Urothelial Tumors of the Renal Pelvis and Ureters Treatment & Management
- Author: David F Jarrard, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS more...
The 2 forms of medical therapy for upper tract transitional cell carcinoma (TCC) are topical treatments and systemic.
Topical chemotherapeutic agents are delivered by instillation and consist of the preferred agent bacille Calmette-Guérin (BCG) or mitomycin C. These agents can be administered either percutaneously or from a retrograde approach through a ureteral catheter. For high-grade disease, topical instillation therapy is most appropriate in patients for whom radical surgery is absolutely or relatively contraindicated — those with bilateral disease and/or limited renal function. The safety of these agents as adjuvant therapy has been well studied in bladder cancer; however, their efficacy in decreasing recurrence rates, delaying tumor progression, and improving survival rates has not been firmly established in upper urinary tract cancer. Furthermore, the administrationof these agents often requires hospitalization and skilled nursing to prevent hyperperfusion and systemic absorption.
BCG is an attenuated form of Mycobacterium tuberculosis, and its use carries a small but significant risk of BCG sepsis. To prevent adverse systemic effects, BCG should not be used in patients with hematuria.
Systemic chemotherapy is often reserved for patients with metastatic disease.
Superficial (Ta, T1) and carcinoma in situ
Primary treatment is with BCG, which can be used for carcinoma in situ and can be curative, but it is reserved for those who are not surgical candidates. Recurrence rates are high (50%).
Adjuvant topical treatments include retrograde or percutaneous instillation of mitomycin C. There is no demonstrable benefit of BCG in these settings. The efficacy of these agents in treating upper tract urothelial carcinoma is not well established because of the small retrospective studies with heterogeneous patients and tumor characteristics.
Keeley and Bagley reported on the use of mitomycin administered via a retrograde catheter in 19 patients. They noted a 54% recurrence rate at a mean follow-up of 30 months. No patient had disease progression. With a single postoperative intravesical dose of mitomycin C administered after nephroureterectomy for TCC, the risk of a bladder tumor was reduced by 40% in the first year following surgery.
The efficacy and safety of doxorubicin as adjuvant therapy has been explored in a limited number of patients. Of 10 patients evaluated, 50% had disease-free upper tracts at 4-53 months. In this series, doxorubicin was given via continuous infusion to improve dwell time and efficacy. No treatment-related toxicities were observed.
Prospective randomized studies are needed to determine the efficacy and optimal use of these agents as adjuvant therapy for superficial upper tract TCC, especially in the setting of endoscopic surgery.
Muscle invasive (T2) and locally advanced (T3-T4) disease
MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) was once considered standard treatment. However, this combination yields only a modest survival advantage, and optimal dosing is often limited owing to severe toxicity.
The response rates, time to progression, and survival rates associated with gemcitabine with cisplatin are similar to those of MVAC, but with less toxicity. Gemcitabine with cisplatin is now considered first-line therapy.
Adjuvant and neoadjuvant chemotherapy
The use and potential benefit of both adjuvant and neoadjuvant chemotherapy is largely extrapolated from bladder cancer data. A recurrence-free rate benefit has been demonstrated (as high as 50%); however, there is not yet a proven survival benefit. Studies addressing the issue have few patients and are nonrandomized.
In a 2009 publication on adjuvant therapy in the Upper Tract Urothelial Carcinoma Collaboration, of 1390 total patients, 542 were identified as high-risk (pT3N0, pT4N0, and/or N+). One hundred and twenty-one (22%) patients received adjuvant therapy. No difference was found in cancer-specific survival; however, those who did receive chemotherapy had higher grade and stage (P < .001).
A compelling study of patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy was compared against historical controls. A significant trend was noted in those patients who were down-staged, and a complete response was seen in 14% of patients. This is noteworthy as it potentially provided a cure in patients who otherwise are at very high risk.
Adjuvant chemotherapy use is limited by renal insufficiency or performance status after nephroureterectomy, as discussed below.
Radiation can play a palliative role in controlling pain and hemorrhage associated with advanced upper tract urothelial carcinoma.
Czito et al (2004) reported on the use of adjuvant radiotherapy after resection of T3 or T4 and/or node-positive upper tract TCC. In this retrospective analysis of 31 patients treated from 1970-1997, radiation with concurrent cisplatin chemotherapy improved 5-year survival rates.
Prospective studies are needed to better define the role of radiation therapy in the multimodal management of upper tract TCC.
Metastatic and node-positive disease
As noted above, MVAC is the historical standard treatment and has been replaced by gemcitabine with cisplatin.
No strong evidence supports the use of systemic chemotherapy in metastatic disease. This is attributed to the relative rarity of metastatic upper tract TCC and the absence of prospective trials.
Furthermore, approximately 50% of patients with metastatic urothelial carcinoma are not candidates for cisplatin-based therapy.
Exclusion criteria for cisplatin-based chemotherapy are as follows:
Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2
Creatinine clearance < 60 mL/min
Grade 2 audiometric hearing loss
Grade 2 or higher peripheral neuropathy
New York Heart Association class III heart failure
In patients with limited renal function, chemotherapy options are limited but can consist of the following:
Methotrexate, carboplatin, and vinblastine  - Overall response rate, 30.3%; median survival, 8.1 months
Gemcitabine and cisplatin given every 2 weeks (split dose)  - Partial response, 39%; stable disease, 31%; median progression-free survival of 3.5 months and overall survival of 8.5 months
De Santis et al randomized patients to gemcitabine and carboplatin versus methotrexate, carboplatin, and vinblastine and found statistically similar outcomes.
According to European Association of Urology (EAU) guidelines, conservative management is appropriate for low-risk upper tract urothelial carcinomas. EAU indications of low risk are as follows:
Tumor size < 1 cm
Low-grade tumor (cytology or biopsies)
No evidence of an infiltrative lesion on CT urography
Understanding of close follow-up
Treatment recommendations (all grade C) for these low-risk tumors are as follows :
Laser should be used in endoscopic treatments
Flexible ureteroscopy is preferable to rigid ureteroscopy
A percutaneous approach can be used in small low-grade caliceal tumors unsuitable for ureteroscopic treatment
Ureteroureterostomy is indicated for noninvasive low-grade tumors of the proximal ureter or midureter that cannot be removed completely via endoscopy
Complete distal ureterectomy and neocystostomy is indicated for noninvasive, low-grade tumors in the distal ureter that cannot be removed completely via endoscopy, and for high-grade, locally invasive tumors
Nephroureterectomy with excision of the bladder cuff is considered the standard therapy in patients with high-volume renal pelvis transitional cell carcinoma (TCC), regionally extensive disease, and high-grade or high-stage lesions.
Segmental ureterectomy coupled with ureteral reimplantation is indicated in patients with ureteral tumors located in the distal ureter, generally of lower grade and stage. Unfortunately, because of the multifocal nature of TCC, the ipsilateral recurrence rate is 25% or greater after segmental ureterectomy.
Renal-sparing surgery, including segmental ureterectomy and endoscopic therapy, maintains a vital role in the management of upper tract urothelial tumors. Typically, patients with small, low-grade superficial lesions are the best candidates for this approach. Some investigators use this approach more frequently in patients with a solitary kidney, bilateral disease, compromised renal function, synchronous tumors, or greater baseline operative risk.
Open radical nephroureterectomy
Nephroureterectomy is the standard for large, high-grade tumors of the renal pelvis and proximal ureter that are organ-confined or locally advanced. Nephroureterectomy is also recommended for multifocal, recurrent, low-grade tumors, which are found to be less amenable to ureteroscopic management.
Classically, this procedure involves removal of the kidney, ureter, and bladder cuff via a thoracoabdominal or flank approach, with a separate lower-quadrant Gibson incision. Laparoscopic approaches to the radical nephroureterectomy are now commonplace and offer some postoperative benefits.
In both open and laparoscopic surgeries, care is taken to excise the entire distal ureter and bladder cuff to prevent local recurrence.
Excision of the cuff has a survival benefit.
There are multiple effective approaches, as follows:
Open excision and repair of cystotomy
Endoscopic ”pluck” technique
Transurethral resection of the intramural ureter
Lymphadenectomy, which generally requires little additional operative time, is performed for staging purposes and potentially offers a therapeutic benefit.
The indications and oncologic surgical principles for laparoscopic nephroureterectomy are similar to those of the open approach.
