Diagnosis and Management of Upper Tract Urothelial Carcinomas

Dear Colleagues,

Upper urinary tract urothelial carcinoma (UTUC) represents approximately 5-10% of all urothelial malignancies and arises from the transitional cells lining the renal collecting system and ureter. The etiology of UTUC is multifactorial, with tobacco exposure being the most significant risk factor. Other important risk factors include occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons from industries such as textiles, printing, and petrochemicals. Chronic analgesic abuse, particularly phenacetin, has been strongly linked to UTUC development. Environmental exposure to aristolochic acid, most notably in regions with Balkan endemic nephropathy, significantly increases risks. Genetic factors also play a role, with Lynch syndrome (hereditary non-polyposis colorectal cancer) conferring a 22-fold increased risk of developing UTUC.

The diagnosis of UTUC typically begins with the evaluation of clinical symptoms, the most common being hematuria, present in 70-80% of cases. Flank pain, usually caused by obstruction or clot passage, occurs in 20-40% of patients, while some cases are discovered incidentally during imaging for unrelated conditions. The diagnostic workup relies heavily on imaging, with contrast-enhanced CT urography being the primary modality due to its ability to detect small masses and evaluate the entire urinary tract. Ureteroscopy with biopsy represents the gold standard for visual assessment and tissue diagnosis, allowing the direct visualization of the tumor and the collection of samples for histopathological evaluation. Urine cytology is specific to high-grade tumors and has limited sensitivity in low-grade lesions.

Risk stratification is crucial in treatment planning. UTUC is classified as low- or high-risk based on factors including tumor size, multifocality, grade on biopsy, invasion depth, and the presence of hydronephrosis. Molecular characterization is increasingly important, with low-grade tumors typically associated with FGFR3 mutations and high-grade tumors showing TP53 and RB pathway alterations.

The management of low-risk UTUC favors kidney-sparing approaches when feasible, including ureteroscopic ablation or resection, which preserves renal function. For high-risk disease, radical nephroureterectomy with bladder cuff excision remains one of the standards of care, often accompanied by lymphadenectomy to improve the staging accuracy and potentially also the therapeutic outcomes. Increasing evidence supports neoadjuvant platinum-based chemotherapy for locally advanced disease, showing survival benefits in selected patients.

Advanced or metastatic UTUC treatment relies on systemic therapies, with platinum-based chemotherapy being a first-line treatment. Immunotherapy with checkpoint inhibitors has revolutionized treatment for platinum-refractory disease, while targeted therapies such as erdafitinib for FGFR2/3-altered tumors are offering new options for specific molecular subtypes. Due to high recurrence rates, particularly in the bladder, rigorous surveillance protocols are essential following treatment, including regular cystoscopy, urinary cytology, and cross-sectional imaging.

Despite therapeutic advances, the prognosis for invasive UTUC remains challenging, with 5-year survival rates declining significantly with an increase in stage and grade. Ongoing research is focused on developing better biomarkers for early detection, refining risk stratification models, and identifying novel targeted therapies based on molecular profiling to improve outcomes in this challenging malignancy.

For this Special Issue, we welcome original research and review articles related to the diagnosis and treatment of UTUC.

Dr. Yao-Chou Tsai
Guest Editor

Dr. Shu-Yu Wu
Guest Editor Assistant

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• upper urinary tract urothelial carcinoma (UTUC)
• nephroureterectomy
• urinary tract biomarkers
• chemotherapy
• endoscopic management
• molecular profiling
• surgical treatment
• target therapy