Treatment of non–muscle invasive disease

is dependent on clinical and pathologic

features and the accurate assessment of

tumor stage and grade.

Dorothy Fox. Clarinetist. Acrylic on canvas, 30˝ × 40˝.

Bladder Cancer: A Review of Non–Muscle Invasive Disease

Wade J. Sexton, MD, Lucas R. Wiegand, MD, José J. Correa, MD, Christos Politis, MD,
Shohreh Iravani Dickinson, MD, and Loveleen C. Kang, MD

Background: Bladder cancer is one of the most common cancers affecting men and women and thus has a
profound impact on health care. The majority of patients (75%) with newly diagnosed urothelial tumors have
non–muscle invasive disease confined to the bladder mucosa or the lamina propria.
Methods: The authors review the literature as well as recently published clinical guidelines regarding the
bladder cancer risk and causative factors, diagnostic and pathologic evaluation, prognostic variables, and
management strategies for patients with non–muscle invasive bladder cancer.
Results: Recurrence and progression remain problematic for many patients and are dependent on multiple
clinical and pathological features, the most important of which are tumor stage, grade, multifocality, size, recurrence
patterns, and the association with carcinoma in situ. Accurate assessment of clinical stage and tumor grade is
critical in determining management and surveillance strategies. Intravesical therapies positively influence
tumor recurrence rates. Disease progression rates may be impacted in high-risk patients who receive both
induction bacille Calmette-Guérin (BCG) and a maintenance BCG regimen. Cystectomy still plays a pivotal
role in patients with high-risk tumors and in patients who fail more conservative attempts to eradicate
non–muscle invasive disease.
Conclusions: Non–muscle invasive bladder cancers represent a broad group of tumors with varying biologic
potential. Successful treatment depends on the careful integration of diagnostic and surveillance tests,
macroablation through transurethral resection, accurate assessment of clinical stage, and the timely and
appropriate delivery of intravesical chemotherapeutic and immunomodulatory agents.

From the Genitourinary Oncology (WJS, LRW, JJC, CP) and Pathol-
ogy (SID) Programs at the H. Lee Moffitt Cancer Center & Research
Institute, Tampa, Florida, and the Department of Pathology at the
James A. Haley Veterans’ Hospital, Tampa, Florida (LCK).
Submitted July 29, 2009; accepted October 6, 2009.
Address correspondence to Wade J. Sexton, MD, Genitourinary
Oncology Program, 12902 Magnolia Drive, Tampa, FL 33612.
E-mail: Wade.Sexton@moffitt.org
Dr Sexton is on the speakers’ bureau for Endo Pharmaceuticals.
The other authors report no significant relationship with the com-
panies/organizations whose products or services may be referenced
in this article.
Introduction
The transformation from normal to malignant urotheli-
um is induced by certain chemical agents, pathogens,
and physical stimuli. Tumor-inciting stimuli can affect
the entire urinary tract from the renal calyces to the
urethra, although 95% of primary urothelial tumors
occur within the bladder. Patients who develop blad-
der cancer are considered to have a “field change” dis-
ease, suggesting that the entire urothelium is at risk for
tumor formation. Recurrences in various sites and par-
ticularly within the bladder are therefore characteristic,
and patients must undergo lifelong surveillance.

