Definition/General

Introduction:
-Cervical Intraepithelial Neoplasia (CIN) represents a spectrum of premalignant squamous epithelial lesions of the cervix caused by persistent high-risk HPV infection
-It is the precursor to invasive squamous cell carcinoma.
Origin:
-Arises from transformation zone of cervix through HPV-mediated transformation
-Develops from normal squamous epithelium through progressive grades (CIN 1, 2, 3) to invasive carcinoma.
Classification:
-Three-tier CIN system: CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia), CIN 3 (severe dysplasia/carcinoma in situ)
-Two-tier HSIL/LSIL system also used.
Epidemiology:
-Peak incidence CIN 1: 20-30 years, CIN 2-3: 25-35 years
-Strong HPV association (99% of cases)
-Most common in sexually active women
-Regression possible in low-grade lesions.

Clinical Features

Presentation:
-Usually asymptomatic
-Detected by cervical screening
-Abnormal Pap smear
-Colposcopic abnormalities
-May have postcoital bleeding.
Symptoms:
-Often completely asymptomatic
-Abnormal vaginal bleeding (rare)
-Postcoital bleeding (uncommon)
-Usually detected on routine screening.
Risk Factors:
-High-risk HPV infection (major factor)
-Multiple sexual partners
-Early sexual activity
-Immunosuppression
-Smoking
-Long-term oral contraceptive use.
Screening:
-Pap smear (cytology)
-HPV testing
-Co-testing (cytology + HPV)
-Colposcopy with directed biopsy
-LEEP/cone biopsy for high-grade lesions.

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Gross Description

Appearance:
-Often not visible grossly
-May appear as white epithelium after acetic acid
-Colposcopic abnormalities include acetowhite areas.
Characteristics:
-Usually not visible to naked eye
-Acetowhite areas on colposcopy
-Punctation and mosaic patterns
-Atypical vessels in high-grade lesions.
Size Location:
-Usually involves transformation zone
-May extend into endocervical canal (high-grade)
-Size variable from focal to extensive.
Multifocality:
-May be multifocal
-Skip lesions possible
-Circumferential involvement in extensive cases
-Field effect with multiple abnormal areas.

Microscopic Description

Histological Features:
-Loss of squamous epithelial maturation with nuclear atypia and increased mitotic activity
-Basement membrane intact (non-invasive)
-Varies by grade.
Cellular Characteristics:
-Nuclear enlargement and hyperchromatism
-Loss of nuclear polarity
-Increased nuclear-cytoplasmic ratio
-Mitotic figures including superficial layers.
Architectural Patterns:
-CIN 1: Lower 1/3 involvement
-CIN 2: Lower 2/3 involvement
-CIN 3: Full thickness or >2/3 involvement
-Surface maturation variable.
Grading Criteria:
-Based on thickness of epithelial involvement and degree of nuclear atypia
-CIN 1: Mild, CIN 2: Moderate, CIN 3: Severe dysplasia/CIS.

Immunohistochemistry

Positive Markers:
-p16 positive (block-type in high-grade)
-Ki-67 positive in basal and parabasal layers
-ProExC positive in high-grade lesions.
Negative Markers:
-HPV L1 capsid protein negative in high-grade (positive in low-grade)
-Involucrin decreased
-Cytokeratin pattern altered.
Diagnostic Utility:
-p16 essential for CIN 2-3 diagnosis
-Ki-67 shows proliferation extent
-p16/Ki-67 dual stain helpful for equivocal cases.
Molecular Subtypes:
-HPV 16/18 associated with higher progression risk
-Different HPV types show varying oncogenic potential.

Molecular/Genetic

Genetic Mutations:
-HPV integration leads to E6/E7 oncogene expression
-p53 and Rb inactivation
-PIK3CA mutations in progression
-TP53 mutations in invasion.
Molecular Markers:
-High-risk HPV DNA detection
-E6/E7 mRNA expression
-p16 overexpression
-Loss of p53 and Rb function
-Chromosomal instability.
Prognostic Significance:
-CIN 1: 60% regression, 10% progression
-CIN 2: 40% regression, 20% progression
-CIN 3: 30% regression, 30% progression to invasion.
Therapeutic Targets:
-HPV vaccines for prevention
-Immune modulators
-Targeted therapy for persistent lesions
-Therapeutic vaccines under development.

Differential Diagnosis

Similar Entities:
-Reactive squamous epithelium
-Immature squamous metaplasia
-Atrophy with inflammation
-Invasive squamous carcinoma
-Condyloma acuminatum.
Distinguishing Features:
-CIN: p16+, loss of maturation
-Reactive: p16-, preserved maturation
-Invasion: Stromal involvement, desmoplasia.
Diagnostic Challenges:
-CIN 1 vs reactive changes
-CIN 2 reproducibility issues
-Assessment of invasion
-Tangential sectioning artifacts.
Rare Variants:
-CIN with koilocytosis
-CIN in pregnancy
-CIN with glandular involvement
-Post-radiation CIN changes.

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

[specimen type], measuring [size] cm in greatest dimension

Diagnosis

[diagnosis name]

Classification

Classification: [classification system] [grade/type]

Histological Features

Shows [architectural pattern] with [nuclear features] and [mitotic activity]

Size and Extent

Size: [X] cm, extent: [local/regional/metastatic]

Margins

Margins are [involved/uninvolved] with closest margin [X] mm

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Lymph Node Status

Lymph nodes: [X] positive out of [X] examined

Special Studies

IHC: [marker]: [result]

Molecular: [test]: [result]

[other study]: [result]

Prognostic Factors

Prognostic factors: [list factors]

Final Diagnosis

Final diagnosis: [complete diagnosis]