Management of Endometrial Hyperplasia

MO PresentationMay 2016

By Winnie Cristal

Introduction

Endometrial hyperplasia irregular proliferation of the endometrial glands with an increase in the

gland to stroma ratio when compared with proliferative endometrium Endometrial Ca

most common gynaecological maglinancy in the western country, endometrial hyperplasia as the precursor

Incidence of endometrial hyperplasia 3 folds higher than endometrial Ca

Fourth most common cancer in women in Peninsular Malaysia [1]

Risks factors when estrogen, unopposed by progesterone, stimulates

endometrial cell growth by binding to estrogen receptors in the nuclei of endometrial cells

Increased BMI Anovulation associated with perimenopause or PCOS Estrogen secreting ovarian tumour (eg: granulosa cell tumour) Drug induced endometrial stimulation (eg: use of systemic

estrogen replacement therapy/ long term tamoxifen) Immunosuppression and infection

Classification

WHO classification of 19941. simple hyperplasia without atypia,2. complex hyperplasia without atypia,3. simple atypical hyperplasia,4. complex atypical hyperplasia

EIN (Endometrial intraepithelial) classification system 2003 Benign (endometrial hyperplasia) Premalignant (diagnosis of EIN based upon 5 subjective histological criteria) Malignant (endometrial Ca)

Latest WHO classification in 2014 Endometrial hyperplasia without atypia Endomterial hyperplasia with atypia/endometrioid intraepithelial neoplasm

Diagnostic and surveillance methods Histology examination – endometrial sampling (outpatient/GA) TVS in pre- and postmenopausal women

Systemic review – 3-4mm cut off, probability of Ca <1% when ET less than the cut off RCOG - <7mm, endometrial is unlikely

Hysteroscopy CT/MRI

CT – not recommended MRI – more evidence needed for surveillance of atypical endometrial hyperplasia in

predicting malignant changes phosphatase and tensin homolog (PTEN), perhaps in combination with B-cell

lymphoma 2 (BCL-2) and BCL-2-like protein 4 (BAX) could be potentially useful More research evidence needed

Endometrial HyperplasiaWithout Atypia With Atypia

Total hysterectomy-TAH/TLHPremenopausal – total hysterectomy + BSO +/- ovarian conservationPost menopausal – Total hysterectomy + BSO

ConservativeCounselingIdentify and address risk factorObservation

- F/up with endometrial biopsies

Failed to regress/symptomatic with

AUBProgestogen

LNG-IUS (Mirena)

Continuous oral progestogen•Medroxyprogesteron•Norestherone

Regress- At least 2 consecutive 6 monthly NEGATIVE biopsies prior discharge

Higher risks of relapse – 2 consecutive negative biopsies then long term f/up with annual endometrial biopsy

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Minimum of 6month treatment

Minimum 6 monthly endometrial biopsy till 2 consecutive Negative biopsies

Endometrial Hyperplasia without Atypia

Initial management Counselling

Progression to endometrial Ca <5% over 20 years Majority of cases regress spontaneously during f/up (74%-81% in 2 cohort

studies) Identify and address reversible risk factor

HRT usage Obesity

Observation with f/up endometrial biopsies Inform patient higher regression rate with progestogens as compared to

observation alone Progestogens treatment

Failed to regress following observation Symptomatic with AUB

1st line medical treatmentLNG-IUS (Mirena) – higher disease regression rate, fewer side effectsContinuous oral progestogen – if declined Mirena

Duration of treatment and f/upLNG-IUS/ oraly progestogen – minimum of 6/12LNG-IUS is encouraged to retained up to 5 years if no fertility concernEndometrial surveillance – minimum 6 monthly, at least 2 consecutive 6monthly negative biopsies prior discharge

Seek referral if AUB recurs after completion of treatment – relapseHigher risks of relapse (eg: BMI >35, treatment wirh oral progestogen)

– 2 consecutive negative biopsies then long term f/up with annual endometrial biopsy

Surgical management

NOT as first line treatment Indicated in women who not wanting to preserve fertility

(i) Progression to atypical hyperplasia occurs during follow-up(ii) No histological regression of hyperplasia despite 12 months of treatment(iii) Relapse of endometrial hyperplasia after completing progestogen treatment(iv) there is persistence of bleeding symptoms(v) the woman declines to undergo endometrial surveillance or comply with medical treatment