256 Cancer Control October 2010, Vol. 17, No. 4

Epidemiology
Bladder cancer is the fourth most common cancer in
men and was estimated to be the eighth leading cause
of cancer-related deaths in men in 2009.1 There is a 4:1
male:female predominance as well as a 2:1 white:black
ratio.2 Caucasian Americans have a more favorable sur-
vival by stage at presentation in part related to the high-
er proportion of nontransitional cell carcinomas seen
in African Americans.3 Caucasian Americans have a 2-
fold increased risk of developing bladder cancer com-
pared with African Americans. Latin Americans have an
even lower risk of bladder cancer development com-
pared with African Americans.1 Bladder cancer is a dis-
ease of senior adults; the overall median age at diagno-
sis is 70 years in men and women combined.4 The rare
adolescent or the younger adult who develops a transi-
tional cell cancer generally has a well-differentiated
low-grade tumor with a better long-term prognosis.5
Histology
Most newly diagnosed bladder cancers (75%) are
non–muscle invasive (confined to the bladder mucosa or
to the lamina propria); the remaining 25% are invasive
into or through the muscularis propria.6 Approximately
90% of patients with bladder cancer have transitional
cell carcinoma (TCC), whereas 5% have squamous cell
carcinomas and 1% to 2% have adenocarcinomas. Smaller
percentages of patients have primary small cell carcinoma
of the bladder or other histological variants of TCC,
including micropapillary (highly aggressive) and lym-
phoepithelioma-like (better prognosis than high-grade
invasive TCC) tumors. Adenocarcinomas arise from the
urachus or from the bladder. A partial cystectomy and
Table 1. — Bladder Tumor Histologies
Malignant
Transitional cell carcinoma (TCC)
Pure TCC
TCC with mixed features (squamous or glandular differentiation)
Micropapillary
Nested
Lymphoepithelioma-like
Squamous cell carcinoma
Adenocarcinoma (primary bladder)
Small cell carcinoma
Carcinosarcoma (mixed epithelial and mesenchymal elements)
Sarcomatoid (epithelial elements only)
Premalignant
Leukoplakia (precursor for squamous cell carcinoma)
Cystitis glandularis (precursor for adenocarcinoma)
Benign
Squamous metaplasia
Nephrogenic adenoma
Cystitis cystica and follicularis
Pseudosarcoma
Malacoplakia
October 2010, Vol. 17, No. 4
pelvic lymphadenectomy should be considered for the
patient with a urachal adenocarcinoma. Small cell car-
cinomas of the bladder are aggressive, are often associ-
ated with a poor prognosis, and should be managed
with neoadjuvant etoposide and cisplatin systemic
chemotherapy followed by cystectomy or localized
external radiation.7 Micropapillary variants of TCC
resemble ovarian micropapillary serous carcinomas, are
usually high stage and grade, are associated with lym-
phovascular invasion, and should be treated with early
radical cystectomy even in the non–muscle invasive
stage.8 Table 1 lists the most frequently encountered
malignant, premalignant, and benign lesions originating
from the bladder urothelium.
Risk Factors
Known risk factors for bladder cancer include male
gender, tobacco use (secondary to the chemical carcino-
gens 4-aminobiphenyl and o-toluidine), occupational
exposure to aryl amines, ionizing radiation, and expo-
sure to cyclophosphamide and phenacetin-containing
analgesics.9 Suspected risk factors for bladder cancer
include dietary factors, chlorination by-products in
drinking water, and various occupational exposures
incurred by dye, rubber, and leather workers, painters,
and truck drivers. Genetic susceptibility to environmen-
tal exposures has been demonstrated in epidemiologic
studies of bladder cancer, including polymorphisms in
detoxifying enzymes such as N-acetyl transferase and
glutathione S-transferase.10 Approximately 8% of patients
with bladder cancer report a positive family history, yet
bladder cancer is thought to be nonhereditary except for
the rare familial Lynch syndrome II (defect in DNA mis-
match repair) where patients are at risk for the develop-
ment of both colon and urothelial tumors.
Tobacco use appears to be the most identifiable risk
factor for bladder cancer. Smokers (particularly greater
than 40 pack-years) have up to a 4-fold increased risk for
bladder cancer compared with patients who have never
smoked.11 In patients who stop using tobacco, the
potential lingering carcinogenic effects of tobacco take
considerably longer to approach the baseline risk for
developing bladder cancer in patients who never
smoked compared with the reduction of risk for lung
and cardiovascular disease. Nevertheless, some data sug-
gest that smoking cessation decreases the rate of tumor
recurrence.12 Chronic cystitis and schistosoma hemato-
bium infections are risk factors for squamous cell carci-
nomas as opposed to transitional cell tumors.13,14
Molecular Characterization
The different potential pathways for bladder cancer
tumorigenesis are shown in Fig 1. Evidence suggests that
the most common chromosomal abnormality is the loss
of large segments of chromosome 9, especially 9q. The
two proposed pathways include (1) the proliferative
Cancer Control 257
route characterized by hyperplasia and simple dyspla-
sia resulting from deletions of chromosome 9q and (2)
activating mutations of fibroblast growth factor recep-
tor 3 (FGFR3) causing genetically stable low-grade pap-
illary tumors. The second pathway is more concerning,
involving the flat, high-grade lesions — high-grade dys-
plasia or carcinoma in situ (CIS) — and is due to early
p53 mutation. These genetically unstable tumors accu-
mulate alterations leading to retinoblastoma (RB) inac-
tivation, 8p deletions, and locus defects in H-ras, p16,
p21, and p27.15
Presenting Signs and Symptoms
Microscopic or gross hematuria is the most important
presenting symptom and occurs in the majority of
patients with bladder cancer. Irritative lower urinary
tract symptoms such as urinary frequency, urgency, and
dysuria are common. The irritative symptoms are more
predominant in patients with high-grade papillary
tumors, CIS, or invasive disease. Mucosuria is possible
in the patient with adenocarcinoma. These signs and
symptoms often lead to an early diagnosis for most
patients with TCC. The discovery of incidental bladder
cancer at autopsies is virtually nonexistent. Thus, there
appears to be little latency between the development
of cancer and symptomatic onset.
Diagnostic Evaluation
Patients with hematuria or lower urinary tract symp-
toms should be considered for upper tract imaging
with CT urography alone or with renal ultrasound com-
bined with intravenous pyelography or retrograde pyel-
ography. A complete urologic evaluation to detect
urothelial tumors includes cystoscopy, which permits
direct visualization of the entire urethra and the blad-
der urothelium. Complementary methods used to
detect urothelial tumors include the evaluation of void-
ed urine or bladder wash specimens for cytology and
increasingly the use of laboratory- and office-based uri-
nary biomarker assays.
Cystoscopy
Diagnostic cystoscopy remains the gold standard for
detecting lower urinary tract malignancies. It can be per-
formed quickly and easily in the office setting with only
a topical-based anesthetic. Grossly, most tumors have
papillary or sessile architecture. The visualization of a
bladder mass clearly warrants endoscopic resection.
However, the detection of premalignant flat urothelial
lesions (dysplasia) and CIS can be challenging with cys-
toscopy alone due to the absence of three-dimensional
tumor characteristics. These lesions can be difficult to
differentiate from reactive urothelial changes seen with

normal urothelium

9q− 9q−
TP53 (± 9p−/9q−)
9p− 9p−

hyperplasia +
hyperplasia dysplasia/CIS dysplasia

FGFR3 FGFR3
cyclin D cyclin D
11p− 11p−
genetically ?
stable
?
papillary carcinoma papillary carcinoma CIS
low grade high grade
genetically
stable RB
recurrence recurrence 8p−
+++
genetically
8p− unstable

?
invasive carcinoma

metastasis

Fig 1. — Potential pathways of urothelial tumorigenesis. From Knowles MA. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?
Carcinogenesis. 2006;27(3):361-373. By permission of Oxford University Press.

