Urothelial Tumors of the Renal Pelvis and Ureters Treatment & Management

Updated: Aug 07, 2020
  • Author: Kyle A Richards, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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Treatment

Medical Therapy

Medical therapy for upper tract urothelial cell carcinoma (UTUC) can be topical or systemic. Topical chemotherapeutic agents are delivered by instillation and consist of bacillus Calmette-Guérin (BCG), which is the preferred agent, or mitomycin C. These agents can be administered either percutaneously or via 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.

In April 2020 the US Food and Drug Administration approved mitomycin pyelocalyceal (Jelmyto) for treatment of low-grade upper tract urothelial cancer (LG-UTUC) in adults. Mitomycin pyelocalyceal is instilled via ureteral catheter or a nephrostomy tube. Approval was based on the OLYMPUS study, in which 41 of 71 patients (58%) achieved a complete response (CR) at 3 months, after receiving 6 weekly instillations of mitomycin pyelocalyceal. Patients with a CR at 3 months then received monthly instillations for a maximum of 11 additional instillations, and 46% of those patients remained in CR at the 12-month visit. [25]

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 gross hematuria.

Because of an ongoing shortage of BCG in the United States, the National Comprehensive Cancer Network [23]  and several urologic societies have recommended strategies on prioritizing use of intravesical BCG and alternative treatment approaches for some patients.

The safety of BCG and mitomycin C as adjuvant therapy has been well studied in bladder cancer; however, their efficacy in decreasing recurrence rates, delaying tumor progression, and improving survival rates in upper urinary tract cancer has not been firmly established. [26]  Furthermore, the administration of these agents often requires hospitalization and skilled nursing to prevent hyperperfusion and systemic absorption.

Systemic chemotherapy is often reserved for patients with metastatic disease. It can also be given as a neoadjuvant approach for patients with larger high-grade urothelial carcinomas, in a paradigm similar to that of neoadjuvant chemotherapy for muscle-invasive bladder cancer

Superficial (Ta, T1) and carcinoma in situ

Primary therapy

Primary treatment is with surgery; the standard is radical nephroureterectomy with excision of bladder cuff. Recurrence rates are high (50%) in patients who do not undergo definitive extirpation and are treated with nephron-sparing approaches. [27] Endoscopic laser ablation is also a treatment option, especially in patients with smaller low-grade tumors where nephron-sparing is more critical.

Adjuvant therapy

Adjuvant topical treatments include retrograde or percutaneous instillation of mitomycin C. There is no demonstrable benefit of BCG in these settings. [28] 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. Topical therapy should be reserved for patients who are not candidates for surgical extirpation due to poor kidney function, bilateral disease, or other co-morbid conditions.

Keeley and Bagley reported on the use of mitomycin administered via a retrograde catheter in 19 patients. [29] 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 UTUC, the risk of a bladder tumor was reduced by 40% in the first year following surgery. [30]

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. [31]

Prospective randomized studies are needed to determine the efficacy and optimal use of these agents as adjuvant therapy for superficial UTUC, especially in the setting of endoscopic surgery.

Muscle invasive (T2) and locally advanced (T3-T4) disease

Chemotherapy

MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], 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 combination of gemcitabine with cisplatin yields response rates, time to progression, and survival rates 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 and retrospective chart reviews, but recent studies have suggested a potential for benefit (see Table 2, below). A recurrence-free rate as high as 50% has been demonstrated; however, a survival benefit has not yet been definitively proven. Studies addressing the issue have few patients and are nonrandomized. [32] One important consideration is the use of neoadjuvant rather than adjuvant chemotherapy in this unique population, as removal of the kidney frequently has a direct impact on the patient's capacity to undergo chemotherapy, due to decreased renal function. Administration of platinum-based chemotherapy may be more challenging after the loss of one kidney.

