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Clinical presentation, diagnosis, and staging of

bladder cancer
Authors: Yair Lotan, MD, Toni K Choueiri, MD
Section Editor: Seth P Lerner, MD
Deputy Editor: Sonali Shah, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2021. | This topic last updated: Feb 13, 2020.

INTRODUCTION

Bladder cancer is the most common malignancy involving the urinary system.
Urothelial (transitional cell) carcinoma is the predominant histologic type in the
United States and Europe, where it accounts for 90 percent of all bladder cancers. In
other areas of the world, non-urothelial carcinomas are more frequent. Much less
commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. (See
"Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the
bladder", section on 'Epidemiology'.)

The spectrum of bladder cancer includes non-muscle invasive (superficial), muscle

invasive, and metastatic disease, each with its own clinical behavior, biology,
prognosis, and treatment.

The clinical presentation, diagnosis, and staging of bladder cancer will be presented
here.

The management of patients with bladder cancer, including specific

recommendations based on the stage of disease, is discussed separately:

● Overview of bladder cancer treatment (see "Overview of the initial approach

:
 and management of urothelial bladder cancer")
● Non-muscle invasive bladder cancer (see "Treatment of primary non-muscle
invasive urothelial bladder cancer")
● Muscle invasive bladder cancer (see "Radical cystectomy and bladder-sparing
treatments for urothelial bladder cancer" and "Neoadjuvant treatment options
for muscle-invasive urothelial bladder cancer")
● Metastatic bladder cancer (see "Treatment of metastatic urothelial cancer of the
bladder and urinary tract")

CLINICAL PRESENTATION

Patients with bladder cancer classically present with painless hematuria (grossly
visible or microscopic), although irritative voiding symptoms (frequency, urgency,
dysuria) can be the initial manifestation. The diagnosis is often delayed due to the
similarity of these symptoms to those of benign disorders (urinary tract infection,
cystitis, prostatitis, passage of renal calculi), and delays can lead to a worsened
prognosis due to more advanced stage at diagnosis [1]. There is evidence to suggest
that delayed diagnosis accounts for the poorer survival in women diagnosed with
bladder cancer compared with men [2]. Furthermore, symptoms are often
intermittent. In some patients, metastases will cause the initial symptoms.
Incidental bladder cancer is rare at autopsy, suggesting that most cancers
eventually become symptomatic [3].

Hematuria — The most common presenting symptom is hematuria, which is

typically intermittent, gross, painless, and present throughout micturition. (See
"Etiology and evaluation of hematuria in adults".)

The likelihood of bladder cancer increases when the hematuria is gross (visible)
rather than microscopic [4,5], with an incidence of bladder cancer of approximately
2 to 5 percent among patients with microscopic hematuria [6-9] and 10 to 20
percent among those with gross hematuria [6,7,10].

Hematuria is typically due to benign causes in most patients and can be seen in up
to 18 percent of normal individuals [7,8,11]. However, because patients with
microscopic hematuria can have bladder cancer, the American Urological
:
 Association (AUA) recommends evaluation of all patients 35 years or older with
asymptomatic microhematuria (ie, three or greater red blood cells [RBCs] per high-
power field [HPF] in the absence of known benign causation) [12]. However,
guidelines among expert groups differ. Recognizing a lower risk among younger
women who do not smoke, the American College of Obstetricians and Gynecologists
(ACOG) and the American Urogynecologic Society (AUGS) recommend that
asymptomatic, low-risk, never-smoking women aged 35 to 50 years undergo
evaluation only if they have more than 25 RBCs per HPF [13].

The importance of evaluating hematuria was illustrated by a study of 1930 patients,

in which 61 percent had no abnormality diagnosed [6]. Abnormalities that were
found included bladder cancer (12 percent), urinary tract infections (13 percent),
medical renal disease (10 percent), stone disease (4 percent), kidney cancer (0.6
percent), and prostate cancer (0.4 percent) [6]. Bladder cancer was much more
frequent in older patients, but seven patients with bladder cancer were younger
than 40 years, including one with microscopic hematuria.

The point at which gross hematuria is noted during urination can be helpful in
localizing its source:

● Hematuria occurring primarily at the beginning of urination is usually from a

urethral source.

● Blood that is only noticed as a discharge between voidings or as a stain on

undergarments, while the voided urine itself appears clear, indicates an origin
at the urethral meatus or the anterior urethra.

● Terminal hematuria, with blood appearing towards the end of voiding, generally
originates from the bladder neck or prostatic urethra.

● Hematuria occurring throughout voiding can originate from anywhere in the

urinary tract, including the bladder, ureters, or kidneys.

Pain — Pain associated with bladder cancer is usually the result of locally advanced
or metastatic tumors. Its distribution is related to the size and location of the
primary tumor or its metastases:

● Flank pain may result when a tumor obstructs the ureter at any level (bladder,
:
 ureter, or renal pelvis). Although obstruction usually is associated with muscle
invasive disease, large noninvasive tumors at the ureteral orifice may also cause
symptoms. The pain is similar to that experienced with the passage of urinary
stones, and may or may not be associated with hematuria. (See "Kidney stones
in adults: Diagnosis and acute management of suspected nephrolithiasis".)

