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

An important limitation of imaging evaluations of the primary tumor is that bladder wall thickening and contrast enhancement may be due to inflammation, edema, or fibrosis, for example, following biopsy, transurethral resection (TUR), or radiation therapy, and cannot be reliably distinguished from tumor (Figure 19-7). Imaging for local staging is best undertaken before biopsy or resection, but this is not always feasible.²⁹

Figure 19-7 Perivesical fat stranding after cystoscopic biopsy, which confounds interpretation of extravesical extension of disease. Note gas in the bladder.

Ultrasonography

A number of ultrasonographic techniques, such as transabdominal, transuretheral, transvaginal, and transrectal, have been investigated to evaluate bladder tumors. Intravesical ultrasound has been reported to have accuracies for T staging ranging from 62% to 92%.^50,51 Ultrasonography has limited general utility because of its general poor visualization of extravesical structures.⁵²

Upper Tracts

Unlike evaluation of the lower tract, detection and evaluation for upper tract tumors rely heavily on imaging because they are relatively inaccessible to direct visualization.

Intravenous urography (IVU) is the standard of care technique for evaluating the upper tracts. Direct pyelography is more invasive, but may be undertaken if IVU cannot be undertaken or is indeterminate; it also allows the potential for cytologic evaluation. Computed tomographic urography (CTU) is a technique being developed and increasingly utilized; it has a variety of advantages and disadvantages compared with IVU. Magnetic resonance urography (MRU) is an evolving technique that has some potential advantages compared with CTU but also some relative disadvantages and is still in development.

Intravenous Urography

Technique

A series of plain films are undertaken of the urinary collecting system after bolus administration of IV contrast medium. Frontal radiographs of the upper tracts may be supplemented by tomographic radiographs of the PC system and prone and oblique films of the ureters. Evaluation of the PC system is typically undertaken with some form of abdominal compression to distend the upper tracts, but it requires exclusion of contraindications (e.g., the presence of abdominal aortic aneurysms). Initial precontrast films are obtained to evaluate for the possibility of radiopaque renal tract calculi.

Imaging Findings

Signs of urothelial tumors in the upper tract include filling defects and strictures, which may be smooth or irregular (Figure 19-8). In the PC system, a stippled appearance may be encountered, which represents contrast medium trapped in papillary fronds of the tumor (see Figure 19-8). Tumors in the region of a calyceal orifice may cause obstruction of the calyx, resulting in lack or delayed excretion of IV contrast medium into that calyx, or “calyceal amputation.” In the ureter or region of the vesicoureteric orifice, tumors may cause ureteric obstruction and hydronephrosis, which may also be associated with delayed or absent excretion of contrast medium. IVU may fail to detect upper tract tumors in as many as 50% to 90% of cases.^53,54

Figure 19-8 Urothelial tumor in upper tracts. Intravenous urography (IVU) shows filling defects in the lower pole calyces of the right pelvicalyceal (PC) system and the proximal right ureter (arrows).

Direct Pyelography

Technique

Direct access to the upper tracts can be obtained via a retrograde or an antegrade approach. Retrograde access requires cystoscopic cannulation of the vesicoureteric orifice. Antegrade access requires percutaneous puncture of the PC system as for a percutaneous nephrostomy. It inevitably requires traversing the kidney and is, therefore, more invasive, but it may be indicated if retrograde access is not possible, for example, with a distal obstructing lesion in the ureter or a distorted or absent bladder from surgery. Both techniques offer the opportunity to radiographically visualize the relevant upper tract after administration of contrast and to sample urine for cytology. In principle, after direct access, ureteroscopic evaluation and biopsy can also be undertaken.

Computed Tomography Urography

Technique

Specific protocols are evolving; however, the fundamental requirements are (1) high-resolution scans to allow detection of small filling defects, urothelial wall thickening, and three-dimensional (3D) re-formations and (2) ureteric distention. Current 16- or higher row multidetector CT scanners have the potential for high-resolution axial scans of 1.5 mm or less that can cover the urinary collecting system within a breathhold. A variety of acquisition techniques are under evaluation. Variations focus on methods to try to distend the ureters during imaging, such as abdominal compression, fluid challenge (which may involve IV administration of normal saline), and forced diuresis (with IV furosemide), or a combination. Some techniques employ two separate administrations of IV contrast (“split bolus”).⁵⁵ Unlike many other CT applications in oncology, positive gastrointestinal contrast media should be avoided because it may complicate subsequent evaluation, particularly the 3D re-formations.

