Emma F.P. Jacobs, MD
Michael O. Koch, MD, FACS
BASICS
DESCRIPTION
Urothelial carcinoma (formerly known as transitional cell carcinoma or TCC) is an epithelial neoplasm of the ureter, renal pelvis, and calyces
EPIDEMIOLOGY
Incidence
• 5–10% of renal tumors are renal pelvis TCC
• 2–5% of urothelial tumors occur in the upper urinary tract (UUT)
• Peak incidence of 10 per 100,000/yr in 75–79 age group
• Mean age at presentation is 65, seldom appear before age 40 yr.
• Incidence is increasing.
Prevalence
Poor data available given rarity of condition
RISK FACTORS
• Bladder cancer (2–4% lifetime risk of UUT TCC)
– Stage, grade, multiplicity, ureteral reflux, recurrent CIS after BCG, and TCC close to ureteral orifice all increase likelihood of UUT TCC in patient with bladder TCC
• Contralateral UUT TCC (1.6–6% risk)
• Risk factors shared with bladder TCC:
– Cigarette smoking (≥3 times risk; only partly declines with smoking cessation)
– Occupational exposure (≥4 times risk):
Aniline dyes, β-naphthylamine, benzidine, coal, coke, asphalt, or tar exposure; chemical, petroleum, or plastics industries
– Cyclophosphamide:
Mesna (Uro-protectant) can be coadministered to neutralize acrolein (urotoxic metabolite)
• Other risk factors specific to UUC TCC:
– Balkan nephropathy (100–200 times risk):
Typically bilateral, multifocal, low-grade
May be environmental rather than genetic
– Analgesic abuse (3.6 times risk):
Phenacetin, aspirin, acetaminophen, codeine
Papillary necrosis (6.9 times risk):
Synergistic with analgesic abuse (20 times risk)
– Chinese weight-loss herb Aristolochia fangchi
Genetics
• Male > Female (3:1)
• White > Black (2:1)
• Lynch II syndrome (HNPCC): Familial syndrome predisposing to GI, endometrial, and UUT neoplasms
PATHOPHYSIOLOGY
• Growth patterns include papillary and nodular
• TMN staging (stage is most important predictor of survival)
– Stage Ta: Papillary, noninvasive
– Stage Tis: CIS
– Stage T1: Invades subepithelial connective tissue
– Stage T2: Invades muscularis
– Stage T3: Invades periureteral fat (renal pelvis only, and/or invades beyond muscularis into perinephric fat or the renal parenchyma
– Stage T4: Invades adjacent organ or through kidney into perinephric fat
ASSOCIATED CONDITIONS
• Bladder TCC: 30–50% risk of developing bladder TCC after UUT TCC
• Balkan nephropathy
• Lynch II syndrome
GENERAL PREVENTION
Avoidance of risk factors
DIAGNOSIS
HISTORY
• Gross hematuria, dull flank pain, acute renal colic, weight loss, anorexia, bone pain
• Social history: Tobacco use, occupational exposures
• Medications: Analgesics (i.e., phenacetin, aspirin), cyclophosphamide, exotic herbs
• Family history: Balkan family, colonic malignancy
PHYSICAL EXAM
• Often asymptomatic
• CVA tenderness
• Flank or abdominal mass
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urine analysis: Gross or microscopic hematuria (60–90% present with hematuria)
• Electrolytes, LFTs normal in absence of urinary obstruction, or metastatic disease
• Voided urine cytology: Low sensitivity for low-grade TCC; better for high-grade, CIS
Imaging
• Intravenous urogram (IVU) or intravenous pyelogram (IVP):—traditional diagnsotic study largely replaced by CT Urograms
• Retrograde pyeloureterography
– Indications: Contrast allergy, renal insufficiency
– More sensitive than IVU or computerized tomographic urography (CTU)
– Use dilute contrast (1/2–1/3).
– Inject through cone-tip or open-ended catheter to fill entire collecting system (10–15 cc).
– Avoid contrast extravasation due to overfilling.
• Computerized tomographic urography (CTU):
– 3D reconstruction image quality is equivalent to IVU for UUT TCC.
– Can differentiate renal parenchymal mass from extrinsic mass, and TCC from calculus
– Can evaluate for locoregional or distant metastatic disease
• Ultrasound (US):
– Can help distinguish stone from tumor in the setting of a fillling defect in the upper urinary tract
Diagnostic Procedures/Surgery
• Cystoscopy: Evaluates lower urinary tract for concomitant TCC
• Ureteroscopy: Provides direct visualization of UUT TCC, aspiration for cytology, cup/basket biopsy, and treatment simultaneously
• Catheterized ureteral or RP washing: 65–73% sensitive
• Ureteroscopic cup/basket biopsy: Most sensitive
• Brush biopsy: 91% sensitive, 88% specific
Pathologic Findings
• Pathologic staging of UUT TCC is difficult due to the limited size of biopsy specimens.
• Staging is predicted by biopsy grade.
• Tumor grade may be a more important prognostic factor than pathologic stage in UUT.
• Sending all biopsies for cytopathologic exam can improve the diagnostic yield (cell block).
DIFFERENTIAL DIAGNOSIS
• TCC is the most common malignant cause of UUT filling defects
• Squamous-cell carcinoma—Often associated with stones and recurrent infections
• Rare malignant tumors (adenocarcinoma, sarcoma, angiosarcoma, and carcinosarcoma)
• RCC—Typically found in conjunction with renal mass; has been reported without associated renal mass as a filling defect in the collecting system
• Benign filling defects of the ureter and renal pelvis:
– Air: Iatrogenic, infectious, fistula
– Blood clot
– Fibroepithelial polyp
– Fungus ball
– Hemangioma
– Inflammatory lesions: Granuloma, malakoplakia, TB
– Inverted papilloma
– Radiolucent calculus
– Rare benign tumors: Leiomyoma, neurofibroma, cholesteatoma
– Renal papilla—Ectopic or end on
– Sloughed papilla
– Extrinsic compression of the ureter
– Mucous (urinary diversion patients)
– Protein matrix
– Ureteritis or pyelitis cystica
– Vascular impression
TREATMENT
GENERAL MEASURES (2)
• Surgical excision is gold standard.
