AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 9  

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• Introduction
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• Differentials
• Workup
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Background

Renal urothelial (transitional cell) carcinoma is a malignant tumor arising from the transitional (urothelial) epithelium lining of the renal pelvis. Urothelial carcinoma (UC) is the most common tumor of the renal pelvis.

Pathophysiology

The predominant histologic pattern of UC is a papillary tumor with stratified, nonkeratinizing epithelium supported on a thin fibrovascular core.

Upper-urinary-tract urothelial tumors may be bilateral in 2-10% of cases. Patients with primary bladder cancer develop upper-tract UC in 2-4% of cases, with a mean interval of 17-170 months. The incidence is higher and the interval is shorter in patients who are treated with bacillus Calmette-Guérin (BCG) for bladder cancer, in patients with bladder carcinoma in situ (CIS) (upper tract UC in these cases may reach 21%) and in those with certain occupational exposures (see Causes). Patients with upper-tract urothelial tumors are at risk of developing bladder tumors, with an estimated occurrence of 20-48%. Bladder cancer usually appears within 5 years.

UC accounts for more than 90% of renal pelvic tumors. Squamous cell carcinomas (SCCs) account for 0.7-7% of upper-tract cancers.

Frequency

United States

The vast majority of urothelial tumors arise in the bladder. Urothelial tumors of the renal pelvis and ureter are rare, comprising approximately 5-6% of all urothelial tumors and 5-9% of approximately 30,000 renal cancers diagnosed annually.

International

Worldwide statistics vary and are inaccurate since renal pelvis tumors are not reported separately. The highest incidence is found in Balkan countries (Bulgaria, Greece, Romania, Yugoslavia), where UCs account for 40% of all renal cancers and are bilateral in 10% of cases.

Mortality/Morbidity

Renal UC is uniformly fatal unless it is treated.

Race

Upper-tract urothelial tumors are twice as common in whites as in blacks.

Sex

Men are affected 2-3 times more frequently than women.

Age

Renal pelvis tumors rarely occur before the age of 40 years. The peak incidence is in the 60- to 70-year age group.

CLINICAL

Section 3 of 9  

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• Clinical
• Differentials
• Workup
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History

Renal urothelial carcinoma (UC) rarely is reported as an incidental finding. Symptoms are significant enough to suggest the diagnosis in a relatively short time after disease development.

• Hematuria
• • Gross hematuria is the most common presenting symptom (75-95%).
  • Microscopic hematuria occurs in 3-11% of patients.
• Pain
• • Approximately 14-37% of patients report pain.
  • Pain is usually dull and is caused by the gradual obstruction of the collecting system.
  • Renal colic also may occur with the passage of blood clots.
• Patients are rarely asymptomatic (1-2%).

Physical

Physical examination usually is not informative or specific, especially in early stage disease.

• A palpable flank mass may be noted in less than 20% of patients.
• The classic clinical triad of hematuria, pain, and mass is also rare (15%), and is usually an indicator of advanced disease.
• Patients with SCC usually present with advanced disease. Renal calculi are present in 14-50% of patients with SCC.
• Primary adenocarcinoma of the renal pelvis constitutes less than 1% of upper-tract urothelial tumors. It is associated with chronic urolithiasis, hydronephrosis, and pyelonephritis. A metastatic lesion must be ruled out before a diagnosis of primary disease can be made.

Causes

The exact cause of upper-tract transitional cell carcinoma (TCC) is not known; however, several risk factors have been identified.

• Workers in the chemical, petrochemical, aniline dye, and plastics industries, and those exposed to coal, coke, tar, and asphalt, are at increased risk for renal pelvis and ureteral tumors.
• Cigarette smoking appears to be the most significant acquired risk factor for upper-tract UC. It is suggested that 70% of upper-tract urothelial tumors in men and 40% in women can be attributable to smoking.
• Balkan endemic nephropathy, a chronic tubulointerstitial disorder, seems to be another risk factor for upper-tract urothelial tumors. This disease is confined to the countries that are located along the Danube River and its tributaries.
• Analgesic abuse is a risk factor; a combination of phenacetin use and papillary necrosis results in a 20-fold increase in risk for renal urothelial tumors.
• Chronic bacterial infection with urinary calculus and obstruction may predispose to development of urothelial cancer. SCC is the most common entity in these cases. Schistosomiasis also may predispose to SCC.
• The chemotherapy drugs cyclophosphamide and ifosfamide are implicated in the development of upper-tract and lower-tract urothelial cancers, particularly following drug-induced hemorrhagic cystitis.

