Continuing Education Activity

Endometrial hyperplasia is a common disorder due to exposure to exogenous or endogenous estrogen along with a relative deficiency of progesterone. It is a precursor of endometrial carcinoma, which is one of the commonest gynecological malignancies. To avoid the development of endometrial carcinoma, it is important that clinician keeps a high vigil for the signs and symptoms of endometrial hyperplasia. This activity reviews the role of the interprofessional team in the diagnosis and management of endometrial hyperplasia.

Objectives:

• Summarize the etiology of endometrial hyperplasia.
• Describe the evaluation of endometrial hyperplasia.
• Review the management options available for endometrial hyperplasia

Introduction

Endometrial hyperplasia is a disordered proliferation of endometrial glands. It results from the unopposed estrogenic stimulation of the endometrial tissue with a relative deficiency of the counterbalancing effects of progesterone.[1] This imbalance in the hormonal milieu can be seen in a number of conditions where the cause of estrogen excess is either endogenous or exogenous.

The irregular growth of the endometrium results in an abnormal gland-to-stroma ratio and presents in a continuum of the spectrum of changes in the endometrium. It involves varying degrees of histopathological complexity and atypical features in the cells and nuclei. Endometrial hyperplasia, if not treated, has the propensity to develop into endometrial cancer.[1][2][3]

Etiology

Endometrial hyperplasia is the result of chronic exposure to estrogen along with a relative deficiency of progesterone. The causes of estrogen excess could be endogenous or exogenous. The risk factors associated with endometrial hyperplasia are as follows [1][3]:

• Age
• Nulliparity
• Obesity
• Genetic
• Diabetes Mellitus
• Anovulatory cycles- PCOS, perimenopause
• Ovarian tumors- granulosa cell tumors
• Hormone replacement therapy- estrogen-only therapy can lead to endometrial hyperplasia at even a minimal dose and is contraindicated in women with a uterus. Over the counter/ herbal preparations may have a high amount of estrogen.[4]
• Immunosuppression (renal graft recipients) and infection may also be involved in the development of endometrial hyperplasia.[5][6]
• Hereditary nonpolyposis colorectal cancer or Lynch syndrome – women with this condition are at a greatly increased risk of endometrial hyperplasia.[7][8]

Epidemiology

Endometrial malignancy is the most common gynecologic cancer in the United States. As per the statistics, it is also the fourth most common cancer in women in the United States. It was estimated that 63,230 women were diagnosed with and 11,350 women succumbed to this malignancy in 2018.[9] The incidence of endometrial hyperplasia has been estimated to be thrice the number of cases of endometrial cancer. Endometrial hyperplasia is thought to be a precursor to endometrial cancer, and if caught early, prevention to progression fo cancer can be performed.[9] In order to limit the number of cases of endometrial malignancy, it is required to diagnose and treat endometrial hyperplasia appropriately.

A large study conducted on the epidemiology of endometrial hyperplasia reported that women who received the diagnosis of hyperplasia without atypia were in the range of 50-54 years. Hyperplasia with atypia was most commonly seen in the age group of 60-64 years, and the disease was quite rare below the age of 30 years.[10]

Pathophysiology

Endometrial hyperplasia results from estrogen predominance and relative progesterone insufficiency. The typical causes for endogenous estrogen excess include anovulatory cycles (perimenopause, polycystic ovarian syndrome (PCOS)), obesity, and estrogen secreting ovarian tumors. The exogenous causes include unopposed estrogen therapy, hormone replacement therapy (HRT), and tamoxifen (used in breast cancer treatment).[11]

The Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) showed that when unopposed estrogen treatment with 0.625 mg of conjugated equine estrogen was given to women for three years, it leads to increased incidence of endometrial hyperplasia.[12] The risk of complex hyperplasia increased by 22.7%, and atypical hyperplasia increased by 11.8%. However, the Women’s Health Initiative (WHI) study showed that the addition of 2.5mg of medroxyprogesterone acetate to 0.625 mg of conjugated equine estrogen did not increase the risk of endometrial cancer.[13]

Histopathology

In the normal menstrual cycle, estrogen leads to proliferative endometrium. After ovulation in the luteal phase, endometrium shows secretory changes under the effect of progesterone. In the follicular phase, normal endometrial tissue shows no glandular crowding, and the ratio of glands to stroma is less than 50%. In the secretory phase, the normal endometrial glands may show features such as minimal crowding and a small increase in gland-to-stroma ratio. Despite these features, the endometrial glands are organized and cells of the glands that do not show mitoses.

