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Urothelial Carcinoma (Bladder Cancer and Upper Tracts)
Introduction
Carcinoma of the urothelium is ’one of the most common tumor to affect the genitourinary system in the United States. The urothelium is the normal epithelium that lines the entire urinary collecting system from the calyces to the prostatic urethra. We will divide the urinary tract into a lower tract (bladder and prostatic urethra) and upper tract (pyelocaliceal system and ureters).
Urothelial cancer is considered a “field defect,” where tumors can develop synchronously or metachronously at multiple sites along the urothelium. If a tumor is found, there is increased propensity to develop further urothelial tumors. It is, therefore, important to consider and evaluate the entire urothelium as a single pathologic landscape. Imaging is fundamental in the staging of lower tract tumors and in the staging and detection of upper tract tumors.
Epidemiology
Urothelial carcinoma of the bladder 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 and 4% of deaths. The incidence is 4:1 men:women and 2:1 White:Black American. The lifetime risk is 3.8% for men and 1.2% for women. There will be approximately 83,700 new cases and 17,000 deaths from bladder cancer in the United States in 2021.
The incidence of upper tract urothelial carcinoma is difficult to estimate, because cancer registries tend to include primary pyelocaliceal system tumors as “renal” cancers. Statistical assumptions calculate that 5% of all renal pelvis tumors correspond to urothelial carcinomas; therefore, we can add approximately 4000 new cases and 883 deaths from upper tract renal pelvis carcinomas.
Additionally, there will be an estimated 4200 new cases and 960 deaths from ureteric cancer in the United States in 2021. Ureteral urothelial cancer, like bladder cancer, is more common in men than in women (ratio 2:1), with the incidence peaking in the eighth decade of life. It is estimated that 6.4% of bladder cancer patients will develop upper tract tumors, and approximately 40% of patients with upper tract malignancy will develop lower tract disease.
Risk Factors
Reported risk factors for urothelial tumors include exposure to aniline dyes, aromatic amines, a high fat diet, radiation, cyclophosphamide, arsenic in drinking water, exposure to diesel fumes, phenacetin abuse, living in urban areas, and substances that are used in the dye, rubber, leather, and aluminum industries. The most important factor remains cigarette smoking. Heavy smokers (>40 pack-years) are four to five times more prone to developing urothelial tumors than nonsmokers.
Balkan nephropathy, an endemic interstitial nephropathy in Eastern Europe that originates with consumption of phytotoxin aristolochic acid, which is contained in a common plant growing in wheat fields, is associated with 100 to 200 times the risk of upper tract urothelial carcinomas that are typically multifocal, but low grade.
Coffee drinking and artificial sweeteners have been considered possible risk factors but are unsubstantiated causes of bladder malignancy.
Genetic factors in the etiology of urothelial tumors are constantly being evaluated, and they may be associated with aggressiveness, such as tumor grade, stage, and propensity for vascular invasion.
Histologically, squamous cell carcinoma is the most common type of bladder cancer worldwide and is associated with chronic inflammation, for example, from infections such as schistosomiasis ( Schistosoma haematobium ) or calculi. Squamous cell carcinomas are the most common type of cancers affecting the urethra in both males and females.
Adenocarcinoma of the bladder can arise from the urachal remnant or occur in the setting of cystitis glandularis (which is also associated with bladder extrophy). 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.
Anatomy and Pathology
The bladder develops from the primitive urogenital sinus that in utero communicates with the umbilicus via the allantois. The urogenital sinus normally involutes by birth into a thick fibrous cord, the urachus, that connects the dome of the bladder with the umbilicus.
The urothelial system collects, temporarily stores, and excretes urine. It includes the renal calyces, renal pelvis, ureters, bladder urethra. The epithelium of the collecting system to the level of the prostatic urethra, the urothelium, consists of the same cell type: transition cells. Deep to the urothelium is a layer of connective tissue with irregular smooth muscle fibers called the submucosa (although this term is incorrect because there is no true muscularis mucosae) or lamina propria. Deep to it, there are three layers of muscle (internal or superficial longitudinal, middle circular, and external or deep longitudinal). Deep to these is the serosa, and then the perivesical or periureteral fat and, at the dome of the bladder, the peritoneum ( Fig. 20.1 ).
