- ≈90% of upper tract tumours are urothelial carcinoma; tumors of the renal pelvis are slightly more common than ureteral tumors (1.2 vs. 0.8/100,000 person-years).
- Ureteral tumours occur more commonly in the lower ureter (70%) than mid (25%) or upper (5%) ureter, likely reflecting downstream implantation.
- M:F incidence ratio is 2:1 (unlike bladder cancer which is 4:1); peak incidence is in the 7th–8th decade; presentation age <60 should raise concern of hereditary UTUC as part of Lynch syndrome.
- Lynch syndrome (HNPCC) accounts for 7–20% of U.S. UTUC cases; patients are younger (mean age 55) and more likely to be female.
- Aristolochic acid (Aristolochia fangchi, A. clematitis) is unique to UTUC risk and is implicated in Balkan endemic nephropathy and Chinese herb nephropathy.
- Cigarette smoking is the most important modifiable risk factor for UTUC; smoking cessation decreases subsequent risk.
- 2–4% of bladder cancer patients subsequently develop UTUC; ≈30% of UTUC patients subsequently develop bladder cancer after nephroureterectomy or nephron-sparing procedures; risk factors for subsequent UTUC after cystectomy include CIS, multifocal tumors, prior UTUC, positive ureteral margin, and prostatic/female urethral involvement (N0 status is NOT a risk factor).
- AJCC 8th edition T-staging: Ta (non-invasive papillary), Tis (CIS), T1 (lamina propria), T2 (muscle), T3 (peripelvic/periureteric fat or renal parenchyma in pelvis), T4 (adjacent organs/perinephric fat).
- Stage (>pT2) is the most important prognostic factor for survival and the most significant predictor of metastases; high-grade tumour on URS biopsy has 60% PPV and 77% NPV for muscle-invasive disease at final pathology.
- Tumors ≥1.5 cm are associated with a >80% risk of invasive disease; tumors <1.5 cm may be optimal for endoscopic ablation.
- Differential of an upper tract filling defect includes: tumour, blood clot, suburothelial hemorrhage, stone, sloughed papilla, hypertrophied papilla, inflammation, fungus ball, tuberculosis, polyureteritis cystics, and retroperitoneal fibrosis.
- Preferred imaging is multiphase CT with excretory phase (sensitivity 92%, specificity 95%); MR urography is used if contrast-enhanced CT is contraindicated (e.g., eGFR <30).
- Cytology has high specificity (~90% with selective cytology) but low sensitivity (~50%); sensitivity is directly related to tumor grade; selective cytology should be collected before contrast use to avoid false positives.
- AUA risk stratification divides UTUC into low-risk and high-risk (further sub-stratified favorable vs. unfavorable) based on biopsy grade, cytology, radiographic and endoscopic appearance, multifocality, size, and lower tract involvement.
- Radical nephroureterectomy with complete bladder cuff excision and lymphadenectomy is the standard of care for high-risk UTUC; the entire intramural ureter and ureteral orifice must be excised due to a 30–75% recurrence risk in a remaining ureteral stump.
- Distal ureterectomy with ureteral reimplant is preferred for HR and unfavorable LR cancers confined to the lower ureter in a functional renal unit.
- UGN-101 (mitomycin in reverse thermosensitive polymer; Jelmyto) is approved for primary chemoablation of low-grade UTUC (OLYMPUS trial: ≈60% complete response at 3 months; 44% ureteric stenosis); carries an FDA label warning for ureteral obstruction, bone marrow suppression, and embryo-fetal toxicity.
- POUT trial established adjuvant gemcitabine-cisplatin (or gem-carbo if GFR 30–49) after RNU for pT2–T4 or pN+ UTUC, improving 3-year DFS by 21% (71% vs. 46%, HR 0.45); CheckMate 274 supports adjuvant nivolumab for high-risk disease after RNU.
- ODMIT-C trial showed a single postoperative intravesical dose of MMC at catheter removal reduces 1-year bladder tumour risk by 11% (16% vs. 27%) after nephroureterectomy.
- The risk of contralateral upper tract recurrence after RNU is ≈2%; most bladder recurrences occur within the first 2 years (median 6–12 months); intra-abdominal recurrence in low-risk patients is very low.
- Most common sites of hematogenous metastases are liver, lung, and bone; lymphatic drainage of renal pelvis/upper ureter is to para-aortic/paracaval nodes, while distal ureteral tumors drain to pelvic nodes.