Pure laparoscopic transperitoneal and retroperitoneal approaches, as well as hand-assisted laparoscopic approaches, have been described. The optimal technique depends largely on surgeon experience.
Management of the bladder cuff remains variable. Some investigators prefer hand-assisted laparoscopic en bloc excision of the distal ureter with closure of the cystotomy defect.
Open versus laparoscopic nephroureterectomy
Operative time is comparable to that of the standard open procedure.
Laparoscopic nephroureterectomy offers the benefits of minimally invasive surgery, including less blood loss, shorter hospitalization, and improved cosmetic result.
Recent studies have shown comparable oncologic outcomes between open and laparoscopic nephroureterectomy.[36, 37]
Simone et al conducted a randomized control trial that demonstrated significantly lower blood loss (104 vs 430 mL, P < .001) and shorter hospital stay (2.30 vs 3.65 d, P < .001) for laparoscopic nephroureterectomy compared with open surgery. Their group also demonstrated a nonsignificant difference in 5-year cancer specific survival (89.9% vs 79.8%) and 5-year metastasis-free survival rates (77.4% vs 72.5%) favoring open surgery.
A 2012 meta-analysis of observational studies comparing open versus laparoscopic nephroureterectomy showed significantly lower urinary recurrence and distant metastasis favoring the laparoscopic approach. Local recurrence was found to be comparable.
Many surgeons consider large and locally advanced (T3/T4) tumors to be contraindications to laparoscopic surgery.
High-grade and/or large distal ureteral tumors are most commonly managed with distal ureterectomy with ureterovesical reimplant. Jeldres et al showed equivalent 5-year cancer-specific survival rates when compared with nephroureterectomy, regardless of stage.
Ureteroscopy offers a renal-preserving alternative to traditional nephroureterectomy and is used in patients with compromised renal function, bilateral upper tract disease, or other medical contraindications to nephroureterectomy. Ureteroscopic ablation is now the preferred choice for low-grade upper tract TCC. However, management of upper tract tumors with this approach is associated with the need for multiple additional procedures versus more definitive surgical management.
Ureteroscopy allows biopsy and treatment of tumors along the entire upper urinary tract. Cold-cup biopsy forceps or a flat-wire basket is used for tissue diagnosis and to determine tumor grade to plan for future intervention.
The use of Nd:YAG and Ho:YAG lasers, as well as small 2F-3F electrosurgical devices, enable ureteroscopic resection, coagulation, and ablation of upper tract tumors under direct vision.
In 2012, a systematic review of ureteroscopic and percutaneous management was conducted by Cutress et al, involving 22 ureteroscopic studies with 736 patients and 11 percutaneous studies with 288 patients. No controlled trials compared radical nephroureterectomy. Approximately 20% patients eventually required nephroureterectomy. Upper tract recurrence was high, at 52% for endoscopy and 37% percutaneous management. Overall survival in the pooled analysis was 72% for ureteroscopic management and 79% for percutaneous approach. The disease-specific survival rate was 91% for ureteroscopy and 89% for percutaneous resection.
Also in 2012, Cutress et al reported their 20-year experience with endoscopic management. Seventy-three patients had longer follow-up than most studies, at a mean of 63 months. Nineteen percent of patients proceeded to nephroureterectomy. The upper tract recurrence rate was 68%. The overall survival rate was 69.7% and the disease-specific survival rate was 88.9% at 5 years.
Another study examined 90 patients with upper tract TCC managed endoscopically who had a history of bladder cancer. They found that the recurrence-free survival rate at 5 years was only 29% in this group. The authors of this study recommended a low threshold for more aggressive surgical intervention based up stage and grade migration.
Grasso et al published their 15-year experience of ureteroscopic and extirpative therapy and concluded that uteroscopic management was an acceptable option for managing low-grade disease.
The following are technical considerations for ureteroscopic treatment of upper tract tumors :
Obtain adequate tissue during initial biopsy for accurate diagnosis and grade
Minimize the risk of stricture with the use of laser rather than the more deeply penetrating electrosurgical devices when ablating ureteral tumors
Drain the bladder with a small catheter or use a ureteral access sheath to improve flow and visibility, which can be limited by bleeding
Facilitate resection by slowing the patient’s respiratory rate, which decreases movement and stabilizes the operative field during resection and ablation
Percutaneous therapy allows the use of larger scopes with improved maneuverability and visibility to ablate larger tumors in the renal pelvis and upper ureter. Percutaneous access may be used to administer topical therapeutic agents such as BCG or mitomycin. This approach is an acceptable alternative to nephroureterectomy in patients with low–grade disease. However, as with all organ-preserving strategies, vigilant follow-up surveillance is required.
