Definition/General

Introduction:
-Vulvar Intraepithelial Neoplasia (VIN) is a precancerous condition of the vulvar epithelium characterized by disordered maturation and nuclear atypia
-It represents the precursor lesion to vulvar squamous cell carcinoma
-HPV-associated (usual type) and HPV-independent (differentiated type) variants exist
-Affects women across all age groups with bimodal distribution.
Origin:
-Arises from squamous epithelium of the vulva
-HPV-related VIN originates from HPV infection (types 16, 18, 31, 33)
-Differentiated VIN arises in background of lichen sclerosus or chronic dermatoses
-Results from progressive accumulation of genetic alterations
-p53 pathway disruption in differentiated type
-Rb pathway disruption in usual type.
Classification:
-Current classification: Low-grade Squamous Intraepithelial Lesion (LSIL) and High-grade Squamous Intraepithelial Lesion (HSIL)
-Usual type VIN (HPV-related, mostly HSIL)
-Differentiated VIN (HPV-independent, high malignant potential)
-Former grading: VIN 1 (mild dysplasia)
-VIN 2 (moderate dysplasia)
-VIN 3 (severe dysplasia/CIS).
Epidemiology:
-Bimodal age distribution: young women (20-35 years, usual type) and elderly women (>60 years, differentiated type)
-HPV-related VIN increasing in younger women
-Risk factors: multiple sexual partners, early sexual activity, immunosuppression
-Progression to carcinoma: usual type 5-10%, differentiated type 30-50%
-Indian population shows increasing incidence.

Clinical Features

Presentation:
-Asymptomatic in 30-50% cases
-Pruritus (most common symptom)
-Burning sensation
-White, gray, or pigmented patches
-Raised or flat lesions
-Multifocal disease common in usual type
-Unifocal lesion typical in differentiated type.
Symptoms:
-Vulvar pruritus (60-80% cases)
-Burning pain (40-60%)
-Vulvar irritation
-Dyspareunia
-Post-coital bleeding
-Discharge
-Vulvar swelling
-Change in vulvar appearance
-Secondary infection common.
Risk Factors:
-HPV infection (types 16, 18, 31, 33)
-Multiple sexual partners
-Early age at first intercourse
-Immunosuppression (HIV, transplant patients)
-Cigarette smoking
-History of cervical dysplasia
-Lichen sclerosus (for differentiated VIN)
-Chronic vulvar dermatoses.
Screening:
-No routine screening program
-Careful visual inspection during gynecological examination
-Vulvoscopy for detailed assessment
-Biopsy of suspicious lesions
-HPV testing may be helpful
-Regular follow-up of high-risk patients
-Photography for lesion mapping.

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Gross Description

Appearance:
-White, gray, or pigmented patches
-Raised or flat lesions
-Rough, hyperkeratotic surface
-May show warty or papillary appearance
-Well-demarcated borders
-Size varies from few millimeters to several centimeters
-May be confluent or discrete.
Characteristics:
-Usual type: multifocal, warty, pigmented
-Differentiated type: unifocal, gray-white, hyperkeratotic
-Acetowhite changes with acetic acid application
-Irregular surface with papillary projections
-May show ulceration if secondary infection.
Size Location:
-Size ranges from 0.5-10 cm
-Most commonly posterior vulva and perineum
-May involve labia majora and minora
-Clitoral involvement possible
-Perianal extension in some cases
-Multifocal disease in 30-60% of usual type.
Multifocality:
-Multifocal disease common in usual type VIN (50-80%)
-Skip lesions may be present
-Satellite lesions around main focus
-Differentiated VIN usually unifocal
-May coexist with lichen sclerosus
-Field cancerization effect possible.

Microscopic Description

Histological Features:
-Loss of epithelial maturation with nuclear atypia
-Increased nuclear-cytoplasmic ratio
-Nuclear hyperchromasia and pleomorphism
-Increased mitotic activity including abnormal forms
-Disorganized architecture
-Hyperkeratosis and parakeratosis often present.
Cellular Characteristics:
-Enlarged nuclei with irregular contours
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Mitotic figures in upper epithelial layers
-Multinucleation may be present
-Koilocytic changes in HPV-related cases
-Dyskeratosis and premature keratinization.
Architectural Patterns:
-Usual type: full-thickness atypia, warty architecture, multinucleation
-Differentiated type: basal atypia with paradoxical maturation, prominent rete ridges
-LSIL: lower one-third involvement
-HSIL: two-thirds or full-thickness involvement
-Surface keratinization common.
Grading Criteria:
-LSIL (VIN 1): atypia confined to lower one-third of epithelium
-HSIL (VIN 2/3): atypia involving two-thirds or full thickness
-Differentiated VIN: basal atypia with abnormal keratinization
-Assessment of nuclear atypia
-Mitotic activity
-Loss of polarity
-Koilocytic changes.

