UTUC - Urothelial/transitional cell cancer of the upper tract (ureter, kidney)

• Upper tract is 5-10% of all urothelial cancer; 7000 US cases/year
• Patients are typically older than in bladder cancer > 70 yo; M:F 3:1
  • Younger than 60 - think of Lynch syndrome/HNPCC (hereditary upper tract TCC), esp. if two 1st degree relatives with Lynch-associated cancers (e.g. colon, GI, endometrial, ovarian, skin)
    • Lynch syndrome - consider yearly screening UA after 30 yo
    • 5% prevalence of UTUC in Lynch syndrome - all path should be tested for MSI
• Risk factors: Smoking, analgesic abuse, arsenic/hydrocarbons, chronic inflammation, Lynch syndrome, aristocholic acid (Balkan/Chinese herb nephropathy)
  • Aristocholic acid innures proximal tubules -> chronic tubulointerstitial disease
  • UTUC is 20-25% of UC in Taiwan (also higher arsenic exposure)
• Mortality rate ~ 50%

Natural history

• Renal pelvis tumors > ureteral tumors 2:1
  • Ureteral tumors more commonly distal (downstream seeding) - must remove entire ureter during nephroureterectomy
• Multifocal 20%
• Concurrent bladder cancer 20%
• Recurrence in bladder 20-50%
• Contralateral recurrence 2-6%
• Invasive at diagnosis 60% (vs 15-25% of bladder cancer)
• Poor prognosis; 20% present with metastatic disease
• Metastasis: renal hilar/para-aortic/para-caval/inter-aortocaval lymph nodes (depending on location of disease), liver, lung, bone
• Genetically most similar to luminal bladder cancer (eg FGFR3 mutations, investigating erdafitinib, infigratinib)
• ~5% of patient with bladder cancer have upper tract recurrence (esp if high grade)

Staging

• Realistically not going to be able to stage disease with biopsy
  • Biopsy only accurately assesses stage in 72%
• Grade is surrogate for stage - high grade is bad (clinical staging almost irrelevant...)
• Preoperative poor prognostic factors: > 3 cm, multifocality, grade, advanced age

• Hematuria (75%)
• Flank pain (30%) (obstruction by tumor or clot)
• 15% asx/with incidental detection

• CT IVP - look for filling defects in urinary tract, obstruction, incomplete filling
  • Soft tissue HU 40-50
  • Limited spatial resolution 2-3mm - will miss smaller tumors
• MR urogram if can't get CT urogram
  • T1 isoattenuating, T2 hyperattenuating
  • Gadolinium contraindicated for CrCl < 30 ml/min
  • T2 turbo spin echo (TSE) - intrinsic high signal of urine
  • Sensitivity not as good (70-80%), 98% specificity
• If unable to get CT/MR, retrograde pyelogram (RPG) - 96-97% sensitivity/specificity
• Cystoscopy to rule out bladder tumor
• Ureteroscopic biopsy if need further confirmation

Risk stratification

(risk of invasive disease pT2 or greater)

(AUA 2023 guidelines)

Endoscopic management/kidney-sparing

• Indications for tumor ablation
  • Preferred management for LR favorable UTUC
  • Can be offered as initial treatment for LR unfavorable
  • Only in select patients with HR favorable disease - low-volume tumors or cannot undergo RNU
    • E.g. - solitary kidney, bilateral tumors, renal insufficiency, medical co-morbidities contraindicating major surgical procedures
  • Tumors < 1.5 cm in size (larger tumors associated with higher risk of invasive disease, lower disease-specific survival)
• ~ 25% recurrence within ipsilateral urinary tract, 15% in bladder
• Surveillance
  • Should have repeat endoscopic evaluation within 3 months to confirm successful treatment
    • Should repeat at 6 mo and 1 year, and then PRN for symptoms or upper tract imaging findings
  • Continue cystoscopy surveillance based on risk stratification
  • CT IVP q3=6 mo for 2-3 years (based on risk), annually up to 5 years
• Can consider upper tract BCG (antegrade through PCN, retrograde through ureteral catheter, or intravesical with JJ stent in place), for HR after complete ablation or CIS
• Jelmyto - chemoablation (mitomycin)
  • Weekly instillation x 6, through PCN
    • Wait 1 week after PCN placement before starting, and 1 week after completion before removing
  • 59% complete response rate in LG tumors 5-15 mm; ~20% rate of ureteral narrowing/stricture
  • Risk for ureteral obstruction, bone marrow suppression

Nephroureterectomy or segmental resection

• Indications
  • High risk disease
  • LR that cannot be treated endoscopically
  • LR with evidence of risk group progression (e.g. becoming multifocal or obstructing)
• Ureterectomy - make sure no tumor elsewhere in tract
  • Distal ureterectomy - best for tumors in distal third of ureter, mobile bladder
  • Segmental ureterectomy - best if can resect < 2 cm ureteral length 
• ​​​​​​​Radical nephroureterectomy with bladder cuff excision
  • Preop - nephrology consultation for GFR < 45, definitely for GFR < 30; optimize risk factors for CKD (diabetes, HTN, smlking)
  • Concomitant adrenalectomy does not affect oncologic control unless suspected to be involved
  • Must remove entire distal ureter (intramural + UO) with bladder cuff
  • Lymph node dissection for HR disease
    • Renal hilar/aortocaval if renal pelvis tumor; pelvic if distal ureteral tumor
    • Similar to bladder cancer - prognostic and therapeutic value in T2-T4 invasive disease.
    • 
    • 
  • Single dose of intravesical chemotherapy after nephU a/w lower risk of bladder recurrence (20% vs 35%)
    • Gemcitabine 2g in 100cc NS
• Role for neoadjuvant therapy - limited data mostly retrospective
  • Consider future renal function - cisplatin eligibility rate (GFR > 45) declines from 80% → 55% after nephU
  • Risk for overtreating
  • Mostly based on bladder cancer data or retrospective data - 11% complete response, ~40% partial response/downstaging with NAC. Improves chance of cure with nephU from ~50 to 60-70%?
    • Prospective phase II 2019 trial - 30 pts with HG UTUC got neoadjuvant MVAC, 14% had complete pathological response, 60% were non-muscle invasive on final path
• Consider adjuvant chemo for anyone ≥ pT2 and did not get NAC
  • POUT trial - adjuvant gem/cis x 4 cycles improved 3-year survival from 67% to ~79%
  • Adjuvant nivolumab could also be used
  • Evidence stronger for adjuvant (level 1) than neoadjuvant chemo (level 2)
• Surveillance
  • Cystoscopy based on risk stratification (36% recurrence in bladder)
  • < T2: CT A/P at 6 mo, annually for 5 years
  • >= T2: CT CAP q6 mo x 3 years, annually for first 5 years

Advanced/metastatic disease

• Node positive disease - treat with systemic therapy; can do consolidative RNU if partial/complete response
• Similar to bladder UC treatment
• Cisplatin-based combination chemotherapy superior to carboplatin or single agent chemo
• Maintenance avelumab if good response to platin-based therapy
• If not able to tolerate cisplatin,
  • PD-1 inhibitor pembrolizumab, nivolumab
  • PD-L1 inhibitor atezolizumab
• If cisplatin-refractory and FGFR mutation, give erdafitinib

Follow-up