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Prof. Giacomo Novara — Urology, University of Padova

Kidney Cancer

Renal parenchymal neoplasm — Renal cell carcinoma

This page covers neoplasms originating from the renal parenchyma, distinct from upper tract urothelial neoplasms. Kidney cancer is one of the most common malignancies in Italy, with a particularly high incidence in the North-East, and in the majority of cases is discovered incidentally during investigations performed for other reasons.

📊 Epidemiology

13,000
New cases/year in Italy (2024 estimate)
4,500
Deaths/year in Italy
150,000
Patients on follow-up in Italy
2 : 1
Male-to-female ratio

The peak incidence occurs around the age of 70 years. Italy — and in particular the North-East — has among the highest incidence rates in the world, comparable to Austria, Slovenia, Croatia, and the Czech Republic. Despite therapeutic advances, mortality has remained substantially stable, confirming the critical importance of early diagnosis.

🔬 Histology

70%
Clear cell carcinoma

Originates from the proximal convoluted tubule. VHL gene mutation on chromosome 3p. Highly vascularised (via HIF). Prognosis varies with grade.

15%
Papillary carcinoma

Type 1 (MET) and type 2 (FH). Less vascularised. Generally better prognosis for type 1, worse for type 2.

10%
Chromophobe carcinoma

Originates from intercalated cells of the collecting duct. Generally favourable prognosis if localised.

<1%
Collecting duct carcinoma

Rare and aggressive. Behaviour similar to upper tract urothelial carcinoma. Poor prognosis.

Note: Angiomyolipoma is the only benign renal tumour identifiable on imaging (presence of fat within the lesion on CT). Resection is not required if <4 cm and asymptomatic.

🧬 Hereditary forms

Approximately 3–5% of renal carcinomas are attributable to hereditary syndromes. Recognising them is fundamental for family counselling and surveillance.

🔵
Von Hippel-Lindau (VHL)
  • VHL gene on chromosome 3p25
  • Bilateral and multifocal clear cell carcinomas
  • Associated with CNS haemangioblastomas, phaeochromocytoma, pancreatic cystadenomas
  • The VHL→HIF→VEGF pathway is the rationale for TKIs
🟡
Birt-Hogg-Dubé (BHD)
  • FLCN gene (folliculin)
  • Chromophobe tumours and oncocytomas
  • Cutaneous fibrofolliculomas, pulmonary cysts, and spontaneous pneumothorax
🟢
Tuberous sclerosis (TSC)
  • TSC1/TSC2 genes (mTOR pathway)
  • Multiple bilateral angiomyolipomas (haemorrhage risk)
  • Clear cell carcinomas rare but possible
  • Everolimus for angiomyolipomas >3 cm symptomatic

Indications for genetic counselling: diagnosis ≤45 years, bilateral/multifocal tumours, positive family history (≥2 first- or second-degree relatives).

🩺 Diagnosis

Kidney cancer is by definition silent. In the majority of cases it is discovered incidentally during an ultrasound or CT performed for other reasons. The classic triad (gross haematuria, flank pain, palpable mass) is today rare and indicates advanced disease.

The diagnostic workup for incidental renal lesions begins with ultrasound as the first approach, followed by multiphase contrast-enhanced CT (pre-contrast, arterial, nephrographic, and excretory phases) to characterise the lesion.

Bosniak classification of renal cysts

I Simple cyst Benign 100%
Thin-walled, aqueous cyst with no septa, calcifications, or enhancement. No follow-up required.
II Minimally complicated cyst Malignant risk <5%
Few thin septa, minimal calcifications, hyperdense (<3 cm). Follow-up not required or at physician's discretion.
IIF Requires follow-up Risk ~15%
Multiple or thick septa, nodular calcifications, hyperdense >3 cm. Follow-up with CT/MRI every 6–12 months for 5 years.
III Indeterminate — consider surgery Risk ~55%
Thick walls or septa with enhancement. Generally indicates surgical resection or close surveillance in selected patients.
IV Clearly malignant Risk >85%
Solid component with enhancement independent of septa. Indicates surgery unless contraindicated.

⭐ Special features

Neoplastic venous thrombosis

Clear cell carcinoma has the distinctive feature of extending a neoplastic thrombus into the renal vein and inferior vena cava, potentially reaching the right atrium. Surgery depends on the level of the thrombus (Neves classification): levels I–II (below the hepatic veins) — standard surgery; levels III–IV (above the hepatic veins or intracardiac) — requires cardiopulmonary bypass with cardiac surgery support.

Bilateral lesions and solitary kidney

In the case of synchronous or metachronous bilateral tumour, or a tumour on a single functioning kidney, nephron sparing is imperative. Robotic partial nephrectomy is preferred; thermoablation (cryoablation, radiofrequency) or active surveillance are alternatives for lesions ≤2 cm at low risk.

