PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The uroepithelium is subject to numerous excretory products and responds with a proliferative process, often as a benign papilloma, which can become multiple, covering most of the bladder epithelium and representing a field carcinogenesis.
PERSPECTIVE AND PATTERNS OF SPREAD
Bladder cancer is a neoplasm of the elderly, peaking at 60 to 80 years of age. Despite its highly varied gross appearance in the bladder, intermittent hematuria, either macroscopic or microscopic, is the major manifestation. Occasionally, it presents as a bladder infection with irritability and dysuria, particularly recurrent in character, that suggests some underlying pathology or tumor. This is the most frequent cancer of the urinary tract, with an estimated 60,000 new cases reported annually. Bladder cancer accounts for 2.5% of all tumors, or 13,000 cancer deaths annually. Although aniline dyes have been implicated, as well as other industrial agents or some carcinogenic metabolite secreted in urine, no true cause of bladder cancer is known. Some infectious agents, however, such as Schistosoma haematobium, have been implicated in Egypt, where the more commonly squamous cell cancer results (Table 37.1).
Worldwide, bladder cancer is among the most common malignancies, in 11th place. North Africa and western Asia are considered high-risk areas. Males predominate in a 3:1 ratio to females.
The pattern of spread is into its wall and then its surrounding structures (Fig. 37.2; Table 37.2).
Cancers of the urinary bladder typically begin as papillomas, a benign proliferative process that can become multiple papillomatosis, covering the bladder surface. Transformation into an invasive cancer results in penetration into the muscular layer, and, as depth increases, the muscle contractility increases its circumferential spread. Inferiorly in males, the prostate can be invaded since there is no capsule to separate it from the bladder. Superior spread is less likely due to its peritoneal covering. Bladder perforation leads to subcutaneous spread of urine along the anterior abdominal wall. Posteriorly the trigone of the bladder, once invaded, can obstruct the ureter(s). Lateral extension to the sidewalls can occur. In the female, invasion of the anterior lip of the cervix is possible, but more usual is the opposite invasion of cervix cancer into the bladder wall posteriorly.
PATHOLOGY
The uroepithelium is subject to numerous excretory products and responds with a proliferative process, often as a benign papilloma, which can become multiple, covering most of the bladder epithelium and representing a field carcinogenesis. The transformation to cancer depends on three criteria: cell type, pattern of growth, and grading. The majority are transitional cell carcinomas that change from mucosal exophytic lesions (grade I) to endophytic, invading into muscle (grades II and III). The patterns of spread are determined by muscular contraction of the bladder; as the tumor penetrates the wall, it spreads circumferentially. Squamous cell cancers are mainly associated with schistosomiasis. Primary adenocarcinomas tend to develop in the dome of the bladder, often from urachal epithelium rests. The various cancers of the urinary bladder are tabulated and their grading is noted (Table 37.1; Figure 37.1).
Figure 37.1 | Left. Urothelial neoplasms. Most tumors occur in the urinary bladder and are classified histologically as urothelial (transitional cell) carcinomas (TCCs). Ureters and the posterior urethra are also lined by transitional epithelium and can give rise to TCCs. TCCs can be flat, papillary, papillary and invasive, or simply invasive. Benign transitional cell papillomas are rare. Right. Urothelial tumors of the urinary bladder. A. Low-grade papillary urothelial carcinoma consists of exophytic papillae that have a central connective tissue core and are lined by slightly disorganized transitional epithelium. B. Low-grade papillary urothelial carcinoma at higher magnification shows mild architectural and cytologic atypia. C. High-grade papillary urothelial carcinoma shows prominent architectural disorganization of the epithelium, which contains cells with pleomorphic hyperchromatic nuclei. D. Invasive high-grade papillary urothelial carcinoma consists of irregular nests of hyperchromatic cells invading into the muscularis.
