Endometrial Hyperplasia

Educational Objectives

The goal of this program is to improve diagnosis and treatment of endometrial disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Define terms used to describe premalignant lesions of the endometrium.
2. Explain the limitations of methods used to assess endometrial malignancies.
3. Outline the surgical procedures used to assess lymph nodes in patients with endometrial carcinoma.

Summary

Uterine cancer: incidence rising 1%/yr in United States, and 3%/yr among black women; deaths from uterine cancer also rising; this increase may be related to nonendometrioid, nonhormonally mediated disease, rather than late diagnosis; rate of death rising 1%/yr for white women and 2% for black women; 25% of affected patients premenopausal; among premenopausal patients, 15% <40 yr of age; reproductive wishes of patient may preclude definitive management; 80% of cancers low grade and exhibit endometrioid histology (driven by estrogen); risk factors for endometrioid cancers include excessive insulin, metabolic syndrome, insulin resistance, polycystic ovary syndrome with anovulation, aberrant progesterone signaling, inflammation, certain growth factors, obesity, nulliparity, late menopause, diabetes, hypertension, and unopposed estrogen; features may include thickened uterine lining, complex hyperplasia, atypical hyperplasia, endometrial intraepithelial neoplasia (EIN), and bleeding

Guidance from American College of Obstetricians and Gynecologists: term EIN replaces atypical hyperplasia; in 1994 criteria from World Health Organization (WHO), histologies included simple atypical hyperplasia (rare) and complex atypical hyperplasia; EIN associated with atypical cells with higher ratio of nucleus to cytoplasm and dark nuclei; recommend hysteroscopy with directed dilation and curettage (D&C) rather than endometrial biopsy (EMB) alone; hysterectomy for definitive management appropriate, depending on concerns about fertility and comorbidities; otherwise, progesterone therapy reasonable; serial sampling should be performed every 3 to 6 mo; patients who do not improve after 6 mo on progestin unlikely to respond; hyperplasias without atypia often regress; patients with hyperplasia must be followed (risk factors ongoing); EIN terminology not commonly used because computerized system needed to calculate D-score; when score <0, lesion considered EIN; EIN reproducible and correlates with progression to endometrioid uterine cancer

Progression to cancer: histologic appearance features crowded, hyperchromatic, atypical cells; in WHO classification, risk for concurrent cancer or progression to cancer 1% for patients with simple hyperplasia, 3% for complex hyperplasia, 8% for simple hyperplasia with atypia, and 30% to 40% for complex hyperplasia with atypia; clinician should consider referring patient with complex hyperplasia with atypia to gynecologic oncologist; WHO added modifications to classification in 2014 or 2015; these divided lesions into hyperplasia without atypia (encompassing older categories of simple and complex hyperplasia) and atypical hyperplasia or EIN

Histologic appearance: cellular changes more pronounced in patients with atypia; EIN encompasses old categories of simple and complex hyperplasia with atypia; cells may show microsatellite instability; stains for expression of PAX2 and PTEN used to differentiate types of uterine cancer

Management: additional biopsies or referral to gynecologic oncologist should be considered because preoperative EMB may not be accurate; study evaluated specimens from biopsies performed at community hospital that confirmed atypical hyperplasia; biopsies reviewed by 3 gynecologic pathologists; diagnosis altered in 50% of cases (25% had less severe lesions; 30% had cancer); at time of hysterectomy, 50% of patients had cancer and 30% had myometrial invasion; 10% had >50% myometrial invasion, with 20% risk for spread to nodes

Endometrial biopsy: 90% to 95% accurate when performed for abnormal uterine bleeding; however, EMB may be less accurate in patient with enlarged uterus or other pathology; nondirected D&C samples <50% of endometrium; directed D&C may be better; hysteroscopy 80% sensitive and specific and has higher positive predictive value than ultrasonography and high negative predictive value; when clinician suspects EMB may have missed something or considers referral to gynecologic oncologist, hysteroscopy reasonable; sensitivity of ultrasonography similar to that of EMB, but specificity and positive predictive value lower

Patients desiring future fertility: magnetic resonance imaging (MRI) preferred over computed tomography (CT) for assessing myometrial invasion; patients with deep myometrial invasion should not be treated conservatively (conservative management controversial in patients with any myometrial invasion); MRI less sensitive in premenopausal patients

Conservative management: Society of Gynecologic Oncology recommends imaging to detect invasive cancer, adenopathy, ovarian metastases, and myometrial invasion; patients with persistent hyperplasia who do not improve after 6 mo should not be medically managed; preferred treatments megestrol (Megace) or levonorgestrel intrauterine device (Mirena); continuous treatment improves compliance

