Approach

Bladder cancer most commonly presents hematuria (visible or nonvisible).[47] Cancer-related hematuria is characteristically intermittent. Urologic evaluation is required in all adults with visible (gross or macroscopic) hematuria and should be considered in adults nonvisible (microscopically confirmed) hematuria in the absence of some demonstrable benign cause.[48]​ Awaiting confirmation of nonvisible hematuria on repeated samples (if potential precipitating causes have been excluded) before more extensive evaluation risks missing clinically significant cancers.[49]

All patients suspected of having bladder cancer require a thorough history and physical exam, although the exam is often unremarkable, particularly in patients with early disease.[40]

Evaluation of nonvisible hematuria

Nonvisible hematuria, defined as ≥3 red blood cells (RBCs) per high-power field, is a common presentation of bladder cancer.[49]​ Screening for nonvisible hematuria in populations at risk, combined with appropriate evaluation, improves survival.[18][50]​​​ In general, the threshold for cytology and cystoscopy should be low in the absence of a clear cause and complete resolution of hematuria.

The American Urological Association recommends evaluation according to risk of urological cancer.[51] 

Low-risk patients meet all of the following criteria:

  • Women ages <50 years, men ages <40 years

  • Never smoker or <10 pack years

  • 3-10 RBC per high-power field on a single urine microscopy

  • No risk factors for urothelial cancer (risk factors include persistent microhematuria, gross hematuria).

Intermediate-risk patients meet one of the following criteria:

  • Women ages 50-59 years, men ages 40-59 years

  • 10-30 pack year smoking history

  • 11-25 RBC per high-power field on a single urine microscopy

  • Low-risk patient with no prior evaluation and 3-10 RBC per high-power field on repeat urine microscopy

  • Additional risk factor for urothelial cancer (additional risk factors include irritative lower urinary tract symptoms, prior pelvic radiation therapy, prior cyclophosphamide/ifosfamide chemotherapy, family history of urothelial cancer, family history of Lynch syndrome, occupational exposure to aromatic amines or benzene chemicals, chronic indwelling foreign body in the urinary tract).

High-risk patients are defined as:

  • Women and men ages ≥60 years

  • >30 pack year smoking history

  • >25 RBC per high-power field on a single urine microscopy

  • History of gross hematuria

For low-risk patients, urine microscopy may be repeated in 6 months or the urinary tract may be investigated with renal ultrasound and cystoscopy. If microhematuria persists on repeat testing, the patient is reclassified as intermediate or high risk. Intermediate-risk patients should be offered renal ultrasound and cystoscopy. High-risk patients should be offered axial renal imaging, ideally with computed tomography (CT) urography, and cystoscopy.[51] Ultrasound has the advantage of avoiding radiation exposure, but provides less detail than CT urogram.

Repeat urinalysis within 12 months should be considered for patients whose workup produces a negative result. A positive repeat urinalysis should prompt shared-decision-making regarding repeat evaluation or observation.[51]

See Evaluation of non-visible hematuria.​

Evaluation of visible hematuria

All patients with visible blood in the urine require investigation, even when related to overanticoagulation. Complete spontaneous cessation of bleeding does not exclude the possibility of life-threatening malignancy.

Symptoms guide the workup: renal colic should prompt imaging studies with CT or plain x-rays for stone disease; acute onset of frequency and dysuria should prompt urine culture (with antibiotic treatment if indicated). Failure to confirm either of these diagnoses should result in evaluation for bladder cancer with urinalysis, urine cytology, and cystoscopy. CT or magnetic resonance (MR) urography is used to evaluate upper tracts and, like bladder ultrasonography, these tests can demonstrate the presence of bladder cancer in many instances.[40][52]​​​ However, the sensitivity of these tests is insufficient to exclude the diagnosis, particularly of carcinoma in situ, so cystoscopy is still required.[47]

See Evaluation of visible hematuria.​

Evaluation of irritative voiding symptoms

Urinary frequency as the sole symptom of bladder cancer is rare, but does occur. Benign prostatic hypertrophy and overactive bladder are more common causes, but if these are not identified and/or do not respond to treatment, urinary cytology and cystoscopy are indicated.

Burning with urination can occur with carcinoma in situ and high-grade bladder cancer.​[53]​​​​​ However, risk of bladder or urinary tract cancer in a patient (≥60 years) presenting with dysuria (in the absence of visible hematuria) is low.[54][55]​​ Common causes of dysuria (e.g., urinary tract infection, prostatitis) should be excluded. See Evaluation of dysuria.

