WHO NEEDS AN ENDOMETRIAL BIOPSY?

Introduction

Endometrial biopsy is a method of sampling the endometrium, which can be done as an office procedure. It is an important diagnostic tool in the evaluation of abnormal uterine bleeding. It is used to exclude the presence of pathologic conditions, such as endometrial cancer and its precursors, especially atypical endometrial hyperplasia. Endometrial biopsy is also used in the evaluation of patients with infertility to diagnose luteal phase defects. However, the focus of this article is the role of endometrial biopsy in determining the cause of abnormal uterine bleeding.

Endometrial Biopsy versus Dilatation and Curettage

Previously, the gold standard method for sampling the endometrium was dilatation and curettage (D&C) under general anesthetic. However, it is now recognized that D&C is really just another blind sampling technique, which often samples less than half of the endometrium.¹

1. it is safer because there is no need for general anesthetic;
2. there is usually no need for cervical dilatation; and
3. there are markedly decreased risks of hemorrhage, infection, and perforation.⁶

Endometrial biopsy is also more convenient and saves time for both the physician and the patient.

Risk Factors for Endometrial Cancer

The majority of endometrial cancers are related to chronic unopposed endogenous or exogenous estrogen. Prolonged exposure to unopposed estrogen can occur in patients with obesity, polycystic ovary syndrome, and chronic anovulation. Unopposed exogenous estrogen is a significant risk factor, thus postmenopausal women with a uterus should not be taking estrogen without appropriate progesterone. Other women at increased risk of endometrial cancer include those with a relatively longer period of exposure to estrogen, such as women with early menarche, late menopause, and nulliparous women. The pattern of abnormal bleeding is also important because women with irregular menstrual cycles are at higher risk of having endometrial cancer than women with regular cycles.⁷

Age is an important risk factor for endometrial cancer. The peak age for endometrial cancer is 60 years.⁸ Most physicians agree that women with age greater than or equal to 40 years are at increased risk. Other risk factors include diabetes and hypertension. Women with diabetes have a 2.8-fold increased risk of endometrial cancer.⁹ In two studies, hypertension was not an independent risk factor when adjusted for body weight.^9,10 Finally, women who are using tamoxifen as adjuvant therapy for breast cancer have an increased risk of endometrial cancer.¹¹ (Level 3 Evidence) This risk is highest in women who have used tamoxifen for more than two years.

Indications for Endometrial Biopsy

1) Postmenopausal Bleeding:

Any woman with postmenopausal bleeding who is not on hormone replacement therapy (HRT) requires endometrial sampling. About 7% of such cases are caused by malignancy.¹² Thus, postmenopausal bleeding should be considered to be from endometrial cancer until proven otherwise.

Most women on cyclic combined HRT experience regular withdrawal bleeding. Women should be counseled about this beforehand and reassured that this is normal. Patients with irregular bleeding, not associated with progesterone withdrawal, should be considered to have an abnormal pattern of bleeding and should have endometrial sampling.^6,8

For women on continuous combined HRT, the endometrium often becomes atrophic, and these women become amenorrheic. Seventy-five percent of these women develop amenorrhea after six months.¹³ If bleeding occurs beyond six months, this should be considered abnormal, and endometrial sampling should be considered.⁶ The Society of Obstetricians and Gynecologists of Canada recommends an endometrial biopsy for patients who continue to experience bleeding after the first six months of treatment with continuous combined HRT.⁸ (Level 4 Evidence)

2) Perimenopausal Bleeding:

During the perimenopausal years, waxing and waning ovarian function produces changes in the menstrual cycle. Women often experience cycles that vary in length as well as amount and duration of flow. The anticipated changes in the menstrual cycle sometimes make it difficult to determine if a patient is having abnormal uterine bleeding.

