Bladder Cancer
Introduction
Background
Bladder cancer is a common urologic cancer. The most
common type of bladder cancer in the United States is
urothelial carcinoma, formerly known as transitional cell
carcinoma (TCC). The urothelium in the entire urinary tract
may be involved, including the renal pelvis, ureter, bladder,
and urethra.
The clinical course of bladder cancer carries a broad
spectrum of aggressiveness and risk. Low-grade, superficial
bladder cancers have minimal risk of progression to death;
however, high-grade muscle-invasive cancers are often
lethal.
Pathophysiology
Almost all bladder cancers are epithelial in origin. The
urothelium consists of a 3- to 7-cell mucosal layer within the
muscular bladder. Of these urothelial tumors, more than 90%
are transitional cell carcinomas. However, up to 5% of
bladder cancers are squamous cell in origin, and 2% are
adenocarcinomas. Nonurothelial primary bladder tumors are
extremely rare and may include small cell carcinoma,
carcinosarcoma, primary lymphoma, and sarcoma.
Bladder cancer is often described as a polyclonal field change
defect with frequent recurrences due to a heightened
potential for malignant transformation. However, bladder
cancer has also been described as a problem with
implantation and migration from a previously affected site.
The World Health Organization classifies bladder cancers as
low grade (grade 1 and 2) or high grade (grade 3). Tumors are
also classified by growth patterns: papillary (70%), sessile or
mixed (20%), and nodular (10%).Carcinoma in situ (CIS) is a
flat, noninvasive, high-grade urothelial carcinoma. The most
significant prognostic factors for bladder cancer are grade,
depth of invasion, and the presence of CIS.
Upon presentation, 55-60% of patients have low-grade
superficial disease, which is usually treated conservatively
with transurethral resection and periodic cystoscopy. Forty to
forty-five percent of patients have high-grade disease, of
which 50% is muscle invasive and is typically treated
with radical cystectomy.
Less than 5% of bladder cancers in the United States are
squamous cell carcinomas (SCCs). However, worldwide, SCC
is the most common form, accounting for 75% of bladder
cancer in underdeveloped nations. In the United States, SCC
is associated with persistent inflammation from long-term
indwelling Foley catheters and bladder stones. In
underdeveloped nations, SCC is associated with bladder
infection by Schistosoma haematobium.
Adenocarcinomas account for less than 2% of primary
bladder tumors. These tumors are observed most commonly
in exstrophic bladders and respond poorly to radiation and
chemotherapy. Radical cystectomy is the treatment of
choice.
Small cell carcinomas are aggressive tumors associated with a
poor prognosis and are thought to arise from neuroendocrine
stem cells.
Carcinosarcomas are highly malignant tumors that contain
both mesenchymal and epithelial elements.
Primary bladder lymphomas arise in the submucosa of the
bladder and are treated with radiation therapy.
Leiomyosarcoma is the most common sarcoma of the
bladder.
Rhabdomyosarcomas most commonly occur in children and
carry a poor prognosis.
Frequency
United States
Bladder cancer is the fourth most common cancer in men in
the United States, after prostate, lung, and colorectal cancer.
Bladder cancer is the 10th most common cancer in women.
From 1985-2000, the number of patients diagnosed annually
with bladder cancer increased by 33%. An annual cohort of
300,000-400,000 patients with bladder cancer is reported in
the United States. The recurrence rate for superficial
transitional cell cancer of the bladder is high, and as many as
80% of patients have at least one recurrence.
International
In developed countries, 90% of bladder cancers are TCC. In
developing countries, 75% of bladder cancers are SCCs, and
most
of
these
cancers
are
secondary
to S
haematobium infection.
Mortality/Morbidity
In 2009, an estimated 70,980 new patients will be diagnosed
with bladder cancer in the United States, and 14,330 of those
patients will die of the disease.1
Race
Bladder cancer is more common in whites than in blacks;
however, blacks have a worse prognosis than whites.
Sex
The male-to-female ratio is 3:1. Women generally have a
worse prognosis than men.
Age
The median age at diagnosis is 68 years, and the incidence
increases with age.
Clinical
History
1. Approximately 80-90% of patients with bladder cancer
present with painless gross hematuria, which is the
classic presentation. Consider all patients with gross
hematuria to have bladder cancer until proven
otherwise. Suspect bladder cancer if any patient
presents with unexplained microscopic hematuria.
2. Twenty to thirty percent of patients with bladder cancer
experience irritative bladder symptoms such as dysuria,
urgency, or frequency of urination that are related to
more advanced muscle-invasive disease or CIS.
3.
Patients with advanced disease can present with pelvic
or bony pain, lower-extremity edema from iliac vessel
compression, or flank pain from ureteral obstruction.
Physical
Superficial bladder cancer is rarely found during a physical
examination.
Occasionally, an abdominal or pelvic mass may be palpable.
Examine for lymphadenopathy.
Causes
Up to 80% of bladder cancer cases are associated with
environmental exposure, which suggests that bladder cancer
is potentially preventable. Smoking is the most commonly
associated risk factor and accounts for approximately 50% of
all bladder cancers. Nitrosamine, 2-naphthylamine, and 4aminobiphenyl are possible carcinogenic agents found in
cigarette smoke. Bladder cancer is also associated with
industrial exposure to aromatic amines in dyes, paints,
solvents, leather dust, inks, combustion products, rubber,
and textiles. Therefore, higher-risk occupations associated
with bladder cancer include painting, driving trucks, and
working with metal.
Several medical risk factors are associated with bladder
cancer. Patients with prior exposure to radiation treatment
of the pelvis have an increased risk of bladder cancer.
