Endometrial Hyperplasia

Overview

Endometrial hyperplasia occurs when the endometrium, or uterine lining, becomes too thick. Endometrial hyperplasia (EH) is a uterine disorder that encompasses a wide range of morphological endometrial changes. When compared to normal proliferative endometrium, it is primarily distinguished by an increase in the endometrial gland-to-stroma ratio.

The clinical relevance of EH stems from the likelihood of development to endometrioid endometrial cancer (EC), and 'atypical' types of EH are considered premalignant lesions. This disorder is not cancer, although it can progress to uterine cancer in some circumstances.

Endometrial Hyperplasia definition

Endometrial hyperplasia is characterized by an abnormal growth of endometrial glands. It is caused by unopposed estrogenic stimulation of endometrial tissue and a relative lack of progesterone's counterbalancing actions. This hormonal imbalance can be found in a variety of circumstances where the origin of estrogen excess is either endogenous or exogenous.

The uneven development of the endometrium results in an aberrant gland-to-stroma ratio and appears on a continuum of the endometrium's spectrum of alterations. It involves varied degrees of histopathological complexity as well as unusual cell and nuclear characteristics. Endometrial hyperplasia, if left untreated, has a high risk of progressing to endometrial cancer.

Epidemiology

The most frequent gynecologic cancer in the United States is endometrial cancer. It is also the fourth most frequent cancer among women in the United States, according to data.

The prevalence of endometrial hyperplasia is believed to be three times that of endometrial cancer. Endometrial hyperplasia is regarded to be a precursor to endometrial cancer, and if detected early, disease progression can be prevented. Endometrial hyperplasia must be properly diagnosed and treated in order to reduce the number of occurrences of endometrial cancer.

According to a comprehensive study on the epidemiology of endometrial hyperplasia, women diagnosed with hyperplasia without atypia were between the ages of 50 and 54. The most prevalent age group for hyperplasia with atypia was 60-64 years, while the condition was fairly rare below the age of 30 years.

Etiology 

Endometrial hyperplasia is caused by continuous estrogen exposure along with a relative lack of progesterone. Excess estrogen can be caused by either endogenous or exogenous factors. The following are the risk factors for endometrial hyperplasia:

• Age
• Nulliparity
• Obesity
• Genetic
• Diabetes Mellitus
• Anovulatory cycles- PCOS, perimenopause
• Ovarian tumors- granulosa cell tumors
• Hormone replacement treatment- even at low doses, estrogen-only therapy can cause endometrial hyperplasia and is not recommended for women who have a uterus. Over-the-counter/herbal medications may contain a high level of estrogen.
• Immunosuppression (renal transplant recipients) and infection may potentially play a role in endometrial hyperplasia development.
• Hereditary nonpolyposis colorectal cancer, often known as Lynch syndrome, puts women at a high risk of endometrial hyperplasia.

Pathophysiology

Endometrial hyperplasia develops as a result of estrogen dominance and relative progesterone deficiency. Endogenous estrogen excess is commonly caused by anovulatory cycles (perimenopause, polycystic ovarian syndrome (PCOS), obesity, and estrogen-secreting ovarian tumors. Unopposed estrogen medication, hormone replacement therapy (HRT), and tamoxifen are examples of exogenous causes.

The Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) discovered that unopposed estrogen therapy with 0.625 mg of conjugated equine estrogen administered to women for three years causes an increase in endometrial hyperplasia. Complex hyperplasia risk rose by 22.7 percent, whereas atypical hyperplasia risk increased by 11.8 percent. The Women's Health Initiative (WHI) research, on the other hand, discovered that combining 2.5mg of medroxyprogesterone acetate with 0.625 mg of conjugated equine estrogen did not raise the risk of endometrial cancer.