258 Cancer Control October 2010, Vol. 17, No. 4

cystitis, which are related to infection, urinary stasis, or has been reported to be as high as 98.3%.21 The sensi-
the prior administration of intravesical therapies. A biop- tivity of cytology for diagnosing low-grade tumors is
sy is necessary to confirm malignant transformation. poor, but fortunately, the progression rate for low-grade
Hexaminolevulinate (HAL) imaging during cys- noninvasive tumors is low.
toscopy enhances the visual detection of flat urothelial “Atypical” cytology is a nonspecific term often used
cancers and small papillary tumors. It is based on the to characterize the appearance of cells in urine cytology
accumulation of endogenous photoactive porphyrins specimens, but the significance of this finding is poorly
(PAPs). When instilled into the bladder through understood. Atypical cells are common in patients with
catheterization, HAL accumulates in tumors and is con- urinary diversions and various conditions leading toward
verted to PAPs that emit a red fluorescence upon blue bladder inflammation or cystitis. If cystoscopy and upper-
light illumination. A recent prospective, multicenter tract evaluation are negative, atypical cells alone usually
phase III study demonstrated superior detection of warrant no further investigation or bladder biopsies.
superficial papillary tumors (95% vs 68%) and CIS (96% Although the presence of “dysplastic” cells warrants fol-
vs 85%) using hervix blue light cystoscopy vs standard low-up, the finding is not diagnostic for a malignancy.
white light cystoscopy.16 Filbeck et al17 demonstrated a “Suspicious” cytology indicates the need for either fur-
higher residual tumor rate of 25.2% in patients under- ther investigation or careful surveillance. Nabi et al22 ob-
going white light transurethral resections compared served that 35% of patients with suspicious cytology but
with 4.5% in patients who underwent resection with no evidence of bladder cancer on initial evaluation sub-
fluorescent light illumination. Drawbacks to fluores- sequently developed transitional cell tumors with a mean
cent light illumination include the diminished speci- time to diagnosis of nearly 6 months.
ficity seen with bladder inflammatory conditions, espe-
cially following intravesical therapy, and the need to Biomarkers
instill the agent into the bladder approximately 30 min- Many biomarkers have been incorporated into strate-
utes prior to cystoscopy. gies for the diagnosis, surveillance, and management of
bladder cancer.23-25 Although the ideal marker is
Cytology unknown, several tests are currently approved for clin-
Urine cytology remains the most specific adjunct to ical use by the US Food and Drug Administration (FDA).
cystoscopy in the detection and surveillance of bladder Fluid-based, qualitative points of care assays include the
cancer.18 Characteristic cytologic changes include cel- NMP22 BladderChek Test (nuclear matrix protein,
lular and nuclear pleomorphism, increased nuclear to Matritech Inc, Newton, MA) and the BTA Stat test (blad-
cytoplasmic ratio, and nuclear irregularity.19 The diag- der tumor antigen, Polymedco, Inc, Cortlandt Manor,
nostic yield of cytology may be improved by bladder NY). The FDA-approved cell-based assays include the
washes or repeated voided samples.20 The specificity is ImmunoCyt test (Diagnocure Inc, Quebec City, Que-
best for patients with higher-grade tumors or CIS and bec, Canada) and the FISH analysis (fluorescence in situ
hybridization, Vysis UroVysion Systems,
Table 2. — Sensitivity and Specificity of Commercially Available Abbott Laboratories,Abbott Park, IL). To
Urinary Marker Assays date, none of the approved biomarker
Sensitivity Specificity assays eliminate the need for diagnostic
Commercially Available Marker Mean (%) Range (%) Mean (%) Range (%) or surveillance cystoscopy. Most mark-
Cytology 48. 16–89 96. 81–100 ers continue to be used in conjunction
with urine or bladder wash cytology.
Hematuria dipstick 68. 40–93 68. 51–97
Sensitivity and specificity of the
NMP22 75. 32–92 75. 51–94
common urinary markers can be seen
NMP22 BladderChek 55.7 85.7 in Table 2. Accuracy of the markers can
BTA Stat 68. 53–89 74. 54–93 be affected by collection technique,
BTA TRAK 61. 17–78 71. 51–89 coexisting benign bladder pathology,
ImmunoCyt 74. 39–100 80. 73–84 and prior intravesical therapy. As an
example, UroVysion is not approved by
UroVysion 77. 73–81 98. 96–100
the FDA to be collected with a bladder
NMP22 BladderChek test (nuclear matrix protein, Matritech Inc, Newton, MA) and the BTA Stat barbotage as this can dislodge large
test (bladder tumor antigen, Bard Diagnostics, Redmond, WA). The FDA-approved cell-based
assays include the ImmunoCyt test (Diagnocure Inc, Quebec City, Quebec, Canada) and the
numbers of normal urothelial cells,
FISH analysis (fluorescence in situ hybridization, UroVysion Systems Vysis, Abbott Labora- leading to a false-negative result. Fur-
tories, Abbott Park, IL). thermore, the BTA Stat test has a lower
specificity when used for surveillance
This Table was published in Section XV, Chapter 76: Bladder; Lower Genitourinary Calculi and
Trauma. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology. after intravesical therapy.26 All markers
9th ed. Page 2464. Copyright © 2007 Elsevier. should be used in conjunction with

October 2010, Vol. 17, No. 4 Cancer Control 259

standard cytology, and no marker has yet supplanted
cystoscopy as the gold standard for bladder tumor A
detection.26 Multiple other markers have been studied
but are not yet approved by the FDA for routine clini-
cal application: BLCA-4, telomerase, survivin, hyaluron-
ic acid, microsatellite analysis, cytokeritins, and Lewisx
blood group antigens.27 Similar to the FDA-approved
markers, all are superior to cytology for sensitivity but
inferior for specificity.

Pathology and Staging

Table 3 demonstrates the current TNM staging for blad-
B
der cancer.28 Non–muscle invasive bladder cancer
includes a heterogeneous group of tumors with vari-
able biologic potential. Non–muscle invasive tumors
are confined to the bladder urothelium (Ta and Tis) and
to the lamina propria (T1) (Fig 2).