Percutaneous techniques allow a renal-sparing approach and are well suited for large-volume disease of the renal pelvis and proximal ureter.
Percutaneous access to the diseased renal unit is established, followed by tract dilation. This allows the passage of nephroscopes, laser fibers, biopsy forceps, and electrosurgical resection devices to completely resect and ablate tumors under direct vision.
Percutaneous access also allows for a deeper resection and more accurate staging than ureteroscopy for tumors of the renal pelvis and kidney.
Tumor seeding of the nephrostomy tract, although rare, has been reported and is associated with high-grade lesions.
Radical nephroureterectomy versus conservative, endoscopic management
No randomized studies have been performed, and no studies have had good long-term follow-up. Selection bias confounds nonstandardized studies. Tumors treated with endoscopic management are generally smaller, of low grade, and of low stage.
The 5-year disease-specific survival rate in patients with low-grade disease is statistically similar for conservative treatment and immediate nephroureterectomy, at 86.2-100% vs 87.4-89%, respectively.[44, 45]
Silberstein et al, in a 2012 study, showed that although oncologic outcomes were similar, a significantly larger decrease in glomerular filtration rate was noted in patients undergoing nephroureterectomy compared with endoscopic treatment.
Lymph node dissection
One study demonstrated a significant survival advantage in patients undergoing extensive regional lymphadenectomy at the time of open nephroureterectomy.
Follow-up is largely determined by tumor grade and stage and the procedure performed. In cases in which a radical nephroureterectomy is performed, local recurrence is uncommon. Bladder recurrence rates vary per report, at 15-50%. The bladder should be surveyed routinely.
In those managed conservatively or with endoscopic techniques, closer follow-up intervals are warranted. Surveillance ureteroscopy under local anesthesia in the clinic is feasible and well tolerated in selected patients. The high rate of recurrence mandates strict postoperative surveillance for any renal-sparing treatment strategy used to manage upper-tract urothelial tumors.
The American Urological Association has no guideline on follow-up and surveillance. A generally accepted surveillance protocol consists of cystoscopy and selective urine cytology at 3-month intervals postoperatively for the first year and every 6 months during the second year. CT urography, excretory urography, or retrograde ureteropyelography can be performed at 3- to 6-month intervals to evaluate the upper tract. Ureteroscopy is the most sensitive tool for detecting recurrence and is performed routinely at 3-month intervals initially, with the frequency increasing to 6 months after the first year. At 2-5 years, cystoscopy and ureteroscopy are continued at 6-month intervals.
As mentioned above, ureteroscopy is the preferred surveillance tool for detecting recurrences after endoscopic ablation of upper tract transitional cell carcinoma (TCC).
Ureteroscopy with biopsy and cytology yields a sensitivity of 93.4% and specificity of 65.2%. In the same series, surveillance with retrograde pyelography had a sensitivity and specificity of 71.7% and 84.7%, respectively.
Voided urine cytology and microscopic hematuria yield a low sensitivity but reasonable specificity in detecting upper tract recurrences.
Upon any recurrence, the endoscopic cycle is restarted.
The contralateral collecting system is studied radiographically once yearly with CT urography, retrograde pyelography, or intravenous pyelography and cytology.
Surveillance cystoscopy and imaging of the contralateral upper tract is also required to detect recurrences in patients treated with nephroureterectomy.
Several novel markers in addition to urine cytology and fluorescence in situ hybridization (FISH) may be helpful in detecting recurrent urothelial carcinoma. Siemens et al conducted a prospective study that reported urinary fibrinogen/fibrin degradation products (FDPs), bladder tumor antigen (BTA), and urine cytology to yield sensitivities of 100%, 50%, and 29%, respectively, in detecting upper-tract TCC. Specificities were 83%, 62%, and 59% for FDPs, BTA, and cytology, respectively.
Complications related to nontreatment include disease progression, obstruction, bleeding, infection, metastasis, and death. See the images below.
