Urothelial Tumors of the Renal Pelvis and Ureters

Updated: Nov 14, 2022
Author: Kyle A Richards, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS 


Practice Essentials

Urothelial tumors of the renal pelvis and ureters (upper urinary tract) are relatively rare. Tumors of the renal pelvis account for approximately 10% of all renal tumors and only 5% of all urothelial tumors of the urinary tract. Ureteral tumors occur about one half as often as tumors located in the renal pelvis. Urothelial carcinomas account for more than 95% of urothelial tumors of the upper urinary tract.


The estimated annual incidence in Western countries is approximately two cases per 100,000 population.[1] However, the incidence may be increasing: a population-based study in Norway reported an incidence of 4.7 per 100,000, representing 13% of all urothelial cancers from 2014-2018.[2]

The mean age in persons who develop upper urinary tract urothelial tumors is 65 years. The incidence of urothelial carcinoma increases with age. The peak incidence is in those in their 70s and 80s.

Upper tract urothelial tumors are more common in men, with a male-to-female ratio of 3:1. Upper tract urothelial tumors are twice as common in white people as in people of African descent.

Unlike bladder cancer, in which 80% of tumors are noninvasive, only 40% of upper tract tumors are noninvasive.


Tobacco smoking is the factor most strongly associated with upper tract urothelial carcinoma (UTUC) and increases the risk more than 3-fold. Estimates point to smoking as the cause of 70% of UTUC in men and 40% in women.

Drinking coffee slightly increases the risk of UTUC; this risk factor is typically observed in people who consume more than seven cups of coffee per day.

Analgesic abuse is also a risk factor for UTUC. It is independent from and synergistic with renal papillary necrosis. Long-term exposure to analgesics, notably phenacetin, induces a nephropathy that raises the risk of UTUC to as high as 70%. Capillarosclerosis, which is characterized by a thickening of the basement membrane, is the pathognomonic finding of analgesic abuse and is found in 15% of patients with upper urinary tract tumors. In contrast, Shih et al demonstrated a risk reduction in UTUC with use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in those patients who quit smoking at least 10 years previously.[3]

Occupational exposure to agents used in the petrochemical, plastic, and tar industries has been linked to an increased risk of UTUC.

Chronic infections, irritation, and calculi may also predispose to squamous cell carcinoma and, less commonly, adenocarcinoma of the upper urinary tract.

Cyclophosphamide has been linked to the development of urothelial tumors. More specifically, a breakdown metabolite called acrolein is thought to be the causative agent. Tumors associated with cyclophosphamide tend to be high-grade.

UTUC is associated with Balkan nephropathy, which is a degenerative interstitial nephritis linked to the consumption of aristolochic acid (contained in some plants in the Balkans). Tumors associated with Balkan nephropathy are generally low-grade, multiple, and bilateral, in contrast to urothelial carcinoma of other etiologies.

Finally, heredity can play a part in the development of urothelial carcinoma. Urothelial carcinoma is associated with Lynch syndrome type II (hereditary nonpolyposis colorectal carcinoma), which is a syndrome characterized by an early onset of proximal colonic nonpolyposis tumors, numerous synchronous and metachronous colonic tumors, and extracolonic tumors. If patients younger than 60 years old are diagnosed with UTUC, a thorough family history should be taken and they should be counseled about genetic testing and Lynch syndrome.


Types of upper urinary tract tumors

Urothelial carcinoma is the most common histology observed, accounting for greater than 95% of upper urinary tract urothelial tumors. As noted above, urothelial carcinomas are strongly associated with smoking.

Squamous cell carcinoma comprises 1-7% of upper tract urothelial tumors. Squamous cell carcinoma is frequently associated with longstanding infected staghorn calculi. Affected patients frequently present with moderately to poorly differentiated tumors and advanced disease.

