Ureter and Renal Pelvis, Transitional Cell Cancer

Introduction

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 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.

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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.

Treatment 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.

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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).


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