Julie M. Riley, MD
Timothy D. Averch, MD, FACS
BASICS
DESCRIPTION
• Tumors of the ureter and renal pelvis are relatively rare.
• Tumors are most often malignant and account for 5% of all urothelial tumors; most commonly TCC (transitional cell carcinoma), also called urothelial cell carcinoma (UCC).
EPIDEMIOLOGY
Incidence
• 1 in 113,333 or ∼2400 cases/yr
• 7% of all kidney tumors
• Ureteric TCC account for 1 in every 25 upper-tract tumors
• Males:female = 2:1
• More common in Caucasian population
– Asians more often have high-grade tumors
Prevalence
Rare <40 yr, peak incidence 6th–7th decade
RISK FACTORS
• Smoking: Risk from 2.6–8.0
– Increases with higher dose and duration
• History of bladder cancer: 2–25% of patients with bladder cancer develop upper-tract TCC
• Occupational exposure: Similar to bladder cancer; risk from 4.0 to 5.5
– ∼20% of TCCs
– Disease latency of 30–50 yr
– Aromatic amines (aniline dyes [color fabrics]), 2-naphthylamine, 4-aminobiphenyl, 4-nitrobiphenyl, 4,4-diaminobiphenyl, 2-amino-1-naphthol, soot from coal, combustion gas, and aliphatic hydrocarbons
– High-risk jobs: Autoworkers, leather workers, painters, truck drivers, met al workers, machinists, dry cleaners, dental technicians, beauticians, and physicians
• Coffee: Minor contribution, relative risk of 1.3
• Analgesic abuse: All components implicated; highest risk with phenacetin abuse; latency of 25 yr (dose of 10–15 g over 10 yr); tend to be women who present with high-stage tumors. Relative risk: 2.4 for men and 4.2 for women
• Cyclophosphamide: Hemorrhagic cystitis and carcinoma; 9 times increased risk of carcinoma after exposure; latency of 6–13 yr
• Infectious agents: Chronic bacterial infection with calculi and obstruction; increased risk of SCC (squamous-cell carcinoma)
• Balkan nephropathy: Endemic to Bulgaria, Greece, Romania, and Yugoslavia
– Carcinogenic potential of Aristolochia fangchi and Aristolochia clematis (plants endemic to the Balkans).
– Often multiple, bilateral, and indolent tumors
– Renal-sparing surgery when possible
• Black Foot disease: Vasculopathy in Taiwan; arsenic contamination of water
• Lynch syndrome
Genetics
• Most have no family history of disease
• Certain familial cancer syndromes show an increased incidence of TCC (Lynch type II)
• Familial clustering exists; difficult to determine if related to environmental factors
• Low-grade superficial TCC: p15 and p16 loss (chromosome 9p)
• High-grade TCC: p53 loss (chromosome 17p)
• Amplification and overexpression of genes that code for growth factors or their receptors
– EGF-R (chromosome 7): Trisomy 7 associated with TCC
– Erb-2 mutations associated with TCC
PATHOPHYSIOLOGY
• >90% upper tract urothelial tumors are TCCs
– ∼70% ureteral TCCs occur in distal ureter, 25% mid ureter, and 5% proximal ureter.
– Tumors of the ureter tend to be less invasive and smaller than those of the renal pelvis.
– Up to 50% of ureteral TCCs are multicentric.
• SCC: 7%; associated with long-term infection, inflammation, and calculi
• Rare malignant tumors include sarcoma, adenocarcinoma, and carcinosarcoma.
• Rare benign tumors include inverted papilloma and fibroepithelial polyp.
ASSOCIATED CONDITIONS
Urothelial carcinoma of the bladder
GENERAL PREVENTION
• Smoking cessation
• Avoid or limit chronic analgesia use.
• Avoid exposure to implicated toxins
DIAGNOSIS
HISTORY
• Age and sex of patient: Peak incidence in mid-60s, male > female
• Hematuria: Most common presenting symptom (75% of patients)
• Dull flank pain due to the gradual distention of collecting system (30% of patients)
• Tobacco use or occupational exposure (up to 20% of TCCs)
• History of analgesia abuse in past: Dose-related effect; phenacetin is most common
• History of recurrent infections and calculi: SCC
• Asymptomatic: Incidental diagnosis in 10–15%
• Rarely, patients present with signs of advanced disease (abdominal or flank mass, anorexia, weight loss, etc.)