Adenocarcinoma accounts for less than 1% of upper tract tumors. Patients with adenocarcinoma of the upper urinary tract may also have associated calculi and long-term obstruction, suggesting an etiologic origin for these processes.

Inverted papilloma is an unusual lesion that is generally considered a benign histologic lesion; however, it may harbor foci of malignant change.

Molecular mechanisms and markers


Several molecular mechanisms have been associated with the development of UTUC. Tumor suppressor genes P19, P16, RB1, and P53 have all been associated with UTUC. Losses of P53, P19, and P16 are associated with low-grade cancers, while a loss of RB1 has been associated with higher-grade, more aggressive tumors.[4]


Tumor microsatellite instability (MSI) has been studied as a prognostic indicator for upper urinary tract tumors. In general, high levels of MSI seem to correlate with a more favorable prognosis, particularly in younger patients with T2 or T3/N0 disease (see Staging).[5, 6]

E-cadherin, hypoxia-inducible factor-1α, Ki-67, survivin (a protein apoptosis inhibitor), epidermal growth factor receptor (EGFR), and telomerase RNA component have been identified as independent markers of advanced disease and/or prognosis. However, none has been externally validated or widely used.[7, 8, 9, 10] In a multivariable analysis, P53 was not an independent predictor of prognosis.[11]

Survivin has been measured in the urine of patients with urothelial carcinoma of the bladder and was found to be highly sensitive and specific for the presence of this malignancy.[12] Further biomarker work in UTUC is needed.

Patterns of spread

Urothelial tumors spread conventionally in a cephalad to caudad direction. For instance, studies have shown a high rate of recurrence in the distal ureteral stump in patients treated with nephrectomy and incomplete ureterectomy. Conversely, urothelial carcinoma rarely recurs proximal to the level of resection of a ureteral lesion.

Approximately 30-75% of patients with UTUC develop bladder tumors at some point during their cancer course. The risk of UTUC in patients with a bladder malignancy is 2-4%, but as high as 21-25% in patients with carcinoma in situ. Thus, higher grade seems to increase the risk of upper tract disease. An analysis of 1069 bladder cancer patients with 10-year follow-up showed an upper urinary tract recurrence in 2.5% of patients at a median time interval of 3.3 years.[13]

Lymphatic extension is another pattern observed in urothelial carcinoma. The most common locations for spread, depending on the site of the primary tumor, include paraaortic, paracaval, ipsilateral common iliac, and the pelvic lymph nodes (for distal ureteral tumors).

Hematogenous seeding also occurs, with the liver, lung, and bone being the most common sites for metastases.

Distribution of upper tract urothelial cell carcinoma

Rates of distribution for UTUC are as follows:

  • Renal pelvis: 58%
  • Ureter: 35% (73% of which are located in the distal ureter)
  • Both renal pelvis and ureter: 7%
  • Bilateral: 2-5%


Clinical manifestations of uurothelial tumors of the renal pelvis and ureters include the following:

  • Gross or microscopic hematuria - 75% of patients; the most common clinical finding
  • Flank pain - 20% of patients; results from gradual obstruction/distention of the collecting system or, in cases of acute colic, from obstruction by a blood clot
  • Dysuria or irritative voiding symptoms - 6% of patients
  • Weight loss, anorexia, flank mass, or bone pain - manifestations of advanced disease that manifest in a minority of patients


Radical nephroureterectomy with excision of the bladder cuff is the criterion standard treatment for all forms of upper tract urothelial carcinoma (UTUC). Laparoscopic or robotic radical nephroureterectomy is being used in many cases and offers the potential benefits of lower blood loss and shorter hospitalization. Cancer control outcomes appear to be equivalent.

Segmental ureterectomy (ie, distal ureterectomy) coupled with ureteral reimplantation can be used for lower-grade superficial urothelial tumors located in the distal ureter, or higher-grade tumors when nephron-sparing is imperative (impaired renal function, solitary kidney, or bilateral tumors).

