Endometrial Hyperplasia

Etiology

The most important risk factor for endometrial hyperplasia and, in turn, endometroid adenocarcinoma is the aforementioned chronic imbalance of or "unopposed" estrogen.[4] The source of exposure to excessive estrogen without the protective effects of progestin can be endogenous, exogenous, or genetic.

Endogenous Sources

• Obesity
  • An increase in adrenal secretory activity is often observed in obese patients, leading to increased androgen precursors, which are converted to estradiol in peripheral tissues.
  • The conversion rate of androstenedione to estrone and estradiol by aromatase rises in obese patients.
  • Higher estradiol concentrations can be found in obese patients as plasma levels of estradiol-binding sex hormone-binding globulin (SHBG) are typically diminished in this patient population.[5]           
• Chronic anovulation
  • When anovulation occurs, sex hormone production is not happening cyclically, and estrogen levels dominate without the opposing effect of progesterone produced by the corpus luteum after ovulation. This imbalance leads to a continued proliferation of the endometrium.[6]
  • Conditions associated with anovulation include polycystic ovary syndrome (PCOS), hyperprolactinemia, and perimenopausal hormonal status.             
• Early menarche, typically defined in individuals younger than 12                                                                       
• Late menopause, usually described in those aged 55 and older                                                                                  
• Presence of estrogen-secreting tumors
  • Granulosa cell tumors represent potentially estrogen-secreting tumors of the ovary. Accordingly, endometrial hyperplasia is diagnosed in 25% to 50% of women with granulosa cell tumors of the ovary.[7]
  • If endometrial hyperplasia is diagnosed in a patient without known risk factors, estrogen-secreting tumors should be excluded.

Exogenous source: Tamoxifen, a selective estrogen receptor modulator (SERM), one of the most common medications used for endocrine treatment of hormone receptor-positive breast cancer, has been associated with an increased risk for developing endometrial hyperplasia in postmenopausal women.[8]

Genetic source: Lynch syndrome is a genetic disease of autosomal dominant inheritance caused by mutation of 1 of 4 genes of the DNA mismatch repair system (MSH2, MLH1, MSH6, and PMS2), leading to microsatellite instability, which confers a markedly elevated risk for several types of cancers, particularly colon, and endometrial. Patients with hereditary nonpolyposis colorectal cancer have a lifetime risk of 40% to 60% for the development of endometrial cancer.[9] Recent studies have recommended screening patients diagnosed with atypical endometrial hyperplasia or endometrial cancer for microsatellite instability.[10]

Epidemiology

EC is the most common gynecologic malignancy in developed countries, the fourth leading cause of cancer, and the sixth cause of cancer death among women.[11] Cancer of the endometrium is rising in the United States, with an estimated incidence of 66,200 cases and 13,030 deaths in 2023.[12] The incidence of EC has increased in many countries over the past few decades, a trend which is hypothesized to be due to the rising prevalence of obesity, as well as shifts towards delaying childbearing.[13] EH is a recognized precursor lesion of the most common type of EC (endometrioid), and its detection offers opportunities for prevention. Prompt diagnosis and treatment can effectively reduce the number of cases of endometrial malignancy.

Pathophysiology

Estrogenic stimulation of the endometrium, unopposed by progestins, causes proliferative glandular epithelial changes or hyperplasia. Endometrial hyperplasia results from estrogen predominance and relative progesterone insufficiency. The typical causes for endogenous estrogen excess include anovulatory cycles (perimenopause, PCOS, obesity, and estrogen-secreting ovarian tumors). The exogenous causes include unopposed estrogen therapy, hormone replacement therapy, and tamoxifen (utilized in breast cancer treatment).[2] Hyperplasia, due to prolonged exposure to estrogens, is biologically distinct from the precancerous lesion—atypical endometrial hyperplasia.

