Bladder carcinoma

I. What every physician needs to know.

Bladder cancer is the most common malignancy of the genitourinary system. More than 90% of incident cases in the United States (US) are transitional cell carcinoma (TCC) now known as urothelial carcinoma (UC).

A strong correlation exists between environmental exposure, advancing age and urothelial carcinoma. However, despite a continued rise in incidence of the disease, there has been a decrease in bladder cancer mortality thought to be due to decrease in smoking, healthier lifestyles and changes in environmental carcinogens. Clear links have been established between the development of bladder carcinoma and exposure to multiple different environmental factors. The most common include known carcinogens in tobacco, industrial chemicals, ionizing radiation, and chemotherapeutic drugs.

Squamous cell carcinoma (SCC) of the bladder is most prevalent in Egypt because of endemic infections by Schistosoma species and renders a higher mortality rate in that population due to its aggressive nature. Unless otherwise specified, the bladder carcinoma referred to in this chapter will be TCC, also known as urothelial carcinoma.

Painless hematuria is the most common presenting symptom of bladder cancer (occurring in approximately 85% of diagnosed cases). Both microscopic and macroscopic hematuria secondary to bladder cancer are intermittent in nature, therefore, even one episode of hematuria warrants urologic evaluation. Note that complete evaluation for source of hematuria includes cystoscopy which evaluates the “lower” genito-urinary tract and computed tomography (CT) urogram which assesses the “upper” tract (ureters and kidneys).

Diagnostic confirmation of bladder carcinoma via cystoscopy and biopsy is critical to determining ultimate treatment algorithm.

Bladder carcinoma is staged via the tumor, lymph node, metastasis (TNM) staging system. There is a high degree of correlation between tumor grade and stage, with higher-grade tumors having a higher likelihood of being invasive. The majority (about 80%) of patients presenting with bladder cancer have tumor involving only the surface of the internal bladder lining (Ta and T1). These types of “superficial” tumors are typically low grade and tend to recur over time, but typically do not invade into the deeper muscular layers of the bladder wall. They are usually treated with transurethral resection and, in some instances, intravesical chemo- or immunotherapy. Invasive carcinoma (T2 and greater) is managed by extirpative surgical resection via radical cystectomy and urinary diversion. Alternatively, platinum based neoadjuvant chemotherapy followed by surgical resection is also done.

Radical cystectomy is a major surgical procedure with significant perioperative morbidity. The pelvic lymph nodes are removed along with the bladder and prostate (in males) and uterus, cervix, ovaries, and fallopian tubes (in females). The risks of the procedure include erectile dysfunction (for men), bleeding requiring blood transfusion, infection, and damage to the rectum or other surrounding structures. In cases of non-organ confined disease, platinum base adjuvant chemotherapy has been shown to provide survival advantage.

Intravesical therapy usually involves BCG (Bacillus Calmette-Guerin). It is utilized for higher risk tumors and is associated with reduced risk of recurrence. Side effects include cystitis, dysuria, hematuria, malaise, low grade fevers. Immunocompromised state precludes use of BCG and Mitomycin is an alternative in some cases. Systemic chemotherapy is usually platinum based.

II. Diagnostic Confirmation: Are you sure your patient has bladder carcinoma?

Microscopic and gross hematuria as well as incidental findings on CT scan (mass, bladder wall thickening) may all be associated with bladder carcinoma. All of these findings warrant urologic referral for cystoscopic examination, upper tract imaging if needed, and urine cytology.

Cystoscopy and direct visualization with concomitant biopsy is the gold standard for diagnostic confirmation. A flexible cystoscopy can be performed at the bedside or in a cystoscopy suite without the need for general anesthetic. This affords a complete view of the bladder mucosa under appropriate conditions. Only minor instrumentation (biopsy, local fulguration) can be performed through a flexible cystoscope.

Rigid cystoscopy is performed in the operating room under anesthesia and affords the urologist multiple options for instrumentation, including biopsy and/or complete resection of suspected tumors.

Urine cytology detects morphologic changes associated with bladder cancer. It has high specificity (96%) and variable sensitivity which increases for high-grade tumors (50%). Fifteen per cent of patients with atypical cytology (not diagnostic of bladder cancer) have a malignancy and hence require further evaluation. Cytology has been shown to not be a cost-effective means of screening a population for bladder cancer.