Endometrial hyperplasia has been classified using three different approaches. These were determined by the histological features of the lesion and its proclivity to develop to cancer. In 1994, WHO established a categorization, which was widely recognized and utilized. Women were followed for an average of 13 years and exhibited varying rates of progression to endometrial cancer. The four major categories were as follows:

1. Simple hyperplasia without atypia: the number of glands grew but the normal architecture was not jeopardized; cancer progression rate was 1%.
2. Simple hyperplasia with atypia: simple hyperplasia with signs of nuclear atypia (marked fluctuation in nuclear form and size, as well as conspicuous nucleoli); 8 percent cancer progression rate
3. Complex hyperplasia without atypia: glands grow increasingly crowded and irregular; cancer progression rate is 3%.
4. Complicated hyperplasia with atypia: complex hyperplasia with atypical characteristics has a 29% chance of progressing to malignancy.

Endometrial cancer can coexist in up to half of instances with complicated atypical hyperplasia. This is exacerbated further by the fact that the histological difference between these two entities can be perplexing. Considering these issues, WHO simplified the classification of endometrial hyperplasia in 2014 and proposed two categories based upon the presence of cytologic atypia: 

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

Endometrial intraepithelial lesion (EIN) categorization was proposed by a group of gynecologic pathologists in the year 2000. A computerized morphometric analysis was used in this method. The D-score is a critical component of this categorization. It is determined as stromal volume divided by total tissue volume. The epithelium, gland lumen, and stromal volume make up the overall tissue volume.

Endometrial hyperplasia symptoms

The majority of patients come with symptoms of abnormal uterine bleeding at first. The shift in monthly bleeding pattern alerts the lady to seek medical attention as soon as possible. This is why, unlike other cancers, most instances of endometrial cancer (more than 70%) are discovered early in stage I, as contrast to other cancers where symptoms remain indolent for several years, allowing disease to spread to regional and distant locations. The value of a complete history and physical examination in the evaluation cannot be overstated.

Clinical record should contain a history of the current disease, a menstrual history, and a list of 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, the transition to perimenopause, and the age of menopause should all be documented. It is critical to take note of the patient's obstetric history and whether or not she desires to conceive in the future.

This is crucial since it can alter the patient's therapy options. It is ethical to examine medical treatment choices for a woman who wants to have a child in the future without jeopardizing her prognosis. A smear and a history of contraception should be obtained. A detailed medical and surgical history should be obtained since it may indicate numerous variables that may play a role in care. The medication history should be properly collected, and particular questions should be asked about the use of HRT, over-the-counter medicines, tamoxifen, and so on. A family and social history should be obtained as well.

A general physical examination, including vitals evaluation, should be included in the examination. Pallor should be sought for because the majority of individuals present with menorrhagia. If the patient seems clinically pale, she should be given an iron prescription and urged to eat an iron-rich diet. To rule out any worrisome lesions, a breast examination should be undertaken. Examine the abdomen for past scars and abdominal lumps.

To rule out vulval, cervical, uterine, and/or ovarian pathology, a careful local examination of the genitalia should be done. A bimanual exam is required to determine the size of the uterus and ovaries, as well as to rule out any abnormalities in the Douglas pouch. To confirm the diagnosis, a diagnostic technique such as an endometrial biopsy is conducted.

Diagnosis

The most frequent symptom is abnormal uterine bleeding, which can manifest as menorrhagia (heavy menstrual bleeding), metrorrhagia (irregular bleeding), unplanned bleeding (HRT patients), or postmenopausal hemorrhage. Some women may have abnormal discharge that is foul-smelling or blood-stained. The PAP smear may reveal aberrant glandular cells or unusual endometrial cells, necessitating additional investigation.

Patients who arrive with these symptoms and a corroborating history raise the possibility of endometrial hyperplasia. The confirmation, however, needs a histological study of endometrial tissue, which can be acquired by either a small outpatient surgery or an inpatient endometrial biopsy.

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

According to research, there may be an overlap between normal and abnormal endometrial thickness in premenopausal women. This implies that ultrasonography is primarily used to detect structural problems. However, the Royal College of Obstetricians and Gynecologists (RCOG) recommends that a TVS be conducted in women who have atypical uterine bleeding, PCOS, and no withdrawal bleed.

When endometrial thickness was less than 7mm, no occurrences of endometrial hyperplasia were found. As a result, the RCOG advice determined that the existence of hyperplasia below 7mm endometrial thickness is improbable.

