Endometrial hyperplasia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Soujanya Thummathati, MBBS [3]

Overview

Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio. The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.

Pathophysiology

Pathogenesis

• Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio.
• The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.
• Normal endometrial changes during menstrual cycle:
  • The proliferative phase is the second phase in normal mentrual cycle when estrogen causes the lining of the uterus to proliferate. As the ovarian follicles mature, they begin to secrete increasing amounts of estradiol and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium.
  • After ovulation, the remains of the dominant follicle in the ovary become a corpus luteum which produces large amounts of progesterone.
  • Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium.
• Unopposed estrogen stimulation may be either from an endogenous or exogenous source.
  • Excessive endogenous estrogen in pre or perimenopausal women may result from chronic anovulation caused by obesity, polycystic ovary disease, and estrogen producing tumors (e.g. granulosa cell tumor).
  • Excessive exogenous estrogen may result from hormone replacement therapy or non-prescription herbal medications.
• Tamoxifen therapy in breast cancer patients results in an endometrial lesion within 6-36 months of therapy.
  • Tamoxifen is a non-steroidal anti-estrogen that binds to the estrogen receptor and is used primarily for adjuvant therapy in breast cancer
  • Tamoxifen may also act as an estrogen agonist in a low estradiol environment
  • Any patient who develops bleeding while on tamoxifen needs evaluation
• Endometrial hyperplasia may rarely result from the peripheral conversion of androgens to estrogens in androgen-secreting tumors of the adrenal cortex.

Genetics

It is assumed that there is association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms. After experiments, it became evident the DNA repair gene XPD and XRCC4 polymorphisms had a role in the pathophysiology of endometrial hyperplasia.

Other Genes involved

• Oncogene bcl-2 in complex hyperplasia

• Mutations in PTEN and KRAS PTEN tumor suppressor gene mutations have also been found

• Fas/FasL gene also has been investigated recently in the development of endometrial hyperplasia

Mtor Signallin pathway

• mTOR signaling is required for estrogen-mediated growth of endometrial cells
• Dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions .

Gross pathology

Endometrial hyperplasia typically represents as:

• A thickened endometrial stripe on transvaginal ultrasound
• Increased volume of endometrial tissue on hysteroscopy or curettage
• Hyperplasia may be associated with abundant endometrial tissue
• In some cases, localized hyperplasia may mimic a polyp, arise in a background of a polyp, or involve adenomyosis, including deep foci

Microscopic Pathology

• Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.
• On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:

Character	Simple hyperplasia	Complex hyperplasia
Gland to stroma ratio	Normal or slightly increased	Increased
Endometrium	Irregularly dilated cystic glands Out‐pouching, infoldings, and budding of the glands may be present	Glandular crowding Luminal outpouching of glands
Mitoses	May or may not be present	Typically present
Location	Generalized	Focal
Nuclear atypia	Not seen	Not seen

• Endometrial hyperplasia is morphologically defined as proliferating endometrium with architectural abnormalities.
• These architectural changes range as :
  • Cystic dilatation
  • Budding and branching
  • Papillary infoldings
  • Villous and villoglandular growths
  • Cribriform structures.
• In addition to abnormal architecture, a diagnosis of hyperplasia usually requires increased glandular density with a gland-to-stroma ratio of ∼3:1.
• Luminal spaces and villoglandular structures are also included in the glandular component for this calculation.
• If the gland-to-stroma ratio fails to meet the required cut-off, a lesion is probably best classified as disordered proliferative endometrium rather than hyperplasia.
• Although hyperplastic endometrium might have cytologic atypia, this criterion is neither required nor sufficient for this diagnosis.
• The assessment of cytologic atypia is poorly understood, but the various criteria include:
  • Nuclear rounding and enlargement
  • Nuclear pleomorphism
  • Loss of polarity
  • Increased nuclear-to-cytoplasm ratio
  • Prominent nucleoli
  • Irregular nuclear borders
  • Vesicular chromatin
  • Clumped chromatin
  • Atypical cells may show tufting and focal stratification

World Health Organization classification of endometrial hyperplasia

• • Simple hyperplasia without atypia
  • Simple hyperplasia is characterized by:
    • Densely packed, cystically dilated, variable sized glands separated by normal intervening stroma ( Figure 10 ). Although
    • 3:1 gland-to-stroma ratio.
    • Ciliated cells
    • squamous morular metaplasia
  • Complex hyperplasia without atypia
  • Complex hyperplasia without atypia is defined as:
    • Glands with abnormal, irregular architecture set in a background of scant intervening stroma
    • Some stroma must be present,
    • Basement membrane lining individual glands and a rim of intervening endometrial-type stroma between them. In addition to back-to-back and cribriform-like arrangements, other glandular architectural abnormalities warranting designation of complex hyperplasia include
    • Outpouchings,
    • Infoldings, and budding
    • Squamous or morular metaplasia
    • Eosinophilic and ciliated cell changes
  • Simple hyperplasia with atypia
  • Complex hyperplasia with atypia
    • Increased gland-to-stroma ratio (≥3:1)
    • Gland complexity—caused by:
      • Branching
      • Outward budding
      • Internal papillary infoldings
      • Internal bridge

Gallery

• 

  Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle

• 

  Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands