Upper tract urothelial carcinoma (UTUC) refers to urothelial tumours arising from the lining of the renal calyces, renal pelvis, or ureter. It is uncommon, so outcome data are limited. Panurothelial disease describes disease involving the bladder plus two extravesical sites — in males this may include one or both upper tracts and/or the prostatic urethra; in females, the bladder plus both upper tracts.
Epidemiology
- Incidence — relatively rare: ~2/100,000 person-years (~7,000 US cases/year). Renal pelvis tumours are slightly more common than ureteral (1.2 vs 0.8/100,000). Ureteral tumours favour the lower ureter (70%) over the mid (25%) and upper (5%) ureter, likely reflecting downstream implantation. Incidence is higher in Balkan countries.
- Age — peak in the 70s–80s (older than bladder cancer). Presentation at <60 years should raise concern for hereditary UTUC (Lynch syndrome).
- Sex — M:F 2:1 (vs 4:1 for bladder cancer).
- Race — US Whites are ~2× more likely than Blacks to develop UTUC.
Risk Factors
Hereditary — Lynch syndrome (HNPCC): accounts for 7–20% of US cases. Affected patients are younger (mean 55 years) and more often female.
Acquired — shared with bladder cancer:
- Cigarette smoking — the most important modifiable risk factor; cessation lowers subsequent risk.
- Occupational exposure — aromatic hydrocarbons (chemical, petrol, plastic industries; coal, asphalt, tar).
- Chronic inflammation/infection/iatrogenesis — chronic infection with stones/obstruction is linked to squamous cell carcinoma (less often adenocarcinoma).
- Alkylating chemotherapy — cyclophosphamide or ifosfamide.
- Analgesic abuse — phenacetin is best described (also codeine, acetaminophen, aspirin); cases have fallen since phenacetin was replaced by acetaminophen.
- Arsenic — e.g. artesian-well drinking water.
- History of bladder cancer — most UTUC are secondary tumours presenting after NMIBC; still, only 2–4% of bladder cancer patients later develop UTUC (interval 17–170 months). Bladder cancer after UTUC is more common than the reverse (downstream seeding, longer carcinogen exposure, greater urothelial cell number).
Acquired — unique to UTUC: aristolochic acid (Aristolochia fangchi and A. clematitis) — mutagenic; implicated in Balkan endemic nephropathy and Chinese herb nephropathy. These plants grow as weeds in Balkan wheat fields; Balkan endemic nephropathy incidence is falling.
Risk factors for subsequent UTUC after cystectomy for bladder cancer: low-grade tumours, non–muscle-invasive tumours, presence of CIS, multiple urothelial recurrences, multifocal tumours, prior UTUC, positive ureteral margin, and prostatic/female urethral involvement (Picozzi 2012 meta-analysis, 27 studies, 13,185 patients). Long-term upper-tract surveillance is therefore important in bladder cancer patients.
Embryology
The bladder is derived from endoderm; the ureter and renal pelvis are derived from mesoderm.
Histology
The upper-tract urothelium resembles that of the bladder except for a markedly thinner muscle layer and proximal abutment of the urothelium to the renal parenchyma. The urothelial layer is continuous from the calyces to the distal ureter and may extend into the collecting ducts (raising the possibility that collecting-duct renal cancers are related to urothelial cancers). The calyceal/pelvic walls have fibrous tissue and two smooth-muscle layers; the ureter's three muscle layers merge with the bladder's three.
Benign / pre-malignant:
- Papillomas and inverted papillomas — generally benign but associated with synchronous/metachronous UTUC; follow inverted papilloma for ≥2 years.
- Von Brunn nests — reactive proliferation, a variant of normal urothelium.
- Metaplasia and dysplasia — UTUC often progresses hyperplasia → dysplasia → CIS.
Malignant:
- Urothelial carcinoma — 90% of upper-tract tumours. Histologically similar to bladder UC, but the thin muscle layer may allow earlier invasion; UTUC is more often invasive and poorly differentiated, though stage-matched outcomes are comparable to bladder UC. Reported variants (squamous, glandular, sarcomatoid, micropapillary, neuroendocrine, lymphoepithelial) are aggressive but — unlike bladder cancer — variant histology has not independently predicted poor outcome after adjusting for clinicopathologic features.
- Squamous cell carcinoma — associated with chronic inflammation, infection, and analgesic abuse; typically more aggressive at presentation; ~6× more common in the renal pelvis than ureter.
- Adenocarcinoma — rare; associated with chronic inflammation, calculi, and chronic obstruction.
Self-Test
1. What are the risk factors for UTUC? Smoking, occupational exposure, chronic inflammation, cyclophosphamide, analgesic abuse, Lynch syndrome, aristolochic acid (Balkan/Chinese herb nephropathy), and arsenic.
2. Which other malignancies are associated with Lynch syndrome? Colonic (most common), endometrial (second most common), prostate, urothelial, adrenal, gastric, pancreatic, uterine, ovarian, and sebaceous carcinomas.
3. What is the risk of subsequent UTUC after bladder cancer, and of subsequent bladder cancer after UTUC? ~2–4% of bladder cancer patients later develop UTUC; ~30% of UTUC patients later develop bladder cancer after nephroureterectomy or nephron-sparing surgery.
4. After cystectomy for bladder cancer, which of these is NOT a risk factor for subsequent UTUC: CIS, N0 status, high-grade tumours, or prostatic/female urethral involvement? N0 status is not a risk factor (the others are).