Atypical Endometrial Hyperplasia

Atypical endometrial hyperplasia (AEH; endometrioid intraepithelial neoplasia, EIN) is the direct precursor of endometrioid endometrial carcinoma. It shows cytological atypia, crowded glands, and nuclear changes.

The risk of progression to cancer is about 8 to 29% over 20 years. 25 to 40% of women with a biopsy diagnosis of AEH have concurrent endometrial carcinoma at hysterectomy.

Risk factors are the same as for endometrial hyperplasia (obesity, anovulation, unopposed oestrogen, tamoxifen, PCOS, diabetes). Lynch syndrome (MLH1, MSH2, MSH6, PMS2) and Cowden syndrome confer a high risk in young women.

The mean age at diagnosis is 50 to 55 years, but about 5 to 10% occur under 40 years, which introduces fertility concerns.

• Abnormal uterine bleeding: postmenopausal bleeding, heavy or irregular premenopausal bleeding, intermenstrual bleeding
• Often found incidentally, or in infertile women with PCOS and anovulation
• Obesity, hirsutism, and metabolic syndrome features in many

• Endometrial biopsy (pipelle or hysteroscopic directed biopsy). Hysteroscopy with D and C is preferred in suspected AEH to reduce underdiagnosis of cancer.
• Histology shows glandular crowding, architectural complexity, nuclear atypia (enlarged, rounded nuclei, loss of polarity, prominent nucleoli), and PTEN loss.
• Mismatch repair immunohistochemistry and molecular testing for Lynch syndrome in young patients
• Transvaginal ultrasound or pelvic MRI to assess myometrial involvement and exclude coexisting cancer. CT chest, abdomen and pelvis in selected cases
• Serum CA-125 when suspicion of cancer
• Genetic counselling for women with a family history or young age

• Standard therapy: total hysterectomy (laparoscopic or robotic preferred; vaginal or abdominal alternatives) with bilateral salpingectomy; bilateral oophorectomy is individualised (postmenopausal women, those with BRCA or Lynch syndromes; ovaries conserved in premenopausal women). Frozen section or sentinel lymph node mapping in selected cases is acceptable, because of the concurrent cancer rate; ensure surgeons with oncology capability (avoid morcellation).
• Fertility sparing treatment (for women who wish to conceive or cannot undergo surgery, after counselling and exclusion of invasive disease by expert pathology and MRI):
  • LNG-IUS 52 mg, with or without oral progestin (megestrol acetate 160 mg daily or medroxyprogesterone acetate 400 to 600 mg daily) for at least 6 months; complete response in about 70 to 85% (relapse in 25 to 40%)
  • GnRH agonists plus aromatase inhibitors (letrozole 2.5 mg daily) are alternatives
  • Metformin 500 to 1,500 mg daily and weight loss as adjuncts
  • Hysteroscopic resection followed by progestogen therapy
  • Endometrial sampling every 3 to 6 months until regression is documented (two consecutive negative biopsies), then maintenance therapy and early pregnancy attempts with assisted reproduction (IVF improves pregnancy rates)
  • After childbearing is complete, definitive hysterectomy is recommended because of the high risk of relapse

• Non-surgical candidates (medical comorbidity): LNG-IUS with ongoing 3 to 6 monthly surveillance
• Lifestyle: weight loss, exercise, treatment of diabetes and PCOS
• Follow up: lifelong awareness of bleeding and long term surveillance of residual hormonal risk in fertility sparing patients