Treatment of non–muscle invasive disease is dependent on clinical and pathologic

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.
Introduction
From the Genitourinary Oncology (WJS, LRW, JJC, CP) and Pathology (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: [email protected]
Dr Sexton is on the speakers’ bureau for Endo Pharmaceuticals.
The other authors report no significant relationship with the companies/organizations whose products or services may be referenced
in this article.
256 Cancer Control
The transformation from normal to malignant urothelium 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 bladder cancer are considered to have a “field change” disease, suggesting that the entire urothelium is at risk for
tumor formation. Recurrences in various sites and particularly within the bladder are therefore characteristic,
and patients must undergo lifelong surveillance.
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 survival by stage at presentation in part related to the higher proportion of nontransitional cell carcinomas seen
in African Americans.3 Caucasian Americans have a 2fold increased risk of developing bladder cancer compared with African Americans. Latin Americans have an
even lower risk of bladder cancer development compared with African Americans.1 Bladder cancer is a disease of senior adults; the overall median age at diagnosis is 70 years in men and women combined.4 The rare
adolescent or the younger adult who develops a transitional 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 lymphoepithelioma-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 carcinomas of the bladder are aggressive, are often associated 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 lymphovascular 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 carcinogens 4-aminobiphenyl and o-toluidine), occupational
exposure to aryl amines, ionizing radiation, and exposure 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 environmental 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 mismatch repair) where patients are at risk for the development 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 suggest that smoking cessation decreases the rate of tumor
recurrence.12 Chronic cystitis and schistosoma hematobium infections are risk factors for squamous cell carcinomas 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 dysplasia resulting from deletions of chromosome 9q and (2)
activating mutations of fibroblast growth factor receptor 3 (FGFR3) causing genetically stable low-grade papillary tumors. The second pathway is more concerning,
involving the flat, high-grade lesions — high-grade dysplasia or carcinoma in situ (CIS) — and is due to early
p53 mutation. These genetically unstable tumors accumulate alterations leading to retinoblastoma (RB) inactivation, 8p deletions, and locus defects in H-ras, p16,
p21, and p27.15
Diagnostic Evaluation
Presenting Signs and Symptoms
Patients with hematuria or lower urinary tract symptoms should be considered for upper tract imaging
with CT urography alone or with renal ultrasound combined with intravenous pyelography or retrograde pyelography. A complete urologic evaluation to detect
urothelial tumors includes cystoscopy, which permits
direct visualization of the entire urethra and the bladder urothelium. Complementary methods used to
detect urothelial tumors include the evaluation of voided urine or bladder wash specimens for cytology and
increasingly the use of laboratory- and office-based urinary biomarker assays.
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.
Cystoscopy
Diagnostic cystoscopy remains the gold standard for
detecting lower urinary tract malignancies. It can be performed 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 cystoscopy 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−
9p−
9q−
9p−
hyperplasia +
dysplasia/CIS
hyperplasia
FGFR3
cyclin D
11p−
genetically
stable
papillary carcinoma
low grade
TP53 (± 9p−/9q−)
dysplasia
FGFR3
cyclin D
11p−
?
?
papillary carcinoma
high grade
CIS
genetically
stable
recurrence
recurrence
8p−
RB
8p−
+++
genetically
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
the prior administration of intravesical therapies. A biopsy is necessary to confirm malignant transformation.
Hexaminolevulinate (HAL) imaging during cystoscopy enhances the visual detection of flat urothelial
cancers and small papillary tumors. It is based on the
accumulation of endogenous photoactive porphyrins
(PAPs). When instilled into the bladder through
catheterization, HAL accumulates in tumors and is converted to PAPs that emit a red fluorescence upon blue
light illumination. A recent prospective, multicenter
phase III study demonstrated superior detection of
superficial papillary tumors (95% vs 68%) and CIS (96%
vs 85%) using hervix blue light cystoscopy vs standard
white light cystoscopy.16 Filbeck et al17 demonstrated a
higher residual tumor rate of 25.2% in patients undergoing white light transurethral resections compared
with 4.5% in patients who underwent resection with
fluorescent light illumination. Drawbacks to fluorescent light illumination include the diminished specificity seen with bladder inflammatory conditions, especially following intravesical therapy, and the need to
instill the agent into the bladder approximately 30 minutes prior to cystoscopy.
has been reported to be as high as 98.3%.21 The sensitivity of cytology for diagnosing low-grade tumors is
poor, but fortunately, the progression rate for low-grade
noninvasive tumors is low.
