Definition/General

Introduction:
-Endometrial Atypical Hyperplasia (EAH) represents a premalignant condition of the endometrium
-It is characterized by architectural complexity and nuclear atypia
-It has a high risk of progression to endometrioid adenocarcinoma
-The WHO 2020 classification terms it Endometrial Intraepithelial Neoplasia (EIN).
Origin:
-Arises from the endometrial glands and surface epithelium
-Results from unopposed estrogen stimulation
-Shows progressive genetic alterations similar to endometrioid carcinoma
-Represents a step in endometrial carcinogenesis pathway
-Associated with PTEN mutations and microsatellite instability.
Classification:
-WHO 2020 classification: Endometrial Intraepithelial Neoplasia (EIN)
-Previously classified as Complex Atypical Hyperplasia
-Distinguished from Endometrial Hyperplasia without Atypia
-Concurrent carcinoma present in 25-50% of cases
-Risk of progression to carcinoma is 15-45%.
Epidemiology:
-Peak incidence in 4th-5th decades
-Associated with obesity and metabolic syndrome
-Risk factors include nulliparity
-PCOS and anovulation
-Tamoxifen therapy
-Lynch syndrome
-Unopposed estrogen therapy
-Higher prevalence in Western countries but increasing in India due to lifestyle changes.

Clinical Features

Presentation:
-Abnormal uterine bleeding (most common)
-Postmenopausal bleeding (20-30%)
-Menorrhagia and metrorrhagia
-Intermenstrual bleeding
-Asymptomatic in some cases
-Pelvic pain (less common)
-Associated with endometrial thickening on imaging.
Symptoms:
-Heavy menstrual bleeding (80-90% cases)
-Irregular bleeding patterns
-Prolonged bleeding
-Postmenopausal bleeding
-Pelvic pressure
-Bloating and discomfort
-Iron deficiency anemia (chronic bleeding)
-Associated symptoms of PCOS or metabolic syndrome.
Risk Factors:
-Unopposed estrogen exposure
-Obesity (BMI >30)
-Nulliparity
-Late menopause (>55 years)
-PCOS and anovulation
-Diabetes mellitus
-Tamoxifen therapy
-Lynch syndrome
-Family history of endometrial/colorectal cancer
-Estrogen-producing tumors.
Screening:
-Endometrial biopsy for abnormal bleeding
-Transvaginal ultrasound (endometrial thickness)
-Pipelle biopsy or D&C
-Hysteroscopy with directed biopsy
-High-risk patients: genetic counseling
-Lynch syndrome screening when appropriate
-Regular follow-up after treatment.

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Gross Description

Appearance:
-Thickened endometrium (>4-5mm postmenopausal)
-May appear polypoid or focally thickened
-Soft, tan-pink tissue with irregular surface
-May show cystic areas
-Focal hemorrhage or necrosis possible
-Associated with endometrial polyps.
Characteristics:
-Increased endometrial thickness on ultrasound
-Heterogeneous echogenicity
-May show focal hyperechoic areas
-Irregular endometrial-myometrial junction
-Possible polypoidal projections
-Associated fluid collection possible.
Size Location:
-Can be focal or diffuse
-Commonly involves fundus and body
-May spare lower uterine segment
-Size varies from microscopic foci to diffuse involvement
-Associated with background hyperplasia
-May coexist with endometrial polyps.
Multifocality:
-Multifocal disease common (60-70%)
-Skip lesions possible
-Background hyperplasia often present
-May progress to well-differentiated adenocarcinoma
-Concurrent carcinoma in 25-50% of cases
-Requires complete endometrial sampling.

Microscopic Description

Histological Features:
-Architectural complexity with crowded glands
-Gland-to-stroma ratio >1:1
-Irregular gland contours
-Back-to-back glands without intervening stroma
-Nuclear atypia in epithelial cells
-Loss of nuclear polarity
-Increased mitotic activity.
Cellular Characteristics:
-Nuclear enlargement and pleomorphism
-Prominent nucleoli
-Increased nuclear-cytoplasmic ratio
-Loss of nuclear polarity
-Chromatin irregularities
-Mitotic figures present
-Cytoplasm may be eosinophilic or clear
-Surface epithelium often involved.
Architectural Patterns:
-Complex architecture with branching glands
-Back-to-back glands
-Irregular gland shapes and sizes
-Cribriform pattern may be present
-Papillary projections
-Focally solid areas
-Intraglandular bridging
-Minimal intervening stroma.
Grading Criteria:
-Based on architectural complexity and nuclear atypia
-EIN criteria: gland area >stroma area
-Nuclear atypia present
-Size >1mm
-Exclude mimics
-D-score >1 (morphometric analysis)
-Distinction from well-differentiated adenocarcinoma challenging.