Histopathology

Histologically, endometrial hyperplasia describes the abnormal proliferation of endometrial glands with a greater gland-to-stroma ratio than healthy proliferative endometrium but without endometrial stromal invasion.[2] Diagnosis is based upon histological assessment of a tissue sample obtained surgically via endometrial biopsy, curettage, or hysterectomy. The most widely used classification system for endometrial hyperplasia is the 2014 World Health Organization (WHO) Classification System, which differentiates between endometrial hyperplasia without atypia (benign endometrial hyperplasia) and atypical endometrial hyperplasia/endometrial intraepithelial neoplasia.

This clinical management of the 2 conditions differs depending on the presence or absence of nuclear atypia. Nuclear atypia is defined as nuclear enlargement with or without prominent nucleoli.[14] Endometrial hyperplasia without atypia is a benign lesion without significant somatic genetic changes, caused by extensive exposure to estrogen that is not counterbalanced by the protective effects of progestins. The hyperplastic changes often regress if physiological progesterone levels are resumed or therapeutic progestins are utilized.[15] Endometrial hyperplasia without atypia rarely progresses to endometrial cancer.

On the molecular level, atypical endometrial hyperplasia shares many similarities with endometrioid endometrial cancer.[16] Studies have documented a risk of as high as 50% for concomitant endometrial cancer in patients with atypical endometrial hyperplasia.

The risk for the development of endometrial cancer in women with atypical endometrial hyperplasia is diminished approximately threefold to fivefold when treated with progestin. However, the risk of progression to endometrial cancer among women with endometrial hyperplasia undergoing progestin treatment remains considerable at 15% to 28%. A retrospective cohort study investigated 242 women with atypical endometrial hyperplasia, of whom 74% received progestin therapy.[16]

Additionally, when considering the concurrent or future risk of endometrial cancer among women with atypical endometrial hyperplasia, clinicians must understand that atypical endometrial hyperplasia/endometrial intraepithelial neoplasia may be difficult to histopathologically from endometrial cancer. Trimble et al found overdiagnosis or underdiagnosis in nearly every third endometrial specimen, which illustrates the difficulty of this distinction.[17] This challenge suggests that treating atypical endometrial hyperplasia as the equivalent of early endometrial cancer when counseling affected patients is reasonable.

History and Physical

Most patients who receive a diagnosis of endometrial hyperplasia present with abnormal uterine bleeding (eg, abnormal postmenopausal bleeding, persistent or recurrent uterine bleeding).[4] This symptom prompts most patients to seek medical attention almost immediately, contributing to the detection of endometrial cancer at an early stage and, in turn, its relatively favorable prognosis (80%-90% 5-year survival rate at stage I) when diagnosed and treated.[18] This favorable outcome stands in contrast to other cancers, such as ovarian cancer, whose symptoms are more vague and can remain indolent for many years, allowing it to progress and metastasize.

The history obtained from the patient at the time of presentation should include the history of the present illness (such as the duration, intensity, and presence or absence of clots associated with the current episode of bleeding) and menstrual history (whether or not the patient has reached menopause, length, and regularity of cycles, flow, the passage of clots, intermenstrual bleeding, and postmenopausal bleeding).

Attention should be paid to the patient’s obstetric history, as nulliparity or delayed childbearing are risk factors for endometrial hyperplasia. Additionally, a patient’s desire to conceive in the future may alter the treatment of endometrial hyperplasia and cause the provider to consider nonsurgical options and close surveillance over hysterectomy.

As with any patient, medical and surgical history should be taken in detail as they may determine contraindications to hormonal treatment or a patient’s candidacy for surgery. For instance, a patient with uncontrolled cardiopulmonary disease may have to undergo medical optimization before surgery or may attempt medical management first. Similarly, a patient with a history of breast cancer or liver disease is not a candidate for oral progestins.[19]

The physical examination should include a general routine examination, including vital signs. If a patient is hypotensive, tachycardic, and actively bleeding, she may need fluid resuscitation or a blood transfusion. As most patients present with menorrhagia, pallor should be assessed, which may suggest anemia. A breast examination should be performed to rule out any suspicious lesions, and in women of the appropriate age, normal mammography results within the last year should be confirmed. Most importantly, a pelvic exam should be performed. A speculum should be placed to visualize the quantity of bleeding, flow, and presence of clots. A foul-smelling discharge may suggest active infection and pose a contraindication to potential intrauterine device (IUD) placement. A bimanual exam can ascertain the size of the uterus and the presence of coexisting fibroids or adnexal masses. During the pelvic exam, an endometrial biopsy can be performed to confirm the diagnosis.[20][21][20]

Evaluation

Confirming a diagnosis of endometrial hyperplasia and subsequently distinguishing between endometrial hyperplasia with and without atypia requires a histological examination of endometrial tissue, which can be obtained either by outpatient or inpatient endometrial sampling.

