What is the next best step for a 59-year-old postmenopausal woman with a history of breast cancer (BCa) on tamoxifen (tamoxifen citrate) presenting with a 2-month history of vaginal bleeding and an inadequate endometrial biopsy?

Hysteroscopy and Biopsy (Option C)

In a postmenopausal woman on tamoxifen presenting with vaginal bleeding and an inadequate endometrial biopsy, hysteroscopy with directed biopsy is the next best step to establish a tissue diagnosis before any treatment decisions. 1

Why Hysteroscopy is Mandatory

• Office endometrial biopsy has a false-negative rate of approximately 10%, and when the biopsy is negative, non-diagnostic, or inadequate in a symptomatic patient, fractional D&C under anesthesia (or hysteroscopy) must be performed. 1

• Hysteroscopy allows direct visualization of the endometrium and targeted biopsy of suspicious lesions such as polyps that blind sampling may miss—this is critical in tamoxifen users who have increased risk of both endometrial polyps and malignancy. 1

• Never accept an inadequate or negative endometrial biopsy as reassuring in a symptomatic postmenopausal woman, especially one on tamoxifen—persistent bleeding mandates further evaluation. 1

• Hysteroscopy has the highest diagnostic accuracy for endometrial pathology and is clinically useful in diagnosing endometrial cancer when initial sampling fails. 1

Why NOT to Stop Tamoxifen First (Option A)

• Stopping tamoxifen does not address the immediate diagnostic imperative—you must establish whether endometrial cancer is present before making any treatment modifications. 1

• Tamoxifen increases the risk of endometrial adenocarcinoma (2.20 per 1000 women-years versus 0.71 for placebo) and uterine sarcoma (0.17 per 1000 women-years versus 0.04 for placebo). 2

• Most women with tamoxifen-associated endometrial cancer present with vaginal spotting as an early symptom, making prompt evaluation essential rather than empiric drug discontinuation. 1

• Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding should be promptly evaluated. 2

Why NOT Hysterectomy First (Option B)

• Hysterectomy is premature without a tissue diagnosis and would be considered only after malignancy is confirmed or if atypical hyperplasia is found. 1

• Proceeding directly to hysterectomy without establishing the diagnosis exposes the patient to unnecessary surgical risk if the pathology is benign. 1

• Preoperative pathological information is crucial for establishing the surgical plan—all patients with risk of cancer should be investigated with endometrial biopsy or curettage to avoid inadequate surgery. 1

Management Algorithm After Hysteroscopy

• If endometrial cancer is confirmed: Discontinue tamoxifen, proceed with staging and definitive surgical treatment. 1

• If benign pathology is found (polyps, hyperplasia without atypia, atrophy): Manage accordingly, consider continuing tamoxifen with close surveillance. 1

• If atypical hyperplasia is found: Hysterectomy is typically recommended given the high progression risk to cancer, especially in the context of tamoxifen use. 1

Critical Clinical Context

• Abnormal uterine bleeding is present in 90% of endometrial cancer cases, particularly in postmenopausal women, making tissue diagnosis essential. 1

• Outpatient hysteroscopy following unsuccessful office endometrial biopsy attempts is feasible, safe, and cost-effective, preventing the need for an operating room-based procedure in 90% of cases. 3

• Outpatient hysteroscopy identified endometrial hyperplasia and cancer in 4.5% and 3% of patients respectively in those with failed initial biopsy. 3