Bladder Cancer

Bladder cancer is a common malignancy typically presenting in older adults, most commonly males with painless haematuria, characterised by urothelial carcinoma on histology and filling defects within the bladder on contrast-enhanced CT.

Description

Bladder cancer represents a group of tumours arising from the urinary bladder’s urothelial lining. It is the most common malignancy of the urinary system and presents mainly in elderly adults, predominantly males. The majority of bladder cancers are urothelial carcinomas (formerly known as transitional cell carcinoma).

Subtypes

• Urothelial carcinoma (Transitional cell carcinoma): Most common subtype, accounting for more than 90% of all bladder cancers. It is more prevalent in males and older adults. It demonstrates papillary fronds on gross examination and malignant urothelial cells histologically. Risk factors include smoking, occupational exposures, and certain genetic conditions like Lynch syndrome. Mutations in FGFR3 and TP53 genes are often identified.
• Squamous cell carcinoma: Less common and often associated with chronic bladder irritation and inflammation, such as recurrent urinary tract infections or bladder stones, and schistosomiasis. It characteristically demonstrates keratinising squamous cells histologically.
• Adenocarcinoma: A rare subtype of bladder cancer, often associated with bladder exstrophy or chronic irritation from urinary diversion procedures. Histologically, it demonstrates glandular differentiation.
• Small cell carcinoma: An extremely rare subtype, histologically identical to small cell lung cancer, and associated with a poor prognosis.

Pathogenesis

• Bladder cancer arises from the urothelial lining of the bladder. The process involves a series of genetic and epigenetic changes leading to uncontrolled cell proliferation.
• The most significant risk factor is smoking, which causes DNA damage due to the carcinogenic compounds found in tobacco smoke.
• Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, common in industries like dye, rubber, and textile manufacturing, is another established risk factor.
• Chronic bladder irritation from infections, bladder stones, or indwelling catheters can lead to squamous metaplasia and dysplasia, predisposing to squamous cell carcinoma.
• Parasitic infection with Schistosoma haematobium, prevalent in certain parts of Africa and the Middle East, is a significant risk factor for squamous cell carcinoma.

Clinical Features

• Haematuria: This is the most common symptom of bladder cancer. Classically painless. It may be visible (gross haematuria) or only detectable on microscopic examination of urine (microscopic haematuria).
• Urinary frequency: An increase in the number of times a person needs to urinate, often without a significant increase in total daily volume.
• Dysuria: This refers to pain or discomfort during urination.
• Urgency: A strong and sudden need to urinate, which is difficult to delay.
• Pelvic pain: Pain located in the lower abdomen or pelvis can occur, especially in advanced cases.
• Weight loss, fatigue, and other systemic symptoms: These are less common and typically associated with more advanced disease or metastasis.

Pathological Features of Bladder Cancer

Histopathology

• Urothelial Carcinoma (Transitional Cell Carcinoma): The most common type, accounting for 90% of bladder cancers. Arises from the urothelial lining of the bladder.
  • Non-invasive papillary carcinoma: Confined to the urothelium, often presenting as papillary fronds.
  • Carcinoma in situ (CIS): Flat, high-grade malignant cells confined to the urothelium.
  • Invasive urothelial carcinoma: Invades the lamina propria, muscularis propria, or beyond.
• Squamous Cell Carcinoma: Represents 5-7% of bladder cancers, often associated with chronic irritation or infection (e.g., Schistosomiasis).
  • Characterised by keratinisation and intercellular bridges.
• Adenocarcinoma: Rare, accounting for 1-2% of bladder cancers. Can arise from the bladder’s glandular structures or as a secondary extension from other organs.
  • Includes primary vesical adenocarcinoma and secondary adenocarcinoma (from colorectal, prostate, etc.).
• Small Cell Carcinoma: Extremely rare, highly aggressive neuroendocrine tumour.
  • Often presents with high-grade features and poor prognosis.
• Other Rare Subtypes: Include sarcomatoid carcinoma, lymphoepithelioma-like carcinoma, and plasmacytoid carcinoma, each with distinct histological characteristics.

