Endometrial Hyperplasia

Question 1

What are the risk factors for endometrial hyperplasia?

Answer 1

• Endometrial hyperplasia is often associated with multiple identifiable risk factors & assessment
  should aim to identify and monitor these factors.

Question 2

How should endometrial hyperplasia be classified?

Answer 2

• Revised 2014 WHO classification is recommended.
• This separates endometrial hyperplasia into 2 groups based upon presence of cytological atypia: i.e. (i) hyperplasia without atypia and (ii) atypical hyperplasia.

Question 3

What diagnostic and surveillance methods are available for endometrial hyperplasia?

Answer 3

• Diagnosis of endometrial hyperplasia requires histological examination of endometrial tissue.
  Endometrial surveillance should include endometrial sampling by outpatient endometrial biopsy.
• Diagnostic hysteroscopy should be considered to facilitate or obtain an endometrial sample, especially
  where outpatient sampling fails or is nondiagnostic.
• Transvaginal ultrasound may have a role in diagnosing endometrial hyperplasia in pre- and postmenopausal women.
• Direct visualisation and biopsy of the uterine cavity using hysteroscopy should be undertaken where
  endometrial hyperplasia has been diagnosed within a polyp or other discrete focal lesion.
• There is insufficient evidence evaluating CT, diffusion-weighted MRI or biomarkers as aids in the management of endometrial hyperplasia and their use is not routinely recommended.

Question 4

What should the initial management of hyperplasia without atypia be?

Answer 4

• Women should be informed that risk of endometrial hyperplasia without atypia progressing to endometrial cancer is less than 5% over 20 years and that the majority of cases of endometrial hyperplasia without atypia will regress spontaneously during follow-up.
• Reversible risk factors such as obesity and the use of HRT should be identified and addressed if possible.
• Observation alone with follow-up endometrial biopsies to ensure disease regression can be considered, especially when identifiable risk factors can be reversed. However, women should be informed that treatment with progestogens has a higher disease regression rate compared with observation alone.
• Progestogen treatment is indicated in women who fail to regress following observation alone and in symptomatic women with abnormal uterine bleeding.

Question 5

What should the first-line medical treatment of hyperplasia without atypia be?

Answer 5

• Both continuous oral and local LNG-IUS progestogens are effective in achieving regression of endometrial hyperplasia without atypia.
• The LNG-IUS should be the first-line medical treatment because compared with oral progestogens it has a higher disease regression rate with a more favourable bleeding profile and it is associated with fewer adverse effects.
• Continuous progestogens should be used (medroxyprogesterone 10–20 mg/day or norethisterone
  10–15 mg/day) for women who decline the LNG-IUS.
• Cyclical progestogens should not be used because they are less effective in inducing regression of endometrial hyperplasia without atypia compared with continuous oral progestogens orthe LNG-IUS.

Question 6

What should the duration of treatment and follow-up of hyperplasia without atypia be?

Answer 6

• Treatment with oral progestogens or LNG-IUS should be for minimum of 6 months in order to induce histological regression of endometrial hyperplasia without atypia.
• If adverse effects are tolerable & fertility is not desired, women should be encouraged to retain LNG-IUS for up to 5 years as this reduces the risk ofrelapse, especially if it alleviates abnormal uterine bleeding symptoms.
• Endometrial surveillance incorporating outpatient endometrial biopsy is recommended after diagnosis of hyperplasia without atypia.
• Endometrial surveillance should be arranged at a minimum of 6-monthly intervals, although review schedules should be individualised and responsive to changes in a woman’s clinical condition. At least two consecutive 6-monthly negative biopsies should be obtained prior to discharge.
• Women should be advised to seek a further referral if abnormal vaginal bleeding recurs after completion of treatment because this may indicate disease relapse.
• In women at higher risk of relapse, such as women with BMI of 35 or greater or those treated with oral progestogens, 6-monthly endometrial biopsies are recommended. Once two consecutive negative endometrial biopsies have been obtained then long-term follow-up should be considered with annual endometrial biopsies.

Question 7

When is surgical management appropriate for women with endometrial hyperplasia without atypia?