Table 2. Adjuvant and Neoadjuvant Trials for Upper Tract Transitional Cell Carcinoma. (Open Table in a new window)

Reference

Study design

Outcome

Number of patients enrolled

Leow JJ, Martin-Doyle W, Fay AP, et al. 2014

 

Systematic review and meta-analysis

Pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; P = 0.023) for adjuvant therapy group compared with controls without adjuvant therapy

Prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy

Porten S, Siefker-Radtke AO, Xiao L, et al. 2014

 

Retrospective review between neoadjuvant chemotherapy group and initial surgery group

Neoadjuvant chemotherapy had improved OS and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = 0.0204 and P = 0.0015, respectively

Neoadjuvant chemotherapy +surgery (n =31) and surgery  only (n= 81)

 

Huang YC, Chen MF, Shi CS, et al. 2015

 

Retrospective review of  patient records  with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy and adjuvant therapy versus control group

Statistically significant differences were found between the adjuvant and control groups in 5-year cancer-specific survival rates (80.5% vs 57.6%, P = 0.010) and recurrence-free survival rates (74.4% vs 52.9%, P = 0.026), but no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072)

Postoperative adjuvant chemotherapy (n= 60) vs surgery only (n=111)

Urakami S, Yuasa T, Yamamoto S, et al.2015

Retrospective analysis of  clinicopathological response to induction chemotherapy and identification of  prognostic factors for OS

Clinically objective response to the induction chemotherapy occurred in 75% of patients. Histopathological analysis indicated pT0 status in 20% and pN0 in 33%. Clinical tumor response correlated significantly with achievement of pathological complete response

 60 urothelial cancer patients; primary cancer site was the urinary bladder (n= 31; 52%) and upper urinary tract (n=29; 48%)

Lucca I, Kassouf W, Kapoor A, et al. 2015

 

Retrospective analysis of data of patients with lymph node (LN)–positive UTUC, who underwent full surgical resection followed by adjuvant chemotherapy (AC)

In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019).

263 patients with LN-positive UTUC underwent full surgical resection. Study group (n=107, 41%) received three to six cycles of AC, while controls (n=156; 59.3%) were treated with RNU alone

Kim DK, Kim JW, Jung HD, et al.2019

Systematic review and meta-analysis of adjuvant therapy after radical nephroureterectomy (RNU) in patients with locally advanced UTUC

 

Compared with patients who underwent RNU only, those who received adjuvant chemotherapy after RNU had HRs for disease-free survival of 0.59 (P = 0.001), cancer-specific survival of 0.73 (P = 0.02), and OS of 0.84 (P = 0.02) 

11 studies, comprising 1496 patients who underwent RNU alone and 798 patients who received ACH after RNU

NCT02412670

 

 

Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC

 

Expected to complete by Feb 2020

NA

NCT01261728

Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC

Expected to complete by Dec 2020

NA

In the Upper Tract Urothelial Carcinoma Collaboration, the use of adjuvant chemotherapy did not result in longer cancer-specific survival; however, in that study, the patients who received chemotherapy had higher grade and stage disease (P < 0.001). The study included 1390 total patients; 542 were identified as high-risk (pT3N0, pT4N0, and/or N+) and 121 (22%) received adjuvant therapy. [33]

A compelling study in which patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy were compared against historical controls noted a complete response in 14% of patients and a significant rate of downstaging. [34] This is noteworthy, as neoadjuvant therapy potentially provided a cure in patients who otherwise are at very high risk.

Neoadjuvant chemotherapy has been shown to confer survival advantage in two retrospective studies. Urakami et al concluded that clinical response of the tumor to neoadjuvant chemotherapy predicts the survival outcome in urothelial carcinoma with clinical lymph node metastasis treated with consolidative surgery. [35] In a retrospective cohort study by Porten et al, patients treated with neoadjuvant chemotherapy had 5-year disease-specific survival of 90% vs 58% without it. [36]

The findings from those non-randomized studies will be the highest level of evidence supporting a survival benefit for neoadjuvant chemotherapy until the data from the two prospective studies currently in progress (NCT02412670 and NCT01261728) become available. Adjuvant chemotherapy use is limited by renal insufficiency or performance status after nephroureterectomy, as discussed below.

Radiation therapy

Radiation can play a palliative role in controlling pain and hemorrhage associated with advanced upper tract urothelial carcinoma.

Czito et al reported on the use of adjuvant radiotherapy after resection of T3 or T4 and/or node-positive UTUC. In this retrospective analysis of 31 patients treated from 1970-1997, radiation with concurrent cisplatin chemotherapy improved 5-year survival rates. [37]

Prospective studies are needed to better define the role of radiation therapy in the multimodal management of UTUC.

