Definition/General

Introduction:
-Simple endometrial hyperplasia is a benign proliferative disorder of the endometrial glands and stroma
-It represents non-atypical hyperplasia in the WHO classification system
-It is characterized by increased gland-to-stroma ratio without architectural complexity
-It has minimal malignant potential (<1-2%).
Origin:
-Results from prolonged unopposed estrogen stimulation
-Arises from proliferative endometrium
-Represents exaggerated proliferative response
-May occur in anovulatory cycles
-Associated with hormonal imbalances
-Reversible condition with appropriate treatment.
Classification:
-WHO 2014 classification includes hyperplasia without atypia
-Formerly classified as simple hyperplasia and complex hyperplasia without atypia
-Current classification focuses on presence or absence of atypia
-Simple type shows minimal architectural complexity
-Distinguished from atypical hyperplasia by nuclear features.
Epidemiology:
-Peak incidence in 4th-5th decades
-Common in perimenopausal women
-Associated with anovulatory cycles
-Risk factors include obesity
-PCOS
-Diabetes mellitus
-Unopposed estrogen therapy
-Nulliparity
-Good prognosis with low cancer risk.

Clinical Features

Presentation:
-Abnormal uterine bleeding (most common)
-Heavy menstrual bleeding (menorrhagia)
-Irregular menstrual cycles
-Intermenstrual bleeding
-Prolonged menstrual periods
-Postmenopausal bleeding (if occurring after menopause)
-Pelvic pressure (rare).
Symptoms:
-Heavy menstrual bleeding (80-90%)
-Irregular cycles
-Prolonged menstruation
-Iron deficiency anemia (secondary)
-Fatigue and weakness
-Dysmenorrhea (may be present)
-Mood changes (hormonal)
-Infertility (anovulatory cycles).
Risk Factors:
-Unopposed estrogen (endogenous or exogenous)
-Obesity (peripheral estrogen conversion)
-PCOS (anovulation)
-Diabetes mellitus
-Nulliparity
-Late menopause
-Estrogen-producing tumors
-Chronic anovulation
-Tamoxifen therapy.
Screening:
-No specific screening guidelines
-Endometrial sampling for abnormal bleeding
-Transvaginal ultrasound (endometrial thickness)
-Hysteroscopy may show polypoid appearance
-Hormonal evaluation (FSH, LH, testosterone)
-Thyroid function tests
-Glucose tolerance test.

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Gross Description

Appearance:
-Thickened endometrium with increased volume
-Soft, spongy texture
-Pale to pink coloration
-May show polypoid areas
-Cut surface shows increased glandular spaces
-Cystic dilatation may be visible.
Characteristics:
-Increased thickness (>4mm postmenopausal, >16mm premenopausal)
-Soft consistency with spongy texture
-Uniform appearance
-May have cystic areas
-Well-vascularized
-No areas of firmness or irregularity.
Size Location:
-Involves entire endometrial cavity diffusely
-Endometrial thickness increased
-Fundal predominance common
-May show focal accentuation
-Polypoid projections possible
-No myometrial invasion.
Multifocality:
-Diffuse involvement typical
-May show focal areas of more pronounced change
-Associated with proliferative endometrium
-Uniform distribution
-No discrete masses
-Background proliferative pattern.

Microscopic Description

Histological Features:
-Increased gland-to-stroma ratio
-Uniform, round to oval glands
-Regular glandular outlines
-Minimal architectural complexity
-Increased stromal component
-No back-to-back glandular arrangement
-Glands separated by intervening stroma.
Cellular Characteristics:
-Proliferative-type epithelium
-Pseudostratified nuclei
-Mitotic activity present but not excessive
-No nuclear atypia
-Uniform nuclear features
-Eosinophilic cytoplasm
-Ciliated cells may be present
-Apoptotic bodies minimal.
Architectural Patterns:
-Simple tubular glands
-Round to oval configuration
-Regular spacing with intervening stroma
-No complex branching
-No papillary infoldings
-Straight or slightly curved glandular profiles
-Uniform glandular distribution.
Grading Criteria:
-No grading system for simple hyperplasia
-Assessment focuses on presence or absence of atypia
-Simple hyperplasia: No atypia, minimal complexity
-Degree of hyperplasia described as mild, moderate, or marked
-Mitotic activity assessed but not graded.