“Atypical” cytology is a nonspecific term often used
to characterize the appearance of cells in urine cytology
specimens, but the significance of this finding is poorly
understood. Atypical cells are common in patients with
urinary diversions and various conditions leading toward
bladder inflammation or cystitis. If cystoscopy and uppertract evaluation are negative, atypical cells alone usually
warrant no further investigation or bladder biopsies.
Although the presence of “dysplastic” cells warrants follow-up, the finding is not diagnostic for a malignancy.
“Suspicious” cytology indicates the need for either further investigation or careful surveillance. Nabi et al22 observed that 35% of patients with suspicious cytology but
no evidence of bladder cancer on initial evaluation subsequently developed transitional cell tumors with a mean
time to diagnosis of nearly 6 months.
Biomarkers
Many biomarkers have been incorporated into strategies for the diagnosis, surveillance, and management of
bladder cancer.23-25 Although the ideal marker is
Cytology
unknown, several tests are currently approved for clinUrine 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 celNMP22 BladderChek Test (nuclear matrix protein,
lular and nuclear pleomorphism, increased nuclear to
Matritech Inc, Newton, MA) and the BTA Stat test (bladcytoplasmic ratio, and nuclear irregularity.19 The diagder 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, Quebest 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
assays eliminate the need for diagnostic
Sensitivity
Specificity
or surveillance cystoscopy. Most markCommercially Available Marker
Mean (%)
Range (%)
Mean (%) Range (%)
ers continue to be used in conjunction
Cytology
48.
16–89
96.
81–100
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,
coexisting benign bladder pathology,
BTA TRAK
61.
17–78
71.
51–89
and prior intravesical therapy. As an
ImmunoCyt
74.
39–100
80.
73–84
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
numbers of normal urothelial cells,
assays include the ImmunoCyt test (Diagnocure Inc, Quebec City, Quebec, Canada) and the
leading to a false-negative result. FurFISH analysis (fluorescence in situ hybridization, UroVysion Systems Vysis, Abbott Laboratories, 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
after intravesical therapy.26 All markers
Trauma. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology.
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
detection.26 Multiple other markers have been studied
but are not yet approved by the FDA for routine clinical application: BLCA-4, telomerase, survivin, hyaluronic 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.
A
Pathology and Staging
Table 3 demonstrates the current TNM staging for bladder cancer.28 Non–muscle invasive bladder cancer
includes a heterogeneous group of tumors with variable biologic potential. Non–muscle invasive tumors
are confined to the bladder urothelium (Ta and Tis) and
to the lamina propria (T1) (Fig 2).
B
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
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
C
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
Stage Grouping
Stage 0a
Ta
Stage 0is Tis
Stage I
T1
Stage II
T2a, b
Stage III
T3a, b
T4a
Stage IV
T4b
Any T
Any T
N0
N0
N0
N0
N0
N0
N0
N1, N2, N3
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
From Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual.
7th ed. New York: Springer; 2010. Reprinted with permission by the
American Joint Committee on Cancer.
260 Cancer Control
Fig 2. — (A) Papillary urothelial neoplasm of low malignant potential
(PUNLMP): papillae contain fibrovascular cores lined by an increased
number of cell layers showing an even distribution (polarity) and layering
of cells with minimum cytologic atypia. The superficial umbrella cell layer
is preserved. There is no nuclear overlapping, and the cells are not densely
arranged (hematoxylin-eosin, magnification ×100). (B) Low-grade papillary
urothelial carcinoma: papillae show an orderly proliferation of densely
arranged cells with mild to moderate atypia without loss of polarity. There
is increased cellularity without nuclear overlapping (hematoxylin-eosin,
magnification ×40). (C) High-grade papillary urothelial carcinoma: papillary
frond with complete architectural disorder and loss of polarity is present.
There is nuclear overlapping, nuclear enlargement, and hyperchromasia
(hematoxylin-eosin, magnification ×400). (D) Urothelial carcinoma invading
into lamina propria: clusters of pleomorphic cells with nuclear enlargement
and hyperchromasia infiltrate the underlying fibroconnective stroma
(hematoxylin-eosin, magnification ×200).