In endometrial hyperplasia without atypia, the glandular to stromal ratio is increased to more than 50 % (Reed SD, Urban RR. Classification and diagnosis of endometrial hyperplasia.) 

The glands may show mild crowding, cystic dilatation with sparingly seen outpouching and mitoses. However, atypical cellular features are not seen.

In endometrial hyperplasia with atypia, the gland-to-stroma ratio is increased further.[14] There is a disorganization of glands with luminal outpouching, cellular mitoses, and nuclear atypia. The distinction between malignant and non-malignant proliferation is quite difficult in non-hysterectomy specimens. In this condition, markers of invasion like cribriform and maze-like pattern with back to back glands often help the pathologists make the diagnosis of an invasive lesion.

There have been three main classification systems used for endometrial hyperplasia. These were based on the histopathological characteristics of the lesion and their propensity to progress to malignancy. WHO proposed a classification in 1994, which was accepted and used widely. It was based on the work of Kurman et al., who performed a retrospective study on 170 women with varying degrees of hyperplasia (architectural complexity and atypical features.[14] These women were followed for a mean duration of 13 years and showed progression to endometrial adenocarcinoma at different rates. The four main categories were:

1. Simple hyperplasia without atypia: the number of glands increased, but the regular architecture was not compromised; progression rate to cancer 1%.
2. Simple hyperplasia with atypia: simple hyperplasia with features of nuclear atypia( marked variation in nuclear shape and size and prominent nucleoli); progression rate to cancer 8%
3. Complex hyperplasia without atypia: glands become more crowded and irregular; progression rate to cancer 3%.
4. Complex hyperplasia with atypia: complex hyperplasia with atypical features, progression rate to cancer 29%.

 Up to half of the cases of complex atypical hyperplasia can have coexistent endometrial adenocarcinoma.[15][16][17][18]This is also complicated by the fact that the histological distinction between these two entities can be confusing.[19] 

 Considering these issues, WHO simplified the classification of endometrial hyperplasia in 2014 and proposed two categories based upon the presence of cytologic atypia:[20]

1. Hyperplasia without atypia
2. Atypical hyperplasia/ endometrioid intraepithelial neoplasia

The terms ‘simple’ and ‘complex’ are not used in this classification.

 In the year 2000, a group of gynecologic pathologists suggested endometrial intraepithelial lesion (EIN) classification.[21][22] This system utilized a computerized morphometric analysis. D-score is an important part of this classification. It can be calculated as stromal volume over total tissue volume. The total tissue volume is comprised of the epithelium, gland lumen, and stromal volume. The endometrial tissue is categorized as benign if D is more than one and EIN if D is less than 0. If D-score is more than 0 and less than 1, it is categorized as indeterminate. EIN is defined as when the volume of glands is greater than the volume of stroma ( stromal volume is less than 55%), a lesion showing cytologic alterations, a lesion larger than 1mm in linear measurement and excludes mimics( polyps, repair, basalis and secretory) and carcinoma(cribriform pattern, solid areas ). Studies showed that WHO 1994 and EIN had similar sensitivities and negative predictive value for coexisting endometrial cancer. Hyperplasia without atypia involves no significant genetic changes, whereas atypical endometrial hyperplasia has been shown to be associated with mutations in PTEN and KRAS.[23]

History and Physical

The majority of patients first present with symptoms of abnormal uterine bleeding. The change in the menstrual bleeding pattern alarms the woman to seek medical help early. This is the reason that most of the cases of endometrial cancer (more than 70%) are diagnosed early in stage I as opposed to other cancer where the symptoms are indolent for many years allowing cancer to spread to regional and distant sites.  The importance of a detailed history and physical examination is of utmost importance in the evaluation.

The clinical documentation should include the history of present illness, menstrual history, and symptoms (duration of the cycle, flow, the passage of clots, intermenstrual bleeding, postmenopausal bleeding, unscheduled bleeding if the woman is on HRT). The age of menarche, transition through perimenopause,  age of menopause should also be recorded. It is important to note the obstetric history and whether the patient wishes to conceive in the future. This is necessary as it can change the course of treatment options for the patient. It is ethical to consider medical treatment options for a woman who is keen on conception in the future without compromising the prognosis. A smear and contraceptive history should be taken. Medical and surgical history should be taken in detail as it may reveal several factors that may play a role in the management. The drug history should be taken meticulously and specifically asked for the intake of HRT, over the counter drugs, tamoxifen, etc. A family and social history should also be taken.