In adult males, chronic bladder outflow obstruction from prostatic hypertrophy commonly leads to hypertrophy of the bladder wall musculature and trabeculation. Outpouchings of mucosa, or diverticula, may also develop.
The vast majority of tumors involving the urothelium are of transitional cell origin (>90%), called urothelial cancer; other subtypes are squamous cell (5%–10%), adenocarcinoma (2%–3%), and small cell carcinoma (<1%). Pure adenocarcinomas can be mucin-secreting tumors, they can form chunky calcifications, and they are most commonly found along the urachal ligament; however, adenocarcinomas mixed with transitional cell histology can be found anywhere along the urothelium.
Other extremely rare tumors include leiomyoma, hemangioma, granular cell tumors, neurofibroma, paraganglioma, pheochromocytoma, leiomyosarcoma, rhabdomyosarcoma, hematopoietic and lymphoid tumors (e.g., non-Hodgkin’s lymphoma), carcinosarcoma, malignant melanoma, metastases, and direct invasion from other primary tumors from adjacent organs.
Bladder
Bladder tumors fall biologically into two specific groups: superficial or not muscle-invasive, accounting for approximately 70% to 80%; and invasive, accounting for approximately 20% to 30%.
Superficial tumors are limited to the mucosa or lamina propria and tend to be papillary (i.e., projecting into the lumen) and of low histologic grade. They usually have a good prognosis, but have a propensity to recur (70% at 3 years), and 10% to 20% may progress to invasive disease (although this can be as high as 46% in patients with T1 disease). Some 70% of patients with superficial tumors have low-grade papillary tumors, and 30% have higher-grade, flat, carcinomas in situ . The latter carry a higher risk of progression and invasion.
Invasive tumors, which involve the muscle layers, tend to be solid, infiltrating, and of high histologic grade. These typically have a poorer 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. 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).
Key Points
Anatomy and Pathology
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The urothelium is lined by transitional cells and extends from the calyces to the prostatic urethra.
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The “upper” urinary collecting tract includes the calyces, renal pelvis, and ureters; the “lower tract” includes the bladder and urethra.
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The entire urothelium is at risk of tumor development once a tumor is found in any location.
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The most common tumor of the collecting system is urothelial carcinoma, previously referred to as transitional cell carcinoma (>90%).
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Urothelial tumors may be superficial (70%) or invasive (30%).
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Muscle invasive tumors are generally of higher histologic grade and more aggressive, with poorer prognosis.
Clinical Presentation
The majority of patients with urothelial tumors present with painless macro- or microscopic hematuria. Other symptoms include frequency, dysuria, urgency, and pyrexia. Pain may be a feature if the tumor or blood clots cause ureteric or bladder outflow obstruction or as a sign of advanced disease. Tumors at the vesicoureteral junction may cause ureteric obstruction resulting in hydronephrosis.
Hematuria can be associated with multiple other conditions such as renal parenchymal tumors or medical renal disease (e.g., nephritis), urinary tract inflammatory conditions (e.g., infections, chemotherapy, radiation), calculi (often associated with pain), endometriosis, prostatic disease, coagulopathy, and trauma or instrumentation.
Patterns of Tumor Spread
Bladder Cancer
Bladder urothelial tumors invade progressively through the bladder wall (i.e., lamina propria, muscle, serosa) 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 muscle) and bones (e.g., the iliac and pubic bones). The bladder is extraperitoneal but is partially covered by peritoneum superiorly. If disease extends into the peritoneal layer, dissemination can occur within the peritoneal cavity, resulting in peritoneal implants and ascites.