Nephron-sparing surgery (including segmental ureterectomy, ureteral ablation, or endoscopic or percutaneous resection) is typically used in patients with small, lower-grade, superficial lesions. Additionally, patients who would be at risk for dialysis after nephroureterectomy and those who are medically unfit for radical surgery can be offered nephron-sparing techniques.

Relevant Anatomy

The renal pelvis is the portion of the urinary collecting system formed by the confluence of two or three major calices. The ureter is a 20- to 30-cm tubular structure lying on the psoas muscle. It follows an S-shaped curve, passing medially to the sacroiliac joint and then coursing laterally near the ischial spine before passing medially to penetrate the base of the bladder. It passes through a submucosal tunnel to empty into the bladder.


The renal pelvis and ureter are lined by a urothelial epithelium. The next layer is the lamina propria. External to the lamina propria is smooth muscle arranged in a spiral and longitudinal manner. The outermost adventitia is composed of fibrous connective tissue.


Relative contraindications that must be addressed prior to surgical treatment include the following:

  • Active infection
  • Uncorrected bleeding disorders
  • Renal insufficiency
  • Severe comorbidities, especially cardiac or pulmonary conditions
  • Advanced age

Surgical treatment is generally not warranted in patients with advanced metastatic disease. Instead, systemic therapy (ie, chemotherapy) should be instituted.



Laboratory Studies

Laboratory studies that should be ordered include the following:

  • Urinalysis – To confirm hematuria and to rule out a coexistent urinary tract infection
  • Basic metabolic panel – To check serum creatinine (to assess kidney function by permitting calculation of the glomerular filtration rate) and electrolytes
  • Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase
  • Complete blood count

Imaging Studies

Excretory urography, commonly referred to as intravenous pyelography (IVP), has traditionally been used to evaluate the upper urothelial tract, but has been primarily replaced with multidetector computed tomography (CT).[14, 15] Approximately 50-75% of patients with urothelial tumors of the renal pelvis and ureters have a radiolucent filling defect that is characteristically irregular and in continuity with the wall of the collecting system. (See the image below.) Approximately 10-30% of such tumors cause obstruction or non-visualization of the collecting system.

Intravenous pyelogram (IVP) demonstrating an upper Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.

Noncontrast CT scanning can be performed, followed by a contrast study, with particular interest in the excretory phase — a so-called CT urogram. Plain radiography, which demonstrates drainage and anatomy, can also be performed after CT scanning. Upper tract urothelial carcinomas (UTUCs) are usually visible as an irregular filling defect. They tend to be hypovascular in comparison with the rest of the kidney and demonstrate minimal increased attenuation (enhancement) following intravenous contrast injection. See the images below.

CT scan demonstrating right renal pelvis upper tra CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
CT scan demonstrating left distal ureteral upper t CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.

CT scanning sensitivities and specificities based on lesion size are as follows:

  • For lesions 5-10 mm in size - 96% sensitivity and 99% specificity
  • For lesions smaller than 5 mm in size - 89% sensitivity
  • For lesions smaller than 3 mm in size - 40% sensitivity

CT scanning has limited value in staging UTUC because stage Ta or superficial lesions cannot be differentiated from T2 or invasive lesions (see Staging). However, CT scanning is helpful in demonstrating peripelvic or periureteral tumor extension, thereby assisting with staging of aggressive disease. Hydronephrosis and obstruction are associated with a higher degree of invasiveness.

As with CT scanning, magnetic resonance imaging (MRI) is also of limited use in staging early UTUC; however, it may have greater utility in more advanced disease or in patients with limited renal function. European Association of Urology guidelines note that although CT urography is generally preferred to MRI urography for diagnosing and staging, MR urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated. However, the use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (creatinine clearance < 30 mL/min), due to the risk of nephrogenic systemic fibrosis.[1]

There is interest in fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT for staging in urothelial carcinoma, but, at present, this technique does not appear to have significant advantages over MRI.[16]

Other Tests

Cytopathology of voided urine samples yields low sensitivity, especially for low-grade tumors, which results in normal cytology results in up to 80% of cases. The sensitivity of cytopathology increases for higher-grade tumors, which tend to shed more tumor cells. Cytology yields an accuracy of 83% in patients with high-grade disease. Cytology is less sensitive for UTUC than for bladder cancer.