DIFFERENTIALS

Section 4 of 9  

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• Clinical
• Differentials
• Workup
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• Follow-up
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Other Problems to be Considered

Pyelonephritis
Fungal infections of the genitourinary tract

WORKUP

Section 5 of 9  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Lab Studies

• Urinalysis and urine culture
• • The presence of microscopic hematuria suggests urinary tract tumors, which must be ruled out even if the hematuria resolves.
  • The presence of more than 2-5 red blood cells in high-power field is considered enough to warrant further investigation to rule out upper-tract TCC.
  • Evaluate for urinary tract infections by urinalysis and urine cultures.
• Cytologic studies
• • Voided-urine cytology is a convenient and noninvasive method of diagnosis, but it is subjective and lacks the necessary sensitivity for diagnosing upper-tract urothelial tumors, especially low-grade neoplasms.
  • Fluoroscopically guided brush biopsy increases diagnostic accuracy to 80-90%.

Imaging Studies

• Intravenous urography
• • Intravenous urography (IVU) was the most commonly used diagnostic method in the evaluation of patients with hematuria in the past. It has been increasingly replaced by CT scan.
  • Filling defects in the upper urinary tract can be demonstrated in 50-75% of patients. Other common causes of filling defects (eg, nonopaque stones, blood clots, papillary necrosis with sloughing, fungus balls) should be ruled out.
  • Nonvisualization of the affected kidney may occur in 13-31% of cases.
• CT scan
• • CT scan is useful in the diagnosis and staging of renal urothelial tumors. It can distinguish between radiolucent renal stones and upper-tract urothelial tumors, since stones appear opaque on CT scans (>200 HU for uric acid stones against 60-80 HU for tumors) (see Images 1-2).
  • CT scan also can be used for determining local extent and distant metastases, but it is of limited value in predicting the pathologic stage of upper-tract urothelial tumors (accurate in 43-77% of cases).

Procedures

• Cystoscopy with retrograde pyelography
• • Cystoscopy may help to localize bleeding site (left, right) and rule out or confirm concomitant bladder lesions.
  • Retrograde pyelography (RPG) is especially useful when the kidney cannot be visualized by IVU, or when IVU cannot be performed because of renal insufficiency or severe contrast allergy.
  • A properly performed RPG is confirmatory in approximately 85% of cases (see Images 3-4).
• Ureteroscopy
• • Ureteroscopy is used routinely in the diagnosis of renal pelvic tumors. Correct diagnosis can be achieved in 80-90% of cases.
  • Gross appearance usually is enough for the diagnosis of upper-tract UC; if needed, however, a biopsy should be obtained.

Histologic Findings

Most TCCs are papillary. They may be single or multiple (see Image 5).

Flat CIS also may develop in the renal pelvis. CIS may be found in the distal ureter of 20-35% of patients who undergo cystectomy for bladder cancer. Presence of CIS warrants further resection of the ureter until a healthy ureteral segment is reached.

UCs can be characterized according to the degree of nuclear anaplasia. Low-grade tumors have a thin, fibrovascular core that is covered by several layers of cytologically benign urothelium, or they can be more broad-based, with hyperplastic urothelium. High-grade tumors usually are solid masses of large cells with irregular nuclei. Tumor grade is an important predictor of prognosis.

Staging

The following information is adapted from the TNM staging system of the International Union Against Cancer (UICC) for upper-tract carcinomas:

• Primary tumor (T)
• • TX: Primary tumor is occult and cannot be assessed
  • T0: No evidence of primary tumor
  • Ta: Papillary noninvasive carcinoma
  • Tis: Carcinoma in situ
  • T1: Carcinoma involves subepithelial connective tissue
  • T2: Carcinoma invades the muscularis
  • T3: Carcinoma invades beyond muscularis into periureteric or peripelvic fat or into renal parenchyma
  • T4: Carcinoma invades adjacent organs or extends through the kidney into perinephric fat
• Regional lymph nodes (N)
• • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension
  • N2: Metastasis in a single lymph node 2 to 5 cm in greatest dimension; or multiple metastatic lymph nodes, none more than 5 cm in greatest dimension
  • N3: Metastasis in a lymph node more than 5 cm in greatest dimension
• Distant metastasis (M)
• • MX: Presence of distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis

TREATMENT

Section 6 of 9  

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• Follow-up
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Medical Care

Medical therapy usually is administered as an adjuvant to surgical therapy or in patients in whom surgical treatment is contraindicated (eg, poor general condition, advanced disease). Local immunotherapy or chemotherapy can be attempted as an independent treatment method in cases of CIS or to reduce the recurrence rate after endoscopic management of the upper-tract UC.