– Preservation of renal unit is preferred when possible (low-grade focal disease) or involving the distal ureter (low- or high-grade disease)
MEDICATION
First Line
• Limited role, benefit has not been consistently demonstrated
– Topical therapy- BCG, mitomycin, thiotepa
Instilled via percutaneous nephrostomy, external urethral catheter, or into bladder with indwelling ureteral stent
Typically given for large, multifocal, or residual tumor burden
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Open radical nephroureterectomy (RNU) with en-bloc excision of peri-ureteric bladder cuff:
– Traditional treatment
– Provides adequate surgical margins, local control, removes need for ipsilateral ureteroscopic surveillance, provides most accurate staging information
– Role of lymphadenectomy is unclear
• Laparoscopic RNU
– Equivalent disease-specific and overall survival compared to open RNU
– Skin incision positioned to allow for distal ureteral dissection and en-bloc specimen removal
• Nephron-sparing surgery—For locally contained low-grade disease or high-grade disease with overwhelming concern for loss of renal function
– Segmental ureterectomy
– Used for noninvasive low-grade TCC of proximal or mid ureter too large for endoscopic ablation
– Distal ureterectomy with reimplantation
Used for distal ureteral TCC to large for endoscopic ablation or high-grade TCC
• Endoscopic treatment
– Indications include solitary kidney, bilateral disease, poor renal function, moderate tumor burden, low-grade disease, high-risk surgical candidates
– Retrograde or percutaneous antegrade approach
– Tumor biopsy with cold-cup or basket
– Treatment techniques include electrosurgical resection, fulguration, laser ablation
– Recurrence rates: 33% for ureteral TCC, 31% for renal pelvic TCC
ADDITIONAL TREATMENT
Radiation Therapy
Possible role for adjuvant radiation after complete excision. Studies have been small and collectively inconclusive.
Additional Therapies
• Consider systemic chemotherapy for high-stage or node-positive disease in patient with adequate renal function
– Standard urothelial agents as used for bladder cancer
Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)
Gemcitabine and cisplatin
Complementary & Alternative Therapies
No accepted therapy
ONGOING CARE
PROGNOSIS
• Overall 5-yr survival based on grade:
– Grade 1–2: 40–87%
– Grade 3–4: 0–33%
• 5-yr survival based on stage:
– Stage Ta, T1, Tis: 60–90%
– Stage T2: 43–75%
– Stage T3: 16–33%
– Stage T4: 0–5%
COMPLICATIONS
Ureteral obstruction, metastatic dissemination
FOLLOW-UP
Patient Monitoring
• If RNU is performed: Cystoscopic surveillance and cytology every 3 mo for 2 yr, then every 6 mo for 2 yr, then yearly thereafter; IVP or CTU yearly
• If nephron-sparing surgery is performed: Ureteroscopic surveillance and cytology every 3 mo until tumor-free, then every 6 mo thereafter; IVP or CTU yearly
Patient Resources
Urology Care Foundation http://www.urologyhealth.org/urology/index.cfm?article=39
REFERENCES
1. Ristau BT, Tomaszewski JJ, Ost MC. Upper tract urothelial carcinoma: Current treatment and outcomes. Urology. 2012;79(4):749–756.
2. Rouprêt M, Babjuk M, Compérat E, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol. 2013;63(6):1059–1071.
ADDITIONAL READING
• Bagley DH. Treatment of upper urinary tract neoplasms. In: Smith AD, Preminger G, Badlani G, et al., eds. Smith’s Textbook of Endourology. St. Louis: QMP; 1996:474–487.
• Blute ML. Treatment of upper urinary tract transitional cell carcinoma. In: Smith AD, Preminger G, Badlani G, et al., eds. Smith’s Textbook of Endourology. St. Louis: QMP; 1996:352–365.
• Chen GL, Bagley DH. Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidney. J Urol. 2000; 164:1173–1176.
• Huben RP, Mounzer AM, Murphy GP. Tumor grade and stage as prognostic variables in upper tract urothelial tumors. Cancer. 1988;62:2016.
• Keeley FX, Kulp DA, Bibbo M, et al. Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol. 1997;157:33–37.
• Painter DJ, Timoney AG, Denton K, et al. The modern management of upper urinary tract urothelial cancer: Tumour diagnosis, grading and staging. BJU Int. 2007;99:973–977.
See Also (Topic, Algorithm, Media)
• Filling Defect, Upper Urinary Tract (Renal Pelvis and Ureter)
• Lynch Syndrome
• Reference Tables: TNM: Renal Pelvis and Ureter Cancer
• Ureter and Renal Pelvic Tumors, General
• Ureter and Renal Pelvis, Squamous-Cell Carcinoma
• Ureter and Renal Pelvis, Urothelial Carcinoma Image 
CODES
ICD9
• 189.1 Malignant neoplasm of renal pelvis
• 189.2 Malignant neoplasm of ureter
ICD10
• C65.1 Malignant neoplasm of right renal pelvis
• C65.9 Malignant neoplasm of unspecified renal pelvis
• C66.9 Malignant neoplasm of unspecified ureter
CLINICAL/SURGICAL PEARLS
Due to the high distal recurrence rate (33–55%), it is prudent to ensure that the entire ureteral stump is removed at the time of radical nephroureterectomy (RNU).