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 bladder distension. In an empty bladder, the urothelium can
be up to seven cells thick. The most superficial or luminal layer of urothelium consists of large, sometimes binucleated cells with abundant eosinophilic cytoplasm
and a rounded free surface; these are called umbrella
cells. The urothelium rests on a thin basement membrane layer, which separates the urothelium from the
underlying lamina propria. The lamina propria is formed
of abundant connective tissue containing vascular network, 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 outermost 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 classification of papillary urothelial lesions confined to the urothelium 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 highgrade papillary carcinoma. Urothelial papilloma is characterized by discrete papillary fronds with nonbranching
or minimally branching arrangement, slender fibrovascular 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 resembles the papilloma but shows increased cellular proliferation 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 pattern of disorder with moderate to marked architectural
and cytological atypia. High-grade tumors have fused
papillae with variable thickness, frequent cell dyscohesion, 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. Invasion of muscularis mucosa within the lamina propria
must be clearly distinguished from invasion of muscularis propria. This distinction is critical in that muscularis 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 surface 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 irregular 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 information. 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 abnormalappearing urothelium or biopsies of the prostatic urethra 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 urothelium may or may not alter the management of the bladder malignancy, and as such, this practice remains controversial except when contemplating a partial cystectomy 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 locally 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 restaging resection in patients with high-risk non–muscle
invasive bladder cancer (ie, large-volume cTa or cT1 disease). First, the repeat resection ensures adequate evaluation 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 cystectomy.35 The restaging transurethral resection of the tumor
Table 4. — Predictors of Recurrence and Progression
Factor
Recurrence
Progression
Number of Tumors
Single
2 to 7
≥8
0
3
6
0
3
3
Tumor Diameter
< 3 cm
≥ 3 cm
0
3
0
3
Prior Recurrence Rate
Primary
≤ 1 recurrence/yr
> 1 recurrence/yr
0
2
4
0
2
2
Category
Ta
T1
0
1
0
4
Concomitant CIS
No
Yes
0
1
0
6
Grade (1973 WHO)
G1
G2
G3
0
1
2
0
0
5
0–17
0–23
Total Score
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.
262 Cancer Control
bed is typically performed within 1 to 4 weeks following the initial TURBT. While highly recommended for
most if not all patients with tumor invasion of the lamina propria, the restaging resection is imperative and recognized as the standard of care for patients with cT1
tumors when adequate sampling of the muscularis propria is not represented in the histological specimen.36
Complications resulting from TURBT include irritative 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 conservatively. Conversely, most patients with intraperitoneal bladder perforations are managed with
exploratory laparotomy and primary repair, particularly
if the perforation is large and is associated with persistent peritonitis, excessive bleeding, or the rare finding of
a bowel injury. Some investigators acknowledge a higher 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 bladder perforation should be based on individual patient
circumstances and careful scrutiny of the clinical findings to optimize recovery and oncologic outcome.
Risk Group Classification
The combination of cystoscopic and pathologic findings determines the need for intravesical therapy and
predicts the risk for cancer recurrence, progression,
and cancer-related mortality.39 Using standard clinical
and pathologic criteria, researchers from the European
Organisation for Research and Treatment of Cancer
(EORTC) developed a scoring system based on the six
most significant risk factors for recurrence and progression. The risk factors were determined from a database containing 2,596 patients with Ta or T1 tumors
(from seven randomized trials) who had undergone a
TURBT yet were not managed with re-resections or
maintenance intravesical BCG therapy. The six predictors included number of tumors, tumor diameter, prior
recurrence rate, clinical T stage, the presence of concomitant CIS, and the tumor grade (Table 4).40,41 Evident
from these data is that regardless of risk group stratification, a large percentage of patients with non–muscle
invasive cancer will recur (Table 5).40 Furthermore, the
presence of recurrent tumor at the initial 3-month surveillance cystoscopy is strongly predictive of continued
tumor recurrences. Patients with grade 3 tumors and
CIS (especially in association with lamina propria invasion) harbor the highest risk for disease progression.
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)
Progression Score
Probability of Progression at 1 Yr
High risk
Probability of Progression at 5 Yrs
%
(95% CI)
%
(95% CI)
0
0.2
(0–0.7)
0.8
(0–1.7)
2–6
1.
(0.4–1.6)
6.
(5–8)
Progression Risk Group
Low risk
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):303314. Reprinted with permission from Elsevier.