● Suprapubic pain is usually a sign of a locally advanced tumor that is either

directly invading the perivesical soft tissues and nerves or obstructing the
bladder outlet and causing urinary retention.

● Hypogastric, rectal, and perineal pain can be signs of disease invading the
obturator fossa, perirectal fat, presacral nerves, or the urogenital diaphragm.

● Abdominal or right upper quadrant pain may signal the presence of abdominal
lymph node or liver metastases.

● Bone pain may indicate the presence of bone metastases.

● Significant and persistent headache or disordered cognitive function may

suggest the presence of intracranial or leptomeningeal metastases.

Voiding symptoms — Voiding symptoms are most common in patients with

carcinoma in situ (CIS) of the bladder and may result from a functional decrease in
the bladder capacity, detrusor overactivity, invasion of the trigone, or obstruction of
the bladder neck or urethra.

● Irritative voiding symptoms (eg, daytime and/or nocturnal frequency, urgency,

dysuria, or urge incontinence) occur in approximately one-third of patients. The
complex of dysuria, frequency, and urgency in particular is highly suggestive of
bladder CIS. (See "Treatment of primary non-muscle invasive urothelial bladder
cancer".)

● Obstructive voiding symptoms are less common and may be due to tumor
location at the bladder neck or prostatic urethra. Symptoms include straining,
an intermittent stream, nocturia, decreased force of stream, and a feeling of
incomplete voiding. On occasion, gross hematuria may result in "clot retention."

Constitutional symptoms — Symptoms such as fatigue, weight loss, anorexia, and

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 failure to thrive are usually signs of advanced or metastatic disease and denote a
poor prognosis. In rare cases, patients may have constitutional symptoms due to
renal failure caused by bilateral ureteral obstruction. (See "Clinical manifestations
and diagnosis of urinary tract obstruction and hydronephrosis".)

PHYSICAL EXAMINATION

A complete physical examination should be performed in patients with bladder

cancer, including a digital rectal examination in men and a bimanual examination of
the vagina and rectum in women.

Although the physical examination is unremarkable in most patients, abnormal

findings that can be seen include the following:

● A solid pelvic mass may be felt in advanced cases.

● Induration of the prostate gland can sometimes be felt on digital rectal

examination if the bladder cancer involves the bladder neck and invades the
prostate. An attempt to palpate the base and lateral walls of the bladder should
be made, looking for induration or fixation.

● Inguinal adenopathy can be present, although the inguinal region is not a

common site of node metastases.

● Nodularity in the periumbilical region can be seen in advanced lesions involving

the dome of the bladder. This is often seen with urachal cancers, which typically
are adenocarcinomas rather than urothelial tumors.

● Abdominal examination may reveal the presence of substantially enlarged para-

aortic lymph nodes or hepatic metastases.

INITIAL EVALUATION

Overview — The presence of otherwise unexplained hematuria may represent

urothelial cancer in individuals over the age of 35 until proven otherwise.
Nevertheless, many causes are benign, such as hematuria from enlarged prostates,
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 urinary tract infection, cystitis, prostatitis, and passage of renal calculi. The goal of
the diagnostic evaluation is to determine the diagnosis, site, and extent of cancer,
and the presence or absence of muscle invasive disease.

A full urologic evaluation of the entire urinary tract is indicated in such patients
unless there is clear evidence of glomerular bleeding (eg, red cell casts, proteinuria,
dysmorphic red cells [particularly acanthocytes], and in patients with gross
hematuria, a smoky brown color). (See "Etiology and evaluation of hematuria in
adults", section on 'Glomerular versus nonglomerular bleeding'.)

This evaluation should consist of cystourethroscopy, urinary cytology, and an

evaluation of the upper tracts, since urothelial malignancy can be multifocal, with
one or more lesions anywhere from the renal pelvis to the proximal urethra.

Radiographic imaging of the upper tract can consist of either a computed

tomography (CT) scan of the abdomen/pelvis with urography with oral and
intravenous contrast or intravenous pyelography (IVP) plus nephrograms or renal
ultrasound (US) to evaluate both the collecting systems and the renal cortex. IVP is
rarely used and has been largely replaced by CT. Contrast magnetic resonance
imaging (MRI) may be used in patients with allergy to iodinated contrast.

Urinalysis — The urinalysis should include a microscopic and gross examination as

well as a dipstick chemical test. Nonrefrigerated urine should be examined within 30
minutes of collection. (See "Urinalysis in the diagnosis of kidney disease".)

The average individual excretes approximately 30,000 red blood cells (RBCs) per
hour, which equates to approximately one RBC per high-power field (HPF) on
microscopic examination. Hematuria is usually not considered significant unless
there are more than three RBCs per HPF. RBC morphology may also suggest the
etiology of the hematuria; cells of glomerular origin are often dysmorphic or formed
in casts, indicating intrinsic renal disease, while normally shaped RBCs are more
likely from an extrinsic source such as calculi, tumor, obstruction, or infection. (See
"Etiology and evaluation of hematuria in adults".)

