• Acquired cystic kidney disease (ACKD) — occurs in CKD; ~80% of dialysis patients develop cysts, and ~7% develop RCC after ~10 years; the most common type is papillary type 1 RCC.
• ADPKD — autosomal dominant, chromosomes 4 & 16, associated with polycystin. Diagnostic cyst-count criteria: <30 yrs → ≥2 cysts; 30–60 yrs → ≥2 cysts per kidney; >60 yrs → ≥4 cysts per kidney. Associated with hepatic and pancreatic cysts; no increased RCC risk.
• ARPKD — autosomal recessive, chromosome 6, associated with congenital hepatic fibrosis and biliary atresia.

Bosniak HU thresholds: classes I/II are <10 HU, IIF is 10–15 HU, III is >15 HU, and IV is >15 HU with enhancement.

Bosniak	Key features	Malignancy risk	Management
I	Thin (≤2 mm) smooth wall, no septa/calcification; <10 HU	~2%	No follow-up
II	Few (1–3) thin septa, any calcification; hyperdense cysts; <10 HU	~10%	No follow-up
IIF	Minimally thickened (3 mm) wall/septa, or ≥4 thin septa; 10–15 HU	~30%	Imaging q6–12 months for year 1, then annually to 5 years
III	Thick (≥4 mm) or irregular enhancing wall/septa; >15 HU	~30–50%	Excise (active surveillance if ≤2 cm; PN preferred)
IV	Enhancing soft-tissue nodule; >15 HU + enhancement	~90%	Excise (PN preferred when feasible)

Biopsy is unhelpful for most Bosniak III cysts (no targetable solid component) but may be considered for a Bosniak IV solid component (>1 cm) if it will change management or precede ablation. Active surveillance suits low-risk or high-surgical-risk patients (intervention triggers: growth >4 cm, >0.5 cm/yr, metastasis, or patient choice). Thermal ablation is an option for Bosniak III/IV cysts ≤3 cm in poor surgical candidates.

Oncocytoma

Arises from the collecting duct / distal tubule (like chromophobe RCC) and shows abundant mitochondria; the classic spoke-wheel angiographic pattern and central stellate scar have poor predictive value, so it is radiographically indistinguishable from RCC. It accounts for ~25% of masses <3 cm and grows slowly (~0.14 cm/year). It is CK7 negative (helping separate it from chromophobe RCC) and is associated with Birt-Hogg-Dubé. Biopsy and even frozen section are unreliable (hard to separate from chromophobe RCC), with a biopsy PPV of ~67%. Management is observation, thermal ablation, or surgery — partial nephrectomy is preferred given its benign nature.

Angiomyolipoma

Composed of blood vessels, smooth muscle, and fat; HMB-45 positive; predominantly in women (hormonal influence). Most are sporadic, but 20–30% occur in tuberous sclerosis (and 50% of TSC patients develop AMLs, often multifocal). It is the only benign renal tumour confidently diagnosed on imaging — macroscopic fat (≤−20 HU) is the landmark (calcification with fat instead suggests RCC; ~5% are fat-poor and mimic RCC, where a T2 fat-suppressed MRI helps). It is associated with lymphangioleiomyomatosis (LAM). The major complication is spontaneous retroperitoneal haemorrhage (Wunderlich syndrome) — AML is its commonest cause, occurring in ~15% — with risk rising with size, aneurysm formation, and pregnancy.

• Asymptomatic <4 cm — observe (imaging at 6–12 months to gauge growth; sporadic AMLs grow ~5%/yr, TSC/multifocal ~20%/yr).
• Symptomatic or >4 cm — intervene (also proactively in women of childbearing age or those with poor access to emergency care): options are partial nephrectomy, selective embolization, thermal ablation, or sirolimus.

In TSC, the mTOR inhibitor everolimus is first-line and reduces tumour size by ~30% in 80% of patients.

Other Benign Tumours

• Papillary adenoma — ≤5 mm (<1 cm), a probable papillary-RCC precursor (47% progress to papillary RCC); AMACR positive, chromosomes 7 & 17; an autopsy finding.
• Metanephric adenoma — rare, female 2:1, resembles Wilms histologically; AMACR negative, WT1/CD57 positive, polycythaemia in 10% (↑ EPO); usually excised for concern of malignancy, with nephron-sparing surgery preferred.
• Cystic nephroma — Bosniak II–III, female 8:1, bimodal age distribution; lacks blastemal and embryonal elements; indistinguishable from cystic RCC (or cystic Wilms in children) → radical nephrectomy in children, partial in adults.
• Mixed epithelial and stromal tumour (MEST) — rare, perimenopausal women on hormone therapy; Bosniak III–IV, usually surgical.
• Juxtaglomerular cell tumour (reninoma) — renin hypersecretion causing hypertension with hypokalaemia, plus polydipsia, polyuria, myalgia, and headache.