Renal Cell Carcinoma (2026 Update)

INTRODUCTION

• The European Association of Urology (EAU) Renal Cell Cancer (RCC) Guidelines Panel provides evidence-based recommendations for management.
• Guidelines help focus decisions based on personal values and individual circumstances but do not replace clinical expertise or legal standards of care.
• The Panel is an international multidisciplinary group including urologists, oncologists, methodologists, a pathologist, a radiologist, and patient advocates (since 2015).
• Available publications include Pocket Guidelines, scientific publications, an EAU chatbot, and a mobile app for iOS and Android.

EPIDEMIOLOGY, AETIOLOGY, AND SCREENING

• Epidemiology Statistics

  • RCC is the 14th most common cancer, representing approximately $2\%$ of all cancers.
  • In 2022: Estimated $434,840$ new cases and $155,953$ deaths globally.
  • Highest incidence occurs in Western countries. Age-standardised incidence rate ($ASR$) is highest in North America; mortality is highest in Eastern Europe.
  • Men to Women ratio: $ASR$ of $13.7$ vs. $6.4$.
  • Europe 2022: $145,721$ cases, $52,347$ deaths.
  • Highest European rates (2022): Belarus, Latvia, and Czechia.
  • Projected increase by 2050: $745,791$ new cases and $304,861$ deaths globally.

• Aetiological Risk Factors

  • Smoking: Hazard Ratio ($HR$) range of $1.23$ to $1.58$.
  • Obesity: $BMI > 35$ vs. $< 25$ ($HR: 1.71$ [$1.06-2.79$]).
  • Hypertension: ($HR: 1.70$ [$1.30-2.22$]).
  • Metabolic Syndrome: Relative Risk ($RR: 1.62$ [$1.41-1.87$]).
  • Genetic/Familial: Having one or more first-degree relatives ($FDR$) doubles the risk.
  • Dietary habits: Ultra-processed food increased risk ($HR: 1.42$); vegetables ($HR: 0.68$), coffee ($HR: 0.85$), and tea ($HR: 0.85$) are associated with lower risk.
  • Alcohol: Moderate consumption has a protective effect ($RR: 0.85$).

• Screening

  • No evidence supports primary screening in the general population.
  • Urinary dipstick: Inadequate due to low sensitivity/specificity ($0.58\%$ incidence of RCC with non-visible haematuria).
  • Yorkshire Kidney Screening Trial: Solid masses or Bosniak 3/4 cysts in $0.62\%$ of participants ($0.25\%$ proven RCCs).
  • High-risk targeting: Recommended for end-stage renal disease ($ESRD$), which has a tenfold increased risk.

HISTOLOGICAL DIAGNOSIS AND PATHOLOGY

• WHO 2022 Classification

  • Standard morphology combined with immunohistochemistry and molecular tests.
  • Classification is shifting from morphology to molecular analyses via next-generation sequencing ($NGS$).

• Main RCC Types and 5-Year Overall Survival ($OS$)

  • Chromophobe RCC ($chRCC$): $91\%$
  • Papillary RCC ($pRCC$): $82\%$
  • Clear Cell RCC ($ccRCC$): $81\%$
  • Collecting Duct RCC: $44\%$

• Subtype Descriptions

  • Clear Cell RCC ($ccRCC$): $70\%$ of cases. Features golden-yellow cut surface, loss of chromosome $3p$, and mutation of VHL gene ($3p25$).
  • Papillary RCC ($pRCC$): $13$ to $20\%$ of renal epithelial tumours. Classified as "classic pattern," "biphasic," "reverse nuclear polarity," and "Warthin-like."
  • Chromophobe RCC ($chRCC$): pale tan, homogenous mass. Typically good prognosis ($10$-year Cancer Specific Survival [$CSS$] of $89.2\%$
  • Sarcomatoid Features: Not a specific subtype; represents dedifferentiation patterns associated with poor outcomes ($5$-year $OS$ for all patients is $18.1\%$

• Rare and Benign Tumours

  • Renal Medullary Carcinoma ($RMC$): $SMARCB1$-deficient. $< 0.5\%$ of RCCs. Predominantly in young adults of African ancestry with sickle cell trait. Highly aggressive (median survival $30\,$ ext{months}).
  • Renal Oncocytoma: Benign, $4$ to $7\%$ of solid renal tumours. Annual growth rate of approximately $2\,$ ext{mm}.
  • Classical Angiomyolipoma ($AML$): Benign mesenchymal tumour ($0.44\%$ prevalence). Risk of spontaneous life-threatening bleeding increases with size.
  • Cystic Renal Neoplasms: Multilocular cystic renal neoplasm of low malignant potential ($MCNLMP$) represents $0.5$ to $2.5\%$ of renal tumours; benign lesion.