Intravesical Therapy
An important strategy in the management of non–muscle
invasive bladder cancer includes the use of intravesical
therapies to treat microscopic tumor persistence and to
prevent tumor reimplantation, new tumor formation,
and possibly tumor grade and stage progression. Intravesical chemotherapeutic and immunomodulatory agents
most commonly utilized in the United States are listed in
Table 6.
Immediate Postresection Intravesical Therapy
There are several reasons to support consideration of
immediate postresection intravesical chemotherapy.
Half of all tumor recurrences may be due to the TURBT
and the mechanical dispursement of tumor cells with
resultant tumor reimplantation at sites of resection.
Animal models support this theory, confirming the ease
of tumor reimplantation onto traumatized urothelial
surfaces.42 Additionally, most synchronous and metachronous tumors appear to be of clonal origin.43
Two peaks of tumor relapse are evident. An early
peak is likely due to tumor recurrence or persistence,
whereas a late peak is likely due to a second primary
tumor. Only the early peak of tumor relapse is affected
by the immediate postresection instillation of an intravesical agent. Available agents include mitomycin C,
thiotepa, and doxorubicin. In the United States, mitomycin C (20 to 40 mg in 20 to 40 mL of sterile water)
has been the most widely utilized agent in the immediate postresection setting. Dwell time within the bladder ranges from 30 to 60 minutes. A therapeutic benefit from a single one-time instillation of mitomycin C
could be achieved up to 24 hours following the TURBT,
although the most desirable time to instill the therapy
may be within the first 2 to 6 hours following resection.40 Mitomycin C and other immediate postresection intravesical therapies should be withheld in cases
of suspected perforation, significant large-volume resecOctober 2010, Vol. 17, No. 4
tions, or significant gross hematuria requiring either
hand irrigation or continuous bladder irrigation with
sterile saline to keep the urinary effluent clear.
Immunomodulatory agents such as BCG or interferon
are never used in the immediate postresection setting.
Published meta-analysis data support the immediate
postresection instillation of chemotherapy following
TURBT. Sylvester et al44 reviewed data from seven randomized trials with tumor recurrence information on
1,476 patients. Intravesical agents included mitomycin
C, thiotepa, epirubicin, and pirarubicin (epirubicin and
pirarubicin are not available in the United States for this
application). In all studies, the instillation was administered within 24 hours. Patients in the treatment group
experienced a 39% decrease in the odds of recurrence
compared with patients managed with observation
alone following TURBT. Recurrence-free percentages
were better for patients with single tumors compared
Table 6. — Chemotherapy and Immunotherapy Drugs for
Intravesical Administration
Chemotherapies
Mechanism of Action
Mitomycin C
Antibiotic; inhibits DNA synthesis
Thiotepa
Alkylating agent; cross-links
nucleic acids
Doxorubicin, valrubicin
Topoisomerase inhibitor;
intercalating agents;
inhibits DNA synthesis
Immunotherapies
Mechanism of Action
Bacille Calmette-Guérin
T-helper type I immune response
(increased interleukin-2 and
interferon gamma)
Interferon *
Lymphocyte activation, potentiates
T-helper type I response
(inhibits production of interleukin-10,
an inhibitory cytokine); antiangiogenic;
antiproliferative
* Used in combination with bacille Calmette-Guérin.
Cancer Control 263
to patients with multiple tumors. Presently, the European Association of Urology (EAU) recommends immediate postresection therapy for all patients undergoing a
complete, uneventful TURBT.40 The American Urological Association (AUA) guidelines recommend postresection 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 highgrade 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 following 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–muscle 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 recommended therapy is induction BCG followed by
maintenance BCG. This has been consistently shown to
be superior to intravesical chemotherapy for preventing 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 + maintenance. 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 progression by 5%.36
Maintenance Intravesical Therapy
Maintenance therapy is defined as the periodic continued exposure of the urothelium to an intravesical agent
following the achievement of a complete response to
an initial induction course of intravesical therapy. Maintenance therapy following initial induction therapy is
264 Cancer Control
an important strategy for decreasing tumor recurrence
and potentially decreasing tumor progression. The 5year 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 highrisk 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 related 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 maintenance 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 incorporated 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, maintenance 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 intravesical chemotherapy (eg, mitomycin C) administered
monthly for 3 to 12 months may impact tumor recurrences, 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 definition 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 BCGresistant 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 following a disease-free period of at least 6 months. Finally, 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
BCG therapy.48,49
Patients who fail an initial induction course of
intravesical chemotherapy respond to intravesical BCG
at a similar rate as treatment-naive patients. On the contrary, patients with BCG refractory disease seldom
respond to salvage intravesical chemotherapy. Following initial BCG induction failure, 30% to 50% of patients
will respond to a second induction course of BCG.