Transvaginal Ultrasound in Premenopausal Women

In premenopausal women, the utility of transvaginal ultrasound (TVUS) mainly lies in the ability to detect myomas, endometrial polyps, pregnancy, and other potential etiologies of abnormal uterine bleeding. The endometrial thickness varies physiologically with the different phases of the menstrual cycle and can reach as high as 18 mm during the secretory phase.[22]

Transvaginal Ultrasound in Postmenopausal Women

An endometrial thickness of ≤4 mm in postmenopausal women has a >99% negative predictive value for endometrial cancer. Therefore, TVUS is pivotal in the initial evaluation of postmenopausal bleeding. There is no consensus regarding which endometrial thickness cut-off should be used when recommending an endometrial biopsy for asymptomatic patients.[23] Failure to adequately identify a thin, distinct endometrial echo in a postmenopausal woman with bleeding should trigger the need for an ultrasound, office hysteroscopy, or endometrial sampling.[24] 

Endometrial Sampling

Multiple methods are available to sample the endometrium. The simplest method, in-office suction endometrial sampling (also known as endometrial biopsy) performed with a plastic cannula (Pipelle), has a long history of safety and efficacy.[25] Endometrial biopsy involves obtaining a tissue sample by inserting a Pipelle into the uterus via the cervix and obtaining a tissue sample via suction technique. Biopsy should be offered to young women with abnormal uterine bleeding and risk factors for EH, as well as nonobese women with unopposed hyperestrogenism, such as those with PCOS or estrogen-producing ovarian masses.[23] In both postmenopausal and premenopausal women, the Pipelle has been shown to have detection rates of 99.6% and 91%, respectively.[26]

However, more recent studies demonstrate a higher rate of endometrial cancer in hysterectomy specimens from patients with preoperative office Pipelle biopsy when compared with uterine dilation and curettage, suggesting that the former method failed to detect endometrial pathology in these instances.[27] It is believed that “mass lesions” that distort the endometrial cavity may deflect the pliable suction catheter and lead to ineffective sampling, potentially missing endometrial pathology.

Hysteroscopic-guided uterine sampling is another recommended method of obtaining endometrial tissue, and data demonstrate its utility for diagnosing endometrial polyps, endometrial cancer, and endometrial hyperplasia.[28] Several tissue-removal devices, such as morcellators or tissue forceps, allow for targeted hysteroscopic-guided resection of the endometrium or any discrete lesions visualized hysteroscopically.[29][30]

Treatment / Management

The risk of benign endometrial hyperplasia without atypia progressing to invasive malignancy is less than 5% over 10 years.[31] Endometrial hyperplasia (and even low-grade endometrioid cancers) can be conservatively managed by progestin therapies (eg, oral or intrauterine progestogens), especially among women who wish to maintain fertility. Spontaneous resolution can occur if reversible causes of estrogen excess are corrected.[29][32](B2)

Disease resolution is more likely with progesterone treatment (89%-96%) than with expectant management (74%-81%).[33] Progestins have historically been the cornerstone of conservative management for atypical endometrial hyperplasia and stage IA endometrioid endometrial cancer without myometrial invasion. GnRH analogs, metformin, and hysteroscopic resection, combined with progestins, appear to increase the overall efficacy of treatment.[34] Although oral progestins (medroxyprogesterone 10 mg to 20 mg daily or norethisterone 10 mg to 15mg daily) have been used historically as the first line for medical management, the levonorgestrel IUD has been shown to achieve a higher histologic regression rate when compared to oral progestogens for complex hyperplasia without atypia (92% vs 66%) and atypical hyperplasia (90% vs 69%).[35] Additionally, levonorgestrel IUDs provide a local higher dose concentration of progestins than the oral route, avoiding the adverse effects linked to the systemic administration of progestogens, with expected increased patient compliance.[34] Lifestyle changes like weight loss may also be advised alongside progesterone therapy.[36](B2)