Immunohistochemistry

Positive Markers:
-Estrogen receptor (ER) - diffusely positive
-Progesterone receptor (PR) - positive
-Ki-67 - increased compared to normal proliferative endometrium
-PAX8 - positive (müllerian origin)
-Cytokeratins - positive
-EMA - positive.
Negative Markers:
-p53 - wild-type staining pattern
-p16 - negative or patchy
-Mismatch repair proteins - retained expression
-PTEN - retained expression
-β-catenin - membranous staining (normal pattern)
-Chromogranin A - negative.
Diagnostic Utility:
-Hormone receptors confirm hormonal responsiveness
-Ki-67 shows increased proliferation
-p53 wild-type pattern distinguishes from serous carcinoma
-PTEN retention distinguishes from atypical hyperplasia/carcinoma
-Usually not necessary for diagnosis of simple hyperplasia.
Molecular Subtypes:
-Hormonally responsive hyperplasia
-Estrogen-driven proliferation
-Normal DNA repair machinery
-No significant molecular alterations
-Reversible condition with hormone modulation
-Low molecular complexity.

Molecular/Genetic

Genetic Mutations:
-Generally normal genetic profile
-No specific mutations associated
-PTEN mutations rare (unlike atypical hyperplasia)
-p53 mutations absent
-Mismatch repair genes intact
-PIK3CA mutations rare.
Molecular Markers:
-Normal hormonal signaling pathways
-Intact tumor suppressor function
-Normal DNA repair mechanisms
-Estrogen/progesterone pathway activation
-No chromosomal instability
-Low mutational burden.
Prognostic Significance:
-Excellent prognosis with appropriate treatment
-Low cancer risk (<1-2%)
-Reversible condition
-Hormone therapy usually effective
-Regular monitoring sufficient
-Progression to atypia uncommon but possible.
Therapeutic Targets:
-Progesterone therapy (first-line treatment)
-Oral contraceptives (combination therapy)
-Levonorgestrel IUD (local therapy)
-GnRH agonists (temporary suppression)
-Metformin (PCOS patients)
-Weight management.

Differential Diagnosis

Similar Entities:
-Normal proliferative endometrium
-Complex hyperplasia without atypia
-Atypical hyperplasia
-Disordered proliferative endometrium
-Endometrial polyp
-Well-differentiated endometrioid carcinoma.
Distinguishing Features:
-Simple hyperplasia: Increased gland-to-stroma ratio
-Simple hyperplasia: No nuclear atypia
-Simple hyperplasia: Regular glandular spacing
-Normal proliferative: Normal gland-to-stroma ratio
-Atypical hyperplasia: Nuclear atypia present
-Atypical hyperplasia: Loss of polarity
-Complex hyperplasia: Architectural complexity
-Complex hyperplasia: Back-to-back glands.
Diagnostic Challenges:
-Distinguishing from normal proliferative endometrium
-Separating from disordered proliferative endometrium
-Excluding nuclear atypia
-Recognizing minimal architectural changes
-Adequate sampling for representative diagnosis.
Rare Variants:
-Focal simple hyperplasia
-Cystic hyperplasia
-Microglandular hyperplasia
-Metaplastic hyperplasia
-Mixed simple and complex patterns.

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 (simple hyperplasia)

Classification

WHO Classification: Hyperplasia without atypia

Histological Features

Increased gland-to-stroma ratio with regular glandular architecture

Nuclear Features

No nuclear atypia present, proliferative-type epithelium

Architectural Pattern

Simple tubular glands with minimal complexity

Background Endometrium

Proliferative-type endometrium

Special Studies

IHC: [if performed] - hormone receptors positive

Molecular studies: [not routinely performed]

Malignant Potential

Low risk of progression to carcinoma (<1-2%)

Recommendations

Clinical correlation recommended. Consider hormonal therapy. Follow-up in [6-12] months

Prognostic Factors

Benign condition with excellent prognosis

Final Diagnosis

Endometrial hyperplasia without atypia (simple hyperplasia)