Urine color can be affected by its concentration, ingestion of certain foods or drugs,
or the presence of bacteria, and can be confused with hematuria.
:
 Urinary pigments that can mimic hematuria include the following:

● Betalain contained in beets (beeturia)

● Phenazopyridine, a urinary analgesic
● Vegetable dyes
● Urates
● Free myoglobin or hemoglobin
● Serratia marcescens
● Phenolphthalein, which used to be a common component of many over-the-
counter laxatives

On occasion, dipstick analysis will be positive for blood, but microscopic

examination fails to show RBCs. This can occur when myoglobin is present in the
urine, since it is chemically similar to hemoglobin. This can also occur when the
RBCs are lysed and in the presence of hemoglobin occurring in the course of
hemolysis.

The specific gravity of a specimen is important to note because of its influence on

the stability of white blood cells or RBCs. For example, when the urinary flow rate is
high and the urine is very dilute, RBCs are lysed and therefore will not be present on
microscopic examination, even in the presence of pathology. (See "Urinalysis in the
diagnosis of kidney disease".)

Cystoscopy — Cystoscopy is the gold standard for the initial diagnosis and staging
of bladder cancer. This procedure is done in the office with a flexible cystoscope and
only has minimal risks, such as bleeding and infection. Risk of infection is minimal
using sterile techniques. In the United States, this is typically done with white light;
fluorescence cystoscopy has been available in Europe and was approved in the
United States in 2010 for use in the operating room and in 2018 for office
cystoscopy. However, the indication for fluorescence cystoscopy has been for cancer
surveillance and not for evaluation of hematuria. (See 'Fluorescence cystoscopy'
below.)

Our approach is as follows:

● Any visible tumor or suspicious lesion seen at the initial (diagnostic) cystoscopy
should be either biopsied or resected transurethrally to determine the histology
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 and depth of invasion into the submucosa and muscle layers of the bladder.

● In patients who presented with a positive urine cytology and whose initial
cystoscopy showed no visible tumor (or suspicious lesion) within the bladder,
biopsy of apparently normal appearing urothelium, prostatic urethra, and
selective catheterization of the ureters/renal pelvis with urine specimens for
cytology from the upper tract is required.

For patients with documented high-risk disease confirmed on a diagnostic

transurethral resection of bladder tumor (TURBT), repeat resection may be indicated
to eliminate the risk of understaging. This issue is discussed elsewhere. (See
"Overview of the initial approach and management of urothelial bladder cancer",
section on 'Transurethral resection'.)

Procedure — The procedure begins with a bimanual examination under

anesthesia (EUA) to determine whether or not a palpable mass is present, and if
present, whether or not it is mobile. An EUA during cystoscopy is effective for
identifying locally advanced disease, which may present as gross extravesical
extension, invasion of adjacent organs, or pelvic sidewall involvement. If a mass is
felt, the bimanual examination is repeated after the resection to see if it is still
present and to differentiate between clinical stage T2 and T3b disease ( table 1).
(See 'Staging' below.)

The cystoscope is then inserted into the bladder, and urine is obtained for cytology.
A bladder wash specimen obtained by irrigating the bladder with sterile saline
provides the highest sensitivity for detection of cancer. The bladder is inspected
visually, and a detailed description of the size, number, appearance, location, and
growth pattern (papillary or solid) of all lesions is recorded. This information serves
as a reference for subsequent cystoscopic examinations. The status of the
uninvolved mucosa is also noted.

The size, stalk, and configuration of the cancer can be predictive of muscle invasion
[14]. In general, low-grade, noninvasive tumors are papillary with a narrow stalk.
High-grade, invasive tumors frequently can appear sessile, solid, or nodular.
Carcinoma in situ (CIS) is a high-grade, noninvasive tumor, which can appear as a
flat velvety lesion and can arise in patches. CIS sometimes involves large parts of the
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 urothelial lining.

Fluorescence cystoscopy — Fluorescence cystoscopy uses an intravesical

photoactive protoporphyrin (such as 5-aminolevulinic acid [5-ALA] and hexyl
aminolevulinic acid [HAL]), which accumulates preferentially in neoplastic rather
than normal tissue. The photoactive substance enhances the visual difference
between normal and neoplastic tissue after illumination with blue light of the
appropriate wavelength [15]. The HAL is instilled one hour prior to cystoscopy.

Randomized trials have confirmed that fluorescence cystoscopy detects more

tumors (both papillary and CIS) than white-light cystoscopy. This improved tumor
identification results in better patient management. The safety profile of
fluorescence cystoscopy is excellent. The improved early detection and treatment of
tumors need to be balanced by a slightly higher false-positive rate (mainly due to
inflammation and scarring), the requirement for a special lens system, the need to
instill the photosensitizer one hour prior to cystoscopy, as well as the higher cost.
The clinical results with fluorescence endoscopy are discussed elsewhere. (See
"Treatment of primary non-muscle invasive urothelial bladder cancer", section on
'Fluorescence endoscopy and narrow band imaging'.)

Urine cytology — Cytology is commonly used as an adjunct to cystoscopy to detect

CIS and upper-tract malignancies. The underlying concept is that cells in the urinary
tract that are proliferating rapidly will be exfoliated. However, urine cytology has a
relatively poor sensitivity, particularly for low-grade tumors. This was illustrated by a
meta-analysis that included 18 studies with 1255 patients [16]. The overall sensitivity
was 34 percent, with sensitivities for grade 1, 2, and 3 tumors of 12, 26, and 64
percent, respectively.

