Definition/General
Introduction:
Esophageal adenocarcinoma (EAC) is a malignant epithelial tumor showing glandular differentiation
It predominantly arises from Barrett esophagus
Increasing incidence in Western countries
Cytological diagnosis requires careful morphological assessment.
Origin:
EAC arises from columnar metaplasia (Barrett esophagus)
Progression: Normal squamous → Intestinal metaplasia → Dysplasia → Adenocarcinoma
Gastroesophageal reflux disease is the primary risk factor
Intestinal-type morphology most common.
Classification:
WHO classification: Adenocarcinoma
Well-differentiated (Grade 1)
Moderately differentiated (Grade 2)
Poorly differentiated (Grade 3)
Subtypes: Intestinal type
Diffuse type
Mixed type.
Epidemiology:
Rising incidence in developed countries
Male predominance (7:1 ratio)
White population more affected
Peak age 60-70 years
Associated with GERD
Obesity as risk factor.
Clinical Features
Presentation:
Progressive dysphagia
Weight loss
Chest pain
Heartburn and reflux symptoms
Early satiety
Nausea and vomiting
Hematemesis.
Symptoms:
Difficulty swallowing solids first
Unintentional weight loss
Retrosternal chest pain
Chronic acid reflux
Regurgitation
Loss of appetite
Fatigue.
Risk Factors:
Barrett esophagus (strongest risk factor)
Gastroesophageal reflux disease
Obesity
Male gender
White race
Smoking
Age >50 years.
Screening:
Barrett esophagus surveillance
High-risk patient screening
Endoscopic surveillance
Biomarker development
Risk stratification.
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Gross Description
Appearance:
Polypoid or ulcerative lesions
Irregular mucosa
Areas of Barrett mucosa
Nodular surface
Color changes
Friable tissue.
Characteristics:
Raised or depressed areas
Irregular surface
Salmon-colored mucosa (Barrett)
Ulceration
Induration
Bleeding surfaces.
Size Location:
Variable size lesions
Distal esophagus (most common)
Gastroesophageal junction
Association with Barrett segment
Multifocal changes possible.
Multifocality:
Field effect in Barrett mucosa
Skip lesions
Synchronous adenomas
High-grade dysplasia adjacent
Metachronous lesions.
Microscopic Description
Histological Features:
Malignant glandular cells
Nuclear atypia and pleomorphism
Increased nuclear-cytoplasmic ratio
Prominent nucleoli
Mitotic activity
Glandular architecture
Mucin production.
Cellular Characteristics:
Enlarged hyperchromatic nuclei
Irregular nuclear contours
Prominent nucleoli
Moderate to abundant cytoplasm
Intracytoplasmic mucin
Signet ring cells (diffuse type).
Architectural Patterns:
Glandular formations
Sheets and clusters
Single cells
Cohesive cell groups
Mucin-filled vacuoles
Signet ring morphology
Necrotic background.
Grading Criteria:
Well-differentiated: Well-formed glands
Moderately differentiated: Moderate gland formation
Poorly differentiated: Solid growth, minimal glands
Nuclear grade assessment.
Immunohistochemistry
Positive Markers:
CK7 (usually positive)
CK20 (variable)
CDX2 (intestinal differentiation)
MUC2 (goblet cells)
Villin
CEA (cytoplasmic)
p53 (often overexpressed).
Negative Markers:
CK5/6 (squamous marker)
p63 (squamous marker)
TTF-1 (lung marker)
Chromogranin
Synaptophysin.
Diagnostic Utility:
Confirms adenocarcinomatous differentiation
Differentiates from squamous cell carcinoma
Intestinal vs gastric type
Primary vs metastatic
Prognostic information.
Molecular Subtypes:
Intestinal type (CDX2+, MUC2+)
Gastric type (MUC5AC+, MUC6+)
Chromosomally unstable
Microsatellite instable (rare)
Genomically stable.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (>70%)
CDKN2A deletions (>50%)
SMAD4 mutations (30%)
PIK3CA mutations (20%)
KRAS mutations (15%)
ARID1A mutations.
Molecular Markers:
HER2 amplification (15-25%)
EGFR expression
VEGF overexpression
PD-L1 expression
Microsatellite instability (2-5%)
Tumor mutational burden.
Prognostic Significance:
Stage most important
Grade affects prognosis
HER2 status predictive
p53 mutations associated with poor prognosis
MSI status affects immunotherapy response.
Therapeutic Targets:
HER2-targeted therapy (trastuzumab)
PD-1/PD-L1 inhibitors
EGFR inhibitors
VEGF inhibitors
FGFR inhibitors
Combination therapies.
Differential Diagnosis
Similar Entities:
Squamous cell carcinoma
High-grade dysplasia
Reactive changes in Barrett
Metastatic adenocarcinoma
Primary gastric carcinoma.
Distinguishing Features:
Adenocarcinoma: Glandular architecture
Adenocarcinoma: CK7 positive
SCC: Squamous markers positive
Dysplasia: Architectural preservation
Reactive: Uniform nuclear features.
Diagnostic Challenges:
Well-differentiated tumors
Crush artifacts
Previous treatment effects
Small biopsies
Inflammation and necrosis.
Rare Variants:
Mucinous adenocarcinoma
Signet ring cell carcinoma
Adenosquamous carcinoma
Undifferentiated carcinoma
Carcinoma with lymphoid stroma.
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 - Adenocarcinoma
Glandular Features
Malignant glandular cells showing [architectural pattern] and [mucin production]
Microscopic Findings
Shows [atypical glandular cells] with [nuclear pleomorphism]
Nuclear Features
Nuclear features: [enlarged, hyperchromatic] with [prominent nucleoli]
Mucin Assessment
Mucin production: [intracellular/extracellular], [intestinal/gastric] type
Differentiation
Differentiation: [well/moderately/poorly] differentiated
Special Studies
IHC: [CK7/CK20/CDX2]: [results]
HER2 testing: [recommended/pending]
Final Diagnosis
Esophageal cytology: Adenocarcinoma