Cytology samples should be taken from as near the suspected lesion as possible (eg, within the calyceal system if the tumor is suspected in that region). Positive cytology has been associated with more advanced (invasive) disease.[17] Selective washings of both the upper tracts and the bladder can aid in tumor localization. Cytology plays a role in urothelial tumor surveillance in conjunction with cystoscopy/ureteroscopy.

Fluorescence in situ hybridization (FISH) can be performed using probes for altered genes on chromosomes 3, 7, 17, and 9p21. FISH (UroVysion) is a useful test for detecting urinary tract cancer, as it yields a greater sensitivity for lower-grade tumors than cytology and other tests (as high as 76.6-100% vs 21-24% for cytology).[18, 19] Ureteral cancer has been detected with FISH during evaluation for hematuria.[20] FISH has equal specificity when compared with cytology (as high as 100%).

Flexible or rigid ureteroscopy can be used for direct visualization of a tumor. Important to note is that it can be used to obtain tissue (biopsy) for a diagnosis (histology) and grade in 90% of cases.[21] Staging information regarding depth of invasion, however, is more difficult to obtain.


Diagnostic Procedures

Each of the following should be obtained in a suspected case of UTUC:

  • Cystoscopy – To rule out bladder tumor
  • Urinary cytology
  • CT urography

For cystoscopy, a small fiberoptic scope is inserted through the urethra in order to visualize the bladder. This ambulatory/clinical procedure is usually well tolerated by both women and men. A 16F flexible cystoscope is typically used. This procedure is mandatory to rule out coexistent bladder lesions, which occur with a frequency of 8-13%.[1] Cystoscopy is also essential for postoperative surveillance to monitor for bladder tumor development; bladder recurrence occurs in 15-51% of patients with UTUC.[22]

In retrograde urography (see image below), contrast is injected into the ureteral orifice with the aid of a cystoscope and a ureteral access catheter. This can be performed with fluoroscopic guidance or with standard radiography plates. Retrograde urography allows better visualization of the collecting system than excretory urography by increasing the distention of the urinary collecting system. Retrograde pyelography is preferable in patients with azotemia and/or contrast allergy. Overall, retrograde urography is more than 75% accurate in establishing a diagnosis of urothelial cancer.

Left retrograde ureterogram demonstrating the clas Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.

Since the advent of rigid and flexible ureteroscopes, ureteropyeloscopy is used increasingly for the diagnosis of upper tract urothelial tumors. Biopsy forceps or cytology brushings can be used to collect tissue. This procedure yields an accuracy of 86% in diagnosing renal pelvis tumors and 90% in diagnosing ureteral tumors. Large size, broad base, and nonpapillary pattern favor tumor invasiveness. Studies have demonstrated that 85% of urothelial lesions in the renal pelvis are papillary papillary in morphology. The complication rate associated with ureteropyeloscopy is approximately 7%; these include perforation, complete disruption, and ureteral stricture.

Percutaneous nephroscopy is not indicated for the diagnosis of urothelial tumors of the renal pelvis and ureters because of the theoretical risk of tumor cell implantation in the retroperitoneum and nephrostomy tube tract. It is used for treatment in selected situations when nephron-sparing approaches are necessary.

Nevertheless, Huang et al concluded that percutaneous biopsy is safe and effective for diagnosis of upper tract urothelial lesions that are not amenable to endoscopic biopsy. In their study of 26 upper tract lesions in 24 patients, percutaneous biopsy provided tissue diagnosis in 85% of cases; the three recurrences in the nephrectomy bed developed at sites remote from the biopsy site and thus were not attributed to tract seeding.[23]


The distribution of tumor stages and grades differs from study to study. Stage and grade yield the greatest prognostic value.

