(UTUC) Study Guide

Introduction and Scope of the EAU Guidelines

• Aim and Scope: These guidelines represent the updated European Association of Urology (EAU) recommendations for the management of Upper Urinary Tract Urothelial Carcinoma (UTUC). They are distinct from EAU guidelines for Non-muscle-invasive Bladder Cancer (NMIBC), Muscle-invasive and Metastatic Bladder Cancer (MIBC), and Primary Urethral Carcinoma (PUC).

• Clinical Application: Recommendations are based on the best available evidence but do not replace clinical expertise. Treatment decisions must account for individual patient values, preferences, and circumstances. These guidelines are not legal mandates or standards of care.

• Panel Composition: The multidisciplinary panel includes urologists, uro-oncologists, a pathologist, and patient representatives. All members provide conflict of interest statements.

• Available Formats: Resources include a full-text version, Pocket Guidelines (abridged), scientific summaries (latest in 2025), and the EAU Guidelines App (iOS/Android) featuring interactive algorithms and calculators.

• Publication History: First published in 2011. The 2026 version is a limited update of the 2025 version.

• Summary of Key Updates for 2026:

  • Discussion of the prognostic value of $FGFR3$ expression in UTUC (Section 3.4).

  • Incorporation of the 9th edition ($2025$) of the Tumour, Node, Metastasis (TNM) classification (Chapter 4).

  • Elaboration on cytology and urinary biomarkers (Section 5.4).

  • Discussion on the lack of data for renal preservation and laser ablation in endoscopic treatments (Section 7.1.2).

  • Refinement of techniques for bladder cuff management (Section 7.2.1.a.2) and lymph node dissection (LND) criteria (Section 7.2.1.a.3).

  • Addition of retrospective studies on distal ureterectomy and chemoimmunotherapy (Sections 7.2.1.b.1 and 7.2.2.a.3).

  • Options for managing clinical locoregional lymph node (LN) metastases (Section 7.3.1).

  • Updated follow-up recommendations for high-risk tumours after kidney-sparing management (Chapter 8).

Methods and Strength of Recommendations

• Data Identification: Search restricted to articles published between 1 May 2024 and 1 May 2025. Databases used: PubMed, Ovid, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. A total of $417$ unique records were screened.

• Recommendation Strength Rating: Factors influencing strength include:

  1. Overall quality of evidence.

  2. Magnitude of effect (individual or combined).

  3. Certainty of results (precision, consistency, heterogeneity).

  4. Balance between desirable and undesirable outcomes.

  5. Impact of patient values and preferences.

• Definitions:

  • Strong Recommendation: High degree of evidence quality and/or favourable benefit-to-harm ratio.

  • Weak Recommendation: Lower quality evidence and/or equivocal balance between benefit and harm.

Epidemiology, Aetiology, and Pathology

• Incidence and Demographics:

  • UTUC accounts for $5-10\%$ of all urothelial carcinomas (UCs); bladder cancer accounts for $90-95\%$.

  • Estimated annual incidence in Western countries: $2$ cases per $100,000$ inhabitants.

  • Peak incidence: Individuals aged $70-90$ years.

  • Male-to-female ratio: $2:1$.

  • Approximately $53.3\%$ of patients are former or current smokers.

  • Incidence is rising due to improved detection and population aging.

• Clinical Presentation and Disease State:

  • $2/3$ of patients have muscle-invasive disease at diagnosis, compared to $15-25\%$ in bladder cancer.

  • Approximately $9\%$ of patients present with metastases.

  • Pyelocaliceal tumours are twice as common as ureteral tumours.

  • Multifocal tumours occur in $10-20\%$ of cases.

  • Concomitant carcinoma in situ (CIS) occurs in $11-36\%$.

  • Concurrent bladder cancer (BC) is present in $17\%$ of cases.

• Environmental Risk Factors:

  • Tobacco: Increases relative risk by $2.5$ to $7.0$ times.

