TUMORS OF THE BLADDER
More than 90% of bladder cancers arise from the mucosa and are known as urothelial (transitional cell) carcinomas. These tumors are the main focus of this section. Less common tumors include squamous cell carcinomas (5% in the United States, but most common worldwide), adenocarcinomas (2%), small cell carcinomas, and nonepithelial tumors. Metastatic tumors from other primary sites including the prostate, ovary, uterus, colon, rectum, and lung have also been described.
EPIDEMIOLOGY AND RISK FACTORS
In the United States, bladder cancer is the fourth most common malignancy among men, affecting an estimated 52,000 in the United States in 2010. It is three times more common in men than in women, and it is twice as common in Caucasian than in African American men. Like upper tract cancer, bladder cancer is generally a disease of older patients, with an average age at diagnosis of approximately 70 years.
The major risk factor for urothelial carcinoma of the bladder is cigarette smoking. Inherited differences in the metabolism of cigarette carcinogens appear to modulate this risk; for example, slower acetylators of N-acetyltransferase (NAT) are at increased risk. Another signiﬁcant risk factor is occupational exposure to aromatic amines, such as 2-naphthylamine, 4-amino-biphenyl, and 4,4-diaminobiphenyl (benzidine). These exposures are most signiﬁcant among textile workers from the aniline dye and rubber industries. Other risk factors include cyclophosphamide exposure and prior pelvic radiation.
These carcinogens appear to induce genetic abnormalities that contribute to the development of urothelial carcinomas, including mutations of the p53 tumor suppressor gene (TP53, on chromosome 17p) and retinoblastoma gene (RB, on chromosome 13q). Since these mutations are generally acquired, a prior family history of bladder cancer appears to cause only a slight increase in risk.
PRESENTATION AND DIAGNOSIS
Approximately 85% of patients with bladder cancer have painless gross hematuria. In adults, this symptom should be considered highly suspicious for cancer unless there is compelling evidence that the blood is of glomerular origin (i.e., large numbers of red blood cell casts or dysmorphic red blood cells are seen). 20% to 30% of patients also experience bladder irritability, urinary frequency, urgency, and/or dysuria. More advanced bladder cancers may rarely be associated with ﬂank pain from ureteral obstruction or lower extremity edema from lymphatic or venous obstruction. On physical examination, a bimanual examination (rectoabdominal in men, vaginoabdominal in women) may reveal a palpable mass in advanced cases; however, most examinations are unremarkable.
Once bladder cancer is suspected, radiographic imaging, urine cytology, and cystoscopy are required for further evaluation.
On high-quality axial imaging using CT or MRI, tumors may be seen as enhancing masses that produce ﬁlling defects in the bladder lumen. Because urothelial tumors arising in the upper urinary tract may seed the bladder, it is also important to perform upper tract imaging. MRI of the bladder may be used to estimate the depth of invasion into the muscularis propria (detrusor muscle) and perivesical structures.
Metastases most frequently occur in lymph nodes, liver, lung, bone, and adrenal glands. CT or MRI of the abdomen and pelvis is used to assess for nodal, liver, and adrenal metastases. Chest radiographs are typically performed to screen for lung metastases, given the high rate of false positives on CT scan. Radionuclide bone scans may be used to determine the presence of skeletal metastases in patients with suggestive symptoms or elevated serum alkaline phosphatase concentrations.
Urine cytology detects malignant urothelial cells in voided urine specimens or bladder washings. Current techniques are highly speciﬁc but only moderately sensitive, with the highest likelihood of a positive result in a patient with an advanced tumor.
Cystoscopy provides direct visual examination of the bladder mucosa, and it is the gold standard for diagnosis. Many grossly visible tumors can be resected during this initial evaluation (see Plate 10-39). Any abnormal-appearing or erythematous areas of mucosa should undergo directed biopsy for histopathologic examination. Random biopsies of normal-appearing areas may also be indicated, especially if urine cytology is positive but no tumor is grossly visible. Additional biopsy sites may include areas adjacent to a tumor, from the opposite bladder wall, dome, trigone, and prostatic urethra. It is essential to obtain deep tissue samples with adequate representation of the bladder wall to perform accurate staging.
Urothelial tumors differ from normal urothelium in architectural growth and cytologic features. They are graded according to World Health Organization/International Society of Urological Pathology Consensus criteria, which were developed in 1998 and revised in 2004.
Noninvasive. Noninvasive tumors, which do not cross the basement membrane into the lamina propria, are classiﬁed as ﬂat or papillary.
Flat lesions include reactive atypia, atypia of unknown signiﬁcance, dysplasia (low-grade intraurothelial neoplasia), or carcinoma in situ (high-grade intraurothelial neoplasia). Carcinoma in situ (CIS) is a precursor of invasive high-grade cancer. It is conﬁned to the epithelial layer, and characteristic features include nuclear enlargement, hyperchromasia, crowding, and atypia.
