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.
Epidemiology
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.
Etiology
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.
Pathophysiology
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
Mechanisms
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]
Markers
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:
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Renal pelvis: 58%
-
Ureter: 35% (73% of which are located in the distal ureter)
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Both renal pelvis and ureter: 7%
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Bilateral: 2-5%
Presentation
Clinical manifestations of uurothelial tumors of the renal pelvis and ureters include the following:
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Gross or microscopic hematuria - 75% of patients; the most common clinical finding
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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
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Dysuria or irritative voiding symptoms - 6% of patients
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Weight loss, anorexia, flank mass, or bone pain - manifestations of advanced disease that manifest in a minority of patients
Indications
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.
Histology
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.
Contraindications
Relative contraindications that must be addressed prior to surgical treatment include the following:
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Active infection
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Uncorrected bleeding disorders
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Renal insufficiency
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Severe comorbidities, especially cardiac or pulmonary conditions
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Advanced age
Surgical treatment is generally not warranted in patients with advanced metastatic disease. Instead, systemic therapy (ie, chemotherapy) should be instituted.
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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.
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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.
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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.
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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.
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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.
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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.
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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%.
Tables
Stage |
Tumor |
Node |
Metastasis |
0a |
Ta |
N0 |
M0 |
0is |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
II |
T2 |
N0 |
M0 |
III |
T3 |
N0 |
M0 |
IV |
T4 |
NX, N0 |
M0 |
Any T |
N1 |
M0 |
|
Any T |
N2 |
M0 |
|
Any T |
Any N |
M1 |
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 |
Margulis V, Puligandla M, Trabulsi EJ, et al. 2020
|
Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC
|
Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy in patients with high-grade UTUC and creatinine clearance > 50 mL/min was safe and demonstrated predefined activity with a 14% pathologic complete response rate. |
23 men and 6 women with a median age of 65 years (range 40 to 84); 80% completed all planned treatments |
NCT01261728 |
Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC |
Expected to complete by Dec 2023 |
NA |
