Urothelial Tumors of the Renal Pelvis and Ureters

Updated: Sep 18, 2016
  • Author: David F Jarrard, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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Overview

Problem

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.

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Epidemiology

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.

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Etiology

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.

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Pathophysiology

Types of upper urinary tract tumors

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.

Molecular mechanisms and markers

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]

Patterns of spread

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.

Distribution of upper tract transitional cell carcinoma

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.

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Presentation

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.

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Indications

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.

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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 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.

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Contraindications

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

  • Active infection
  • Uncorrected bleeding disorders
  • Renal insufficiency
  • Severe comorbidities
  • Advanced age

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

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