MBBS Pathology Notes: Ulcerative Dysplasia & Non-Ulcerative Dysplasia

PART 1 - DYSPLASIA: GENERAL CONCEPTS

Hallmarks of Dysplasia (General)

Key distinction from reactive/regenerative changes: in inflammation, epithelial cells mature as they reach the mucosal surface; in dysplasia, cells remain cytologically immature at the surface.

• Robbins & Kumar Basic Pathology, p. 557
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 749

PART 2 - ULCERATIVE DYSPLASIA

Pathogenesis

• Long-standing UC causes repeated cycles of mucosal injury and regeneration
• Inflammation-related free radical damage accumulates genetic alterations
• Key molecular events: p53 mutation (early), p16 inactivation, oncogene activation, genomic instability
• Two pathways to cancer: (1) step-wise accumulation of mutations, (2) whole-genome doubling (faster pathway)

Risk Factors for Cancer in UC

1. Duration - risk rises sharply after 8-10 years of disease
2. Extent - pancolitis > left-sided disease; proctitis alone has no increased risk
3. Severity of inflammation - greater frequency and severity of neutrophilic infiltration = higher risk
4. Coexisting Primary Sclerosing Cholangitis (PSC) - 4x increased risk; begin surveillance at diagnosis
5. Family history of CRC in first-degree relative <50 years
6. Male gender, prior history of dysplasia, stricturing disease in UC

Classification of Ulcerative Dysplasia (IBD-Associated)

• Visible dysplasia - detected in clearly identifiable lesions:
  • Polypoid (pedunculated/sessile)
  • Non-polypoid (superficially elevated, flat, or depressed)
• Invisible dysplasia - detected only in random biopsy samples, not visible endoscopically

The old terms "DALM" (dysplasia-associated lesion or mass) and "sporadic adenoma" are now abandoned and replaced by "visible" and "invisible" dysplasia.

• Clinical Gastrointestinal Endoscopy Expert Consult 3e, p. 588

Morphology (Histology)

• Nuclei are pencil-shaped (elongated), hyperchromatic
• Nuclear stratification confined to lower half of cell
• Cytoplasm shows some maturation towards surface
• Glandular architecture mildly distorted

• Nuclei rounded, markedly enlarged, prominent nucleoli
• Nuclear stratification throughout full thickness of epithelium
• Loss of cytoplasmic maturation
• Architectural disarray: cribriform glands, villiform surfaces, back-to-back glands
• Atypical mitoses prominent
• Robbins, Cotran & Kumar Pathologic Basis of Disease

Clinical Importance of Ulcerative Dysplasia

• Dysplasia is a precursor of colitis-associated carcinoma
• Dysplasia can occur in flat (endoscopically normal) mucosa - hence need for systematic biopsies
• Interobserver variability is HIGH for LGD (<50% agreement); BETTER for HGD (~85%)
• Second opinion from specialist GI pathologist is mandatory when dysplasia is detected

Surveillance Protocol

• Screening colonoscopy 8-10 years after IBD onset (even in isolated proctitis)
• Annual surveillance for highest risk: PSC + UC, extensive active inflammation, family history CRC <50 yrs, prior dysplasia, stricturing disease
• Random biopsies: 4-quadrant biopsies every 10 cm throughout colon (33 biopsies needed for 90% sensitivity)
• High-definition colonoscopy + chromoendoscopy preferred over random biopsies
• Clinical Gastrointestinal Endoscopy Expert Consult 3e

Management Based on Dysplasia Grade

PART 3 - NON-ULCERATIVE DYSPLASIA

1. Gastric epithelium (in chronic gastritis, without active ulceration)
2. Esophageal/Barrett epithelium
3. Squamous epithelium (oral cavity, larynx, cervix, vulva)

3A. GASTRIC DYSPLASIA (Non-Ulcerative)

Normal gastric mucosa → Chronic gastritis → Atrophy → Intestinal metaplasia → Dysplasia → Adenocarcinoma (Correa cascade)

• Variations in epithelial size, shape, and orientation
• Coarse chromatin, hyperchromasia, nuclear enlargement
• Reactive/regenerative cells mature at the surface; dysplastic cells do not

• LGD: tubular architecture preserved, mild cytologic atypia
• HGD: loss of architecture, marked nuclear atypia, atypical mitoses