Findings

As with the “luminal” (IVU and direct urography) techniques, urothelial lesions may be detected as filling defects or strictures in the upper tracts. However, because of its intrinsic cross-sectional acquisition, CTU has the capability to visualize urothelial wall thickening (Figure 19-9). There is increasing evidence that urothelial wall thickening may be an important sign for urothelial disease; however, the relative importance and accuracy of the signs are yet to be determined.⁵⁶ TCCs may also appear as fine encrusted calcifications, mimicking renal calculi.

Figure 19-9 A, Tumor in the PC system on computed tomographic urography (CTU). Axial and coronal maximum intensity projection (MIP) CTUs show tumor, and the coronal nephrographic image shows the infiltrative nature of the tumor (arrow). This patient had a previous cystectomy for bladder transitional cell cancer (TCC). B, Tumor on CTU. Filling defect in the solitary left upper ureter (arrow) (previous right nephroureterectomy for TCC).

In the PC system, T1 or T2 disease can be suggested by the presence of a fat plane or contrast medium between the lesion and the renal parenchyma. T3 tumors are suggested by the loss of renal sinus fat and abnormal enhancement of the adjacent parenchyma. T4 tumors show invasion of adjacent organs.

Urothelial tumors in the PC system can be difficult to differentiate from primary renal tumors; the former, however, are typically infiltrative and tend to preserve the contour of the kidney.⁵⁷ The CT equivalent of calyceal amputation can occasionally be observed (Figure 19-10).

Figure 19-10 Urothelial tumor in the upper tracts. Focal dilatation of the calyces in the upper pole of the left kidney (arrow; “calyceal amputation”) due to tumor in the calyceal orifice.

CTU probably has higher sensitivity for detecting upper tract disease than IVU, with a reported pooled sensitivity on meta-analysis of 96%, compared with sensitivities for IVU of 50% to 60%.^58–60

CTU is also able to assess for nodal and metastatic disease, thus offering a comprehensive overall evaluation in one examination. An important consideration in the utilization of CTU is its relatively high radiation dose burden, which may be up to 40 mSv.⁶¹

Magnetic Resonance Urography

MRU has several advantages over CTU, including (1) lack of ionizing radiation, (2) lack of iodinated contrast media (and associated allergy and nephrotoxicity), (3) higher contrast resolution, and (4) direct multiplanar imaging. However, its relative disadvantages include (1) poorer spatial resolution, (2) relatively prolonged acquisition times, and (3) motion artifacts.

Technique

Techniques are being developed and evaluated. There are two different MRU approaches, either utilizing IV contrast medium or not. In the latter, the short T2 relaxitivity of urine (water) is leveraged by employing fast T2-weighted sequences, such as SSFSE or Half fourier Acquisition Single shot Turbo spin Echo (HASTE) (Figure 19-11). In techniques relying on intravenously administered MRI contrast agents, images are acquired when contrast is excreted into the collecting systems, using angiographic-type sequences. Advantages of the noncontrast techniques are that the collecting systems can be visualized without the intervention of IV contrast (and the attendant risks of nephrogenic systemic fibrosis (NSF) in patients with renal impairment) and when the system(s) are obstructed or nonfunctioning (because they do not rely on the excretion of intravenously administered contrast media). Both of these techniques are essentially directed at obtaining visualization of luminal features; detecting urothelial wall thickening, which may be an important sign of disease, would require supplementary sequences. Further research is required to optimize these techniques and to determine whether they have the necessary accuracy for lesion detection.

Figure 19-11 Magnetic resonance urography using a heavily T2-weighted sequence with fat suppression shows the left PC system and ureter.

The presence of ureteric stents or nephrostomy tubes can mask the presence of upper tract tumors. In addition, signs of tumors, such as urothelial wall thickening and/or periureteric stranding, can occur in association with surgery, biopsy, or inflammatory conditions (e.g., radiation or stents).

Ultrasonography

Ultrasonography has a very limited role in the detection and evaluation of upper tract tumors. Urothelial tumors in the renal pelvis may appear as soft tissue masses within the otherwise echogenic renal sinus, without or with hydronephrosis. Infundibular tumors may cause focal calyceal dilatation (the equivalent of the amputated calyx on IVU).¹⁹

Nodal Disease (N)

Nodal metastases from primary bladder tumors typically involve pelvic nodes and then progress superiorly toward retroperitoneal nodes. In advanced disease, metastatic adenopathy can involve mediastinal, hilar, and cervical nodes. Nodal metastases from ureteric tumors typically involve adjacent nodes in the retroperitoneum or pelvis.