Lower-grade tumors have fewer morphologic alterations that may lead to the loss of
intercellular attachments and adhesiveness. Thus, they may not exfoliate as easily
as higher-grade tumors. When they are exfoliated, low-grade tumors are shed in
large papillary fragments with uniform size, minimal alterations in nuclear to
cytoplasmic ratio, and small or absent nucleoli. Higher-grade tumor cells tend to be
more isolated in loose clusters and elongated with marked pleomorphism,
increased nuclear to cytoplasmic ratios, and variable nucleoli size.
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 False-positive results are rare with urine cytology (specificity >98 percent in most
studies) [16]. Thus, any positive cytology should be assumed to represent
malignancy. If no disease is evident in the bladder, the upper urinary tracts and
prostatic urethra should be thoroughly evaluated. Enhanced cystoscopy with
fluorescent cystoscopy or narrow band imaging can be helpful in these cases to
improve detection of CIS. If no lesion is discernible, selective ureteral and renal
pelvis washings may be performed; however, the diagnostic accuracy of these
procedures is debated because of possible contamination from the bladder. (See
"Malignancies of the renal pelvis and ureter" and 'Fluorescence cystoscopy' above.)

Urine cytology specimens must be properly collected and stored in order to

maintain a high level of diagnostic accuracy. Catheterized specimens can denude
normal surface epithelial cells; coalescence in papillary groups may be
misinterpreted as low-grade transitional cell carcinoma (TCC). Voided specimens
with prolonged exposure to concentrated urine or specimens from women that are
contaminated with vaginal, cervical, or endometrial cells can also be misinterpreted.
Cytology specimens should be processed promptly, as cells will degrade after 10 to
15 minutes at room temperature. One study showed a lower diagnostic yield with
voided urine specimens when compared with bladder washings [17]. Chronic
urinary tract infections, inflammatory conditions, stone disease, recent
instrumentation or intravesical therapy, and bowel substitutions for the bladder (eg,
ileal conduits or orthotopic neobladders) can create degenerative cellular changes
and atypia, which can be misinterpreted. (See "Urinary diversion and reconstruction
following cystectomy".)

Urine-based markers — Multiple urine-based tumor markers have been developed

because of the low sensitivity of cytology and the need for a noninvasive diagnostic
tool to supplement cystoscopy. These urine biomarkers are discussed in detail
elsewhere. (See "Urine biomarkers for the detection of urothelial (transitional cell)
carcinoma of the bladder".)

Urine-based tumor markers have been developed that are based on differential
expression of tumor-related proteins, DNA, RNA, methylation changes, or cellular
markers [18,19]. The pooled sensitivity of urine-based tumor markers ranges from
50 to 80 percent, and specificity ranges from 70 to 90 percent, depending on the
analysis [18,19]. The sensitivity of markers and cytology correlates closely with stage
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 and grade.

Most urine-based molecular markers are more sensitive than urine cytology in the
detection of urothelial cancer, especially for low-grade tumors, but the specificity of
molecular markers is inferior to that of urine cytology.

None of these markers has sufficient sensitivity to replace cystoscopy in the

assessment of an individual suspected to have bladder cancer, and their clinical use
has not been recommended by consensus panels. There is potential benefit for
surveillance in patients with a history of urothelial cancer by reducing the frequency
of cystoscopy. There is evidence that use of markers such as a fluorescent in situ
hybridization (FISH) assay or RNA panels [20] may help management of patients
with atypical findings on cytology or cystoscopy [21,22]. Furthermore, urine markers
may help in predicting outcomes for patients being treated with intravesical
immunotherapy, but this awaits validation [23]. (See "Urine biomarkers for the
detection of urothelial (transitional cell) carcinoma of the bladder", section on 'Gene
expression panels'.)

One issue with markers is the finding of a positive marker with normal cystoscopy.
These findings have been termed "anticipatory" positives, and some studies suggest
they detect cancer prior to visualization [24].

Additional clinical trials are necessary to determine the incremental benefit of

markers and the cost-effectiveness of their use.

Urinary tract imaging — Imaging studies may be used to define the location and
extent of tumor as well as to detect sites of multifocal disease. CT scan is replacing
IVP as the procedure of choice, but IVP remains an appropriate alternative where CT
is not readily available.

Computed tomography scan — CT, with and without contrast, is the preferred
study for all patients with bladder cancer, regardless of stage [25]. CT scans should
include both the abdomen and pelvis, and should include delayed images to identify
defects in the collecting system. CT may demonstrate extravesical extension, nodal
involvement in the pelvis or retroperitoneum, visceral, pulmonary, or osseous
metastasis, and tumor involvement or obstruction of the upper urinary tract.
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 Although CT provides better visualization of tumors than US, it may miss tumors <1
cm in size, particularly those in the bladder trigone or dome, and it cannot
differentiate depth of bladder-wall invasion (ie, mucosal versus lamina propria or
muscularis propria).

