Urothelial carcinoma, the most common bladder cancer, predominantly affects older adults characterised by urothelial cell abnormalities and frequent mutations in the TP53, FGFR3 and RAS genes, typically presents as filling defects within the urinary bladder on urography.
Description
Urothelial carcinoma, formerly known as transitional cell carcinoma, is the most common malignancy of the urinary tract. It represents the majority of bladder cancer cases and is characterised by malignant transformation of the urothelial cells lining the urinary tract, particularly in the bladder.
Pathogenesis
The pathogenesis of urothelial carcinoma is complex and multifactorial. It involves genetic alterations, including frequent mutations in the TP53, FGFR3 and RAS genes, that lead to unchecked cell proliferation. In addition, environmental factors, particularly cigarette smoking and occupational exposure to certain chemicals, play a significant role in the disease development.
Subtypes
Urothelial carcinoma has several histological variants which include:
- Papillary urothelial carcinoma: This is the most common subtype (90% of cases) and it grows in a papillary or frond-like pattern into the bladder cavity. It is usually non-invasive and carries a better prognosis compared to other types. It can be further divided into low-grade and high-grade papillary urothelial carcinoma, with the high-grade subtype having a higher propensity for invasion and progression.
- Non-papillary (invasive) urothelial carcinoma: This subtype grows directly into the bladder wall and carries a worse prognosis due to its higher potential for invasion and metastasis.
- Flat carcinoma in situ (CIS): This subtype presents as a flat, high-grade non-invasive lesion. Despite not invading the bladder wall, it has a high risk of progression to invasive disease and requires aggressive management.
- Micropapillary urothelial carcinoma: This is a rare and aggressive variant that often presents at a higher stage and has a worse prognosis.
- Plasmacytoid urothelial carcinoma: Another rare variant that resembles plasma cells under the microscope and has a propensity for early dissemination and poor prognosis.
- Nested urothelial carcinoma: This subtype is characterised by nests of bland-appearing urothelial cells and generally has a favourable prognosis.
Epidemiology, Risk Factors & Associations
- Urothelial carcinoma is the fourth most common cancer in men and the tenth in women, with incidence peaking in the 70s.
- Age (typically 70-80 years old)
- Male sex (about 3 times more common in men than in women)
- Cigarette smoking (major risk factor, increases risk 2-4 fold)
- Occupational exposure to chemicals used in the dye, rubber, and leather industries
- Long-term usage of cyclophosphamide or pioglitazone
- Chronic bladder inflammation, such as recurrent urinary tract infections or long-standing indwelling catheters
- Long-term use of the analgesic phenacetin (now banned) is also associated with increased risk.
Clinical Features
- Painless haematuria (most common presenting symptom)
- Gross haematuria confers higher risk of malignancy than microscopic, usually arising from bladder.
- Dysuria
- Frequency and urgency of micturition
- Advanced disease may present with pelvic pain or symptoms related to metastatic disease
Complications
- Local invasion and metastasis, most commonly to the lymph nodes, lungs, liver, and bone
- Ureteral obstruction and hydronephrosis
Pathological Features
Histopathology
- Macroscopic: Tumours can be papillary or flat, ranging in size, and may present as a solitary lesion or multiple lesions
- Microscopic: Reveals malignant urothelial cells, which may demonstrate varying degrees of architectural patterns and differentiation. High-grade tumours show marked cellular atypia, while low-grade tumours resemble normal urothelium.
Serology
- Urinary cytology: Can detect exfoliated malignant cells but is more sensitive for high-grade tumours
Biochemistry
- No specific biochemical markers
Radiological Features
General Features
- Typically presents as irregular filling defects within the urinary bladder on contrast-enhanced CT urography
- Location: Bladder (90%) > Kidney (8%) > Ureter (2%)
- Following detection, it is important to assess entire urinary tract as synchronous lesions are very common (e.g. 40% chance of developing bladder TCC if an upper tract TCC is present).
CT
- Non-contrast: May reveal a thickened bladder wall or a mass
- Post-contrast: Best demonstrates mass as lobulated irregular bladder wall thickening which enhances greater than bladder wall.
