Definition/General
Introduction:
Small cell carcinoma of the bladder is a rare malignancy comprising less than 1% of all bladder cancers
It demonstrates neuroendocrine differentiation and aggressive biological behavior similar to pulmonary small cell carcinoma
Cytological recognition requires identification of characteristic small blue cells with high nuclear-to-cytoplasmic ratio
Early recognition is crucial due to its aggressive nature and need for specialized treatment.
Origin:
Arises from neuroendocrine cells scattered throughout the bladder mucosa or from metaplastic transformation of urothelial cells
May develop de novo or in association with conventional urothelial carcinoma
Field cancerization effect may result in multifocal disease
Rarely occurs as metastasis from lung or other primary sites.
Classification:
WHO classification recognizes pure small cell carcinoma and mixed forms with urothelial or squamous components
Small cell neuroendocrine carcinoma is the preferred terminology
Graded as high-grade malignancy by definition
Large cell neuroendocrine carcinoma is a related but distinct entity
Combined small cell and urothelial carcinoma requires separate reporting.
Epidemiology:
Extremely rare with male predominance (3:1 ratio)
Peak incidence in 6th-7th decades
Often presents at advanced stage (>50% have metastases at diagnosis)
Strong association with smoking similar to pulmonary small cell carcinoma
Poor prognosis with median survival of 12-18 months.
Clinical Features
Presentation:
Gross hematuria is the most common presenting symptom (85% of cases)
Irritative voiding symptoms including dysuria, frequency, and urgency
Constitutional symptoms including weight loss, fatigue, and night sweats
Paraneoplastic syndromes may occur including SIADH and Cushing syndrome
Advanced disease often present at diagnosis.
Symptoms:
Persistent gross hematuria with clot formation in advanced cases
Severe constitutional symptoms disproportionate to local disease
Bone pain from frequent skeletal metastases
Respiratory symptoms from pulmonary metastases
Neurological symptoms from brain metastases or paraneoplastic effects.
Risk Factors:
Cigarette smoking is the strongest risk factor (similar to lung small cell carcinoma)
Male gender with 3:1 male predominance
Advanced age (typically >60 years)
History of urothelial carcinoma may predispose to mixed tumors
Occupational carcinogen exposure may contribute to development.
Screening:
No specific screening recommended due to rarity
High index of suspicion in smokers with hematuria and constitutional symptoms
Surveillance of patients with previous bladder cancer for mixed components
Investigation of constitutional symptoms in appropriate clinical context
Paraneoplastic syndrome workup may lead to diagnosis.
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Gross Description
Appearance:
Urine specimens typically show gross hematuria ranging from pink-tinged to frank bleeding
May appear cloudy or turbid due to high cellular content
No specific gross characteristics distinguish from other bladder malignancies
Fresh specimens essential for optimal morphological preservation
May contain tissue fragments in advanced cases.
Characteristics:
High cellularity with abundant small malignant cells
Extensive cellular necrosis and debris in advanced cases
Mixed inflammatory infiltrate in the background
May show crush artifact due to fragile nature of small cells
Bacterial contamination may complicate interpretation.
Microscopic Description
Immunohistochemistry
Positive Markers:
Chromogranin A shows cytoplasmic positivity in 60-80% of cases
Synaptophysin demonstrates cytoplasmic staining in 70-90% of cases
CD56 (NCAM) positive in most cases
TTF-1 may be positive, especially in pulmonary-type small cell carcinoma
CK7 may show focal positivity.
Negative Markers:
Typically negative for CK5/6 and p63, distinguishing from squamous carcinoma
GATA3 usually negative, distinguishing from urothelial carcinoma
PSA negative, excluding prostatic origin
Leukocyte common antigen negative, excluding lymphoma
S-100 negative in most cases.
Diagnostic Utility:
Neuroendocrine markers confirm small cell neuroendocrine carcinoma diagnosis
TTF-1 positivity may suggest pulmonary origin requiring clinical correlation
Chromogranin and synaptophysin are most reliable markers
CD56 highly sensitive but less specific
Ki-67 shows very high proliferation index (>80%).
Molecular Subtypes:
Small cell carcinomas lack well-defined molecular subtypes unlike other bladder cancers
Rb pathway inactivation is characteristic
p53 pathway alterations are common
MYC amplification may be present
Neuroendocrine transcription factors including ASCL1 may be expressed.
Molecular/Genetic
Genetic Mutations:
RB1 mutations present in >90% of small cell carcinomas
TP53 mutations found in 80-90% of cases
MYC family amplifications present in 20-30% of cases
PTEN deletions may be present
NOTCH pathway alterations less common than in other neuroendocrine tumors.
Molecular Markers:
Rb protein loss characteristic and nearly universal
p53 overexpression correlates with TP53 mutations
Ki-67 proliferation index extremely high (typically >80%)
MYC overexpression in amplified cases
p16 overexpression may result from Rb pathway loss.
Prognostic Significance:
All small cell carcinomas have poor prognosis regardless of molecular features
Stage at diagnosis most important prognostic factor
Response to chemotherapy may predict survival
MYC amplification may indicate even worse prognosis
CNS metastases predict very poor outcome.
Therapeutic Targets:
Platinum-based chemotherapy (similar to lung small cell carcinoma)
Topoisomerase inhibitors effective in combination regimens
Immunotherapy with PD-1/PD-L1 inhibitors showing promise
PARP inhibitors may be effective due to DNA repair defects
Aurora kinase inhibitors under investigation.
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 morphology
Background
Necrotic background with tumor diathesis and inflammatory infiltrate
Microscopic Findings
Small malignant cells with scant cytoplasm and hyperchromatic nuclei. Nuclear molding and high nuclear-to-cytoplasmic ratio characteristic.
Cytomorphological Features
Small blue cells measuring [size] with [nuclear characteristics]. Extensive necrosis and apoptotic debris present.
Cytological Diagnosis
Malignant cells consistent with small cell neuroendocrine carcinoma
Immunocytochemistry
Neuroendocrine markers: Chromogranin A [result], Synaptophysin [result], CD56 [result]
Grade
High-grade neuroendocrine carcinoma by definition
Urgent Recommendations
URGENT: Immediate cystoscopy, tissue biopsy, and staging studies. Oncology consultation recommended. Exclude pulmonary primary.