Definition/General
Introduction:
Complex endometrial hyperplasia is a proliferative disorder characterized by increased architectural complexity of endometrial glands
It includes hyperplasia without atypia and atypical hyperplasia/EIN in WHO classification
It shows crowded, irregularly shaped glands
Atypical hyperplasia has significant malignant potential (25-30%).
Origin:
Results from prolonged unopposed estrogen stimulation
Represents progressive architectural distortion
May progress from simple hyperplasia
Atypical hyperplasia shows additional nuclear changes
Associated with clonal proliferation
Precursor lesion to endometrioid carcinoma.
Classification:
WHO 2014 classification includes hyperplasia without atypia and atypical hyperplasia/endometrioid intraepithelial neoplasia (EIN)
Complex hyperplasia without atypia: Architectural complexity, no nuclear atypia
Atypical hyperplasia/EIN: Nuclear atypia present, high cancer risk
Replaces old complex atypical hyperplasia terminology.
Epidemiology:
Peak incidence in 4th-5th decades
Perimenopausal women most affected
Risk factors similar to endometrial carcinoma
PCOS commonly associated
Obesity strongly associated
Complex with atypia has 25-30% cancer risk
Without atypia has 2-5% cancer risk.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Heavy menstrual bleeding
Irregular menstrual cycles
Intermenstrual bleeding
Postmenopausal bleeding
Prolonged menstruation
Pelvic pressure (enlarged uterus)
Infertility (anovulatory cycles).
Symptoms:
Abnormal uterine bleeding (90%)
Menorrhagia
Metrorrhagia
Iron deficiency anemia
Fatigue and weakness
Pelvic pain (may be present)
Dysmenorrhea
Mood changes
Weight gain (hormonal).
Risk Factors:
Unopposed estrogen (endogenous/exogenous)
Obesity (BMI >30)
PCOS
Diabetes mellitus
Nulliparity
Late menopause
Lynch syndrome (hereditary)
Tamoxifen therapy
Estrogen-producing tumors
Chronic anovulation.
Screening:
No routine screening
Endometrial sampling for abnormal bleeding
Transvaginal ultrasound (endometrial thickness)
Hysteroscopy with targeted biopsy
MRI for complex cases
CA-125 may be elevated
Genetic counseling (Lynch syndrome).
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Gross Description
Appearance:
Markedly thickened endometrium
Irregular, polypoid surface
Soft, spongy consistency
Pale to hemorrhagic areas
Cut surface shows cystic spaces
Nodular or lobulated appearance
May have focal firm areas.
Characteristics:
Increased endometrial thickness (>5mm postmenopausal)
Heterogeneous appearance
Polypoid projections common
Cystic dilatation of glands
Areas of hemorrhage
Variable consistency
Well-vascularized.
Size Location:
Diffuse involvement of endometrial cavity
May show focal accentuation
Fundal predominance common
Cornual extension possible
No myometrial invasion (by definition)
May be polypoid.
Multifocality:
Multifocal distribution common
Skip lesions possible
Coexisting simple hyperplasia
Background proliferative endometrium
Associated polyps possible
Heterogeneous involvement.
Microscopic Description
Histological Features:
Crowded, irregularly shaped glands
Back-to-back arrangement
Increased gland-to-stroma ratio
Loss of intervening stroma
Complex architectural patterns
Branching and budding of glands
Papillary infoldings.
Cellular Characteristics:
Without atypia: Uniform nuclei, maintained polarity
With atypia/EIN: Nuclear enlargement, hyperchromasia, loss of polarity
Increased mitotic activity
Nucleolar prominence (atypical)
Cytoplasmic eosinophilia
Loss of ciliated cells.
Architectural Patterns:
Complex branching of glands
Papillary projections
Cribriform patterns
Back-to-back glands
Glandular budding
Decreased stroma (<55% in EIN)
Irregular glandular contours.
Grading Criteria:
Without atypia: Complex architecture, no nuclear atypia
With atypia (EIN): Nuclear atypia present, glands occupy >55% of tissue
EIN criteria: Size >1mm, clonal proliferation, exclude mimics
D-score system may be used.
Immunohistochemistry
Positive Markers:
Estrogen receptor (ER) - positive but may be reduced
Progesterone receptor (PR) - variable, often reduced
Ki-67 - increased proliferation
PAX8 - positive
PTEN - lost in 60-80% of EIN cases
β-catenin - nuclear staining in some cases.
