Endometrial hyperplasia is an irregular proliferation of endometrial glands accompanied by an increase in the glandular/mesenchymal ratio. In Western countries, endometrial cancer is the most common gynecologic malignancy; data show that in 2012 alone, there were 8,617 new cases of endometrial cancer in the United Kingdom. Endometrial hyperplasia is a precancerous lesion of endometrial cancer, and its incidence is at least three times higher than that of endometrial cancer, and may progress to endometrial cancer if left untreated. The most common first symptom of endometrial hyperplasia is abnormal uterine bleeding, including increased menstrual bleeding, intermenstrual bleeding, irregular bleeding, irregular bleeding on estrogen supplementation therapy, and postmenopausal uterine bleeding.
In February 2016, the Royal College of Obstetricians and Gynaecologists (RCOG) and the British Society for Gynecologic Endoscopy (BSGE) jointly published Guidelines for the Management of Endometrial Hyperplasia. As the first edition of the guidelines for the management of endometrial hyperplasia, this guideline aims to provide clinicians with the most up-to-date evidence-based guidance on the clinical management of endometrial hyperplasia. The key points of its content are as follows.
The development of endometrial hyperplasia is associated with multiple identifiable risk factors, and targeted assessment should be performed to identify and monitor possible risk factors. The application of the 2014 revised WHO classification is recommended, which classifies endometrial hyperplasia into 2 categories based on the presence or absence of cellular atypia: (1) endometrial hyperplasia without atypia and (2) endometrial atypia.
The definitive diagnosis of endometrial hyperplasia relies on endometrial histology, and the required histological specimens are obtained mainly by endometrial biopsy. Diagnostic hysteroscopy is more helpful in obtaining specimens than plain endometrial biopsy; its advantages are especially pronounced when plain endometrial biopsy specimens fail to obtain specimens or when the specimens taken fail to be diagnostic. In addition, if a plain endoscopic biopsy reveals the presence of endothelial hyperplasia within a polyp or within a scattered lesion, a localized endothelial biopsy should be performed under direct hysteroscopic view to obtain a meaningful histologic specimen. Among the physical examination tools, transvaginal ultrasound Doppler is diagnostic for endometrial hyperplasia, while CT, MRI, and biomarkers have insufficient evidence of diagnostic value and are therefore not routinely recommended.
Initial management of endometrial hyperplasia without atypia?
Endometrial hyperplasia without atypia has a less than 5% risk of progression to endometrial cancer within 20 years, and most cases resolve spontaneously during follow-up. On the other hand, some reversible risk factors, such as obesity and hormone supplementation therapy (HRT), should be of concern. In view of these two points, observation only and regular histological follow-up may be considered for cases without atypical endometrial hyperplasia, especially those with well-defined and reversible risk factors, to determine that the endometrial hyperplastic state is in remission. However, progestin therapy can achieve a higher rate of remission than observation alone; therefore, progestin therapy is recommended for cases that do not remit spontaneously at follow-up or in the presence of abnormal uterine bleeding symptoms.
First-line medication for endometrial hyperplasia without atypia?
Pharmacological treatments that provide effective remission of the endometrial hyperplastic state include continuous oral progestin and topical intrauterine application of progestin (intrauterine levonorgestrel-releasing system, LNG-IUS). LNG-IUS is recommended as a first-line agent because of its ability to achieve higher remission rates than oral progestins and because treatment-related bleeding events with LNG-IUS application are more acceptable and have fewer side effects. Continuous oral progestin (10-20 mg/day of medroxyprogesterone acetate or 10-15 mg/day of norethindrone) is an option for cases refusing LNG-IUS treatment. Cyclic oral progestin is not recommended because this dosing method is not as effective in inducing remission compared to continuous dosing or LNG-IUS.
Treatment cycles and follow-up for endometrial hyperplasia without atypia?
To obtain histological remission of endometrial hyperplasia, oral progestin or LNG-IUS therapy should be administered for a minimum of 6 months. If the side effects are tolerated and there are no fertility requirements, LNG-IUS is recommended for 5 years, as it reduces the risk of recurrence, especially if it reduces the symptoms of abnormal bleeding. Once diagnosed, endometrial hyperplasia without atypia should be included in the histological evaluation and follow-up, which can be individualized according to the specific clinical presentation of the case, with a minimum follow-up interval of 6 months. Discontinuation of follow-up should be considered only after at least 2 consecutive negative histological findings at 6-month intervals. If abnormal bleeding reappears after the end of treatment, it is indicative of possible recurrence and further treatment is recommended. For women with risk factors for recurrence (e.g., body mass index greater than 35 or oral progestin), endometrial histologic evaluation should be performed at 6-month intervals, and the follow-up histologic evaluation interval may be extended to 1 year after 2 consecutive negative results are obtained.
Indications for surgical treatment of endometrial hyperplasia without atypia?