Outcomes with conservative therapy: ≈75% of patients treated conservatively experience regression, but 40% relapse; 2% progress to higher stage of cancer during medical treatment; largest study of Mirena included 334 women with complex hyperplasia; 221 had regression; failure of treatment more likely in those with higher body mass index; meta-analysis of 5 randomized trials reported higher rate of regression in nonobese women treated with IUD than in those on oral progestins, but rates of regression similar (in obese women); 50% of patients with cancer experience long-term benefit, but rate of recurrence one-third

Preserving fertility: 6 small studies (largest 26 patients) evaluated hysteroscopic resection for preservation of fertility; patients with polypoid lesions may respond best; when patients treated with hysteroscopic resection and then progesterone compared with those treated with progesterone alone, hysteroscopic group had higher rate of regression (98%), higher birth rate (≈50%), and lower rate of recurrence

Metformin: in some studies, metformin associated with reversion of atypical hyperplasia; mechanism of action may be decreased cellular proliferation; among patients with uterine cancer, those on metformin have higher rate of survival; Gynecologic Oncology Group studying standard chemotherapy with or without metformin; metformin inexpensive and may be given with progestin; in phase 2 trial conducted in patients with low-grade endometrioid cancers and complex atypical hyperplasia, 81% of those on metformin plus progestin had complete response

Referral: gynecologist may perform hysterectomy for non-EIN lesion, but patients with atypia (especially complex atypia or EIN) at risk for cancer; 19% to 29% of patients with diagnosis of EIN have cancer on hysterectomy specimen; such women should consult gynecologic oncologist; they may need surgical staging or biopsy of sentinel node

Sentinel node: supported by level II evidence; requires robot or laparoscope that detects fluorescent dye; methylene blue less sensitive than indocyanine green (ICG) for detecting sentinel node; 1.5 mL of 1:20 dilution of ICG injected into cervix (mucosa and stroma) at 3 and 9 o’clock positions; dye may not travel well in patients with involvement of lower segment or cervix; sentinel nodes must be removed before performing hysterectomy; patient may be able to avoid full staging lymphadenectomy; bilateral sentinel nodes seen in 86% of cases; sentinel nodes in pelvis in two-thirds of cases (in periaortic region in remaining one-third); if bilateral sentinel nodes detected, additional staging not needed; full surgical staging based on high-risk factors (myometrial invasion, grade, node >2 cm, and cervical involvement) may be performed on frozen sections; sensitivity of this approach 97%

Examination of sentinel nodes: sentinel nodes not sent for frozen section; instead, nodes evaluated as part of permanent specimen; nodes must be finely cut and stained to detect microscopic spread

Preoperative evaluation: when sentinel node dissection planned, CT may be used to look for adenopathy or bulky nodes; large nodes should be removed during surgery; intraoperative assessment of nodes may be inaccurate, even when performed by gynecologic oncologist

Case example 1: 39-yr-old para 1 with irregular bleeding desired future fertility; ultrasonography showed enlarged uterus; EMB showed complex hyperplasia (not EIN); treatment with progesterone reasonable

Case example 2: 40-yr-old who desired future fertility presented with irregular bleeding; EMB showed complex hyperplasia (not EIN); ultrasonography showed thickened stripe and 1.5-cm polypoid mass; hysteroscopy with resection may be considered, followed by progesterone; biopsy should be repeated in 6 mo

Suggested Reading

Chandra V et al: Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol 2016 Jan;27(1):e8; Committee on Gynecologic Practice, Society of Gynecologic Oncology: The American College of Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia. Obstet Gynecol 2015 May;125(5):1272-8; Falcone F et al: Fertility preserving treatment with hysteroscopic resection followed by progestin therapy in young women with early endometrial cancer. J Gynecol Oncol 2017 Jan;28(1):e2; Gallos ID et al: LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Hum Reprod 2013 Nov;28(11):2966-71; Kurman RJ et al: The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985 Jul 15;56(2):403-12; Louie M et al: Comparison of the levonorgestrel-releasing intrauterine system, hysterectomy, and endometrial ablation for heavy menstrual bleeding in a decision analysis model. Int J Gynaecol Obstet 2017 Nov;139(2):121-9; Ørbo A et al: Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008 Oct;111(1):68-73; Trimble CL et al: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006 Feb 15;106(4):812-9; Yuk JS et al: Levonorgestrel-releasing intrauterine systems versus oral cyclic medroxyprogesterone acetate in endometrial hyperplasia therapy: a meta-analysis. Ann Surg Oncol 2017 May;24(5):1322-9.