🗺️ Metastatic sites

🫁Lung50–60%
🦴Bone30–40%
🧠Brain5–10%
🫀Pancreas5% — typical of ccRCC, often isolated and resectable
🫁Adrenal5%
🔴Liver20–30%

Isolated pancreatic metastases from ccRCC, typically hypervascular on CT, can be resected with curative intent with favourable survival outcomes.

🔪 Treatment of localised disease

Robotic partial nephrectomy

Gold standard for resectable lesions with preservation of healthy parenchyma. The PADUA Score and R.E.N.A.L. Score stratify surgical complexity based on lesion position (hilar, renal sinus, vascular contact). Warm ischaemia (renal artery clamping) must be minimised (ideally <25 minutes). The main complications are: post-operative embolisation for haemorrhage (1–3%) and urinary fistula/leakage (1–2%).

Radical nephrectomy

Reserved for lesions not amenable to a partial approach (size, position, normal contralateral renal function). Includes ipsilateral adrenalectomy only in cases of direct adrenal involvement or suspicious upper pole lesions. Laparoscopic or robotic approach.

❄️
Thermoablation
  • Cryoablation or radiofrequency ablation
  • Lesions ≤3–4 cm, inoperable patient or solitary kidney
  • Local control rate 85–90% at 5 years
  • CT-guided percutaneous or laparoscopic approach
👁️
Active surveillance
  • Lesions <2 cm (often benign or low grade)
  • Elderly patient, high comorbidity burden, reduced life expectancy
  • CT/MRI every 3–6 months for 2 years, then annually
  • Treatment trigger: growth >0.5 cm/year or >4 cm
🛡️
Adjuvant pembrolizumab (KEYNOTE-564)
  • Indicated after nephrectomy in pT2 G4 / pT3+ / pT4 or N+ (ccRCC)
  • 32% reduction in recurrence risk vs placebo
  • 17 cycles (1 year) every 3 weeks
  • New standard of care in the high-risk adjuvant setting

💊 Treatment of metastatic disease

💉
TKI (tyrosine kinase inhibitors)
  • Sunitinib, pazopanib — now second line
  • Cabozantinib, axitinib — combinations and second line
  • Targets: VEGFR, PDGFR, c-MET, AXL
🛡️
Immunotherapy — IO/TKI first line
  • Nivolumab + ipilimumab (intermediate/high risk — CheckMate 214)
  • Pembrolizumab + axitinib (KEYNOTE-426)
  • Nivolumab + cabozantinib (CheckMate 9ER)
  • Pembrolizumab + lenvatinib (CLEAR)
📋
IMDC stratification
  • Score 0: favourable risk → TKI + IO or IO/IO
  • Score 1–2: intermediate risk → IO/IO or IO/TKI
  • Score ≥3: high risk → IO/IO (nivo + ipi)

Cytoreductive surgery (CARMENA + SurTime)

The CARMENA trial demonstrated that sunitinib alone is not inferior to cytoreductive nephrectomy + sunitinib in patients at intermediate/high IMDC risk. Cytoreductive nephrectomy remains indicated in highly selected patients (favourable risk, good performance status, low metastatic burden). The SurTime study showed an advantage from deferred nephrectomy (after response to systemic therapy) in patients with synchronous metastatic disease.

❓ Frequently asked questions

Kidney cancer is sometimes called the "tumour of silence" precisely because it produces no symptoms in the vast majority of cases while it remains localised. Incidental discovery during an ultrasound or CT performed for other reasons (abdominal pain, investigation of other organs) is now the most frequent mode of presentation. This is paradoxically a positive element: early diagnosis significantly improves the chances of cure.
Partial nephrectomy aims to preserve as much functioning parenchyma as possible. In the majority of cases ≥75% of the operated kidney's parenchyma is conserved, resulting in a modest and acceptable reduction in overall renal function. Creatinine may rise transiently and then stabilise. Warm ischaemia time (the period during which the kidney is without blood flow during surgery) must be kept as short as possible to minimise damage. Follow-up with blood tests (creatinine, GFR) is part of post-operative surveillance.
No. Renal parenchymal carcinoma is traditionally unresponsive to conventional chemotherapy. The effective treatments for advanced disease are tyrosine kinase inhibitors (TKIs) and immunotherapeutic agents (checkpoint inhibitors), used today always in combination. In the majority of cases these drugs succeed in converting the disease into a chronic condition, allowing survival of several years even at a metastatic stage.
The majority of kidney cancers are sporadic. However, if you have two or more first- or second-degree relatives with kidney cancer, or if the diagnosis was made at a young age (<45 years), genetic counselling may be appropriate. Certain hereditary syndromes (Von Hippel-Lindau, Birt-Hogg-Dubé, tuberous sclerosis) are associated with multiple bilateral renal tumours and require specific surveillance protocols. Please discuss this with your urologist.

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