With open nephroureterectomy, the potential risks of surgery include bleeding, infection, injury to surrounding bowel or viscera, and abdominal wall laxity due to neurapraxia. Open procedures are associated with an increased risk of postoperative pulmonary complications relative to the laparoscopic approach. Risk of 30-day perioperative mortality is 1.8%. Risk of positive surgical margin is 8.5%.
With laparoscopic nephroureterectomy, bleeding, infection, injury to surrounding bowel or viscera, and port site hernia are potential complications that should be fully discussed with patients during the informed consent process.
With endoscopic surgery, the overall complication rate is 14% for ureteroscopic intervention (11% stricture rate) and 27% for percutaneous management. Ureteral perforation, delayed ureteral stricture, extraluminal tumor spillage, and tumor propagation are some of the complications associated with ureteroscopic surgery. In addition, the reliability in staging tumors is lacking with this approach. Percutaneous surgery carries a risk of immediate and delayed bleeding, a theoretical risk of tumor seeding, and a risk of pleural cavity violation, potentially resulting in hydrothorax that necessitates chest tube drainage.
With medical therapy, instillation of topical chemotherapeutic agents is associated with collecting system scarring, obstruction, systemic absorption, sepsis, and toxic agranulocytosis due to heightened perfusion pressures. Medical therapy carries a complication profile similar to that of nontreatment.
Outcome and Prognosis
Survival after total nephroureterectomy (5-year survival by stage) is as follows:
Tis – 82-100%
Ta – 93-100%
T1 – 91-95%
T2 – 70-75%
T3 – 40-54%
T4 – 12-14%
For all comers with upper tract urothelial cancer, the unadjusted 5-year survival rate is approximately 57%. On multivariate analysis, only stage and age were significant prognostic factors for survival.
Recurrence rates vary in the literature. Rink et al (2012) report an overall recurrence rate of 24% in their study population of 2494 patients treated with radical nephroureterectomy. Approximately 80% of those patients who had recurrence died within 24 months after the recurrence. A shorter time of recurrence to death was related to pT3 and pT4 stages, ureteral tumor location, omission of a lymph node dissection, and shorter time to recurrence. Biopsy grade is generally accepted as accurate and correlates to pathologic findings. Conversely, owing to the difficulties in obtaining muscle in biopsy specimens and the limitations of imaging, the up-staging rate is 45%.
Advanced age has previously been shown to be related to poor clinical outcomes, including cancer-specific and overall survival. However, a study by Chromecki et al found that a high percentage of elderly patients who underwent the procedure were cured, leading to the belief that chronological age alone is an unreliable criterion for outcome in older patients.
Non-Hispanic black race is associated with worse 5- and 10-year survival.
American Society of Anesthesiologists scores significantly correlate with cancer-specific survival after radical nephroureterectomy.
Active smoking, a smoking history of at least 20 years, and smoking at least 1 cigarette per day is significantly associated with advanced disease, greater recurrence, and worse cancer-specific mortality. Patients who quit smoking more than 10 years ago have better oncologic outcomes.
Tumor location, that is renal pelvis versus ureter, is inconsistently reported to affect prognosis, with some articles suggesting a worse prognosis for ureteric location and others showing no difference.
Hydronephrosis predicts advanced pathologic stage, metastasis, and cancer-specific survival.[13, 58, 59]
For patients with a higher body mass index who were treated with radical nephroureterectomy, a study by Ehdaie et al found overall survival rates were diminished.
A history of bladder cancer, a delay to definitive therapy, pathologic stage, pathologic grade, presence of carcinoma in situ, lymph node invasion, lymphovascular invasion tumor multifocality, sessile growth pattern, tumor size, tumor necrosis, and positive surgical margins predict worse outcomes.[10, 61]
Future and Controversies
Endoscopic ablative procedures will be used more commonly for low-grade, low-stage disease and in patients in whom renal-sparing therapy is indicated.
New agents for topical instillation therapy of upper tract urothelial tumors are being developed.
New markers are being investigated for diagnosis, prognostication, and surveillance. Mini-array comparative hybridization-based tests, like those under new investigation for bladder cancer, may be helpful in the future.
Staging is often inadequate with currently available imaging. Future approaches should include the capability to delineate invasive from superficial disease.
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