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Background

UTUC by the numbers

• Bilateral: 1-5%
• Multifocal: 10-20%
• History bladder cancer: 4-41%, depending on population
• Disease recurrence: 22-47% in bladder, 2-6% in contralateral renal unit
• Spread: 60% are invasive, 7% are metastatic

Risk Factors

• Lynch syndrome (HPNCC): suspect if UTUC and age < 60, or first degree relatives x2 with HPNCC-related cancers (colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer), Amsterdam II criteria (3+ relatives w/ HPNCC cancer, 2+ generations affected, 1+ tumors before 50yo)
• Tobacco: increases risk 2.5-7x
• Occupational: exposure to aromatic amines increases risk 4-5.5x
• Aristolochic acid (Chinese herb) nephropathy: Aristolochia fangchi produces a compound that induces p53 mutation, resulting in ESRD and UTUC
• Arsenic: associated with UTUC and peripheral vascular disease (blackfoot disease)
• Inflammation: chronic upper tract irritation from stones or UTI increases cancer risk

Standard ureteroscopy reporting, from AUA Guidelines

Risk stratification, from AUA guidelines

Probability of non-organ confined disease, from Margulis et al

Follow-up after initial management, from AUA guidelines

Initial Evaluation

Workup

• Symptoms: hematuria (56-98%), flank pain (20-30%), lumbar mass (10%) - incidental diagnosis (15%)
• Initial evaluation: cystoscopy (asssess for synchronous bladder cancer) and upper tract imaging (CT/MR), ultrasound not recommended for initial evaluation
• Hydronephrosis: seen with invasive ureteral tumors in 80%
• Positive lymph nodes: high specificity (91%) vs low sensitivity (25%) for pathologic disease, consider systemic treatment if concern for LN+ disease prior to surgery (per Pallauf 2023)
• Further imaging: obtain only if concern for high-grade or invasive disease - obtain chest imaging, bone scan and brain imaging on select patients
• Genetic testing: 7-20% have Lynch syndrome, genetics referral recommended if < 60yo, personal/family history of UTUC or Lynch syndrome cancers

Endoscopic diagnosis

• Ureteroscopy: recommended unless diagnosis can be made from combination imaging and cytology, do not perform if biopsy will not affect management (expectant management), tissue diagnosis relatively accurate (Sens 83-91%, Spec 88-100%), can be performed antegrade if necessary (potential risk of tract seeding)
• Ureteroscopy risks: stricture (5-25%, more common with cautery than laser), perforation (uncommon), seeding (rare)
• Cytology classification (Paris System): nondiagnostic, negative for HG cells (NHGUC), atypical (AUC), suspicious (SHGUC), HGUC, low-grade urothelial neoplasm (LGUN), and other malignancies
• Recurrence after endoscopic complete resection: 30-50% at 5yr, 20-30% will require NUx

Ureteroscopy tips

• Biopsy options: use stone basket or forceps (Piranha, BIGopsy), brush, laser (with basket), or loop resection if performing antegrade
• Unable to access tumor: consider pre-stenting and returning, consider cytology only (collect prior to retrograde pyelogram), consider antegrade access
• Synchronous bladder tumor: resect at same time as upper tract lesion
• Contralateral ureteroscopy: not recommended if imaging otherwise negative - potential risk for seeding

Post-diagnosis evaluation

• Risk group assessment: see table from AUA guidelines to help determine best treatment option
• Nephrology evaluation: potential postoperative risk for CKD, consider if baseline GFT < 45 or patient has proteinuria

Organ-sparing treatments

Endoscopic ablation

• Absolute indications (all must be present): low grade pathology, no high grade cytology, papillary (not sessile), tumor < 1.5cm, solitary tumor, no invasion on iamging, no variant histology, no hydronephrosis, no prior cystectomy for HG bladder cancer
• Relative indications (not required): poor renal function, solitary kidney, poor surgical candidate, bilateral tumors, favorable HR or unfavorable LR with low tumor burden (< 1.5cm)
• Tips: can perform antegrade/retrograde, assess for recurrence at 3 months
• Adjuvant intraluminal chemotherapy: evidence extrapolated from bladder cancer data, can instill via nephrostomy tube, ureteral catheter, or into bladder with double-J stent

Jelmyto (Mitomycin hydrogel)

