Bladder Cancer

Overview

Bladder cancer is a disease in which malignant cells form in the tissues of the bladder, the hollow organ in the lower pelvis that stores urine. It is the fourth most common cancer in men and the ninth most common in women in the United States. The bladder has several layers of tissue, and most bladder cancers begin in the innermost lining called the urothelium or transitional epithelium.

The bladder's primary function is to store urine produced by the kidneys until it can be eliminated from the body. The bladder wall has several layers: the innermost urothelium, the lamina propria (connective tissue), the muscularis propria (muscle layer), and the outer fatty tissue. Understanding these layers is crucial because the depth of cancer invasion determines staging and treatment options.

Bladder cancer has a unique characteristic among cancers: it has a high recurrence rate, with up to 70% of patients experiencing tumor recurrence after initial treatment. However, most bladder cancers are diagnosed at an early stage when they are highly treatable. The 5-year survival rate for localized bladder cancer is approximately 70%, but this drops significantly for cancers that have spread to distant parts of the body.

One of the most important aspects of bladder cancer is its strong association with environmental and lifestyle factors, particularly smoking. This makes bladder cancer one of the most preventable cancers. Early detection through prompt evaluation of symptoms, particularly blood in the urine, is crucial for successful treatment outcomes.

Symptoms

Bladder cancer often presents with distinctive urinary symptoms, though early-stage disease may be asymptomatic. The most common and often earliest sign is blood in the urine, which should always prompt medical evaluation.

Additional Common Symptoms

• Urinary frequency: Need to urinate more often than usual
• Urinary urgency: Sudden, strong need to urinate immediately
• Dysuria: Pain or burning sensation during urination
• Pelvic pain: Discomfort in the lower abdomen or pelvis
• Back pain: May indicate kidney involvement or metastases
• Unintentional weight loss: Common in advanced disease
• Fatigue: Due to anemia from chronic blood loss or cancer
• Loss of appetite: Often accompanies advanced cancer
• Swelling in feet: May occur with lymphatic obstruction
• Bone pain: If cancer has spread to bones

Causes

Bladder cancer develops when cells in the bladder undergo genetic mutations that cause them to grow and divide uncontrollably. While the exact mechanisms aren't fully understood, several factors are known to damage bladder cell DNA and increase cancer risk.

Carcinogen Exposure

The bladder is particularly vulnerable to cancer-causing substances because it stores urine containing concentrated waste products and potential carcinogens for extended periods.

Tobacco Smoke

Smoking is the single most important risk factor for bladder cancer:

• Causes about half of all bladder cancers
• Tobacco smoke contains numerous carcinogens that are filtered by kidneys into urine
• Risk increases with duration and intensity of smoking
• Former smokers have lower risk than current smokers but higher than never-smokers

Occupational Chemical Exposure

Certain industrial chemicals are known bladder carcinogens:

• Aromatic amines: Used in dye, rubber, leather, and printing industries
• Polycyclic aromatic hydrocarbons: Found in coal tar, diesel exhaust
• Specific chemicals: Benzidine, beta-naphthylamine, 4-aminobiphenyl
• Risk may not appear until 10-50 years after exposure

Chronic Bladder Irritation

Long-term inflammation may increase cancer risk through:

• Chronic infections: Particularly with Schistosoma haematobium parasite
• Bladder stones: Chronic irritation from stones
• Indwelling catheters: Long-term catheter use
• Chronic cystitis: Repeated bladder infections

Medical Treatments

Certain cancer treatments increase bladder cancer risk:

• Cyclophosphamide: Chemotherapy drug that irritates bladder lining
• Pelvic radiation: For other cancers can damage bladder cells
• Pioglitazone: Diabetes medication linked to increased risk

Genetic Factors

While most bladder cancers are not inherited, genetic factors play a role:

• Mutations in genes like FGFR3, TP53, RB1
• Lynch syndrome increases risk
• Variations in genes that process carcinogens
• Family history doubles risk

Risk Factors

Understanding risk factors helps identify individuals who may benefit from enhanced surveillance and preventive measures. Multiple risk factors often interact to increase overall risk.

Medical Conditions That Increase Risk

• Chronic bladder infections: Especially with indwelling catheters
• Schistosomiasis: Parasitic infection common in Middle East and Africa
• Neurogenic bladder: From spinal cord injuries
• Lynch syndrome: Hereditary cancer syndrome
• Previous pelvic cancer: Treatment may damage bladder

Risk Assessment Tools

Healthcare providers may use risk calculators considering:

• Age and sex
• Smoking history (pack-years)
• Occupational exposures
• Family history
• Previous bladder conditions

Types of Bladder Cancer

Bladder cancer is classified based on the type of cell where cancer begins and how deeply it has invaded the bladder wall. Understanding these distinctions is crucial for treatment planning.