Figure 37.2 | Patterns of spread (cancer crab) of urinary bladder cancer are color coded for stage: Tis or Ta, yellow; T1, green; T2, blue; T3, purple; T4, red; and metastatic, black. Correlate patterns of spread with the SIMLAP Table 37.2. The anatomic site invaded is color coded for T stage of advancement.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
In their initial phase, bladder cancers tend to be multiple, superficial mucosal and submucosal lesions (stage T1; Fig. 37.3). With invasion into the muscular wall (T2), the tumor spreads, first in depth and then circumferentially in the submucosal and muscular lymphatics. There is a relationship between depth of invasion and circumferential spread; the tumor infiltration in the wall is massaged due to the contractility of this viscus. The capacity of the bladder to expand and contract is altered somewhat as the tumor invades its walls. When circumferential spread is extensive (T2B), akin to linitis plastica of the stomach, a permanently contracted bladder results with little capacity.
Once the tumor reaches the serosal surface, invasion of perivesical fat (T3) and adjacent structures occurs (T4). Anteriorly, it can become fixed to, but rarely destroys, the bony pubis; laterally, the cancer can extend to the pelvic wall and invades lymphatics, and enlarged pelvic lymph nodes can compress the iliac vessels. Direct posterior invasion into the rectum rarely occurs in males; the same is true of direct invasion of posterior gynecological structures in females. This pattern of invasion is more representative of late or recurrent disease.
Tumors of the trigone usually result in ureteral obstruction owing to the entry of the ureters at this juncture. If secondary infection and edema cause the obstruction, it may be reversible. Once unilateral obstruction of the ureter occurs, hydronephrosis results; if unrelieved, the kidney stops functioning and atrophies. Secondary infection may lead to an ascending pyelonephritis and septicemia. Bilateral obstruction can result in renal failure and uremia.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Primary staging: T4 disease defined as including prostatic stromal invasion directly from bladder cancer. Subepithelial invasion of prostatic urethra will not constitute T4 staging status (Fig. 37.3).
• Grading: a low-and high-grade designation will replace previous four grade system to match current World Health Organization/International Society of Urologic Pathology (WHO/ISUP) recommended grading system.
• Nodal Classification
• Common iliac nodes defined as secondary drainage region as regional nodes and not as metastatic disease
• N staging system change
• N1: single positive node in primary drainage regions
• N2: multiple positive nodes in primary drainage regions
• N3: common iliac node involvement
The TNM Staging Matrix is color coded for identification of stage group once T and N stages are determined (Table 37.3). The T stage determines stage group.
BLADDER
Figure 37.3 | TNM urinary bladder cancer diagram. Urinary bladder cancers can be solitary but are often multiple in a field of epithelial carcinogenesis. Stage I (green) papillomas are conservatively resected transurethrally, stage II (blue) with partial cystectomies, stage III (purple) require total cystectomy and urethral diversion, and stage IV (red) are no longer completely resectable. Vertically arranged with T definitions on the left and stage groupings on the right. Color bars are coded for stage: stages 0is and 0a, yellow; I, green; II, blue; III, purple; IV, red; and metastatic, black.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The isocenter for the urinary bladder varies depending on its fullness or whether it is empty. Most often it is depicted empty and as a pelvic organ at the S4/S5 level (Fig. 37.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views. A. Coronal, B. Sagittal, C. Transverse Axial. (Fig. 37.5A/B). The bladder's location requires knowledge of adjacent genital structures and disease. Symptomatology depends, in part, on gender.
• Coronal: In the male, the bladder is intimately related to the seminal vesicles posteriorly, the prostate inferiorly, and the pubis and peritoneum anteriorly.
• Sagittal: The relationship of the ureters to surrounding blood vessels is important. The bladder is not a fixed structure but has considerable capacity and mobility, altering its contour and contact with the colointestinal viscera as it fills with urine. The bladder is a retroperitoneal structure, whereas the gastrointestinal tract is intraperitoneal except for the rectum.