• Gastric adenoma (10% of gastric polyps) exhibits dysplasia - risk of malignant transformation far greater than colonic polyps
• Carcinoma found in up to 30% of gastric adenomas at time of excision
• Risk significantly elevated with lesions >2 cm
• Robbins & Kumar Basic Pathology, p. 557

3B. ESOPHAGEAL (BARRETT) DYSPLASIA (Non-Ulcerative)

1. Negative for dysplasia
2. Indefinite for dysplasia
3. Low-grade dysplasia (LGD)
4. High-grade dysplasia (HGD)

• p53 mutation occurs early (in metaplastic Barrett cells)
• Then: p16 inactivation → oncogene activation → genomic instability
• OR: p53-mutant cells undergo whole-genome doubling → rapid cancer formation

• Nuclear changes: enlargement, pleomorphism, hyperchromatism, stratification, atypical mitoses
• Loss of cytoplasmic maturation (surface cells remain immature)
• Crowding of tubules and villiform surfaces (architectural distortion)

• HGD: radiofrequency ablation (RFA) or esophagectomy
• LGD: surveillance every 6-12 months, RFA increasingly recommended
• Sleisenger & Fordtran's GI and Liver Disease

3C. SQUAMOUS EPITHELIAL DYSPLASIA (Oral/Laryngeal - Non-Ulcerative)

• Loss of basal cell polarity, "streaming" of spinous layer toward surface
• Nuclear hyperchromatism, pleomorphism
• Increased mitoses including atypical forms
• Drop-shaped rete ridges

• White patch that cannot be wiped off (keratosis)
• Dysplasia/carcinoma in situ/invasive carcinoma found in 17-25% of leukoplakia biopsies
• Risk areas: floor of mouth, lateral tongue, soft palate (high risk)
• Erythematous/granular/ulcerated areas should be biopsied first

• Benign/mild dysplasia: observe or elective excision
• Moderate or worse: mandatory removal (scalpel, laser, cryoablation, electrocautery)
• No proven chemoprevention strategy (retinoids under study)
• Cummings Otolaryngology Head & Neck Surgery, p. 1581

3D. CERVICAL/VULVAR DYSPLASIA (CIN/VIN - Non-Ulcerative)

• Cervical Intraepithelial Neoplasia (CIN) / Vulvar Intraepithelial Neoplasia (VIN) - NOT caused by ulceration; caused by HPV
• Graded as CIN I (mild), CIN II (moderate), CIN III (severe/CIS)
• Managed according to grade: observation (CIN I), colposcopy/LEEP/cone biopsy (CIN II-III)

PART 4 - KEY COMPARISON TABLE: ULCERATIVE vs. NON-ULCERATIVE DYSPLASIA

PART 5 - HIGH-YIELD EXAM POINTS

1. Dysplasia = pre-invasive, cytologically abnormal epithelium without basement membrane breach
2. In UC, dysplasia surveillance starts 8-10 years after onset; PSC patients start at time of diagnosis
3. "Indefinite for dysplasia" is a valid category in IBD biopsies - confirm with second GI pathologist
4. Old DALM terminology is abandoned - use "visible" vs. "invisible" dysplasia instead
5. Reactive epithelium matures at the surface; dysplastic epithelium does not
6. Squamous dysplasia graded by how many thirds of epithelium are involved (lower 1/3, 2/3, full thickness)
7. Barrett LGD: <50% interobserver agreement; HGD: ~85% agreement
8. Colitis-associated dysplasia is often multifocal and can be flat/invisible - need systematic biopsies
9. Non-ulcerative dysplasia in gastric adenoma carries risk of carcinoma in up to 30% of cases
10. HGD in any setting = colectomy (IBD) or ablation/resection (Barrett/oral)

• Robbins & Kumar Basic Pathology, p. 557 (gastric dysplasia, general concepts)
• Robbins, Cotran & Kumar Pathologic Basis of Disease (colitis-associated neoplasia; Barrett dysplasia)
• Sleisenger & Fordtran's GI and Liver Disease (Barrett dysplasia pathway, IBD surveillance)
• Clinical Gastrointestinal Endoscopy Expert Consult 3e (IBD dysplasia classification, AGA guidelines)
• Cummings Otolaryngology Head & Neck Surgery, p. 1581 (squamous epithelial dysplasia, oral leukoplakia)