Chemotherapy with cyclophosphamide increases the risk of
bladder cancer via exposure to acrolein, a urinary metabolite
of cyclophosphamide. Patients with spinal cord injuries who
have long-term indwelling catheters have a 16- to 20-fold
increased risk of developing SCC of the bladder.
Coffee consumption does not increase the risk of developing
bladder cancer. Early studies of rodents and a minority of
human studies suggested a weak connection between
artificial sweeteners (eg, saccharin, cyclamate) and bladder
cancer; however, most recent studies show no significant
correlation.
Although no convincing evidence exists for a hereditary
factor in the development of bladder cancer, familial clusters
of bladder cancer have been reported. Several genetic
mutations have been identified in bladder cancer. Mutations
of the tumor suppressor gene for p53, found on chromosome
17, are associated with high-grade bladder cancer and CIS.
Mutations
of
the
tumor
suppressor
gene
for p15 and p16, found on chromosome 9, are associated
with low-grade and superficial tumors. Retinoblastoma (Rb)
tumor suppressor gene mutations are also noted. Bladder
cancer is associated with increased expression of the
epidermal growth factor gene and the erb- b2 oncogene, and
mutations of the oncogenes p21 ras, c-myc, and c-jun.
Differential Diagnoses
Hemorrhagic
Noninfectious
Cystitis: Urinary
Females
Nephrolithiasis
Tract
Urinary Tract Infection, Males
Renal Cell Carcinoma
Transitional Cell Carcinoma, Renal
Infection,
Ureteral Trauma
Workup
Laboratory Studies
1. Any patient with gross or microscopic hematuria should
be urologically evaluated. Microscopic hematuria from
bladder cancer may be intermittent; therefore, a repeat
negative result on urinalysis does not exclude the
diagnosis. Infection may cause hematuria and is usually
associated with irritative voiding symptoms (eg, dysuria,
frequency, urgency). Irritative voiding symptoms may
also be caused by CIS or muscle-invasive bladder cancer.
Further evaluate irritative voiding symptoms caused by a
urinary tract infection that do not resolve with
treatment.
 Urinalysis with microscopy
 Urine culture to rule out infection, if suspected
 Voided urinary cytology (This may be helpful if results
are positive, but a negative cytology result cannot be
considered definitive. Urinary cytology for routine
screening is controversial.)
2. Newer molecular and genetic markers may help in the
early detection and prediction of urothelial carcinoma.
 Newer, voided urine assays (ie, bladder tumor antigen
[BTA-Stat, BTA-TRAK], nuclear matrix protein [NMP-22],
fibrin/fibrinogen degradation products [FDP]) are being
used for the detection and surveillance of urothelial
carcinoma. These tests have high false-positive and falsenegative rates. In the future, other newer assays based
on telomerase and microsatellite analysis may prove to
be a better detection method than urinary cytology.
 Chromosomal alterations have been associated with
urothelial carcinoma. One encouraging test is a
multitarget interphase fluorescence in situ hybridization
(FISH) assay called UroVysion that consists of probes to
the centromeres of chromosomes 3, 7, 17, and the 9p21
region. Aneuploidy of chromosomes 3, 7, and 17 and
deletion of chromosome 9 has been associated with high
sensitivity and specificity to detect bladder cancer.
Often, this is an anticipatory positive result with a
positive finding preceding visual evidence of bladder
tumor.
 However, at this time, no urinary assay has been shown
to effectively replace cystoscopy for the detection of
bladder tumors.
Imaging Studies
1. Upper-tract imaging is necessary for the hematuria
workup and should be able to visualize both the kidneys
and the urothelium.
2. The American Urologic Association Best Practice Policy
recommends CT scanning of the abdomen and pelvis
with preinfusion and postinfusion phases. This is ideally
performed with a CT urography or followed by
radiography of the kidneys, ureters, and bladder (KUB) to
obtain images similar to those produced with
intravenous pyelography (IVP).
3.
Two commonly used alternative studies are IVP and
renal ultrasonography.
 The IVP is the traditional standard for upper-tract
urothelium imaging; however, it is poor for evaluating
the renal parenchyma.
 Ultrasonography is also commonly used; however,
urothelial tumors of the upper tract and small stones are
easily missed.
4. Conduct retrograde pyelography in patients in whom
contrast CT scanning cannot be performed because of
azotemia or a severe allergy to intravenous contrast.
Procedures
1. Cystoscopy
 Obtain biopsy samples of suspicious lesions during
cystoscopy. Attempt to include the bladder muscle in the
biopsy specimen. This allows the pathologist to
determine whether the tumor is muscle invasive.
 Transitional cell tumors are typically papillary or sessile,
and CIS may appear as an erythematous, velvety lesion.
Unless the lesion is in a bladder diverticulum
(pseudodiverticulum), attempt to resect the primary
tumor completely.
 A bladder diverticulum lacks a surrounding muscle layer,
and a deep biopsy of a lesion within a diverticulum risks
perforating the bladder and extravesical extravasation of
cancer cells.
 Because no muscle layer surrounds the bladder
diverticulum, the next step in the progression of a
superficial tumor is extravesical spread, requiring more
aggressive surgical therapy (eg, partial cystectomy, open
diverticulectomy) rather than a simple resection
followed by surveillance.
 Further investigate efflux of blood from either ureteral
orifice with retrograde pyelography, ureteroscopy, or
both.
2. Urine cytology
 Perform urine cytology at the same time as cystoscopy,
although its routine use for screening is controversial.
 Urine cytology is associated with a significant falsenegative rate, especially for low-grade carcinoma (1050% accuracy rate).
 The false-positive rate is 1-12%, but it has a 95%
accuracy rate for diagnosing high-grade carcinoma and
CIS.
 The sensitivity of urine cytology can be increased by
obtaining a bladder barbotage cytology (70%) as
opposed to a voided cytology (30%).