Although a thickened bladder wall on CT suggests the presence of muscle invasive

disease, tissue is required for diagnosis. In contrast, CT is approximately 80 percent
accurate in differentiating locally advanced tumors involving extravesical adipose
tissue or surrounding structures from less invasive tumors ( image 1) [26]. An
important caveat is that in most instances, CT is performed after a transurethral
resection, which complicates its interpretation. It may be difficult to distinguish
inflammatory or iatrogenic edematous changes from true extravesical tumor
extension.

The sensitivity of CT for identification of nodal involvement is relatively low (false-

negative rate 68 percent, false-positive rate 16 percent) and requires a needle or
excisional biopsy for confirmation [27].

Intravenous pyelogram — An IVP can visualize both the bladder and upper
urinary tracts. IVP is an appropriate choice for patients with microscopic or gross
hematuria or suspected urothelial cancer [6,28]. IVP is more sensitive for detection
of small lesions of the ureter or renal pelvis, while CT scan and renal US are better
tests for the evaluation of renal parenchymal disease. Ideally, if IVP is obtained, it
should be done prior to TURBT to avoid misinterpretation of postoperative changes.
(See "Diagnostic approach to adult patients with subacute kidney injury in an
outpatient setting".)

IVP may not be appropriate in patients with renal insufficiency, diabetes mellitus, or
other conditions due to the risk of acute renal injury. IVP may also not be
appropriate in patients with a history of allergies to radiocontrast agents, although
prophylactic corticosteroids and antihistamines may be useful. In patients in whom
the ureters and renal pelvis are poorly visualized by IVP, retrograde pyelograms may
be performed during cystoscopy. (See "Prevention of contrast-induced acute kidney
injury associated with angiography" and "Prevention of contrast-induced acute
kidney injury associated with angiography", section on 'Epidemiology' and "Patient
evaluation prior to oral or iodinated intravenous contrast for computed
:
 tomography", section on 'Prevention'.)

The cystogram phase of the IVP detects 60 to 85 percent of large bladder tumors,
but smaller tumors are missed more frequently. Both the cystogram phase and the
post-void film should be examined for filling defects ( image 2), which are usually
irregular, frond-like, or nodular, and persistent from film to film. Filling defects may
be the result of parietal tumor implantation, the uneven jagged contours of
papillary fronds, or obstruction of a ureter with proximal dilation. The classic
urographic findings of an upper tract TCC are a meniscus-shaped ureteral filling
defect known as the "goblet" or "Bergmann" sign and the "stipple sign," produced
by contrast being trapped in the fronds of a papillary tumor.

Approximately 50 percent of patients with a filling defect in the renal pelvis or ureter
will have associated hydronephrosis, hydroureter, or nonvisualization of the kidney
secondary to obstruction [29]. Invasive bladder tumors may cause distal ureteral
obstruction and secondary hydronephrosis. Although the lack of this finding does
not rule out invasive disease, its presence signals an invasive cancer in over 90
percent of cases and extravesical disease in 70 percent [30] for unilateral and 90
percent for bilateral hydronephrosis [26]. Nonvisualization of the kidney is usually
seen in advanced disease and is frequently associated with invasion of tumor into
the renal parenchyma. Stenosis is also a specific sign of infiltrating disease and is
more commonly seen in the ureter ( image 3).

Magnetic resonance imaging — MRI is as reliable as CT for staging of invasive

or locally advanced disease and may be better at evaluating tumors at the base and
dome of the bladder. Gadolinium-enhanced MRI may be superior to CT to detect
superficial and multiple tumors, extravesical tumor extension, and surrounding
organ invasion [31-34].

Although MRI is useful for patients with contrast dye allergy, it is difficult to tolerate
by claustrophobic patients and cannot be used in patients with pacemakers or other
metallic foreign bodies. Open MRI imaging may be better tolerated, but image
resolution is poorer due to the smaller magnet used with this modification in
imaging.

Ultrasound — US is not very useful for the diagnosis or staging of bladder

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 cancer. US can confirm the presence of a soft tissue mass, but usually cannot
determine depth of invasion, extravesical extension, or nodal status. US may be
useful in evaluating the upper tracts for renal parenchymal disease, hydronephrosis,
and to differentiate a non-radiopaque stone from a soft tissue mass by differences
in echogenicity [35]. (See "Diagnostic approach to adult patients with subacute
kidney injury in an outpatient setting".)

Imaging for metastatic disease — Once the diagnosis and clinical stage of bladder
cancer are established, other imaging studies may be useful to evaluate for
metastatic disease.

The decision whether or not to perform additional diagnostic studies is based on

the results of the physical and bimanual examination, cystoscopy, and the
histologic/cytologic evaluation. The guidelines recommend imaging of the chest for
all patients with muscle invasive bladder cancer, but they do not specify the type of
scan, so both chest radiographs and CT scan are acceptable. Bone scan and imaging
of the brain are reserved for symptomatic patients. Positron emission tomography
(PET)/CT is typically only used in patients with suspicious lymph nodes, but it is not
commonly used.

Because bladder tumors often occur in older adults, a general medical evaluation is
also essential to document significant comorbid conditions, which might interfere
with appropriate treatment regimens (ie, ability to tolerate general anesthesia,
prolonged surgery, chemotherapy). (See "Preoperative medical evaluation of the
healthy adult patient".)