Immunohistochemistry

Positive Markers:
-PTEN loss (60-80% of cases)
-PAX2 loss (focal)
-ER positive (usually retained)
-PR positive (may be decreased)
-CK AE1/AE3 positive
-Vimentin negative (unlike stroma)
-MLH1
-MSH2
-MSH6
-PMS2 (Lynch syndrome screening).
Negative Markers:
-p53 wild-type pattern (unlike serous carcinoma)
-p16 negative (patchy staining)
-CD10 negative (in epithelium)
-Smooth muscle actin negative
-Vimentin negative in epithelium
-WT1 negative.
Diagnostic Utility:
-PTEN loss supports EIN diagnosis
-PAX2 loss helps distinguish from reactive changes
-p53 wild-type excludes serous pathology
-Mismatch repair proteins for Lynch syndrome screening
-ER/PR for hormonal therapy guidance
-Morphometric analysis when available.
Molecular Subtypes:
-PTEN-deficient type (most common)
-Microsatellite unstable (Lynch syndrome)
-Hormone receptor positive
-Associated with PIK3CA mutations
-KRAS mutations possible
-Beta-catenin mutations in some cases.

Molecular/Genetic

Genetic Mutations:
-PTEN mutations (60-80%)
-PAX2 loss
-PIK3CA mutations (30-40%)
-KRAS mutations (15-25%)
-CTNNB1 mutations (beta-catenin)
-ARID1A mutations
-Mismatch repair gene defects (Lynch syndrome).
Molecular Markers:
-PTEN protein loss by IHC
-PAX2 loss
-Microsatellite instability (MSI)
-PIK3CA overexpression
-Wnt pathway activation
-Hormone receptor expression
-p53 wild-type pattern.
Prognostic Significance:
-Risk of progression to adenocarcinoma (15-45%)
-PTEN loss indicates higher risk
-MSI associated with Lynch syndrome
-Concurrent carcinoma in 25-50% of hysterectomy specimens
-Size >1mm correlates with progression risk
-Age and obesity influence prognosis.
Therapeutic Targets:
-Hormonal therapy: Progestins (medroxyprogesterone, megestrol)
-LNG-IUD (levonorgestrel-releasing device)
-GnRH agonists
-Aromatase inhibitors
-Metformin (insulin sensitizer)
-mTOR inhibitors (research)
-Bariatric surgery for obesity.

Differential Diagnosis

Similar Entities:
-Endometrial hyperplasia without atypia
-Well-differentiated endometrioid adenocarcinoma
-Secretory endometrium
-Arias-Stella reaction
-Endometrial polyp with hyperplasia
-Metaplastic changes
-Artifact from fragmentation.
Distinguishing Features:
-EAH: Nuclear atypia and architectural complexity
-EAH: PTEN loss and PAX2 loss
-Hyperplasia without atypia: No nuclear atypia
-Well-differentiated adenocarcinoma: Stromal invasion
-Secretory endometrium: Secretory changes
-Arias-Stella: Gestational history.
Diagnostic Challenges:
-Distinguishing from well-differentiated adenocarcinoma
-Crush artifact obscuring morphology
-Fragmented specimens
-Overlapping features with complex hyperplasia
-Concurrent carcinoma sampling issue
-Morphometric analysis when morphology equivocal.
Rare Variants:
-Ciliated cell metaplasia with atypia
-Mucinous metaplasia with atypia
-Squamous metaplasia with atypia
-Hobnail-type atypia
-Clear cell-like changes
-Papillary syncytial metaplasia.

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.

Patient Information

Name: [Patient Name]\nAge: [X] years\nMRN: [Medical Record Number]\nDate of Procedure: [Date]

Clinical History

Clinical indication: [Abnormal uterine bleeding/Postmenopausal bleeding/Other]\nClinical findings: [Relevant history and examination findings]

Specimen Received

Specimen type: Endometrial [biopsy/curettage]\nSpecimen volume: [X] cc of tissue fragments\nFixative: 10% neutral buffered formalin

Gross Examination

The specimen consists of [X] cc of tan-pink, soft tissue fragments measuring up to [X] cm in aggregate. The tissue is entirely submitted for histological examination in [X] cassettes.

Microscopic Examination

Sections show endometrium with complex glandular architecture characterized by gland-to-stroma ratio greater than 1:1. The glands display irregular contours with back-to-back arrangement and minimal intervening stroma. Nuclear atypia is present with enlarged nuclei, prominent nucleoli, and loss of polarity. Mitotic activity is increased. Background endometrium shows [proliferative/secretory/atrophic/hyperplastic] pattern.

Immunohistochemistry

PTEN: [Lost expression in atypical glands/Retained expression]\nPAX2: [Lost expression in atypical glands/Retained expression]\nMismatch Repair Proteins (MLH1, MSH2, MSH6, PMS2): [Intact/Deficient - specify which protein]

Final Diagnosis

ENDOMETRIAL ATYPICAL HYPERPLASIA (ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA - EIN)\n\nWHO 2020 Classification: Endometrial Intraepithelial Neoplasia\nExtent: [Focal/Diffuse]

Comments

ā€¢ Endometrial atypical hyperplasia (EIN) is a premalignant lesion with 15-45% risk of progression to endometrioid adenocarcinoma.\nā€¢ Concurrent adenocarcinoma is present in 25-50% of hysterectomy specimens.\nā€¢ Clinical correlation and multidisciplinary team discussion recommended for optimal management.\nā€¢ Consider hormonal therapy (progestins) or hysterectomy based on patient age, fertility desires, and risk factors.\nā€¢ Regular follow-up with endometrial sampling recommended if conservative management chosen.

Reported By

Dr. [Pathologist Name], MD\nConsultant Pathologist\nDate: [Report Date]