Introduction
Background
Embryologic derivation of the collecting system of the urinary tract occurs from the fetal mesonephros. As a result of this development, tumors of the renal collecting system have cell origins different from those of the renal parenchyma. These tumors are classified on the basis of their respective mesodermal or epithelial tissue origin. Primary neoplasms of the renal collecting system represent 10% of renal tumors, of which approximately 80% are malignant. Most are transitional cell carcinomas (TCCs).
Bladder TCC is 50 times more common than renal pelvic tumors. Often, TCCs are multiple, involving any part or all of the collecting system. The tumors are traditionally classified into papillary and nonpapillary types. Nonpapillary tumors are considered malignant.
For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.
An intravenous urogram in a 36-year old woman who presented with evidence of a urinary tract infection and gross hematuria. A 10-minute intravenous urogram shows a filling defect in the lower pole calyx on the right. A provisional diagnosis of transitional cell carcinoma was made. Subsequent investigations and the course of events proved that the filling defect was caused by a blood clot related to the hematuria secondary to acute pyelonephritis.
Nonenhanced (top) and enhanced (bottom) CT scans through the kidneys in the same patient as in Images 1-2 (see Images 1-2 in Multimedia) show a mass in the right renal pelvis. The histologic diagnosis was a right renal pelvis neurofibroma and a bladder transitional cell carcinoma.
Longitudinal sonogram through left kidney in the same patient as in Images 12-13 (see Images 12-13 in Multimedia) shows that the filling defects are due to calculi. Ultrasonography is an efficient means for differentiating between radiolucent calculi and uroepithelial tumors.
Left posterior view of a technetium-99m dimercaptosuccinate (99mTc DMSA) scan in the same patient as in Image 10 (see Image 10 in Multimedia) shows a photon-deficient mass in the upper pole of the left kidney; this finding indicates a genuine mass in this region. At partial nephrectomy, transitional cell carcinoma was confirmed.
Pathophysiology
Causative agents
Exposure to a large variety of noxious stimuli is thought to play a major role in the etiology of TCC, although many of these stimuli have no known direct link. A variety of chemical carcinogens have been linked to the development of TCC. These include tobacco; aniline dyes; benzidine; aromatic amines; rubber; and azo dyes used in textiles, printing, and plastic manufacturing. These carcinogens have essentially been removed from the workplace (by the US Environmental Protection Agency).
The underlying pathophysiology is thought to involve hyperplastic metaplastic changes secondary to chronic irritation, particularly within the ureter. Chemical carcinogens act locally on the epithelium, causing a field change; their action is enhanced by the contact time (exacerbated by urinary stasis or diverticula). Bladder tumors are thought to be more common partly because of the time required for the agents to be activated by hydrolyzing enzymes to produce their carcinogenic effect. Partial obstruction may account for increased exposure to the upper tracts (eg, increased incidence of TCC in horseshoe kidney).
Risk factors and causative agents include tobacco use (which is postulated to increase the risk 2-3 times); occupational exposure; abuse of analgesics (eg, phenacetin, which increases the risk 8 times); cyclophosphamide therapy (6-y lag time), particularly after drug-induced hemorrhagic cystitis; Balkan nephritis, with progressive renal failure; multiple bilateral tumors (etiology unknown); recurrent or chronic infection; and urinary calculi (squamous cell carcinoma [SCC] is the most common entity in such cases).
Of great importance is the multiplicity of TCCs of both synchronous and metachronous natures.1 There is a frequent association of papillomas in patients with TCCs. Almost 25% of patients with renal pelvic papillomas develop a carcinoma. Of those with multiple papillomas, 50% develop carcinomas.
When both renal pelves are involved, synchronous tumors occur with a prevalence of 1-2%.1 With both ureters, the prevalence is 2-9%. The bladder is affected in 24% of cases with primary pelvic involvement, in 39% of cases with primary ureteral involvement, and in 2% of cases with primary bladder involvement.
Ureteric TCC may be solitary, but TCC has a marked propensity for unilateral multicentricity. The reason is unknown, but this distribution may result from antegrade and/or retrograde seeding or the fact that the entire ureteral mucosa is exposed to the carcinogen.