PHYSICAL EXAM
Usually normal; flank or abdominal mass with advanced disease
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urine analysis: Hematuria (gross or microscopic)
• Cytopathology:
– Voided specimen: Low sensitivity for upper-tract TCC; ureteral catheterization specimens are more sensitive.
– Accuracy increases with increasing grade of tumor.
Imaging
• Intravenous pyelogram (IVP):
– 50–75%: Radiolucent filling defect; irregular and continuous with the wall
– 10–30% show obstruction or non-visualization of the collecting system, which indicates more invasive disease
– Assess contralateral kidney for lesion and function
• Retrograde pyelography (RGP): Better visualization than IVP (>75% accuracy)
• Antegrade pyelography:
– Used only if not possible to visualize collecting system via retrograde approach utilizing a percutaneous nephrostomy tube.
• Computed Tomography Urogram (CTU): Primary imaging study, used for diagnosis and staging of tumors (image)
• Magnetic resonance imaging (MRI): For staging
Diagnostic Procedures/Surgery
• Ureteroscopy (URS) and nephroscopy (image):
– Diagnostic accuracy of 58–83%.
– Not accurate for staging TCCs due to difficulty in determining the depth of invasion, particularly renal pelvic TCC
• Brush biopsy:
– High positive predictive value, overall accuracy of 78%
– significant risk of bleeding and perforation
• Selective cytology barbotage (repeated injection and aspiration of saline): Localize tumor
Pathologic Findings
• Urothelial carcinoma: Papillary (exophytic) predominate:
– Slender stalks or endophytic (flat)
– Invasive or noninvasive
– Almost no tumors of low malignant potential in the upper tract
• SCC is characterized by sheets of cells with well-defined cell borders, deeply eosinophilic cytoplasm, and focal keratin pearl formation.
DIFFERENTIAL DIAGNOSIS
• Malignant filling defect of ureter and renal pelvis:
– TCC Urothelial cell carcinoma: The most common malignant cause of upper urinary tract filling defects.
– Squamous cell carcinoma (SCC)
– Rare malignant tumors: Adenocarcinoma, sarcoma, angiosarcoma, and carcinosarcoma
– Renal cell carcinoma (RCC)
• Benign filling defect of the ureter and renal pelvis:
– Air: Iatrogenic, infectious, or due to fistula
– Blood clot
– Fibroepithelial polyp
– Fungus ball
– Hemangioma
– Inflammatory lesions: Granuloma, malakoplakia, tuberculosis
– Inverted papilloma
– Radiolucent calculus
– Rare benign tumors: Leiomyoma, neurofibroma, cholesteatoma
– Renal or sloughed papilla
– Extrinsic compression on the ureter
– Mucus: Urinary diversion patients
– Protein matrix
– Ureteritis or pyelitis cystica
– Vascular impression
TREATMENT
GENERAL MEASURES
• If positive cytology is the only sign of upper tract TCC, close follow-up is required.
• Standard treatment is surgical for most benign and malignant lesions.