  • Aristolochic Acid: Found in Aristolochia plants (herbal remedies or environmental contamination). Causes irreversible injury to renal proximal tubules and UTUC. Induces a unique mutational spectrum ($A > T$ transversions).

  • Arsenic: Linked to UTUC in Taiwan and Chile via drinking water.

  • Alcohol: Risk threshold of $> 15\,g/\text{day}$ of alcohol ($OR: 1.23$).

• Genetic Risk Factors (Lynch Syndrome):

  • UTUC is the 3rd most common malignancy in Lynch syndrome (after colorectal and endometrial).

  • Caused by germline mutations in mismatch repair (MMR) genes: $MSH2$, $MSH6$, $MLH1$, or $PMS2$.

  • Found in up to $9\%$ of UTUC patients.

  • Amsterdam II Criteria for screening: At least three relatives with Lynch-associated cancer; one is a first-degree relative; at least two successive generations; one relative diagnosed before age $50$.

  • Simplified screening tool for UTUC: Age $< 60$ yr at diagnosis OR personal history of Lynch-spectrum cancer OR specific family history criteria.

• Histology:

  • Predominantly UCs. Histological subtypes/divergent differentiation (e.g., squamous, micropapillary, sarcomatoid) present in $14\%$ of cases and often indicate worse prognosis.

  • Molecular Background: Common alterations in $FGFR3$, $KMT2D$, $KDM6A$, and $TP53$. $FGFR3$ expression is linked to an "immune cold" phenotype and suggests favourable prognosis.

Staging and Classification Systems

• TNM Classification (2025 Edition):

  • T - Primary Tumour:

    • $Ta$: Non-invasive papillary carcinoma.

    • $Tis$: Carcinoma in situ.

    • $T1$: Invades subepithelial connective tissue.

    • $T2$: Invades muscularis.

    • $T3$: Invades beyond muscularis into peripelvic/periureteric fat or renal parenchyma.

    • $T4$: Invades adjacent organs or through kidney into perinephric fat.

  • N - Regional Lymph Nodes:

    • $N0$: No regional LN metastasis.

    • $N1$: Metastasis in a single LN $\le 2\,cm$.

    • $N2$: Metastasis in a single LN $> 2\,cm$ or multiple LNs.

  • M - Distant Metastasis:

    • $M0$: No distant metastasis.

    • $M1$: Distant metastasis.

• Tumour Grade: Based on WHO $1973$ and $2004/2016/2022$ classifications (low-grade vs. high-grade). Grade is a critical surrogate for pathological stage.

Diagnosis and Imaging

• Symptoms: Haematuria (most common), flank pain ($20-32\%$), and systemic symptoms (anorexia, weight loss) suggesting metastasis.

• Imaging:

  • CT Urography: Gold standard. Sensitivity $92\%$, Specificity $95\%$.

  • MR Urography: For patients where CT/contrast is contraindicated. Sensitivity $75\%$ for tumours $< 2\,cm$.

  • FDG-PET/CT: Sensitivity $82\%$, specificity $84\%$ for nodal metastasis.

• Cystoscopy and Cytology: Urethrocystoscopy is essential to rule out concurrent bladder cancer. Barbotage cytology is preferred (detects up to $91\%$ of tumours).

• Urinary Markers: RNA-based and DNA methylation panels show promise. $ctDNA$ (plasma copy number burden $> 6.5$) may predict invasive disease.

• Diagnostic Ureteroscopy (URS): Targeted biopsy determines grade in $> 90\%$ of cases. However, URS with biopsy increases the risk of intravesical recurrence.

• Molecular Testing: Test for $FGFR2/3$ alterations in the metastatic setting for potential treatment with erdafitinib.

Risk Stratification for Clinical Decision-Making

• Low-Risk UTUC (All factors must be present):

  • Unifocal disease.

  • Tumour size $< 2\,cm$.

  • Negative for high-grade cytology.

  • Low-grade URS biopsy.

  • No invasive aspect on CT.

