Endometrial hyperplasia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Swathi Venkatesan, M.B.B.S.[2]

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.^[1] 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.^[2][1] Endometrial hyperplasia may be broadly classified based on histology into simple and complex types. Endometrial hyperplasia may also be classified based on the presence or absence of cellular atypia (hyperplasia with cellular atypia and hyperplasia without cellular atypia).^[3][4][5] Endometrial hyperplasia must be differentiated from conditions that have similar ultrasound appearances such as normal thickening during the secretory phase, sessile endometrial polyp, submucosal uterine fibroids, endometrial cancer, adherent intrauterine blood clot,and pregnancy.^[4][6][7] Women of all age groups may develop endometrial hyperplasia.^[8] However, endometrial hyperplasia is more common in postmenopausal women. The majority of cases of endometrial hyperplasia, except complex atypical hyperplasia resolve spontaneously with time.^[9] If left untreated, 30% of patients with atypical hyperplasia may progress to develop endometrial carcinoma.^[10] Malignant transformation into endometrial cancer is the most common complication of endometrial hyperpasia.^[11] Prognosis is generally good with treatment. Pelvic ultrasound on days 5 to 10 of menstrual cycle reduce the variability in endometrial thickness and may be helpful in the diagnosis of endometrial hyperplasia. On pelvic ultrasound, endometrial hyperplasia is characterized by a homogeneous increase in the endometrial thickness in the majority of patients. However, endometrial hyperplasia may also cause asymmetric or focal thickening with surface irregularity which should raise a suspicion for malignancy.^[12] Progesterone therapy is the preferred drug for the treatment of benign hyperplasia. The management of endometrial hyperplasia depends upon the desire for future childbearing.^[13] Total hysterectomy is curative for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia.^[14]

Endometrial hyperplasia may be broadly classified based on histology into simple and complex types. Endometrial hyperplasia may also be classified based on the presence or absence of cellular atypia (hyperplasia with cellular atypia and hyperplasia without cellular atypia).^[3][4][5]

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.^[1] Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium. Unopposed oestrogen stimulation may be either from an endogenous or exogenous source.^[1][2]

Endometrial hyperplasia is caused by high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily counteract estrogen‘s proliferative effects on this tissue.^[12]

Endometrial hyperplasia must be differentiated from conditions that have similar ultrasound appearances such as normal thickening during the secretory phase, sessile endometrial polyp, submucosal uterine fibroids, endometrial cancer, adherent intrauterine blood clot, and pregnancy.^[4][6][7]

Women of all age groups may develop endometrial hyperplasia.^[8] However, endometrial hyperplasia is more common in postmenopausal women.

Common risk factors in the development of endometrial hyperplasia include age>35 years, white race, nulliparity, late menopause, early menarche, tamoxifen therapy, obesity, Lynch syndrome, history of diabetes, gallbladder disease, or thyroid disease, and family history of ovarian, colon, or uterine cancers.^[15]

Routine screening for endometrial hyperplasia or endometrial carcinoma is not recommended.

The majority of cases of endometrial hyperplasia, except complex atypical hyperplasia resolve spontaneously with time.^[9] If left untreated, 30% of patients with atypical hyperplasia may progress to develop endometrial carcinoma.^[10] Malignant transformation into endometrial cancer is the most common complication of endometrial hyperpasia.^[11] Prognosis is generally good with treatment.

A positive history of irregular menstrual cycles (PCOD) may be present.^[12] A detailed drug history may be helpful in the assessment of possible risk factors for endometrial hyperplasia. A history of inappropriate hormone replacement therapy in post menopausal women and history of tamoxifen use in breast cancer patients may be present.^[13][16][17]

Patients with endometrial hyperplasia usually appear well. Physical examination of patients with endometrial hyperplasia is usually not remarkable for any physical findings.

Routine laboratory tests are usually normal among patients with endometrial hyperplasia. Some patients with endometrial hyperplasia may have abnormal complete blood count, which is usually suggestive of anemia from prolonged vaginal bleeding.^[18]

There are no CT findings associated with endometrial hyperplasia.

There are no MRI findings associated with endometrial hyperplasia.

Pelvic ultrasound on days 5 to 10 of menstrual cycle reduce the variability in endometrial thickness and may be helpful in the diagnosis of endometrial hyperplasia. On pelvic ultrasound, endometrial hyperplasia is characterized by a homogeneous increase in the endometrial thickness in the majority of patients. However, endometrial hyperplasia may also cause asymmetric or focal thickening with surface irregularity which should raise a suspicion for malignancy.^[12]

There are no other imaging findings associated with endometrial hyperplasia.