• Indications: Ta, T1, or CiS
• Technique: can administer antegrade/retrograde, stays in kidney then dissolves (reverse thermal gel), administer weekly for 6 weeks, 58% showed complete response at 3mo (56% sustained response at 12mo)
• Tips: wait 3-4wks after endoscopic surgery, do not perform if perforation, check CBC each time, alkalinize urine (1.3g NaBicarb night before and morning of), measure renal pelvis volume with contrast
• Side effects: ureteral stenosis/stricture (44%), UTI (32%), hematuria (31%), flank pain (30%), nausea (24%), myelosuppression (3%), contact dermatitis

BCG

• Indications: HR favorable disease after complete resection or CiS
• Efficacy: questionable, depends on the study
• Side effects: cystitis, stricture, sepsis, renal TB, stricture, pericarditis

Watchful waiting

• Indications: significant comorbidities/risk of mortality, high risk for ESRD with any interventions
• Symptomatic progression: bleeding, obstruction, infection, pain - palliative options may be limited when these occur

Excisional surgeries

Nephroureterectomy

• Indications: HR disease and able to tolerate surgery
• Principles: complete excision of ipsilateral urothelium, removal of bladder cuff, avoidance of urinary spillage,
• Bladder cuff: decreases recurrence risk (otherwise 16-58%), excisional technique preferred over transurethral (higher recurrence risk, more difficult to give intravesical chemotherapy if bladder not closed)
• Nephroureterectomy with bladder cuff is gold standard for any high-grade or invasive lesions, prevents ipsilateral recurrence (15-44%), low risk for contralateral recurrence (< 8%)
• Intravesical chemotherapy: give single dose mitomycin or gemcitabine immediately postoperatively to decrease risk for bladder cancer
• Not taking bladder cuff: recurrence risk 16-58%
• 5yr survival after nephroureterectomy: Ta/T1 60-90%, T2 43-75%, T3 16-33%, T4 0-5%, N1+ 0-4%, M1+ 0%

Distal ureterectomy with reimplant

• Indications: tumor isolated to lower-third of ureter, bladder mobile with good capacity for reimplant
• Tips: use only for distal third of ureter, unclear benefit to non-refluxing reimplant

Segmental ureterectomy

• Indications: < 1cm tumor requiring resection of < 2cm
• Tips: reanastomose over a stent, avoid tumor spillage, send frozen margin to confirm prior to anastomosis

Other surgical options

• Partial nephrectomy: need to be able to remove portion of collecting system without urine leak
• Ureterectomy + ileal ureter: poor candidate for segmental ureterectomy, has higher risk for complications

Lymph node dissection

• Indications: high grade, high risk, potentially invasive
• Volume: recommended to remove 8+ nodes to confirm pN0 status
• Renal pelvis tumor template: remove from renal vein to at least IMA and overlying ipsilateral great vessel
• Proximal/middle ureter template: remove from renal vein to aortic bifurcation and overlying ipsilateral great vessel
• Distal ureter template: remove external iliac and obturator nodes, remove internal and common iliac nodes as indicated

Non-Surgical Treatments

Peri-Surgical Chemotherapy

• Neoadjuvant chemo: complete response rate 14-19%, indicated if postoperative eGFR will be < 60 or other postoperative factors will prevent receiving cisplatin-based chemotherapy
• Perioperative intravesical chemo: instill at time of surgery or up to 48 hours afterwards, can use mitomycin or gemcitabine, per ODMIT-C trial (O'Brien et al), 1 dose mitomycin immediately postoperatively decreased bladder cancer risk from 27% to 17% at 1yr
• Adjuvant chemo: indicated if no neoadjuvant chemotherapy and pT2-T4 or N1-N3, per POUT trial (Birtle et al) it improves disease-free survival (HR=0.48 at 30mo), can use gem/cis (GFR > 50) or gem/carbo (GFR < 50)

Adjuvant nivolumab

• Indications: neoadjuvant chemo was given and path shows ypT2-4 or ypN+ or patients who are ineligible/refuse adjuvant cisplatin
• Side effects: pruritus (23%), fatigue (17%), diarrhea (17%), elevated lipase/amylase (3-5%), colitis (1%), pneumonitis (1%)

Metastatic disease (cN1-3 or c/pM+)

• Management: systemic chemotherapy over up-front surgery, consider surgery adequate radiographic response
• XRT: indicated only for symptom control