Patients with endometrial hyperplasia mostly present with abnormal uterine bleeding. Women in the reproductive age group present in the form of menorrhagia and metrorrhagia, while postmenopausal bleeding is the presentation in the post-reproductive period. Occasionally patients may present with vaginal discharge. Some patients may be detected due to abnormal glandular or endometrial cells in the Pap smear.[19]

A detailed history and physical examination are required to determine and rule out other sources and causes of the presenting complaints or bleeding. A thorough and focused examination of the lower genital tract for pathologies and lesions of the lower genital tract, e.g., vulva, vagina, cervix, along with uterus and ovaries, should be done. This should include a pelvic examination. In obese patients where the pelvic examination may be difficult to interpret radiological investigations such as pelvic ultrasonography may be used. Pelvic ultrasonography is helpful in ruling out ovarian and other pathologies like uterine fibroids etc.[20]

Imaging the endometrium for diagnostic purposes is done on days 5-10 of the patient’s cycle. Endometrial hyperplasia can be reliably excluded if the endometrium measures less than 6 mm in thickness in pre-menopausal women and less than 5 mm thick in post-menopausal women.[20][21] The endometrium may appear smooth or more often will show an irregular surface with asymmetric/focal thickening. Cystic changes may be present. However, it is not possible to reliably differentiate EH from EC by ultrasonography;[20] unless frank myometrium invasion is seen.

In pre-menopausal patients who present with abnormal bleeding, a pregnancy test should always be done to exclude pregnancy. In all patients (pre- and post-menopausal) with abnormal vaginal bleeding, assessment of the coagulation profile with total platelet counts, prothrombin time, and partial thromboplastin time should be done to exclude coagulation and platelet disorders. A complete blood count should be ordered to assess anemia resulting from excessive blood loss (both chronic and acute).[22]

The final diagnosis of endometrial hyperplasia is usually made by hysteroscopy and direct biopsy sampling of the endometrium. Obtaining tissue via biopsy ideally needs to be done when the patient is not taking progestin-based hormones. If a patient is currently on hormonal therapy, a biopsy should be obtained 2 to 4 weeks after stopping therapy. Assessment of premalignant etiology may include molecular analysis (see etiology section).[23]

According to the American College of Obstetrics and Gynecologists (ACOG), the management plan for patients diagnosed with premalignant endometrial lesions includes:[24]

• Ruling out the concurrent presence of endometrial carcinoma
• Strategic management plan designed to accommodate late diagnosis of occult carcinoma
• Prevention of progression to endometrial cancer

Management options of premalignant endometrial lesions include 1) surgical and 2) non-surgical options. A total hysterectomy (not supracervical hysterectomy) is the treatment of choice for premalignant endometrial lesions. In younger patients wanting to have children, high-dose progestin therapy with appropriate close histological monitoring is preferred.[24]

Surgical Management: Total hysterectomy is the current standard of care for premalignant lesions of the endometrium. ACOG recommends that in clinically appropriate situations, total hysterectomy provides definitive treatment and assessment for a possible concurrent carcinoma. The supracervical hysterectomy, morcellation, and endometrial ablation are not recommended because of concerns of underlying carcinoma, which may be missed. Total hysterectomy with removal of the cervix with or without bilateral salpingo-oophorectomy (BSO), along with peritoneal washings, can provide proper staging of any incidentally discovered endometrial neoplasia and mitigates the risk of leaving behind any undetected or residual disease.

Surgical options include abdominal, vaginal, and minimally invasive procedures (such as laparoscopic or robotic approach) and may be chosen depending on the extent of the planned surgery and surgical skills of the operating surgeon. In contrast to abdominal hysterectomy, laparoscopic or vaginal hysterectomy is associated with less pain, earlier hospital discharge, and quicker recovery. However, the vaginal approach may not permit a comprehensive surgical staging, and removal of ovaries should intraoperative assessment require it. The scope of the surgery may change based on intraoperative frozen section guided pathologic review. Pathologic evaluation includes an assessment of myometrial invasion.[24] Lymphadenectomy is not recommended and is considered overtreatment and increased surgical risk for a majority of patients with premalignant lesions of the endometrium.

Non-surgical Management: Non-surgical management is offered to younger patients wanting to preserve fertility or patients with medical comorbidities; therefore, poor surgical candidates due to increased risk of complications. The therapeutic goal is 1) complete clearance of disease, 2) reversion to normal endometrium, and 3) prevention of invasive carcinoma.