MEDICATION
First Line
N/A
Second Line
• Instillation therapy with BCG or mitomycin not proven to increase survival:
– Appears to be safe
– May be useful in multiple superficial tumors or bilateral disease
– Difficult to deliver the agent in adequate doses and dwell time
SURGERY/OTHER PROCEDURES
• Standard treatment is nephroureterectomy (NU): Laparoscopic or open
• Renal-sparing surgery indicated: Solitary kidney, bilateral disease, poor function of contralateral kidney, or low grade and stage
• Survival related to stage and grade of tumor rather than to treatment modality
• Radical NU and excision of bladder cuff
– 80–90% 5-yr survival (low grade and stage)
– 30–75% recurrence rate in ureteral stump
– Radical lymphadenectomy not shown to improve survival
– Endoscopic approach to bladder cuff resection has slightly higher rate of bladder recurrence (1)
• Endoscopic treatment (ureteroscopy [URS]) or percutaneous):
– Indications: solitary kidney, poor renal function, bilateral disease, moderate tumor burden, low-grade, poor surgery candidate
– Risk of perforation is higher than that in bladder (overall complication rate: 7%)
– Requires close follow-up due to high recurrence rate (recurrence free survival ∼ 20% at 10 yr) (2)
– Laser ablation in low-grade or multiple tumors
– Seeding of percutaneous tract is low (0.03%) (3)
• Segmental ureteral resection: Solitary low-grade upper and mid-ureteral lesions:
– Recurrence rate of 6%; higher if multifocal
• Distal ureterectomy and ureteroneocystostomy: Distal, solitary ureteral lesions
• Benign tumors such as fibroepithelial polyp or inverted papilloma: Endoscopic management
ADDITIONAL TREATMENT
Radiation Therapy
Can be used for advanced tumors not amenable to surgery, with decreased efficacy
Additional Therapies
• Neoadjuvant/adjuvant chemotherapy has not been established as in bladder cancer (3)
– Cisplatin therapies have been successful
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Recurrence rate reduced with more aggressive resection of tumor:
– 48% recurrence with nephrectomy
– 32% with nephrectomy plus partial ureterectomy
– 24% with nephrectomy plus subtotal ureterectomy
– 12% with NU
• Prognosis largely unchanged in locally advanced disease for last 20 yr
• Better survival for tumors in renal pelvis than ureteral in T3 or higher disease
COMPLICATIONS
• Obstruction of urinary tract
• Development of metastatic disease
FOLLOW-UP
Patient Monitoring
• Cystoscopy with cytology every 3–6 mo for 2–3 yr, then yearly
• 6-mo CT urogram + chest x-ray, then annually
• URS is more sensitive than radiologic techniques for follow-up of upper-tract TCC
Patient Resources
Urology Care Foundation http://www.urologyhealth.org/urology/index.cfm?article=39
REFERENCES
1. Xylinas E, Rink M, Cha EK, et al. Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol. 2012; 65(1):210–217.
2. Cutress ML, Stewart GD, Wells-Cole S, et al. Long-term endoscopic management of upper tract urothelial carcinoma: 20 year single centre experience. BJU Int. 2012;110(11):1608–1617.
3. Alva AS, Matin SF, Lerner SP, et al. Perioperative chemotherapy for upper tract urothelial cancer. Nat Rev Urol. 2012;9(5):266–273.
ADDITIONAL READING
• Cutress ML, Stewart GD, Zakikhani P, et al. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma: A systematic review. BJU Int. 2012;110(5):614–628.
• Ristau BT, Tomaszewski JJ, Ost MC. Upper tract urothelial carcinoma: Current treatment and outcomes. Urology. 2012;79(4):749–756.
• Rouprêt M, Babjuk M, Compérat E, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol. 2013;63(6):1059–1071.
See Also (Topic, Algorithm, Media)
• Filling Defect, Upper Urinary Tract (Renal Pelvis and Ureter)
• Reference Tables: TNM: Renal Pelvis and Ureter Cancer
• Ureter and Renal Pelvic Tumors, General Considerations Images 
• Ureter and Renal Pelvis, Squamous Cell Carcinoma
• Ureter and Renal Pelvis, Urothelial Carcinoma
CODES
ICD9
• 189.1 Malignant neoplasm of renal pelvis
• 189.2 Malignant neoplasm of ureter
• 239.5 Neoplasm of unspecified nature of other genitourinary organs
ICD10
• C65.9 Malignant neoplasm of unspecified renal pelvis
• C66.9 Malignant neoplasm of unspecified ureter
• D49.5 Neoplasm of unspecified behavior of other genitourinary organs
CLINICAL/SURGICAL PEARLS
• Ureteral and renal pelvic tumors are rare.
• Management remains surgical with NU being the gold standard.
• Endoscopic management is becoming more accepted but the risk of under staging and under grading remains.
• Close follow-up is warranted and ureteroscopy remains the most sensitive surveillance test.