Metastatic and node-positive disease

Chemotherapy

As noted above, gemcitabine with cisplatin has replaced MVAC, which was the historical standard treatment, as gemcitabine and cisplatin tend to be better tolerated. However, no strong evidence supports the use of systemic chemotherapy in metastatic disease. This is attributed to the relative rarity of metastatic UTUC and the absence of prospective trials. [32] Furthermore, approximately 50% of patients with metastatic urothelial carcinoma are not candidates for cisplatin-based therapy. [38]

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:

  • Gemcitabine and carboplatin [39] – Overall response rate, 41.2%; median survival, 9.3 months
  • Methotrexate, carboplatin, and vinblastine [39] – Overall response rate, 30.3%; median survival, 8.1 months
  • Gemcitabine and cisplatin given every 2 weeks (split dose) [40] – 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. [39]

A retrospective study by Huang et demonstrated the benefit of aljuvant chemotherapy in the setting of pT3 disease. The study included 171 patients with pT3N0M0 disease treated with nephroureterectomy between 2004 and 2014. Median followup was 35.8 months. Patients who received adjuvant therapy (n=60) had statistically significantly better 5-year cancer-specific survival, compared with those treated with surgery alone (n=111); (80.5% vs 57.6%, P = 0.010), as well as better recurrence-free survival (74.4% vs 52.9%, P = 0.026). [41]

Although there was no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072), there was a trend toward better overall survival in the patients who received postoperative chemotherapy. On multivariable analysis, age (P = 0.018), tumor location (P = 0.003), and adjuvant chemotherapy use (P = 0.001) were predictors of cancer-specific survival. [41]

A retrospective study by Lucca et al in 263 patients who underwent radical nephroureterectomy for lymph node–positive upper tract urothelial carcinoma, 107 (41%) of whom received three to six cycles of adjuvant chemotherapy, the use of adjuvant chemoterapy had no significant impact on cancer-related mortality, on univariable (P = 0.49) and multivariable (P = 0.11) analysis. However a stratified analysis showed a 34% reduction of cancer-related mortality with adjuvant chemotherapy in the subgroup with pT3-4 with lymph node positivity (P = 0.019). [42]

Non–cisplatin-based chemotherapy has been tried as a less toxic alternative. However, a comprehensive search of the literature did not find benefit from it. [43]

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Surgical Therapy

According to European Association of Urology (EAU) guidelines, conservative management is appropriate for low-risk upper tract urothelial carcinomas. [1] EAU indications of low risk are all of the following:

  • Unifocal tumor
  • Tumor size < 2 cm
  • Low-grade cytology 
  • Low-grade ureteroscopic biopsy
  • No evidence of an invasive lesion on CT urography

The EAU recommends offering kidney-sparing surgery as the primary treatment option for these low-risk tumors. [1]  Possible approaches are as follows:

  • Flexible ureteroscopy can be considered if complete tumor resection, laser ablation, or destruction can be achieved, but a risk of understaging and undergrading remains and closer, more stringent surveillance is needed.
  • A percutaneous approach can be used in lower caliceal tumors unsuitable for flexible ureteroscopic treatment; however, this approach is being used less frequently due to advances in equipment, including distal-tip deflection of ureteroscopes and laser technology, [44]  and it carries the risk of tumor seeding.

  • Segmental ureteral resection with wide margins provides adequate pathological specimens for staging and grading while preserving the ipsilateral kidney and permitting lymphadenectomy.

  • Complete distal ureterectomy and neocystostomy is indicated for noninvasive, low-grade tumors in the distal ureter that cannot be removed completely via endoscopy. This approach can also be utilized in select patients with high-grade tumors if renal preservation is imperative.

Nephroureterectomy with excision of the bladder cuff is considered the standard therapy in patients with high-volume renal pelvis UTUC, 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 urothelial carcinoma, 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, perinephric fat, ureter, and bladder cuff via a thoracoabdominal or flank approach, with a separate lower-quadrant Gibson or low midline incision. Laparoscopic approaches to the radical nephroureterectomy are now commonplace and offer some postoperative benefits. Open, pure laparoscopy; hand-assisted laparoscopy; and, recently, robotic-assisted laparoscopic nephroureterectomy are the currently employed techniques.