• Transverse: The seminal vesicles are situated between the bladder and rectum. In the female, the vagina and cervix are located posterior to the bladder and the body of the uterus, superiorly. The bladder is extraperitoneal, although the sigmoid colon and terminal portions of the ileum can be in contact with its superior surface.
In the female, the bladder is intimately related to the uterus and vagina. The trigone of the bladder is in direct contact on its posterior surface with the anterior lip of the cervix and anterior fornix of the vagina. The urethra is located in the anterior wall of the vagina. Cancers of the bladder rarely invade the female genital tract, but cancers of the cervix infiltrate and invade the bladder. The ureters, which have a horizontal course, straddle the cervix and are commonly strapped and obstructed by parametrial invasion.
• Coronal view: The opened bladder is situated above the pubis. The trigone and ureteral orifices are noted in the corners, with the ureter coursing superiorly alongside the cervix. The uterus is anteflexed and rests on the bladder.
• Sagittal view: The bladder is anterior and the rectum posterior to the female genital organs.
• Axial view: The superior axial section shows the intimate relationship of the cervix to the bladder wall. The inferior axial section shows the relationship of the urethra in the anterior wall of the vagina.
Figure 37.4 | Orientation of T-oncoanatomy. The anatomic isocenter for three-planar anatomy of renal pelvis and ureter is at the S1 to S5 level. A. Coronal. B. Sagittal.
Figure 37.5 | The color code for the anatomic sites correlates with the color code for the stage group (Fig. 37.3) and patterns of spread (Fig. 37.2) and SIMLAP table (Table 37.2). Connecting the dots in similar colors provides an appreciation for the three-dimensional oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Lymph node invasion is common once the tumor has penetrated into the deep muscular layer and the serosa. The lymph nodes most commonly involved are the obturator or hypogastric nodes and the internal iliacs on the pelvic wall. All of these first station nodes are bilateral; however, the node at risk depends on the location of the primary tumor in the bladder. Eventually, invasion of the common iliac and para-aortic retroperitoneal nodes occurs, and drainage into the thoracic duct could naturally progress to supraclavicular node metastases; this is a rare presentation for a metastatic neck node with obscure etiology (Fig. 37.6A; Table 37.4A, and 4B).
The regional or pelvic lymph nodes, located below the bifurcation of the common iliac arteries, include the internal iliacs, the hypogastric, the common iliac located above the pelvic basin, and the posterior, presacral, and anterior perivesical nodes. The juxtaregional lymph nodes are the inguinal nodes, the high common iliac, and the para-aortic nodes. The vessels, nerves, and lymphatics lie on the inner wall of the true pelvis, below the pelvis basin on the obturator internus muscle.
In the female as in the male, the lymphatic drainage is to perivesical channels into the internal iliacs and to common iliac and then para-aortic nodes.
The incidence of lymph node metastases increases with stage of primary cancer (Table 37.4B).
M-ONCOANATOMY
Vascular spread, although uncommon, is usually a late event. Dissemination follows the vesical veins into the internal iliac veins and inferior vena cava. Tumor cells could reach the right side of the heart and then manifest as pulmonary metastases. Once the left heart is reached, the tumor cells could target to any other distant remote site (Fig. 37.6B).
REGIONAL LYMPH NODES
The regional lymph nodes draining the bladder include primary and secondary nodal drainage regions. Primary lymph nodes include the external iliac, hypogastric, and obturator basins. The presacral lymph nodes are classified as a primary drainage region; however, mapping studies have found this area to be a less frequent site of primary regional metastases. Primary nodal regions drain into the common iliac nodes, which constitute a secondary drainage region. Regional lymph node staging is of significant prognostic importance, given the negative impact on recurrence after treatment and long-term survival. The relevant information from regional lymph node staging is obtained from the extent of disease within the nodes (number of positive nodes, extranodal extension), not from whether metastases are unilateral or contralateral. Overall 5-year survival in node-positive bladder cancer following definitive local therapy is approximately 33%; however, patients with a greater node burden may be expected to do significantly worse.*
*Preceding passage from Edge SB, Byrd DR and Compton CC, et al. AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 498.