Lung lesions — Chest radiographs are used for the initial evaluation and for
periodic monitoring in patients at risk for pulmonary metastasis, although they are
insensitive for lesions <1 cm. Metastatic lesions are typically non-calcified soft tissue
densities. CT may be preferred over chest radiographs if patients are at "higher
risk," such as muscle invasive disease, and it is definitely indicated if abdominal
imaging reveals abdominal or lymph node metastases.

Bone scan — Radionuclide bone scans to detect bone metastases are

recommended only in patients with invasive or locally advanced tumors and either
skeletal symptoms or unexplained elevations in serum alkaline phosphatase.
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 Increased uptake is a nonspecific finding, which may be due to degenerative
change, trauma, and previous fracture sites, as well as metastatic disease. Plain
radiographs, CT, or MRI of suspicious areas may be necessary to confirm a
metastasis. Bone biopsy can be performed to document metastatic disease if
necessary.

Positron emission tomography — PET has limited value and does not yet have
an established role in patients with localized bladder cancer due to urinary excretion
of 18F-fluorodeoxyglucose (FDG) [36].

Preoperatively, PET/CT is a promising tool to detect metastatic disease, especially in

high-risk disease where the CT or MRI remained inconclusive on distant metastases.
In a study of 55 patients with bladder cancer, integrated PET/CT improved the
preoperative tumor, node, metastasis (TNM) staging compared with CT alone in 15
percent of patients [37].

PET may have a larger role in detecting disseminated disease in patients who are
locally advanced. In another study, 46 patients were evaluated with PET scans [38].
Sensitivity for metastases to adrenal, bone, kidney, lymph node, and soft tissue were
all 80 percent or greater.

HISTOLOGIC GRADE

The World Health Organization (WHO) and the International Society of Urological
Pathology (ISUP) have established a consensus classification system for urothelial
(transitional cell) neoplasms, in which urothelial cancer is classified as low grade and
high grade. Typically, invasive urothelial cancers are high grade. (See "Pathology of
bladder neoplasms", section on 'Classification'.)

STAGING

Stage is the most important independent prognostic variable for progression and
overall survival for invasive bladder cancer. The eighth edition (2017) of the tumor,
node, metastasis (TNM) system is used to stage bladder cancer.
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 Comprehensive pathologic staging requires cystectomy (with lymphadenectomy).
However, clinical staging can be applied for those patients who will undergo
neoadjuvant therapy. For patients with non-muscle invasive cancer (Ta, T1, Tis),
stage is determined by transurethral resection of bladder tumor (TURBT) and
bladder biopsies.

Clinical staging — Clinical staging is based on information derived from bimanual

examination and imaging studies as well as pathology results from the cystoscopic
biopsy or TURBT. However, the initial pathology obtained from cystoscopy
specimens does not always accurately reflect the pathologic stage based on radical
cystectomy.

The limitations of clinical staging are illustrated by a study of 778 consecutive

patients with bladder urothelial carcinoma who were treated with radical
cystectomy and pelvic lymphadenectomy [39]. Pathologic upstaging occurred in 42
percent of patients. This included patients thought to have non-muscle invasive
disease who had muscle invasion in the pathologic specimen and those thought to
have organ-confined clinical stage in whom non-organ confined tumor was
identified (≥pT3N0, or any pT and N positive ( table 1)). Pathologic downstaging
occurred in 22 percent of cases.

The detection of lymph node metastases with imaging is poor. Approximately 20 to

30 percent of patients who undergo cystectomy with clinically node-negative
disease by computed tomography (CT) criteria have pathologic positive nodes at
lymphadenectomy [40,41].

Pathologic staging — The standard staging system is the TNM system, which is
based on pathologic studies of cystectomy specimens ( table 1) [42]. This staging
system is applied to urothelial carcinoma, squamous cell carcinoma,
undifferentiated carcinoma, and adenocarcinoma arising in the bladder.

Tumor (T) stage

● Ta lesions – Ta tumors are exophytic (papillary) lesions that tend to recur, but
these are relatively benign and generally do not invade.

● Tis – Carcinoma in situ (CIS) or flat tumors.

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 ● T1 lesions – If a tumor invades the submucosa or lamina propria, it is classified
as a T1 tumor.

● T2 lesions – In T2 lesions, invasion into muscle is present. For T2 tumors,

cystectomy is considered "standard therapy." When muscle invasion is present,
the probability of nodal and distant metastases is increased. The 2017 TNM
staging system divides muscle-infiltrating (T2) disease into superficial (T2a) or
deep (T2b) invasion, with disease still confined within the bladder [42].

● T3 lesions – T3 tumors extend beyond muscle into the perivesical fat. CT or

magnetic resonance imaging (MRI) scans may help to identify disease that has
spread outside the bladder. T3 stage is stratified between T3a (microscopic) and
T3b (macroscopic).

● T4 lesions – The TNM system differentiates tumors extending into adjacent

organs (T4) from those extending into perivesical fat (T3). Tumor invading the
prostate, vagina, uterus, or bowel is classified as T4a, while tumor fixed to the
abdominal wall, pelvic wall, or other organs is T4b. Urothelial tumors may grow
into the prostate along the prostatic ducts; these are noninvasive lesions with a
good prognosis when resected. Alternatively, they may directly invade the
prostatic stroma, which indicates a worse prognosis [43].

