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
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
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
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.
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.
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
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.
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
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.