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

• Upper tract is 5-10% of all urothelial cancer
• 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
• 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
• If unable to get CT IVP, retrograde pyelogram (RPG)
• Similar diagnostic accuracy - 96-97% sensitivity/specificity
• MR urogram 2nd line after 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
• Cystoscopy to rule out bladder tumor
• Ureteroscopic biopsy if need further confirmation

Low risk - consider endoscopic management

• Unifocal disease < 2 cm
• Low grade cytology/biopsy
• Noninvasive on CT

Kidney-sparing management

• Offer to all low-risk disease
• Imperative indications - solitary kidney, bilateral tumors, renal insufficiency, medical co-morbidities contraindicating major surgical procedures
• Will need stringent surveillance - URS every 3 months
• Can consider upper tract BCG for CIS in some patients
• Mitogel (upper tract mitomycin C) for LG (6 weekly treatments) 
  • 60% complete response in low grade tumors. (very expensive, 30% rate of severe adverse events, of which 44% are stricture)

High risk - nephroureterectomy

• Tumor > 2 cm, hydro, multifocal disease
• High grade cytology/biopsy
• Variant histology
• Prior radical cystectomy for high grade bladder cancer

If in ureter, could treat with uretero-ureterostomy (distal ureterectomy below level of iliacs is most realistic)

• For low risk disease that cannot be treated endoscopically completely
• High risk disease when kidney sparing is desired (must make sure no proximal tumor) (weak recommendation)

Radical nephroureterectomy with bladder cuff excision

• Concomitant adrenalectomy does not affect oncologic control unless suspected to be involved
• Must remove entire distal ureter (intramural + UO) with bladder cuff
• Can cauterize UO during cystoscopy; make an intramural tunnel with help of a ureteral catheter, then retract ureter and staple
• Stapling interferes with analysis of distal margin/higher risk of positive margin and decreased survival. Contraindicated in distal ureteral tumor.
• Intussusception
• Lymph node dissection templates similar to RPLND
• Renal hilar/aortocaval if renal pelvis tumor; pelvic if ureteral tumor
• Similar to bladder cancer - prognostic and therapeutic value in T2-T4 invasive disease.
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• Single dose of intravesical chemotherapy after nephU a/w lower risk of bladder recurrence (20% vs 35%)
• Gemcitabine 2g in 100cc NS
• Conservative treatment - recurrence rate 30-50%
• 7% recurrence rate in ipsilateral kidney, 50-70% recurrence in the bladder
• 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%
• Evidence stronger for adjuvant (level 1) than neoadjuvant chemo (level 2)

Metastatic disease

• 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