Computed Tomography

Lymph node size is the main criterion for assessing nodal involvement (Figures 19-12 and 19-13). Unfortunately, as with metastases from other malignancies, small nodes can contain tumor, leading to false-negative results, and enlarged nodes may be reactive and may not contain tumor, causing false-positive results. The challenge of detecting lymph node metastases is compounded because urothelial cancers frequently cause little nodal enlargement.⁶²

Figure 19-12 Nodal metastases. Bilateral enlarged external iliac nodes (arrows) confirmed metastases on percutaneous biopsy.

Figure 19-13 Urothelial tumor in upper tracts. A, Enhancing wall thickening (arrow) in the left PC system. B, Subsequent left para-aortic lymph node recurrence (arrow).

Fluoro-2-deoxy-D-glucose Positron-Emission Tomography

The role of fluoro-2-deoxy-D-glucose (FDG)-positron-emission tomography (PET) in urothelial cancers is under evaluation. FDG-PET is of limited value in assessing the primary tumor because of excretion of activity into the entire urinary tract. Metastatic lymph nodes may demonstrate increased FDG avidity (Figure 19-14); however, the combination of the poor spatial resolution of PET and the frequency of small nodes containing metastatic disease limits its utility in general staging.⁶³

Figure 19-14 Pelvic adenopathy on fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT). Recurrent disease after cystectomy. Hypermetabolic node (arrow) in right internal iliac territory.

FDG-PET may be able to assist in treatment evaluation and the differentiation of tumor recurrence from posttreatment (radiation) fibrosis.

Other PET tracers are under investigation, for example, a study with ¹¹C-methionine-PET (which is not renally eliminated) has suggested some correlation with tumor grade, but it did not improve staging accuracy.⁶⁷

Metastatic Disease (M)

Hematogenous metastases are less common than nodal metastatic disease. Typical sites include the liver, lungs, and bones.

Computed Tomography

Although CT has its limitations in staging of the primary bladder tumor, it is in general the workhorse for screening and staging for nodal and hematogenous metastatic disease for urothelial tumors (Figures 19-15 and 19-16). If more detailed characterization of lesions, for example, in the liver, is required or if contrast-enhanced CT cannot be undertaken, then MRI might be considered.

Figure 19-15 Liver metastasis from primary urothelial tumor in bladder. Contrast-enhanced CT with a hypodense lesion (arrow) in the right lobe of the liver. The other smaller, hypodense lesion is a cyst.

Figure 19-16 A and B, Metastatic disease to the lungs. Multiple pulmonary nodules. Note cavitation of some nodules with chemotherapy as a sign of treatment response (arrow).

Nuclear Medicine (Other than Positron-Emission Tomography)

Skeletal metastases are relatively uncommon in urothelial tumors, and bone scintigraphy is not generally indicated unless there are relevant symptoms, such as pain. Bone scintigraphy can be supplemented with plain radiography and/or MRI (Figure 19-17).

Figure 19-17 Metastatic disease to bone. Bone scintigram (A) shows activity in the L1 vertebral body, with lucency on associated CT (arrow) (B).

Surgery

Initial diagnosis of urothelial carcinoma of the bladder involves cystoscopy with visual identification of an intravesical tumor as well as complete TUR of the tumor. Initial TUR should result in complete resection of all visible tumors and be extensive enough that the specimens should include muscularis propria with a minimum of cautery artifact. In patients who have high-grade tumors resected but no muscle present in the specimen, a repeat resection is recommended. For patients diagnosed with high-risk noninvasive tumors (see definitions later), a second restaging TUR is recommended because upstaging occurs in 49% to 64% of patients with initial apparent T1 lesions. The authors routinely perform the restaging TUR at 4 to 6 weeks to ensure more confident staging and a more accurate gauge of the biology of the disease by identifying tumors with rapid growth potential. This timing also avoids the typical delay of 12 weeks to identify T2 disease; upstaging of many muscle-invasive tumors has been shown with delays greater than 12 weeks.⁶⁸

Whereas the mainstay of treatment for non–muscle-invasive urothelial carcinoma of the bladder is complete TUR of all visible lesions, up to 70% of bladder tumors recur even with aggressive resection, and as many as 10% to 30% progress. Thus, certain subgroups of patients with bladder cancer have been identified as being at higher risk for recurrence and progression, and they should be considered for intravesical therapy after TUR. These high-risk groups include patients with tumors classified as high grade (which are associated with a 45% risk of progression at 3 yr and the greatest risk of cancer-related death), and patients with CIS (which is associated with a 54% rate of progression to muscle-invasive disease). In addition, irrespective of grade, patients with large lesions (>3 cm), multifocal tumors, evidence of lamina propria invasion, or early recurrence (within 2 yr) have been shown to be at increased risk. In these high-risk groups, aggressive intervention with intravesical therapy leads to response rates up to 85%. However, because even solitary, low-grade, Ta lesions can recur, these must also be considered for adjunctive intravesical therapy, albeit of lesser intensity.⁶⁹