Perimenopausal women with abnormal bleeding are at increased risk of endometrial cancer secondary to their age and anovulatory cycles. Thus, all women with abnormal uterine bleeding in the perimenopausal period require endometrial sampling.^9,14 The most suspicious patterns are persistently increased menstrual flow, decreased menstrual interval, and intermenstrual bleeding.¹⁴ (Level 4 Evidence)

3) Premenopausal Bleeding:

The indications for endometrial biopsy in premenopausal women with abnormal bleeding are not as straightforward. Adolescents generally do not require sampling because their abnormal bleeding is often due to anovulation secondary to an immature hypothalamic-pituitary-ovarian axis. Less commonly, an underlying inherited coagulopathy may be the cause. However, after the adolescent period, endometrial cancer should be considered in the differential diagnosis of abnormal bleeding because up to 10% of women with endometrial cancer are diagnosed before the age of 45.¹⁰

The risk factors for endometrial cancer need to be considered when determining if an endometrial biopsy is needed in a premenopausal woman. In women less than age 40 with no risk factors, the risk of endometrial cancer is minimal.⁷ Thus, it may be appropriate to initiate hormonal treatment after an endocrine workup, and then only sample the endometrium if there is no response to treatment. On the other hand, women with one or more risk factors are at increased risk of endometrial cancer and probably should be sampled. The most important risk factor in premenopausal women is irregular menstrual cycles, which is associated with a 14% risk of an abnormal endometrial biopsy, including benign and malignant lesions.⁷ Thus, an endometrial biopsy should be considered for almost all women with irregular cycles.

4) Tamoxifen:

Because of the estrogen-like effects of tamoxifen on the endometrial lining, patients taking tamoxifen who experience abnormal vaginal bleeding should have endometrial sampling with an endometrial biopsy.⁸ (Level 4 Evidence)

5) Abnormal Pap Smear Cytology:

In postmenopausal women, the presence of any endometrial cells on Pap smear is an indication for endometrial sampling.^6,9 In other women, the presence of atypical endometrial cells also warrants an endometrial biopsy. Patients with malignant endometrial cells on Pap smear are at significant risk of having endometrial cancer, often a high-grade malignancy.¹⁵

6) Follow-up:

Women who have been treated for endometrial hyperplasia with hormonal therapy require a follow-up endometrial biopsy in 3 to 6 months to ensure the hyperplasia has regressed.

7) Role for Screening with Endometrial Biopsy:

There is no role for screening women who do not present with abnormal bleeding. Asymptomatic women are at low risk for endometrial cancer,¹⁶ and the accuracy of endometrial biopsy is poor for well-differentiated, low-volume, minimally invasive tumors, which makes endometrial sampling a poor screening test.¹⁷

Accuracy

The accuracy of endometrial biopsy to detect endometrial disease, especially endometrial cancer, is highly acceptable. In studies comparing endometrial biopsies to hysterectomy specimens, endometrial biopsy had sensitivities ranging from 83 to 96% for the detection of endometrial cancer.^18,19,20,21

Indications for D&C

Although endometrial biopsy has replaced D&C as the first line test for abnormal bleeding, there are still definite circumstances where D&C may be indicated. If an endometrial biopsy cannot be performed, if the sample is insufficient, or if the patient has persistent bleeding after a negative biopsy, then further investigation is needed. To determine the next appropriate step, patients should be triaged according to their risk for endometrial cancer. If a patient is at high risk for endometrial cancer, she requires a D&C. However, if she is at relatively low risk for endometrial cancer or is at increased anesthetic risk, then a transvaginal ultrasound (TVS) may be done to guide further management. If the TVS demonstrates an endometrial thickness of less than or equal to 4 mm, then the risk of having significant endometrial pathology is low and probably no further investigation is required, other than close follow-up.^8,22 If the TVS shows a thickness of greater than 4 mm, then the patient should probably have sampling by D&C.^8,23

Summary

Endometrial biopsy is an important diagnostic tool in the investigation of abnormal uterine bleeding. It has replaced D&C as the first line diagnostic test because it has similar accuracy, yet has the advantages of being safer, quicker, and more convenient. Primary care physicians and gynecologists should be aware of the risk factors for endometrial cancer in order to understand who requires an endometrial biopsy. All postmenopausal women with uterine bleeding who are not on HRT require endometrial sampling. All women on HRT with unexpected uterine bleeding need an endometrial biopsy. All perimenopausal women with abnormal bleeding should be sampled. Premenopausal women with irregular cycles or with one or more other risk factors for endometrial cancer should have an endometrial biopsy. In cases where an endometrial biopsy cannot be performed, produces insufficient tissue, or the patient has persistent bleeding after a negative biopsy, TVS can help to guide further decisions about who to sample with D&C versus who to monitor with close follow-up.

- Sheri-Lee Samson and Donna Gilmour

Thanks to Dr. Don Wescott at St. Martha's Regional Hospital in Antigonish Nova Scotia, for reviewing the draft copy of this article.

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