The examination should include a general physical examination, including vitals assessment. As most of the patients present with menorrhagia, pallor should be looked for. If the patient looks clinically pale, she should be advised iron prescription and iron-rich diet. A breast examination should be performed to rule out any suspicious lesion. Per-abdomen examination to look for any previous scars and abdominal lump (coexisting fibroid, ovarian cyst, and other intraperitoneal pathology). Careful local examination of the genitalia should be performed to rule out vulval, cervical, uterine, and/or ovarian pathology. It is important to perform a bimanual exam to ascertain the size of the uterus, ovaries, and to rule out any findings in the pouch of Douglas. A diagnostic procedure like an endometrial biopsy is then performed to confirm the diagnosis.[24]

Evaluation

The most common presentation is abnormal uterine bleeding, which may be in the form of menorrhagia (heavy menstrual bleeding), metrorrhagia (irregular bleeding), unscheduled bleeding (patients on HRT) or postmenopausal bleeding. Some women may present with abnormal discharge, which may be foul-smelling or blood-stained. The PAP smear may show abnormal glandular cells or atypical endometrial cells, which warrant further evaluation.

Patients presenting with these symptoms with a corroborating history evoke a clinical suspicion of endometrial hyperplasia. However, the confirmation requires a histological examination of endometrial tissue, which can be obtained either by a minor outpatient procedure or by an inpatient endometrial sampling.

The investigations required are basic blood work, PAP smear, and a transvaginal ultrasound to rule out focal endometrial pathologies such as a polyp, small submucous myoma, and ovarian status.

Role of Transvaginal Ultrasound in Premenopausal Women

Studies have shown that in premenopausal women, there could be an overlap between normal and abnormal endometrial thickness. This suggests that the ultrasound mainly plays the role of picking up structural abnormalities. However, as per the Royal College of Obstetrician and Gynecologists (RCOG) guidance, a TVS should be performed in women with abnormal uterine bleeding, PCOS, and absent withdrawal bleed. A prospective study in women with  PCOS had shown that when the endometrial thickness was less than 7mm, no cases of endometrial hyperplasia were detected in these women. The RCOG guidance thus concluded that the presence of hyperplasia below 7mm thickness of the endometrium is unlikely.

Role of Transvaginal Ultrasound in Postmenopausal Women

Postmenopausal women with bleeding per vagina are advised to have a transvaginal sonogram (TVS). If TVS shows an increased endometrial thickness or irregular endometrium, it is advisable to do an endometrial biopsy. Systematic reviews have suggested that when the endometrial thickness is less than 3 or 4 mm, the probability of endometrial cancer is reduced to less than 1%, and thus sampling is not required.[25][26][27] In women taking HRT or on tamoxifen, the cut off has been increased.[28] Further evaluations like sonohysterography, office hysteroscopy, or endometrial biopsy are indicated if the endometrial thickness is greater than 4 mm or it cannot be visualized properly. Asymptomatic postmenopausal women who have been incidentally diagnosed to have an endometrial thickness more than 4 mm do not routinely need evaluation.[29]

Endometrial Sampling

The most important criteria for any tissue sampling technique are high sensitivity and specificity towards detecting endometrial hyperplasia and exclusion of endometrial carcinoma. It is quite challenging for the pathologists to rule out completely invasive cancer in non-hysterectomy specimens. Almost 40% of the patients who are diagnosed as having precancerous endometrial hyperplasia by endometrial suction curette are found to have a postoperative concurrent endometrial malignancy in the hysterectomy specimen.[30]

The endometrial sample can be obtained through outpatient endometrial biopsy. A systematic review evaluating the efficacy of office endometrial biopsy has reported a pooled likelihood ratio (LR) of 12.0 (95% Confidence Interval (CI) 7.8-18.6) for a positive test. On the other side, a negative office biopsy test has a likelihood ratio of 0.2 (95% CI 0.1-0.3).[31] However, if the patient does not tolerate an office biopsy, has cervical stenosis, or the transvaginal ultrasound shows a polyp, an inpatient diagnostic hysteroscopy guided procedure has to be performed instead.