For patients with invasive urothelial carcinoma of the bladder, with no clinical evidence of metastasis, the first decision required in treatment planning is whether to pursue a radical cystectomy plus lymph node dissection (RC+LND) or a bladder-sparing approach. There is some evidence that a bladder-sparing approach is reasonable in very carefully selected patients (with aggressive TUR, partial cystectomy, or chemoradiation); however, these are used only in very select groups of patients. RC+LND is widely regarded in the United States as the gold standard for the management of invasive bladder cancer.⁷⁰

Once a patient is considered surgically resectable and able to undergo RC+LND, the next decision is whether to proceed directly to surgery followed by adjuvant chemotherapy or surgery with neoadjuvant chemotherapy. The merits and details of neoadjuvant and adjuvant chemotherapy are subjects of controversy. At M. D. Anderson Cancer Center, an individualized approach is adopted, with neoadjuvant chemotherapy offered to patients considered to be at high risk for occult metastatic disease or those who have a historically poor survival with surgery alone. The latter includes patients with cT3 disease, preoperative hydronephrosis, or presence of features on TUR specimen such as lymphovascular invasion, variant histology (e.g., small cell carcinoma or micropapillary cancer).^70,71

In males, some surgeons have tried performing a cystectomy alone (so-called prostate-sparing cystectomy) instead of a cystoprostatectomy. This approach carries a significant risk of poor cancer control, especially given the inability to exclude prostatic involvement by urothelial carcinoma or prostatic adenocarcinoma before surgery. Furthermore, for patients with bladder cancer, this leaves behind the prostatic urothelial surface as a site of occult recurrence, which can be fatal.

Although chemotherapy can be used to augment results of radical cystectomy, it must be emphasized that surgical technique is critical in the management of bladder cancer. Specifically, data demonstrate that the extent of lymphadenectomy and the incidence of positive margins, both critically important in determining outcome, are superior in the hands of experienced surgeons.⁷² Whereas minimally invasive techniques (e.g., robot-assisted radical cystectomy or laparoscopic assisted radical cystectomy) have been used for this disease, the gold standard, especially for patients with high-risk disease, remains open radical cystectomy.

Options for urinary diversion after radical cystectomy include continent orthoptic diversion (neobladder), continent cutaneous diversions (catheterizable pouches), or noncontinent cutaneous diversion (ileal loop stoma) (Figure 19-18).

Figure 19-18 Schematics of surgical bladder reconstructions. Ileal pouch, catheterizable continent cutaneous diversion, neobladder.

Intravesical Therapy

Whereas some non–muscle-invasive urothelial carcinomas can have an indolent course, a significant subset of patients present with disease associated with an increased risk of recurrence or progression. Several intravesical therapies can decrease these risks and proper selection of patients for intravesical therapy is important to improve prognosis and save the patient’s bladder as well as her or his life.

For patients with non–muscle-invasive bladder cancer, we recommend complete TUR of all visible disease followed by intravesical instillation of one dose of chemotherapy. The most commonly used intravesical agent in this setting is mitomycin; however, data suggest that most chemotherapeutic agents have similar efficacy. This therapy may be the only treatment necessary for patients with Ta lesions, in whom mitomycin is associated with a 39% decrease in the odds of recurrence. Patients with high-grade or T1 tumors must undergo re-resection as noted previously, following which, they are selected for either intravesical therapy or radical cystectomy based on various parameters.

Intravesical bacillus Calmette-Guérin (BCG) has been the benchmark against which all other intravesical therapies are compared, since its approval by the U.S. Food and Drug Administration (FDA) in 1990 for the treatment of CIS of the bladder. The exact mechanism of action of BCG is unknown. BCG attaches to the bladder epithelium, where it is incorporated into the cell, leaving behind surface glycoproteins that are thought to stimulate an immune response. This immune stimulation is nonspecific and includes macrophages, T lymphocytes, B lymphocytes, natural killer cells, and a variety of cytokines. Recently, tumor necrosis factor–related apoptosis-inducing ligand has been implicated as having a role in BCG’s mechanism of action. Intravesical therapy with BCG is performed on an outpatient basis—it is instilled weekly into the bladder of patients via a Foley catheter. The course of therapy is one 6-week induction course followed by maintenance therapy with 3 weeks of BCG at 3 months, 6 months, and then every 6 months for up to 3 years (the Southwest Oncology Group [SWOG] protocol).⁷³ If further recurrence is noted, salvage therapies are available; however, operative intervention with cystectomy should be considered.