Table 3. — TNM Classification of Carcinomas of the

Urinary Bladder Cancer

Primary Tumor (T)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor C
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ: “flat tumor”
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades muscle
pT2a Tumor invades superficial muscle (inner half)
pT2b Tumor invades deep muscle (outer half)
T3 Tumor invades perivesicle tissue
pT3a Microscopically
pT3b Macroscopically (extravesical tissue)
T4 Tumor invades any of the following: prostate, uterus, vagina,
pelvic wall, abdominal wall
T4a Tumor invades prostate stroma, uterus or vagina
T4b Tumor invades pelvic wall or abdominal wall
D
Regional Lymph Nodes (N)
Common iliac nodes defined as secondary drainage region as
regional nodes and not as metastatic disease
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Single positive node in primary drainage region
N2 Multiple positive nodes in primary drainage region
N3 Common iliac node involvement
Distant Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Fig 2. — (A) Papillary urothelial neoplasm of low malignant potential
Stage Grouping (PUNLMP): papillae contain fibrovascular cores lined by an increased
Stage 0a Ta N0 M0 number of cell layers showing an even distribution (polarity) and layering
Stage 0is Tis N0 M0 of cells with minimum cytologic atypia. The superficial umbrella cell layer
Stage I T1 N0 M0 is preserved. There is no nuclear overlapping, and the cells are not densely
Stage II T2a, b N0 M0 arranged (hematoxylin-eosin, magnification ×100). (B) Low-grade papillary
Stage III T3a, b N0 M0 urothelial carcinoma: papillae show an orderly proliferation of densely
T4a N0 M0 arranged cells with mild to moderate atypia without loss of polarity. There
Stage IV T4b N0 M0 is increased cellularity without nuclear overlapping (hematoxylin-eosin,
magnification ×40). (C) High-grade papillary urothelial carcinoma: papillary
Any T N1, N2, N3 M0
frond with complete architectural disorder and loss of polarity is present.
Any T Any N M1
There is nuclear overlapping, nuclear enlargement, and hyperchromasia
(hematoxylin-eosin, magnification ×400). (D) Urothelial carcinoma invading
From Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. into lamina propria: clusters of pleomorphic cells with nuclear enlargement
7th ed. New York: Springer; 2010. Reprinted with permission by the and hyperchromasia infiltrate the underlying fibroconnective stroma
American Joint Committee on Cancer. (hematoxylin-eosin, magnification ×200).

260 Cancer Control October 2010, Vol. 17, No. 4

 All of the urinary excretory passages are lined by
urothelium. The wall of the bladder is formed by four
layers: urothelium, lamina propria, muscularis propria,
and adventitia or serosa. Depending on the location,
these layers may be surrounded by perivesical fat. The
thickness of the urothelium and the shape of the
urothelial cells vary depending on the degree of blad-
der distension. In an empty bladder, the urothelium can
be up to seven cells thick. The most superficial or lumi-
nal layer of urothelium consists of large, sometimes bi-
nucleated cells with abundant eosinophilic cytoplasm
and a rounded free surface; these are called umbrella
cells. The urothelium rests on a thin basement mem-
brane layer, which separates the urothelium from the
underlying lamina propria. The lamina propria is formed
of abundant connective tissue containing vascular net-
work, lymphatic channels, sensory nerve endings, a few
elastic fibers, and small fascicles of smooth muscle. The
smooth muscle fascicles are present in the superficial
lamina propria and may form complete or incomplete
muscularis mucosa. The muscularis mucosa is distinctly
separate from the underlying muscularis propria, also
known as detrusor muscle. The muscularis propria has
loosely anastomosing, ill-defined internal and external
longitudinal layers and a middle circular layer of muscle.
The bundles of muscularis propria are much larger than
muscle fascicles in the muscularis mucosa. The outer-
most layer of the viscus is an adventitia of connective
tissue; only the superior surface is covered by serosa of
the pelvic peritoneum.29
The World Health Organization/International Society
of Urologic Pathology (WHO/ISUP) consensus classifica-
tion of papillary urothelial lesions confined to the urothe-
lium includes papillary hyperplasia as a distinct category
having markedly thickened mucosa without cytological
atypia.30 There is no evidence suggesting that papillary
hyperplasia alone has any premalignant potential.
Papillary neoplasms include urothelial papilloma,
papillary urothelial neoplasm of low malignant potential
(PUNLMP), low-grade papillary carcinoma, and high-
grade papillary carcinoma. Urothelial papilloma is char-
acterized by discrete papillary fronds with nonbranching
or minimally branching arrangement, slender fibrovascu-
lar stalks, and a predominantly exophytic pattern. The
urothelium is within normal limits of thickness, lacks
atypia, and has prominent umbrella cells. Urothelial
papilloma rarely recurs after complete resection.
PUNLMP is a papillary urothelial tumor that resem-
bles the papilloma but shows increased cellular prolifer-
ation exceeding the thickness of normal urothelium. The
polarity is preserved, and variation in architectural and
nuclear features is either absence or minimal. The nuclei
are slightly enlarged compared with normal nuclei, and
mitoses are rare. The umbrella cell layer is preserved.
In contrast to papilloma and PUNLMP, low-grade
papillary carcinoma has papillary fronds with frequent
October 2010, Vol. 17, No. 4
branching and an orderly appearance, but with easily
recognizable variations in nuclear polarity, size, shape,
and chromatin pattern. Inconspicuous nucleoli may be
present and mitotic figures are infrequent. Contrary to
the orderly appearance of low-grade carcinoma, the
high-grade papillary carcinoma has a predominant pat-
tern of disorder with moderate to marked architectural
and cytological atypia. High-grade tumors have fused
papillae with variable thickness, frequent cell dyscohe-
sion, frequent mitoses, and marked variation in nuclear
features with prominent nucleoli. The neoplastic cells
of papillary carcinomas invade the bladder wall as
nests, cords, trabeculae, small clusters, or single cells
that are often separated by desmoplastic stroma. Inva-
sion of muscularis mucosa within the lamina propria
must be clearly distinguished from invasion of muscu-
laris propria. This distinction is critical in that muscu-
laris propria invasion (T2+) often dictates the need for
more aggressive management including systemic
chemotherapy and cystectomy.
CIS is a nonpapillary flat lesion in which the sur-
face epithelium contains cells that are cytologically
malignant. The nuclear anaplasia observed in CIS is
identical to high-grade urothelial carcinoma. Mitoses
are common, and there is loss of cell polarity with irreg-
ular nuclear crowding. The neoplastic changes may or
may not involve the entire thickness of the urothelium.
Individual neoplastic cells may be seen scattered
among normal-appearing urothelial cells; this is termed
pagetoid spread. CIS is commonly multifocal and may
be diffuse.
Transurethral Resection
Transurethral resection of the bladder tumor (TURBT)
is the first step in the initial management of bladder
cancer. A TURBT is both diagnostic and therapeutic,
and the procedure provides critical staging informa-
tion. In the setting of a TURBT, the configuration (flat,
sessile, or papillary), location (trigone, base, dome, or
lateral walls), size (centimeters), and number of tumors
should be noted. Tumors are completely resected, and
other than for superficial appearing low-grade tumors,
muscularis propria must be included in the specimen
to ensure adequate resection, thorough histological
evaluation, and accurate clinical staging. Management
might include directed bladder biopsies of abnormal-
appearing urothelium or biopsies of the prostatic ure-
thra to exclude “protected sanctuaries” of cancer such
as CIS. Biopsy or resection of the prostatic urethra also
should be considered if the patient has tumor at the
bladder neck or if tumor is within the prostatic urethra.
Random biopsies of normal-appearing bladder urotheli-
um may or may not alter the management of the blad-
der malignancy, and as such, this practice remains con-
troversial except when contemplating a partial cystec-
tomy or other bladder-sparing approaches to rule out
Cancer Control 261
coincident CIS or when the cytology is positive and yet
the tumor appears papillary and noninvasive.31,32
Immediately before and following tumor resection, an
examination under anesthesia is performed. Bladder
pedicle thickening or a palpable three-dimensional
mass suggests the possibility of muscle invasive disease
or a more locally advanced bladder malignancy. If local-
ly advanced disease is evident, attention should be
given to the mobility of the bladder and the adjacent
pelvic viscera.
There are several reasons for considering a restag-
ing resection in patients with high-risk non–muscle
invasive bladder cancer (ie, large-volume cTa or cT1 dis-
ease). First, the repeat resection ensures adequate eval-
uation of the muscularis propria while detecting and
treating persistent tumor in approximately 75% of
patients. Under such circumstances, retrospective data
suggest that the restaging transurethral resection
improves the initial response rate to intravesical bacille
Calmette-Guérin (BCG) therapy, reduces the frequency
of subsequent tumor recurrence, and appears to delay
early tumor progression.33 Secondly, a re-resection
results in clinical upstaging to muscle invasive tumor in
up to 30% of patients.34 Finally, patients with persistent
high-grade cT1 tumors on repeat resection are at high
risk for early progression to muscle-invasive disease and
thus might be appropriate candidates for early cystecto-
my.35 The restaging transurethral resection of the tumor
Table 4. — Predictors of Recurrence and Progression
bed is typically performed within 1 to 4 weeks follow-
ing the initial TURBT. While highly recommended for
most if not all patients with tumor invasion of the lami-
na propria, the restaging resection is imperative and rec-
ognized as the standard of care for patients with cT1
tumors when adequate sampling of the muscularis pro-
pria is not represented in the histological specimen.36
Complications resulting from TURBT include irrita-
tive lower urinary tract symptoms, bleeding, bladder
perforation, urethral stricturing, and scarring of the
ureteral orifices that could potentially lead to renal
obstruction. Extensive resection or persistent bleeding
requires placement of a Foley catheter postresection
and continuous irrigation. Most patients who suffer an
extraperitoneal bladder perforation are managed con-
servatively. Conversely, most patients with intraperi-
toneal bladder perforations are managed with
exploratory laparotomy and primary repair, particularly
if the perforation is large and is associated with persis-
tent peritonitis, excessive bleeding, or the rare finding of
a bowel injury. Some investigators acknowledge a high-
er risk of extravesical bladder cancer seeding when
patients with intraperitoneal ruptures from TURBT
were managed with laparotomy and primary bladder
repair compared with those managed conservatively
with prolonged catheter drainage and/or percutaneous
drain placement.37,38 Thus, the decision to repair a blad-
der perforation should be based on individual patient
circumstances and careful scrutiny of the clinical find-
ings to optimize recovery and oncologic outcome.