The methods of obtaining tissue samples through dilatation and curettage (D&C) or suction curette have been shown to detect endometrial carcinoma with an equal rate in women with abnormal uterine bleeding.[32] However, these methods have their own side effects. Less than 50% of the uterine cavity was sampled in approximately 60% of these procedures.[30] The presence of a mass lesions in the uterus can deflect the flexible curette, which can curtail the proper sampling of the endometrium. As per the American College of Obstetricians and Gynecologists (ACOG) Committee opinion on tissue sampling methods, hysteroscopy with directed D&C can sample both focal pathology and background endometrium and may yield a higher detection rate.[33]  However, if the treatment procedure is a hysterectomy, it makes the type of sampling procedure less important. This is because the chance of missing an invasion is far less in a uterine specimen on the final pathology result as compared to a tissue biopsy specimen.[32]

Treatment / Management

The main guiding principles of management are as follows:

1. To prevent the development/progression of endometrial malignancy.
2. To rule out the presence of a coexisting endometrial malignancy.
3. To offer a treatment plan that best suits the needs of the patient.

Management of benign endometrial hyperplasia/ hyperplasia without atypia:

The risk of progression to invasive malignancy is less than 5 % over 20 years. Spontaneous resolution can occur if the hormonal milieu is corrected (reversible causes of estrogen excess like obesity and use of HRT/ over the counter preparations that may contain a high dose of estrogen). Progestogen therapy has a higher disease resolution rate (89-96%) than observation ( 74.2- 81%) alone.[14][34][35] Both local intrauterine( levonorgestrel-releasing intrauterine system [LNG-IUS]) and continuous oral progestogens can be used for the treatment. However, LNG-IUS is preferred because it has lower side effects, a higher rate of disease resolution, and bleeding per vagina.[36] This increased efficacy can be attributed to the higher local concentration of LNG at the endometrium achieved with LNG-IUS.

Women who refuse LNG-IUS can be started on continuous oral progestogens in the following dose:  medroxyprogesterone 10-20 mg /day or norethisterone 10-15mg/day (cyclical progestogens are not recommended by the Royal College of Obstetricians and Gynaecologists (RCOG).[37]

Treatment duration and follow up:

In order to induce the regression of the hyperplasia, treatment should be for at least six months. Endometrial surveillance with office endometrial biopsy is recommended at six-monthly intervals. Before discharging the patient, two consecutive 6 – monthly negative biopsies should be obtained. Women who have a BMI of more than 35 and who were treated with oral progestogens are at a higher risk of relapse and should be advised annual follow -up. All women should be advised to come for a follow -up if they experience the symptoms of abnormal uterine bleeding.[2]

Indications for surgical management of benign endometrial hyperplasia/ hyperplasia without atypia:

 Surgery is not a first-line treatment in these patients as medical management has a high cure rate in this category.

Indications for hysterectomy:

1. Atypical hyperplasia develops during the treatment period
2. No resolution of the disease after 12 months of treatment
3. Relapse of endometrial hyperplasia
4. Non-resolution of bleeding
5. A non-compliant patient who declines surveillance and follow-up

A postmenopausal patient needing surgery for benign endometrial hyperplasia/hyperplasia without atypia can be offered total hysterectomy with bilateral salpingo-oophorectomy. 

If a premenopausal woman requires a hysterectomy, performing oophorectomy should be on a case to case basis. It would be a good practice to consider bilateral salpingectomy as it decreases the risk of developing ovarian cancer.

A laparoscopic procedure is preferred to an abdominal procedure because it has several advantages like lesser postoperative pain, faster recovery, and a shorter inpatient duration. [2] Uterine morcellation, endometrial ablation, and supracervical hysterectomy are not recommended for the management of endometrial hyperplasia as they may lead to residual disease and formation of intrauterine synechiae which may make future follow -up and diagnosis difficult.[1]

Management of  endometrial intraepithelial neoplasia/ hyperplasia with atypia:

Endometrial intraepithelial neoplasia / Atypical hyperplasia has a high risk of progression to invasive malignancy. Considering the risk of progression to endometrial adenocarcinoma, a total hysterectomy has been recommended. A laparoscopic procedure is preferred. Routine lymphadenectomy and frozen section analysis of the uterine lining do not confer an advantage.[37]

