Epidemiology

Bladder cancer is the most common tumor of the urinary tract. In the United States, it is the fourth most common malignancy in males, accounting for 7% of all male malignancies. There will be an estimated 70,530 new cases and 14,680 deaths from bladder cancer in the United States in 2010.¹ The peak incidence is in the ninth decade, although there is a suggestion of a trend toward presentations at a younger age. The incidence is four times higher in men than in women. The lifetime risk for men is 3.8% and for women is 1.2%.¹ The tumor is twice as common in whites as in African Americans. In the United Kingdom, bladder cancer is overall the seventh most common malignancy, with an age-standardized rate of 11.4 per 100,000.²

The incidence of upper tract disease is less easily estimated because cancer registries tend to include primary PC system tumors as “renal” cancers. If one makes the assumption that 15% of such “renal” tumors are of PC system origin, there will be 8740 new cases and 1960 deaths from renal pelvic cancer in the USA in 2010.¹ There will be an estimated 2490 new cases and 830 deaths from ureteric cancer in the United States in 2010.¹ Ureteral transitional cell cancer (TCC), like bladder cancer, is more common in men than in women (ratio 2:1), and the incidence peaks in the eighth decade of life.

For patients with a bladder cancer, up to 6.4% will develop upper tract tumors.^3,4 Conversely, for patients with upper tract tumors, up to 40% will develop lower tract disease.⁵

Risk Factors

Reported risk factors for urothelial tumors include exposure to aniline, aromatic amines, diesel fumes, phenacetin abuse, cigarette smoking, arsenic, and living in urban areas. Heavy smokers (>40 pack-yr) are five times more prone to develop TCC than nonsmokers.⁶ Balkan nephropathy, an endemic degenerative interstitial nephropathy in Eastern Europe of unknown etiology, is associated with 100 to 200 times the risk of upper tract TCC. These tumors are typical multifocal, but of low grade.^7,8 Coffee drinking and artificial sweeteners have been considered to be possible risk factors, but these have not been fully substantiated as a cause of this malignancy.⁹

Genetic factors in the etiology of urothelial tumors are emerging, and these may be associated with the aggressiveness of the tumor, such as tumor grade, stage, and propensity for vascular invasion.¹⁰

Worldwide, squamous cell carcinomas are the most common histology and are associated with chronic inflammation, for example, chronic urinary tract infection or calculi and schistosomiasis (Schistosoma haematobium). Squamous cell carcinomas are the most common type of cancers affecting the urethra in both males and females. However, in industrialized countries such as the United States where chemical exposure and tobacco use are more prevalent, TCCs are the most frequent histology.

Adenocarcinomas of the bladder mucosa are associated with a persistent urachal remnant and cystitis glandularis (which is associated with bladder extrophy).¹¹ In addition, micropapillary and small cell tumors have been reported and are signs of an aggressive histology associated with worse outcomes, likely as a result of early micrometastases.^12,13 The rarity of these two histologies has limited our abilities to determine definitive associations; their frequent finding in combination with TCCs would lead one to expect an association with carcinogen exposure.

Bladder

Bladder tumors fall morphologically into two broad groups: superficial, accounting for approximately 70% to 80%, and invasive, accounting for approximately 20% to 30%.

The majority of superficial tumors, which are limited to the mucosa and lamina propria, tend to be papillary (i.e., projecting into the lumen) and of low histologic grade. They tend to carry a good prognosis, although they have a propensity to recur (70% at 3 yr), and 10% to 20% may progress to invasive disease (although this is as high as 46% in patients with T1 disease).¹⁴ Seventy percent of patients with superficial tumors have low-grade papillary tumors, and 30% have higher-grade, flat, carcinomas in situ. Flat carcinomas in situ carry a higher risk of progression and invasion.¹⁵

Invasive tumors, which involve the muscle layers, tend to be solid, infiltrating, and of high histologic grade and typically have a poor prognosis.