Factor Recurrence Progression Risk Group Classification

Number of Tumors The combination of cystoscopic and pathologic find-
Single 0 0 ings determines the need for intravesical therapy and
2 to 7 3 3 predicts the risk for cancer recurrence, progression,
≥8 6 3 and cancer-related mortality.39 Using standard clinical
Tumor Diameter and pathologic criteria, researchers from the European
< 3 cm 0 0 Organisation for Research and Treatment of Cancer
≥ 3 cm 3 3
(EORTC) developed a scoring system based on the six
Prior Recurrence Rate most significant risk factors for recurrence and pro-
Primary 0 0
≤ 1 recurrence/yr 2 2 gression. The risk factors were determined from a data-
> 1 recurrence/yr 4 2 base containing 2,596 patients with Ta or T1 tumors
Category (from seven randomized trials) who had undergone a
Ta 0 0 TURBT yet were not managed with re-resections or
T1 1 4 maintenance intravesical BCG therapy. The six predic-
Concomitant CIS tors included number of tumors, tumor diameter, prior
No 0 0 recurrence rate, clinical T stage, the presence of con-
Yes 1 6 comitant CIS, and the tumor grade (Table 4).40,41 Evident
Grade (1973 WHO) from these data is that regardless of risk group stratifi-
G1 0 0 cation, a large percentage of patients with non–muscle
G2 1 0
G3 2 5 invasive cancer will recur (Table 5).40 Furthermore, the
presence of recurrent tumor at the initial 3-month sur-
Total Score 0–17 0–23
veillance cystoscopy is strongly predictive of continued
tumor recurrences. Patients with grade 3 tumors and
From Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on
non–muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2008; CIS (especially in association with lamina propria inva-
54(2):303-314. Reprinted with permission from Elsevier. sion) harbor the highest risk for disease progression.

262 Cancer Control October 2010, Vol. 17, No. 4

 Table 5. — Scoring System for Calculation of Recurrence Risk and Progression for Non–Muscle Invasive Bladder Tumors

Recurrence Score Probability of Recurrence at 1 Yr Probability of Recurrence at 5 Yrs Recurrent Risk Group
% (95% CI) % (95% CI)
0 15. (10–19) 31. (24–37) Low risk
1–4 24. (21–26) 46. (42–49) Intermediate risk
5–9 38. (35–41) 62. (58–65) Intermediate risk
10–17 61. (55–67) 78. (73–84) High risk
Progression Score Probability of Progression at 1 Yr Probability of Progression at 5 Yrs Progression Risk Group
% (95% CI) % (95% CI)
0 0.2 (0–0.7) 0.8 (0–1.7) Low risk
2–6 1. (0.4–1.6) 6. (5–8) Intermediate risk
7–13 5. (4–7) 17. (14–20) High risk
14–23 17. (10–24) 45. (35–55) High risk

From Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non–muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2008;54(2):303-
314. Reprinted with permission from Elsevier.