The National Comprehensive Cancer Network (NCCN) guidelines grade urothelial histologies according to the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) classification, as follows[24] :

  • Low grade 
  • High grade 

Squamous cell carcinoma and adenocarcinoma use the following grading classifications[24] :

  • GX—Grade cannot be assessed
  • G1—Well differentiated
  • G2—Moderately differentiated
  • G3—Poorly differentiated 

Staging is based on the depth of tumor invasion and classified using the tumor, node, metastases (TNM) system.[25]  

Primary tumor categories are as follows:

  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • Ta - Papillary noninvasive carcinoma
  • Tis - Carcinoma in situ
  • T1 - Subepithelial connective tissue invasion (lamina propria invasion)
  • T2 - Muscularis invasion
  • T3 – For renal pelvis only: Tumor invades beyond muscularis into peripelvic fat or the renal parenchyma
  • T3 - For ureter only - Tumor invades beyond muscularis into periureteric fat
  • T4 - Tumor invades adjacent organs, or through the kidney into the perinephric fat 

Regional lymph node categories are as follows:

  • NX - Regional lymph nodes cannot be assessed
  • N0 - Negative nodes
  • N1 - Metastasis ≤2 cm in greatest dimension in a single lymph node
  • N2 - Metastasis  > 2 cm in a single lymph node, or multiple lymph nodes

Distant metastasis categories are as follows:

  • M0 - No distant metastasis
  • M1 - Distant metastasis

The location of the tumor can affect the findings. Renal pelvis tumors are more commonly invasive than bladder tumors, possibly because of delayed diagnosis and a less well-developed muscle layer.

Table 1. American Joint Committee on Cancer Prognostic Groups (Open Table in a new window)



























NX, N0


Any T



Any T



Any T

Any N




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 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.[26]

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[24]  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.[27]  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.[28] 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.[29] 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.[30] 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.[31]

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.[32]

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


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.[33] 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)


Study design


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




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


Expected to complete by Feb 2020



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

Expected to complete by Dec 2020


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.[34]

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.[35] 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.[36] 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.[37]

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.[38]

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

Metastatic and node-positive disease


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.[33] Furthermore, approximately 50% of patients with metastatic urothelial carcinoma are not candidates for cisplatin-based therapy.[39]

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 [40] – Overall response rate, 41.2%; median survival, 9.3 months
  • Methotrexate, carboplatin, and vinblastine [40] – Overall response rate, 30.3%; median survival, 8.1 months
  • Gemcitabine and cisplatin given every 2 weeks (split dose) [41] – 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.[40]

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).[42]

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.[42]

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).[43]

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.[44]

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
  • Negative for high-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,[45]  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.[46]

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.[47]

There are multiple effective approaches,[48] 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.[49]

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.[50]

Recent studies have shown comparable oncologic outcomes with open and laparoscopic nephroureterectomy.[50, 51]

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.[50]

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.[52]

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.[53] 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.[27]

Cutress et al also reported their 20-year experience with endoscopic management.[54] 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.[55]

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.[56]

The following are technical considerations for ureteroscopic treatment of upper tract tumors[57] :

  • 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.[57, 58]

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.[59]

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).[60]

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.[61] 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%.[61]

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.[61]

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.[61]

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.[61]

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.[62]


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.[63]

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[64] :

  • 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.