Upper Tracts

In the ureter, the frequency distribution of urothelial tumors is distal (73%), mid (24%), and proximal (3%). Bilateral disease may occur in 2% to 5% of cases. The tumors are histologically similar to those in the bladder.¹⁶ As with urothelial tumors in the bladder, upper tract tumors may be superficial (85%) or infiltrating (15%).

Several histopathologic grading systems relate to the epithelial tumors. The most commonly used is a three-grade system: low grade (grade I), moderate (grade II), and high grade or poorly differentiated (grade III).

Bladder

Bladder urothelial tumors may invade progressively through the bladder wall (i.e., lamina propria, superficial muscle, deep muscle) and eventually to extravesical structures. In advanced local disease, tumor may extend to involve adjacent structures, such as the rectum, anterior abdominal wall, pelvic side wall muscles (e.g., the obturator internus) and bones (e.g., the iliac and pubic bones). The bladder has an extraperitoneal (inferior) and an intraperitoneal (superior) component. If disease extends into the latter, dissemination can occur within the peritoneal cavity, resulting in widespread peritoneal implants and ascites.

Disease may spread lymphatically, typically in a contiguous fashion from pelvic (internal iliac, obturator, and external iliac) to common iliac and retroperitoneal nodes. In advanced disease, lymphatic spread may extend above the diaphragm to mediastinal, hilar, and cervical nodes. The incidence of nodal metastasis is approximately 30% in tumors that involve the bladder wall and approximately 60% in those with extravesical invasion.¹⁷ Nodal staging has an important impact on prognosis.

The tumor may also metastasize hematogenously, with the liver being the most common site for metastatic disease, followed by bones and lungs.¹⁸

The risk for lymphatic and/or hematogenous spread increases with increasing tumor size and stage (see later), and the incidence of distant metastases increases with increasing tumor (T) and node (N) stages.

Urothelial disease in the bladder neck may extend into the urethra. Urethral disease may involve adjacent structure, including the vaginal wall and the corpora of the penis. In males, TCC involving the urethra is commonly found in the prostatic urethra, where it may invade locally into the prostate gland itself.

Urachal tumors, because they arise from the remnant urachus that extends from the dome of the bladder to the umbilicus, have a propensity to spread within the peritoneal cavity and may also involve the anterior abdominal wall.

When seen, in males, TCC of the urethra is commonly found in the prostatic urethra.

Upper Tracts

Primary urothelial tumors in the upper tracts spread locally to involve periureteral and peripelvic fat. In the region of the renal pelvis, urothelial tumors can infiltrate into the renal parenchyma, where unlike primary renal tumors, they tend to preserve the contour of the kidney. Infiltrating tumors of the ureters tend to be more aggressive than those in the bladder, probably because of the thinner wall of the ureter.^19,20

Lymphatic spread is to locoregional periureteral and perihilar lymph nodes. The former are typically retroperitoneal, common iliac, and internal iliac nodes.

Local invasion and lymphatic spread of disease are more common in upper tract tumors than hematogenous spread, probably because of the relatively thin wall and rich lymphatic drainage of the ureter and upper tracts. The sites of hematogenous spread are similar to those encountered with bladder tumors.

Bladder

The two main staging classification systems for tumors are (1) the tumor-node-metastasis (TNM; Tables 19-1 and 19-2) and (2) the Jewett-Strong-Marshall classification (Table 19-3). The TNM staging system is the more widely used and comprehensive. T stage mainly describes the depth of local bladder wall invasion of the tumor as related to normal bladder wall layers. N stage is based on the size and number of nodes involved by metastatic disease. M stage describes whether there are disseminated hematogenous metastases or not. Retroperitoneal adenopathy is classified as M stage disease.

Table 19-1 Tumor-Node-Metastasis Staging for Bladder Cancer by the American Joint Committee on Cancer

Suffix “is,” associated carcinoma in situ; suffix “m,” multiple tumors.

From Bladder cancer. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:569-577.

Table 19-2 Staging for Bladder Cancer, with Tumor-Node-Metastasis Equivalent

TNM, tumor-node-metastasis.