The most important prognostic determinant that is derived from staging is whether
the tumor is organ confined (≤T2) or non-organ confined (≥T3). The accuracy of
available methods for determining the degree of muscle invasiveness
preoperatively is modest. Even in experienced hands, the correlation between depth
of invasion, as assessed by cystoscopic evaluation and TURBT, and the pathologic
examination of the bladder at the time of cystectomy is only approximately 70
percent. One study highlighted several features associated with a high risk of T3, T4,
and/or node-positive disease, including detection of a three dimensional mass on
examination under anesthesia (EUA), hydronephrosis, lymphovascular invasion, and
aberrant histology (eg, micropapillary, neuroendocrine) [44].

Nodal (N) disease — The TNM system categorizes nodal disease based on the
number and size of the involved nodes. It also accounts for metastases to specific
sites.
:
 In the 2017 TNM staging system, a single lymph node metastasis in the true pelvis is
considered N1 disease, multiple nodes in the true pelvis are classified as N2 disease,
and nodal involvement of the common iliac nodes is classified as a secondary
lymphatic drainage area (N3) rather than metastatic disease. Lymph node sampling
should include excision of an average of >12 lymph nodes [42].

Patients with nodal metastases but without disseminated disease may be treated
with cystectomy or combined-modality approaches. (See "Radical cystectomy and
bladder-sparing treatments for urothelial bladder cancer" and "Neoadjuvant
treatment options for muscle-invasive urothelial bladder cancer".)

Metastatic (M) disease — The presence of disseminated metastases (eg, lung,

liver, bone) portends the need for systemic therapy. Despite significant advances,
the long-term prognosis is poor for most patients. (See "Treatment of metastatic
urothelial cancer of the bladder and urinary tract".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Bladder cancer".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond
the Basics." The Basics patient education pieces are written in plain language, at the
5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical
jargon.

Here are the patient education articles that are relevant to this topic. We encourage
:
 you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and
staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment;
non-muscle invasive (superficial) cancer (Beyond the Basics)" and "Patient
education: Bladder cancer treatment; invasive cancer (Beyond the Basics)")

SUMMARY

● Patients with urothelial bladder cancer typically present with painless

hematuria, and the presence of unexplained hematuria in individuals over 35
years of age requires evaluation for possible malignancy. (See 'Clinical
presentation' above.)

● Cystoscopy is the initial procedure for both the diagnosis and management of
urothelial malignancy. Cystoscopy is used to establish the diagnosis, assess
whether or not muscle invasion is present, and provide initial therapy for non-
muscle invasive lesions. (See 'Cystoscopy' above.)

● Urine cytology is widely used in combination with cystoscopy to assess for the
presence of carcinoma in situ and to evaluate for the presence of upper urinary
tract lesions. Computed tomography (CT) is the preferred imaging procedure to
assess the local extent of disease and to further examine the renal pelvis and
ureters. (See 'Urine cytology' above and 'Urinary tract imaging' above and
"Malignancies of the renal pelvis and ureter".)

● Stage is the most important independent prognostic variable for assessing the
probability of progression and survival. The standard approach is the tumor,
node, metastasis (TNM) staging system, which requires cystectomy ( table 1).
For patients who will undergo neoadjuvant therapy, clinical staging is
appropriate. (See 'Staging' above.)

● An overview of the treatment of bladder cancer is presented separately. (See

"Overview of the initial approach and management of urothelial bladder
:
 cancer".)

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 2989 Version 31.0
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 GRAPHICS

Bladder cancer TNM staging AJCC UICC 8th edition

Primary tumor (T)

T category T criteria

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Ta Noninvasive papillary carcinoma

Tis Urothelial carcinoma in situ: "Flat tumor"

T1 Tumor invades lamina propria (subepithelial connective tissue)

T2 Tumor invades muscularis propria

pT2a Tumor invades superficial muscularis propria (inner half)

pT2b Tumor invades deep muscularis propria (outer half)

T3 Tumor invades perivesical soft tissue

pT3a Microscopically

pT3b Macroscopically (extravesical mass)

T4 Extravesical tumor directly invades any of the following: Prostatic

stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall

T4a Extravesical tumor invades directly into prostatic stroma, seminal

vesicles, uterus, vagina

T4b Extravesical tumor invades pelvic wall, abdominal wall

Regional lymph nodes (N)

N category N criteria

NX Lymph nodes cannot be assessed

N0 No lymph node metastasis

N1 Single regional lymph node metastasis in the true pelvis (perivesical,

obturator, internal and external iliac, or sacral lymph node)

N2 Multiple regional lymph node metastasis in the true pelvis

(perivesical, obturator, internal and external iliac, or sacral lymph
node metastasis)
:
 N3 Lymph node metastasis to the common iliac lymph nodes

Distant metastasis (M)

M category M criteria

M0 No distant metastasis

M1 Distant metastasis

M1a Distant metastasis limited to lymph nodes beyond the common iliacs

M1b Non-lymph-node distant metastases

Prognostic stage groups

When T is... And N is... And M is... Then the stage
group is...