Debate: Endometrial Ablation for Heavy Menstrual Bleeding

Kelly N. Wright, MD, Assistant Professor of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA

Matthew T. Siedhoff, MD, MSCR, Associate Professor of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA

Case example 1: 32-yr-old nulligravida with premature ovarian failure treated for bleeding with oral contraceptives, then endometrial ablation (EA); referring clinician intended to treat vasomotor symptoms with estrogen alone after EA, but noted that unburned areas introduce risk for hyperplasia

Case example 2: 50-yr-old with fibroids and 18-wk-sized uterus had EA 2 yr earlier; procedure helped some with bleeding but patient still had pelvic pain and dysmenorrhea; endometrial biopsy (EMB) before EA negative; patient had history of tubal ligation, diabetes, hyperlipidemia, severe hypertension, and renal disease; body mass index 36

Safety: concerns about excess fluid absorption and hyponatremic encephalopathy led to development of safer devices; in systematic review of 25 trials and >4000 women, newer devices associated with shorter operative time and fewer complications than resectoscope; complications included fluid overload, uterine perforation, cervical laceration, and hematometra; in 2008, EA most common treatment for heavy menstrual bleeding (HMB); rate of amenorrhea <50%

Indications: EA indicated for premenopausal women with HMB who have completed childbearing; EA contraindicated in women with genital infection, endometrial hyperplasia, malignancy, or desire for pregnancy; EA controversial in women at increased risk for endometrial cancer (eg, those with Lynch syndrome)

Endometrial cancer: although EA theoretically could mask future endometrial cancer, studies do not bear this out; in Finnish study of 5484 women who underwent EA at mean age of 42 yr, 3 developed new endometrial cancers over 18 yr (vs expected rate of 5 cases); EA may provide some protective effect; in study of >230,000 women with abnormal uterine bleeding, 4776 underwent EA; others treated medically; 3 women in EA group and 601 in medical group developed endometrial cancer; median time to diagnosis 237 days in EA group and 299 in medical group; study concluded that EA did not delay diagnosis; EMB should be performed in office before EA, and dilation and curettage should be performed in operating room just before performing EA

Criticisms of studies: studies included mostly healthy, premenopausal patients without risk factors for cancer; study performed in Finland compared patients with age-matched cohort, after removing those treated with hysterectomy; obese patients with comorbidities at higher risk for cancer

Abnormal bleeding after EA: utility of EMB after EA unknown, but only samples ≈4% of endometrium; ultrasonography unreliable after EA; bleeding should prompt hysteroscopic biopsy and curettage, but scarring may limit procedure and place patient at risk for complications such as perforation; when cancer cannot be ruled out, hysterectomy may be needed; patients with cancer may need oophorectomy or nodal dissection, and may have benefited from initial hysterectomy rather than EA; study of patients who underwent hysterectomy after EA showed that tissue diagnosis insufficient in >50% of women (pathologic findings on EMB often inconsistent with findings at hysterectomy); levonorgestrel intrauterine device (IUD) may be better option in poor surgical candidates

Alternatives: EA good alternative to medical therapy; hormonal treatment associated with emotional swings, clots, and breast cancer; systematic review compared hysterectomy, EA, and Mirena IUD; rates of satisfaction similar in EA and IUD groups; hysterectomy associated with highest rate of complications; EA associated with poor obstetric outcomes including prematurity, morbidly adherent placenta, uterine rupture, cesarean delivery, cesarean hysterectomy, and perinatal mortality; contraception important after EA; other complications include pain from hematometra; women with postablation tubal sterilization syndrome have regrowth of endometrium in cornua; hysterectomy more effective than salpingectomy for such patients; hysteroscopic sterilization may be performed during EA, but waiting 3 mo recommended (hysterectomy or IUD may be simpler); many patients with EA go on to have hysterectomy

Serious adverse events (SAEs): reports in Manufacturer and User Facility Device Experience database indicate that 8% of SAEs caused by off-label practices, including completing EA in patient with uterine perforation, allowing sheath to rest on skin, failing to support device during use, continuing procedure after change in cavity length, reapplying applicator after previous or partial treatment, repeating EA, poor ultrasonographic visualization during cryotherapy, adding too much fluid during thermal balloon ablation, cycling longer than recommended, and removing device without retracting its active component

Postablation hysterectomy: in retrospective study of 437 women followed for 2 yr after EA, 21% developed pelvic pain; risk factors for postablation pain included dysmenorrhea, age <40 yr, tubal ligation, and smoking; another study of 270 women reported similar findings; 23% developed new or worsening pelvic pain, and many had fibroids or adenomyosis; 19% had hysterectomy; risk factors for pain dysmenorrhea, tubal ligation, and nonwhite race; another review concluded that women at high risk for failure of treatment should not undergo EA; risk factors included age, sterilization, dysmenorrhea, parity >5, and intrauterine lesion such as adenomyosis

Special populations: women who may not benefit from EA include those with submucosal myoma (submucosal resection preferred); EA should be carefully considered in patients with pelvic pain; EA difficult in small, nulligravid uterus; in randomized trial that compared EA with IUD, rates of hysterectomy significantly higher in EA group (20% to 25%); IUD group had greater improvement in bleeding and greater satisfaction

