What are the indications for an endometrial biopsy in women with abnormal uterine bleeding, particularly in postmenopausal women or those with risk factors for endometrial cancer, such as obesity, diabetes, hypertension, or a history of unopposed estrogen therapy?

Indications for Endometrial Biopsy

Endometrial biopsy is indicated for all postmenopausal women with vaginal bleeding, all women ≥45 years with abnormal uterine bleeding, and younger women (<45 years) with abnormal bleeding plus risk factors for endometrial cancer. 1

Primary Indications

Postmenopausal Bleeding

• Any postmenopausal bleeding warrants endometrial evaluation, as abnormal uterine bleeding is present in 90% of endometrial cancer cases, particularly in this population 1
• Endometrial biopsy is mandatory when transvaginal ultrasound shows endometrial thickness ≥4-5 mm 1, 2
• Even with endometrial thickness ≤4 mm, if bleeding persists or recurs, biopsy is required due to the 10% false-negative rate of initial sampling 1, 3

Premenopausal Women ≥45 Years

• All women ≥45 years with abnormal uterine bleeding require endometrial biopsy regardless of risk factors 4
• This age cutoff reflects the sharp increase in endometrial cancer risk after age 45 5

Premenopausal Women <45 Years with Risk Factors

Endometrial biopsy is indicated in younger women with abnormal uterine bleeding when any of the following risk factors are present 1, 4, 5:

• Unopposed estrogen exposure (including polycystic ovary syndrome, anovulation, estrogen therapy without progestin)
• Obesity (major risk factor due to peripheral estrogen conversion)
• Diabetes mellitus
• Hypertension
• Tamoxifen therapy
• Nulliparity
• Infertility or chronic anovulation

Special High-Risk Populations Requiring Surveillance

Lynch Syndrome

• Annual endometrial biopsy starting at age 30-35 years is recommended due to 30-60% lifetime risk of endometrial cancer 1
• Continue annual surveillance even with normal results, as these patients remain at persistently elevated risk 1

Atypical Glandular Cells on Cervical Cytology

• All women ≥35 years with atypical glandular cells (AGC) on Pap smear require endometrial biopsy as part of initial evaluation 1
• Women <35 years with AGC need endometrial biopsy if they have risk factors for endometrial cancer or abnormal bleeding 1

Tamoxifen Users

• Women on tamoxifen with any vaginal bleeding require immediate endometrial evaluation 1
• Tamoxifen increases endometrial adenocarcinoma risk to 2.20 per 1000 women-years versus 0.71 for placebo 1
• Women with sonographic endometrial thickness >4 mm while on tamoxifen should undergo hysteroscopic endometrial biopsy 6

Diagnostic Algorithm

Initial Evaluation

1. Transvaginal ultrasound (TVUS) is the first-line imaging study to assess endometrial thickness and structural abnormalities 1, 2
2. Endometrial thickness thresholds for postmenopausal women:
   • ≤4 mm: Negative predictive value for cancer nearly 100%; no biopsy needed if asymptomatic 2
   • ≥5 mm: Endometrial tissue sampling recommended 2, 7
   • Note: Some guidelines use ≥3 mm as a more conservative cutoff 2

When Initial Biopsy is Inadequate or Negative

• Office endometrial biopsy has a 10% false-negative rate 1, 3
• If symptoms persist despite negative biopsy, proceed to hysteroscopy with directed biopsy or fractional D&C under anesthesia 1, 6
• Never accept a negative biopsy as reassuring in a symptomatic postmenopausal woman—persistent bleeding mandates escalation 1

Focal Lesions

• Hysteroscopy with directed biopsy is preferred over blind sampling for suspected focal lesions (polyps, submucosal fibroids) 1, 6
• Blind suction techniques are not reliable for diagnosing endometrial polyps 6
• Saline infusion sonohysterography can help distinguish focal from diffuse pathology when TVUS is inconclusive 1, 2

Diagnostic Accuracy

Office-Based Sampling

• Pipelle and Vabra devices have extremely high sensitivity (99.6% and 97.1% respectively) for detecting endometrial carcinoma 1
• These devices are highly effective for diffuse endometrial pathology but may miss focal lesions 3

Hysteroscopy with Biopsy

• Hysteroscopy has the highest diagnostic accuracy and allows direct visualization with targeted biopsy 1, 6
• Should be used as the final step when initial sampling is inadequate or symptoms persist 1

Critical Pitfalls to Avoid

• Do not rely on ultrasound alone: TVUS cannot reliably determine the etiology of endometrial thickening, only measure thickness 2, 7
• Do not accept inadequate sampling: If insufficient tissue is obtained, repeat biopsy or proceed to hysteroscopy 1, 3
• Do not delay in tamoxifen users: Establish tissue diagnosis before modifying treatment—stopping tamoxifen does not address the diagnostic imperative 1
• Do not assume fibroids explain postmenopausal bleeding: Fibroids typically shrink after menopause; bleeding requires malignancy exclusion first 2
• Do not perform routine surveillance in average-risk asymptomatic women: There is no evidence that screening reduces endometrial cancer mortality in the general population 1