As with the earlier category, postmenopausal women who require surgery should be offered total hysterectomy with bilateral salpingo-oophorectomy. Also, premenopausal women require a hysterectomy should have an individualized decision making regarding oophorectomy. Conservative surgeries are not recommended. Management of endometrial intraepithelial neoplasia/ hyperplasia with atypia in women who wish to preserve their fertility or who are not suitable for surgery, there are several risks involved with the conservative management of endometrial intraepithelial neoplasia. These could be coexistent / progression to invasive disease, coexistent ovarian malignancy, systemic involvement, metastases, and death. The woman should be carefully counseled about the risks involved. 

The investigation results, including tumor markers, radiological findings, and histopathology, should be discussed in a multidisciplinary meeting involving gynecologic oncologists. The treatment should be planned on an individualized approach. It is possible to provide fertility-sparing treatment to these women if indicated, but this data is based on very small studies.[37]

 Hormone replacement therapy (HRT) and endometrial hyperplasia:

Systemic estrogen-only HRT should not be prescribed. Women should be counseled to report unscheduled bleeding to their care provider promptly. Those on sequential HRT preparation who wish to continue HRT and have endometrial hyperplasia should be counseled to switch to continuous combined HRT preparation / LNG-IUS. Women on continuous combined HRT with endometrial hyperplasia should be counseled for the lack of substantial evidence for the optimal progestogen. It would be a good practice to review the symptom profile to assess the need for HRT.

Tamoxifen treatment and endometrial hyperplasia:

The management plan should be individualized and developed with the involvement of the woman’s oncologist.[38] The routine use of LNG-IUS is not recommended in women on tamoxifen for breast cancer. This is because of the lack of evidence about the effects of LNG on breast cancer. 

Management of endometrial hyperplasia confined to an endometrial polyp:

The uterine polyp should be removed completely, and the rest of the endometrium should be sampled. In the absence of hyperplasia in the surrounding endometrium, it is considered curative. If the surrounding endometrium shows hyperplasia, it should be treated accordingly. 

Prevention of recurrence by providing long term medical therapy may be associated with adverse effects. Many clinicians counsel patients for lifestyle changes leading to weight loss or bariatric surgery, which can help them to revert the risk factors like obesity and thus reducing the risk.

Differential Diagnosis

The potential differential diagnosis for endometrial hyperplasia are conditions which can result in focal or generalized thickening  of the endometrium:

1. Endometrial cancer: Histopathological examination of the endometrial tissue can show markers of invasions in endometrial cancer.
2. Endometrial polyp: Hydrosonography can be helpful in diagnosing endometrial polyp by enhancing visualization.  Diagnostic hysteroscopy can confirm the presence of a polyp.
3. Endometritis: Irregular endometrium and focal thickness are the hallmarks of endometritis.

Prognosis

Progestogens induce secretory changes in the endometrium and counterbalance the stimulatory effects of estrogen. Several studies have shown that progestogen therapy leads to a high rate of regression in hyperplasia without atypia (89% to 96%).[35] (RCOG. Management of Endometrial Hyperplasia (Green-top Guideline No. 67)) However, in the presence of endometrial intraepithelial neoplasia, there is a reduction in the success rate of therapy.[18]

Complications

The clinical significance of endometrial hyperplasia is that it can be a precursor to endometrial adenocarcinoma. The presence of atypia/ EIN has a higher risk of progression to invasive malignancy- as high as 27.5% if not treated.[39]  Also, this entity has a possibility of coexistent endometrial malignancy in 43% of cases.[18]

Deterrence and Patient Education

Women can be counseled about the risk factors of endometrial hyperplasia such as obesity and increased body mass index. They can be encouraged for lifestyle modification and weight loss which can lead to reduced endogenous production of estrogen.

Enhancing Healthcare Team Outcomes

Most patients with endometrial hyperplasia present with abnormal uterine bleeding. Often times, they may come to nurse-practitioners or general physicians, and therefore an understanding of the potential causes and the interprofessional coordination with the gynecologist becomes important.  The radiologist and histopathologist are key diagnosticians along with the gynecologist in this setting. They should be provided with the relevant clinical history to aid a correct diagnosis.  Most international bodies of gynecology have their recommendations on the diagnosis and management of endometrial hyperplasia based on the evidence from large studies.[1]