Cost: in analysis of cost-effectiveness, IUD most cost-effective treatment and hysterectomy associated with highest quality of life; unlike IUD, EA offers no protection against endometrial cancer; EA may be performed as outpatient procedure; despite up-front costs, hysterectomy more cost effective than EA

Suggested Reading

Carey ET et al: Pathologic characteristics of hysterectomy specimens in women undergoing hysterectomy after global endometrial ablation. J Minim Invasive Gynecol 2011 Jan-Feb;18(1):96-9; Dood RL et al: Endometrial cancer after endometrial ablation vs medical management of abnormal uterine bleeding. J Minim Invasive Gynecol 2014 Sep-Oct;21(5):744-52; Ghazizadeh S et al: A randomized clinical trial to compare levonorgestrel-releasing intrauterine system (Mirena) vs trans-cervical endometrial resection for treatment of menorrhagia. Int J Womens Health 2011;3:207-11; Kaunitz AM et al: Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet Gynecol 2009 May;113(5):1104-16; Lethaby A et al: Endometrial resection and ablation techniques for heavy menstrual bleeding. Cochrane Database Syst Rev 2013 Aug 30;(8):CD001501; Louie M et al: The case against endometrial ablation for treatment of heavy menstrual bleeding. Curr Opin Obstet Gynecol 2018 Apr 27 [Epub ahead of print]; Qiu J et al: Levonorgestrel-releasing intrauterine system versus medical therapy for menorrhagia: a systematic review and meta-analysis. Med Sci Monit 2014 Sep 23;20:1700-13; Soini T et al: Long-term follow-up after endometrial ablation in Finland: cancer risks and later hysterectomies. Obstet Gynecol 2017 Sep;130(3):554-60; Spencer JC et al: Cost-effectiveness of treatments for heavy menstrual bleeding. Am J Obstet Gynecol 2017 Nov;217(5):574.e1-574.e9; Thomassee MS et al: Predicting pelvic pain after endometrial ablation: which preoperative patient characteristics are associated? J Minim Invasive Gynecol 2013 Sep-Oct;20(5):642-7; Valle RF, Baggish MS: Endometrial carcinoma after endometrial ablation: high-risk factors predicting its occurrence. Am J Obstet Gynecol 1998 Sep;179(3 Pt 1):569-72; Wishall KM et al: Postablation risk factors for pain and subsequent hysterectomy. Obstet Gynecol 2014 Nov;124(5):904-10.

Acknowledgments

Dr. Udea was recorded at 2017 Obstetrics and Gynecology Update: What Does the Evidence Tell Us?, presented by the UCSF Department of Obstetrics, Gynecology, and Reproductive Sciences and held October 18-20, 2017, in San Francisco, CA. Dr. Wright and Dr. Siedhoff spoke at the 4th Annual Cedars-Sinai Update in Obstetrics and Gynecology Conference, presented by the Cedars-Sinai Department of Obstetrics and Gynecology and held March 9, 2018, in Los Angeles, CA. For information on CME meetings presented by UCSF, please visit meded.ucsf.edu/cme. For more information on CME meetings presented by Cedars-Sinai’s Department of Obstetrics and Gynecology, please visit cedars-sinai.edu/obgyncme. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Readings

Chandra V et al: Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol 2016 Jan;27(1):e8; Committee on Gynecologic Practice, Society of Gynecologic Oncology: The American College of Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia. Obstet Gynecol 2015 May;125(5):1272-8; Falcone F et al: Fertility preserving treatment with hysteroscopic resection followed by progestin therapy in young women with early endometrial cancer. J Gynecol Oncol 2017 Jan;28(1):e2; Gallos ID et al: LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Hum Reprod 2013 Nov;28(11):2966-71; Kurman RJ et al: The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985 Jul 15;56(2):403-12; Louie M et al: Comparison of the levonorgestrel-releasing intrauterine system, hysterectomy, and endometrial ablation for heavy menstrual bleeding in a decision analysis model. Int J Gynaecol Obstet 2017 Nov;139(2):121-9; Ørbo A et al: Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008 Oct;111(1):68-73; Trimble CL et al: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006 Feb 15;106(4):812-9; Yuk JS et al: Levonorgestrel-releasing intrauterine systems versus oral cyclic medroxyprogesterone acetate in endometrial hyperplasia therapy: a meta-analysis. Ann Surg Oncol 2017 May;24(5):1322-9.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. Dr. Udea presents information in her lecture related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Udea was recorded at 2017 Obstetrics and Gynecology Update: What Does the Evidence Tell Us?, presented by the UCSF Department of Obstetrics, Gynecology, and Reproductive Sciences and held October 18-20, 2017, in San Francisco, CA. For information on CME meetings presented by UCSF, please visit meded.ucsf.edu/cme. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

OB651401

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This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.