Squamous Metaplasia

Definition

"Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. It often represents an adaptive response in which one cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment."

• Robbins, Cotran & Kumar: Pathologic Basis of Disease

Schematic Diagram

Mechanism

1. Reprogramming of local tissue stem cells - Environmental signals (cytokines, growth factors, extracellular matrix components) alter gene expression in resident progenitor/stem cells, driving differentiation toward a squamous phenotype.
2. Colonization by differentiated cells from adjacent areas (less common).

• Robbins, Cotran & Kumar: Pathologic Basis of Disease

Histology

Common Sites and Causes

Key Concept: Adaptive but Costly

• The new squamous epithelium is more resistant to physical stress and chemical insult
• But it loses key protective functions of the original epithelium (e.g., mucus secretion and ciliary clearance in the airways)
• It is therefore generally an undesirable adaptive change, not a beneficial one

Clinical Significance and Malignant Risk

• If the causative stimulus persists, metaplastic epithelium can undergo dysplastic transformation and progress to carcinoma in situ, and ultimately invasive squamous cell carcinoma.
• Classic example: chronic smokers develop squamous metaplasia in the bronchi -> squamous cell carcinoma of the lung
• Bladder schistosomiasis leads to squamous metaplasia -> squamous cell carcinoma of the bladder
• Cervical transformation zone metaplasia -> cervical dysplasia (CIN) -> cervical squamous cell carcinoma (especially with high-risk HPV)

"If the factors (i.e., tobacco smoking) that predispose to squamous metaplasia are not eliminated, the metaplastic epithelium may undergo malignant transformation. In this way, one of the two most common forms of cancer of the respiratory tract, squamous cell carcinoma, originates from squamous metaplastic cells."

• Histology: A Text and Atlas (Pawlina)

Reversibility

Squamous Metaplasia vs. Dysplasia

• Robbins, Cotran & Kumar: Pathologic Basis of Disease (Pathologic Basis of Disease)
• Histology: A Text and Atlas with Correlated Cell and Molecular Biology (Pawlina)
• Pfenninger and Fowler's Procedures for Primary Care

Diseases of the Cervix: Neoplastic and Non-Neoplastic

ANATOMY REVIEW (Context)

• Ectocervix - covered by mature stratified squamous epithelium; visible on vaginal examination
• Endocervical canal - lined by columnar, mucus-secreting epithelium
• Squamocolumnar junction (SCJ) - the meeting point; its position varies with age and hormonal status
• Transformation zone (TZ) - the area where columnar epithelium undergoes squamous metaplasia; this is the most HPV-susceptible region and the site where virtually all precancerous and cancerous lesions arise

Fig. 22.12 Cervical squamocolumnar junction. Immature basal squamous cells and endocervical glandular cells are HPV-susceptible. - Robbins, Cotran & Kumar

NON-NEOPLASTIC DISEASES

1. Cervicitis

Etiology

Pathogenesis

Clinical Features

• Purulent or mucopurulent vaginal discharge
• May cause abnormal Pap test results due to reactive epithelial changes
• Treatment: empiric antibiotics active against chlamydia and gonococcus; nucleic acid amplification tests (NAATs) on vaginal fluid

2. Endocervical Polyp

• Common benign exophytic growths arising from the endocervical canal
• Range from small sessile lesions to large masses protruding through the cervical os
• Histology: fibrous stroma covered by mucus-secreting endocervical glands with inflammation
• Clinical significance: may cause irregular vaginal spotting/bleeding, raising suspicion of a serious lesion; however, they have no malignant potential
• Treatment: simple curettage or surgical excision is curative

NEOPLASTIC DISEASES

Overview: The HPV-Carcinogenesis Axis

Key HPV Biology

• HPV-16: accounts for ~60% of cervical cancer cases
• HPV-18: accounts for ~10% of cases
• Low-risk types (6, 11): cause condyloma acuminatum, not cancer

Molecular Mechanism of HPV Carcinogenesis

• E7 - binds and promotes proteasomal degradation of RB (retinoblastoma protein); also binds and inhibits p21 and p27 (CDK inhibitors) → cell cycle progression despite DNA damage
• E6 - binds and promotes proteasomal degradation of p53 (in high-risk HPVs only); also upregulates telomerase → cellular immortalization