• Topical immunotherapy or chemotherapy
• • Local treatment in general is administered as adjuvant, after endoscopic treatment of the urothelial carcinoma (UC), to decrease the recurrence rate.
  • Methods of delivery vary (eg, irrigation through ureteroscopic catheter, intravesical instillation after ensuring vesicoureteral reflux); however, irrigation through percutaneous nephrostomy catheter is the most reliable method.
  • BCG instillation through a percutaneous catheter resulted in conversion of urine cytology from positive to negative in 7 of 10 patients with upper-tract CIS. BCG sepsis was observed in 1 patient and was treated successfully.
  • Administration of BCG as a prophylactic agent after endoscopic treatment of superficial urothelial tumors resulted in a recurrence rate of 12.5% in one study. However, some studies stated a recurrence rate of up to 50%.
  • Mitomycin-C irrigation reduced the recurrence rate to 14.2%.
  • Unlike bladder cancer, the ability of BCG to treat high-grade UC of the upper tract or reduce the progression rate is not determined. Therefore, high-grade upper-tract UC requires radical surgical intervention.
  • BCG does not have an advantage of reducing the progression rate in upper-tract UC in comparison with mitomycin-C, and the recurrence rate after the use of either of these agents is comparable. However, the possibility of complications is much less with mitomycin-C, making it more attractive as a first-line agent in the prophylaxis of upper-tract UC.
• Systemic chemotherapy
• • The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the best-studied chemotherapy regimen for upper-tract TCC. Durable, complete responses were obtained in only 5-10% of patients. Serious complications were encountered in 41% of patients; treatment-related mortality rate was 2-4%. Gemcitabine-based combinations (gemcitabine + cisplatin or carboplatin) have activity similar to MVAC in bladder cancer with less toxicity.
  • Some studies claimed comparable effectiveness of the gemcitabine + paclitaxel combination as well, with less nephrotoxicity in comparison with cisplatin-based therapies.
• Radiation therapy
• • The role of radiation therapy in the management of upper-tract TCC is not well defined.
  • Some studies suggest that radiation therapy may have some effect as adjuvant therapy to improve local control after radical surgical treatment for high-grade disease.

Surgical Care

Treatment is mandatory for upper-tract TCC after making the diagnosis. Surgical intervention is the main form of radical treatment for localized disease.

• In choosing a treatment, the following should be considerations:
• • Patients with low-stage, low-grade tumors respond well to either radical or conservative treatment.
  • Patients with high-stage, high-grade tumors respond poorly to either radical surgery or conservative surgery.
  • Patients with positive cytologic findings but normal radiographic and endoscopic examinations are not treated, but are monitored closely by periodic IVU or RPG.
• Radical nephroureterectomy
• • Traditional radical surgery for renal UC consists of total nephroureterectomy with excision of a bladder cuff around the ureteral orifice. Otherwise, 30-75% of patients develop tumor recurrence in the ureteral stump or around the ipsilateral ureteral orifice.
  • Avoid transection of the ureter, because of the high risk of tumor spillage in the retroperitoneum.
  • Laparoscopic or hand-assisted laparoscopic nephroureterectomy is as effective oncologically as an open technique for localized disease. In general, the laparoscopic approach is accompanied by less blood loss, less pain and discomfort, faster recovery, and shorter hospital stay. Trocar site recurrence is very rare (3 cases have been reported so far).
  • Patients with poorly differentiated tumors or high-stage disease (especially those with microscopic lymph node involvement) may benefit from extensive retroperitoneal lymphadenectomy. The benefit, however, is marginal, and appropriate candidates must be chosen carefully.
• Conservative open surgical treatment
• • Conservative excision for upper-tract urothelial tumors includes segmental ureteral resection with reanastomosis or ureteroneocystostomy and partial nephrectomy.
  • Conservative management is especially appropriate for solitary or functionally dominant kidneys, bilateral tumors, or small, low-grade ureteral tumors.
  • Upper ureteral and midureteral tumors may be treated with segmental resections if they are low-grade, solitary lesions.
  • Manage distal ureteral tumors with distal ureterectomy and ureteral reimplantation if no evidence of multifocality is noted. In these cases, distal ureterectomy may be as successful as total nephroureterectomy, since proximal spread of UC after resection is rare.
  • Partial nephrectomy may be performed in patients with localized renal pelvic tumors; however, employ this approach only in situations requiring avoidance of renal failure.
• Endoscopic treatment
• • Urothelial tumors of the upper urinary tract can be excised using an endoscope, similar to superficial bladder tumors.
  • Indications for endoscopic management are the same as for conservative resection and include low-grade tumors, bilateral involvement, and compromised renal function that necessitates a nephron-sparing approach.
  • Electrocautery and fulguration are used most commonly in the endoscopic setting. Currently, lasers (Ho:YAG and Nd:YAG) are being used for management of upper-tract low-grade urothelial tumors. In cases of larger low-grade tumors with low metastatic potential, which cannot be eliminated during one session, ureteroscopic management can be performed several times.
  • Tumor size (>1.5 cm), multifocal disease, and high-grade tumors are the main risk factors for recurrence after ureteroscopic management of upper-tract UC.
  • The presence of high-grade or invasive tumors, which cannot be eradicated endoscopically, necessitates radical surgical intervention (open or laparoscopic nephroureterectomy in most cases).