Chemotherapy

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (M-VAC) has been the gold standard by which other chemotherapy has been compared and is the combination having level 1 evidence showing benefit in the neoadjuvant setting.74–78 Gemcitabine cisplatin has been largely adopted as the standard in the metastatic setting after randomized data suggest equivalent survival but an improved toxicity profile compared with M-VAC.⁷⁹ A dose-dense modification of M-VAC, in which treatment was given every 2 weeks with growth factor support, showed an improved toxicity profile and improved complete response rate compared with classic M-VAC.⁸⁰ Although there was no difference in median survival, there was an intriguing improvement in 5 year survival. As a result, M. D. Anderson Cancer Center has adopted the dose-dense approach and are currently studying it on a clinical trial in the neoadjuvant setting.

Radiation Therapy

Currently, the use of radiation therapy with or without concomitant chemotherapy has been the subject of much debate. Whereas some groups advocate aggressively for its use, it is important to note that trials using radiation as a bladder-sparing approach have generally enrolled a very select cohort of patients. This group of patients has also been considered for other bladder-sparing approaches, such as aggressive TUR or partial cystectomy. As a result, radiation therapy remains largely the subject for clinical investigation and is not considered standard for the treatment of this disease.

Upper Tract Therapies

Upper tract urothelial carcinoma of the renal pelvis and ureters is relatively rare. These tumors might arise as primary tumors without a history of bladder tumors or as recurrences in the upper tract in patients who have a history of bladder cancer. Radiologic survey of the upper tracts remains an important part of the surveillance of patients with bladder cancer, although the optimal interval and modality remain to be identified.

The optimal method of confirming a diagnosis of upper tract urothelial carcinoma is with ureteroscopic evaluation of the lesion. Most of these lesions are classic in appearance and a biopsy is not needed for diagnosis per se. However, a biopsy does help in the decision-making process relating to the type of therapy chosen.⁸¹ The main treatment for patients with upper tract urothelial carcinoma and a normal contralateral kidney is a complete nephroureterectomy (open or laparoscopic) with removal of a cuff of urinary bladder and regional node dissection. In situations in which there is suspicion for locally advanced disease, we have advocated for neoadjuvant chemotherapy, similar to that used in bladder cancer.

In specific situations in which an individual patient might have compromised renal function or medical comorbidities, renal-sparing therapy might be considered. Herein, the tumor is ablated or segmental resection is undertaken and then topical chemotherapies or BCG is used as adjuvant treatments. The problem with the studies utilizing minimally invasive techniques is that the durability of response thus far lacks long-term follow-up. If endoscopic management has been performed, a strict follow-up protocol with imaging and endoscopy is necessary.

Monitoring Tumor Response

Evaluation of treatment response is essentially based on changes in tumor size, which may be based on the primary tumor or metastatic disease. This can be undertaken by some form of cross-sectional imaging, most commonly CT. For disease limited to the bladder urothelium, cystoscopy may be the only effective way of assessing treatment response.

Detection of Recurrence

Recurrent disease may occur at the site of the primary tumor or at sites of potential nodal or hematogenous metastases. Importantly, because of the propensity of urothelial tumors for multifocality, recurrent disease can occur in any part of the urothelium and at any time, which therefore requires life-long surveillance of the urothelium. Surveillance of the lower collecting system is best undertaken by cystoscopy. Upper tract surveillance, however, requires some form of imaging, traditionally IVU; the utility of CTU for this purpose is yet to be determined. General screening of the urothelium can also be undertaken by urine cytology

The detection of recurrent disease at nodal or visceral sites is best undertaken by some form of cross-sectional imaging, most commonly CT. Prior imaging is probably the most helpful adjunct because increase in size or change in morphology of a node or lesion is the most reliable indicator of new or recurrent disease. Following dissection or irradiation of nodal beds, recurrent disease can appear to “skip” nodal stations (Figures 19-19 and 19-20).

Figure 19-19 Pelvic lymph node recurrence after cystectomy. Right external iliac node (arrow) is larger than on the previous study.

Figure 19-20 Retroperitoneal lymph node recurrence (arrow) after cystectomy and no adenopathy inferior to this location. Note apparent bypassing of pelvic adenopathy because of prior pelvic lymph node dissection.

In cases in which there is uncertainty about the nature of a lesion, percutaneous fine-needle aspiration cytology or biopsy should be considered.

The role for FDG-PET in surveillance for recurrent disease is currently limited, although it may have some utility in specific cases. Limitations arise because of the typical small size of nodes that contain metastases and the presence of FDG activity in excreted urine.