Answer 7

• Hysterectomy should not be considered as first-line treatment for hyperplasia without atypia b/c progestogen therapy induces histological & symptomatic remission in majority of women & avoids morbidity associated with major surgery.
• Hysterectomy is indicated in women not wanting to preserve their fertility when (i) progression to atypical hyperplasia occurs during follow-up, or (ii) there is no histological regression of hyperplasia despite 12 months of treatment, or (iii) there is relapse of endometrial hyperplasia after completing progestogen treatment, or (iv) there is persistence of bleeding symptoms, or (v) the woman declines to undergo endometrial surveillance or comply with medical treatment.
• Postmenopausal women requiring surgical MX for endometrial hyperplasia without atypia should be offered a bilateral salpingo-oophorectomy together with the total hysterectomy.
• For premenopausal women, the decision to remove ovaries should be individualised; however, bilateral salpingectomy should be considered as this may reduce the risk of a future ovarian malignancy.
• A laparoscopic approach to total hysterectomy is preferable to abdominal approach as it is associated with a shorter hospital stay, less postoperative pain and quicker recovery.
• Endometrial ablation is not recommended for treatment of endometrial hyperplasia b/c complete and persistent endometrial destruction cannot be ensured and intrauterine adhesion formation may preclude future endometrial histological surveillance.

Question 8

What should the initial management of atypical hyperplasia be?

Answer 8

• Women with atypical hyperplasia should undergo a total hysterectomy because of risk of underlying malignancy or progression to cancer.
• A laparoscopic approach to total hysterectomy is preferable to an abdominal approach as it is associated with a shorter hospital stay, less postoperative pain and quicker recovery.
• There is no benefit from intraoperative frozen section analysis of endometrium or routine lymphadenectomy.
• Postmenopausal women with atypical hyperplasia should be offered bilateral salpingo-oophorectomy
  together with total hysterectomy.
• For premenopausal women, decision to remove ovaries should be individualised; however, bilateral salpingectomy should be considered as this may reduce the risk of a future ovarian malignancy.
• Endometrial ablation is not recommended b/c complete and persistent endometrial destruction
  cannot be ensured and intrauterine adhesion formation may preclude endometrial histological surveillance.

Question 9

How should women with atypical hyperplasia who wish to preserve their fertility or who are not suitable for surgery be managed?

Answer 9

• Women wishing to retain theirfertility should be counselled about risks of underlying malignancy & subsequent progression to endometrial cancer.
• Pretreatment investigations should aim to rule out invasive endometrial cancer or co-existing ovarian
  cancer.
• Histology, imaging and tumour marker results should be reviewed in a multidisciplinary meeting and
  a plan for management and ongoing endometrial surveillance formulated.
• First-line treatment with the LNG-IUS should be recommended, with oral progestogens as second-best alternative
• Once fertility is no longer required, hysterectomy should be offered in view of high risk of disease relapse.

Question 10

How should women with atypical hyperplasia not undergoing hysterectomy be followed up?

Answer 10

• Routine endometrial surveillance should include endometrial biopsy. Review schedules should be
  individualised & be responsive to changes in woman’s clinical condition. Review intervals should be every 3 months until two consecutive negative biopsies are obtained.
• In asymptomatic women with uterus and evidence of histological disease regression, based upon minimum of two consecutive negative endometrial biopsies, long-term follow-up with endometrial biopsy every 6–12 months is recommended until a hysterectomy is performed.

Question 11

How should endometrial hyperplasia be managed in women wishing to conceive?

Answer 11

• Disease regression should be achieved on at least 1 endometrial sample before women attempt to conceive.
• Women with endometrial hyperplasia who wish to conceive should be referred to fertility specialist to discuss the options for attempting conception, further assessment and appropriate treatment.
• Assisted reproduction may be considered as the live birth rate is higher and it may prevent relapse compared with women who attempt natural conception.
• Prior to assisted reproduction, regression of endometrial hyperplasia should be achieved as this
  associated with higher implantation & clinical pregnancy rates.

Question 12

HRT and endometrial hyperplasia

Answer 12

• Systemic estrogen-only HRT should not be used in women with a uterus.
• All women taking HRT should be encouraged to report any unscheduled vaginal bleeding promptly.
• Women with endometrial hyperplasia taking sequential HRT preparation who wish to continue HRT should be advised to change to continuous progestogen intake using the LNG-IUS or a continuous combinedHRT preparation. Subsequent management should be as described in the preceding sections of the guideline.
• Women with endometrial hyperplasia taking continuous combined preparation who wish to continue
  HRT should have their need to continueHRT reviewed. Discuss the limitations ofthe available evidence
  regarding the optimal progestogen regimen in this context. Consider using the LNG-IUS as a source of
  progestogen replacement. Subsequent MX should be as described in the preceding sections of guideline.