National Surgical Quality Improvement Program (ACS NSQIP) data on nephroureterectomy showed that 69% of cases between 2006 and 2012 were completed with a minimally invasive approach and that perioperative complications were similar for open and minimally invasive techniques. Length of hospital stay, however, was shorter for minimally invasive nephroureterectomy. [45]

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. [46]

There are multiple effective approaches, [47] as follows:

  • Open excision and repair of cystotomy
  • Endoscopic ”pluck” technique
  • Transurethral resection of the intramural ureter
  • Intussusception technique

Xylinas et al retrospectively compared transvesical, extravesical, and endoscopic methods of bladder cuff excision, and found that  recurrence-free survival, cancer-specific survival, and overall survival were similar with all three approaches. However, the endoscopic approach was associated with a higher risk of subsequent bladder recurrence. The study population included 2681 patients from 24 international centers. [48]

Lymphadenectomy is performed for staging purposes, and potentially offers a therapeutic benefit. However, a formal lymphadenectomy requires some additional operative time and poses the following unique risks:

  • Injury to major vessels
  • Injury to nerves
  • Lymphedema
  • Lymphatic leakage

Laparoscopic nephroureterectomy

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. [49]

Recent studies have shown comparable oncologic outcomes with open and laparoscopic nephroureterectomy. [49, 50]

Simone et al conducted a randomized controlled trial that demonstrated significantly lower blood loss (104 vs 430 mL, P< 0.001) and shorter hospital stay (2.30 vs 3.65 d, P< 0.001) 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. [49]

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. [51]

Many surgeons consider large and locally advanced (T3/T4) tumors to be a relative contraindication to laparoscopic surgery. Other relative contraindications to laparoscopic surgery include prior abdominal surgery and severe chronic obstructive pulmonary disease.

Distal ureterectomy

Distal ureteral tumors may be 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. [52] A psoas hitch may be necessary for a tension-free ureteral re-implantation. Consideration should be given for an ipsilateral pelvic lymph node dissection at the time of distal ureterectomy.

Ureteroscopic treatment

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. Baskets can also be used to excise larger papillary tumors.

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.

A systematic review of ureteroscopic and percutaneous management by Cutress et al determined that approximately 20% of 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. [26]

Cutress et al also reported their 20-year experience with endoscopic management. [53] 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.

In another study of 90 patients with UTUC managed endoscopically who had a history of bladder cancer, the recurrence-free survival rate at 5 years was only 29%. The authors of this study recommended a low threshold for more aggressive surgical intervention based upon stage and grade migration. [54]

Grasso et al published their 15-year experience of ureteroscopic and extirpative therapy and concluded that ureteroscopic management was an acceptable option for managing low-grade disease. [55]

The following are technical considerations for ureteroscopic treatment of upper tract tumors [56] :

  • Obtain adequate tissue during initial biopsy for accurate diagnosis and grade

  • When ablating ureteral tumors, minimize the risk of stricture with the use of laser rather than the more deeply penetrating electrosurgical devices

  • 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 treatment

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 and then 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 non-standardized 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. [56, 57]

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. [58]

Lymph node dissection

Several studies have demonstrated a significant survival advantage in patients undergoing extensive regional lymphadenectomy at the time of open nephroureterectomy. In a retrospective analysis of 169 patients who underwent nephroureterectomy for non-metastatic upper tract urothelial carcinoma, Kondo et al reported a definite survival advantage in lymph node–positive patients with higher T stages, namely pT3 and above, who underwent a complete lymphadenectomy. Multivariable analysis showed that complete lymphadenectomy was a significant prognostic factor for cancer-specific survival (P = 0.009) as well as T stage (pT3 or less, P = 0.0004) and tumor grade (G3, P = 0.0001). [59]

A multi-institutional retrospective study by Matin et al identified characteristic patterns of lymph node metastasis in UTUC, depending on the side and anatomical location (eg, renal pelvis; proximal, mid-, or distal ureter) of the primary tumor. On the basis of those data, these authors constructed standardized templates for lymph node dissection. [60] See the image below.