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%.[65]

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.[27] 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 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.[65]

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.[66]

A multivariate competing risk regression model showed that besides age and stage, risk factors for higher cancer-specific mortality included the following[66] :

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

Bladder cancer mortality correlated with ureteral location, stage, and grade.[66]

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.[67]

Biopsy grade is generally accepted as accurate and correlates to pathologic findings.[11] Conversely, owing to the difficulties in obtaining muscle in biopsy specimens and the limitations of imaging, the up-staging rate is 45%.[68]

Advanced age has previously been shown to be related to poor clinical outcomes, including cancer-specific and overall survival.[69] 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.[70]

American Society of Anesthesiologists scores significantly correlate with cancer-specific survival after radical nephroureterectomy.[71]

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.[72]

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.[11]

Hydronephrosis predicts advanced pathologic stage, metastasis, and cancer-specific survival.[17, 73, 74]

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.[75]

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[11, 76] :

  • 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

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.[77]

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.[78]

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.[79]

 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.[80]

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.[81]

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.[82]

Updated safety and efficacy results were presented at the Genitourinary Cancers Symposium in January 2016.[83] 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.[84]

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.[85]

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 .[86]

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



Guidelines Summary

Guidelines on the diagnosis and treatment of urothelial tumors of the renal pelvis and ureters have been published by the following organizations:

  • National Comprehensive Cancer Network (NCCN)
  • European Association of Urology (EAU)


The NCCN guidelines recommend including the following tests in the workup of suspected renal pelvic and ureteral tumors[24] :

  • Cystoscopy
  • CT or MR urography
  • Renal ultrasound or CT without contrast with retrograde pyelography for patients who cannot receive iodinated or gadolinium-based contrast agentsl.
  • Ureteroscopy with biopsy and/or selective washings.
  • Kidney function tests
  • Chest x-ray to help evaluate for possible metastasis and assess for comorbidities
  • Urine cytology to help identify carcinoma cells

Additional imaging studies, such as renal or bone scanning, may be indicated by the test results or presence of specific symptoms. Evaluation for Lynch syndrome should be considered for those at high risk.

The EAU guidelines in general concur with NCCN and include the following key recommendations[1] :

  • Cystoscopy is performed to rule out concurrent bladder tumor
  • CT urography is performed for upper tract evaluation and staging
  • Diagnostic ureteroscopy and biopsy are performed only in cases where additional information will impact treatment decisions
  • Magnetic resonance urography or  18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT may be used when CT is contraindicated.


The NCCN guidelines provide treatment recommendations based on grade and tumor location. For low-grade renal pelvic tumors, the guidelines recommend the following treatment[24] :

  • Nephroureterectomy with cuff of bladder with or without perioperative intravesical chemotherapy or
  • Endoscopic resection with or without postsurgical intrapelvic chemotherapy or bacillus Calmette-Guerin (BCG) 

For high-grade renal pelvic tumors and upper ureter tumors, NCCN treatment recommendations include the following[24] :

  • Nephroureterectomy with cuff of bladder and regional lymphadenectomy with or without perioperative intravesical chemotherapy
  • Neoadjuvant chemotherapy may be considered in selected patients

For low-grade upper- and mid-ureter tumors, NCCN recommended treatment options include the following[24] :

  • Endoscopic resection

For high-grade upper- and mid-ureter tumors, NCCN recommended treatment options include the following[24] :

  • Nephroureterectomy with cuff of bladder and regional lymphadenectomy
  • Consider neoadjuvant chemotherapy in selective patients
  • Excision and ureteroureterostomy/ileal ureter in highly selected patients

For distal ureter tumors, NCCN recommended treatment options include the following[24] :

  • Distal ureterectomy and regional lymphadenectomy (high grade) and reimplantation of ureter (preferred if clinically feasible) and consider neoadjuvant chemotherapy in selected patients
  • Endoscopic resection (low grade)
  • Nephroureterectomy with cuff of bladder and regional lymphadenectomy and consider neoadjuvant chemotherapy in selected patients

For metastatic disease in both renal pelvis and ureter tumors, systemic therapy is recommended by both guidelines.[1, 24]

The EAU guidelines include the following key treatment recommendations[1]

  • Kidney-sparing management is the primary treatment option for low-risk tumors.
  • Kidney-sparing management should be offered to patients with high-risk distal ureteral tumors.
  • Kidney-sparing management should be offered to select patients with solitary kidney and/or impaired renal function, provided it will not compromise survival.
  • For high-risk tumors, radical nephroureterectomy with cuff of bladder and regional lymphadenectomy and postoperative bladder instillation of chemotherapy should be offered.