Acceptable non-surgical treatments include hormonal therapy. Endometrial ablation is not advised as the completeness of ablation cannot be assessed. Additionally, it may cause fibrosis with adhesions in the endometrial cavity and making subsequent follow-up surveillance difficult or impossible. However, there are no standardized guidelines for optimal dosage and duration.[24][15][21]

Hormonal therapy includes mainly progestins or suppression of estrogenic effects. In addition to this, selective estrogen receptor modulators (SERMS) may be used. Other agents used to reduce estrogenic effects are aromatase inhibitors, gonadotropin-releasing hormone (GnRH) antagonists, and sulfatase inhibitors. Hormonal therapy using progesterone derivatives is used extensively for any patient wanting to preserve fertility. Medroxyprogesterone acetate (MPA) and megestrol acetate, with different doses and schedules, are the most commonly used progesterones. Nearly 75% of atypical hyperplasia resolve with long-term high dosage progestin therapy.[24][21][15]

Progesterone acts as a counterbalance to the mitogenic effects of estrogens. It induces secretory differentiation of the glandular epithelium.[25] Progesterone is normally well-tolerated and with side effects e.g., infrequent edema, gastrointestinal disturbances that are well tolerated. However, occasionally it may lead to thromboembolic events. It is also a reasonable option for any patient with a hyperplastic or pre-cancerous lesion who desires uterine retention. It can also be used for most elderly patients with medical comorbidities with either premalignant endometrial hyperplasia or low-grade malignancy.[15] 

A full and detailed histopathologic examination of the endometrium is required to measure regression, persistence, or progression. Therefore examination of the entire uterus after hysterectomy is considered the “gold standard.” However, this option is not available for patients who receive non-surgical management in order to preserve fertility. These patients should be followed up with hysteroscopy and direct endometrial sampling when undergoing fertility-sparing management. No serum or tissue marker is available for follow up. Imaging modalities do not have the required specificity, so again follow up with hysteroscopy, and direct endometrial sampling is needed.[21] A repeated endometrial biopsy may lead to the elimination of the premalignant lesion nidus, yielding false-positive responses for hormonal therapy.

Hormonal therapy resistance is seen in nearly 30% of patients. This is thought to be due to a decreased availability of progesterone receptors and alteration of the apoptotic signaling pathway of the endometrial glandular cells.[21][15] Additional factors that may be responsible include the down-regulation of progesterone receptor and activation of the transforming growth factor signaling pathway. Less likely, resistance to hormonal therapy could result from mutations in PR or possibly paracrine effects. The histologic response of the glands of AEH/EIN is strongly coupled to the decidual response in the stroma, so the possibility of a paracrine effect is plausible, but the epithelial-stromal interactions of the endometrium are incompletely understood.[21][15][26][27]

Although the criteria for AH/EIN are well defined, several conditions may mimic the cytological picture. Many of these lesions are interpreted by the pathologist as 'gland crowding.' Localized groups of altered and crowded endometrial glands may be misdiagnosed as premalignant or malignant lesions. In one study, follow-up outcomes of "gland-crowding" reports show 77% benign lesions (proliferative endometrium, secretory endometrium, endometrial polyp, etc.), 19% premalignant lesions, and 4% EC.[28] 

Other benign lesions that may mimic premalignant and malignant lesions when biopsies are examined may include mucinous metaplasia, papillary mucinous metaplasia, and endometrial polyps. If the history of pregnancy is not available, then the Arias-Stella reaction may be misinterpreted as the premalignant lesion. Endometrial hyperplasia with secretory changes may occasionally be difficult to distinguish from the "cork-screw" shaped extensive and proliferative glands of a late secretory endometrium.[28][29]

AH has been reported to progress to endometrial carcinoma in 29% of cases, with a mean duration of the progression being 4.1 years.[11] Additionally, AH may carry a higher risk of coexistent invasive carcinoma.[17] Recent studies report that up to 50% of women with atypia are found to have EC in subsequent hysterectomy specimens.[17][15] On the other hand, EC with concomitant hyperplasia tends to be of a lower grade and stage and higher 5-year survival rates.[30]

Complications of atypical hyperplasia may include severe uterine hemorrhage, requiring emergency medical or surgical management. Acute hemorrhage may be severe enough to require a blood transfusion.

EC until recently was thought of as a predominantly postmenopausal disease. However, due to the increase in rates of obesity in the US, we are starting to see signs of a shift towards a rising incidence of EH/EIN and cancer amongst pre- and peri-menopausal women as well. Diagnosis and management of EH, therefore, cause a challenge for the treating physician.[6] Early physician intervention and patient education discussing modifiable risk factors such as smoking, diet, and sedentary lifestyle could potentially stem effects on disease development.

Enhancing our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions. This involves an interprofessional team approach. Patients will often present to their primary care provider with abnormal vaginal bleeding. These physicians, physician assistants, and nurse practitioners in obstetrics/gynecology and family medicine will be the first-line providers to assess the patient. To assist with the diagnosis, these providers will rely on pathologists to review and diagnose endometrial tissue samples.

For radiological evaluation, radiology technicians conduct ultrasound exams on the patients, while radiologists interpret the images. The lab and imaging results communicated to the primary care provider allows the diagnostic picture to come together. If surgery is the chosen treatment, the obstetrician/gynecologist and the surgical team manage the patient. Nurses care for the patients in the outpatient environment, as well as the pre- and post-operative settings. Medical management involves pharmacists who dispense the hormone therapies to the patient and answer any drug-related questions.

Involving and recognizing the interprofessional team’s involvement in the process will help with better care and outcomes. The correct diagnosis, if made early enough in the course of the disease, can lower the risk of advancement to malignancy.[24]