Renal Cell Carcinoma
Renal cell carcinoma is the most common primary renal malignancy, classically presenting with haematuria, loin pain, and a palpable mass, though increasingly detected incidentally on imaging.
Key Facts
Renal cell carcinoma (RCC) accounts for 85% of primary renal cancers; approximately 13,300 new cases/year in the UK Clear cell RCC is the most common subtype (75-80%); associated with VHL gene loss on chromosome 3p Classic triad of haematuria, loin pain, palpable mass present in only 10-15% (late presentation); >50% now detected incidentally NICE NG12: 2-week wait referral for adults aged ≥45 with unexplained visible haematuria Nephrectomy (radical or partial) is the mainstay of treatment for localised disease Metastatic RCC: combination immunotherapy (nivolumab + ipilimumab — CheckMate-214) or TKI + immunotherapy (pembrolizumab + axitinib — KEYNOTE-426) first-line RCC is resistant to conventional chemotherapy and radiotherapy Paraneoplastic syndromes in 20-30%: polycythaemia (EPO), hypercalcaemia (PTHrP), hypertension (renin), Stauffer syndrome (hepatic dysfunction)
Overview
Key Facts
RCC is notable for its resistance to chemotherapy and radiotherapy, but the introduction of targeted therapies and immunotherapy has significantly improved outcomes in advanced disease.
Epidemiology
- Approximately 13,300 new cases/year in the UK
- Male:female ratio 2:1
- Peak incidence age 60-70 years
- Incidence rising (partly due to increased incidental detection)
Aetiology
- Smoking: strongest modifiable risk factor (2× risk)
- Obesity: 2× risk (especially in women)
- Hypertension: independent risk factor
- Von Hippel-Lindau (VHL) syndrome: autosomal dominant; bilateral/multifocal clear cell RCC
- Acquired cystic kidney disease: in dialysis patients (50× risk)
- Family history: 2-4× risk with first-degree relative
Pathophysiology
- Clear cell RCC (75-80%): VHL gene inactivation → HIF accumulation → upregulation of VEGF and PDGF → angiogenesis
- Papillary RCC (10-15%): types 1 and 2; MET pathway activation
- Chromophobe RCC (5%): better prognosis
- RCC characteristically extends into the renal vein and IVC (tumour thrombus)
- Metastatic spread: lung (75%), bone, liver, brain, contralateral kidney
Clinical Presentation
Classic Triad (only 10-15%)
- Haematuria (visible or non-visible)
- Loin/flank pain
- Palpable abdominal/loin mass
Other Features
- Incidental finding on imaging (>50% of cases)
- Unexplained weight loss
- Fever of unknown origin
- Varicocele (left-sided, does not disappear on lying down — left renal vein obstruction)
- Paraneoplastic syndromes (20-30%)
Paraneoplastic Syndromes
- Polycythaemia (EPO secretion)
- Hypercalcaemia (PTHrP)
- Hypertension (renin secretion)
- Stauffer syndrome (non-metastatic hepatic dysfunction; raised ALP, deranged LFTs)
Red Flags
- Visible haematuria in adults ≥45 (2-week wait referral)
- Non-visible haematuria with raised PSA or symptoms
- Palpable renal mass
- Left varicocele that does not decompress on lying flat
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Transitional cell carcinoma (urothelial) | Painless haematuria, filling defect in collecting system | CT urogram, cytology |
| Renal cyst (simple) | Asymptomatic, thin-walled, no enhancement | USS, Bosniak classification |
| Angiomyolipoma | Fat-containing renal mass, associated with tuberous sclerosis | CT (fat density) |
| Renal abscess | Fever, loin pain, raised CRP | CT, blood cultures |
| Oncocytoma | Benign tumour, central scar on imaging | CT/MRI (often indistinguishable pre-op) |
| Lymphoma (renal involvement) | Multiple renal masses, lymphadenopathy | CT, biopsy |
Diagnosis / Investigation
Bedside
- Urinalysis (haematuria)
- Blood pressure