STAGING AND CLASSIFICATION SYSTEMS

• 2017 TNM Classification

  • T1: Tumour $\le 7\,$ ext{cm} (limited to kidney). $T1a \le 4\,$ ext{cm}; $T1b > 4\,$ ext{cm} but $\le 7\,$ ext{cm}.
  • T2: Tumour $> 7\,$ ext{cm} (limited to kidney). $T2a > 7\,$ ext{cm} but $\le 10\,$ ext{cm}; $T2b > 10\,$ ext{cm}.
  • T3: Extends into major veins or perinephric tissues. $T3a$ includes renal vein, segmental branches, or renal sinus fat.
  • T4: Invades beyond Gerota fascia.
  • N status: $N0$ (none), $N1$ (metastasis in regional lymph nodes).
  • M status: $M0$ (none), $M1$ (distant metastasis).

• Anatomic Scoring Systems

  • Examples: $PADUA$, $R.E.N.A.L.$ nephrometry, $SPARE$, $C-index$, $DAP$, and $MAP$ score.
  • $SPARE$ recorded highest predictive accuracy for partial nephrectomy ($PN$) completion (Area Under the Curve [$AUC$] of $0.89$).

DIAGNOSTIC EVALUATION

• Symptoms

  • Most are incidental ($60\%$ overall; $87\%$ for $T1a$).
  • Classic Triad: Flank pain, visible haematuria, palpable mass (only $0.6\%$ of cases).
  • Paraneoplastic Syndromes ($PNS$) found in $33\%$ of symptomatic patients.

• Imaging

  • Computed Tomography ($CT$): Standard for diagnosis. Enhancement is defined as a change of $15\,$ ext{HU} or more using intravenous contrast.
  • Magnetic Resonance Imaging ($MRI$): Preferred for evaluating venous involvement or in cases of contrast allergy/pregnancy. Uses high-resolution $T2$-weighted images for thrombus delineation.
  • Contrast-enhanced Ultrasound ($CEUS$): High sensitivity ($100\%$
  • Bosniak Classification of Cystic Masses: Updated 2019 version include $MRI$ criteria. Risk of malignancy in $BIII$ is $80\%$; $BIV$ is $88\%$

• Renal Tumour Biopsy ($RTB$)

  • Indications: Radio-indeterminate masses, candidates for active surveillance ($AS$), or prior to ablation.
  • Technique: $18$-gauge needles; coaxial technique required to avoid tumour seeding.
  • Accuracy: Core biopsies have $99.1\%$ sensitivity and $99.7\%$ specificity for malignancy. Concordance for histotype is $90.3\%$
  • Morbidity: Low. Significant bleeding in $0.7\%$; subcapsular haematoma in $4.3\%$

PROGNOSTIC FACTORS

• Histological Factors

  • WHO/ISUP Grade: Replaced Fuhrman system. Based on nucleolar prominence (Grades 1-3) and sarcomatoid/rhabdoid features (Grade 4).

• Clinical Factors

  • Neutrophil-to-lymphocyte ratio ($NLR$): High preoperative $NLR$ linked to poor prognosis.
  • Body Mass Index ($BMI$): High $BMI$ associated with improved survival in mRCC ("obesity paradox" for cancer-specific mortality).
  • Frailty: Endorsed Geriatric 8 ($G8$) screening tool (Score $\le 14 / 17$ requires Comprehensive Geriatric Assessment [$CGA$]).

• Molecular Markers

  • PROMISING: Carbonic anhydrase IX ($CaIX$), $Ki67$, $p53$, $BAP1$, and $PBRM1$.
  • Kidney-Injury Molecule-1 ($KIM-1$): Glycoprotein marker of tubular injury; potential prognostic marker in $ccRCC$ and $pRCC$.

• Prognostic Models

  • Leibovich Score (2003): For clear cell RCC; predicts short/long-term metastasis risk ($0-2$: low, $3-5$: intermediate, $\ge 6$: high).
  • VENUSS Score: For papillary RCC recurrence.
  • IMDC/MSKCC Models: For metastatic disease. $IMDC$ uses $6$ factors (Karnofsky $PS < 80\%$, time since diagnosis $< 1\,$ ext{year}, Hg, Calcium, Neutrophils, Platelets).

DISEASE MANAGEMENT: LOCALISED RCC

• Nephron-Sparing Surgery ($NSS$) vs. Radical Nephrectomy ($RN$)

  • T1 RCC: $PN$ is the treatment of choice. Comparable noninferiority of $CSS$ ($HR: 2.06$).
  • T2 RCC: $RN$ is standard, but $PN$ can be considered for functional benefits if technically feasible.
  • T3a upstaged: $PN$ shows no significant difference in $OS$ or $RFS$ compared to $RN$ in meta-analysis.