Medication Summary

Chemotherapy and BCG are often administered intravesically. Intravesical therapy may reduce or delay the progression of cancer to a higher stage. Most commonly used chemotherapy agents are mitomycin and gemcitabine.[24]

Patients may also receive systemic chemotherapy depending on severity and recurrence of the tumors. Neoadjuvant chemotherapy may be considered for select patients with UTUC (eg, higher stage, grade tumor).

Antineoplastics, Antibiotic

Mitomycin pyelocalyceal (Jelmyto, Vesigel)

Mitomycin is an alkylating drug isolated from the broth of Streptomyces caespitosus. It inhibits DNA synthesis. At high concentrations of mitomycin, cellular RNA and protein synthesis are also suppressed. This formulation is for pyelocalyceal use only. It is indicated for treatment of adults with low-grade upper tract urothelial cancer (LG-UTUC).


Mitomycin selectively inhibits DNA synthesis. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Like BCG intravesical, this formulation of mitomycin is for intravesical use.

Biological Response Modifiers

Class Summary

These agents modify immune responses, either by enhancing or suppressing it.

BCG intravesical live (Tice BCG)

BCG intravesical contains live, attenuated mycobacteria. It is indicated for prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection (TUR). Not recommended for stage TaG1 papillary tumors, unless diagnosed as high risk of tumor recurrence.

Antineoplastics, Antimetabolite

Class Summary

These agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.


Methotrexate inhibits dihydrofolate reductase (DHFR), causing a block in the reduction of dihydrofolate to tetrahydrofolate. This inhibits the formation of thymidylate and purines and arrests DNA, RNA, and protein synthesis. It is one of the components in the MVAC regimen and is used for the treatment of urothelial carcinoma. 

Gemcitabine (Gemzar)

Gemcitabine is a pyrimidine analog. After intracellular metabolism to its active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used in combination with cisplatin is the preferred perioperative chemotherapy regimen for urothelial cancer.

Antineoplastics, Vinca Alkaloid

Class Summary

Vinca alkaloids act on the M and S phases of mitosis, inhibiting microtubule formation and inhibiting DNA/RNA synthesis.


A vinca alkaloid with a cytotoxic effect (as a result of causing mitotic arrest), vinblastine binds to a specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. It used as a treatment for urothelial carcinoma in the MVAC regimen.

Antineoplastics, Anthracycline

Class Summary

Anthracyclines inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.


Doxorubicin is an anthracycline antineoplastic that causes DNA strand breakage through effects on topoisomerase II and direct intercalation into DNA, which causes DNA polymerase inhibition. It used as a treatment for urothelial carcinoma in the MVAC regimen.

Antineoplastics, Alkylating

Class Summary

Alkylating agents inhibit cell growth and proliferation. They inhibit DNA synthesis by the formation of DNA cross-links.


Cisplatin is a platinum-containing compound that covalently binds to DNA, binds to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. This may interference with DNA transcription and/or replication, which may trigger cytotoxic effects.


Questions & Answers


What are urothelial tumors of the renal pelvis and ureters?

What is the prevalence of urothelial tumors of the renal pelvis and ureters?

What causes urothelial tumors of the renal pelvis and ureters?

What are the histologic types of urothelial tumors of the renal pelvis and ureters?

What is the role of molecular mechanisms in the pathophysiology of urothelial tumors of the renal pelvis and ureters?

What are the molecular markers for urothelial tumors of the renal pelvis and ureters?