Disease may spread through lymphatics, typically in a contiguous fashion from pelvic (internal iliac, obturator, and external iliac) to common iliac to 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. Nodal staging has a very 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.
The risk for lymphatic and/or hematogenous spread increases with increasing tumor size and stage, 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 also involve adjacent structures such as the vaginal wall and the corpora of the penis. In males, urothelial cancer involving the urethra is commonly found in the prostatic urethra, where it may invade locally into the prostate gland itself.
Urachal adenocarcinomas, because they arise from the remnant urachus, have a propensity to spread within the peritoneal cavity and the anterior abdominal wall.
Upper Tracts
Primary urothelial tumors in the upper tracts spread locally to involve periureteral and peripelvic fat. In 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.
Lymphatic spread is to locoregional periureteral (retroperitoneal, common iliac, and internal iliac) nodes.
Local invasion and lymphatic spread are more common with upper tract tumors than hematogenous spread, likely because of the relatively thin wall and rich lymphatic drainage of the ureters and upper tracts. The sites of hematogenous spread are similar to those of bladder tumors (liver, bones, and lungs).
Key Points
Patterns of Tumor Spread
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Tumor typically spreads by lymphatics before using the hematogenous pathway.
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Risk of metastatic disease increases with higher tumor and node stages and the histologic grade of the tumor.
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Distant metastases are less common and may involve liver, bones, and lungs in order of frequency.
Staging Evaluation
Bladder
The two main staging classification systems for tumors are (1) the tumor-node-metastasis (TNM) and (2) Jewett-Strong-Marshall classifications ( Table 20.1 ). The TNM system is widely used and very comprehensive. T stage mainly describes the depth of local bladder wall invasion of the tumor in relation 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 metastases or not. Retroperitoneal adenopathy is classified as M-stage disease.
Table 20.1
Comparison of American Joint Committee on Cancer and Jewett–Strong–Marshall Staging Systems
(From National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Staging: Comparison of AJCC & Jewell-Strong-Marshall Staging Systems. Available at https://training.seer.cancer.gov/bladder/abstract-code-stage/staging.html . Accessed May 23 2019.)
| STAGE | DISEASE EXTENT | TNM CLOSEST EQUIVALENT |
|---|---|---|
| 0 | Limited to mucosa, flat in situ or papillary | Tis or Ta |
| A | Lamina propria invaded | T1 |
| B1 | < halfway through muscularis | T2a |
| B2 | > halfway through muscularis | T2b |
| C | Perivesical fat,prostate, uterus or vagina, pelvic wall or abdominal wall | T3, T4a, T4b |
| D1 | Pelvic lymph node(s) involved | N1-N3 |
| D2 | Distant metastases | M1 |
TNM , Tumor-node-metastasis.
T staging is presented in Fig. 20.1A and B . Superficial tumors are considered Tis, Ta, and T1; infiltrative tumors are T2, T3, and T4.
Prognosis worsens with increasing T, N, and M stage and higher classes of Jewett-Strong-Marshall staging. The overall 5-year survival rate is 95.8% for in situ , 69.5% localized, 36.3% regional, and 4.6% distant disease. Nodal status and organ confinement remain independent predictors of survival.
Urothelial tumors may develop in bladder diverticula and 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 . Of note, these latter factors are not currently reflected in staging classifications.
Treatment options are influenced by tumor stage. Cystoscopy and biopsy are critical in the primary staging evaluation of bladder cancer, particularly for wall invasion. Clinical staging can underestimate the extent of disease in up to 50% of cases as compared with pathology, thus the importance of adequate use of imaging modalities according to the area of involvement to reduce error.
Upper Tracts
As with bladder staging, T staging of the upper tracts is assessed in relation to depth of invasion into the various layers of the wall of the ureter (see Fig. 20.1C ).
Key Points
Staging
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T staging reflects the depth of bladder wall and perivesicle invasion.
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Cystoscopy and biopsy are critical in the primary staging evaluation of bladder cancer.