Classification by Cell Type

Urothelial Carcinoma (Transitional Cell Carcinoma)

• Accounts for 90-95% of bladder cancers in the United States
• Originates in urothelial cells lining the bladder
• Can occur anywhere in the urinary tract (renal pelvis, ureters, urethra)
• Subtypes include:
  • Papillary: Finger-like projections into bladder lumen
  • Flat: Grows along bladder wall
  • Mixed: Contains both patterns

Squamous Cell Carcinoma

• 1-2% of bladder cancers in the US; more common in areas with schistosomiasis
• Associated with chronic irritation and inflammation
• Often more aggressive than urothelial carcinoma
• Usually invasive at diagnosis

Adenocarcinoma

• 1-2% of bladder cancers
• Can be primary (arising in bladder) or secondary (spread from other organs)
• Primary types:
  • Urachal: From embryonic remnant
  • Non-urachal: From bladder glands

Small Cell Carcinoma

• Less than 1% of bladder cancers
• Highly aggressive neuroendocrine tumor
• Often presents with advanced disease
• Treated similarly to small cell lung cancer

Classification by Invasion Depth

Non-muscle Invasive Bladder Cancer (NMIBC)

• 75% of newly diagnosed cases
• Confined to inner layers (urothelium and lamina propria)
• Includes:
  • Ta: Papillary tumor confined to urothelium
  • Tis (CIS): Flat tumor in urothelium only
  • T1: Invades lamina propria but not muscle
• High recurrence rate but rarely life-threatening

Muscle Invasive Bladder Cancer (MIBC)

• 25% of newly diagnosed cases
• Invades muscle layer (T2) or beyond
• More aggressive with higher metastatic potential
• Requires aggressive treatment

Grade Classification

• Low-grade: Cells look more like normal cells, grow slowly
• High-grade: Cells look very abnormal, grow rapidly, more likely to invade

Diagnosis

Accurate diagnosis of bladder cancer requires a systematic approach combining various tests. Early and accurate diagnosis is crucial for optimal treatment outcomes.

Initial Evaluation

Medical History and Physical Examination

• Detailed symptom history, especially hematuria episodes
• Risk factor assessment (smoking, occupational exposures)
• Physical exam including abdominal and pelvic examination
• Digital rectal exam (men) or pelvic exam (women) for advanced disease

Urinalysis and Urine Tests

• Urinalysis: Detects blood, infection, abnormal cells
• Urine cytology: Examines cells for cancer; better for high-grade tumors
• Urine tumor markers:
  • BTA stat/BTA TRAK
  • NMP22
  • UroVysion FISH
  • Immunocyt

Imaging Studies

CT Urography

• Preferred imaging for complete urinary tract evaluation
• Detects tumors, stones, and other abnormalities
• Includes pre-contrast, nephrogenic, and excretory phases

Other Imaging Options

• MRI: Alternative when CT contraindicated
• Ultrasound: Can detect larger tumors, hydronephrosis
• Retrograde pyelography: If upper tract needs evaluation
• Chest X-ray or CT: Staging for metastatic disease

Cystoscopy

The gold standard for bladder cancer diagnosis:

• Flexible cystoscopy: Office procedure for initial evaluation
• Rigid cystoscopy: Under anesthesia for biopsy/treatment
• Blue light cystoscopy: Uses photosensitizer to enhance tumor detection
• Narrow band imaging: Enhances visualization of blood vessels

Tissue Diagnosis

Transurethral Resection of Bladder Tumor (TURBT)

• Both diagnostic and therapeutic procedure
• Complete resection of visible tumor
• Sampling of muscle layer crucial for staging
• Random biopsies if CIS suspected
• Prostatic urethral biopsy in certain cases

Pathology Evaluation

• Tumor type and grade
• Presence of muscle in specimen
• Depth of invasion
• Presence of carcinoma in situ
• Lymphovascular invasion

Staging Workup

For muscle-invasive disease:

• CT chest/abdomen/pelvis or PET/CT
• Bone scan if symptoms suggest metastases
• MRI for local staging in select cases
• Laboratory tests: CBC, comprehensive metabolic panel, alkaline phosphatase

Staging

Bladder cancer staging describes the extent of cancer spread and is crucial for treatment planning and prognosis. The TNM system is universally used.

TNM Classification

T (Primary Tumor)

N (Regional Lymph Nodes)

• N0: No regional lymph node metastasis
• N1: Single regional lymph node in pelvis
• N2: Multiple regional lymph nodes in pelvis
• N3: Common iliac lymph node metastasis

M (Distant Metastasis)

• M0: No distant metastasis
• M1a: Non-regional lymph nodes
• M1b: Other distant metastasis

Stage Groupings

• Stage 0a: Ta, N0, M0
• Stage 0is: Tis, N0, M0
• Stage I: T1, N0, M0
• Stage II: T2a or T2b, N0, M0
• Stage III: T3a, T3b, or T4a, N0, M0
• Stage IV: T4b, any N, M0; or any T, N1-3, M0; or any T, any N, M1

Risk Stratification for Non-muscle Invasive Disease

Low Risk

• Solitary Ta low-grade tumor <3 cm
• No CIS

Intermediate Risk

• Multiple or recurrent Ta low-grade tumors
• Solitary Ta low-grade >3 cm

High Risk

• Any T1 tumor
• Any high-grade tumor
• CIS
• Multiple, recurrent, large Ta low-grade tumors

Very High Risk

• T1 high-grade with additional risk factors
• Variant histology
• Lymphovascular invasion
• Prostatic urethral involvement

Treatment Options

Treatment depends on cancer stage, grade, patient health, and preferences. The approach differs significantly between non-muscle invasive and muscle-invasive disease.