Within the upper renal tracts, metachronous TCC appears in 12% of pelvic and ureteric primary tumors within 25 months and in 4% of bladder primary tumors (two thirds within 2 years, the others as long as 20 years later). Within the bladder, metachronous TCC occurs in 23-40% of primary renal TCCs after 15-48 months and in 20-50% of primary ureteral TCCs after 10-24 months.
Zhou and associates have reported a 10-fold increase in urologic malignancies, especially TCC, in renal allograft recipients.2
Pathology/histology
TCCs usually have the following broad classification: (1) exophytic papillary lesion (85%) with a frondlike structure and central fibrovascular core lined by an epithelial layer (broad based and pedunculated); (2) nonpapillary, noninfiltrating; (3) infiltrating, usually of higher grade and less common; and (4) carcinoma in situ.
Although no staging method is universally recommended, the following tumor, nodes, metastases (TNM) system of the American Joint Committee on Cancer (AJCC) is useful for upper-tract and ureteral lesions: Tis 0 indicates an in situ lesion; Ta, noninvasive papillary carcinoma; T1 I, invasion of the subepithelial connective tissue; T2 II, tumor confined to the muscularis layer; T3 III, invasion of the renal parenchyma and/or peripelvic soft tissues; and T4 IV, extension beyond the renal capsule.
The grade is usually correlated with the stage, as follows: 1 indicates that the cells are slightly anaplastic; 2, that intermediate features are present; and 3, that marked cellular pleomorphism is present.
Within the upper tracts, grade I papillary lesions remain controversial because some believe that these lesions represent nonmalignant neoplastic proliferation of transitional epithelial cells, which are often associated with independent TCCs. Transitional cell mucosa has the capacity for both benign and malignant squamous and/or glandular differentiation. TCC occurs with a frequency of approximately 90% in the renal pelvis, although care must be taken in its identification because pure cell types are rare.3
Nonpapillary, noninfiltrating TCC of the renal pelvis may show no gross changes other than slight planar thickening and occasional mild hyperemia and/or hemorrhage. Invasion may occur en bloc or in a tentacle-like fashion. Within the ureter, papillary tumors are attached by a broad pedicle, with surrounding edema if the infiltration is deep. Infiltration by ureteral papillary tumors is less common (40%) than infiltration by tumors in the renal pelvis. However, multiplicity is more common. Approximately 40% of tumors are nonpapillary. Surface ulceration is common; it is associated with early invasion and metastases.
The stage of tumors in the bladder, as assessed by the depth of infiltration, is the single most important prognostic parameter when treatment is initiated. Clinical staging has an accuracy of 50%; by way of comparison, CT has an accuracy of 32-80%, and MRI has an accuracy of 73%. Overstaging commonly occurs as a result of edema after endoscopy and/or endoscopic resection and as a result of fibrosis from radiation therapy.4,5,6,7,8
A staging classification that incorporates the TMN and Jewett-Strong-Marshall (JSM) systems is useful. The stages are as follows: T1 A indicates lesions involving the mucosa and submucosa; T2 B1, invasion of the superficial muscle layer; T3a B2, invasion of the deep muscular wall; T3b C, invasion of perivesical fat; T4a D1, extension to perivesical organs; T4b, invasion of the pelvic and/or abdominal wall; and D2, distant metastases.
TCC in situ is a term used to describe full-thickness dysplastic changes present in flat, nonpapillary urothelium. This is consistently seen in the bladders of patients with invasive TCC, and it is thought to be a precursor of this lesion. About 80% of all bladder TCCs are low-stage superficial papillary neoplasms (multifocal in a third); these become invasive in 10-20% of cases. These invasive tumors are almost always solitary. Nonpapillary or sessile bladder tumors are typically more invasive than the exophytic types, although both may coexist. Early lymphatic invasion and bladder wall infiltration are associated with a poor prognosis.
Metastases
Hematogenous spread is less frequent with renal pelvic tumors than with hypernephromas. Lymphatic supply is extensive, and lymphogenous involvement occurs early in the disease process. Metastases occur to the lung, lymph nodes, and liver; direct extension into the retroperitoneum is common.