From Bladder cancer. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:569-577.

Table 19-3 Comparison of AJCC and Jewett-Strong-Marshall Staging Systems

TNM, tumor-node-metastasis.

From National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Training Modules Staging: Comparison of AJCC & Jewell-Strong-Marshall Staging Systems. Available at http://training.seer.cancer.gov/bladder/abstract-code-staging.html (accessed October 27, 2011).

A schematic of the TNM T staging is presented in Figure 19-1A and B. Superficial tumors are considered Tis, Ta, and T1; infiltrative tumors are T2, T3, and T4.^21,22

Prognosis worsens with increasing T, N, and M stage and higher classes of Jewett-Strong-Marshall staging. The overall 5-year survival is 97.2%, 74.3%, 36.2%, and 5.8%, for in situ, localized, regional, and distant disease, respectively.²³ Nodal status and organ confinement are independent predictors of survival.²⁴

Urothelial tumors may develop in the bladder diverticulae. Urothelial tumors may also arise or involve the prostatic urethra. Both of these have a poorer prognosis, the former because there is no muscle layer to act as a barrier to tumor spread.

Prognosis is also affected by tumor grade, the presence of vascular and lymphatic invasion, and diffuse carcinoma in situ (CIS). Of note, these latter factors are not currently reflected in staging classifications.²⁵

Treatment options are influenced by tumor stage. Clinical staging can underestimate the extent of disease in up to 50% of cases as compared with pathology.²⁵ Imaging has the potential to improve this.

Upper Tracts

The TNM staging system for urothelial tumors of the upper tracts is presented in Tables 19-4 and 19-5. As with bladder staging, T staging of the upper tracts is assessed in

Table 19-4 Tumor-Node-Metastasis Staging of Upper Urinary Tract Transitional Cell Carcinoma

TNM, tumor-node-metastasis.

From Renal pelvis & ureter. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:561-567.

relation to depth of invasion into the various layers of the wall of the ureter (see Figure 19-1C).

Primary Tumor (T)

Bladder

In low T stage disease, cystoscopy and deep biopsy with histologic evaluation is the standard of care. For more deeply invasive tumors (stage T3, T4), clinical staging, which includes bimanual examination under anesthesia to assess the bladder mass and fixity to adjacent organ, has reported errors of both under- and overstaging, of 25% to 50%.26–29 Imaging plays a role in the evaluation of such tumors, especially for nodal and hematogenous metastatic disease.

Tumors in narrow neck diverticulae may escape cystoscopic detection, for which imaging may be able to make a contribution. Computed tomography (CT) is the mainstay for staging in these tumors, but magnetic resonance imaging (MRI) has the additional advantages of better tissue contrast resolution and direct multiplanar capability.

Computed Tomography

Technique

Thin-section rapid scanning in the portal venous phase at 60 to 80 seconds after commencement of intravenous (IV) contrast medium (125-150 mL at 2.5-3.0 mL/sec) allows detection of tumor enhancement in the bladder wall before excreted IV contrast medium reaches the bladder. Delayed images (180 sec) allow detection of soft tissue density masses against the background of IV contrast within the bladder lumen. Thin-section acquisition allows multiplanar re-formations. Oral and rectal contrast media assist in delineation of adjacent organs in the pelvis. The bladder should be moderately distended. Care should be taken not to over- or underdistend the bladder because the former may flatten small tumors and underdistention may result in spurious bladder wall thickening. If a urinary catheter is in place, it should be clamped for a period before and during the examination.

Findings

Urothelial tumors in the bladder may appear as foci of thickening in the wall or as filling defects, which may be polypodial (Figure 19-2). Fine calcification may be seen on the mucosal surface. The lesions may demonstrate early enhancement after IV contrast media infusion, probably a reflection of angiogenic activity in the tumor (Figure 19-3). CT is unable to resolve the various bladder wall layers and is, therefore, unable to resolve low T stage disease. Retraction of the outer bladder wall at the site of the tumor is suggestive of deep muscle involvement (stage T2b).