 With a normal finding on cystoscopic examination,
further evaluate a positive cytology result on urine study
with an upper-tract study and random biopsies of the
bladder. Obtain biopsy samples of the prostatic urethra
in men.
3. Other urine markers for bladder cancer

The use of additional urine markers such as UroVysion
(FISH), BTA, and NMP-22 in the initial diagnosis of
bladder cancer is controversial. All of these assays may
yield false-positive and false-negative results.
 These other tests should not replace urine cytology and
cystoscopy, with or without biopsy, for the diagnosis of
bladder cancer. However, they may be useful adjuncts to
urine cytology and cystoscopy.
Histologic Findings
More than 90% of bladder cancer cases are TCC,
approximately 5% are SCC, and less than 2% are
adenocarcinoma. Both the stage and tumor grade correlate
independently with prognosis.
Staging
The International Union Against Cancer and the American
Joint Committee on Cancer Staging developed the tumor,
node, and metastases (TNM) staging system, which is used to
stage bladder cancer (see below). Ta and T1 tumors and CIS
were once considered superficial bladder tumors. T2, T3, and
T4 tumors were traditionally described as invasive bladder
cancer. However, urologic oncologists now recommend
avoiding the term superficial bladder cancer to describe Ta,
T1, and CIS tumors because it is a misnomer and tends to
group patients who may require different treatments and
who may have differing prognoses. Urothelial carcinoma is
histologically graded as low grade (formerly graded 1-2) or
high grade (formerly graded 3). CIS is characterized by full
mucosal thickness and high-grade dysplasia of the bladder
epithelium and is associated with a poorer prognosis.
The following is the TNM staging system for bladder cancer:
1. CIS - Carcinoma in situ, high-grade dysplasia, confined to
the epithelium
2. Ta - Papillary tumor confined to the epithelium
3. T1 - Tumor invasion into the lamina propria
4. T2 - Tumor invasion into the muscularis propria
5. T3 - Tumor involvement of the perivesical fat
6. T4 - Tumor involvement of adjacent organs such as
prostate, rectum, or pelvic sidewall
7. N+ - Lymph node metastasis
8. M+ - Metastasis
More than 70% of all newly diagnosed bladder cancers are
non–muscle invasive, approximately 50-70% are Ta, 20-30%
are T1, and 10% are CIS. Approximately 5% of patients
present with metastatic disease, which commonly involves
the lymph nodes, lung, liver, bone, and central nervous
system. Approximately 25% of affected patients have muscleinvasive disease at diagnosis.
1. Clinically stage a patient who has muscle-invasive
disease with CT scanning of the abdomen and pelvis,
chest radiography, and serum chemistries.
2. If the patient is asymptomatic with normal calcium and
alkaline phosphatase levels, a bone scan is unnecessary.
3.
As many as 50% of patients with muscle-invasive bladder
cancer may have occult metastases that become
clinically apparent within 5 years of initial diagnosis.
4. Most patients with overt metastatic disease die within 2
years despite chemotherapy.
5. Approximately 25-30% of patients with only limited
regional lymph node metastasis discovered during
cystectomy and pelvic lymph node dissection may
survive beyond 5 years.
Treatment
Medical Care
The treatment of non–muscle-invasive (Ta, T1, CIS) and
muscle-invasive bladder cancer should be differentiated.
Treatments within each category include both surgical and
medical approaches.
1. Non–muscle-invasive disease (Ta, T1, CIS)
a) Intravesical immunotherapy (Bacillus Calmette-Guérin
[BCG] immunotherapy)
 BCG immunotherapy is used in the treatment of Ta, T1,
and CIS urothelial carcinoma of the bladder and may
help to decrease the rate of recurrence and progression.
 BCG immunotherapy is the most effective intravesical
therapy and involves a live attenuated strain
of Mycobacterium bovis.Some early studies purported
that an immune response against BCG surface antigens
cross-reacted with putative bladder tumor antigens, and
this was proposed as the mechanism for the therapeutic
effect of BCG; however, multiple subsequent studies
refute this claim and demonstrate that BCG induces a
nonspecific, cytokine-mediated immune response to
foreign protein.
 Because BCG is a live attenuated organism, it can cause
an acute disseminated tuberculosislike illness if it enters
the bloodstream (BCG sepsis), possibly resulting in
death. Therefore, the use of BCG is contraindicated in
patients with gross hematuria.
 BCG typically causes mild systemic symptoms that
resolve within 24-48 hours after intravesical instillation.
BCG can also cause granulomatous cystitis or prostatitis
with bladder contraction.
 BCG is recommended for CIS, T1 tumors, and high-risk Ta
tumors (large, high-grade, recurrent, or multifocal
tumors). This therapy is less effective in reducing the 5year recurrence rate for low-grade and low-stage
urothelial carcinoma (see Table 1 below).
 Typically, BCG is administered weekly for 6 weeks.
Another 6-week course may be administered if a repeat
cystoscopy reveals tumor persistence or recurrence.
Recent evidence indicates that maintenance therapy
with a weekly treatment for 3 weeks every 6 months for
1-3 years may provide more lasting results.
 Consider patients with recurrent CIS for an early
cystectomy. At 5 and 10 years, approximately 70% and
30% of patients with CIS who are treated with BCG are
disease free, respectively. Recurrent CIS, despite
intravesical BCG, is associated with a 63% risk of
progression to muscle-invasive bladder cancer.
Recurrence after BCG treatment may also occur in the
upper urinary tract or prostatic urethra.
