Endometrium: Simple and complex (cytoglandular and adenomatous) hyperplasia -aetiology and morphology.
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Endometrial Hyperplasia: Simple and Complex (Cytoglandular and Adenomatous)
Definition
Endometrial hyperplasia is an abnormal proliferation of the endometrial glands relative to the stroma, resulting in an increased gland-to-stroma ratio compared with normal proliferative endometrium. It is an important cause of abnormal uterine bleeding and a significant precursor to endometrial carcinoma. - Robbins, Cotran & Kumar Pathologic Basis of Disease
Classification
The WHO / International Society of Gynecological Pathologists (ISGP) system classifies hyperplasia into four subtypes based on architecture (simple vs. complex) and cytologic features (with or without atypia):
| Type | Old synonym | Progression to Carcinoma |
|---|---|---|
| Simple (without atypia) | Cystic / Cytoglandular hyperplasia | ~1% |
| Complex (without atypia) | Adenomatous hyperplasia | ~3% |
| Simple atypical | Cystic atypical | ~8% |
| Complex atypical | Adenomatous with atypia | ~29% |
(Kurman et al., Cancer 1985 - landmark study of 170 untreated patients followed for mean 13.4 years, via Berek & Novak's Gynecology)
Note on modern terminology: The 2015 WHO/ACOG update replaced this 4-tier system with a simpler 2-tier system: hyperplasia without atypia (benign) and atypical hyperplasia/EIN (premalignant). However, the older cytoglandular/adenomatous classification remains widely used and tested.
Aetiology (Pathogenesis)
The fundamental driver in all forms is prolonged, unopposed estrogenic stimulation of the endometrium - i.e., estrogen excess without the counterbalancing effect of progesterone. This leads to continuous stimulation of glandular and stromal proliferation.
Causes of Unopposed Estrogen
| Mechanism | Example |
|---|---|
| Anovulatory cycles | Perimenopause, adolescence |
| Polycystic ovarian syndrome (PCOS) | Chronic anovulation |
| Estrogen-producing ovarian tumors | Granulosa-theca cell tumors |
| Excessive ovarian cortical function | Cortical stromal hyperplasia |
| Obesity | Peripheral conversion of androgens to estrogens in adipose tissue |
| Exogenous estrogen | Estrogen replacement therapy without progestin |
| Tamoxifen use | Acts as partial estrogen agonist on endometrium |
(Robbins, Cotran & Kumar Pathologic Basis of Disease; Berek & Novak's Gynecology)
Molecular Basis - PTEN
A key molecular finding linking hyperplasia to carcinoma is PTEN tumor suppressor gene inactivation:
- PTEN encodes a lipid phosphatase that negatively regulates the PI3K/AKT growth pathway
- Loss of PTEN → PI3K/AKT overactivity → enhanced estrogen receptor signaling → glandular overgrowth
- PTEN mutations occur in >20% of hyperplasias (both with and without atypia) and in 30-80% of endometrial carcinomas
- Their presence confirms hyperplasia and endometrial carcinoma share early genetic events
- Patients with Cowden syndrome (germline PTEN mutations) have high incidence of endometrial carcinoma
(Robbins, Cotran & Kumar Pathologic Basis of Disease)
Morphology
1. Simple Hyperplasia (Cytoglandular / Cystic Hyperplasia)
Architecture:
- Increased gland-to-stroma ratio, but no glandular crowding
- Glands are dilated or cystic ("Swiss cheese" endometrium) with round to slightly irregular shapes
- Some variation in gland size and shape
- Intervening stroma is preserved - glands are not back-to-back
- The term "cystic hyperplasia" (older terminology) reflects the dilated, cyst-like appearance of glands
Cytology:
- No nuclear atypia - cells retain normal columnar morphology and maintain polarity perpendicular to the basement membrane
- Nuclei remain regular, small, and basally oriented
Behavior:
- Low malignant potential (~1% progression to carcinoma)
- Often regresses with progestin therapy or withdrawal of estrogen stimulus
- May evolve into cystic atrophy when estrogen is withdrawn
2. Complex Hyperplasia (Adenomatous Hyperplasia)
Architecture:
- More marked architectural disorganization
- Glands show budding, infolding, and branching - architecturally complex outlines
- Glandular crowding with markedly reduced intervening stroma
- Glands may be back-to-back focally, but some stroma is usually retained (distinguishing it from carcinoma)
- The term "adenomatous" reflects the proliferative, gland-rich (adeno = gland) appearance
Cytology:
- No nuclear atypia - despite architectural complexity, the cells lining the glands remain cytologically normal
- Nuclei are regular, cells maintain orderly orientation
Behavior:
- Moderate malignant potential (~3% progression to carcinoma without atypia; jumps to ~29% when atypia is added)
- Treated with progestins; hysterectomy if atypia present or fertility no longer desired
Atypical Features (for completeness)
When cytologic atypia supervenes on either simple or complex architecture, the lesion is classified as atypical hyperplasia / EIN. Features of cytologic atypia include:
- Large nuclei of variable size and shape
- Loss of nuclear polarity (cells no longer perpendicular to basement membrane)
- Rounded, vesicular (open) chromatin with prominent nucleoli
- Increased nuclear-to-cytoplasmic ratio
- Irregular chromatin clumping with parachromatin clearing
Atypical hyperplasia has considerable morphologic and genetic overlap with well-differentiated endometrioid adenocarcinoma, and up to 40-43% of women with a pre-operative diagnosis of atypical hyperplasia are found to have concurrent carcinoma on hysterectomy. (Robbins, Cotran & Kumar Pathologic Basis of Disease; Berek & Novak's Gynecology)
Summary Table
| Feature | Simple (Cytoglandular) | Complex (Adenomatous) |
|---|---|---|
| Old synonyms | Cystic hyperplasia | Adenomatous hyperplasia |
| Gland:stroma ratio | Increased | More markedly increased |
| Gland shape | Dilated, cystic, round | Budding, infolding, complex |
| Glandular crowding | Absent | Present |
| Cytologic atypia | Absent | Absent |
| Stroma | Preserved between glands | Markedly reduced |
| Malignant risk (without atypia) | ~1% | ~3% |
| With atypia | ~8% | ~29% |
| Key driver | Unopposed estrogen | Unopposed estrogen |
| Molecular change | PTEN mutation (>20%) | PTEN mutation (>20%) |
Sources: - Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), pp. 2804-2852 | - Robbins & Kumar Basic Pathology (11th ed.), pp. 609-621 | - Berek & Novak's Gynecology, pp. 4135-4148 and pp. 2145-2147 | - Pfenninger & Fowler's Procedures for Primary Care (3rd ed.), pp. 510-519
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