Renal-cell carcinoma

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Renal-cell carcinoma is a group of renal cortical malignancies led by clear-cell, papillary and chromophobe subtypes; stage, histology, tumour complexity, renal reserve and metastatic risk determine local and systemic choices. Smoking, obesity and hypertension increase RCC risk; chronic kidney disease and acquired cystic kidneys create an additional high-risk renal environment. Loss of VHL function stabilises hypoxia-inducible factors, increasing VEGF signalling and angiogenesis in most clear-cell RCC. HIF accumulation drives highly vascular tumours and explains both vivid contrast enhancement and sensitivity to VEGF-pathway inhibitors. Papillary, chromophobe, collecting-duct and translocation cancers have different molecular drivers, prognoses and systemic-treatment evidence.

Recognition depends on the tempo, host context and anatomical pattern rather than one isolated result. Many localised tumours are found on imaging for another reason and require dedicated characterisation rather than immediate radical nephrectomy. Intermittent blood in urine may arise from RCC, urothelial cancer or benign disease and requires bladder and upper-tract assessment. Persistent flank pain, weight loss, fever, night sweats, anaemia or polycythaemia suggests larger or biologically active disease. Investigation should answer immediate safety, diagnostic confirmation and extent in that order. Renal-protocol multiphase CT A solid enhancing cortical mass is suspicious; enhancement pattern suggests but does not prove subtype, and complex cysts require Bosniak classification. MRI renal and venous assessment Use when CT is inconclusive or venous anatomy affects surgery; avoid treating bland and tumour thrombus as interchangeable. Chest and metastatic staging CT chest is standard for higher-risk disease; brain, bone or spine imaging is symptom-directed rather than routine in every small renal mass.

Management is determined by physiological urgency, disease extent, treatment intent and the person's priorities. The pathway moves through define mass, kidney and spread, then preserve nephrons without losing control, then select systemic treatment by risk and histology; each transition requires named multidisciplinary ownership. Follow-up must anticipate venous tumour thrombus, chronic kidney disease, skeletal and cerebral metastases while measuring function and treatment toxicity.

Key points

Incidental renal mass is a pivotal clue in Renal-cell carcinoma: Many localised tumours are found on imaging for another reason and require dedicated characterisation rather than immediate radical nephrectomy.
Immediate priority in unstable Renal-cell carcinoma: Resuscitate, correct obstruction with urgent urology, obtain contrast imaging when feasible and involve interventional radiology, vascular and renal cancer teams for embolisation, thrombectomy or surgery according to the cause.
Renal-protocol multiphase CT is used early to characterise enhancement, anatomy, local invasion, renal vein and IVC extension and the contralateral kidney. A solid enhancing cortical mass is suspicious; enhancement pattern suggests but does not prove subtype, and complex cysts require Bosniak classification.
MRI renal and venous assessment refines the next decision because use when CT is inconclusive or venous anatomy affects surgery; avoid treating bland and tumour thrombus as interchangeable.
Define mass, kidney and spread: Obtain renal-protocol multiphase imaging and assess size, complexity, nodes, renal vein or IVC extension and contralateral renal reserve.
Preserve nephrons without losing control: Use radical nephrectomy for tumours not safely amenable to nephron-sparing surgery, planning IVC thrombectomy in a specialist centre when needed.
A major avoidable harm is venous tumour thrombus; Extension into the IVC can cause embolic symptoms, hepatic outflow problems and complex surgery requiring vascular and cardiothoracic planning.
A common diagnostic trap is oncocytoma: A benign enhancing renal neoplasm can mimic RCC on imaging; biopsy may help when surveillance or ablation is considered.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Smoking and metabolic risk

Smoking, obesity and hypertension increase RCC risk; chronic kidney disease and acquired cystic kidneys create an additional high-risk renal environment.

VHL pathway

Loss of VHL function stabilises hypoxia-inducible factors, increasing VEGF signalling and angiogenesis in most clear-cell RCC.