 Interferon alpha or gamma has been used in the
treatment of stages Ta, T1 and CIS urothelial carcinoma,
either as a single agent therapy or in combination with
BCG. Its role has primarily been in post-BCG failure with
early promising results. Although BCG with interferon
has shown a 42% response with tolerable side effects
after BCG failure, no evidence has indicated that retreating with BCG with interferon is superior to retreating with BCG alone.
b) Intravesical chemotherapy
 Valrubicin has recently been approved as intravesical
chemotherapy for CIS that is refractory to BCG. In
patients whose conditions do not respond to BCG, the
overall response rate to valrubicin is approximately 20%,
and some patients can delay time to cystectomy.
Valrubicin is presently not commercially available.
 Other forms of adjuvant intravesical chemotherapy for
bladder
cancer
include
intravesical
triethylenethiophosphoramide (thiotepa [Thioplex]),
mitomycin-C, doxorubicin, and epirubicin. Although
these agents may increase the time to disease
recurrence, no evidence indicates that these therapies
prevent disease progression.
 No evidence suggests that these adjuvant therapies are
as effective as BCG.
2. Muscle-invasive disease (T2 and greater)
a) Adjuvant and neoadjuvant chemotherapy
 Neoadjuvant chemotherapy prior to either radical
cystectomy or external beam radiotherapy is
controversial.
 The Southwestern Oncology Group (SWOG) conducted a
multicenter randomized prospective study that
compared neoadjuvant therapy using a methotrexate,
vinblastine, doxorubicin (Adriamycin), and cisplatin
(MVAC) combination with surgery alone. The group
concluded that neoadjuvant therapy conferred a
treatment benefit compared with surgery alone.
However, several criticisms of this study exist. The study
was purposely underpowered because of slow
recruitment (317 patients over 11 y), because 20% of the
patients who were to undergo cystectomy alone never
underwent surgery, and because there was no
comparison to neoadjuvant therapy alone. In addition, a
recent study re-evaluated the SWOG data and found that
surgical factors significantly affected outcomes.
 In one small series, the T4 tumors of 45% of affected
patients responded to chemotherapy, making potentially
curative cystectomy possible.

Although no definite evidence of benefit exists, patients
with P3-P4 or N+ urothelial carcinoma in the United
States are typically advised to receive adjuvant
chemotherapy.
b) Chemotherapeutic agents for metastatic disease
 MVAC is the standard treatment of metastatic bladder
cancer. MVAC has an objective response rate of 57-70%,
a complete response rate of 15-20%, and a 2-year
survival rate of 15-20%.
 Gemcitabine and cisplatin (GC) is a newer regimen and
has been shown to be as efficacious as MVAC, but with
less toxicity. GC is now considered a first-line treatment
agent for bladder cancer.
 Several novel compounds have shown activity against
transitional cell bladder cancer and are now being tested
in combination chemotherapy trials. Some of these
promising agents are ifosfamide, paclitaxel, docetaxel,
and carboplatin.
Table 1. Recurrence and Progression Rates at 5 Years for Ta,
T1, and CIS TCC of the Bladder Treated With BCG
Stage Recurrence, % Progression, %
Ta
55
11
T1
61
31
CIS
45
23
G1
61
7
G2
56
19
G3
45
23
Surgical Care
1. Ta, T1, and CIS
a) Endoscopic treatment
 Transurethral resection of bladder tumor (TURBT) is the
first-line treatment to diagnose, to stage, and to treat
visible tumors.
 Patients with bulky, high-grade, or multifocal tumors
should undergo a second procedure to ensure complete
resection and accurate staging. Approximately 50% of
stage T1 tumors are upgraded to muscle-invasive
disease.
 Electrocautery or laser fulguration of the bladder tumor
is sufficient for low-grade, small-volume, papillary
tumors.
 No further metastatic workup is needed for obviously
superficial tumors.
 Because bladder cancer is a polyclonal field change
defect, continued surveillance is mandatory.
b) Radical cystectomy
 Although typically reserved for muscle-invasive disease,
radical surgery is more appropriately used to treat some
cases of non–muscle-invasive bladder cancer.
 Thirty-five to fifty percent of patients who undergo
cystectomy for Ta, T1, or CIS are discovered to have
muscle-invasive disease, with 10-15% demonstrating
microscopic lymph node metastasis.
 The CIS in upwards of 80% of affected patients
progresses to muscle-invasive disease, with 20% of
patients found to have muscle-invasive disease at the
time of cystectomy.
 High-grade T1 tumors that recur despite BCG have a 50%
likelihood of progressing to muscle-invasive disease.
Cystectomy performed prior to progression yields a 90%
5-year survival rate. The 5-year survival rate drops to 5060% in muscle-invasive disease.
 Patients with unresectable large superficial tumors,
prostatic urethra involvement, and BCG failure should
also undergo radical cystectomy.
 In 2009, the Society of Urologic Oncology (SUO)
discussed the current status of robot-assisted radical
cystectomy (RARC). Experienced surgeons demonstrated
the possibility of reduced blood loss, opiate requirement,
and hospital stay. Surgeons performing this procedure
need to provide detailed informed consent and a full
description of potential complications and outcomes
when confronting a serious disease with profound
postoperative quality-of-life changes, as this is a
relatively new procedure.2
2. Muscle-invasive disease (T2 and greater)
a) Radical cystoprostatectomy (men)
 In men, this is the criterion standard for organ-confined,
muscle-invasive bladder cancer (eg, T2, T3).
 Remove the bladder, prostate, and pelvic lymph nodes.
 Perform a total urethrectomy for anterior urethral
involvement, involvement of the prostatic stroma, or
diffuse CIS that involves the prostate.
b) Anterior pelvic exenteration (women)
 Perform this procedure in women diagnosed with
muscle-invasive bladder cancer.
 The procedure involves removal of the bladder, urethra,
uterus, ovaries, anterior vaginal wall, and pelvic lymph
nodes.