Intravesical Therapy tions, or significant gross hematuria requiring either

An important strategy in the management of non–muscle hand irrigation or continuous bladder irrigation with
invasive bladder cancer includes the use of intravesical sterile saline to keep the urinary effluent clear.
therapies to treat microscopic tumor persistence and to Immunomodulatory agents such as BCG or interferon
prevent tumor reimplantation, new tumor formation, are never used in the immediate postresection setting.
and possibly tumor grade and stage progression. Intra- Published meta-analysis data support the immediate
vesical chemotherapeutic and immunomodulatory agents postresection instillation of chemotherapy following
most commonly utilized in the United States are listed in TURBT. Sylvester et al44 reviewed data from seven ran-
Table 6. domized trials with tumor recurrence information on
1,476 patients. Intravesical agents included mitomycin
Immediate Postresection Intravesical Therapy C, thiotepa, epirubicin, and pirarubicin (epirubicin and
There are several reasons to support consideration of pirarubicin are not available in the United States for this
immediate postresection intravesical chemotherapy. application). In all studies, the instillation was adminis-
Half of all tumor recurrences may be due to the TURBT tered within 24 hours. Patients in the treatment group
and the mechanical dispursement of tumor cells with experienced a 39% decrease in the odds of recurrence
resultant tumor reimplantation at sites of resection. compared with patients managed with observation
Animal models support this theory, confirming the ease alone following TURBT. Recurrence-free percentages
of tumor reimplantation onto traumatized urothelial were better for patients with single tumors compared
surfaces.42 Additionally, most synchronous and meta-
chronous tumors appear to be of clonal origin.43 Table 6. — Chemotherapy and Immunotherapy Drugs for
Two peaks of tumor relapse are evident. An early Intravesical Administration
peak is likely due to tumor recurrence or persistence, Chemotherapies Mechanism of Action
whereas a late peak is likely due to a second primary
Mitomycin C Antibiotic; inhibits DNA synthesis
tumor. Only the early peak of tumor relapse is affected
Thiotepa Alkylating agent; cross-links
by the immediate postresection instillation of an intra- nucleic acids
vesical agent. Available agents include mitomycin C,
Doxorubicin, valrubicin Topoisomerase inhibitor;
thiotepa, and doxorubicin. In the United States, mito- intercalating agents;
mycin C (20 to 40 mg in 20 to 40 mL of sterile water) inhibits DNA synthesis
has been the most widely utilized agent in the immedi- Immunotherapies Mechanism of Action
ate postresection setting. Dwell time within the blad- Bacille Calmette-Guérin T-helper type I immune response
der ranges from 30 to 60 minutes. A therapeutic bene- (increased interleukin-2 and
fit from a single one-time instillation of mitomycin C interferon gamma)
could be achieved up to 24 hours following the TURBT, Interferon * Lymphocyte activation, potentiates
T-helper type I response
although the most desirable time to instill the therapy (inhibits production of interleukin-10,
may be within the first 2 to 6 hours following resec- an inhibitory cytokine); antiangiogenic;
tion.40 Mitomycin C and other immediate postresec- antiproliferative
tion intravesical therapies should be withheld in cases * Used in combination with bacille Calmette-Guérin.
of suspected perforation, significant large-volume resec-