1. Disrupts the HPV gene that negatively regulates E6/E7 → increased E6/E7 expression
2. Increases genomic instability → acquisition of additional pro-oncogenic mutations

3. Squamous Intraepithelial Lesion (SIL) / Cervical Intraepithelial Neoplasia (CIN)

Classification - Two Systems in Use

Morphology

• LSIL/CIN I: Dysplastic changes in the lower 1/3 of epithelium + koilocytic change (nuclear enlargement, perinuclear "halos") in superficial layers - indicates productive HPV replication
• HSIL/CIN II-III: Immature atypical cells extend into the upper 2/3 or full thickness; nuclear pleomorphism, hyperchromasia, increased mitoses; koilocytic change absent or minimal

Fig. 22.15 HPV pathology in the cervix: A=LSIL (koilocytes), B=HPV DNA ISH, C=Ki-67, D=p16. - Robbins, Cotran & Kumar

Natural History (2-year follow-up data)

• LSIL is NOT considered premalignant - majority regress spontaneously
• HSIL is precancerous - arrested maturation, high proliferation, integration of virus
• ~20% of HSIL develops de novo, not from preexisting LSIL
• Progression to invasive carcinoma, when it occurs, takes decades on average

Diagnosis and Screening

• Pap (Papanicolaou) test: cells scraped from transformation zone; most successful cancer screening test ever developed; has reduced cervical cancer mortality by 75% in the US
• HPV DNA testing: highly sensitive; most useful in women ≥30 years (negative test at this age confers ~5-year low risk); less useful <30 due to high HPV prevalence
• Colposcopy + biopsy: for abnormal Pap/HPV results
• HPV vaccination: Quadrivalent (types 6, 11, 16, 18) and 9-valent vaccines; recommended at ages 11-12; 81% drop in HPV infections and 40% reduction in SIL reported with vaccination

4. Invasive Cervical Carcinoma

Epidemiology

• 4th most common cancer in females worldwide (~604,000 new cases in 2020; >50% fatal)

• 85% of cases in resource-limited countries (lack of screening)

• Peak age: ~45-50 years (10-15 years after peak of SIL at ~30 years)
• US: 75% mortality decline since screening began; >50% of invasive cancers occur in unscreened women

Histologic Subtypes

Morphology

• Develops in the transformation zone
• Gross: fungating (exophytic) or infiltrating masses; "barrel cervix" when encircling the cervix
• Squamous cell carcinoma: nests and tongues of malignant squamous cells invading stroma; desmoplastic stromal response; keratinizing tumors form keratin pearls
• Adenocarcinoma: malignant endocervical glands with large hyperchromatic nuclei, mucin-depleted cytoplasm (dark appearance vs. normal pale endocervix)

Fig. 22.17 Adenocarcinoma of the cervix. - Robbins, Cotran & Kumar

Spread

• Direct extension: paracervical soft tissue, urinary bladder, ureters (hydronephrosis), rectum, vagina
• Lymphovascular invasion: pelvic and para-aortic lymph nodes
• Distant metastases: liver, lungs, bone marrow

Staging (FIGO/Robbins)

Prognosis

• Superficially invasive SCC (Ia1): 5-year survival ~100%
• Tumors extending beyond pelvis: <20% 5-year survival
• Neuroendocrine carcinoma and gastric-type HPV-independent adenocarcinoma: very poor prognosis
• Risk of LN metastasis: <1% for tumors <3 mm depth; >10% for invasion >3 mm

Treatment

• Ia1: cone biopsy (excision) may be sufficient
• Ia2 / Ib: radical hysterectomy + pelvic lymph node dissection
• Advanced (Stage II-IV): radiation + cisplatin-based chemotherapy

Summary: Spectrum of Cervical Disease

Normal cervix
    ↓ HPV infection (especially in transformation zone)
    ↓
LSIL (CIN I) — productive infection, koilocytes → 60% REGRESS
    ↓ (persistent high-risk HPV)
HSIL (CIN II/III) — arrested maturation, full-thickness dysplasia → 30% regress; 10% progress
    ↓ (over years to decades)
Microinvasive carcinoma (Stage Ia)
    ↓
Invasive carcinoma (Stages Ib-IV)

• Robbins, Cotran & Kumar: Pathologic Basis of Disease - Chapter 22 (Female Genital Tract)
• Robbins & Kumar: Basic Pathology - Chapter 17 (Female Genital System)