A. History Part I: Pattern Recognition:

The most common presenting symptom of bladder cancer is painless hematuria (85% of patients). Therefore, any evidence of spontaneous hematuria, gross or microscopic, warrants cystoscopy. The threshold for cystoscopy should be even lower in patients older than 60 or anyone with a history of smoking or exposure to known carcinogens.

The second most common presentation of a patient with bladder carcinoma is that of a symptom complex of bladder irritability, urinary frequency, urgency, and dysuria. This symptom complex is more commonly associated with carcinoma in situ (CIS). These symptoms also rarely occur without microscopic hematuria.

Other (later stage) clinical symptoms can include lower extremity edema (lymphatic obstruction), flank pain (ureteral obstruction) and palpable pelvic mass. Nearly all patients will present with symptoms before the archetypal late stage cancer symptoms (unintentional weight loss, cachexia, bone pain).

A typical patient with this disease will be a man in his 60s with a long history of smoking cigarettes (many quit “several years ago”) and was told by his family physician that he had “some blood show up on his urinalysis”. His age and high likelihood of concomitant symptoms of benign prostatic hyperplasia (BPH) make it very important to distinguish the classic obstructive symptoms of BPH (weak stream, hesitancy, intermittency, nocturia) from irritative voiding symptoms (frequency, urgency, dysuria), which are associated with the high grade CIS.

B. History Part 2: Epidemiology

Bladder carcinoma is the 4^th most common cancer in males and 7^th most common cancer in females. It is approximately twice as common in white men as opposed to African-American men and one and one-half times as common in white women as opposed to African-American women. The overall incidence of bladder carcinoma increases directly with age and median age at diagnosis is 70 years.

The largest risk factors in the development of bladder carcinoma are carcinogen environmental exposures. The single greatest risk factor is tobacco exposure, which confers an approximate 2-4 increase in the risk of developing bladder cancer. Latency from exposure is estimated at 20 years and smoking cessation does reduce risk profile. It is important to ask about occupational exposure as certain populations are at risk (such as painters, leather, chemical and metal workers, dry cleaners, truck drivers, hairdressers). Both cyclophospamide and ifosfamide are risk factors with or without the known side effect of hemorraghic cystitis. Pelvic irradiation (such as external beam radiation therapy used to treat prostate cancer) confers an increased risk as well. Indwelling catheters and bladder calculi increase risk for squamous cell carcinoma.

C. History Part 3: Competing diagnoses that can mimic bladder carcinoma.

As the most common presenting symptom of bladder carcinoma is painless hematuria, any disease process that causes hematuria can mimic the disease. Most common amongst these are urinary tract infections and kidney stones, or primary neoplasm elsewhere in the genito-urinary tract. A history of trauma and any recent instrumentation should be elicited. In females, endometriosis should be considered. Rheumatologic causes such as Goodpasture syndrome, immunoglobulin A (IgA) nephropathy and glomerular diseases are possible.

D. Physical Examination Findings.

By the time bladder carcinoma becomes physically evident on physical examination it is at an advanced stage. At that point, a palpable (hard) tumor mass may be palpable on rectal examination, perineal exam, abdominal exam, or in a woman on routine vaginal examination. Notably, the urologist does perform bimanual examination under anesthesia in the operating room before and after a transurethral resection of a bladder tumor for complete clinical staging.

E. What diagnostic tests should be performed?

The diagnostic work-up for possible bladder carcinoma is usually completed by the urologist once hematuria has been detected or irritating voiding symptoms occur. However, in a patient with hematuria and adequate renal function an upper tract evaluation will be needed as well, therefore CT-IV pyelogram (CT abdomen and pelvis with and without IV contrast in addition to delayed sequence imaging) may be a useful study prior to the patient presenting for cystoscopy. CT (with and without intravenous (IV) contrast) has largely replaced excretory urography as a radiologic modality for evaluation of hematuria but it still lacks the sensitivity and specificity of cystoscopy in lower tract evaluation. It is useful in evaluation for possible metastatic work-up if T2 or greater disease is suspected/confirmed. Urine cytology has poor sensitivity and good specificity in cases of a definitively positive result. Defer ordering of urine cytology to a urologist as it is mostly done on specimens obtained during cystoscopy which increases yield. Nuclear matrix protein 22 (NMP22) is a point of care assay to be used by urologists in conjunction with cystoscopy only, as there are many nuances to its use and interpretation. With bladder biopsy/bladder tumor resection, transurethral resection of a bladder tumor can be both diagnostic and therapeutic.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Check a urinalysis if there is concern for an ongoing bladder infection leading to hematuria. If suspicious for infection, check a reflex culture and consider appropriate antimicrobial therapy.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Upper tract imaging is addressed above.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Urine cytology or NMP22 sent at inappropriate times or from inappropriate samples will have a high rate of false positive results.