October 2010, Vol. 17, No. 4 Cancer Control 263

to patients with multiple tumors. Presently, the Euro-
pean Association of Urology (EAU) recommends imme-
diate postresection therapy for all patients undergoing a
complete, uneventful TURBT.40 The American Urologi-
cal Association (AUA) guidelines recommend postresec-
tion therapy when there is a suspected recurrence of
low-grade, noninvasive bladder cancer. However, this
recommendation is described as an option in cases
where stage and grade are not known, citing concerns
about cost, uncertain pathology, side effects, and the
lack of efficacy for muscle invasive tumors.36
Induction Intravesical Therapy
Generally, accepted criteria for induction intravesical
therapy following TURBT include the presence of high-
grade tumors, T1 tumors, CIS, tumor multifocality (ⱖ 3
tumors), large-volume tumors, and tumor recurrence.
Induction therapy is defined as a weekly administration
of an intravesical agent for at least 6 consecutive weeks.
Therapy is initiated approximately 2 to 4 weeks follow-
ing the patient’s TURBT. For low-grade, larger-volume
tumors, there is no clear superiority of an induction
course of any particular intravesical chemotherapy (eg,
mitomycin C) or of BCG over other therapies. The AUA
guideline panel members recommend that an induction
course of either intravesical chemotherapy or BCG
should be administered for the treatment of non–mus-
cle invasive bladder cancers that have an increased risk
of recurrence but a low risk of progression.36
For patients with high-risk tumors (high-grade Ta,
high-grade T1, CIS, or a combination thereof), the rec-
ommended therapy is induction BCG followed by
maintenance BCG. This has been consistently shown to
be superior to intravesical chemotherapy for prevent-
ing tumor recurrences. BCG is an inactivated form of
mycobacterium tuberculosis and has been shown to
induce a cellular and cytokine-induced antiangiogenic
environment that aids in inhibiting future tumor growth
and progression.45 BCG is the foundation of intravesical
therapy for intermediate- and high-risk tumors. The AUA
panel’s single-arm meta-analysis of high-risk patients
revealed an estimated 5-year recurrence rate of 34% in
patients treated with BCG + maintenance compared
with 62% in patients treated with mitomycin C + main-
tenance. Furthermore, the AUA meta-analysis of all risk
groups revealed that compared to TURBT + mitomycin
C maintenance, TURBT + BCG maintenance decreased
tumor recurrences by 17% and decreased tumor pro-
gression by 5%.36
Maintenance Intravesical Therapy
Maintenance therapy is defined as the periodic contin-
ued exposure of the urothelium to an intravesical agent
following the achievement of a complete response to
an initial induction course of intravesical therapy. Main-
tenance therapy following initial induction therapy is
264 Cancer Control
an important strategy for decreasing tumor recurrence
and potentially decreasing tumor progression. The 5-
year progression rates for high-risk tumors range from
15% to 50% (highest for multifocal high-grade T1 + CIS).
In the high-risk setting, intravesical BCG significantly
reduces the risk of recurrence and progression after
transurethral resection in patients with non–muscle
invasive bladder cancer who receive maintenance BCG
therapy.46 The best level evidence for maintenance
BCG therapy comes from a trial of the Southwest
Oncology Group (SWOG 8507).47 Patients with high-
risk TCC who were BCG responders were randomized
to 3 weekly maintenance courses at 3, 6, and 12 months
and every 6 months out to 3 years. Only 16% of
patients completed 36 months of therapy, mostly relat-
ed to BCG toxicity. The 5-year recurrence-free survival
rate was 60% in the maintenance arm compared with
41% in the no-maintenance arm (P ⬍ .0001). The 5-year
progression-free survival rate was 76% in the mainte-
nance arm compared with 70% in the no-maintenance
arm (P = .04). This trial also provided the best evidence
for a maintenance schedule that is most widely incor-
porated into clinical practice.47
The 5-year progression rates with low-risk tumors
(low-grade, solitary, Ta) and intermediate-risk tumors
(recurrent Ta/T1 low-grade, multifocal Ta/T1 low-grade)
are ⬍ 5% and ⬍ 15%, respectively.40 To date, mainte-
nance therapy (chemotherapy or BCG) in these risk
groups has not impacted progression rates due to the
overall low number of observed (progression) events.
In patients with low-grade tumors, maintenance intra-
vesical chemotherapy (eg, mitomycin C) administered
monthly for 3 to 12 months may impact tumor recur-
rences, although there are no clear data regarding the
duration of therapy.
BCG Failures and Salvage Intravesical Therapy
Patients who fail BCG should be categorized into more
specific groups in order to provide a more uniform def-
inition of BCG failure. BCG-refractory patients fail to
achieve a disease-free state by 6 months after initial
BCG therapy with either maintenance or re-treatment
at 3 months because of either persistent or rapidly
recurrent tumor. The BCG-refractory category also
includes any progression in stage, grade, or disease
extent after the first cycle of BCG. Patients with BCG-
resistant disease have recurrent or persistent tumor at
3 months following an induction cycle but of lesser
degree, stage, or grade that subsequently is no longer
present at 6 months. Essentially, the disease improves
and then resolves with further BCG therapy. Patients
with BCG-relapsing disease have recurrent tumor fol-
lowing a disease-free period of at least 6 months. Final-
ly, BCG-intolerant patients include those whose disease
recurs after a less-than-adequate course of therapy
because of a serious adverse event or symptomatic
October 2010, Vol. 17, No. 4
intolerance that mandates discontinuation of further Complications of Intravesical Therapy
BCG therapy.48,49 Table 7 details the toxicities most commonly associated
Patients who fail an initial induction course of with the use of different intravesical therapies.36,58 BCG-
intravesical chemotherapy respond to intravesical BCG related side effects dominate the toxicity profile, largely
at a similar rate as treatment-naive patients. On the con- due to the more frequent use and administration of BCG.
trary, patients with BCG refractory disease seldom BCG toxicity can be subdivided into different grades of
respond to salvage intravesical chemotherapy. Follow- severity. Accordingly, higher grades result in the need for
ing initial BCG induction failure, 30% to 50% of patients more intense evaluation and management (Table 8). The
will respond to a second induction course of BCG. irritative lower urinary tract symptoms mostly attributed
High-risk patients who fail two induction courses of to non-infectious (inflammatory) cystitis are the most
BCG should be considered BCG-refractory50 and frequently reported side effects. Several maneuvers are
offered cystectomy (an AUA guideline recommenda- employed to treat the BCG-related symptoms; these
tion) since ⬍ 20% of patients respond to continued include administering anticholinergic agents, reducing
attempts to eradicate tumor utilizing BCG.36 BCG dose (half, one-third, one-tenth strength BCG
Several other salvage regimens have been studied administration), decreasing dwell time (at least 30 min-
in patients who are BCG-refractory or BCG-intolerant. utes dwell may be as effective as 1 to 2 hours), utilizing
Intravesical interferon monotherapy results in a 2-year antibiotics (ofloxacin 8 and 20 hours following BCG
disease-free survival rate of less than 15% in patients instillation), and spacing treatments from weekly to
who fail BCG therapy.51 However, in combination with every 2 weeks.59,60 Antibiotic use, especially quinolones,
low-dose BCG, the 2-year disease-free survival rate is can theoretically decrease BCG viability, but this has not
40% to 50% in patients who failed prior BCG induction yet been shown clinically.61
(± maintenance BCG) or were BCG-intolerant.52,53 For grade II BCG infections, therapy should be dis-
Valrubicin (a semisynthetic derivative of the anthracy- continued and consideration given to hospitalization
cline antibiotic doxorubicin) is approved by the FDA with initiation of intravenous antibiotics, isoniazid, and
for the treatment of BCG-refractory CIS of the bladder pyridoxine. In the patient with grade III toxicity,
for whom immediate cystectomy would be associated including suspected BCG sepsis, therapy would also
with unacceptable morbidity or mortality.54 Gemcita- include rifampin, ethambutol, fluoroquinolones, and
bine and docetaxel are additional investigational intravenous corticosteroids.
chemotherapeutic agents that are being studied in the
BCG-failure population of patients.55-57 Both have ac- Follow-Up
ceptable toxicity, but the usefulness for BCG-refractory The high rate and frequency of recurrence and the con-
patients is unclear until additional prospective trials cern for disease progression — especially in patients
have been completed. with high-risk tumors — mandate careful strategies for
tumor surveillance. Cytology
Table 7. — Complications of Commonly Used Intravesical Therapies for Transitional Cell Carcinoma and commercially available
biomarkers do not obviate
Drug Side Effects Patients Affected (%)
the need for cystoscopy. The
Bacille Calmette-Guérin Cystitis (noninfectious) > 50 schema most commonly
Fever (low grade), chills, malaise 25
Symptomatic prostatitis <5 adopted for high-risk patients
Epididymitis <2 includes assessment with cys-
Fever (≥ 103°F) 3 toscopy and cytology every 3
Sepsis < 0.5
Distant organ (ie, pulmonary miliary pattern) Rare months for 2 years, then
every 6 months for 2 years,
Mitomycin C Chemical cystitis 10
Myelosuppression < 10 and then annually. In the low-
Rash (hypersensitivity dermatitis) < 10 risk patient, if the initial 3-
Bladder contracture < 2 month cystoscopy following
Tissue necrosis Rare
TURBT appears normal, it is
Thiotepa Chemical cystitis 20
Myelosuppression 10
acceptable to consider earlier
initiation of every 6- to 12-
Doxorubicin Chemical cystitis 25
Allergic reaction 1 month cystoscopy and cytol-
ogy. Bladder biopsies should
Sources: be performed to assess suspi-
Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer cious mucosal lesions and to
(stages Ta, T1, and Tis): 2007 update. J Urol. 2007;178(6):2314-2330.
evaluate treatment response
Lamm DL, McGee WR, Hale K. Bladder cancer: current optimal intravesical treatment. Urol Nurs. 2005;25(5):
323-326, 331-332. for patients with CIS, and also
if the cytology becomes posi-