Hysteroscopy may be helpful in the direct visualization of precancerous lesions.^[14] Diagnosis of endometrial hyperplasia is usually performed through curettage of the uterine cavity to obtain endometrial tissue for histopathologic analysis.^[18]

Progesterone therapy is the preferred drug for the treatment of benign hyperplasia. The management of endometrial hyperplasia depends upon the desire for future childbearing.^[13]

Total hysterectomy is curative for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia.^[14]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Swathi Venkatesan, M.B.B.S.[2]

The history of endometrial hyperplasia goes back to the 1900s. Initially endometrial carcinoma was discovered and with the development of histological grades, endometrial hyperplasia was explored.The association between estrogen and development of endometrial cancer was first reported in the 1970s. During this time, the incidence of endometrial cancer significantly increased between 1970 and 1975 following the introduction of estrogen replacement therapy.

• The earliest descriptions of endometrial cancer were reported in the early 1900s.
• The association between estrogen and development of endometrial cancer was first reported in the 1970s when the incidence of endometrial cancer significantly increased between 1970 and 1975 following the introduction of estrogen replacement therapy.^[1]
• Surgical staging of endometrial cancer was first suggested in 1988 and was later revised in 2009.^[2]
• The first laparoscopic hysterectomy was reported in 1992.^[3]

The current use of estrogen therapy (ET) and estrogen–progestin therapy (EPT) is the end result of many years of research and clinical practice.

• The history of estrogen goes back to 1900s, when ovarian extracts were used for treatment of dysmenorrhea and amenorrhea.
• In 1923, researchers isolated the use of ovarian extract.
• In the late 1920s researchers evaluated the impact of ovarian extracts on menopausal symptoms.
• In 1928, the first commercially available injectable estrogen was developed.
• In 1942, Ayerst Laboratories commercially introduced the first orally active estrogen, Premarin (conjugated estrogens) in the United States.
• In the mid-1970s, researchers recognized the association between unopposed estrogen therapy and endometrial cancer.
• In the following decades, it was observered that long-term estrogen therapy and estrogen progestin therapy use was associated with a small increase in the risk of breast cancer.
• In 1990s, estrogen therapy and estrogen progestin therapy was prescribed for the prevention and the treatment of menopausal symptoms.

• In 2002, the estrogen progestin therapy was withdrawn because of small increases in the risk of breast cancer and CHD.
• In 2004, the estrogen therpay arm of the Women’s Health Initiative (WHI) was also prematurely discontinued.
• The WHI reported, estrogen therapy had no effect on CHD risk and increased the risk of stroke and deep venous thrombosis (DVT) in this population.^{[4][5][6][7][8][9]}

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Swathi Venkatesan, M.B.B.S.[2]

Endometrial hyperplasia is further classified based on histology into simple and complex types. Endometrial hyperplasia can also be classified based on the presence or absence of cellular atypia; hyperplasia with cellular atypia and hyperplasia without cellular atypia.

• Endometrial hyperplasia may be classified based on glandular complexity and nuclear atypicality into the following types:^[1][2][3]

• The updated WHO classification has been proposed to simplify clinical decision making, particularly when making treatment choices.^[4]
  • 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
  • Hyperplasia without atypia
  • Atypical hyperplasia/endometrioid intraepithelial neoplasia

Endometrial changes may be classified according to the International Endometrial Collaborative Group into two types:^[5][6]

• Benign hyperplasia (a hormone dependent diffuse lesion, which is polyclonal)
  • Benign endometrial hyperplasia is mostly observed with anovulation or after prolonged exposure to estrogen.
  • The morphology of endometrial hyperplasia varies from proliferative endometrium with a few cysts to heavier endometria with many dilated and contorted glands that are designated as “cystic glandular hyperplasia,” “mild hyperplasia,” or “simple hyperplasia.”

• Endometrial intraepithelial neoplasia
  • Endometrial precancers
  • Epithelial crowding depicts less stromal volume which is approximately half of total tissue volume in non secretory endometrium
  • Typically cells appear morphologically clonal and distinct from the surrounding endometrium.
  • With advanced stage, it may become a more diffuse lesion
  • In the beginning a localized clonal proliferation, which is monoclonal and neoplastic (EIN)
• The D-score is an integral part of the EIN classification :
  • It is a measure of stromal volume as a proportion of total tissue volume (stroma + epithelium + gland lumen)

• The D-score is assigned based on evaluation with computerized morphometry
  • Using this method, specimens are classified as:
    • Benign (D >1)
    • Indeterminate (0< D <1)
    • EIN (D <0).^[7]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

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.