 If no tumor involvement of the bladder neck is present,
the urethra and anterior vaginal wall may be spared with
the construction of an orthotopic neobladder.
c) Pelvic lymphadenectomy
 Approximately 25% of patients undergoing radical
cystectomy have lymph node metastases at the time of
surgery.
 Bilateral pelvic lymphadenectomy (PLND) should be
performed
in
conjunction
with
radical
cystoprostatectomy and anterior pelvic exenteration.
 PLND adds prognostic information by appropriately
staging the patient and may confer a therapeutic benefit.
 The boundaries of a standard PLND include the
bifurcation of the common iliac artery and vein
superiorly, the genitofemoral nerve laterally, the
obturator fossa posteriorly, and the circumflex iliac vein
(or node of Cloquet) inferiorly.
 Extended PLND includes the lymph nodes in the
presacral region and those surrounding the common iliac
vessels to the level of the aortic bifurcation. The
additional benefit of an extended PLND is controversial.
Based on several retrospective studies, some experts
believe that an extended dissection provides additional
staging information and offers a survival benefit.
However, no randomized trials to date have proven that
an extended PLND is more beneficial than a standard
PLND.
d) After performing a cystectomy, a urinary diversion must
be created from an intestinal segment. The various types
of urinary diversions can be separated into the following
continent and incontinent diversions:
 Conduit (incontinent diversion; see image below):
Conduits can be constructed from either ileum or colon.
The ileal conduit is the most common incontinent
diversion performed and has been used for more than 40
years with excellent reliability and minimal morbidity. A
small segment of ileum (at least 15 cm proximal to the
ileocecal valve) is taken out of gastrointestinal continuity
but maintained on its mesentery, with care to preserve
its blood supply. The gastrointestinal tract is restored
with a small-bowel anastomosis. The ureters are
anastomosed to an end or side of this intestinal segment
and the other end is brought out as a stoma to the
abdominal wall. Urine continuously collects in an
external collection device worn over the stoma.
In an ileal conduit, a
small segment of
ileum is taken out of
continuity with the
gastrointestinal tract
but is maintained on
its mesentery. Ureters
are anastomosed to
one end of this ileal
segment, and the
other end is brought
out as a stoma to the
abdominal wall.

Indiana pouch (continent diversion; see image below):
This is a continent urinary reservoir created from a
detubularized right colon and an efferent limb of
terminal ileum. The terminal ileum is plicated and
brought to the abdominal wall. The ileocecal valve acts
as a continence mechanism. The Indiana pouch is
emptied with a clean intermittent catheterization 4-6
times per day.
In an Indiana pouch, a urinary
reservoir is created from
detubularized right colon and
an efferent limb of terminal
ileum. Terminal ileum is
plicated and brought to the
abdominal
wall.
The
continence mechanism is the
ileocecal valve.

Neobladder (continent diversion; see image below):
Various segments of intestine including ileum, ileum and
colon, and sigmoid colon can be used to construct a
reservoir. The ureters are implanted to the reservoir, and
the reservoir is anastomosed to the urethra. This
operation has been performed successfully in men for
more than 20 years and, more recently, in women. The
orthotopic neobladder most closely restores the natural
storage and voiding function of the native bladder.
Patients have volitional control of urination and void by
Valsalva. Contraindications to performing continent
urinary diversions include multiple comorbid health
problems, chronic renal insufficiency, hepatic
dysfunction, and advanced disease stage.
In
an
orthotopic
neobladder, a segment of
ileum is used to construct
a neobladder, which is
connected to the urethra.
Orthotopic
neobladder
most closely restores the
natural storage and
voiding function of the
native bladder.
e)

Laparoscopic and robotic surgery
Recently, laparoscopic and robotic-assisted radical
cystectomies have been performed in small numbers at
select tertiary academic centers.
The urinary diversion is almost universally performed
extracorporeally through a miniature laparotomy
incision. Initially, some centers attempted to create the
urinary diversion laparoscopically, but this was
abandoned because of inferior outcomes. 3
Immediate postoperative complication rates and
functional outcomes appear to be similar to those of
open radical cystectomy and urinary diversion. In
addition, a few studies suggest faster recovery of bowel
function and less use of postoperative narcotics.
However, these findings have not been corroborated by
other contemporary studies.
Intermediate and long-term oncologic outcomes for
these minimally invasive approaches remain undefined.
At this time, open radical cystectomy and urinary
diversion should be considered the standard of care for
invasive bladder cancer, and patients should be
counseled to this end.
Both laparoscopic and robotic-assisted radical
cystectomy remain investigative procedures that should
be performed only at major academic medical centers
after appropriate informed consent.
Radiation therapy
External beam radiation therapy has been shown to be
inferior to radical cystectomy for the treatment of





f)

bladder cancer. The overall 5-year survival rate after
treatment with external beam radiation is 20-40%
compared to a 90% 5-year survival after cystectomy for
organ-confined disease.
 Although inferior to radical cystectomy, external beam
radiation therapy is used in various countries other than
the United States for T2-T3 urothelial carcinoma of the
bladder.
 Neoadjuvant external beam radiation therapy has been
attempted for muscle-invasive bladder cancer, with no
improvement in survival rate.
g) In certain facilities, a bladder-preserving strategy for T2T3 urothelial carcinoma is applied using a combination of
external beam radiation, chemotherapy, and endoscopic
resection.
 Survival rates associated with this approach are
comparable with those of cystectomy in selected
patients.
 This combination has a widespread application that is
limited by the complexity of the protocol, its toxicity, and

a high mortality rate.
 The mortality rate in the 2 largest US series with the
longest follow-up study is 4-5%. In comparison, the
mortality rate for most modern cystectomy series is 12%.
 In addition, a significant number of patients ultimately
require salvage cystectomy, which is associated with
significantly increased morbidity and decreased options
for urinary diversions. In some series, local recurrence of
bladder cancer is as high as 50-60% despite the
completion of bladder-preserving therapy.
