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PA2.{3,6-7} | Cellular Adaptations, Accumulations & Aging — SDL Guide (Part 2)

Hyperplasia

Hyperplasia is an increase in cell number in a tissue or organ, driven by increased mitotic activity in cells capable of division. It often accompanies hypertrophy.

Physiologic hyperplasia:
• Hormonal — endometrial hyperplasia at puberty/pregnancy; breast glandular hyperplasia in pregnancy
• Compensatory — liver regeneration after partial hepatectomy (up to 70% resection)

Pathologic hyperplasia:
• Endometrial hyperplasia from excess oestrogen (post-menopausal oestrogenic stimulation → risk of endometrial carcinoma)
• Benign prostatic hyperplasia (BPH) — glandular and stromal hyperplasia from dihydrotestosterone excess
• Skin warts — HPV-driven epithelial hyperplasia

Hyperplasia vs Neoplasia:

Feature	Hyperplasia	Neoplasia
Growth stimulus	External (hormones, GFs)	Autonomous (mutation)
Growth control	Halts when stimulus removed	Continues without stimulus
Architecture	Preserved	Disrupted
Reversibility	Yes	No

Pathologic hyperplasia, while controlled, provides fertile ground for neoplasia: if a proliferating cell acquires a mutation, that cell may escape normal growth control.

Metaplasia

Metaplasia is a reversible change in which one differentiated cell type is replaced by another, usually in response to chronic irritation or abnormal microenvironment.

Squamous metaplasia (most common):
• Respiratory tract: bronchial pseudostratified columnar epithelium → squamous epithelium in chronic smokers
• Cervix: endocervical columnar → squamous at transformation zone (normal physiologic variant → pathologic with HPV)
• Urinary bladder, gallbladder with chronic inflammation

Columnar (glandular) metaplasia:
• Barrett oesophagus: normal stratified squamous oesophageal epithelium → specialised intestinal-type columnar epithelium, driven by chronic GORD. Clinically significant because it is a pre-neoplastic lesion (risk of oesophageal adenocarcinoma ×30–40).

Mechanism: Reprogramming of stem cells — the resident (or migrating) stem cells differentiate down a different pathway in response to altered signals (retinoic acid, BMP). The mature cells themselves do not transdifferentiate; new cells emerge with a different phenotype.

Reversibility and risk: Metaplasia is reversible if the stimulus is removed (e.g., bronchial metaplasia partially regresses on smoking cessation). However, the new epithelium may be less functional (loss of cilia → impaired mucociliary clearance) and carries a risk of malignant transformation if the stimulus persists — particularly if squamous metaplasia passes through a dysplastic phase.

Four-panel diagram explaining metaplasia as reversible stem cell reprogramming with bronchial squamous metaplasia, Barrett oesophagus, and risk of dysplasia and carcinoma. — **Panel A:** Normal differentiated epithelium, stem cell niche, chronic irritation, abnormal microenvironment, reprogramming of stem cells, altered differentiation pathway, mature cells do not transdifferentiate. **Panel B:** Bronchial pseudostratified ciliated columnar epithelium, goblet cells, cigarette smoke, squamous metaplasia, stratified squamous epithelium, loss of cilia, impaired mucociliary clearance. **Panel C:** Normal stratified squamous oesophageal epithelium, chronic GORD, acid reflux, specialised intestinal-type columnar epithelium, goblet cells, Barrett oesophagus, risk of oesophageal adenocarcinoma. **Panel D:** Removed stimulus, reversibility, persistent stimulus, metaplasia, dysplasia, carcinoma, smoking cessation, GORD control, malignant transformation risk.

CLINICAL PEARL

Barrett's oesophagus is detected on endoscopy as 'salmon-pink' tongues of mucosa extending up from the gastro-oesophageal junction. Histological confirmation requires goblet cells (alcian blue positive). Surveillance biopsies every 3–5 years look for progression to dysplasia. Low-grade dysplasia → high-grade → adenocarcinoma is the classic sequence. Never call Barrett's 'just metaplasia' in a clinical setting — it demands active surveillance.

Dysplasia — Disordered Growth and Pre-neoplastic Risk

Dysplasia (literally 'disordered growth') refers to a spectrum of architectural and cytological abnormalities in a tissue, intermediate between normal and carcinoma in situ. It is not synonymous with metaplasia, nor with cancer.

Cytological features of dysplasia:
• Pleomorphism — variation in cell size and shape
• ↑ Nuclear-cytoplasmic ratio
• Nuclear hyperchromatism
• Loss of polarity — cells no longer arranged perpendicular to basement membrane
• Abnormal mitotic figures
• Premature keratinisation (dyskeratosis)

Grading — cervical intraepithelial neoplasia (CIN) as prototype:
• CIN 1 (mild dysplasia): changes confined to lower ⅓ of epithelium
• CIN 2 (moderate): lower and middle ⅓
• CIN 3 / CIS (severe/carcinoma in situ): full thickness, basement membrane intact

Dysplasia vs Metaplasia vs Cancer:

	Metaplasia	Dysplasia	Carcinoma in situ	Invasive carcinoma
BM intact	Yes	Yes	Yes	No
Architecture	Preserved	Partially disrupted	Fully disrupted	Invasive
Reversibility	Yes	Partially	No	No
Cytological atypia	Absent	Present	Marked	Marked

Dysplasia is pre-neoplastic, not malignant. Low-grade dysplasia may regress; high-grade dysplasia (CIN 3) has significant risk of progression and is treated.

Diagram showing dysplastic epithelial changes, CIN grading by epithelial thickness, and comparison with metaplasia, carcinoma in situ, and invasive carcinoma. — **Panel A:** Normal stratified squamous epithelium, dysplastic epithelium, basement membrane, pleomorphism, increased nuclear-cytoplasmic ratio, nuclear hyperchromatism, loss of polarity, abnormal mitotic figures, dyskeratosis. **Panel B:** CIN 1 mild dysplasia limited to lower one-third, CIN 2 moderate dysplasia involving lower and middle two-thirds, CIN 3 / carcinoma in situ involving full epithelial thickness, intact basement membrane. **Panel C:** Metaplasia with intact basement membrane and orderly architecture, dysplasia with intact basement membrane and disordered architecture, carcinoma in situ with full-thickness atypia and intact basement membrane, invasive carcinoma with basement membrane breach and stromal invasion.

SELF-CHECK

A 28-year-old woman's Pap smear shows cells with a high nuclear-cytoplasmic ratio, nuclear hyperchromatism, and loss of polarity. Colposcopic biopsy confirms changes confined to the lower two-thirds of the cervical epithelium with an intact basement membrane. What is the correct diagnosis?

A. Squamous metaplasia of the cervix

B. CIN 1 (mild dysplasia)

C. CIN 2 (moderate dysplasia)

D. Invasive squamous cell carcinoma

Reveal Answer

Answer: C. CIN 2 (moderate dysplasia)

Changes extending through the lower two-thirds of the epithelium with cytological atypia (↑ N:C ratio, hyperchromatism, loss of polarity) and an intact basement membrane define CIN 2. CIN 1 involves only the lower third; CIN 3/CIS involves full thickness. Invasion requires basement membrane breach. Metaplasia lacks cytological atypia.