Postmenopausal – TAHBSO Premonopausal – TAH/TLH + Bilateral salphingectomy (recommended) +/-

ovarian conservation Endometrial ablation – not recommended (persistent endometrial

destruction, endometrial adhesion preclude future endometrial surveillance

Atypical Endometrial Hyperplasia

Initial management Total hysterectomy (suprecervical hysterectomy should

not be perform) Laparoscopic approach is preferable No benefit from intra-op frozen section analysis of

endometrium or routine lymphadenectomy Post menopausal – TAH + BSO Premenopausal – TAH + bilateral salphingesctmy +/-

ovarian conservation Endometrial ablation – not recommended

Management for those who wish to preserve fertility/not suitable for surgery

Women wishing to retain their fertility counsel about the risks of underlying malignancy and subsequent progression to

endometrial cancer Pretreatment investigations

aim to rule out invasive endometrial cancer or co-existing ovarian cancer Histology, imaging and tumour marker results

To be review in a multidisciplinary meeting for a plan of management and subsequent endometrial surveillance

First line treatment LNG-IUS

Second best alternative oral progestogens

Once fertility is no longer required hysterectomy - in view of the high risk of disease relapse

Follow up on women not undergoing hysterectomy

Those cases are best to be discuss in a gynaecological oncology multidisciplinary meeting

Review every 3 monthly with endometrial surveillance until 2 consecutive negative biopsies Review schedules to be individualized according to women’s clinical condition

Asymptomatic women + evidence of histological disease regression and minimum of 2 consecutive negative endometrial biopsies Long term follow up with biopsy 6-12 monthly until hysterectomy done

If fertility therapy failed to induce regression of the disease by 12 months, strongly recommended for hysterectmy

Management of women wishing to conceive

Disease regression should be achieved on at least one endometrial sample before women attempt to conceive.

Referral to a fertility specialist to discuss the options for attempting conception, further assessment and appropriate treatment. Aim for BMI < 30 for obese women

Assisted reproduction may be considered as The live birth rate is higher May prevent relapse compared with women who attempt natural

conception. Regression of endometrial hyperplasia should be achieved prior to

assisted conception Associated with higher implantation and clinical pregnancy rates.

HRT and Endometrial Hyperplasia 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 a sequential HRT

preparation who wish to continue HRT should be advised to change to continuous progestogen intake using the LNG-IUS or a continuous combined HRT preparation. Subsequent management as per recommended by the guideline.

Women with endometrial hyperplasia taking a continuous combined preparation who wish to continue HRT should have their need to continue HRT reviewed Consider using the LNG-IUS as a source of progestogen replacement.

Subsequent management as per recommended by the guideline.

Management of endometrial in women on adjuvant treatment for breast cancer

Inform regarding the increased risks of developing endometrial hyperplasia and Ca (Tamoxifen) Increase risk with both dose and duration Statistically significant increase risk in women age 50 and above

Encourage them to report if any abnormal vaginal bleeding/ discharge promptly

Aromatase inhibitors (anastrazole, exemestane, letrozole) Inform that these medication not known to increase risk of

endometrial hyperplasia and Ca

Prophylactic Progestogen in women on Tamoxifen?

Evidence of LNG-IUS prevent polyp formation and reduce incidence of endometrial hyperplasia Effect of LNG-IUS on breast Ca recurrence risk uncertain, so routine use

cannot be recommended

Women who develop endometrial hyperplasia while on Tamoxifen for breast ca

Need for Tamoxifen to be reassess and manage accordingly to the histological classification of endometrial hyperplasia in conjunction with the oncologist

Endometrial hyperplasia confined to an endometrial polyp Complete removal of the polyp + endometrial biopsy

to sample background endometrium Manage according to the histological classification of

endometrial hyperplasia

Endometrial HyperplasiaWithout Atypia With Atypia

Total hysterectomy-TAH/TLHPremenopausal – total hysterectomy + BSO +/- ovarian conservationPost menopausal – Total hysterectomy + BSO

ConservativeCounselingIdentify and address risk factorObservation

- F/up with endometrial biopsies

Failed to regress/symptomatic with

AUBProgestogen

LNG-IUS (Mirena)

Continuous oral progestogen•Medroxyprogesteron•Norestherone

Regress- At least 2 consecutive 6 monthly NEGATIVE biopsies prior discharge

Higher risks of relapse – 2 consecutive negative biopsies then long term f/up with annual endometrial biopsy

↓ ↓

↓

↓

↙

↙ ↘

↘

Minimum of 6month treatment

Minimum 6 monthly endometrial biopsy till 2 consecutive Negative biopsies

THANK YOU