What is the progression of urothelial tumors of the renal pelvis and ureters?

What is the site distribution of upper tract transitional cell carcinoma (TCC)?

What are the signs and symptoms of urothelial tumors of the renal pelvis and ureters?

When is surgery indicated for urothelial tumors of the renal pelvis and ureters?

What is the anatomy of the kidney relevant to urothelial tumors of the renal pelvis and ureters?

What are the contraindications to surgery for urothelial tumors of the renal pelvis and ureters?


What is the role of lab tests in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of imaging studies in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of CT scanning in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of 18 F-FDG PET/CT in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of cytology in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of fluorescence in situ hybridization (FISH) in the workup of urothelial tumors of the renal pelvis and ureters?

What is the role of ureteroscopy in the workup of urothelial tumors of the renal pelvis and ureters?

How is upper tract transitional cell carcinoma (TCC) diagnosed?

How are urothelial tumors of the renal pelvis and ureters staged?


How is upper tract transitional cell carcinoma (TCC) treated?

How are superficial (Ta, T1) and carcinoma in situ urothelial tumors of the renal pelvis and ureters treated?

How are muscle invasive (T2) and locally advanced (T3, T4) urothelial tumors of the renal pelvis and ureters treated?

How are metastatic and node-positive urothelial tumors of the renal pelvis and ureters treated?

What are the EAU guidelines on the treatment of low-risk upper tract urothelial carcinomas?

What is the role of nephroureterectomy in the treatment of urothelial tumors of the renal pelvis and ureters?

What is the role of segmental ureterectomy with ureteral reimplantation in the treatment of urothelial tumors of the renal pelvis and ureters?

What is the role of renal-sparing surgery in the treatment of urothelial tumors of the renal pelvis and ureters?

How is open radical nephroureterectomy performed for the treatment of urothelial tumors of the renal pelvis and ureters?

What are indications for laparoscopic nephroureterectomy in the surgical treatment of urothelial tumors of the renal pelvis and ureters?

What are differences between open and laparoscopic nephroureterectomy in the surgical treatment of urothelial tumors of the renal pelvis and ureters?

What is the role of distal ureterectomy in the surgical treatment of urothelial tumors of the renal pelvis and ureters?

What is the role of ureteroscopy in the treatment of urothelial tumors of the renal pelvis and ureters?

What is the role of percutaneous therapy in the treatment of urothelial tumors of the renal pelvis and ureters?

What are the differences in outcomes between radical nephroureterectomy and conservative, endoscopic management of urothelial tumors of the renal pelvis and ureters?

What is the role of lymph node dissection in the surgical treatment of urothelial tumors of the renal pelvis and ureters?

What is included in the long-term monitoring of urothelial tumors of the renal pelvis and ureters?

What are the possible complications of urothelial tumors of the renal pelvis and ureters?

What are the survival rates for urothelial tumors of the renal pelvis and ureters following total nephroureterectomy?

What is the prognosis of urothelial tumors of the renal pelvis and ureters after treatment?

Which factors are associated with poor prognosis of urothelial tumors of the renal pelvis and ureters?

Which treatments are being investigated for urothelial tumors of the renal pelvis and ureters?


Which organizations have released guidelines on urothelial tumors of the renal pelvis and ureters?

What are the guidelines on the diagnosis of urothelial tumors of the renal pelvis and ureters?

What are the NCCN treatment guidelines for urothelial tumors of the renal pelvis and ureters?

What are the ESMO guidelines on the treatment of on treatment of urothelial tumors of the renal pelvis and ureters?


Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?

Which medications in the drug class Antineoplastics, Anthracycline are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?

Which medications in the drug class Antineoplastics, Vinca Alkaloid are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?

Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?

Which medications in the drug class Biological Response Modifiers are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?

Which medications in the drug class Antineoplastics, Antibiotic are used in the treatment of Urothelial Tumors of the Renal Pelvis and Ureters?