Medication
MVAC is the standard treatment for metastatic bladder
cancer. No proven role exists for adjuvant chemotherapy.
When selecting therapy, the MVAC combination has
substantial toxicity and must be weighed against the
expected benefit. The major dose-limiting toxicity is
myelosuppression. The new combination regimens (eg,
gemcitabine, cisplatin) show response rates and median
survival comparable to MVAC but with less toxicity.
Antineoplastic agents
These agents inhibit cell growth and proliferation.
Methotrexate (Folex PFS)
Inhibits dihydrofolate reductase (DHFR), causing a block in
the reduction of dihydrofolate to tetrahydrofolate. This
inhibits the formation of thymidylate and purines and arrests
DNA, RNA, and protein synthesis.
Adult
30 mg/m2 IV on day 1; repeat on days 15 and 22 if WBC count
>2000/µL and platelet count >50,000/µL
Vinblastine (Velban, Alkaban-AQ)
Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to
specific site on tubulin, prevents polymerization of tubulin
dimers, and inhibits microtubule formation. Intrathecal (IT)
administration use may result in death.
Adult
3 mg/m2 IV on day 2; repeat on days 15 and 22 if WBC count
>2000/µL and platelet count >50,000/µL
Doxorubicin (Adriamycin)
Anthracycline antibiotic that causes DNA strand breakage
through effects on topoisomerase II and direct intercalation
into DNA, which causes DNA polymerase inhibition. This drug
is both mutagenic and carcinogenic.
Adult
30 mg/m2 IV on day 2
Cisplatin (Platinol)
A platinum-containing compound that exerts an
antineoplastic effect by covalently binding to DNA, with
preferential binding to N-7 position of guanine and
adenosine. Can react with 2 different sites on DNA to
produce cross-links. Platinum complex also can bind to
nucleus and cytoplasmic protein.
Adult
50-70 mg/m2 IV on day 2
Gemcitabine (Gemzar)
Cytidine analog. After intracellular metabolism to active
nucleotide, inhibits ribonucleotide reductase and competes
with deoxycytidine triphosphate for incorporation into DNA.
Adult
1 g/m2 IV
Follow-up
Further Outpatient Care
The high rate of disease recurrence and progression in non–
muscle invasive bladder cancer underscores the need for
careful follow-up studies. Surveillance for these patients
includes cystoscopy and bladder wash cytologies every 3
months for 2 years, then every 6 months for 2 years, and
then at least yearly.
Cystoscopy
Cystoscopy is the primary diagnostic modality for the
diagnosis of bladder carcinoma because it confers low risk
and can be performed in the physician's office. Although it is
the criterion standard for detecting bladder cancer,
cystoscopy is invasive and relatively expensive.4 Moreover,
visibility can be reduced by bleeding, and flat urothelial
lesions such as CIS may be difficult to distinguish from normal
bladder tissue. Thus, cytologic analysis of voided urine is
frequently used as an adjunctive test to aid in identifying
occult cancers.
Cytology
Voided urine cytology is the standard noninvasive method for
diagnosis in the detection of bladder carcinoma. Cytology is
used to assess morphologic changes in intact cells.
Unfortunately, however, the sensitivity of cytology is low,
with various studies reporting values between 11% and
76%.5 Sensitivity depends largely on the degree of tumor
differentiation.
High-grade
tumors
with
marked
pleomorphism and distinctly abnormal nuclear features are
identified more accurately.
Small and/or well-differentiated tumors are less likely to
exfoliate cells because intercellular attachments are better
preserved and the degree of morphological departure from
normal is smaller, complicating cytologic recognition.6This
results in poor sensitivity in low-grade and early-stage
cancers. Several other factors affect the sensitivity of
cytology, including specimen quality, number of exfoliated
cells, and pathologist expertise. The overall low sensitivity of
cytology is due to its low sensitivity in detecting low-grade
bladder tumors.7
In addition, instrumentation may cause reactive cellular
changes, contributing to variability in interpretation. Falsepositive reports of malignant cells are uncommon, but
ambiguous reports of atypical cells are frequent. Bladder
wash cytology yields more tumor cells in the sample and is
more sensitive in identifying cancer, especially for high-grade
tumors, but it also yields a higher false-positive rate than
voided urine cytology.8
Noninvasive urine markers can offer an alternative to the
standard means of detecting bladder cancer or can be used
as an adjunct to cystoscopy.9
Genetic aberrations
The study of genetic aberrations commonly associated with
urothelial carcinoma provides a more objective assessment
for diagnosing and detecting recurrent disease. Homozygous
loss of chromosome band 9p21, the site for the tumor
suppressor gene p16, is a known early genetic event in the
development of papillary carcinoma and urothelial CIS.10
Increased chromosomal instability and aneuploidy have been
implicated in tumor progression. A study by Sokolova et al of
9 genetic markers for detecting urothelial carcinoma showed
that polysomy of chromosomes 3, 7, and 17 and deletion of
9p21 were the most sensitive and specific markers, detecting
95% of recurrent urothelial carcinoma. 11 Halling et al
established that a threshold of 5 or more cells with polysomy
was 84% sensitive and 92% specific for detecting recurrent
urothelial cancer.10
Fluorescence in situ hybridization
A commercial FISH assay (UroVysion), which includes probes
for the centromeres for chromosomes 3, 7, and 17 and has a
locus-specific probe for 9p21, was developed to screen for
recurrent urothelial carcinoma and was recently approved by
the US Food and Drug Administration (FDA) for diagnostic
studies.