Inherited syndromes

VHL disease, hereditary leiomyomatosis and RCC, Birt–Hogg–Dubé and hereditary papillary RCC produce distinctive age, multiplicity and histology.

Treatment and environmental exposure

Previous renal irradiation, long-term dialysis and selected occupational exposures contribute, while many sporadic tumours lack an identifiable cause.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Angiogenic clear-cell growth
HIF accumulation drives highly vascular tumours and explains both vivid contrast enhancement and sensitivity to VEGF-pathway inhibitors.
2
Histological heterogeneity
Papillary, chromophobe, collecting-duct and translocation cancers have different molecular drivers, prognoses and systemic-treatment evidence. In Renal-cell carcinoma, this distinction materially changes mechanistic assessment.
3
Venous extension
Tumour can grow contiguously into renal vein and inferior vena cava without necessarily representing distant haematogenous metastasis.
4
Immune responsiveness
RCC can respond durably to checkpoint inhibition, reflecting an immune-active microenvironment, but immune resistance and toxicity are heterogeneous.
5
Metastatic tropism
Lung, bone, nodes, liver, brain and adrenal are common sites, sometimes years after apparently localised nephrectomy.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Incidental renal mass

Many localised tumours are found on imaging for another reason and require dedicated characterisation rather than immediate radical nephrectomy.

Visible haematuria

Intermittent blood in urine may arise from RCC, urothelial cancer or benign disease and requires bladder and upper-tract assessment.

Flank or systemic symptoms

Persistent flank pain, weight loss, fever, night sweats, anaemia or polycythaemia suggests larger or biologically active disease.

Venous extension

New varicocele, leg oedema, pulmonary embolus or prominent abdominal veins can accompany renal-vein or caval tumour thrombus.

Paraneoplastic pattern

Hypercalcaemia, hypertension, hepatic dysfunction without metastasis and erythrocytosis may improve with tumour control.

Acute bleedingRed flag

Clot retention, falling haemoglobin or shock from urinary or retroperitoneal bleeding requires emergency escalation.

Red flags requiring action

Visible haematuria, flank pain or a palpable mass warrants urgent urinary-tract assessment, although the full triad is late.
Clot retention, symptomatic anaemia or haemodynamic bleeding requires immediate urological care.
New varicocele that persists supine, leg oedema or venous thrombosis may reflect renal-vein or IVC tumour extension.
Unexplained bone pain, cough, weight loss, hypercalcaemia or neurological symptoms suggests metastatic disease.
A renal mass appears in a young patient or is bilateral, multifocal or associated with a syndromic family history.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Renal-protocol multiphase CTFirst step
Why
Characterise enhancement, anatomy, local invasion, renal vein and IVC extension and the contralateral kidney.
Interpretation and limitations
A solid enhancing cortical mass is suspicious; enhancement pattern suggests but does not prove subtype, and complex cysts require Bosniak classification.
02
MRI renal and venous assessment
Why
Clarify contrast-limited lesions, complex cysts or the cranial extent and wall invasion of caval thrombus.
Interpretation and limitations
Use when CT is inconclusive or venous anatomy affects surgery; avoid treating bland and tumour thrombus as interchangeable.
03
Chest and metastatic staging
Why
Assess lung, nodes and other metastatic sites in tumours with meaningful spread risk.
Interpretation and limitations
CT chest is standard for higher-risk disease; brain, bone or spine imaging is symptom-directed rather than routine in every small renal mass.
04
Percutaneous renal-mass biopsy
Why
Obtain histology before ablation or systemic therapy and when surveillance versus treatment remains uncertain.
Interpretation and limitations
Core biopsy is not mandatory before every surgically managed classic mass; non-diagnostic sampling may need repeat, while benign histology must fit imaging.
05
Renal and cardiovascular assessment
Why
Measure eGFR, urinalysis, proteinuria, blood pressure and split function when nephron planning requires it.
Interpretation and limitations
Baseline kidney and cardiovascular risk influences partial versus radical surgery and later VEGF-inhibitor safety.
06
Genetic evaluation
Why
Identify hereditary RCC in young, bilateral, multifocal, unusual-histology or family-cluster presentations.
Interpretation and limitations
Syndrome diagnosis changes nephron-sparing thresholds, surveillance of both kidneys and screening of relatives.
07
Metastatic-site biopsy
Why
Confirm histology when a renal mass and distant lesions could represent another primary or non-malignant process.
Interpretation and limitations
Sample the safest informative site before systemic therapy, especially with atypical imaging or a second cancer history.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Oncocytoma