MRI
- T1: Lesion is isointense to hypointense compared to the bladder wall
- T2: Lesion is hyperintense compared to the bladder wall
- T1 Gad+: Enhancement of the tumour
US
- B-mode: can show a mass protruding into the bladder lumen, or focal bladder wall thickening
NM
- PET FDG: not typically used in the initial diagnosis, but may be used for staging or assessing for metastatic disease
Grading and Staging
- TNM Staging of Bladder Cancer
- The TNM staging system, developed by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), is used to classify the extent of bladder cancer based on three parameters: Tumour size and extent (T), lymph Node involvement (N), and the presence of distant Metastasis (M).
- T: Tumour
- TX: Primary tumour cannot be assessed.
- T0: No evidence of primary tumour.
- Ta: Non-invasive papillary carcinoma.
- Tis: Carcinoma in situ (flat tumour).
- T1: Tumour invades the subepithelial connective tissue (lamina propria).
- T2: Tumour invades the muscularis propria (muscle layer).
- T2a: Tumour invades the superficial muscle (inner half of the muscularis propria).
- T2b: Tumour invades the deep muscle (outer half of the muscularis propria).
- T3: Tumour invades the perivesical tissue (beyond the muscle layer).
- T3a: Microscopic invasion of the perivesical tissue.
- T3b: Macroscopic invasion (extravesical mass).
- T4: Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall.
- T4a: Tumour invades the prostate, uterus, or vagina.
- T4b: Tumour invades the pelvic wall or abdominal wall.
N: Regional Lymph Nodes
- NX: Regional lymph nodes cannot be assessed.
- N0: No regional lymph node metastasis.
- N1: Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral).
- N2: Metastasis in multiple lymph nodes in the true pelvis.
- N3: Metastasis in common iliac lymph nodes.
M: Distant Metastasis
- M0: No distant metastasis.
- M1: Distant metastasis present.
- M1a: Non-regional lymph node metastasis.
- M1b: Distant organ metastasis.
Staging Groups
- Stage 0a: Ta, N0, M0
- Stage 0is: Tis, N0, M0
- Stage I: T1, N0, M0
- Stage II: T2a/b, N0, M0
- Stage IIIA: T3a/b, N0, M0 or T4a, N0, M0 or T1-T4a, N1, M0
- Stage IIIB: T1-T4a, N2-N3, M0
- Stage IVA: T4b, Any N, M0 or Any T, Any N, M1a
- Stage IVB: Any T, Any N, M1b
Diagnosis
- Diagnosis requires a tissue biopsy, typically obtained via transurethral resection of bladder tumour (TURBT)
Differential Diagnosis
- Neuroendocrine (small cell) carcinoma of the bladder: A rare subtype that resembles small cell lung cancer under the microscope, it is extremely aggressive with a poor prognosis.
- Squamous and glandular differentiation: Urothelial carcinomas may also show areas of squamous or glandular differentiation. When these areas are extensive, the tumour is classified as squamous cell carcinoma or adenocarcinoma of the bladder, respectively.
- Bladder calculi: Can also present as a filling defect on imaging, but typically demonstrate posterior acoustic shadowing on ultrasound
- Benign prostatic hyperplasia (BPH) in men: Can cause bladder outlet obstruction and subsequent bladder wall thickening
- Cystitis: Can cause bladder wall thickening, but is usually accompanied by symptoms of a urinary tract infection
- Leiomyoma: Smooth bladder wall mass.
Prognosis
- The 5-year survival rate depends on the stage of disease at diagnosis. For localised disease, the 5-year survival rate is approximately 70%, but this drops significantly with advanced or metastatic disease.
Management
- Management generally involves a multidisciplinary team, including urology, medical oncology, and radiation oncology. The mainstay of treatment for non-metastatic disease is surgical resection, potentially followed by chemotherapy or immunotherapy.
- Non-invasive papillary tumours are usually managed by transurethral resection, possibly with intravesical therapy to prevent recurrence.
- Muscle-invasive disease often requires radical cystectomy with urinary diversion, often combined with neoadjuvant or adjuvant chemotherapy.
- Metastatic disease is treated primarily with systemic chemotherapy, with immune checkpoint inhibitors playing an increasing role.