If fertility preservation is not desired, total hysterectomy is generally recommended for women with atypical endometrial hyperplasia due to the presumed significant risk of concurrent future endometrial cancer and for women with persistent non–atypical endometrial hyperplasia.[37] Postmenopausal women should be offered a total hysterectomy with bilateral salpingo-oophrectomy. Accurately quantifying endometrial cancer risk in women diagnosed with endometrial hyperplasia is, therefore, pivotal to informed shared decision-making regarding the most appropriate clinical management strategies.

The most recent clinical guidelines recommend that in women with endometrial hyperplasia who undergo medical management, an endometrial biopsy should be undertaken at least every 3 months until 2 consecutive negative biopsies are obtained, especially in patients with atypical endometrial hyperplasia.[21] More extensive evaluations, such as sentinel lymph node assessment in patients with atypical endometrial hyperplasia, have not been shown to be beneficial in current studies and are not recommended.[38](A1)

Differential Diagnosis

The differential diagnosis for endometrial hyperplasia includes conditions that can result in focal or generalized thickening of the endometrium as follows:

• Endometrial cancer: Histopathological examination of the endometrial tissue can show markers of invasion in endometrial cancer.                         
• Endometrial polyp: Hydrosonography can enhance visualization and help diagnose endometrial polyps. Diagnostic hysteroscopy can confirm the presence of a polyp.                                                                                                                               
• Endometritis: An irregular-appearing endometrium and increased focal thickness are hallmarks of endometritis.[39] 

Prognosis

While endometrial hyperplasia can progress to endometrial cancer, the rate of progression depends on factors such as the degree of architectural abnormality and the presence or absence of nuclear atypia.[14] It is well-established that progression to endometrial cancer is higher in women with atypical compared with non–atypical endometrial hyperplasia. Recent meta-analyses describe the concurrent prevalence of endometrial cancer in those diagnosed with atypical endometrial hyperplasia as approximately 33%. The risk of progression to cancer in those with atypical endometrial hyperplasia was approximated at 8.2% annually if untreated and 2.6% annually in those with non–atypical endometrial hyperplasia in the same study.[21]

Studies have found high rates of disease regression in patients who decide against surgical management and, instead, are managed medically. A systematic review of outcomes in patients with endometrial intraepithelial neoplasia–atypical endometrial hyperplasia or grade 1 adenocarcinoma demonstrated an initial response to progestins of 86%, with a complete response of 66% for those with atypical endometrial hyperplasia. Oral, intrauterine, and combined modes of administration are effective. Recent studies have identified complete response rates of 43% and 82% for endometrial adenocarcinoma and atypical endometrial hyperplasia, respectively, after 6 months of treating these conditions with the levonorgestrel IUD.[40]

Complications

Endometrial hyperplasia, if left untreated or poorly managed, can lead to various complications, the most significant being the development of endometrial cancer. The abnormal proliferation of endometrial cells increases the risk of malignant transformation, particularly in cases of complex or atypical endometrial hyperplasia. Furthermore, untreated hyperplasia can exacerbate abnormal uterine bleeding, leading to chronic anemia and its associated complications, such as fatigue and impaired physical functioning. In cases where hyperplasia is hormonally driven, such as in estrogen-secreting tumors or conditions like PCOS, there's a heightened risk of exacerbating hormonal imbalances, potentially leading to further reproductive health issues or metabolic disturbances. Additionally, the psychological impact of living with a condition linked to cancer risk can induce significant anxiety and distress in affected individuals. Prompt diagnosis and appropriate management of endometrial hyperplasia are crucial to mitigate these potential complications and improve patient outcomes.[41]