Definition/General
Introduction:
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor arising from the squamous epithelium of the esophagus
It is the predominant histologic type of esophageal cancer worldwide, accounting for 80-90% of cases globally.
Origin:
Arises from esophageal squamous epithelium through progressive dysplastic changes
Develops from squamous dysplasia (low-grade and high-grade) progressing to invasive carcinoma.
Classification:
WHO Classification based on degree of differentiation: well-differentiated, moderately differentiated, and poorly differentiated
Special variants include verrucous carcinoma and basaloid squamous cell carcinoma.
Epidemiology:
Higher incidence in developing countries, especially China, Iran, and Southern Africa
Male predominance (3:1)
Peak incidence 50-70 years
Strong geographic clustering suggests environmental factors.
Clinical Features
Presentation:
Progressive dysphagia (solid to liquid)
Odynophagia
Weight loss
Chest pain
Regurgitation
Hoarseness (recurrent laryngeal nerve involvement)
Aspiration pneumonia.
Symptoms:
Dysphagia (90% of patients)
Unintentional weight loss (>10% body weight)
Chest or back pain
Regurgitation of food
Persistent cough
Hoarseness.
Risk Factors:
Tobacco use (smoking and chewing)
Alcohol consumption
Hot beverages and food
Nutritional deficiencies (zinc, selenium)
Achalasia
Tylosis
Previous head/neck cancer.
Screening:
Endoscopy in high-risk populations
Lugol chromoendoscopy
Narrow-band imaging
Balloon cytology in some regions
Biomarker development ongoing.
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Gross Description
Appearance:
Three growth patterns: polypoid/fungating (early), ulcerative (most common), infiltrative (advanced)
Gray-white to tan coloration
Firm consistency.
Characteristics:
Size varies from small early lesions to large circumferential tumors
Surface may be ulcerated, necrotic, or keratotic
Well-defined to poorly demarcated margins.
Size Location:
Upper third (cervical): 10%
Middle third (thoracic): 50%
Lower third (abdominal): 40%
May involve multiple anatomic segments.
Multifocality:
Multifocal disease in 10-15% of cases
Skip lesions possible
Associated with field cancerization
Synchronous head/neck primaries in 5-10%.
Microscopic Description
Histological Features:
Malignant squamous epithelium with keratin production
Intercellular bridges (desmosomes)
Variable keratinization
Nuclear pleomorphism
Mitotic activity.
Cellular Characteristics:
Large polygonal cells with abundant eosinophilic cytoplasm
Enlarged hyperchromatic nuclei
Prominent nucleoli
Intercellular bridges
Keratin pearls (well-differentiated).
Architectural Patterns:
Solid nests and sheets
Keratin pearl formation
Single-cell infiltration
Desmoplastic stromal response
Surface ulceration common.
Grading Criteria:
Well differentiated: >75% keratinization, minimal pleomorphism
Moderately differentiated: 25-75% keratinization
Poorly differentiated: <25% keratinization, marked pleomorphism.
Immunohistochemistry
Positive Markers:
p63 positive (nuclear, 95%)
p40 positive (more specific)
CK5/6 positive
CK14 positive
34βE12 positive
SOX2 positive.
Negative Markers:
TTF-1 negative
CDX2 negative
CK7 usually negative
CK20 negative
Napsin A negative
Thyroglobulin negative.
Diagnostic Utility:
p63/p40 confirms squamous differentiation
CK5/6 supports squamous phenotype
Helps distinguish from adenocarcinoma and poorly differentiated carcinoma.
Molecular Subtypes:
TP53 mutations common (80-90%)
PIK3CA mutations (20%)
CDKN2A alterations
SOX2 amplification
FGFR1 amplification in some cases.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (80-93%)
PIK3CA mutations (10-20%)
NOTCH1 mutations (15-20%)
KMT2D mutations
NFE2L2 mutations
CDKN2A deletions.
Molecular Markers:
High tumor mutational burden
Chromosomal instability
Copy number alterations common
SOX2 amplification in 20% of cases.
Prognostic Significance:
Stage most important prognostic factor
Depth of invasion and lymph node status critical
Molecular markers under investigation.
Therapeutic Targets:
Limited targeted therapy options
EGFR inhibitors under investigation
Immune checkpoint inhibitors (pembrolizumab) for advanced disease
HER2 targeting in amplified cases.
Differential Diagnosis
Similar Entities:
Esophageal adenocarcinoma
Poorly differentiated carcinoma
Basaloid squamous cell carcinoma
Spindle cell carcinoma
Metastatic squamous cell carcinoma
Severe dysplasia.
Distinguishing Features:
ESCC: p63+, keratinization, intercellular bridges
Adenocarcinoma: TTF-1+ (lung), CDX2+ (GI), mucin production
Metastatic: clinical history, imaging.
Diagnostic Challenges:
Distinction from adenocarcinoma in poorly differentiated tumors
Recognition of basaloid variant
Differentiating from severe dysplasia.
Rare Variants:
Verrucous carcinoma (HPV-associated)
Basaloid squamous cell carcinoma
Spindle cell carcinoma (sarcomatoid)
Lymphoepithelioma-like carcinoma
Small cell 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
Esophagectomy specimen measuring [length] cm
Tumor Location
Tumor located in [upper/middle/lower] third of esophagus, [distance] cm from [landmark]
Tumor Size
Tumor measures [X] x [Y] cm, involves [circumference]% of circumference
Histologic Type
Squamous cell carcinoma, [conventional/variant] type
Histologic Grade
[Well/Moderately/Poorly] differentiated
Depth of Invasion
Tumor invades [mucosa/submucosa/muscularis propria/adventitia] (pT[X])
Lymph Nodes
[X] of [Y] lymph nodes involved (pN[X])
Margins
Proximal margin: [negative/positive], Distal margin: [negative/positive], Radial margin: [negative/positive]
Lymphovascular Invasion
Lymphovascular invasion: [Present/Absent]
Perineural Invasion
Perineural invasion: [Present/Absent]
Background Changes
Background esophagus shows [normal/dysplasia/inflammation]
TNM Staging
pT[X]N[X]M[X], Stage [I/II/III/IV]
Final Diagnosis
Final diagnosis: Esophageal squamous cell carcinoma, [grade], pT[X]N[X]M[X], Stage [X]