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Treatment options are directly influenced by tumor stage.
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Clinical staging can underestimate the extent of disease in up to 50% of cases.
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Imaging aids appropriate staging.
Imaging
There are no established primary screening programs for detecting urothelial tumors. The majority of tumors are detected while investigating hematuria. Primary lower tract tumors are detected and evaluated by cystoscopy, and primary upper tract tumors are detected by imaging, most frequently computed tomography (CT) of the abdomen or CT urogram.
Primary Tumor (T)
Bladder
In early, low–T stage disease (Tis–T1), cystoscopy and deep biopsy with histologic evaluation is the standard of care. For more deeply invasive tumors (T2–T4), clinical staging, which includes bimanual examination under anesthesia to assess the bladder mass and fixation to adjacent organs, has reported rates of both under- and overstaging of 25% to 50%. Imaging plays a fundamental role in the evaluation of such tumors, especially for nodal and hematogenous metastasis.
Tumor in a narrow neck diverticulum may escape cystoscopic detection, for which imaging can help. CT is the standard for staging these tumors, but magnetic resonance imaging (MRI) has proven to have additional advantages, such as better tissue contrast resolution and functional imaging that can aid local staging, including bladder wall and adjacent organ involvement, particularly of bladder tumors.
The American College of Radiology (ACR) advocates the use of the ACR Appropriateness Criteria, which categorize the modalities as: (a) favorable, (b) may be appropriate (agreement and disagreement components), and (c) usually not appropriate. Their most recent expert panel consensus in 2018 advises that CT or MRI of the abdomen and pelvis without and with intravenous (IV) contrast, plain film of the chest, and CT or MRI of the pelvis with contrast are usually appropriate for collecting system tumors.
Computed Tomography
Technique
Scanning in the portal venous phase at 60 to 80 seconds after initiation of IV contrast medium (100–150 mL at 2.5–3.0 mL/sec) allows detection of tumor enhancement in the bladder wall, during the corticomedullary phase of the kidneys, before excreted IV contrast medium reaches the bladder. Delayed images (180–300 seconds) allow detection of soft tissue density masses/filling defects against the background of IV contrast within the bladder lumen. Thin-slice (0.625 mm) isovoxel acquisition aids multiplanar reformations. Oral and rectal contrast may assist in delineation of adjacent organs in the pelvis. The bladder should be moderately distended. If a urinary catheter is in place, it should be clamped for a period of time before and during the examination.
Confounders that may limit the evaluation of the bladder and interpretation on CT or MRI include underdistention of the bladder, inflammation, infectious or radiation cystitis, postbiopsy changes, or ureteral jets.
Overall, accuracy for staging is between 55% and 95%, with optimal detection when scanned during corticomedullary phase with a full bladder. CT urogram can have a sensitivity of up to 93% and a specificity of up to 99%. CT is most useful for tumors that are stage T3b or higher.
Findings
Urothelial tumors in the bladder may appear as foci of thickening in the wall ( Fig. 20.2 ), (i.e., flat tumors), or as enhancing filling defects, (i.e., papillary tumors) ( Fig. 20.3 ). Fine calcification can be seen on the mucosal surface. The lesions most commonly demonstrate early enhancement after IV contrast, which is thought reflect angiogenic activity of the tumor ( Fig. 20.3 ). CT is unable to resolve the various bladder wall layers and is therefore, unable to resolve less than T3b-stage disease. However, retraction of the outer bladder wall at the site of the tumor is suggestive of deep muscle involvement (stage T2b).
Stage T3b representing gross disease beyond the bladder wall 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 often better undertaken by MRI than by CT because of better soft tissue contract of pelvic organs by MRI.
Tumors close to the vesicoureteral junction may cause ureteral obstruction, which may be a presenting feature of the disease ( Fig. 20.4 ). Tumors may also be detected in bladder diverticula ( Fig. 20.5 ), which importantly may not be visible on cystoscopy.
Magnetic Resonance Imaging
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