FOLLOW-UP

Section 7 of 9  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Further Outpatient Care

• Because of the high risk of local and bladder recurrences, long-term follow-up care for these patients is mandatory. Include ureteroscopy, cystoscopy, and either IVU or RPG in the routine follow-up procedures.
• Urine markers are used more and more frequently in the follow-up of patients with UCs. Specificity of these tests (eg, BTA Stat, ImmunoCyt, FISH) is acceptable for follow-up, and their sensitivity is much better than that of urine cytology.

Complications

• Perforation (0-10%) and stricture formation (5-13%) are the major complications of ureteroscopic treatment.
• Use of lasers (especially Ho:YAG laser, with low tissue penetration) may decrease the rate of stricture formation.
• Seeding through the nephrostomy tract (at least one case has been reported) remains a concern during percutaneous management.
• Other serious complications of percutaneous treatment include perforation (5.5%) and uretero-pelvic-junction stricture (1.4%). Frequency of stricture is much less than after ureteroscopy.

Prognosis

• Tumor stage is the most important prognostic factor for upper-tract UC. Survival correlates closely with tumor stage. The TNM staging system of the UICC for upper-tract carcinomas is the most comprehensive (see Staging).
• Tumor grade is another predictor of prognosis (see Histologic Findings). Tumor grade usually follows tumor stage, and patients with high-grade carcinomas have more advanced (ie, high-stage) disease. Stage and grade correlate in up to 83% of cases, although stage remains a more accurate predictor of prognosis. Stage T3 renal tumors have a better prognosis than ureteral tumors.
• Five-year survival rate after radical surgery depends on disease stage.
• • Stages Tis, Ta, or T1: 91%
  • Stage T2: 43%
  • Stages T3, T4, N1, or N2: 23%
  • Stages N3 or M1: 0%
• Tumors recur in the contralateral kidney after radical nephroureterectomy in 2% of cases.
• The 5-year survival rate in selected patients after conservative surgery is reported to be 70-90%.
• Recurrences in the remaining urothelium after conservative treatment are relatively frequent because of the multifocal nature of TCCs. Ipsilateral recurrence rates may reach 25-50%. Most low-grade recurrences can be treated with repeat conservative excision. Five-year survival rates in these patients with low-grade low-stage disease can approach 100%.
• The prognosis is poor for patients with advanced SCC.

Patient Education

• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.

MULTIMEDIA

Section 8 of 9  

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Media file 1:  CT scan with contrast, vascular phase. Mass can be seen in the left renal pelvis (black arrows). Patient underwent nephroureterectomy. Tumor was high-grade urothelial carcinoma invading subepithelial tissue (stage T1) and measuring 7.5 X 3.2 X 3 cm.
	View Full Size Image
Media type:  CT

Media file 2:  CT scan of the same patient as in Image 1, delayed phase. Enhancing mass can be visualized in the left renal pelvis (white arrows).
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Media type:  CT

Media file 3:  Retrograde pyelography. Filling defect can be seen in the left renal pelvis and lower calix (black arrows). Patient underwent left nephroureterectomy. Tumor was low-grade urothelial carcinoma measuring 2.5 X 2 X 1 cm.
	View Full Size Image
Media type:  X-RAY

Media file 4:  This radiograph shows a right retrograde pyelogram demonstrating a large filling defect in the mid-ureter due to transitional cell carcinoma (large arrow). Note the characteristic appearance of radiographic contrast material just distal to the obstruction (small arrow), which gives rise to the so-called goblet sign. Contrast is also visible beyond the partially obstructed segment of the ureter in the renal pelvis and collecting system.
	View Full Size Image
Media type:  X-RAY

Media file 5:  Urothelial tumor of the renal pelvis (white arrows), pathology specimen.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

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• Michaelson MD, Kaufman DS, Oh WK. Transitional cell carcinoma of the upper uroepithelial tract. Clin Adv Hematol Oncol. Feb 2003;1(2):102-4; discussion 105.
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• Pohar KS, Sheinfeld J. When is partial ureterectomy acceptable for transitional-cell carcinoma of the ureter?. J Endourol. May 2001;15(4):405-8; discussion 409. [Medline].
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Article Last Updated: Jul 27, 2006