Initial comparisons of urine cytology with FISH for detecting
bladder cancer recurrence showed that FISH yielded a
greater sensitivity.12 FISH is 42-83% sensitive for detecting
pTa and pT1 lesions and 92-100% sensitive for pT2-4 invasive
lesions in patients with known bladder cancer, while urine
cytology yields sensitivities of 24-50% for pTa and pT1 lesions
and 78-85% for pT2-4 invasive lesions.13 For suspected new
cases of urothelial carcinoma, cytology yields a reported
diagnostic sensitivity of 48%, while no data are available for
FISH evaluation of these cases.14
Laudadio et al compared the diagnostic sensitivity of FISH
with concurrent biopsy and cytological assessments.15FISH
analysis was found to yield a high sensitivity for detecting
new cases of urothelial carcinoma, as well as recurrences.
Their study showed FISH detected 95% of cases with highgrade carcinoma, while cytology detected 41% of such cases.
FISH yielded an overall specificity of 65%, compared to 93%
with cytology. From this data, the authors concluded that
FISH is considerably more sensitive and only slightly less
specific than cytology in diagnosing urothelial carcinoma.
They recommended FISH as a useful initial diagnostic tool in
patients suspected of both new and recurrent bladder
cancer.
Nuclear matrix protein-22
Nuclear matrix, first described in 1974, is the nonchromatin
structure that supports nuclear shape and organizes DNA. It
also takes part in DNA replication and transcription, as well
as RNA processing.16,17,18 NMP-22 is involved in the proper
distribution of chromatin to daughter cells during cell division
and is found in the nuclear matrix of all cell types. NMP-22 is
thought to be released from the nuclei of tumor cells after
they die and can be detected in the urine. Research has
found that persons with bladder cancer may have urinary
NMP-22 levels up to 25 times that in healthy persons.19
The NMP-22 BladderChek test is an in vitro immunoassay
intended for the qualitative detection of NMP-22 in urine. It
determines whether NMP-22 is present in urine and provides
an absolute positive or negative test result, much in the same
manner as a pregnancy test. The NMP-22 assay detects
elevated amounts of nuclear mitotic apparatus protein, a
component of the nuclear matrix essential for cell division
that is released into the urine during cell death. Unlike
cytologic examinations and FISH-based tests, detection of
NMP-22 protein does not depend on the recovery of intact
cells. It is a painless and noninvasive assay that provides
results within 30 minutes and is the only in-office test
approved by the FDA for the diagnosis of bladder cancer.
Grossman et al compared the NMP-22 BladderChek test with
cystoscopy and voided urine cytology for surveillance of
recurrent bladder cancer.6 Initial cystoscopy alone detected
91% of the cancers. The combination of the NMP-22 test with
cystoscopy increased overall sensitivity to 99% (P =0.005).
The NMP-22 test was significantly more sensitive than
cytologic analysis of voided urine. The authors concluded
that, when combined with cystoscopy, the NMP-22 test
improves the detection of recurrence in patients with a
history of bladder cancer. Unlike cytologic analysis, this test
does not require expert analysis or laboratory time, does not
depend on intact cells, and provides unambiguous results. In
addition, the NMP-22 test provides results during the patient
visit, and its cost is less than half that of cytology.
Of concern with the NMP-22 assay is its variability of
performance in detecting bladder cancer. A report by Shariat
et al assessed the variability in the diagnostic performance of
NMP-22 for detecting recurrence and progression in patients
with Ta, T1, and/or CIS TCC of the bladder.20 NMP-22 voided
urine levels were measured in 2,871 patients who underwent
office cystoscopy for monitoring previous stage Ta, T1,
and/or CIS bladder cancer at 12 institutions. Their results
showed that the manufacturer cutoff of 10 U/mL detected
57% of cases with a 19% false-positive rate. For each NMP-22
cutoff assessed, NMP-22 had a higher sensitivity for detecting
grade III and stage T2 or greater bladder cancer than for
detecting any cancer.
No optimal cutoffs for detecting any or aggressive bladder
cancer could be derived based on NMP-22 values. The
authors concluded that there is a substantial degree of
heterogeneity in the diagnostic performance of NMP-22
applied to populations from different institutions. There was
no clearly defined NMP-22 cutoff, but there was a continuum
of risk for recurrence and progression.
Conclusions
Several reviews have been performed to assess the myriad
urine markers proposed for bladder cancer surveillance. They
note that none of the markers has been proven sensitive and
specific enough to replace cystoscopy.21 While FISH and NMP22 are promising, the clinical evidence is insufficient to
warrant the substitution of the cystoscopic follow-up scheme
with any of the currently available urine marker tests.22
If FISH and NMP-22 are considered to have some utility when
used to complement or replace cytology, a dilemma arises
when their results conflict with each other. Of particular
interest is how to treat a patient with positive cytology
and/or FISH findings when cystoscopy findings are negative.
Because cytology is the most reliable urine test for detecting
bladder cancer, a positive cytology finding should be treated
as cancer until proven otherwise. If cystoscopy findings are
negative in the setting of positive cytology findings, further
evaluation of the urinary tract is required. The upper urinary
tract should be evaluated with contrast imaging. Cystoscopy
with bilateral retrograde pyelography and bilateral ureteral
washings should be performed. At the time of this procedure,
ureteroscopy may also be performed if possible upper tract
disease is suspected. The urinary tract distal to the bladder—
the shorter urethra in women or the longer urethra in men,
with its prostatic, bulbar, and penile portions—must also be
assessed during cystoscopy. If the findings of all of these
examinations remain negative, one must maintain a
heightened suspicion and perform routine surveillance with
more regularity.
In the setting of negative cystoscopy findings, negative urine
cytology findings, and positive FISH findings, 2 possible
scenarios arise. This result is either falsely positive, or it may
be an anticipatory positive result, meaning that such patients
have a 30% chance of developing a bladder tumor over 2
years, despite having negative cytology and cystoscopic
evaluation findings. Patients in this category should also
undergo surveillance with increased frequency (see Table 2).
