Definition/General
Introduction:
Esophageal squamous cell carcinoma (ESCC) is the most common primary malignancy of the esophagus globally
It arises from the stratified squamous epithelium
Cytological diagnosis is highly accurate with proper sampling
Early detection is crucial for improved survival outcomes.
Origin:
ESCC arises from dysplastic transformation of normal squamous epithelium
Sequential progression: Normal → Dysplasia → Carcinoma in situ → Invasive carcinoma
Field cancerization effect common
Multiple risk factors contribute to carcinogenesis.
Classification:
WHO classification: Squamous cell carcinoma
Well-differentiated (Grade 1)
Moderately differentiated (Grade 2)
Poorly differentiated (Grade 3)
Undifferentiated (Grade 4)
Variants include basaloid, spindle cell, verrucous.
Epidemiology:
High incidence in developing countries
Male predominance (3:1 ratio)
Peak age 50-70 years
Geographic variation: High in Asia, Africa
"Esophageal cancer belt" from Iran to China
Environmental and genetic factors.
Clinical Features
Presentation:
Progressive dysphagia (90% of cases)
Weight loss (80% of cases)
Chest pain (50% of cases)
Regurgitation
Hoarseness (recurrent laryngeal nerve involvement)
Hematemesis
Respiratory symptoms (aspiration).
Symptoms:
Solid food dysphagia progressing to liquids
Unintentional weight loss >10% body weight
Retrosternal chest pain
Persistent cough
Chronic aspiration
Fatigue
Anemia symptoms.
Risk Factors:
Tobacco use (smoking and chewing)
Alcohol consumption
Hot beverage consumption
Nutritional deficiencies
Achalasia
Caustic injury
Human papillomavirus
Genetic predisposition.
Screening:
High-risk population screening
Endoscopic surveillance
Lugol chromoendoscopy
Narrow band imaging
Balloon cytology in resource-limited settings
Biomarker development.
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Gross Description
Appearance:
Ulcerative lesions (most common)
Fungating masses
Infiltrative growth
Circumferential involvement
Luminal narrowing
Necrosis and hemorrhage.
Characteristics:
Irregular, ulcerated surface
Firm consistency
Gray-white appearance
Areas of necrosis
Hemorrhage
Stricture formation.
Size Location:
Variable size (2-15 cm)
Upper third (15%)
Middle third (50%)
Lower third (35%)
Multifocal disease possible
Skip lesions.
Multifocality:
Field cancerization common
Synchronous lesions (5-10%)
Skip areas
Submucosal spread
Lymphatic invasion early.
Microscopic Description
Histological Features:
Malignant squamous cells with nuclear atypia
Increased nuclear-cytoplasmic ratio
Nuclear pleomorphism
Prominent nucleoli
Frequent mitoses
Abnormal mitotic figures
Keratinization variable.
Cellular Characteristics:
Enlarged, hyperchromatic nuclei
Irregular nuclear contours
Coarse chromatin pattern
Prominent nucleoli
Abundant eosinophilic cytoplasm
Intercellular bridges
Keratin formation.
Architectural Patterns:
Single cells and clusters
Syncytial arrangements
Pearl formation (well-differentiated)
Tadpole cells
Fiber cells
Orangeophilic cells
Background necrosis.
Grading Criteria:
Well-differentiated: Prominent keratinization
Moderately differentiated: Moderate keratinization
Poorly differentiated: Minimal keratinization
Undifferentiated: No keratinization
Nuclear grade assessment.
Immunohistochemistry
Positive Markers:
CK5/6 (squamous marker)
CK14
p63 (nuclear)
p40 (squamous-specific)
Involucrin
High molecular weight cytokeratins
p53 (often overexpressed).
Negative Markers:
CK7 (usually negative)
CK20 (negative)
CDX2 (negative)
TTF-1 (negative)
Chromogranin (negative)
Synaptophysin (negative).
Diagnostic Utility:
Confirms squamous differentiation
Differentiates from adenocarcinoma
Subtype classification
Prognostic information
Therapeutic target identification.
Molecular Subtypes:
HPV-associated (p16 positive)
HPV-negative (p16 negative)
Chromosomal instability subtype
Normal-like subtype
Immunotherapy-responsive subtypes.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (>90%)
CDKN2A deletions (50%)
PIK3CA mutations (20%)
NOTCH1 mutations (15%)
KMT2D mutations
FBXW7 mutations.
Molecular Markers:
p53 overexpression
EGFR amplification
Cyclin D1 amplification
c-MYC amplification
PD-L1 expression
Microsatellite instability (rare).
Prognostic Significance:
Stage most important prognostic factor
Grade affects prognosis
Lymph node involvement
p53 mutations associated with poor prognosis
HPV status affects treatment response.
Therapeutic Targets:
EGFR inhibitors
PD-1/PD-L1 inhibitors
Anti-angiogenic agents
PI3K/AKT pathway inhibitors
CDK4/6 inhibitors
Targeted therapy combinations.
Differential Diagnosis
Similar Entities:
Adenocarcinoma (glandular features)
High-grade dysplasia (architectural preservation)
Reactive changes (uniform atypia)
Metastatic carcinoma
Poorly differentiated carcinoma.
Distinguishing Features:
SCC: Squamous markers positive
SCC: Keratinization
Adenocarcinoma: CK7 positive
Dysplasia: Architectural preservation
Reactive: Smooth nuclear contours
Metastatic: Clinical history.
Diagnostic Challenges:
Poor differentiation
Small specimens
Crush artifacts
Inflammation and necrosis
Previous treatment effects
Sampling adequacy.
Rare Variants:
Basaloid squamous carcinoma
Spindle cell carcinoma
Verrucous carcinoma
Adenosquamous carcinoma
Small cell carcinoma
Undifferentiated carcinoma.
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
Esophageal cytology, [technique used], adequate for evaluation
Diagnosis
Malignant - Squamous cell carcinoma
Malignant Features
Malignant squamous cells showing [nuclear atypia] and [cellular features]
Microscopic Findings
Shows [atypical squamous cells] with [nuclear pleomorphism]
Nuclear Features
Nuclear features: [enlarged, hyperchromatic] with [irregular contours]
Differentiation
Differentiation: [well/moderately/poorly] differentiated
Background Findings
Background: [necrotic debris] and [inflammatory cells]
Special Studies
IHC: [squamous markers]: [positive results]
Molecular studies: [recommended for staging]
Final Diagnosis
Esophageal cytology: Squamous cell carcinoma