Definition/General

Introduction:
-Cervical Adenocarcinoma In Situ (AIS) is a premalignant glandular lesion representing the precursor to invasive endocervical adenocarcinoma
-It shows full-thickness replacement of endocervical epithelium without stromal invasion.
Origin:
-Arises from endocervical glandular epithelium through HPV-mediated transformation
-Develops from normal endocervical epithelium to AIS to invasive adenocarcinoma progression.
Classification:
-WHO Classification recognizes AIS as precursor to endocervical adenocarcinoma
-No grading system for AIS (either present or absent)
-Strong HPV association.
Epidemiology:
-Peak incidence 30-40 years (10 years older than CIN peak)
-Increasing incidence
-Strong HPV 18 association (70% of cases)
-Less common than CIN but more likely to progress.

Clinical Features

Presentation:
-Often asymptomatic
-Abnormal Pap smear showing atypical glandular cells
-May have abnormal vaginal bleeding or discharge.
Symptoms:
-Usually asymptomatic
-Abnormal vaginal bleeding (irregular)
-Abnormal vaginal discharge
-Detected on routine cervical screening.
Risk Factors:
-High-risk HPV infection (especially HPV 18)
-Oral contraceptive use
-Multiple sexual partners
-Early sexual activity
-Smoking.
Screening:
-Pap smear less sensitive than for squamous lesions
-HPV testing important
-Endocervical curettage essential
-Colposcopy with endocervical assessment.

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Gross Description

Appearance:
-Usually not visible grossly
-Cervix may appear normal
-Possible subtle areas of erythema or granularity.
Characteristics:
-Often no gross abnormality
-May have subtle mucosal changes
-Endocervical canal involvement may not be visible externally.
Size Location:
-Arises within endocervical canal
-May extend to transformation zone
-Often involves upper endocervix
-Multifocal involvement possible.
Multifocality:
-Often multifocal
-Skip lesions common
-May involve extensive length of endocervical canal
-Associated with CIN lesions possible.

Microscopic Description

Histological Features:
-Replacement of normal endocervical epithelium by malignant glandular epithelium
-Intact basement membrane (no invasion)
-Loss of nuclear polarity and architecture.
Cellular Characteristics:
-Enlarged, hyperchromatic nuclei
-Loss of nuclear polarity
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Mitotic figures including apical portions.
Architectural Patterns:
-Glands lined by stratified epithelium
-Complex architectural patterns
-Cribriform areas
-Back-to-back gland arrangement
-Feathering at surface.
Grading Criteria:
-No grading system for AIS
-Diagnosis is binary (present vs absent)
-High-grade lesion by definition
-Distinction from reactive changes important.

Immunohistochemistry

Positive Markers:
-p16 diffuse positive (block-type)
-Ki-67 positive throughout epithelium
-CEA positive
-Mucin stains positive.
Negative Markers:
-Normal endocervical markers may be reduced
-p53 usually shows wild-type pattern
-Estrogen receptor variable.
Diagnostic Utility:
-p16 essential for diagnosis (>90% positive)
-Ki-67 shows full-thickness proliferation
-Helps distinguish from reactive changes.
Molecular Subtypes:
-HPV-associated AIS (majority)
-HPV 18 most common type
-HPV-independent cases rare.

Molecular/Genetic

Genetic Mutations:
-HPV integration with E6/E7 expression
-p53 and Rb pathway inactivation
-PIK3CA mutations
-KRAS mutations less common.
Molecular Markers:
-High-risk HPV DNA (especially HPV 18)
-p16 overexpression
-Loss of p53 and Rb function
-High proliferation markers.
Prognostic Significance:
-High progression risk to invasive adenocarcinoma (30-50%)
-Risk factors for progression include positive margins and HPV 18.
Therapeutic Targets:
-HPV vaccines for prevention
-Complete excision essential
-Immune modulators under investigation.

Differential Diagnosis

Similar Entities:
-Reactive endocervical changes
-Tubal metaplasia
-Endometrial contamination
-Microglandular hyperplasia
-Early invasive adenocarcinoma.
Distinguishing Features:
-AIS: p16+, loss of polarity, full thickness
-Reactive: p16-, preserved polarity
-Invasion: Stromal involvement, desmoplasia.
Diagnostic Challenges:
-Distinction from reactive changes
-Assessment of invasion
-Tangential sectioning
-Adequate sampling of endocervix.
Rare Variants:
-Mixed AIS and CIN
-AIS with squamous differentiation
-Gastric-type AIS
-Intestinal-type AIS.

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]