October 2010, Vol. 17, No. 4 Cancer Control 265

tive in the absence of visible urothelial tumors. Upper-
tract imaging should be performed every 1 to 2 years,
especially for the high-risk patient.
Cystectomy
Several strong indications point to recommending
early cystectomy in patients with non–muscle invasive
bladder cancer: unfavorable histology (micropapillary,
adenocarcinoma, squamous cell carcinoma), lympho-
vascular invasion in patients with clinical stage T1
tumor, incomplete resection of multifocal T1 high-
grade tumor, BCG induction failure in patients with T1
high-grade tumors or CIS, deep prostatic ductal involve-
ment with TCC, and the bladder-crippled patient with
significant lower urinary tract symptoms and recurrent
tumor.8,36,48,62 The AUA considers early cystectomy as
an option for patients with any high-grade Ta/T1 tumor
or CIS at initial presentation dependent on the volume
of disease, the completeness of resection, and a discus-
sion of the potential risks and benefits associated with
intravesical therapy.36 Prolonged attempts to treat
patients with high-risk tumors using ineffective intra-
vesical therapies might lead to local or even distant dis-
ease progression. Overall and disease-specific survival
is more favorable for patients with organ-confined
tumors (ⱕ T2) at the time of cystectomy compared
to patients with extravesical or node-positive disease
(⬎ T2 or N+).63
Conclusions
Bladder cancer recurrence and progression are depen-
dent on multiple clinical and pathologic features as
well as successful macro- and microablation using tra-
ditional endoscopic surgical techniques and intravesi-
cal therapies, respectively. Urine cytology remains the
most specific test for detecting de novo or recurrent
transitional cell tumors. Compared to cytology, several
fluid-based and cell-based urinary assays maintain supe-
rior sensitivity for cancer detection, yet no marker is as
valuable as cystoscopy for bladder cancer diagnosis and
surveillance. Intravesical chemotherapeutic and
immunotherapeutic agents prolong recurrence-free
survival, and BCG therapy in particular may positively
alter rates of cancer progression when combined with

Table 8. — Severity and Management of Bacille Calmette-Guérin Toxicity

Grade 1: Moderate Symptoms < 48 Hours

Mild/moderate irritative voiding symptoms, mild hematuria, fever < 38.5°C.
Assessment
Possible urine culture to rule out bacterial urinary tract infection.
Symptom Management
Anticholinergics, topical antispasmodics (phenazopyridine), analgesics, nonsteroidal anti-inflammatory drugs.

Grade 2: Severe Symptoms and/or > 48 Hours

Severe irritative voiding symptoms, hematuria, or symptoms lasting > 48 hours.
All maneuvers for grade 1, plus:
Assessment
Urine culture, chest radiograph, liver function tests.
Management
Timely infectious disease consultation with physician experienced in management of mycobacterial infections/complications.
Consider dose reduction to one half to one third of dose when instillations resume.
Treat culture results as appropriate.
Antimicrobial Agents
Isoniazid and rifampins, 300 mg/day and 600 mg/day, orally until symptom resolution.
Monotherapy not recommended.
Observe for rifampin drug-drug interactions (eg, warfarin, many others).

Grade 3: Serious Complications (Hemodynamic Changes, Persistent High-Grade Fever)

Allergic Reactions (Joint Pain, Rash)
Perform all maneuvers described for grades 1 and 2, plus:
Isoniazid 300 mg/day and rifampin 600 mg/day for 3 to 6 months depending on response.
Solid Organ Involvement (Epididymitis, Liver, Lung, Kidney, Osteomyelitis, Prostate)
Isoniazid 300 mg/day, rifampin 600 mg/day, and ethambutol 15 mg/kg/day single daily dose for 3 to 6 months.
Cycloserine often causes severe psychiatric symptoms and is to be strongly discouraged.
Bacille Calmette-Guérin is almost uniformly resistant to pyrazinamide, so this drug has no role.
Consider prednisone 40 mg/day, when response is inadequate or for septic shock (never given without effective antibacterial therapy).

This Table was published in Section XV, Chapter 76: Bladder; Lower Genitourinary Calculi and Trauma. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW,
Peters CA, eds. Campbell-Walsh Urology. 9th ed. Page 2458. Copyright © 2007 Elsevier.

266 Cancer Control October 2010, Vol. 17, No. 4

maintenance strategies in patients with high-risk
tumors. Cystectomy is the mainstay of treatment for
most patients at risk for cancer progression or who fail
more conservative measures to eradicate non–muscle
invasive disease.
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