Figure 37.6 | A. N-oncoanatomy. Male: Regional nodes are obturator and internal iliac nodes. B. M-oncoanatomy. Medial view.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Primary evaluation is done preferentially under anesthesia before and after endoscopic surgery, providing histologic verification of depth of invasion. After transurethral resection, the bladder is palpated against the endoscope. No thickening in the wall suggests T1; some induration, T2. A thickened wall or mass suggests T3, and, if fixed or massive, T4. Modern modalities or enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are most useful (Fig. 37.7); positron emission tomography is more investigational. Multiple biopsies are advised for field effect and presence of Tis. The entire urinary tract should be fully evaluated to exclude renal pelvis and ureters as sites of disease. Metastases workup should be considered for advanced-stage bladder cancer (Table 37.5).
Oncoimaging Annotations
• Transabdominal ultrasonography can be used for bladder cancer surveillance, detecting 80% to 90% of tumors >5 mm in size.
• Virtual CT and MRI cystoscopy are being evaluated.
• Superficial bladder cancer (i.e., that which has not extended into the muscular layer of the bladder, stages T1 and below) is treated by transurethral resection.
• Muscle invasive bladder cancer, either alone (T2 or T3A) or with spread to the perivesical fat (T3B), to contiguous organs (T4), or to regional lymph nodes, requires radical surgical resection, often with radiotherapy.
• The critical distinction between superficial and muscleinvasive bladder cancer is established by transurethral resection and not by imaging. Clinical staging is not accurate for advanced disease.
• Cross-sectional imaging using either CT or MRI aids in the preoperative evaluation of locally advanced bladder cancer by demonstrating involvement of perivesical fat, invasion of contiguous organs, spread to the pelvic sidewall or anterior abdominal wall, or locoregional adenopathy.
• CT or MRI staging should be performed either before or 2 weeks after cystoscopy to minimize diagnostic errors and avoid misinterpretation.
• Both CT and MRI have a tendency to overestimate muscle and perivesical extension; both have excellent negative predictive value in excluding extravesical extension. MRI is superior to CT and transurethral ultrasonography in the evaluation of lesions located at the base or dome of the bladder.
• Differentiation of granulation tissue from persistent tumor after transurethral resection is better with MRI than CT, but limitations persist for both modalities.
Figure 37.7 | CT level of the inferior aspect of the actabulum correlates with Fig. 37.5C. Male UB = urinary bladder. 1. Seminal vesicles. 2. Rectum.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Table 37.6.
CANCER STATISTICS AND SURVIVAL
When considered together, the male genital and urinary systems are major sites of malignancy. Prostate cancer alone accounts for 200,000 new patients annually. There are 100,000 new urinary tract cancers and 2.5-fold more male genital cancers: 250,000 cases annually.
The dramatic gains in survival are due to multidisciplinary achievements in screening, early detection, precise diagnoses, and effective multimodal therapies. The cancer statistics reveal perhaps the greatest gains in survival in oncology over the last five decades. In local stage I, male genitourinary tumors, all are 90% to 100% curable according to the latest Surveillance Epidemiology and End Results data: kidney, 90%; bladder, 94%; testes, 99%; and prostate, 100%. Mortality rates are declining. The pediatric Wilms’ tumor was the first malignancy in childhood to be cured, achieving ≤90% long-term survival and heralding the success of multimodal treatment that would be achieved in adult tumors in urology (Table 37.7; Fig. 37.8).
Figure 37.8 | Five-year survival of urinary bladder cancer. (Data from Edge SB, Byrd DR, and Compton CC, et al. AJCC Cancer Staging Manual, 7th edition, New York, Springer, 2010.)