TNM Staging (AJCC 8th edition)
| T stage | Definition |
|---|---|
| Ta | Non-invasive papillary carcinoma (confined to mucosa) |
| Tis | Carcinoma in situ |
| T1 | Invades lamina propria (subepithelial connective tissue) |
| T2 | Invades muscle |
| T3 | Renal pelvis — beyond muscularis into peripelvic fat or renal parenchyma; ureter — beyond muscularis into periureteric fat |
| T4 | Invades adjacent organs, or through the kidney into perinephric fat |
N stage: N0 (none); N1 (single node ≤2 cm); N2 (single node >2 cm, or multiple nodes). M stage: M0 / M1 (distant metastasis).
Natural History
At diagnosis, ~25% present as localized disease, >50% as regionally advanced, and ~20% as distant disease. Most occur in a single renal unit; synchronous bilateral UTUC is rare (<2%), but CIS increases the risk of bilateral and multifocal disease. Metachronous recurrence is ~80% after bladder cancer and 2–6% after contralateral UTUC. Spread routes:
- Lymphatic (depth-dependent) — renal pelvis/upper ureter drain to hilar then para-aortic/paracaval nodes; distal ureteral tumours drain to pelvic nodes.
- Hematogenous — most often liver, lung, and bone.
- Epithelial seeding — antegrade (more common; explains recurrence in a ureteral stump left after incomplete ureterectomy) and retrograde.
Diagnosis and Evaluation
Per the 2023 AUA UTUC guidelines, work-up includes a personal/family history (to identify Lynch syndrome), labs (selective ipsilateral upper-tract cytology and eGFR/serum creatinine), CT urography, cystoscopy, upper-tract endoscopy with biopsy, and universal histologic testing (IHC or microsatellite instability). FISH and retrograde pyelography are optional.
History and physical — the most common presenting sign is hematuria; flank pain is second (usually dull from gradual obstruction, occasionally colicky from clot passage). Many are asymptomatic, found incidentally. A personal/family history positive for Lynch-associated disease warrants genetic counselling referral and raises the possibility of contralateral involvement.
Labs:
- Selective ipsilateral upper-tract cytology supplements biopsy — high-grade cytology with a low-grade biopsy suggests higher-risk features were missed. High specificity (~90% selective) but low sensitivity (~50%), directly related to grade; reported by the 7-category Paris System. Collect before contrast (contrast and inflammation/stones cause false positives). Selective collection (barbotage or saline washings) is preferred over voided cytology to improve yield, avoid contamination from bladder/urethral disease, and avoid dilution from the normal contralateral unit.
- Renal function — serum creatinine/eGFR (MDRD or CKD-EPI); split-function testing if refined assessment is needed. With obstructing tumours, decompress (ureteric stent preferred over nephrostomy, which risks tract seeding) and rehydrate for 7–14 days before rechecking eGFR; contralateral atrophy can cause over-estimation of post-op function.
Imaging:
- Multiphase CT with excretory-phase urography is preferred (pooled sensitivity 92%, specificity 95%). If contrast-enhanced CT is contraindicated (e.g. eGFR <30, untreatable iodine allergy), use MR urography (less sensitive, similar specificity); if both are contraindicated, use retrograde pyelography with non-contrast axial imaging (US). Typical findings: radiolucent filling defect, non-visualization of the collecting system, obstruction. UTUC enhances on the arterial/early-nephrographic phase and is dark on the urographic phase, with more infiltrative features than RCC.
| Differential of an upper-tract filling defect |
|---|
| Tumour (UTUC, RCC, renal lymphoma, fibroepithelial polyp); blood clot; suburothelial hemorrhage; stone (higher HU than UC); renal papillary necrosis/sloughed papilla; hypertrophied papilla; inflammation; fungus ball; tuberculosis; polyureteritis cystica; retroperitoneal fibrosis |
- Metastatic staging — chest X-ray; bone scan only if bone pain, hypercalcemia, or elevated alkaline phosphatase; PET is not routine (selective use when contrast CT/MRI cannot be obtained).
Cystoscopy is mandatory (most UTUC associate with bladder cancer).
Upper-tract endoscopy ± biopsy allows direct visualization and biopsy. Indications: a radiographic mass/urothelial thickening, lateralizing hematuria, or suspicious selective cytology. It may be omitted when findings would not change management (severe comorbidity, or diagnosis already clear from HG cytology plus convincing imaging). Biopsy is by ureteroscopic forceps or fluoroscopic retrograde brush; small instruments limit specimen size, so the urologist's visual grade impression is correct only ~70% of the time. Diagnostic accuracy (Subiela 2020 meta-analysis, 23 studies, 2,232 patients): PPV for muscle-invasive 94%, NPV for non-invasive 60%; HG match 97%, LG match 66%; overall 32% undergrading and 46% understaging. Avoid scoping a normal contralateral tract (seeding/injury risk). Perforation risks extra-urinary seeding — stop and stent/decompress if it occurs; pre-stenting reduces injury risk.
- Universal histologic testing (IHC, microsatellite instability) identifies Lynch-associated/MSI-high tumours — relevant for checkpoint-inhibitor and cisplatin sensitivity and for germline testing.
- Percutaneous biopsy is safe/effective for lesions not amenable to endoscopic biopsy.
Positive upper-tract cytology with no visible lesion — first repeat to confirm (infection/stones cause false positives); then CT urography and cystoscopy. Treat a bladder tumour if found; if cytology stays positive after a negative/treated bladder, evaluate extravesical sites with selective cytologies (and prostatic urethral sampling in men) plus ureteropyeloscopy. Upper-tract CIS is a presumptive diagnosis made by unequivocally positive selective cytology in the absence of radiographic/endoscopic findings.
Risk Stratification of Localized UTUC
The 2023 AUA guideline stratifies into low- vs high-risk of progression/≥pT2 disease, based primarily on biopsy grade (HG biopsy predicts ≥pT2: PPV 60%, NPV 77%), then sub-stratified favorable vs unfavorable using:
- Cytology;
- Radiographic appearance — multifocality, size, invasive features (heterogeneous texture suggests invasion), urinary obstruction, locoregional progression (suspicious nodes), and metastatic disease;
- Endoscopic appearance — sessile/papillary/flat, multifocality, and size (tumours ≥1.5 cm carry >80% risk of invasive disease);
- Lower-tract involvement — panurothelial disease (prior cystectomy, concomitant/metachronous lower-tract UC, or contralateral UTUC).
Self-Test
1. What is the differential diagnosis of a filling defect in the collecting system? Tumour, blood clot, stone, sloughed papilla, fungus ball, inflammation, suburothelial hemorrhage, tuberculosis, polyureteritis cystica, retroperitoneal fibrosis (and external compression/overlying bowel gas as artifacts).
2. What is the preferred imaging modality, and what are its test characteristics? Multiphase CT with excretory-phase urography — sensitivity ~92%, specificity ~95%.
3. What are the test characteristics of selective upper-tract cytology, and when should it be collected? High specificity (~90%) but low sensitivity (~50%), proportional to grade; collect before any contrast to avoid false positives.