Negative Markers:
p53 - wild-type pattern (patchy staining)
p16 - negative or patchy
Mismatch repair proteins - may be lost in Lynch syndrome
Vimentin - stromal cells positive
CD10 - stromal cells positive.
Diagnostic Utility:
PTEN loss supports diagnosis of EIN
Mismatch repair proteins screening for Lynch syndrome
Ki-67 shows increased proliferation in atypical areas
β-catenin nuclear staining may indicate progression risk
p53 staining excludes serous pathology.
Molecular Subtypes:
PTEN-null subtype (most EIN cases)
Microsatellite instable (Lynch syndrome)
POLE-mutated (rare)
β-catenin activated subtype
Hormonal pathway driven
Precursor molecular profile.
Molecular/Genetic
Genetic Mutations:
PTEN mutations (60-80% of EIN)
PIK3CA mutations (20-30%)
KRAS mutations (10-15%)
Mismatch repair gene mutations (Lynch syndrome)
ARID1A mutations
CTNNB1 mutations (β-catenin)
POLE mutations (rare).
Molecular Markers:
PTEN loss (immunohistochemistry)
PIK3CA overexpression
Microsatellite instability (Lynch cases)
β-catenin nuclear accumulation
Increased Ki-67
Altered hormone receptor expression.
Prognostic Significance:
PTEN loss indicates higher cancer risk
Microsatellite instability may predict better prognosis if cancer develops
Multiple mutations indicate higher progression risk
Molecular profile similar to grade 1 endometrioid carcinoma
Clonal expansion precedes invasion.
Therapeutic Targets:
Progestins (first-line therapy)
Levonorgestrel IUD (local therapy)
Metformin (insulin sensitizer)
Aromatase inhibitors (postmenopausal)
GnRH agonists
Bariatric surgery (morbid obesity)
PI3K inhibitors (investigational).
Differential Diagnosis
Similar Entities:
Simple hyperplasia
Well-differentiated endometrioid carcinoma
Endometrial polyp
Secretory endometrium
Arias-Stella reaction
Disordered proliferative endometrium
Breakdown endometrium.
Distinguishing Features:
Complex hyperplasia: Crowded glands
Complex hyperplasia: Back-to-back arrangement
Complex hyperplasia: No stromal invasion
Simple hyperplasia: Regular glandular spacing
Carcinoma: Stromal invasion present
Carcinoma: Confluent growth
EIN: PTEN loss
EIN: Nuclear atypia
Polyp: Thick-walled vessels.
Diagnostic Challenges:
Distinguishing EIN from early carcinoma
Recognizing focal atypical areas
Separating from artifact (tangential sections)
Identifying stromal invasion
Sampling adequacy assessment
Hormonal effects recognition.
Rare Variants:
Microglandular hyperplasia
Clear cell change in hyperplasia
Squamous metaplasia with hyperplasia
Ciliated cell change
Surface syncytial change
Secretory hyperplasia.
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
Endometrial biopsy/curettage specimen consisting of [amount] of tissue
Specimen Adequacy
Adequate for histopathological evaluation
Diagnosis
Endometrial hyperplasia [without atypia/with atypia (EIN)]
Classification
WHO Classification: [Hyperplasia without atypia/Atypical hyperplasia (EIN)]
Histological Features
Complex architectural pattern with crowded, irregularly shaped glands
Nuclear Features
[No nuclear atypia/Nuclear atypia present] - [details]
Architectural Pattern
Complex glandular architecture with [back-to-back arrangement/branching/papillary infoldings]
Stromal Assessment
Gland-to-stroma ratio: [increased], stromal volume: [<55%/>55%]
Special Studies
PTEN: [retained/lost], Mismatch repair proteins: [intact/lost]
Molecular studies: [if performed]
Malignant Potential
[Without atypia: 2-5% cancer risk/With atypia: 25-30% cancer risk]
Recommendations
[Conservative management with progestins/Consider hysterectomy for atypical hyperplasia]
Follow-up
[3-6 month follow-up for without atypia/Close follow-up or definitive surgery for EIN]
Prognostic Factors
Presence of atypia, patient age, response to therapy
Final Diagnosis
Endometrial [complex hyperplasia without atypia/atypical hyperplasia (EIN)]