Non-muscle Invasive Bladder Cancer (NMIBC)

Transurethral Resection (TURBT)

• First-line treatment for all NMIBC
• Complete visible tumor removal
• Re-resection within 2-6 weeks for T1 or high-grade tumors
• Enhanced techniques: Blue light, narrow band imaging

Intravesical Therapy

BCG-Unresponsive Disease Options

• Pembrolizumab (FDA-approved immunotherapy)
• Clinical trials with novel agents
• Radical cystectomy
• Combination intravesical therapies

Muscle Invasive Bladder Cancer (MIBC)

Neoadjuvant Chemotherapy

• Cisplatin-based combinations (MVAC, GC)
• Improves survival by 5-8%
• Recommended for T2-T4a, N0 disease
• Requires adequate renal function

Radical Cystectomy

• Gold standard for muscle-invasive disease
• Removal of bladder, nearby organs, lymph nodes
• Men: Prostate, seminal vesicles
• Women: Uterus, ovaries, anterior vaginal wall
• Urinary diversion required:
  • Ileal conduit (urostomy)
  • Continent cutaneous diversion
  • Orthotopic neobladder

Bladder Preservation (Trimodality Therapy)

• For selected patients who refuse or cannot undergo cystectomy
• Maximal TURBT
• Concurrent chemotherapy and radiation
• Close surveillance with salvage cystectomy if needed
• 5-year survival similar to cystectomy in appropriate patients

Advanced and Metastatic Disease

First-line Systemic Therapy

• Cisplatin-eligible: Gemcitabine + cisplatin or MVAC
• Cisplatin-ineligible: Gemcitabine + carboplatin or immunotherapy
• Maintenance therapy: Avelumab for responders

Second-line and Beyond

• Immunotherapy: Pembrolizumab, atezolizumab, nivolumab
• Antibody-drug conjugates: Enfortumab vedotin, sacituzumab govitecan
• FGFR inhibitors: Erdafitinib for FGFR alterations
• Clinical trials

Supportive Care

• Pain management
• Nutritional support
• Management of treatment side effects
• Psychological support
• Palliative care for quality of life
• Survivorship programs

Prevention

While not all bladder cancers can be prevented, many cases could be avoided by addressing modifiable risk factors.

Primary Prevention

Smoking Cessation

• Most important preventive measure
• Risk decreases after quitting but remains elevated for years
• Resources: Counseling, nicotine replacement, medications
• Benefits extend beyond bladder cancer prevention

Occupational Safety

• Follow safety protocols when handling chemicals
• Use protective equipment (gloves, masks, ventilation)
• Regular health screenings for at-risk workers
• Know your workplace chemical exposures

Lifestyle Factors

• Hydration: Drink plenty of fluids to dilute urine
• Diet: Eat fruits and vegetables rich in antioxidants
• Limit processed meats: May contain carcinogenic compounds
• Avoid aristolochic acid: Found in some herbal remedies

Secondary Prevention (Early Detection)

High-Risk Screening

Consider screening for:

• Heavy smokers (>40 pack-years) over age 50
• Occupational chemical exposure history
• Previous bladder cancer
• Certain genetic syndromes

Hematuria Evaluation

• Never ignore blood in urine
• Complete evaluation even if bleeding stops
• Annual urinalysis for high-risk individuals

Chemoprevention

Under investigation but not yet standard:

• Vitamins and supplements (limited evidence)
• NSAIDs (potential benefit, risks must be weighed)
• Statins (observational studies suggest benefit)

Prevention of Recurrence

• Comply with surveillance schedule
• Complete intravesical therapy courses
• Maintain smoking cessation
• Stay hydrated
• Report new symptoms promptly

When to See a Doctor

Early detection of bladder cancer significantly improves treatment outcomes. Know when to seek medical evaluation.

Seek Immediate Evaluation For:

• Visible blood in urine: Even if painless or occurs only once
• Persistent urinary symptoms: Frequency, urgency, or pain lasting >2 weeks
• Recurrent UTIs: Multiple infections despite treatment
• New pelvic pain: Especially with urinary symptoms
• Inability to urinate: Complete urinary retention

Schedule an Appointment For:

• Microscopic blood in urine found on routine testing
• Changes in urinary patterns
• Unexplained fatigue or weight loss
• Lower back pain on one side
• Swelling in legs or feet

Risk-Based Screening Discussions

Talk to your doctor about screening if you have:

• Long history of smoking (especially >20 pack-years)
• Occupational chemical exposures
• Family history of bladder cancer
• Previous pelvic radiation
• Chronic bladder problems

Follow-up After Treatment

Strict adherence to surveillance is crucial:

• Cystoscopy every 3-4 months initially
• Annual upper tract imaging
• Immediate evaluation of new symptoms
• Lifelong monitoring due to recurrence risk

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