Papillary tumors include papillomas, papillary urothelial neoplasms of low malignant potential (PUNLMP), and low-or high-grade papillary urothelial carcinomas (LGPUC and HGPUC). Papillomas are benign lesions. PUNLMP have a low recurrence risk and only a rare association with carcinoma. The major differentiating feature between papilloma and PUNLMP is the presence of thicker urothelium and enlarged nuclei in the latter.
LGPUC and HGPUC are malignant lesions. These feature proliferation of malignant urothelial cells along exophytic ﬁbrovascular cores, as well as papillary frond fusion and branching complexity. LGPUC features neoplastic cells that vary in polarity and possess cytologic atypia and some mitotic ﬁgures. HGPUC, in turn, features marked nuclear pleomorphism, a high nuclear cytoplasmic ratio, and frequent mitotic ﬁgures. HGPUC has a higher rate of progression than LGPUC, as well as a higher probability of invasive disease and concomitant CIS at diagnosis. Heterogeneous tumors are graded based on the highest grade represented.
Invasive. Invasive carcinomas (crossing the basement membrane into the lamina propria, possibly into the muscularis propria) are also differentiated as low or high grade. Low-grade carcinomas have an ordered appearance but with nuclear variation and enlargement compared with normal urothelium. High-grade carcinomas have a disordered appearance with marked nuclear pleomorphism. The vast majority of invasive urothelial carcinomas are high grade.
Although grading can only be performed by histologic examination of tissue, cystoscopic ﬁndings may have some predictive value. For example, a histologically benign papilloma or a low-grade papillary tumor usually appears as a ﬁne villous structure attached to the bladder by a thin pedicle. By contrast, a higher-grade papillary carcinoma is usually denser with a cauliﬂower appearance and a thicker pedicle. CIS is a ﬂat lesion. Deeper invasion may be indicated by a nodular or sessile appearance, sometimes with necrosis. If there is tumor obstruction of the ureteric oriﬁce, there is likely deeper inﬁltration.
Staging of a bladder tumor, performed according to the 2010 TNM classiﬁcation system, measures the precise extent of the tumor’s spread both within and beyond the bladder wall. It relies on information from biopsy and imaging.
The staging of a bladder tumor offers important prognostic information. Prognosis also correlates with tumor size, multiplicity, papillary versus sessile conﬁguration, presence of lymphovascular invasion, and status of the remaining urothelium.
The speciﬁc treatment plan must be based on the tumor stage and the clinical condition of the patient. A key factor is whether the tumor invades the muscularis propria, and if so, whether aggressive treatment is likely to be curative.
Low-risk, noninvasive tumors (i.e., low-grade Ta) are typically treated with transurethral resection (TURBT, see Plate 10-39), generally performed at the time of initial cystoscopic evaluation, as well as intravesical chemotherapy (i.e., mitomycin C). The patient, however, must undergo routine cystoscopic surveillance because recurrence is common.
High-risk, noninvasive tumors (high-grade Ta, Tis, or T1) are typically treated with transurethral resection and intravesical immunotherapy with bacillus Calmette-Guérin (BCG), an attenuated mycobacterium that induces a local, antitumor immune response that decreases recurrence and progression rates. Patients failing this treatment may be offered second line intravesical therapy (BCG-interferon or alternative chemotherapy), but radical cystectomy should be strongly considered.
Local muscularis propria-invasive tumors are aggressively treated, typically using a combination of neoadjuvant, cisplatin-based chemotherapy and radical cystectomy with urinary diversion. Randomized trials have shown that a multiagent chemotherapeutic regimen followed by radical cystectomy is more likely to eliminate cancer than radical cystectomy alone. The relative reduction of 25% to 40% in all-cause and cancer-speciﬁc mortality is associated with an improvement of median overall survival by 2.5 years. Nonrandomized clinical trials have demonstrated the efﬁcacy of neoadjuvant chemotherapy and external radiation therapy in select patients. Adjuvant systemic chemotherapy may provide a survival advantage for locoregional disease with pelvic lymph node involvement, with up to 9% improvement in survival at 3 years.
Unresectable or metastatic bladder cancer is treated with systemic, cisplatin-based chemotherapy alone.
Patients with noninvasive bladder cancers that are treated with TURBT, either with or without intravesical therapy, should undergo routine follow-up with ﬂexible cystoscopy and urine cytology every 3 months for 1 to 3 years. The frequency can then be reduced to every 6 months for an additional 2 to 3 years, and then annually, as long as there has been no recurrence.
Disease status at the initial 3-month treatment is important in predicting tumor behavior in the future. In addition to these measures, contrast-enhanced CT or retrograde pyelogram should be performed at least every 1 to 2 years.
Patients with invasive disease treated with cystectomy should undergo lifelong follow-up, with a chest radiograph, complete metabolic panel, liver function tests, contrast-enhanced CT, and urine cytology performed every 6 to 12 months. If an ileal conduit has been created, vitamin B12 levels should also be checked each year. If urethrectomy was not performed at the time of cystectomy, urethral wash cytology should be performed every 6 to 12 months. If patients experience urethral symptoms or are at increased risk for urethral recurrence, urethroscopy may be indicated.