• Surgical Techniques

  • Laparoscopic $RN$: Lower morbidity and shorter hospital stay than open $RN$.
  • Robot-assisted $PN$ ($RAPN$): Associated with lower estimated blood loss ($EBL$) and shorter hospital stay than open $PN$.
  • Drain placement: Omitting a drain does not increase complication rates.

• Alternatives to Surgery

  • Watchful Waiting ($WW$): For frail patients with reduced life expectancy.
  • Active Surveillance ($AS$): Initial monitoring via imaging. Metastasis rate is $1\%$ to $2\%$ in SRM cohorts. $ccRCC$ grows faster ($0.25\,$ ext{cm/year}) than $pRCC$ ($0.02\,$ ext{cm/year}).
  • Tumour Ablation: Cryoablation, Radiofrequency Ablation ($RFA$), and Microwave Ablation ($MWA$). Most recurrence occurs locally.
  • Stereotactic Ablative Radiotherapy ($SABR$): Emerging for inoperable patients. $FASTRACK II$ trial reported $100\%$ local control after $12\,$ ext{months}.

LOCALLY ADVANCED AND METASTATIC RCC

• Locally Advanced Management

  • Venous Thrombus: Mayo levels $0$ to $4$. Requires complete surgical excision. $MDCT$ or $MRI$ for staging.
  • Adjuvant Therapy: Pembrolizumab (Keynote-564 trial) demonstrates DFS and OS benefits ($HR: 0.62$ after $57.2\,$ ext{months}). Recommended for high-risk resected $ccRCC$.

• Metastatic RCC (mRCC)

  • Cytoreductive Nephrectomy ($CN$): CARMENA trial found Sunitinib alone noninferior to $CN$ plus Sunitinib in intermediate/poor risk patients. Upfront IO combo therapy is current standard.
  • Systemic Therapy First-line ($ccRCC$):
  • Doublet therapy ($IMDC$ Intermediate/Poor): Nivolumab + Ipilimumab, Pembrolizumab + Axitinib, Lenvatinib + Pembrolizumab, or Nivolumab + Cabozantinib.
  • IMDC Favourable: TKI monotherapy (Sunitinib/Pazopanib) is an additional standard of care.
  • Triplet therapy: Cabozantinib + Nivolumab + Ipilimumab (COSMIC-313 trial) improved $PFS$ ($HR: 0.73$) but carries $73\%$ Grade III/IV toxicity.\n\n- **Sequencing mRCC Therapy**\n - Post-IO progression: Offer Cabozantinib (most robust data) or other VEGF$-$TKI.\n - Belzutifan: Attractive alternative to Everolimus after \ge 2 prior lines.\n\n# FOLLOW-UP\n\n- **Risk-Stratified Follow-up Schedule (EAU Expert Opinion)**\n - **Low risk (ccRCC$Leibovich$0-2$):**$CT$of chest/abdomen at$6$,$12$,$18$,$24$,$30$,$36\,\text{months}, then once every two years.\n - **Intermediate risk (Leibovich 3-5$):**$CT$at$6\,$\text{months}, then every$6\,$\text{months} up to$3\,$\text{years}, then annually up to$5\,\text{years}.\n - **High risk (Leibovich \ge 6$):**$CT$at$3\,$and$6\,$\text{months}, then every$6\,$\text{months} up to$3\,\text{years}, then annually.\n- Recurrence in the contralateral kidney is rare (1$to$2\%\n\n# HEREDITARY RCC SYNDROMES\n\n- Accounts for 5$to$8\%$of cases; median age of onset is$37\,\text{years}.\n- **Syndromes and Genes:**\n - **VHL (VHL):** 30$to$40\%$risk.$ccRCC$. Surveillance recommended until tumour reaches$3\,\text{cm}.\n - **BHD (FLCN):** 30\%$risk. Hybrid oncocytic/$chRCC.\n - **HPRCC (MET):** 100\% risk. Papillary RCC.\n - **FH-deficient (FH):** 15$to$32\% risk. Highly aggressive; early surgery required.\n- **Treatment:** Belzutifan (HIF-2\alpha$inhibitor) approved for$VHL$-associated tumours ($ORR$of$67\%\n\n# SUMMARY OF RECOMMENDATIONS\n\n- **Strong Recommendations:**\n - Stop smoking and reduce weight.\n - Use multiphasic contrast-enhanced CT for staging.\n - Offer PN$for$T1 tumours.\n - Use WHO/ISUP grading.\n - Offer adjuvant Pembrolizumab in high-risk ccRCC (Keynote-564 criteria).\n - Employ shared decision-making.\n- **Weak Recommendations:**\n - Omit chest CT$in incidental$cT1a disease.\n - Offer AS to biopsy-proven oncocytoma.\n - Use intermittent VEGF$-$TKI$in case of stable disease for$> 6\,$$ ext{months} in mRCC.