Definition/General
Introduction:
Esophageal dysplasia represents neoplastic epithelial proliferation confined within the basement membrane
Most commonly occurs in Barrett's esophagus (intestinal metaplasia)
Classified as low-grade or high-grade dysplasia
Represents precursor lesion to esophageal adenocarcinoma
Shows progressive accumulation of genetic alterations.
Origin:
Arises from metaplastic columnar epithelium in Barrett's esophagus
Results from chronic gastroesophageal reflux
Develops through metaplasia-dysplasia-carcinoma sequence
Associated with p53 mutations and other genetic alterations
May rarely occur in squamous epithelium (squamous dysplasia).
Classification:
WHO classification includes low-grade dysplasia (indefinite for dysplasia, low-grade)
High-grade dysplasia (includes intramucosal carcinoma)
Negative for dysplasia
Vienna classification system also used
Indefinite for dysplasia category for borderline cases.
Epidemiology:
Occurs in 8-15% of Barrett's esophagus patients
Prevalence increases with length of Barrett's segment
Male predominance (3:1 ratio)
Peak incidence in 6th-7th decades
Higher prevalence in Caucasian population
Associated with GERD duration.
Clinical Features
Presentation:
Usually asymptomatic (detected on surveillance)
GERD symptoms (heartburn, regurgitation)
Dysphagia (advanced cases)
Chest pain or discomfort
Barrett's esophagus background
Iron deficiency anemia (occult bleeding)
Incidental finding on endoscopy.
Symptoms:
Heartburn and acid regurgitation
Dysphagia (usually absent in dysplasia alone)
Chest pain or burning sensation
Nocturnal symptoms
Water brash
Chronic cough
Asymptomatic in majority of cases
Symptoms mainly from underlying GERD.
Risk Factors:
Barrett's esophagus (most important)
Chronic GERD (>5 years)
Male gender
Age >50 years
Caucasian race
Obesity (especially central)
Tobacco smoking
Family history of Barrett's or esophageal adenocarcinoma
Hiatal hernia.
Screening:
Surveillance endoscopy in Barrett's patients
Seattle protocol for biopsy sampling
Chromoendoscopy to enhance dysplasia detection
Advanced imaging (narrow-band imaging, confocal endomicroscopy)
High-resolution endoscopy
Biomarker testing under investigation.
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Gross Description
Appearance:
Endoscopic features: subtle mucosal irregularities
Flat lesions most common
Slightly raised areas or nodularity
Erosions or ulcerations
Irregular mucosal pattern
Color changes (reddish or pale areas)
Barrett's mucosa background with salmon-colored appearance.
Characteristics:
Subtle endoscopic changes in most cases
High-grade dysplasia may show more obvious abnormalities
Mucosal nodularity or irregularity
Friable areas
Loss of normal vascular pattern
May be endoscopically invisible
Requires systematic biopsy for detection.
Size Location:
Usually multifocal within Barrett's segment
Patchy distribution common
May be focal or extensive
Location corresponds to Barrett's esophagus distribution
Distal esophagus most common site
Circumferential or tongues of involvement.
Multifocality:
Multifocal disease typical (60-80% cases)
Skip lesions common
Geographic distribution within Barrett's mucosa
Progression from low-grade to high-grade
Heterogeneous within same biopsy
Field effect changes.
Microscopic Description
Histological Features:
Low-grade dysplasia: enlarged, hyperchromatic nuclei, increased mitotic activity, maintained polarity
High-grade dysplasia: severe nuclear atypia, loss of polarity, complex architecture
Dysplastic epithelium confined to basement membrane
Intestinal metaplasia background
Goblet cell depletion with increasing grade.
Cellular Characteristics:
Nuclear enlargement and hyperchromatism
Increased nuclear-cytoplasmic ratio
Prominent nucleoli (especially high-grade)
Loss of nuclear polarity (high-grade)
Mitotic figures increased and may be atypical
Chromatin clumping
Pseudostratification of nuclei.
Architectural Patterns:
Low-grade: preserved glandular architecture with nuclear atypia
High-grade: complex glandular patterns, cribriforming, papillary projections
Back-to-back glands
Villiform surface changes
Nuclear crowding and overlap
Surface maturation may be lost.