• Macroscopic: Bladder tumours can appear as papillary, nodular, or flat lesions. Non-invasive papillary carcinomas typically present as frond-like projections into the bladder lumen. Invasive tumours may show thickening of the bladder wall and infiltrative growth patterns.
• Microscopic:
  • Urothelial carcinoma: Demonstrates varying degrees of architectural and cytological atypia. Low-grade tumours have orderly cell arrangement with mild atypia, while high-grade tumours show disorganised growth, marked atypia, and frequent mitoses.
  • Squamous cell carcinoma: Shows keratin pearls and intercellular bridges.
  • Adenocarcinoma: Glandular formation with mucin production, resembling colorectal adenocarcinoma.
  • Small cell carcinoma: Small, round to oval cells with scant cytoplasm, nuclear moulding, and high mitotic rate.

Serology

• Not typically used in the diagnosis of bladder cancer, but tumour markers such as urinary NMP22, BTA (bladder tumour antigen), and survivin can aid in diagnosis and monitoring.

Biochemistry

• No specific biochemical markers, though elevated serum creatinine may indicate renal impairment due to obstruction.

Immunohistochemistry

• Urothelial carcinoma: Positive for markers such as CK7, CK20, uroplakin, GATA3, and p63.
• Squamous cell carcinoma: Positive for CK5/6, p63, and negative for GATA3.
• Adenocarcinoma: Positive for CK20, CDX2, and sometimes CK7.
• Small cell carcinoma: Positive for neuroendocrine markers such as synaptophysin, chromogranin, and CD56.

Molecular

• Urothelial carcinoma: Common genetic alterations include mutations in FGFR3, TP53, RB1, and deletions on chromosome 9.
• Squamous cell carcinoma: Often associated with HPV infection in some regions, genetic mutations less well-defined.
• Adenocarcinoma: Can exhibit mutations similar to those seen in colorectal cancer, such as KRAS, BRAF, and mismatch repair deficiency.

Genetics

• Lynch syndrome (associated with urothelial carcinoma)
• Cowden syndrome (associated with increased risk for various cancers including bladder).

Radiological Features

General Features

• Bladder wall thickening, intraluminal mass, or filling defect.

CT

• Non-contrast: Limited role, may show bladder wall thickening or mass; used primarily to identify gross haematuria causes or calcifications.
• C+ Venous: Enhancement of bladder wall and tumour; helps to delineate the tumour from surrounding structures and assess for local invasion.
• C+ Delayed: Important for identifying urothelial lesions, as the bladder fills with contrast, enhancing any filling defects or masses.

MRI

• T1: Tumours typically appear as hypointense compared to the bladder wall.
• T2: Tumours usually present as hyperintense relative to the normal bladder wall; helps in differentiating tumour from muscle.
• FLAIR: Not typically used.
• DWI/ADC: Tumours show restricted diffusion with high signal on DWI and low ADC values, useful for detecting and characterizing lesions.
• T1 Gad+: Tumours enhance after gadolinium administration; helps in assessing local invasion and differentiating tumour from benign conditions.
• SWI/GRE: Not typically used.
• In-Out-Phase: Not typically used.
• Papillary tumour is best seen on T1 (higher signal than surrounding urine), usually hidden on T2.
• Use of surface (endorectal) coils improves visualisation and staging of T2-T3b tumours.
• Disruption of low-signal bladder wall, perivesical fat stranding and irregularity of the outer bladder wall suggests T3b disease.
• Visualisation of low intensity bladder wall on T2 between tumour and perivesical fat helps differentiate T2b tumour from T3 tumour.
• Dynamic contrast-induced MRI improves bladder cancer staging accuracy by helping differentiation of tumour (enhances earlier) from inflammatory post-biopsy changes in the bladder wall or perivesical fat (slower rate of enhancement). It is also useful in staging nodes, because abnormal nodes (normal or abnormal by size) enhance earlier than non-metastatic lymph nodes.
• Seminal vesicle invasion: increased sized, reduced T2 signal, obliateration of angle between seminal vesical and posterior bladder wall
• Prostate and rectum invasion: increased T2 signal

US

• B-mode: Can identify bladder wall thickening, intraluminal masses, or filling defects; useful for initial evaluation.
• Colour: Doppler may help in assessing vascularity of the tumour, though less specific than CT or MRI.

NM

• PET FDG: Limited use in primary diagnosis, but may be employed for staging, particularly in assessing metastatic disease.