Ta N0 M0 0a

Tis N0 M0 0is

T1 N0 M0 I

T2a N0 M0 II

T2b N0 M0 II

T3a, T3b, T4a N0 M0 IIIA

T1-T4a N1 M0 IIIA

T1-T4a N2, N3 M0 IIIB

T4b Any N M0 IVA

Any T Any N M1a IVA

Any T Any N M1b IVB

TNM: tumor, node, metastasis; AJCC: American Joint Committee on Cancer; UICC: Union for
International Cancer Control.

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International
Publishing. Corrected at 4th printing, 2018.

Graphic 110763 Version 8.0

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 Locally advanced bladder cancer

CT scan images of the abdomen (A) and pelvis (B) demonstrating a locally
advanced bladder tumor (arrows, right panels) and obstructing both ureters
(arrowheads, left panel).

Courtesy of Machele Donat, MD.

Graphic 52521 Version 3.0

:
 Characteristics of bladder cancer on IVP

Intravenous pyelogram (IVP) study, which demonstrates a bladder tumor

(arrows) on the cystogram (panel A) and postvoid phases (panel B).

Courtesy of Machele Donat, MD.

Graphic 68718 Version 2.0

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 IVP findings with ureteral tumor

Intravenous pyelogram (IVP) demonstrating a distal left ureteral tumor,

causing stenosis (arrows) and mild ureteral obstruction.

Courtesy of Machele Donat, MD.

Graphic 75824 Version 2.0

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 Contributor Disclosures
Yair Lotan, MD Equity Ownership/Stock Options: Vessi Medical; CAPs Medical; C2I Genomics
[Bladder cancer]. Grant/Research/Clinical Trial Support: Abbott [Bladder cancer]; MDxHealth
[Bladder cancer]; Cepheid [Bladder cancer]; Pacific Edge Bladder cancer [Bladder cancer];
Genomedx [Bladder cancer]; Stor [Bladder cancer]z; FKD [Bladder cancer]. Consultant/Advisory
Boards: Cepheid [Bladder cancer]; Pacific Edge Bladder cancer [Bladder cancer]; Photocure
[Cystoscopy]; AstraZeneca [Bladder cancer]; Merck [Bladder cancer]; Fergene [Bladder cancer];
Ferring Research [Bladder cancer]; BMS [Bladder cancer]; AbbVie [Bladder cancer]; Seattle
Genetics [Bladder cancer]; Hitachi [Bladder cancer]; Verity Pharmaceuticals [Bladder cancer];
Virtuouso Surgical [Bladder cancer]. Toni K Choueiri, MD Equity Ownership/Stock Options:
Pionyr [Oncology]; Tempest [Oncology]; Osel [Oncology]. Grant/Research/Clinical Trial Support:
BMS [Oncology]; Pfizer [Genitourinary cancer]; Exelixis [Genitourinary cancer]; Roche
[Genitourinary cancer]; Eisai [Genitourinary cancer]; Merck [Genitourinary cancer]; AstraZeneca
[Genitourinary cancer]; Novartis [Genitourinary cancer]. Consultant/Advisory Boards: Pfizer
[Genitourinary cancer]; Bristol-Myers Squibb [Genitourinary cancer]; Merck [Genitourinary
cancer]; Novartis/GlaxoSmithKline [Genitourinary cancer]; Exelixis/Ipsen [Genitourinary cancer];
Eisai [Genitourinary cancer]; EMD Serono [Genitourinary cancer]; Lilly Oncology [Genitourinary
cancer]; Infinity [Genitourinary cancer]; IQVA [Genitourinary cancer]; Calithera [Genitourinary
cancer]; Surface Oncology [Genitourinary cancer]; Janssen [Genitourinary cancer]; Aveo
[Genitourinary cancer]. Other Financial Interest: KidneyCan [Board of Directors, unpaid]; Aravive
[member of DMC]. Seth P Lerner, MD Equity Ownership/Stock Options: C2i Genomics [Bladder
cancer]. Patent Holder: Broad Institute [Bladder cancer]. Grant/Research/Clinical Trial Support:
Endo [Bladder cancer]; FKD [Bladder cancer]; JBL [Bladder cancer]; Genentech [Bladder cancer];
QED Therapeutics [Bladder cancer]; Vaxiion [Bladder cancer]; Viventia [Bladder cancer]; UroGen
[Bladder cancer]. Consultant/Advisory Boards: Aura Bioscience [Bladder and upper urinary tract
cancers]; C2i Genomics [Bladder and upper urinary tract cancers]; UroGen [Bladder and upper
urinary tract cancers]; Vaxiion [Bladder cancer]; QED Therapeutics [Bladder cancer]; Ferring
[Bladder cancer]; Verity [Bladder cancer]; Merck [Bladder cancer]; Genentech [Bladder cancer];
Pfizer [Bladder cancer]; FerGene [Bladder cancer]; Astra Zeneca [Bladder cancer]. Other
Financial Interest: Grand Rounds Urology [Speaker honoraria]; Ology; UroToday; Co-Editor
Bladder Cancer Research Journal. Sonali Shah, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements
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