Immunohistochemistry

Positive Markers:
-p16 (diffuse positive in usual type HSIL)
-Ki-67 (increased proliferation index)
-p53 (mutant pattern in differentiated VIN)
-CK5/6 (squamous differentiation)
-p63 (basal/parabasal layers)
-CK14 (basal layer marker)
-Cyclin D1 (increased expression).
Negative Markers:
-p16 (negative/patchy in differentiated VIN)
-HPV in situ hybridization (negative in differentiated VIN)
-p53 (wild-type pattern in usual VIN)
-CK7 (usually negative)
-CEA (negative)
-EMA (negative).
Diagnostic Utility:
-p16 immunostaining distinguishes usual from differentiated VIN
-p53 pattern helps identify differentiated VIN
-Ki-67 assessment of proliferation
-HPV in situ hybridization confirms viral etiology
-p63 confirms squamous nature
-Essential for differential diagnosis.
Molecular Subtypes:
-Usual type VIN: p16 diffuse positive, p53 wild-type
-Differentiated VIN: p16 negative/patchy, p53 mutant pattern
-HPV-positive: ISH positive for HPV DNA
-HPV-negative: ISH negative
-High-risk HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68.

Molecular/Genetic

Genetic Mutations:
-Usual type: HPV E6/E7 proteins inactivate p53/Rb pathways
-Differentiated type: TP53 mutations (70-90%)
-NOTCH1 mutations (20-30%)
-PIK3CA mutations (15-25%)
-HRAS mutations (10-20%)
-CDKN2A deletions (p16 locus)
-TERT promoter mutations.
Molecular Markers:
-HPV integration in usual type
-Chromosomal instability in differentiated type
-p53 pathway disruption
-Rb pathway alterations
-DNA methylation changes
-Telomerase activation
-Microsatellite instability (rare).
Prognostic Significance:
-Differentiated VIN has higher malignant potential (30-50% progression)
-Usual type VIN lower progression risk (5-10%)
-p53 mutations associated with progression risk
-Multifocal disease may increase recurrence
-Immunosuppression increases progression risk
-Age >60 years associated with higher risk.
Therapeutic Targets:
-Topical immunomodulators: Imiquimod 5% cream
-Laser therapy: CO2 laser vaporization
-Surgical excision: wide local excision
-Photodynamic therapy
-Topical 5-fluorouracil
-HPV vaccination for prevention
-Interferon therapy (investigational).

Differential Diagnosis

Similar Entities:
-Lichen sclerosus
-Lichen planus
-Lichen simplex chronicus
-Psoriasis
-Contact dermatitis
-Seborrheic keratosis
-Condyloma acuminatum
-Invasive squamous cell carcinoma.
Distinguishing Features:
-VIN: nuclear atypia and increased mitoses
-VIN: p16 positive (usual type)
-Lichen sclerosus: hyalinized dermis, minimal atypia
-Condyloma: koilocytes without significant atypia
-SCC: invasion through basement membrane
-Dermatitis: inflammatory changes, no atypia
-Immunohistochemistry helpful.
Diagnostic Challenges:
-Distinguishing HSIL from invasive carcinoma
-Differentiated VIN can be subtle and underdiagnosed
-Lichen sclerosus with atypia vs differentiated VIN
-Condyloma with atypia vs usual VIN
-Artifact vs true atypia
-Sampling adequacy important.
Rare Variants:
-VIN with warty features
-VIN with basaloid features
-Bowenoid papulosis (young women, multifocal)
-VIN with sebaceous features
-VIN with apocrine features
-Pagetoid VIN
-VIN in background of lichen sclerosus.

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

Vulvar excision from [site], measuring [size] cm in greatest dimension

Diagnosis

Vulvar intraepithelial neoplasia ([LSIL/HSIL])

Classification

Classification: [HSIL/LSIL], type: [usual/differentiated]

Histological Features

Shows [degree of atypia] with [architectural changes] and [keratinization pattern]

Extent of Involvement

VIN involves [thickness of epithelium] with [multifocal/unifocal] distribution

Margins

Margins: [clear/involved], closest margin [X] mm from VIN

Associated Lesions

Associated lesions: [lichen sclerosus/condyloma/none identified]

HPV Status

HPV association: [suggested by morphology and p16 staining/not determined]

Special Studies

IHC: p16: [diffuse positive/negative/patchy], p53: [wild-type/mutant pattern]

HPV ISH: [positive/negative/not performed]

[other study]: [result]

Prognostic Factors

Risk factors: VIN type, margin status, multifocality, patient age

Final Diagnosis

Vulvar intraepithelial neoplasia, [grade], [type], margins [status]