Urothelial Tumors of the Renal Pelvis and Ureters: Practice Essentials, Epidemiology, Etiology (original) (raw)

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.

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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.

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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.

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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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Presentation

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

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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.

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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.

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Contraindications

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, systemic therapy (ie, chemotherapy) should be instituted.

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Author

Kyle A Richards, MD, FACS Assistant Professor, Department of Urology, University of Wisconsin School of Medicine and Public Health; Chief of Urology, Division of Urology, William S Middleton Memorial Veterans Hospital

Kyle A Richards, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Urological Association

Disclosure: Nothing to disclose.

Coauthor(s)

David F Jarrard, MD Professor of Urologic Surgery and Molecular and Environmental Toxicology, Clinical Vice Chair, John P Livesey Chair in Urologic Oncology, Associate Director for Translational Reserach, Carbone Cancer Center, 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.

Specialty Editor Board

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.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Frank and Linda Vala Endowed Chair of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Division of Urology, 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 Laparoscopic and Robotic Surgeons, Society of University Urologists

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Endourological Society Board of Directors
Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical
Received research grant from: Cook Medical.

Additional Contributors

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, The Scientific Research Honor Society, 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.

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.

Acknowledgements

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.