Figure 19-2 Urothelial tumor in the bladder. Enhancing polypoidal nodule (arrow).

Figure 19-3 Urothelial tumor in the bladder. Enhancing thickening (arrow) in the right posterolateral wall of the bladder.

Stage T3b disease is suggested by irregularity and loss of definition of the outer bladder wall and/or nodules and stranding in the perivesical fat. T3a (microscopic perivesical) disease cannot be detected.

Evaluation of stage T4 disease, with adjacent organ involvement, is better undertaken by MRI than by CT because of the limitations of contrast resolution and acquisition plane of CT.

Tumors close to the vesicoureteric junction may cause ureteric obstruction, which may be a presenting feature of the disease (Figure 19-4). Tumors may also be detected in bladder diverticulae, which importantly may not be visible on cystoscopy (Figure 19-5).

Figure 19-4 Urothelial tumor in the bladder. Enhancing thickening in the left posterolateral wall of the bladder causing vesicoureteric obstruction (arrow). Note the presence of a ureteric stent.

Figure 19-5 Urothelial tumor (arrow) arising in a bladder diverticulum.

Magnetic Resonance Imaging

Technique

Combinations of coronal, sagittal, and axial planes with T1 and T2 weighting, and fat suppression, together with intravenous contrast medium, provide the principal images. Imaging planes can be optimized according to the location of the tumor: the coronal plane is able to delineate lesions in the lateral walls, whereas the sagittal plane is best for posterior and anterior wall lesions. The coronal and sagittal planes provide better evaluation of lesions in the dome and base of the bladder, compared with the axial plane. Attention should also be paid to the direction of phase encoding because chemical shift artifact occurring in this direction can lead to a false impression of wall thickening. IV glucagon can be administered to reduce artifacts derived from bowel motion. The bladder should be moderately distended (overdistention will cause patient discomfort and restlessness and may, consequently, contribute to suboptimal imaging).

Findings

The signs of bladder tumors are similar to those on CT. Tumors are usually hyperintense to muscle on T2-weighted images and isointense to muscle on T1-weighted images (Figure 19-6A). On occasion, the combination of T2-weighted and contrast-enhanced T1 weighted images can help to delineate between stages T2a and T2b tumors, with preservation of T2-weighted hypointensity of bladder muscle adjacent to enhancing tumor.

Figure 19-6 Bladder tumor on axial T1-weighted (A1) and coronal T2-weighted (A2) magnetic resonance imaging (MRI) shows irregular thickening (arrows) in the right lateral wall of the bladder. Note stranding and nodularity in the perivesical fat, which in this case was due to T3b disease. B, Sagittal MRI shows the posterior bladder tumor (arrows) closely abutting the vagina. The rectum is posterior to the vagina.

The corresponding findings of T3b disease described previously for CT appear as hypointense nodules or stranding within the T1-weighted and T2-weighted hyperintense perivesical fat (see Figure 19-6A). These findings may be more conspicuous with the use of contrast-enhanced T1-weighted fat-suppressed images, in which enhancing tissue is seen in the surrounding hypointense (suppressed) perivesical fat.³⁰

MRI is superior to CT in staging T4 disease because of its better intrinsic contrast resolution and multiplanar capability. For example, the combination of sagittal and axial images on MRI allows good delineation of the rectum and vagina (see Figure 19-6B). It should be noted that abutment of structures does not necessarily indicate invasion, and conversely, involvement cannot be excluded; invasion is more likely if foci of infiltration can be identified.

Overall, studies of CT and MRI suggest that MRI is more accurate in staging with accuracies ranging from 73% to 96% compared with CT accuracies of 40% to 95%. This is largely because of the superior ability of MRI in assessing deep muscle layer involvement and earlier detection of adjacent organ invasion. It should be noted that most reported MRI evaluations have been undertaken with body and not pelvic phase array coils, and MRI accuracy may be improved further with such higher-resolution coils.^17,31–49

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