Role of Transvaginal Ultrasound in Postmenopausal Women

Transvaginal sonograms are recommended for postmenopausal women who suffer vaginal bleeding (TVS). An endometrial biopsy is recommended if TVS reveals increased uterine thickness or uneven endometrium. When the endometrial thickness is less than 3 or 4 mm, the risk of endometrial cancer is less than 1%, and hence no sampling is necessary.

The cut off for women on HRT or tamoxifen has been raised. If the endometrial thickness is larger than 4 mm or cannot be viewed well, further tests such as sonohysterography, office hysteroscopy, or endometrial biopsy are recommended. Asymptomatic postmenopausal women who have been diagnosed with an endometrial thickness more than 4 mm do not require routine examination.

Endometrial Sampling

High sensitivity and specificity in diagnosing endometrial hyperplasia and excluding endometrial cancer are the most critical parameters for any tissue sample approach. Pathologists have a difficult time ruling out totally invasive malignancy in non-hysterectomy tissues. Almost 40% of individuals identified with precancerous endometrial hyperplasia with an endometrial suction curette had a postoperative concomitant endometrial malignancy in the hysterectomy specimen. 

Endometrial cancer has been detected with an equal rate in women with abnormal uterine bleeding using dilatation and curettage (D&C) or suction curette techniques of acquiring tissue samples. These solutions, however, offer their own set of drawbacks. In nearly 60% of these surgeries, less than 50% of the uterine cavity was sampled.

The presence of a large lesion in the uterus might deflect the flexible curette, preventing appropriate endometrial sampling. According to the American College of Obstetricians and Gynecologists' (ACOG) Committee on Tissue Sampling Methods, hysteroscopy with guided D&C can sample both localized pathology and background endometrium and may result in a greater detection rate.

If the treatment technique is a hysterectomy, the type of sampling process becomes less significant. This is because the likelihood of missing an invasion on the final pathology result in a uterine specimen is much lower than in a tissue biopsy specimen.

Endometrial hyperplasia treatment

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:

Over a 20-year period, the probability of development to invasive cancer is less than 5%. If the hormonal milieu is rectified (reversible sources of estrogen excess such as obesity and use of HRT/over-the-counter medicines that may contain a high dosage of estrogen), spontaneous remission can occur. Progestogen treatment had a greater illness resolution rate (89-96%) than observation alone (74.2-81%). 

The therapy can include both local intrauterine (levonorgestrel-releasing intrauterine system [LNG-IUS]) and continuous oral progestogens. LNG-IUS, on the other hand, is recommended since it has less adverse effects, a better incidence of illness resolution, and less bleeding per vagina. This improved effectiveness is due to the greater local concentration of LNG at the endometrial obtained with LNG-IUS.

Women who refuse LNG-IUS can begin taking continuous oral progestogens at the following doses: medroxyprogesterone 10-20 mg/day or norethisterone 10-15mg/day (cyclical progestogens are not suggested by the Royal College of Obstetricians and Gynecologists) (RCOG).

Treatment duration and follow up:

Treatment should last at least six months in order to achieve hyperplasia regression. Endometrial monitoring with office endometrial biopsy is advised every six months. Two consecutive 6 – monthly negative biopsies should be obtained before the patient is discharged. Women with a BMI more than 35 who have been treated with oral progestogens are at a higher risk of recurrence and should be monitored on an annual basis. If a woman exhibits signs of abnormal uterine bleeding, she should be urged to schedule a follow-up appointment.

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 woman with benign endometrial hyperplasia/hyperplasia without atypia may be offered complete hysterectomy with bilateral salpingo-oophorectomy. If a premenopausal woman necessitates a hysterectomy, oophorectomy should be performed on a case-by-case basis. Bilateral salpingectomy is a recommended technique since it lowers the chance of getting ovarian cancer.

A laparoscopic operation is favored over an abdominal treatment because it offers various advantages such as reduced postoperative discomfort, faster healing, and a shorter stay in the hospital. Endometrial ablation, uterine morcellation, and supracervical hysterectomy are not advised for the treatment of endometrial hyperplasia because they may result in residual illness and the creation of intrauterine synechiae, making future follow-up and diagnosis difficult.