Progestin therapy provides histologic and symptomatic remission in the majority of cases and evades surgery-related adverse events; therefore, hysterectomy should not be the treatment of choice for endometrial hyperplasia without atypia. In women without reproductive requirements, hysterectomy should be considered only if the following factors are present: 1) progression to endometrial atypical hyperplasia at follow-up, 2) no histologic remission after more than 12 months of pharmacologic therapy, 3) reappearance of endometrial hyperplasia after completion of progestin therapy, 4) persistence of bleeding symptoms, and 5) refusal of endometrial follow-up or pharmacologic therapy. Postmenopausal women who require surgical treatment should have both fallopian tubes removed along with the uterus, and the choice of whether to remove the ovaries at the same time should be individualized; however, removal of both fallopian tubes is necessary because it reduces the risk of future ovarian malignancy. Laparoscopic surgery is recommended because of its short hospital stay, mild postoperative pain, and quick recovery. In the treatment of endometrial hyperplasia, the application of endometrial ablation is not recommended because this treatment modality does not guarantee complete and durable endometrial destruction and because the secondary postoperative uterine adhesions can be an obstacle to future endometrial histological monitoring.
Initial management of endometrial atypical hyperplasia?
Endometrial atypical hyperplasia is at risk of potential malignancy and progression to cancer, and therefore total hysterectomy should be performed. Laparoscopic surgery is recommended because of its shorter hospital stay, less postoperative pain and faster recovery compared to open surgery. Intraoperative endometrial cryopathology and conventional lymph node dissection do not provide clear benefit. Postmenopausal women should have their uterus removed along with both fallopian tubes and ovaries. The choice of whether to remove the ovaries in premenopausal women is individualized; however, to reduce the risk of future ovarian malignancy, prophylactic resection of both fallopian tubes should be performed. Similarly, endometrial ablation is not recommended for the same reasons as above.
Management of cases of endometrial atypical hyperplasia who wish to preserve fertility and who are not candidates for surgery?
Women who wish to preserve their fertility should be adequately informed of the risk of potential malignancy and progression of endometrial atypical hyperplasia to endometrial cancer. Before proceeding with treatment, a thorough evaluation should be performed to exclude endometrial invasive carcinoma and the possible coexistence of ovarian cancer. A multidisciplinary consultation should be performed to develop a management and follow-up plan, taking into account histological and imaging features and tumor marker expression. The preferred conservative treatment should be LNG-IUS, followed by oral progestin. Given the higher recurrence rate of conservative treatment, surgical hysterectomy should be performed once the patient is able to forgo fertility preservation.
Follow-up of non-surgical treatment of endometrial atypical hyperplasia?
Routine surveillance follow-up consists mainly of performing an endometrial biopsy, the timing of which can be individualized on a case-by-case basis. Follow-up is performed at 3-month intervals until 2 consecutive negative histological results are obtained. In asymptomatic cases with histologically confirmed remission, if 2 consecutive negative results have been obtained, the follow-up interval can be extended to 6-12 months until surgical removal of the uterus is possible.
Management of endometrial hyperplasia cases with fertility requirements?
There should be at least one histologic evaluation confirming remission of the disease prior to initiating attempts at conception. Consultation with a reproductive medicine specialist is recommended to learn about matters related to trying to conceive, what the future evaluation will consist of, and the necessary treatment. The use of assisted reproduction is recommended because it increases the live birth rate compared to natural conception and prevents the recurrence of endometrial hyperplasia. Before starting assisted reproduction, it is important to make sure that the endometrial hyperplasia has resolved, as this is the only way to ensure a high rate of embryo implantation and pregnancy.
Hormone supplementation therapy with estrogen alone is not recommended for women with a uterus. It should be ensured that all women undergoing HRT are able to inform their physicians immediately in case of abnormal bleeding. Once endometrial proliferation is detected in women on sequential HRT, it is recommended to switch to continuous progestin therapy with LNG-IUS or continuous estrogen-progestin combined with HRT if you wish to continue HRT, with subsequent management as described in the previous section of this guideline. Women applying continuous combined HRT who find endometrial hyperplasia should be re-evaluated for the need to continue HRT if they wish to continue HRT. Regarding the exploration of the most desirable route of progestin administration, it is likely that LNG-IUS will be an effective alternative to oral progestin, although there is very limited evidence to refer to at this time.
The risk of endometrial hyperplasia in breast cancer drug therapy cases?
Patients treated with tamoxifen for breast cancer should be aware that taking this drug increases the risk of endometrial hyperplasia and endometrial cancer and should inform their doctor immediately if they experience abnormal vaginal bleeding or changes in discharge while on the drug. Aromatase inhibitors do not increase the risk of endometrial hyperplasia or endometrial cancer.
Do patients treated with tamoxifen need to receive prophylactic progestin therapy?
There is evidence that LNG-IUS can prevent the formation of endometrial polyps and reduce the risk of endometrial hyperplasia in women taking tamoxifen. However, the exact effect of LHG-IUS application on breast cancer recurrence is uncertain, and therefore it is not recommended for routine use.
What is the management of endometrial hyperplasia found during the treatment with tamoxifen?
In these cases, the need for tamoxifen treatment should be re-evaluated and the specific treatment should be determined by the histological classification of the endometrial hyperplasia and the opinion of the oncologist should be sought.
What is the management of endometrial hyperplasia combined with endometrial polyps?
Endometrial polyps should be surgically removed and an endometrial biopsy should be performed to obtain histological information about the endometrial background. Subsequently, specific management should be performed according to the histological classification of the endometrial hyperplasia.