Additional Notes

• Complications: Imaging may show signs of complications such as hydronephrosis due to obstruction, local invasion into surrounding tissues, or distant metastases.
• Important measurements: Assess tumour size, depth of invasion (T stage), involvement of surrounding organs, lymph nodes, and presence of metastasis.
• Associated findings: May include thickened ureter, pelvic lymphadenopathy, or bone lesions in metastatic disease.
• Pitfalls: Differentiating tumour recurrence from post-treatment changes such as fibrosis; careful assessment with contrast-enhanced studies and correlation with clinical history is essential.

Grading and Staging

Bladder cancer is classified according to the World Health Organisation (WHO) grading system and the TNM staging system.

• Low grade: Displays well-differentiated neoplastic cells.
• High grade: Displays poorly differentiated neoplastic cells.

TNM Staging

T stage: Determines the depth of bladder wall invasion.

• Tis: Carcinoma in situ. (flat-tumour)
• Ta: Non-invasive papillary carcinoma.
• T1: Tumour invades the subepithelial connective tissue.
• T2: Tumour invades muscle.
  • T2a: Tumour invades superficial muscle (inner half).
  • T2b: Tumour invades deep muscle (outer half).
• T3: Tumour invades perivesical tissue.
  • T3a: Microscopically.
  • T3b: Macroscopically (extravesical mass).
• T4: Tumour invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, or abdominal wall.

N stage: Determines the involvement of regional lymph nodes.

• N0: No regional lymph node metastasis.
• N1: Metastasis in a single lymph node in true pelvis (hypogastric, obturator, external iliac, or presacral nodes).
• N2: Metastasis in multiple lymph nodes in true pelvis.
• N3: Metastasis in common iliac lymph nodes.

M stage: Determines the presence of distant metastases.

• M0: No distant metastasis.
• M1: Distant metastasis.

Notes:

• Tumours which arise in a bladder diverticula tend to invade perivesical fat early (due to absence of muscular layer in diverticulum and therefore cannot be assigned T2) and are assigned either T1 (confined to diverticula) or T3 (invading perivesical tissue)

Stages

• Stage 0: The cancer is non-invasive and has not spread past the inner lining of the bladder. This stage includes Ta, Tis, and T1 classifications of the T stage, but without any regional or distant metastases (N0, M0).
• Stage I: The cancer has invaded the subepithelial connective tissue but has not yet spread to the muscle layer of the bladder. This corresponds to the T1 classification of the T stage, but without any regional or distant metastases (N0, M0).
• Stage II: The cancer has invaded the muscle layer of the bladder but has not spread to regional lymph nodes or distant organs. This corresponds to the T2 classification of the T stage, without any regional or distant metastases (N0, M0).
• Stage III: The cancer has spread beyond the bladder to surrounding tissues such as the perivesical tissue or prostate in men or the uterus or vagina in women, but has not spread to the regional lymph nodes or distant organs. This corresponds to the T3 or T4a classifications of the T stage, without any regional or distant metastases (N0, M0).
• Stage IV: The cancer has either:
  • Invaded the pelvic wall or abdominal wall (T4b), or
  • Spread to regional lymph nodes (N1-3), or
  • Spread to distant organs (M1).

Diagnosis

The diagnosis of bladder cancer involves a combination of history, examination, urinalysis, urine cytology, and imaging. Cystoscopy and biopsy provide the definitive diagnosis, allowing direct visualisation and histological assessment of the tumour.

Differential Diagnosis

• Bladder calculi: These are generally radiopaque on plain radiograph, distinct from the soft-tissue attenuation of bladder cancer on CT. They appear as echogenic foci with posterior acoustic shadowing on ultrasound.
• Bladder diverticulum: It is an outpouching of the bladder wall and appears as an extra lumen on CT or ultrasound. Unlike cancer, it lacks a solid mass and tends to change in size and shape with filling and emptying of the bladder.
• Urachal anomalies: These are typically midline and may contain calcifications. Urachal cancer, a rare form of bladder cancer, could arise from urachal remnants but is typically located in the bladder dome.

Management

Bladder cancer is managed by a multidisciplinary team led by urologists. Initial management usually involves transurethral resection of the bladder tumour (TURBT). Further management options depend on the stage and grade of the tumour and can range from intravesical therapy for superficial tumours to radical cystectomy for muscle-invasive disease. Chemotherapy and radiation therapy may also be used, especially in patients unfit for surgery or for palliative purposes.