Definition/General
Introduction:
Urothelial carcinoma (formerly transitional cell carcinoma) is the most common malignancy of the urinary tract, comprising 90% of all bladder cancers
In urine cytology, it demonstrates characteristic nuclear atypia and cellular abnormalities that aid in diagnosis
The Paris System for reporting urinary cytology emphasizes detection of high-grade urothelial carcinoma
Early cytological detection is crucial for patient prognosis and management.
Origin:
Urothelial carcinoma arises from the transitional epithelium lining the urinary tract including bladder, ureters, renal pelvis, and proximal urethra
Most cases (75%) originate in the bladder, particularly the lateral and posterior walls
The tumor develops through multistep carcinogenesis involving genetic alterations
Field cancerization effect may result in multifocal disease throughout the urinary tract.
Classification:
WHO classification divides urothelial carcinoma into non-invasive and invasive forms
Non-invasive includes papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade, and high-grade carcinoma
Invasive urothelial carcinoma shows stromal invasion
The Paris System categories include: Negative, Atypical, Suspicious, and High-grade urothelial carcinoma
Grading follows WHO/ISUP system (low-grade vs high-grade).
Epidemiology:
Peak incidence in 6th-7th decades with male predominance (3:1 ratio)
In India, incidence is 5-10 per 100,000 with regional variations
Smoking is the most important risk factor (4-fold increased risk)
Occupational carcinogens (aromatic amines, benzidine) account for 10-15% of cases
Chronic cystitis and Schistosoma haematobium infection are additional risk factors in endemic areas.
Clinical Features
Presentation:
Painless gross hematuria is the most common presentation (85% of cases)
Microscopic hematuria detected on routine urinalysis
Irritative voiding symptoms including dysuria, urgency, and frequency
Flank pain may indicate upper tract involvement or ureteral obstruction
Constitutional symptoms including weight loss and fatigue in advanced cases.
Symptoms:
Intermittent gross hematuria with clot formation in severe cases
Dysuria and burning sensation during micturition (30-40% of patients)
Urinary frequency and urgency mimicking urinary tract infection
Nocturia and incomplete bladder emptying sensation
Suprapubic pain and discomfort in advanced local disease.
Risk Factors:
Cigarette smoking (most significant risk factor with 4-fold increase)
Occupational exposure to aromatic amines, benzidine, and rubber chemicals
Chronic cyclophosphamide therapy increases risk significantly
Prior pelvic radiation therapy for other malignancies
Chronic bacterial cystitis and indwelling catheter use
Schistosoma haematobium infection in endemic areas.
Screening:
High-risk occupational screening with annual urine cytology for exposed workers
Surveillance cystoscopy and cytology for patients with previous bladder cancer
Not recommended for general population screening due to low specificity
Targeted screening for patients with unexplained hematuria or irritative symptoms
Family history of urological malignancies may warrant earlier screening.
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Gross Description
Appearance:
Urine specimens often appear grossly bloody or tea-colored with high-grade lesions
May show clot formation indicating significant bleeding from tumor
Turbid appearance due to increased cellular content and debris
Color ranges from pink-tinged to frank red depending on degree of hematuria
Fresh specimens are essential for optimal cytological evaluation.
Characteristics:
High cellularity specimens with increased cellular debris and background material
May contain tissue fragments and three-dimensional cell clusters
Necrotic background (tumor diathesis) in high-grade lesions
Specimens may show mixed inflammatory infiltrate with tumor cells
Mucin production may be evident in variant forms.
Microscopic Description
Immunohistochemistry
Positive Markers:
CK7 shows diffuse cytoplasmic positivity in most urothelial carcinomas
CK20 demonstrates variable expression, often in superficial cells
GATA3 is highly sensitive and specific for urothelial origin
p63 shows nuclear positivity, particularly in high-grade lesions
Uroplakin II is specific but less sensitive marker for urothelial differentiation.
Negative Markers:
Typically negative for CK5/6 except in squamous differentiation
TTF-1 is negative, helping exclude lung primary
CDX-2 negativity helps exclude gastrointestinal origin
PSA and PSAP are negative, excluding prostatic origin
PAX-8 may be negative, distinguishing from renal cell carcinoma.
Diagnostic Utility:
Immunocytochemistry helps confirm urothelial origin in metastatic workup
CK7+/CK20+ pattern supports urothelial carcinoma diagnosis
GATA3 is particularly useful for poorly differentiated cases
p63 helps distinguish from adenocarcinoma
Markers aid in determining primary site in cases with multiple tumors.
Molecular Subtypes:
Luminal subtypes show expression of FOXA1, GATA3, and KRT20
Basal-squamous subtype expresses CD44, KRT5, and KRT14
Neuronal subtype shows neuroendocrine markers
These subtypes have different therapeutic implications and prognosis
Molecular classification guides targeted therapy selection.
Molecular/Genetic
Genetic Mutations:
TP53 mutations present in 40-60% of high-grade urothelial carcinomas
FGFR3 mutations more common in low-grade, non-invasive tumors (70-80%)
PIK3CA mutations found in 15-25% of cases across all grades
RB1 pathway alterations including CDKN2A deletions in muscle-invasive disease
TERT promoter mutations present in 60-80% of urothelial carcinomas.
Molecular Markers:
p53 overexpression correlates with TP53 mutations and poor prognosis
FGFR3 expression associated with better prognosis in non-invasive disease
Ki-67 proliferation index elevated in high-grade lesions (>20%)
p21 expression may be lost in TP53-mutated cases
ERBB2 (HER2) amplification present in 10-15% of cases.
Prognostic Significance:
Molecular subtypes have different prognoses with luminal tumors showing better outcomes
TP53 mutations indicate aggressive behavior and poor prognosis
FGFR3 mutations associated with better prognosis but frequent recurrence
Microsatellite instability predicts response to immunotherapy
DNA damage response defects predict platinum sensitivity.
Therapeutic Targets:
FGFR3 targeted therapy with erdafitinib for mutated cases
PD-1/PD-L1 inhibitors for immunotherapy in advanced disease
ERBB2 (HER2) targeted therapy with trastuzumab in amplified cases
CDK4/6 inhibitors for RB1 pathway intact tumors
PARP inhibitors for DNA repair deficient tumors.
Differential Diagnosis
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Urine cytology specimen, [collection method], adequate cellularity
Specimen Adequacy
Adequate: Sufficient cellular material with good preservation for evaluation
Background
[Clean/inflammatory/hemorrhagic] background with [presence/absence] of tumor diathesis
Microscopic Findings
Malignant cells with marked nuclear pleomorphism, hyperchromasia, and irregular nuclear contours. Increased nuclear-to-cytoplasmic ratio and prominent nucleoli identified.
Cytomorphological Features
High-grade nuclear features including [specific features]. Loss of cellular cohesion with [pattern of arrangement].
Cytological Diagnosis
High-grade urothelial carcinoma (Paris System Category: High-grade urothelial carcinoma)
Recommendations
Immediate cystoscopy and tissue biopsy for histological confirmation and staging. Clinical correlation recommended.