Management of endometrial intraepithelial neoplasia/ hyperplasia with atypia:

Endometrial intraepithelial neoplasia / Atypical hyperplasia has a significant chance of developing into invasive cancer. A complete hysterectomy has been suggested due to the possibility of progression to endometrial cancer. Laparoscopic surgery is preferable. Routine lymphadenectomy and frozen section examination of the uterine lining provide little benefit.

Postmenopausal women who require surgery, like the previous category, should be provided complete hysterectomy with bilateral salpingo-oophorectomy. Furthermore, premenopausal women who undergo a hysterectomy should make an informed decision on oophorectomy. Conservative procedures are not advised.

Endometrial intraepithelial neoplasia/hyperplasia with atypia management There are various concerns associated with conservative care of endometrial intraepithelial neoplasia in women who want to retain their fertility or who are not surgical candidates. Coexistence / progression to invasive illness, coexistent ovarian cancer, systemic involvement, metastases, and mortality are all possibilities. The lady should be advised thoroughly about the hazards involved. 

The findings of the study, including tumor markers, radiographic findings, and histology, should be addressed in a multidisciplinary conference with gynecologic oncologists. Treatment should be planned on an individual basis. If appropriate, these women can get fertility-sparing medication, however the data is based on relatively small trials.

Hormone replacement therapy (HRT) and endometrial hyperplasia:

HRT based only on estrogen should not be prescribed. Women should be advised to notify their healthcare professional as soon as possible if they have unexplained bleeding. Those who are on sequential HRT preparation and have endometrial hyperplasia should be advised to transition to continuous combination HRT preparation / LNG-IUS. Women on continuous combined HRT for endometrial hyperplasia should be advised due to a lack of solid evidence for the best progestogen. It is a good idea to analyze the symptom profile to determine whether HRT is required.

Tamoxifen treatment and endometrial hyperplasia:

The management plan should be tailored to the woman's specific needs and created in collaboration with her oncologist. The regular use of LNG-IUS in women on tamoxifen for breast cancer is not advised. This is due to a paucity of data about the effects of LNG on breast cancer.

Management of endometrial hyperplasia confined to an endometrial polyp:

The uterine polyp should be thoroughly removed, and the remaining endometrium should be sampled. It is deemed curative if there is no hyperplasia in the surrounding endometrium. If the surrounding endometrium displays signs of hyperplasia, it should be treated as such.

Long-term medicinal treatment for recurrence prevention may have unintended consequences. Many physicians advise patients to make lifestyle changes that result in weight reduction or bariatric surgery, which can help them reverse risk factors such as obesity and so lower their risk.

Differential Diagnosis

The following disorders can cause localized or widespread endometrial thickening and are potential differential diagnoses for endometrial hyperplasia:

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 cause secretory changes in the endometrium and counteract estrogen's stimulatory effects. Several investigations have found that progestogen treatment increases the rate of regression in hyperplasia without atypia (89 to 96 %). However, the success rate of treatment is reduced in the presence of endometrial intraepithelial neoplasia. 

Complications

Endometrial hyperplasia is clinically significant since it might be a precursor to endometrial cancer. If untreated, the presence of atypia/EIN increases the chance of progression to invasive malignancy by as much as 27.5 percent. In addition, this entity has a 43 percent chance of coexisting endometrial cancer.

Conclusion 

Endometrial hyperplasia is a disorder in which the endometrium (uterine lining) thickens abnormally. Endometrial hyperplasia is classified into four categories. The number of aberrant cells and the presence of cell alterations determine the kind. Simple endometrial hyperplasia, complex endometrial hyperplasia, simple atypical endometrial hyperplasia, and complex atypical endometrial hyperplasia are the four forms.

Endometrial hyperplasia typically produces vaginal bleeding that differs from your regular pattern. Some women may experience unexpected bleeding between cycles. Periods may grow heavier or more irregular in some women. You may suffer sudden bleeding if you have already ceased having periods and are in menopause.

An endometrial biopsy involves extracting cells from the womb lining. This is frequently done to rule out any underlying reasons of irregular vaginal bleeding. Treatment options for endometrial hyperplasia vary depending on the kind.