Table 2. Clinical Findings and Recommended Action
Cysto
Urine
FISH
Action
scopy
Cyto
Findings
Findings logy
Findings
Negative Negative Negative Routine follow-up
Negative Negative Positive
Increased frequency of
surveillance, whether FISH
findings are false-positive
or anticipatory positive
Negative Positive
Negative Cancer
until
proven
otherwise
or
 Upper tract imaging
positive
with contrast
 Cystoscopy
with
retrograde
pyelography,
washings,
and/or
ureteroscopy
 Evaluate urethra
 Increased frequency
of surveillance upon
negative findings
Patients who have undergone radical cystectomy require
routine surveillance to monitor for local recurrence or the
development of metastatic disease. Abdominal and pelvic CT
scanning and chest radiography should be performed
annually. Some patients with more adverse pathology at the
time of cystectomy (eg, locally advanced disease, lymph node
metastases) may require more frequent imaging.
The retained male urethra is at risk for cancer recurrence
after radical cystoprostatectomy. Urethral recurrence occurs
in approximately 7% of patients after cystoprostatectomy.
1. Cancer involving the prostate (urothelium or stroma) at
the time of cystoprostatectomy is the most significant
risk factor for urethral recurrence.
2. Monitoring the retained urethra has historically included
periodic urethral cytology with subsequent biopsy, if
indicated. However, some small studies have suggested
monitoring with urethral washings does not confer a
survival benefit.23
3. Gross hematuria or bloody urethral discharge requires
immediate workup.
4. A positive urethral cytology or biopsy finding warrants
immediate urethrectomy.
Complications
1. The morbidity of untreated bladder cancer is significant
and includes hematuria, dysuria, irritative urinary
symptoms, urinary retention, incontinence, ureteral
obstruction, and pelvic pain.
2. The radical cystectomy perioperative mortality rate is 12%.
3. The local recurrence rate is 5-10%; however, it increases
to 15-25% for T3-T4 disease.
4.
The 2 most common complications are small-bowel
obstruction and ureteroenteric stricture (see Table 3 at
the end of this section).
5. Radical cystectomy
 The reported overall early and late complication rate
associated with radical cystectomy is approximately
25%-30%. However, this may be an underestimation of
the true complication rate because of a lack of
standardized reporting in published studies.
 Many patients undergo a radical cystectomy and have
multiple comorbid health risk factors (eg, advanced age,
cardiovascular disease, pulmonary disease).
 Despite these difficulties, this procedure may be
performed safely in patients older than 80 years.
 Following a radical cystectomy, all men are impotent if
the parasympathetic nerves from the pelvic plexus (S2S4) to the corpora cavernosum are not spared at the
time of surgery; however, a nerve-sparing approach may
reduce the impotency rate to approximately 40-50%.
6. Orthotopic neobladder
 With the recent advances in surgical technique, this
procedure is becoming the diversion of choice.
 Risk factors include daytime and nighttime urinary
incontinence of approximately 10% and 15%,
respectively.
 Urinary incontinence may develop from multiple factors,
including injury to the external urethral sphincter,
increased urine production from solute absorption, and
relaxation of the external sphincter, which is greater at
night.
Table 3. Most Common Complications of Radical Cystectomy
Early Complications Rate,% Late Complication Rate,%
Ileus
5.9
Small bowel
7.4
obstruction
Wound infection
5.5
Ureteroenteric
7.0
stricture
Sepsis
4.9
Renal calculi
3.9
Pelvic abscess
4.7
Acute
3.1
pyelonephritis
Hemorrhage
3.4
Parastomal hernia
2.8
Wound dehiscence
3.3
Stomal stenosis
2.8
Bowel obstruction
3.0
Incisional hernia
2.2
Enterocutaneous
2.2
Fistula
1.3
fistula
Rectal injury
2.2
Rectal
<1
complications
Prognosis
1. Non–muscle invasive bladder cancer has a good
prognosis, with 5-year survival rates of 82-100%.
 The 5-year survival rate decreases with increasing stage,
as follows:
a) Ta, T1, CIS – 82-100%
b) T2 – 63-83%
c) T3a – 67-71%
d) T3b – 17-57%
e) T4 – 0-22%
2.
3.
4.
5.
6.





Prognosis for metastatic urothelial cancer is dismal, with
only 5% of patients living 2 years after diagnosis.
Early diagnosis and improvements in treatment of
bladder cancer may be responsible for the improved
survival rate.
Further studies of molecular determinants of bladder
cancer development and progression aid in prevention,
earlier diagnosis, and treatment. Much progress has
been made in the treatment of advanced bladder cancer;
however, researchers must further elucidate optimal
agents and regimens.
The underlying genetic changes that result in a bladder
tumor occur in the entire urothelium, making the whole
lining of the urinary system susceptible to tumor
recurrence (ie, 70% within 5 y).
Non–muscle invasive bladder cancer
The risk of progression, defined as an increased tumor
grade or stage, depends primarily on the tumor grade.
The risk of progression increases with tumor grade, as
follows:
a) Grade I – 10-15%
b) Grade II – 14-37%
c) Grade III – 33-64%
CIS alone, or in association with Ta or T1 papillary tumor,
carries a poorer prognosis and a recurrence rate of 6392%.
Diffuse CIS is an especially ominous finding, with 78%
progressing to muscle-invasive disease in one study.
Other risk factors for recurrence and progression include
the tumor size, multifocality, number of tumors, high
tumor grade, advanced stage, the presence of CIS, and
the time interval to recurrence. Patients with tumor
recurrences within 2 years, and especially with
recurrences within 3 months, have an aggressive tumor
and an increased risk of disease progression.