• 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.^[1]
• Normal endometrial changes during menstrual cycle:^[2]
  • 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.^[3][1]
  • 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.^[4]
  • 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.^[5][6]

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.^[7]

• Oncogene bcl-2 in complex hyperplasia^[8][9]

• Mutations in PTEN and KRAS PTEN tumor suppressor gene mutations have also been found^[10]

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

• 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 .^[11][12][13]

Endometrial hyperplasia typically represents as: ^[14]

• 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

• Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.^[3]
• On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:^[15]

• Endometrial hyperplasia is morphologically defined as proliferating endometrium with architectural abnormalities.
• These architectural changes are :
  • 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 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

• 
  Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle^[16]
• 
  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^[17]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Endometrial hyperplasia is caused by high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily counteract estrogen‘s proliferative effects on this tissue.^[1]

• Endometrial hyperplasia is caused by high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily counteract estrogen‘s proliferative effects on this tissue.^[1]
• High estrogen may be caused by:^[1]
  • Obesity
  • Polycystic ovarian syndrome
  • Estrogen producing tumors (e.g. granulosa cell tumor)
  • Estrogen replacement therapy

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Endometrial hyperplasia must be differentiated from conditions that have a similar ultrasound findings such as normal thickening during the secretory phase, sessile endometrial polyp, submucosal uterine fibroids, endometrial cancer, an adherent intrauterine blood clot, and pregnancy.

• Endometrial hyperplasia must be differentiated from the following conditions that have abnormal thickening of the uterus:^[1][2][3]

• Early pregnancy prior to sac being visualized (<5 weeks of gestation)
• Ectopic pregnancy (thickened endometrium and sometimes fluid collection or pseudogestational sac can be associated)
• Retained products of conception (heterogeneously thickened endometrium with increased vascularity)
• Adherent intra-uterine blood clot (heterogeneous endometrium with no vascularity)
• Molar pregnancy thickened with multiple small cystic spaces
• Endometritis (prominent hyperechoic endometrium with of without fluid and debris)

• Endometrial carcinoma (variable appearance)
• Endometrial polyp or polyps (usually hyperechoic, often focal, look for vascular stalk)
• Submucosal uterine fibroids
• Intrauterine adhesions (irregular echogenic areas with focal thickening)

• The absence of PAX2 expression on immunohistochemistry is helpful in delineating EIN^[4][5][6][7]
• MMP-9
• BCL-2 overexpression

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Women of all age groups may develop endometrial hyperplasia. However, endometrial hyperplasia is more common in postmenopausal women.

• The incidence endometrial hyperplasia is approximately 133 per 100,000 woman per year worldwide. ^[1]

• The incidence of endometrial hyperplasia increases with age; the median age at diagnosis is 50-54 years.^[1]
• The incidence of atypical hyperplasia is greatest in 60–64 year old women.^[1]

• There is no racial predilection to endometrial hyperplasia.

• endometrial hyperplasia affects women.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Women of all age groups may develop endometrial hyperplasia. However, endometrial hyperplasia is more common in postmenopausal women.

• The incidence endometrial hyperplasia is approximately 133 per 100,000 woman per year worldwide. ^[1]

• The incidence of endometrial hyperplasia increases with age; the median age at diagnosis is 50-54 years.^[1]
• The incidence of atypical hyperplasia is greatest in 60–64 year old women.^[1]

• There is no racial predilection to endometrial hyperplasia.

• endometrial hyperplasia affects women.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Routine screening for endometrial hyperplasia or endometrial carcinoma is not recommended.

• Women receiving unopposed estrogens should undergo endometrial sampling once every 2 years. ^[1]
• Particularly if endometrial hyperstimulation was documented previously and is not been treated by short-term progestins.
• If high-risk individual requests an endometrial evaluation before or during HRT.
• Women at high risk for endometrial carcinoma, such as history of Lynch II syndrome.

Template:WikiDoc Sources

Please help WikiDoc by adding content here. It’s easy! Click here to learn about editing.

Template:WikiDoc Sources

 complications and prognosis