Bladder ultrasound is inadequate for evaluation.

III. Default Management.

If hematuria (microscopic or gross) is appreciated, refer to a urologist. Presence of urinary infection does not preclude urologic evaluation. Depending on a patient’s risk factors for bladder carcinoma, further evaluation may still need to be pursued.

A. Immediate management.

If a patient is having gross hematuria and is hemodynamically stable, they may be seen with prompt outpatient urologic consultation. If a patient is hemodynamically unstable, clinically symptomatic or having episodes of clot retention he or she needs to be seen by a urologist immediately for evaluation. Typically, bleeding that is significant enough to cause acute blood loss anemia will result in clot retention, necessitating urologic intervention for Foley placement and bladder irrigation.

B. Physical Examination Tips to Guide Management.

Findings of a bladder tumor on physical exam are quite rare and typically indicative of a highly advanced disease stage.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Response to treatment of localized bladder carcinoma requires direct visualization with cystoscopy. The frequency of this surveillance is dependent on multiple variables about the patient’s pathology, but will likely never be less frequent than annual. Any “new patients” with history of “bladder cancer” therefore require urologic referral for surveillance cystoscopy at a minimum.

Post cystectomy surveillance does require cross-sectional imaging for a defined period of time, but will likely be ordered by the urologist who performed the procedure.

Notably, any patient who has previously received a urinary diversion requires lifelong surveillance of the upper tracts with both imaging and creatinine as these patients have an increased risk of renal dysfunction over time.

D. Long-term management.

Confirm that any patient with a history of bladder carcinoma of any type is followed by a urologist. Patients with metastatic bladder carcinoma also need evaluation by and follow-up with a medical oncologist for consideration of systemic combination chemotherapy.

E. Common Pitfalls and Side-Effects of Management.

A common pitfall in the work-up for bladder carcinoma is missed diagnosis. Any episode of gross hematuria requires a full urologic hematuria work-up. A common missed presentation of bladder cancer is that of a patient with one episode of gross hematuria who is diagnosed with a kidney stone or urinary tract infection. Successful treatment of the kidney stone does not preclude the patient from the full hematuria work-up. Urologic evaluation should still be sought in patients who have been treated for urinary infection and concurrent hematuria as they may require surveillance urinanalysis or thorough hematuria evaluation.

Urinary intestinal diversion performed as part of surgical treatment for bladder cancer may result in metabolic complications due to altered solute absorption across the intestinal segment. These include electrolyte abnormalities (vary depending on which segment of bowel is used), altered sensorium, abnormal drug metabolism, osteomalacia, and formation of renal calculi.

IV. Management with Co-Morbidities.

Due to the high perioperative morbidity associated with radical cystectomy done for invasive bladder cancer, patients being considered for it require a thorough pre-operative evaluation. If a patient is not a surgical candidate (due to comorbidities, poor functional status rendering high surgical risk) he/she should be considered for systemic chemotherapy and radiation. Evaluation with a medical oncologist preferably with expertise in genitourinary cancers should be arranged.

A. Renal Insufficiency.

Renal insufficiency does not preclude patients from the treatment of bladder carcinoma, but it does limit the options for urinary diversion. Patients with compromised glomerular filtration rate (GFR) cannot receive a continent diversion/neobladder after cystectomy. The diversion of choice in these patients is an ileal conduit. Abnormal renal function also precludes use of Cisplatin-based chemotherapy regimens.

B. Liver Insufficiency.

No change in standard management though extent of liver disease (such as underlying cirrhosis) renders higher preoperative risk.

C. Systolic and Diastolic Heart Failure.

No change in standard management though severity of cardiac illness may impact preoperative surgical risk.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

If a second malignancy is present, overall prognosis should be considered prior to invasive or high risk procedures. Due to the complexity of the situation, multidisciplinary evaluation by a medical oncologist and urologist and sometimes radiation oncologist is required.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients with severe immunosuppression cannot receive intravesicular Bacillus Calmette-Guerin (BCG).

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management other than potential for affecting preoperative risk depending on severity of lung disease.

I. Gastrointestinal or Nutrition Issues.

No change in standard management. Close monitoring for metabolic abnormalities will be needed after urinary diversion.

J. Hematologic or Coagulation Issues.

Coagulopathy requires reversal/treatment for any major surgical interventions.

K. Dementia or Psychiatric Illness/Treatment.

Patients without a high level of autonomous function should not receive continent/catheterizable neobladders after cystectomy and instead should be diverted with an ileal conduit.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Hematuria is not an emergency, unless the patient is actively in clot retention or is there is a concern that is resulting in acute blood loss anemia. If noted during hospitalization, evaluation by the Urology service is warranted depending on the extent of hematuria, comorbidities, and need for bladder irrigation.

B. Anticipated Length of Stay.

N/A

C. When is the Patient Ready for Discharge.

A patient is ready for discharge when they are voiding spontaneously and clinic/outpatient follow-up for a full hematuria work-up has been definitively scheduled.

D. Arranging for Clinic Follow-up.

Hematuria (i.e. rule out bladder carcinoma) requires a cystoscopy to evaluate the lower tract and some form of upper tract cross-sectional imaging. Your urologist should be able to schedule both of these for your patient.

1. When should clinic follow up be arranged and with whom.

As soon as possible with a urologist.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

It is very helpful to the consulting urologist if the upper tract cross-sectional imaging is complete at the time of the clinic follow-up. In a patient with adequate GFR (more than 50 milliliters/minute) a CT scan of the abdomen/pelvis with and without IV contrast with an added delayed series will be adequate. At many medical centers, this is called a “CT-IV pyelogram” or a “CT-Urogram”.

This allows the urologist to perform the cystoscopy (lower tract evaluation) at the first clinic visit and further streamline the patient’s consultation. If any doubt exists as to what cross-sectional imaging is needed for the upper tract evaluation, the patient should be sent for consultation.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

See above.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

The most important prognostic indicator of bladder carcinoma is staging. This will be determined at the time of transurethral resection of a bladder tumor. Low stage disease is associated with a significantly improved prognosis in comparison to high stage disease. Prognostic survival related details are typically discussed with the patient at the time of discussion of surgical pathology.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Smoking is a significant risk factor for the development of all urothelial carcinomas, including carcinoma of the bladder. Indwelling foley catheterization (more than 3 years) has been associated with squamous cell carcinoma of the bladder.

VII. What’s the evidence?

Messing, EM, Wein. “Urothelial Tumors of the Bladder”. . 2007. pp. 2407-2446.

Jones, JS, Campbell, SC, Wein. “Non-Muscle-Invasive Bladder Cancer (Ta, T1, and CIS)”. . 2007. pp. 2447-2467.

Schoenberg, MP, Gonzalgo, ML, Wein. “Management of Invasive and Metastatic Bladder Cancer”. . 2007. pp. 2468-2478.

Malkowicz, SB, Vaughn, DJ, Wein, AJ, Hanno, PM. “Adult Genitourinary Cancer-Prostate and Bladder”. . 2007. pp. 523-570.

Wieder, JA, Wieder, JA. “Bladder Tumors”. . 2010. pp. 35-55.

David, P, Wood, Jr, Wein. “Urothelial Tumors of the Bladder”. Campbell-Walsh Urolog.

Stephen Jones, J, Larchian, William A, Wein. “Non-muscle-invasive Bladder Cancer (Ta, T1, and CIS)”. Campbell-Walsk Urolog.

Lerner, Seth P., Stemberg, Cora N., Wein. “Management of Metastatic and Invasive Bladder Cancer”. Campbell-Walsk Urolog.

Young, Matthew A, Prasad, Sandip M., Gomella, Leornard G.. “Bladder Cancer, General”. The 5-Minute Urology Consult.

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