Definition/General
Introduction:
Primary squamous cell carcinoma of the urinary tract is a rare malignancy comprising 2-5% of all bladder cancers
It demonstrates keratinizing features and squamous differentiation in cytological specimens
Most cases arise from chronic inflammation and squamous metaplasia of the urothelium
Recognition requires identification of characteristic keratinization and intercellular bridge formation in malignant cells.
Origin:
Primary squamous cell carcinoma typically arises from metaplastic squamous epithelium in the bladder or urethra
Chronic irritation from indwelling catheters, recurrent infections, or Schistosoma haematobium infection predisposes to squamous metaplasia
The transformation sequence progresses from reactive squamous metaplasia to dysplasia to invasive carcinoma
Field cancerization may result in multifocal disease.
Classification:
WHO classification recognizes pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation
Pure squamous cell carcinoma shows complete squamous differentiation without urothelial components
Keratinizing and non-keratinizing variants are recognized
Grading follows conventional squamous cell carcinoma criteria (well, moderately, poorly differentiated)
Verrucous carcinoma is a rare well-differentiated variant.
Epidemiology:
More common in endemic schistosomiasis regions (Africa, Middle East) where it may comprise 50-75% of bladder cancers
In non-endemic areas, accounts for 2-5% of bladder malignancies
Shows slight female predominance (1.2:1 ratio)
Peak incidence in 5th-6th decades
In India, higher incidence in regions with poor sanitation and chronic cystitis.
Clinical Features
Presentation:
Gross hematuria is the most common presenting symptom (80-90% of cases)
Irritative voiding symptoms including severe dysuria and frequency
Chronic pelvic pain and suprapubic discomfort
Recurrent urinary tract infections due to associated chronic cystitis
Obstructive symptoms may develop with advanced local disease.
Symptoms:
Persistent gross hematuria with blood clots in advanced cases
Severe dysuria and burning sensation more prominent than in urothelial carcinoma
Urinary frequency and urgency with small volume voids
Incomplete bladder emptying sensation
Constitutional symptoms including weight loss and fatigue in advanced disease.
Risk Factors:
Schistosoma haematobium infection is the strongest risk factor in endemic areas
Chronic indwelling catheterization increases risk significantly
Chronic bacterial cystitis and recurrent urinary tract infections
Chronic irritation from bladder stones or foreign bodies
Previous pelvic radiation therapy
Smoking has weaker association compared to urothelial carcinoma.
Screening:
High-risk screening in schistosomiasis-endemic regions with annual urine cytology
Surveillance of patients with chronic indwelling catheters
Monitoring patients with recurrent squamous metaplasia on previous biopsies
Not routinely recommended for general population screening
Targeted screening for patients with persistent irritative symptoms despite treatment.
Master Squamous Cell Carcinoma in Urine Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Urine specimens typically show gross hematuria with dark red or brown coloration
May contain visible tissue fragments and keratinous debris
Turbid appearance due to inflammatory cells and necrotic material
Foul odor may be present due to secondary bacterial infection
Fresh specimens are crucial for identifying keratinization.
Characteristics:
High cellularity specimens with abundant keratinous material and cellular debris
Inflammatory background with mixed inflammatory infiltrate
Necrotic tissue fragments may be visible macroscopically
Specimens often show secondary bacterial contamination
Thick, viscous consistency due to keratin and mucus production.
Microscopic Description
Immunohistochemistry
Positive Markers:
CK5/6 shows strong and diffuse cytoplasmic positivity in squamous cells
p63 demonstrates nuclear positivity in malignant squamous cells
CK14 and CK17 are positive in squamous differentiation
p40 is specific for squamous differentiation
Involucrin and filaggrin mark terminal squamous differentiation.
Negative Markers:
Typically negative for CK7 and CK20, distinguishing from urothelial carcinoma
GATA3 is usually negative in pure squamous cell carcinoma
TTF-1 negativity helps exclude lung primary
CDX-2 negativity excludes gastrointestinal origin
ER and PR are negative, excluding gynecological primary.
Diagnostic Utility:
Immunocytochemistry confirms squamous differentiation in cytological specimens
p63 and CK5/6 positivity supports squamous cell carcinoma diagnosis
Helps distinguish from urothelial carcinoma with squamous differentiation
Primary vs metastatic differentiation requires clinical correlation and additional markers
Useful for poorly differentiated cases lacking obvious keratinization.
Molecular Subtypes:
Squamous cell carcinomas lack the molecular subtypes defined for urothelial carcinoma
HPV-related vs HPV-independent pathways may be relevant in some cases
p16 overexpression suggests HPV involvement (rare in bladder)
EGFR overexpression is common and represents potential therapeutic target
TP53 mutations are frequent and indicate aggressive behavior.
Molecular/Genetic
Genetic Mutations:
TP53 mutations are present in 60-80% of squamous cell carcinomas
CDKN2A (p16) deletions are common and associated with poor prognosis
PIK3CA mutations found in 10-20% of cases
FGFR3 mutations are rare, distinguishing from urothelial carcinoma
RB1 pathway alterations including CCND1 amplification.
Molecular Markers:
p53 overexpression correlates with TP53 mutations and aggressive behavior
p16 loss indicates CDKN2A alterations and poor prognosis
EGFR overexpression present in 50-70% of cases
Ki-67 proliferation index typically elevated (>30% in high-grade lesions)
Cyclin D1 overexpression associated with cell cycle dysregulation.
Prognostic Significance:
Squamous cell carcinoma generally has worse prognosis than urothelial carcinoma
TP53 mutations predict aggressive behavior and poor response to therapy
High Ki-67 index correlates with poor prognosis
EGFR overexpression may predict response to targeted therapy
Stage at diagnosis is the most important prognostic factor.
Therapeutic Targets:
EGFR inhibitors may be effective in cases with EGFR overexpression
Anti-angiogenic therapy for advanced disease
Immunotherapy with PD-1/PD-L1 inhibitors showing promise
Platinum-based chemotherapy remains standard treatment
Radiation sensitizers may enhance local therapy effectiveness.
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 recognizable morphological features
Background
Inflammatory background with keratinous debris and [inflammatory infiltrate]. [Presence/absence] of necrotic material.
Microscopic Findings
Malignant squamous cells with keratinized cytoplasm and nuclear pleomorphism. Intercellular bridges and individual cell keratinization identified.
Cytomorphological Features
[Well/moderately/poorly] differentiated squamous cell carcinoma with [degree] of keratinization
Cytological Diagnosis
Malignant cells consistent with squamous cell carcinoma
Grade
[Well/moderately/poorly] differentiated squamous cell carcinoma
Recommendations
Cystoscopy and tissue biopsy for histological confirmation and staging. Clinical correlation with risk factors recommended.