Urothelial Tumors of the Renal Pelvis and Ureters
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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. Transitional cell carcinoma (TCC) accounts for more than 95% of urothelial tumors of the upper urinary tract.
The estimated annual incidence in Western countries is approximately two per 100,000 population. [1]
The mean age in persons who develop upper urinary tract urothelial tumors is 65 years.
The incidence of transitional cell carcinoma (TCC) 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 transitional cell carcinoma (TCC) and increases the risk more than 3-fold. Estimates point to smoking as the cause of 70% of upper tract tumors in men and 40% in women.
Drinking coffee slightly increases the risk of upper tract TCC; 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 urothelial malignancy. 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 upper tract TCC 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 upper tract TCC with use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAID)s in those patients who quit smoking at least 10 years ago. [2]
Occupational exposure to agents used in the petrochemical, plastic, and tar industries has been linked to an increased risk of TCC.
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.
Upper tract TCC 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 TCC of other etiologies.
Finally, heredity can play a part in the development of TCC. TCC 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 upper tract TCC, a thorough family history should be taken and they should be counseled about genetic testing and Lynch syndrome.
Transitional cell carcinoma (TCC) is the most common histology observed, accounting for greater than 95% of upper urinary tract urothelial tumors. TCCs 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.
Mechanisms
Several molecular mechanisms have been associated with the development of upper urinary tract TCC. Tumor suppressor genes P19, P16, RB1, and P53 have all been associated with upper urinary tract TCC. 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. [3]
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). [4, 5]
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. [6, 7, 8, 9] In a multivariate analysis, P53 was not an independent predictor of prognosis. [10]
Survivin was recently measured in the urine of patients with TCC of the bladder and was found to be highly sensitive and specific for the presence of this malignancy. [11]
Transitional 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, TCC rarely recurs proximal to the level of resection of a ureteral lesion.
Approximately 30-75% of patients with upper tract urothelial tumors develop bladder tumors at some point during their cancer course. The risk of upper tract TCC 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. [12]
Lymphatic extension is another pattern observed in TCC. 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.
Hematogenous seeding also occurs, with the liver, lung, and bone being common sites for metastases.
Rates of distribution for transitional cell carcinoma are 58% for the renal pelvis, 35% for the ureter (73% of which are located in the distal ureter), 7% for both the renal pelvis and ureter, and 2-5% for bilateral involvement.
Gross or microscopic hematuria (75%) is the most common clinical presentation of urothelial tumors of the renal pelvis and ureters.
Flank pain (20%) results from gradual obstruction/distention of the collecting system or acute colic due to obstruction by a blood clot.
Lumbar mass is noted in 10-20%.
Dysuria (6%) is reported; some patients report irritative lower urinary tract symptomatology such as burning upon urination.
Weight loss, anorexia, flank mass, or bone pain are symptoms of advanced disease that manifest in a minority of patients.
Nephroureterectomy with excision of the bladder cuff is the criterion standard treatment for all forms of upper tract transitional cell carcinoma (TCC). Contemporaneously, it is indicated in patients with large-volume renal pelvis TCC, regionally extensive disease, and high-grade or high-stage lesions.
Laparoscopic 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 coupled with ureteral reimplantation can be used for lower-grade superficial urothelial tumors located in the distal ureter.
Renal-sparing surgery (including segmental ureterectomy 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 minimally invasive and renal-sparing techniques.
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 transitional 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:
Surgical treatment is generally not warranted in patients with advanced metastatic disease. Instead, medical management (ie, chemotherapy) should be instituted.
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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
NCT02412670
Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC
Expected to complete by Feb 2020
NA
NCT01261728
Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC
Expected to complete by Dec 2017
NA
David F Jarrard, MD Professor of Urology and Molecular and Environmental Toxicology, University of Wisconsin School of Medicine and Public Health
David F Jarrard, MD is a member of the following medical societies: American Urological Association
Disclosure: Nothing to disclose.
Shivashankar Damodaran, MB, MCh Fellow in Urologic Oncology, Department of Urology, University of Wisconsin School of Medicine and Public Health
Shivashankar Damodaran, MB, MCh is a member of the following medical societies: American Urological Association
Disclosure: Nothing to disclose.
Aaron M Potretzke, MD Resident Physician, Department of Urology, University of Wisconsin Hospital and Clinics
Aaron M Potretzke, MD is a member of the following medical societies: American Medical Association, Minnesota Medical Association
Disclosure: Nothing to disclose.
Tracy Downs, MD Associate Professor of Urology, University of Wisconsin School of Medicine and Public Health
Tracy Downs, MD is a member of the following medical societies: American College of Surgeons, American Urological Association, Society of Urologic Oncology
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, Society of University Urologists
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical; Olympus.
Leonard Gabriel Gomella, MD, FACS The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Leonard Gabriel Gomella, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Urological Association, Sigma Xi, Society for Basic Urologic Research, Society of University Urologists, Society of Urologic Oncology
Disclosure: Received consulting fee from GSK for consulting; Received honoraria from Astra Zeneca for speaking and teaching; Received consulting fee from Watson Pharmaceuticals for consulting.
Daniel M Kaplon, MD Fellow in Endourology, Laparoscopy, and Robotics, Department of Urology, University of Wisconsin Medical School
Disclosure: Nothing to disclose.
John N Papadopoulos, MD Resident Physician, Department of Urology, Veterans Administration Hospital and Meriter Hospital
Disclosure: Nothing to disclose.
Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership
Michael N Wilkin, MD Staff Physician, Division of Urology, University of Wisconsin Hospital and Clinics
Disclosure: Nothing to disclose.
Urothelial Tumors of the Renal Pelvis and Ureters
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