UK guidelines recommend an urgent specialist referral for patients ages ≥60 years who have unexplained nonvisible hematuria and dysuria.[56]

Cystoscopy and upper tract imaging

Cystoscopy is key to making the diagnosis.[40][47][53]​​​​​​ Low-grade tumors are papillary and easy to visualize, but high-grade tumors can be papillary, flat, or in situ and difficult to visualize with white light. Visualization at cystoscopy may be improved by narrow-band imaging or blue light (fluorescence) cystoscopy in addition to white light; both appear to improve diagnostic accuracy compared with white light alone.[40][43][57]​​​​[58]

If a patient undergoes cystoscopy and a lesion suspicious of a urothelial bladder tumor is identified, the patient should be scheduled for TURBT, which will allow the diagnosis to be confirmed pathologically and the extent of the disease to be assessed.

  • Features suggestive of noninvasive (Ta) disease include papillary tumors having a narrow stalk. Invasive tumors more commonly have a thick stalk or solid configuration. Rough erythematous patches can be indicative of Tis (carcinoma in situ), although urothelium often appears normal. Random biopsies or biopsy of areas positive on blue light or narrow band cystoscopy are needed to properly diagnose Tis.[59]

  • Features suggestive of muscle-invasive (T2) disease include multifocal tumors that are sessile. Vascularity around the tumor is increased. Tumors are often large (>3 cm in diameter), solid, or sessile. Bimanual exam may reveal the mass to extend beyond the bladder (T3-4).

All patients with suspicious lesions detected at cystoscopy should undergo imaging of the upper tract collecting system if they have not already done so. This serves to identify nodal metastasis and obstruction (hydronephrosis).[40] CT urography, which images the urinary tract with contrast during the excretory phase, is the preferred modality.

MR urography is an alternative if CT with contrast is contraindicated. Renal ultrasound with retrograde pyelogram is an alternative third-line option for patients if CT and MRI are contraindicated or unavailable.[40][43][51]​ Imaging may be obtained before or after TURBT, but the National Comprehensive Cancer Network (NCCN) guideline recommends CT or MRI before resection if possible.[43] 

[Figure caption and citation for the preceding image starts]: Low-grade, noninvasive (Ta) papillary urothelial carcinoma. Note adjacent satellite tumor, illustrating the field effectFrom the collection of Donald Lamm, MD, FACS [Citation ends].com.bmj.content.model.Caption@5d188dfd[Figure caption and citation for the preceding image starts]: Low-grade urothelial carcinoma seeding in the prostatic urethra; illustrated is the loop electrode used to resect bladder tumorsFrom the collection of Donald Lamm, MD, FACS [Citation ends].com.bmj.content.model.Caption@445041f2[Figure caption and citation for the preceding image starts]: Low-grade tumors surrounded by small satellite tumors with small, uniform fronds. In the foreground is a solid tumor on a broad base, a typical appearance of high-grade tumors. Low- and high-grade tumors often occur in the same patientFrom the collection of Donald Lamm, MD, FACS [Citation ends].com.bmj.content.model.Caption@69d5e267[Figure caption and citation for the preceding image starts]: Methylene blue-stained tumor at the right bladder neck. Staining with 0.2% methylene blue (or use of the now Food and Drug Administration-approved hexaminolevulinate blue-light fluorescence cystoscopy) can help identify tumors not seen otherwiseFrom the collection of Donald Lamm, MD, FACS [Citation ends].com.bmj.content.model.Caption@50b8e92a[Figure caption and citation for the preceding image starts]: Carcinoma in situ of the bladder; this can appear as a rough, erythematous patch in the bladder, but often the urothelium appears normal; random biopsy or biopsy of areas stained by 0.2% methylene blue, illustrated here, is needed to make the diagnosisFrom the collection of Donald Lamm, MD, FACS [Citation ends].com.bmj.content.model.Caption@7b6ccc72

Transurethral resection of a bladder tumor (TURBT)

TURBT is both therapeutic and diagnostic. Initial resection allows pathologic confirmation of the diagnosis with assessment of histology, grade, and depth of invasion. Fragments must be of adequate size and depth to allow for a proper assessment of detrusor muscle invasion. Bimanual exam under anesthesia is performed at the time of TURBT to assess for a palpable mass or fixation to the pelvic wall.[53]​