Graphic representation of templates for lymph node Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.

For tumors in the right pelvis and upper ureter, Matin et al concluded that a dissection template encompassing the right hilar, paracaval, and retrocaval regions will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region to the template will improve coverage to 95.8%. [60]

For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes will increase the coverage to 90.2% of involved nodes. [60]

The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. [60]

For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side. However, adding paracaval groups for tumors on the left side and para-aortic groups for those on the right side will improve coverage to almost 100%.The final decision regarding the utility and extent of lymphadenectomy is at the discretion of the surgeon and can be modified by the intraoperative findings. [60]

Lymphadenectomy has both diagnostic and therapeutic purposes. In the TALL (T staging, architecture [papillary vs sessile], lymphovascular invasion, lymphadenectomy) multivariable prognostic variable created by Youssef et al, the absence of lymphadenectomy is a poor prognostic factor. [61]

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Follow-up

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, from 15-50%. The bladder should be surveyed routinely.

In patients 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 for 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 urothelial carcinoma (UTUC).

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. [62]

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. A prospective study by Siemens et al determined that the accuracy of diagnostic markers was as follows [63] :

  • Urinary fibrinogen/fibrin degradation products (FDPs) – Sensitivity 100%, specificity 83%
  • Bladder tumor antigen (BTA) – Sensitivity 50%, specificity 62%
  • Urine cytology – Sensitivity 29%, specificity 59%

For patient education resources, see the Guide to Kidney Cancer.

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Complications

Complications related to nontreatment include disease progression, obstruction, bleeding, infection, metastasis, and death. See the images below.

CT scan demonstrating bulky right renal pelvis upp CT scan demonstrating bulky right renal pelvis upper tract urothelial carcinoma (UTUC) replacing the majority of the renal parenchyma. A pericaval lymph node metastasis is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
CT scan demonstrating metastatic upper tract uroth CT scan demonstrating metastatic upper tract urothelial carcinoma (UTUC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the spine. The superior portion of the right kidney is observed. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.

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. The 30-day perioperative mortality is 1.8%. The risk of a positive surgical margin is 8.5%. [64]

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. [26] 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.

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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 patients with upper tract urothelial cancer, the unadjusted 5-year survival rate is approximately 57%. On multivariable analysis, only stage and age were significant prognostic factors for survival. [64]

Gandaglia et al examined the Surveillance, Epidemiology, and End Results (SEER) database of 9899 upper tract urothelial carcinoma (UTUC) patients undergoing radical nephroureterectomy and determined that cancer-specific mortality was 18.1%, other-cause mortality was 9.1%, and bladder cancer mortality was 31.2%. Both cancer-specific mortality and other-cause mortality increased with age. Although cancer-specific mortality and bladder cancer mortality increased with advancing stage, all-cause mortality remained stable. [65]

A multivariate competing risk regression model showed that besides age and stage, risk factors for higher cancer-specific mortality included the following [65] :

  • Type of surgery
  • Female sex
  • Tumor location
  • Tumor grade

Bladder cancer mortality correlated with ureteral location, stage, and grade. [65]

Reported recurrence rates vary. 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. [66]

Biopsy grade is generally accepted as accurate and correlates to pathologic findings. [10] Conversely, owing to the difficulties in obtaining muscle in biopsy specimens and the limitations of imaging, the up-staging rate is 45%. [67]

Advanced age has previously been shown to be related to poor clinical outcomes, including cancer-specific and overall survival. [68] However, a study by Chromecki et al found that a high percentage of elderly patients who underwent radical nephroureterectomy were cured, suggesting that chronological age alone is an unreliable criterion for outcome in older patients. [69]

American Society of Anesthesiologists scores significantly correlate with cancer-specific survival after radical nephroureterectomy. [70]

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. [71]

Tumor location, (ie, 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. [10]

Hydronephrosis predicts advanced pathologic stage, metastasis, and cancer-specific survival. [16, 72, 73]

For patients with a higher body mass index who were treated with radical nephroureterectomy, a study by Ehdaie et al found that overall survival rates were diminished. [74]