Grading Criteria:
Low-grade dysplasia: nuclear atypia, preserved architecture, surface maturation present
High-grade dysplasia: severe nuclear atypia, architectural complexity, loss of surface maturation
Indefinite for dysplasia: features suspicious but not definitive
Assessment requires absence of inflammation.
Immunohistochemistry
Positive Markers:
p53 expression increases with dysplasia grade
Ki-67 proliferation index increases with grade
CK7 positive
CK20 positive (goblet cells)
CDX2 positive (intestinal differentiation)
MUC2 positive (goblet cells)
α-methylacyl-CoA racemase (AMACR) positive.
Negative Markers:
CK5/6 negative (squamous markers)
p63 negative
TTF-1 negative
Chromogranin A and synaptophysin may be focally positive
D2-40 negative (lymphatic marker)
CD68 negative.
Diagnostic Utility:
p53 staining pattern helpful in dysplasia assessment
Complete absence or strong diffuse positivity suggests high-grade dysplasia
Ki-67 shows increased proliferation
Intestinal markers (CDX2, MUC2) confirm intestinal metaplasia
AMACR may highlight dysplastic glands.
Molecular Subtypes:
p53-mutated subtype (pathway to adenocarcinoma)
Non-p53 pathway (rare)
Microsatellite unstable cases (uncommon)
CpG island methylator phenotype (CIMP)
Chromosomal instability pathway most common.
Molecular/Genetic
Genetic Mutations:
p53 mutations (60-80% high-grade dysplasia)
APC mutations (early event)
KRAS mutations (15-30%)
PIK3CA mutations (20%)
SMAD4 mutations (progression to carcinoma)
TP16/CDKN2A inactivation (50%)
ARID1A mutations (30%).
Molecular Markers:
p53 protein accumulation or complete loss
p16 protein loss
Rb protein abnormalities
Cyclin D1 overexpression
EGFR overexpression
HER2/neu amplification (rare)
Aneuploidy increases with dysplasia grade.
Prognostic Significance:
High-grade dysplasia has 30-60% risk of progression to adenocarcinoma
p53 mutations indicate higher progression risk
Aneuploidy predicts progression
Loss of heterozygosity at multiple loci indicates instability
Telomerase activity associated with progression risk.
Therapeutic Targets:
Proton pump inhibitors for acid suppression
Endoscopic therapy (radiofrequency ablation, cryotherapy)
Photodynamic therapy
Endoscopic mucosal resection
Aspirin/NSAIDs may have protective effect
Surveillance protocols for management.
Differential Diagnosis
Similar Entities:
Reactive epithelial changes due to inflammation
Regenerative changes
Cardiac-type mucosa
Adenocarcinoma (invasion through basement membrane)
Indefinite for dysplasia
Specialized intestinal metaplasia without dysplasia.
Distinguishing Features:
Dysplasia: nuclear atypia beyond inflammation
Dysplasia: architectural complexity
Reactive changes: surface maturation preserved
Reactive: prominent nucleoli, vesicular nuclei
Carcinoma: invasion through basement membrane
Carcinoma: desmoplastic stroma.
Diagnostic Challenges:
Distinguishing dysplasia from reactive changes
Inflammation can mimic dysplasia
Surface erosion causing regenerative atypia
Indefinite for dysplasia category management
Interobserver variability in diagnosis
Sampling issues in Barrett's esophagus.
Rare Variants:
Squamous dysplasia (in squamous epithelium)
Adenoma-like dysplasia (raised lesions)
Serrated dysplasia (rare pattern)
Foveolar-type dysplasia
Mixed intestinal and gastric-type dysplasia
Dysplasia in cardiac mucosa.
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 biopsies from [location] with endoscopic findings of [description]
Background Mucosa
Background shows [intestinal metaplasia/Barrett esophagus] with [goblet cells present/absent]
Inflammation
Inflammation: [none/mild/moderate/severe]. Surface [intact/eroded/ulcerated]
Dysplasia Assessment
Nuclear atypia: [grade]. Architectural changes: [description]. Polarity: [maintained/lost]
Diagnosis
[Negative for dysplasia/Indefinite for dysplasia/Low-grade dysplasia/High-grade dysplasia]
Special Studies
p53: [pattern], Ki-67: [percentage], CDX2: [positive/negative] if performed
Recommendations
Follow-up: [interval] based on dysplasia grade. [Additional recommendations]
Final Diagnosis
Barrett esophagus with [dysplasia grade] on a background of intestinal metaplasia