Bladder Cancer

Bladder cancer is a malignant neoplasm arising from the tissues of the urinary bladder, most commonly from the urothelial lining. It progresses through uncontrolled cellular proliferation that may form a tumour capable of invading the bladder wall and spreading to other organs. The condition is one of the most frequent urinary tract malignancies worldwide, with an estimated half-million new diagnoses and approximately 200,000 deaths each year. It predominantly affects older adults, with risk increasing markedly with age; the average age of diagnosis is around 73 years. Tobacco smoking is the major modifiable risk factor, contributing to roughly half of all cases, while exposure to industrial carcinogens and infection with Schistosoma haematobium in endemic areas also increases risk.

Clinical presentation and symptomatology

The most common presenting feature of bladder cancer is visible haematuria, which occurs irrespective of pain during urination. Around three-quarters of affected individuals exhibit noticeable blood in the urine at some stage. Others present with microscopic haematuria, detected only during urinalysis, or experience dysuria, urinary frequency, or may be entirely asymptomatic, with tumours discovered incidentally during imaging for unrelated conditions.
Obstruction of urinary flow can occur when a tumour blocks the ureteric orifice, leading to hydronephrosis and flank pain due to urinary backpressure. Importantly, most individuals with haematuria do not have bladder cancer; only around 22% of those with visible haematuria and 5% of those with microscopic haematuria are ultimately diagnosed with the disease. Women are more likely to be misdiagnosed with urinary tract infections, which can delay appropriate evaluation.
Approximately 3% of patients present with metastatic disease at initial diagnosis. Metastases most frequently involve the bones, lungs, liver, and regional lymph nodes. Symptoms vary with metastatic site: bone involvement may result in pain or pathological fractures; pulmonary spread can lead to persistent cough, haemoptysis, dyspnoea, or recurrent chest infections; hepatic metastases can cause anorexia, malaise, weight loss, abdominal discomfort, ascites, jaundice, or pruritus. Lymphatic spread may produce swelling and discomfort in the abdomen or groin.

Diagnostic methods

Diagnosis of bladder cancer requires a structured approach to identify the presence, characteristics, and extent of any tumours. Cystoscopy remains the gold standard investigation. During this procedure, a flexible scope is inserted through the urethra to allow direct visualisation of the bladder mucosa. It is particularly effective for detecting papillary tumours that project into the bladder cavity, although carcinoma in situ is more challenging to identify. Blue-light cystoscopy, using intravesical hexaminolevulinate that fluoresces under blue light, enhances the detection of flat or small lesions.
When suspicious growths are observed, they are removed using transurethral resection of bladder tumour (TURBT). This procedure excises all visible tumours along with a sample of the underlying bladder muscle. Histopathological examination confirms malignancy, determines tumour grade, and identifies whether muscle invasion is present. High-risk or incompletely resected tumours require repeat TURBT within four to six weeks.
Non-invasive investigations complement cystoscopy. A physical examination may include digital rectal or pelvic assessment to detect abnormal masses. Urine cytology evaluates shed tumour cells and is particularly useful for high-grade lesions, though it is less sensitive for low-grade disease. Additional urine-based tests detect tumour-associated proteins such as BTA or NMP22, tumour-associated mRNA, or use fluorescence techniques with higher sensitivity and specificity than conventional microscopy.
Assessment of the upper urinary tract is essential in cases of haematuria or suspected spread. CT urography is commonly used, involving intravenous contrast that is filtered by the kidneys to outline the urinary tract. Magnetic resonance imaging is preferred when renal function is insufficient to handle contrast agents. Ultrasonography is an alternative where cross-sectional imaging is unsuitable.

Classification and pathological features

Bladder tumours are classified primarily by their cellular origin. More than 90% arise from the transitional epithelium and are termed urothelial carcinomas. Approximately 5% are squamous cell carcinomas, associated more frequently with chronic irritation or schistosomiasis in endemic regions. Up to 2% are adenocarcinomas, originating from glandular cells. Rare forms include sarcomas of the bladder muscle and small-cell carcinomas derived from neuroendocrine cells.
Tumour grading reflects the degree to which cancer cells differ from normal urothelial cells. Low-grade cancers resemble normal tissue more closely and tend to grow slowly, while high-grade cancers exhibit marked atypia and have a greater likelihood of invasion and metastasis.

Staging of bladder cancer

The TNM staging system is used to describe tumour progression:

• T (Tumour):
  • Tis designates carcinoma in situ.
  • Ta refers to non-invasive papillary tumours.
  • T1 tumours penetrate the connective tissue beneath the urothelium.
  • T2 indicates invasion into the muscle layer.
  • T3 describes extension into surrounding fatty tissue.
  • T4 indicates tumour spread beyond the bladder, potentially involving adjacent organs.
• N (Nodes):
  • N0 signals no lymph node involvement.
  • N1 indicates spread to a single local lymph node.
  • N2 involves multiple lymph nodes in the pelvic region.
  • N3 signifies spread to lymph nodes beyond the pelvis.
• M (Metastasis):
  • M0 denotes no distant metastasis.
  • M1 identifies spread to organs outside the urinary tract.

Combined TNM results classify cases into stages 0 to 4. Around 75% of patients present with non-muscle-invasive bladder cancer (NMIBC), defined by Tis, Ta, or T1 tumours confined to the bladder lining. Approximately 18% have muscle-invasive bladder cancer (MIBC), while around 3% have metastatic disease at diagnosis.

Treatment approaches

Management of bladder cancer varies with stage, risk category, and tumour characteristics. NMIBC is primarily managed by TURBT to remove all detectable lesions. A single intravesical chemotherapy dose—typically mitomycin C, epirubicin, or gemcitabine—administered shortly after surgery reduces recurrence risk by about 40% in low-risk cases.
Higher-risk NMIBC requires intravesical Bacillus Calmette–Guérin (BCG) therapy. Administered weekly for six weeks, BCG stimulates a local immune response that substantially reduces recurrence and progression rates. Long-term maintenance therapy over a year or more offers additional benefit. Tumours resistant to BCG can be treated with alternative immunotherapies such as nadofaragene firadenovec, which induces production of interferon-α, nogapendekin alfa inbakicept, or pembrolizumab, an immune checkpoint inhibitor used particularly in high-risk BCG-unresponsive carcinoma in situ.
In MIBC, treatment options often include radical cystectomy, the surgical removal of the bladder, frequently combined with urinary diversion procedures. Neoadjuvant chemotherapy may be administered to improve survival outcomes. Individuals not eligible for surgery may undergo combined radiotherapy and chemotherapy.
For metastatic bladder cancer, systemic chemotherapy forms the initial treatment, commonly followed by immune checkpoint inhibitors to prolong survival. Enfortumab vedotin, an antibody–drug conjugate, is increasingly used following immunotherapy in advanced cases.