• High-Risk UTUC (Strong criteria; any must be present):

  • High-grade cytology or URS biopsy.

  • Local invasion on CT.

  • Histological subtype (e.g., micropapillary).

• Weak Criteria for High-Risk: Multifocal disease, tumour size $\ge 2\,cm$, and hydronephrosis (indicative but not definitive for invasion in low-grade cases).

Disease Management: Low-Risk Disease

• Kidney-Sparing Surgery: Preferred for low-risk disease to preserve renal function without compromising survival.

• Endoscopic Ablation: Using flexible ureteroscopes and lasers. Requires mandatory second-look URS within $8$ weeks.

• Percutaneous Antegrade Access: Consider for large or inaccessible renal pelvis tumours.

• Ureteral Resection: Segmental or distal ureterectomy. Distal ureterectomy for distal tumours has low recurrence rates ($0-18\%$).

• Chemoablation: Mitomycin-containing reverse thermal gel ($UGN-101$) showed a complete response (CR) rate of $58\%$. Adverse events include ureteric stenosis ($44\%\%$

Disease Management: Localised High-Risk Disease

• Radical Nephroureterectomy (RNU): Standard for high-risk UTUC. Includes en bloc removal of kidney, ureter, and bladder cuff.

  • Approach: Open, laparoscopic, or robotic approaches show similar oncological outcomes.

  • Bladder Cuff: Complete excision is mandatory. Endoscopic approaches may have higher recurrence risk.

  • Lymph Node Dissection (LND): Template-based LND may improve survival in muscle-invasive disease.

• Perioperative Treatments:

  • Neoadjuvant Chemotherapy (NAC): Cisplatin-based. Pathological CR rates $14-19\%$. Improved OS and CSS in meta-analyses.

  • Adjuvant Chemotherapy (AC): Gemcitabine-platinum combination (POUT trial). Significant improvement in DFS ($71\%$ vs. $50\%$ at $3$ years).

  • Intravesical Instillation: A single postoperative dose of chemotherapy (e.g., mitomycin C) within $2-10$ days reduces bladder recurrence risk by approximately $30\%$.

  • Adjuvant Immunotherapy: Nivolumab approved for $PD-L1\,positive\,(\ge 1\%)$ patients at high risk post-surgery.

Disease Management: Metastatic Disease

• First-Line Setting:

  • Enfortumab Vedotin (EV) + Pembrolizumab: The new standard of care (EV302 study). Significant improvement in PFS ($HR: 0.45$) and OS ($HR: 0.47$). Benefit regardless of cisplatin eligibility.

  • Cisplatin-Eligible (if EV+P unavailable): Gemcitabine-cisplatin plus nivolumab (CheckMate 901 study).

  • Cisplatin-Ineligible (if EV+P unavailable): Gemcitabine-carboplatin followed by maintenance avelumab for those who do not progress after $4-6$ cycles.

• Later-Line Setting:

  • Pembrolizumab: For platinum-resistant disease.

  • Erdafitinib: For patients with $FGFR2/3$ alterations after platinum therapy.

  • Novel Agents: Enfortumab vedotin (monotherapy) and Sacituzumab govitecan.

• Surgery: Palliative RNU for symptomatic control. Metastasectomy considered on an individual basis following response to systemic therapy.

Follow-Up and Quality Indicators

• Follow-Up Schedules:

  • Low-risk after RNU: Cystoscopy at $3$ months, then at $12$ months, then yearly for $5$ years.

  • High-risk after RNU: Cystoscopy/cytology at $3$ months, then every $3-6$ months for $2$ years, then yearly. CT urography and chest CT every $6$ months for $2$ years, then yearly.

  • After Kidney-Sparing: More intensive upper tract surveillance (CT urography + URS) required.

• Quality Indicators (QIs):

  • Achievement of "Pentafecta" in RNU: Negative margins, complete bladder cuff removal, no major complications, no recurrence at $12$ months, and tailored LND.

  • Hospital volume: Centers treating $> 6$ RNU cases per year show improved outcomes.