Endometrial intraepithelial neoplasia (hyperplasia) and carcinoma: Clinical sciences

Endometrial intraepithelial neoplasia, or simply EIN, also known as complex atypical endometrial hyperplasia, is a precursor lesion to type I endometrial carcinoma.

Endometrial carcinoma, or uterine cancer, is the most common genital tract malignancy with a lifetime prevalence of 2-3% in biological females. It is classified into two categories based on histology. Type I represents endometrial adenocarcinoma, while type II encompasses non-endometrioid carcinoma, including clear cell and papillary serous histologies. In general, type I accounts for the vast majority of all endometrial carcinoma cases, with most being low grade and confined to the uterus at the time of diagnosis. Type II carcinomas are considered high grade with an increased risk of extrauterine diseases and have a poorer prognosis compared to type I disease.

When evaluating a patient with a chief concern suggesting EIN or endometrial carcinoma, your first step is to obtain a focused history and physical exam, as well as a pregnancy test with hCG if your patient is premenopausal.

The hallmark symptom of a patient with EIN or endometrial carcinoma is abnormal uterine bleeding, or AUB, or postmenopausal bleeding. Your patient might also report less specific symptoms such as abdominal or pelvic pain and bloating. Risk factors include a history of unopposed estrogen exposure. This can be endogenous, such as from chronic anovulation in conditions like polycystic ovarian syndrome, or from conversion of androgens to estrone in adipose tissue, as seen in obesity. Unopposed estrogen exposure can also be exogenous, such as in patients using estrogen therapy without progesterone, which is not recommended in those with a uterus.

Other risk factors include type 2 diabetes, age of 45 or greater, nulliparity, early age of menarche, late age of menopause, and a personal or family history of Lynch syndrome.

On physical exam, you may find uterine bleeding and palpate an enlarged, globular uterus, but most often the exam is benign. Finally, hCG is negative. Based on these findings, you should suspect EIN or endometrial carcinoma and obtain a transvaginal ultrasound, or TVUS, which assesses the uterus, cervix, and ovaries.

On ultrasound, there will be no structural causes of AUB, but you might see abnormally thickened endometrium. In a postmenopausal patient, an endometrial lining of more than 4 mm is abnormal. On the other hand, in a premenopausal patient, there is no standardized “normal” endometrial thickness, as the endometrium is constantly changing with the menstrual cycle. As such, it is generally considered an incidental finding.

Here’s a clinical pearl! If you discover endometrial thickening in postmenopausal patients incidentally, you don’t need to start the evaluation for EIN or endometrial carcinoma right away. Be sure to individually assess the need for further tests based on the patient's characteristics and risk factors.

Okay, the next step is to assess your patient's age and menopausal status.

If your patient is less than 45 years old, premenopausal, and has no risk factors for EIN or endometrial carcinoma, management involves monitoring and assessing for other causes of AUB. These include non-structural causes like coagulopathy or ovulatory dysfunction. If they continue to have AUB without an identifiable cause, consider an endometrial biopsy.

On the flip side, if your patient is less than 45 years old and premenopausal but has risk factors, OR if they have failed medical management, OR if they have persistent AUB, your next step is to obtain an endometrial biopsy.

Finally, keep in mind that in all postmenopausal individuals with ultrasound findings of endometrial thickness greater than 4 mm or inadequate endometrial visualization, you should proceed with endometrial biopsy.

Endometrial biopsy is used to assess the endometrial tissue for benign glandular cells, EIN, or endometrial carcinoma. While there are different ways to obtain a sample of the endometrial tissue, the most common is by using an endometrial pipelle, which can be performed in the office. Occasionally the results may be unsatisfactory for diagnosis.

If this is the case and your suspicion is high for EIN or endometrial carcinoma, then hysteroscopy with direct endometrial sampling is typically indicated. Alternatively, hysteroscopy with direct biopsy may be performed instead of a blind endometrial biopsy.

Okay, if the pathology report shows regular spacing of endometrial glands within the stroma, your diagnosis is a benign endometrium. Management includes monitoring, however, if your patient continues to have AUB, consider further diagnostic intervention.