A history of bladder cancer and a delay to definitive therapy are associated with worse outcomes. Tumor characteristics that predict worse outcomes include the following [10, 75] :

  • Higher pathologic stage
  • Higher pathologic grade
  • Presence of carcinoma in situ
  • Lymph node invasion
  • Lymphovascular invasion
  • Tumor multifocality
  • Sessile growth pattern
  • Larger tumor size
  • Tumor necrosis
  • Positive surgical margins
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Future and Controversies

In the future, 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. [76]

Makise et al identified Melanoma Associated Antigen A (MAGE-A) as a promising prognostic indicator, as well as a potential future immunotherapeutic target for UTUC. Expression of MAGE A was associated with higher histologic grade; concomitant carcinoma in situ; higher Ki -67 proliferation index; and infiltration of CD3-, CD8-, and CD45RO-positive lymphocytes. High MAGE-A expression was significantly associated with shorter metastasis-free survival after nephroureterectomy. [77]

UTUC tumors also demonstrate mismatch repair deficiency, which can be utilized for targeted immunotherapy. Castro et al demonstrated, through molecular profiling, the presence of the hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy in a patient with sporadic, high-grade urothelial carcinoma of the renal pelvis. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6. Immunohistochemical staining for programmed cell death ligand-1 (PD-L1) revealed 2+ staining in 80% of cells. The patient had a complete remission with immunotherapy utilizing MEDI4736 and MEDI0680, demonstrating the potential of this therapy in selected patients. [78]

 Urothelial carcinoma is also susceptible to checkpoint inhibition. In a landmark paper, Alexandrov et al characterized the prevalence of somatic mutations across human cancer types. Leading the way with the highest mutational burden were melanoma and non–small cell lung cancer (both adenocarcinoma and squamous cell carcinoma), the tumor types for which checkpoint inhibition have proven the most efficacious to date, followed closely by urothelial carcinoma. [79]

The first studies evaluating checkpoint inhibitors in urothelial carcinoma of the bladder involved ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte–associated antigen. In a "window of opportunity" study, 12 patients with high-grade T1/2 urothelial carcinoma who received two doses of ipilimumab prior to radical cystectomy demonstrated measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. Increased frequency of those cells may be a biomarker that correlates with increased likelihood of clinical benefit. [80]

In a subsequent study (NCT01524991), the addition of ipilimumab to chemotherapy with gemcitabine and cisplatin led to increased levels of circulating CD4+ and CD8+ cells and induced a potentially more immunostimulatory environment. [81]

Updated safety and efficacy results were presented at the Genitourinary Cancers Symposium in January 2016. [82] In 36 evaluable patients, the overall response rate was 64%, with 5 patients (14%) achieving a pathologic complete response. A high rate of adverse events were noted, namely 72% grade 3/4 adverse events and autoimmune adverse events. The study did not meet its primary endpoint of improved 1-year overall survival (OS).

Use of the PD-1 inhibitor pembrolizumab (MK-3475) in a large, multi-arm phase I trial that included 33 patients with recurrent or metastatic PD-L1–positive urothelial carcinoma resulted in an overall response rate of 28%. The median OS was reported as 12.7 months. Three patients achieved complete remission. [83]

Data have also emerged for atezolizumab. In the MPDL3280A trial, which accepted urothelial carcinoma patients irrespective of PDL-1 staining status, the overall response rate was 34%, with 87 total patients evaluable, but notably, the response rate was 50% in the 46 patients with immune clel 2/3 status, with nine complete responses. Azetolizumab has been granted a “breakthrough therapy designation “ based on those results. [84]

Another PD-1 inhibitor, nivolumab, is currently being studied in a phase II single-arm study in patients with platinum-refractory metastatic urothelial carcinoma. In the near future, checkpoint inhibitors could be combined for better results. The above studies on metastatic urothelial carcinoma could be extrapolated to UTUC in the future.

In the near future, personalized genetic profiling of primary or metastatic tumor cells may become readily available for routine clinical decision-making, potentially allowing for identification of patients who are likely to respond to systemic therapy . [85]

Staging is often inadequate with currently available imaging. Future approaches should include the capability to delineate invasive from superficial disease.

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