Frequency
United States
Primary renal pelvis neoplasms account for less than 10% of all renal tumors. Of these, approximately 75% are considered malignant; most are TCCs. TCCs involving the extrarenal part of the renal pelvis are more common than those in the infundibulocaliceal region. They are far less common than hypernephromas (ratio, 1:5) and 3 times more common than ureteric neoplasms. Conversely, bladder tumors are 50 times more common than renal pelvis tumors, which are thought to stem from the relatively larger surface area of bladder mucosa. The incidence of ureteric TCC, determined on the basis of combined autopsy reports, is 1 per 1000-3600; these account for 1 in every 25 upper-tract tumors. The lower third is usually most affected (70%).
Bladder TCC accounts for approximately 5% of all new malignant neoplasms; as such, it is the most common tumor of the genitourinary tract, accounting for approximately 2% of all cancer deaths in the United States. The lateral wall of the bladder and bladder diverticula are more frequently involved. An increased incidence of TCC of the bladder and ureter has been seen in patients with multiple ureteral diverticula; these patients should be closely screened for TCC.
International
The true incidence of TCC internationally is not known; however, the incidence of TCC is expected to be higher in regions of the world where schistosomiasis is endemic.
Mortality/Morbidity
Approximately 90% of TCCs are curable in patients with superficial, confined tumors. Those with deeply invasive tumors that are still confined to the renal pelvis and ureter have a 10-15% likelihood of cure. Usually, distant metastases that penetrate the urothelial wall cannot be cured with current forms of treatment.
Metastases from ureteral TCC are far more common than those from bladder cancer, partly because the ureteral wall is thin and acts as a poor barrier. Metastases occur in approximately 11% of cases, in the following sites: retroperitoneal nodes (34%); distant lymph nodes (17%); liver (17%); lumbar vertebrae (13%); lungs (9%); kidneys (8%); adrenals (4%); spleen (2%); sacral vertebrae (2%); brain (2%); pancreas (2%); and skin (2%). In addition, isolated metastases occur in the colon, broad ligament, diaphragm, humerus, omentum, pericardium, pleura, prostate, and vagina.
Race
No particular racial prevalence has been demonstrated.
Sex
The male-to-female ratio is 3-4:1, except when tumors occur in people who abuse analgesics or when the tumors occur in association with Balkan nephropathy, which affects both sexes equally.
Age
The mean age of onset is 50-70 years.9
Anatomy
Embryologic derivation of the urinary tract collecting system occurs from the fetal mesonephros. As a result of this development, tumors of the collecting system of the renal tract have cell origins different from those of the renal parenchyma. These tumors are classified on basis of their respective mesodermal or epithelial tissue origin.
The uroepithelium is the mucosal lining of the calyces, infundibula, ureters, urinary bladder, and portions of the urethra. The uroepithelium has a characteristic microscopic appearance that is midway between glandular and squamous tissue — hence its name, transitional epithelium. With regard to distribution, in addition to the uroepithelium, TCC can develop anywhere from the calyces to parts of the urethra with uroepithelial lining.
Presentation
Hematuria is a common symptom that occurs in as many as 80% of patients; it may be frank or microscopic. Hematuria may occur early or late in the development of the disease. In cases of TCC of the upper tract, pain, abdominal mass, and pyuria occur with approximately the same frequency as they do in cases involving other renal tumors. Dysuria and frequency are more commonly reported with ureteral tumors. Pain is usually dull and colicky and results from obstruction, although a second type of pain results from direct tumoral extension. This second type of pain is frequently severe, constant, and penetrating.
Rare instances of spontaneous urinary extravasation caused by rupture have been reported; this often results in an acute abdomen. Other rare findings include hypercalcemia, secondary amyloidosis, and elevated chorionic gonadotropin levels.
Preferred Examination
Elevated urinary lactate dehydrogenase (LDH) levels have been reported, but this finding is nonspecific. However, cytology can play a significant role, with a 60% accuracy rate in the diagnosis of renal pelvic and ureteral TCC. Cytology is particularly useful in cases involving tumors of more advanced stage; in such cases, the accuracy rate improves to 80%. Selective lavage, ureteral urine collection, brush biopsy, or ureteroscopy may be performed to obtain specimens.