A benign enhancing renal neoplasm can mimic RCC on imaging; biopsy may help when surveillance or ablation is considered.

Fat-poor angiomyolipoma

Minimal visible fat can make this benign lesion resemble RCC, requiring expert multiphase imaging and sometimes tissue.

Upper-tract urothelial carcinoma

A collecting-system-centred lesion or positive cytology follows ureteroscopic and nephroureterectomy rather than cortical RCC planning. In Renal-cell carcinoma, this distinction materially changes diagnostic assessment.

Renal abscess

Fever, inflammatory change and a complex lesion can mimic necrotic tumour; infection and malignancy may coexist.

Renal metastasis or lymphoma

Bilateral infiltrative or atypical masses may represent systemic disease and particularly benefit from biopsy before nephrectomy.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01CharacteriseDefine mass, kidney and spreadFirst stepImaging identifies a solid or complex cystic renal mass.

1Obtain renal-protocol multiphase imaging and assess size, complexity, nodes, renal vein or IVC extension and contralateral renal reserve.
2Stage the chest and investigate bone, brain or other sites when tumour risk or symptoms warrant it.
3Use core biopsy before ablation or systemic treatment and when histology will resolve surveillance versus intervention; offer genetics review for hereditary features.

02LocalisedPreserve nephrons without losing controlRCC appears confined to the kidney or locally resectable.

1Offer partial nephrectomy when technically and oncologically suitable, especially for smaller tumours, solitary kidney, bilateral disease or chronic kidney risk.
2Use radical nephrectomy for tumours not safely amenable to nephron-sparing surgery, planning IVC thrombectomy in a specialist centre when needed.
3Consider active surveillance or thermal ablation for selected small masses when age, comorbidity, growth and biopsy favour lower procedural burden.

03MetastaticSelect systemic treatment by risk and histologyBiopsy confirms advanced RCC or distant recurrence requiring therapy.

1Classify histology, IMDC risk, disease tempo, symptoms, organ function, autoimmune history and need for rapid shrinkage.
2For clear-cell disease, use an approved immune–VEGF combination or nivolumab–ipilimumab according to risk, contraindications and current NHS access.
3Consider cytoreductive nephrectomy or metastasis-directed treatment only in selected biology after systemic and surgical MDT review, not automatically at diagnosis.

04Follow-upSurveil recurrence and renal healthLocal treatment is complete or systemic disease is controlled.

1Use pathology-based chest and abdominal imaging intervals, extending follow-up for higher stage, grade, sarcomatoid or hereditary disease.
2Monitor eGFR, proteinuria, blood pressure and cardiovascular risk and minimise avoidable nephrotoxic exposure.
3Investigate new bone pain, cough, neurological change, haematuria or constitutional decline promptly because RCC can recur late.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provides first-line immune and VEGF-pathway treatment for eligible advanced clear-cell RCC.

Pembrolizumab with axitinib

Use pembrolizumab 200 mg IV every 3 weeks or 400 mg every 6 weeks with axitinib 5 mg orally twice daily, with axitinib interruption, reduction or escalation according to the specialist protocol.

Monitor immune toxicity, blood pressure, urine protein, thyroid, renal and liver function, diarrhoea, hand–foot symptoms, bleeding, thrombosis and wound healing; pause axitinib around major surgery.