High-risk patients who fail two induction courses of
BCG should be considered BCG-refractory50 and
offered cystectomy (an AUA guideline recommendation) since ⬍ 20% of patients respond to continued
attempts to eradicate tumor utilizing BCG.36
Several other salvage regimens have been studied
in patients who are BCG-refractory or BCG-intolerant.
Intravesical interferon monotherapy results in a 2-year
disease-free survival rate of less than 15% in patients
who fail BCG therapy.51 However, in combination with
low-dose BCG, the 2-year disease-free survival rate is
40% to 50% in patients who failed prior BCG induction
(± maintenance BCG) or were BCG-intolerant.52,53
Valrubicin (a semisynthetic derivative of the anthracycline antibiotic doxorubicin) is approved by the FDA
for the treatment of BCG-refractory CIS of the bladder
for whom immediate cystectomy would be associated
with unacceptable morbidity or mortality.54 Gemcitabine and docetaxel are additional investigational
chemotherapeutic agents that are being studied in the
BCG-failure population of patients.55-57 Both have acceptable toxicity, but the usefulness for BCG-refractory
patients is unclear until additional prospective trials
have been completed.
Complications of Intravesical Therapy
Table 7 details the toxicities most commonly associated
with the use of different intravesical therapies.36,58 BCGrelated side effects dominate the toxicity profile, largely
due to the more frequent use and administration of BCG.
BCG toxicity can be subdivided into different grades of
severity. Accordingly, higher grades result in the need for
more intense evaluation and management (Table 8). The
irritative lower urinary tract symptoms mostly attributed
to non-infectious (inflammatory) cystitis are the most
frequently reported side effects. Several maneuvers are
employed to treat the BCG-related symptoms; these
include administering anticholinergic agents, reducing
BCG dose (half, one-third, one-tenth strength BCG
administration), decreasing dwell time (at least 30 minutes dwell may be as effective as 1 to 2 hours), utilizing
antibiotics (ofloxacin 8 and 20 hours following BCG
instillation), and spacing treatments from weekly to
every 2 weeks.59,60 Antibiotic use, especially quinolones,
can theoretically decrease BCG viability, but this has not
yet been shown clinically.61
For grade II BCG infections, therapy should be discontinued and consideration given to hospitalization
with initiation of intravenous antibiotics, isoniazid, and
pyridoxine. In the patient with grade III toxicity,
including suspected BCG sepsis, therapy would also
include rifampin, ethambutol, fluoroquinolones, and
intravenous corticosteroids.
Follow-Up
The high rate and frequency of recurrence and the concern for disease progression — especially in patients
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
adopted for high-risk patients
Symptomatic prostatitis
<5
includes assessment with cysEpididymitis
<2
Fever (≥ 103°F)
3
toscopy and cytology every 3
Sepsis
< 0.5
months for 2 years, then
Distant organ (ie, pulmonary miliary pattern)
Rare
every 6 months for 2 years,
Mitomycin C
Chemical cystitis
10
and then annually. In the lowMyelosuppression
< 10
Rash (hypersensitivity dermatitis)
< 10
risk patient, if the initial 3Bladder contracture
< 2
month cystoscopy following
Tissue necrosis
Rare
TURBT appears normal, it is
Thiotepa
Chemical cystitis
20
acceptable to consider earlier
Myelosuppression
10
initiation of every 6- to 12Doxorubicin
Chemical cystitis
25
month cystoscopy and cytolAllergic reaction
1
ogy. Bladder biopsies should
Sources:
be performed to assess suspiHall 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):
for patients with CIS, and also
323-326, 331-332.
if the cytology becomes posi-
October 2010, Vol. 17, No. 4
Cancer Control 265
tive in the absence of visible urothelial tumors. Uppertract 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), lymphovascular invasion in patients with clinical stage T1
tumor, incomplete resection of multifocal T1 highgrade tumor, BCG induction failure in patients with T1
high-grade tumors or CIS, deep prostatic ductal involvement 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 discussion 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 disease 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 dependent on multiple clinical and pathologic features as
well as successful macro- and microablation using traditional endoscopic surgical techniques and intravesical 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 superior 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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