Enhanced cystoscopy (narrow-band imaging or fluorescence) may improve detection of difficult-to-visualize lesions when used to guide TURBT.[40][43][60][61]​​​​​​[62]​​​​ Blue light (fluorescence) cystoscopy is preferred to guide TURBT because it reduces the risk of recurrence.[40][60][61]​​​ The evidence for reduced recurrence is less certain for narrow-band imaging cystoscopy.[40][61][62][63][64]

Multiple bladder biopsies can be done at the time of initial resection to detect carcinoma in situ, which may alter the treatment and increases the risk of upper tract and urethral carcinoma. Carcinoma of the prostatic urethra, if untreated, can progress to aggressive invasive disease. Early invasion of the prostate may be managed by transurethral resection of the prostate if the resection margins are free of disease, but deep invasion carries a poor prognosis even with radical cystectomy.

Guideline-directed risk stratification based on grade and stage determines further treatment after initial TURBT. Repeat resection or simultaneous resection of the prostate may be recommended for some patients to reduce the risk of recurrence. See Management approach.​

Further workup for muscle-invasive bladder cancer

Patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer should have a complete blood count, chemistry profile (including alkaline phosphatase), chest x-ray, and abdominal/pelvic CT or MRI.[43][65]​ ​MRI is considered the best modality for local staging of bladder cancer due to superior soft tissue contrast resolution compared with CT.[53][65]​​​​​​ One meta-analysis demonstrated that positron emission tomography (PET)/CT scan is useful in patients at high risk of metastatic disease (e.g., those with muscle invasion and lymphovascular invasion).[66]​ Another meta-analysis reported that CT, MRI, and PET/CT have similar specificities for detection of nodal metastasis, but MRI and PET/CT have superior sensitivity.[67]

Patients with symptoms or clinical suspicion of bone metastasis (e.g., bone pain or elevated alkaline phosphatase) should be evaluated with MRI, fluorodeoxyglucose-PET/CT, or a bone scan.[43][65]

Urine cytology and markers of bladder cancer

Cytology remains the standard and most accepted urinary marker for bladder cancer, but false-negatives are common.

Cytology is not routinely indicated for initial evaluation of hematuria.[51][68]​​​​​​ However, urine cytology has a high sensitivity for high-grade tumors and may be a useful adjunct for patients with irritative voiding symptoms or other risk factors for carcinoma in situ (e.g., smoking, exposure to chemicals, family history).[47][51]​ Urine cytology can also be used for posttreatment surveillance.[43][47]

The sensitivity of urine cytology for low-grade tumors is limited.[47][69]​​ Using the Paris System for Reporting Urinary Cytology (TPS) improves the screening and surveillance potential of urine cytology.[70]

Urine biomarkers for bladder cancer have increased sensitivity compared with urine cytology, but specificity is lower.[43][71]​ These biomarkers include bladder tumor antigen (BTA), nuclear matrix protein 22 (NMP22), ImmunoCyt/uCyt+ (a fluorescence immunocytologic diagnostic test using 3 tumor-related monoclonal antibodies), and UroVysion (a fluorescent in situ hybridization [FISH] of centromeres of chromosomes 3, 7, and 17 and to the 9p21 locus of chromosome 9 associated with bladder cancer).

Urine biomarkers for bladder cancer may help to determine the most appropriate frequency for follow-up cystoscopy and aid in the diagnosis of high-risk patients, but do not replace cystoscopy.[71]

UroVysion® FISH or ImmunoCyt™ may be useful if cytology results are atypical or equivocal cancer.[40] Persistence of positive UroVysion® FISH following intravesical BCG (in nonmuscle-invasive bladder cancer) suggests poor response and higher risk of progression.[40][72][73]​​​​

In a review of published series, sensitivity (SN) and specificity (SP) were as follows:[74]

  • Hematuria dipstick: 47% to 93% SN, 51% to 84% SP

  • Cytology: 12% to 85% SN, 78% to 100% SP

  • BTA Trak: 51% to 100% SN, 73% to 92% SP

  • NMP22 BladderChek: 50% to 65% SN, 40% to 90% SP

  • ImmunoCyt/uCyt+: 81% to 89% SN, 61% to 78% SP

  • UroVysion FISH: 69% to 100% SN, 65% to 96% SP.

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