- Abdominal examination
Bloods
- FBC (polycythaemia or anaemia), U&Es, LFTs, calcium, ALP, LDH
- ESR/CRP (may be raised as paraneoplastic)
Imaging
- CT chest/abdomen/pelvis with contrast: investigation of choice for diagnosis and staging
- Renal mass with contrast enhancement is RCC until proven otherwise
- CT renal angiography: pre-operative vascular mapping for partial nephrectomy
- MRI: IVC tumour thrombus assessment, indeterminate lesions
- Bone scan/PET-CT: if bone metastases or advanced disease suspected
Special Tests
- Renal biopsy: not routinely required for solid enhancing masses (risk of seeding); used for small masses (<4cm) if active surveillance considered, or metastatic disease for histological confirmation
- Bosniak classification: for cystic renal lesions (I-IV; III-IV warrant surgery)
- Genetic testing if VHL or hereditary syndrome suspected
Management
Non-pharmacological
- Active surveillance: for small renal masses (<4cm) in elderly/frail patients
- MDT discussion mandatory
Pharmacological
- Metastatic RCC — first-line:
- Favourable/intermediate risk: nivolumab + ipilimumab (CheckMate-214) or pembrolizumab + axitinib (KEYNOTE-426)
- Poor risk: nivolumab + ipilimumab
- Alternative: cabozantinib monotherapy
- Second-line: nivolumab monotherapy (CheckMate-025), cabozantinib, lenvatinib + everolimus
- Adjuvant: pembrolizumab for high-risk RCC post-nephrectomy (KEYNOTE-564)
- Cytokine therapy (historical): IL-2, interferon-alpha (largely replaced)
Surgical/Interventional
- Partial nephrectomy: standard for T1a (<4cm) and selected T1b (4-7cm); nephron-sparing
- Radical nephrectomy: for larger/more advanced tumours (T2+, tumour thrombus)
- IVC thrombectomy: for tumour thrombus extending into IVC (may require cardiopulmonary bypass if atrial extension)
- Metastasectomy: selected patients with limited metastatic disease (oligometastatic)
- Ablation (cryotherapy/radiofrequency): small tumours in non-surgical candidates
- Cytoreductive nephrectomy: in metastatic RCC, role now more selective (CARMENA trial)
Referral Criteria
- Visible haematuria in ≥45: 2-week wait urology referral
- Suspicious renal mass on imaging: urgent urology referral
- All confirmed RCC: renal cancer MDT
Prognosis
- Stage I (T1): 5-year survival >90% (with surgery)
- Stage II (T2): 5-year survival 75-85%
- Stage III (T3/N1): 5-year survival 50-60%
- Stage IV (metastatic): 5-year survival 10-20% (improving with immunotherapy)
- IMDC favourable risk: median OS >4 years
- IMDC poor risk: median OS 12-18 months
- Median survival with untreated metastatic RCC: 6-12 months
- Spontaneous regression of metastases after nephrectomy: rare but documented (<1%)
- Late recurrence can occur >10 years after initial treatment
Other Relevant Information
IMDC (Heng) Prognostic Criteria for Metastatic RCC
| Risk Factor | Definition |
|---|---|
| Time from diagnosis to treatment | <1 year |
| Karnofsky PS | <80% |
| Haemoglobin | Below lower limit of normal |
| Corrected calcium | Above upper limit of normal |
| Neutrophils | Above upper limit of normal |
| Platelets | Above upper limit of normal |
| 0 factors | Favourable (median OS >40 months) |
| 1-2 factors | Intermediate (median OS ~27 months) |
| 3-6 factors | Poor (median OS ~9 months) |
Bosniak Classification of Cystic Renal Masses
| Category | Features | Malignancy Risk | Management |
|---|---|---|---|
| I | Simple cyst, thin wall, no enhancement | 0% | No follow-up |
| II | Few thin septations, fine calcification, <3cm | 0% | No follow-up |
| IIF | More septations, minimal thickening | 5% | Follow-up imaging |
| III | Thick septations, nodular calcification | 50% | Surgery |
| IV | Enhancing soft tissue component | >80% | Surgery |