Provides durable first-line immune treatment for eligible intermediate- or poor-risk advanced clear-cell RCC.

Nivolumab with ipilimumab

Give nivolumab 3 mg/kg plus ipilimumab 1 mg/kg IV every 3 weeks for 4 doses, then nivolumab maintenance using a licensed flat-dose schedule such as 240 mg every 2 weeks or 480 mg every 4 weeks.

Combination therapy increases serious immune hepatitis, colitis, pneumonitis, endocrinopathy, nephritis, myocarditis and neurological toxicity; baseline and symptom-triggered organ assessment must be rapid.

Targets VEGF receptors and can be used in approved advanced RCC sequences or as part of combination treatment.

Axitinib alone

Start 5 mg orally twice daily about 12 hours apart, with food or without, and adjust from 2 mg to 10 mg twice daily according to tolerability, blood pressure and the licensed regimen.

Check blood pressure before and during therapy, urine protein, thyroid, liver function and diarrhoea; review bleeding, thrombosis, fistula, gastrointestinal perforation and planned procedures.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Venous tumour thrombus

Extension into the IVC can cause embolic symptoms, hepatic outflow problems and complex surgery requiring vascular and cardiothoracic planning.

Chronic kidney disease

Radical nephrectomy, contrast, hypertension and systemic therapy can reduce renal reserve and cardiovascular health. In Renal-cell carcinoma, this distinction materially changes complication assessment.

Skeletal and cerebral metastases

Bone lesions cause fracture or cord compression, while brain metastases cause seizure, haemorrhage and focal deficit.

Immune-related toxicity

Checkpoint treatment can inflame lung, bowel, liver, endocrine organs, kidney, heart or nervous system and may occur after stopping therapy.

VEGF-inhibitor toxicity

Hypertension, proteinuria, thrombosis, bleeding, diarrhoea, hand–foot symptoms and wound-healing impairment need proactive monitoring. In Renal-cell carcinoma, this distinction materially changes complication assessment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

After surgery or ablation, use stage- and grade-based chest and abdominal imaging and investigate symptoms between scheduled scans.
Trend eGFR, urine protein, blood pressure and cardiovascular risk after nephron loss and during VEGF-targeted therapy.
During checkpoint therapy, ask actively about cough, diarrhoea, rash, jaundice, headache, fatigue, weakness, chest pain and urinary change at each contact.
Check blood count, renal, liver, thyroid and metabolic profiles at regimen-defined intervals and respond to trends before severe toxicity.
Reimage venous thrombus and metastatic sites with consistent technique, distinguishing immune pseudoprogression from genuine deterioration through clinical review.
For hereditary disease, maintain bilateral renal and syndrome-specific organ surveillance and cascade family referral.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Not every mass needs biopsy

Classic resectable imaging can proceed to surgery, while tissue is essential before ablation or systemic treatment and useful when diagnosis changes management.

Partial nephrectomy has two goals

It preserves renal function only when achieved without compromising cancer clearance or creating disproportionate operative harm.

Tumour thrombus is contiguous

IVC extension is locally advanced disease and can remain surgically curable in selected patients without distant metastasis.

RCC can recur late

New symptoms years after nephrectomy deserve investigation rather than reassurance from an elapsed five-year interval.

Toxicity can mimic progression

Checkpoint pneumonitis, hepatitis and nephritis or VEGF hypertension can produce decline while imaging appears stable or ambiguous.

11Common pitfallsFrequent interpretation and management errors.

01
Performing radical nephrectomy for every small renal mass without considering surveillance, biopsy or partial surgery.
02
Starting systemic therapy without histological confirmation.
03
Treating IVC tumour thrombus as ordinary venous thromboembolism alone.
04
Ignoring renal and cardiovascular outcomes after cancer control.
05
Continuing VEGF inhibition through uncontrolled hypertension or major surgery.
06
Missing late immune toxicity after treatment has stopped.