Question 13

What is the risk of developing endometrial hyperplasia on adjuvant treatment for breast cancer?

Answer 13

• Women taking tamoxifen should be informed about the increased risks of developing endometrial hyperplasia and cancer. They should be encouraged to report any abnormal vaginal bleeding or discharge promptly.
• Women taking aromatase inhibitors (such as anastrozole, exemestane and letrozole) should be
  informed that these medications are not known to increase the risk of endometrial hyperplasia and
  cancer.

Question 14

Should women on tamoxifen be treated with prophylactic progestogen therapy?

Answer 14

• There is evidence that LNG-IUS prevents polyp formation and that it reduces incidence of endometrial hyperplasia in women on tamoxifen. The effect ofthe LNG-IUS on breast cancerrecurrence risk remains uncertain so its routine use cannot be recommended.

Question 15

How should women who develop endometrial hyperplasia while on tamoxifen treatment for breast cancer be managed?

Answer 15

• The need fortamoxifen should be reassessed and management should be according to the histological
  classification of endometrial hyperplasia and in conjunction with the woman’s oncologist.

Question 16

How should endometrial hyperplasia confined to an endometrial polyp be managed?

Answer 16

• Complete removal of uterine polyp(s) is recommended and an endometrial biopsy should be obtained to sample the background endometrium. Subsequent management should be according to the histological classification of endometrial hyperplasia

Question 17

a. Risk factors for endometrial hyperplasia

Answer 17

1 - obesity,
2 - HRT regimens,
3 - tamoxifen therapy and
4 - anovulation..

Question 18

b. Consider ovarian conservation in TAH for endometrial hyperplasia

Answer 18

b. Consider ovarian conservation according to
1 - age,
2 - menopausal status and
3 - patient preferences.

In addition to nonregression of EH or persistence of AUB symptoms following nonsurgical treatments, a total hysterectomy may be indicated where there are
(i) adverse effects associated with medical treatment,
(ii) concerns over compliance with
treatment or follow-up, or
(iii) patient preferences e.g. high levels of anxiety.

Question 19

endometrial hyperplasia

c. The follow-up interval should be customised to each woman, taking into account

Answer 19

1 - baseline risk factors,
2 - associated symptoms and
3 - response to treatment.

Question 20

endometrial hyperplasia surveillance results

Regression

persistence –

progression –

relapse –

Answer 20

Regression – nonhyperplastic or nonmalignant endometrial sample or nondiagnostic endometrial sample from an appropriately placed endometrial sampling device;

persistence – no regression or progression of initial EH subtype after 3 or more months;

progression – development of AH or EC;

relapse – recurrence of EH or AH after one or more negative EB result(s).

Question 21

endometrial hyperplasia

e. In general, advise continuation of the LNG-IUS for the duration of its 5-year use,
especially if

Answer 21

1 - EH associated with AUB or
2 - other baseline risk factorsa and
3 - no adverse effects.

Question 22

endometrial hyperplasia Persistence beyond 12 months

MX

Answer 22

• Start medical management if EH not treated initially.
• The decision to persist with medical MX taken after careful consideration & discussion with woman regarding risks and benefits of prolonged medical treatment compared with total hysterectomy with or without BSO.

Persisitence >12 months is associated with

• significant risk of underlying malignancy and
• a high risk of failure to regress
• such that a total hysterectomy with or without BSO should be recommended.

Question 23

Arrange follow-up (medical management)
EH BMI < 35: ≥ two consecutive negative EBs at 6-month intervals, then discharge

g. At discharge, inform the woman of

Answer 23

1 - her estimated individual risk of recurrence,
2 - of need to continue any risk-reducing strategies and
3 - to present for an urgent review if any further episodes of AUB.

Question 24

Arrange follow-up (medical management)
- EH: BMI ≥ 35 or treated with oral progestogens: ≥ two
consecutive negative EBs at 6-month intervals, thereafter annual EB and reviewh

• AH ≥ two consecutive negative EBs at 3-month intervals, thereafter 6–12-monthly EB
  and review

-In above situationswhat additional to be considered to for appropriateness of ongoing endometrial surveillance, continuation of medical MX or TAH + /- BSO based on factors such as baseline risk factors including

Answer 24

1 - BMI,
2 - AUB symptoms,
3 - fertility requirements,
4 - compliance with treatment and follow-up,
5 - medical comorbidities and
6 - risk–benefit ratio for total hysterectomy with or without BSO.