Plain radiographic findings, such as calcifications, are not specific in the diagnosis of urothelial tumors, and they usually contribute little to the diagnosis. Intravenous urography (IVU) is a common diagnostic test in patients with hematuria, although the early detection of small urothelial tumors may be difficult. A meticulous IVU technique is required. Multidetector-row CT with postprocessing image manipulation (contour imaging) is increasingly coming to challenge IVU.
Retrograde pyelography is useful when the kidney cannot be visualized by means of IVU or when IVU cannot be performed because of renal disease or an adverse response to the contrast agent. Retrograde pyelography also has the advantage of being able to be combined with various biopsy techniques.10
CT is becoming increasingly sensitive for the staging of early TCC. Developments such as virtual cystoscopy and postmicturition scanning should improve the overall accuracy of staging by the use of CT.6,11,12
MRI has the advantages of high intrinsic soft tissue contrast, direct multiplanar capability, and the availability of nontoxic renally excreted contrast agents. MRI appears to be at least as useful as CT in the evaluation of perivesical fat involvement, and it may be superior to CT in the detection of invasion of the adjacent organs. However, MRI cannot depict well the superficial invasion by TCC of the upper urinary tract.6,7,8,13,14,15,16,17
Both CT and MRI have been shown to perform better than cystography in the diagnosis of tumors in the bladder diverticula that are not depicted on cystograms because of obstruction at the diverticular orifice.
Ultrasonography is inaccurate for diagnosing early TCC; it is useful in the diagnosis of obstructive uropathy.18,19,20 Ureteric lesions are particularly difficult to visualize unless they cause hydronephrosis and hydroureter. Other limitations of ultrasonography are that it is inaccurate in the staging of bladder TCC, particularly Ta and T1 tumors, and in the detection of pelvic lymph node involvement.
Isotope renography is an extremely sensitive means of assessing relative renal function and obstructive uropathy before surgery. Isotope bone scanning is a useful technique in the investigation of skeletal metastases.21
Limitations of Techniques
Elevated urinary LDH levels are nonspecific. Urine cytologic results may be negative in as many as 40% of cases of TCC; this finding is useful in only advanced-stage tumors.
Plain radiographic findings are nonspecific, particularly the presence of calcification, which has a wide differential diagnosis. Filling defects in the renal collecting system and the bladder, as seen with IVU, CT, and retrograde pyelography, are present in a number of other pathologies. These findings are not specific to TCC.
On CT scans, a hyperattenuating TCC may be confused with a blood clot, particularly in the early stages of the disease. Also, inhomogeneous renal fatty attenuation of any cause in a patient with undiagnosed early-stage TCC may hinder accurate diagnosis.
MRI is expensive and has limited availability. False-positive diagnoses have been reported. In staging bladder TCC, tumor extension is overstaged according to the TNM classification in 7.5% of patients; it is understaged in 32.5% of patients.
On sonograms, calculi may be confused with high-grade TCCs, which can be densely echogenic. No sonographic features are specific for TCC, and many filling defects within the renal collecting system and bladder have a nonspecific appearance. It is also difficult to discern nondilated ureters on ultrasonography.
Differential Diagnoses
Other Problems to Be Considered
Nonneoplastic lesions — Lucent calculi, blood clot, fungus balls, pus, sloughed papillae, pyeloureteritis cystica
Primary epithelial tumors — Papilloma, SCC, adenocarcinoma, carcinosarcoma, undifferentiated tumors
Mesodermal smooth muscle tumors — Leiomyoma, leiomyoblastoma, leiomyosarcoma
Mesodermal neural tumors — Neurofibroma, neurilemoma
Other sarcomas - Spindle cell, osteosarcoma
Mesodermal vascular tumors — Hemangioma, lymphangioma, hemangiosarcoma
Mesodermal fibrous tumors — Fibroepithelial polyp, renal medullary fibroma
Mesodermal mixed tumors — Fibromyoma, fibrolipoma, fibromyxoma
Lymphoma
Metastases or direct invasion of the uroepithelial by tumors
More on Transitional Cell Carcinoma |
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Further Reading
Keywords
TCC, transitional cell carcinoma in situ, uroepithelial tumors, epithelial tumor of the bladder, papillary carcinomas, grade 1 papillary carcinomas, nonpapillary carcinomas
