What is the best course of action 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 postmenopausal bleeding and an inadequate endometrial biopsy?

Hysteroscopy with Directed Biopsy (Option C)

In a 59-year-old postmenopausal woman on tamoxifen presenting with 2 months of bleeding and an inadequate endometrial biopsy, hysteroscopy with directed biopsy is the mandatory next step before any other intervention. 1, 2

Rationale for Hysteroscopy

• 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 must be performed. 1

• Hysteroscopy should be used as the final step in the diagnostic pathway for women with postmenopausal bleeding, particularly when initial sampling is inadequate, as it allows direct visualization of the endometrium and targeted biopsy of suspicious lesions such as polyps. 3, 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 with directed biopsy is more sensitive in disclosing all types of uterine lesions than dilatation and curettage, with sensitivity of 100% versus missing 21 cases with D&C alone. 4, 5

Why Not 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. 3

• 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 0.0 for placebo). 3

• Most women with tamoxifen-associated endometrial cancer present with vaginal spotting as an early symptom, making prompt evaluation essential rather than empiric drug discontinuation. 3

• The decision to discontinue tamoxifen should only be made after establishing the diagnosis—if early-stage endometrial cancer is found, tamoxifen should be discontinued until cancer is fully treated, then may be resumed. 3

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. 2

• Proceeding directly to hysterectomy without establishing the diagnosis exposes the patient to unnecessary surgical risk if the pathology is benign (could be polyps, hyperplasia, or atrophy). 2

• 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. 3

Clinical Algorithm

1. Perform hysteroscopy with directed endometrial biopsy to obtain adequate tissue diagnosis 1, 4

2. Based on histology results:

   • If endometrial cancer confirmed: Discontinue tamoxifen, proceed with staging and definitive surgical treatment 3
   • If atypical hyperplasia: Consider hysterectomy as definitive treatment, discontinue tamoxifen 2
   • If benign pathology (polyps, simple hyperplasia, atrophy): Manage accordingly, consider continuing tamoxifen with close surveillance 3

3. If hysteroscopy still yields inadequate tissue, proceed to fractional D&C under anesthesia 1

Critical Pitfalls to Avoid

• Do not rely on transvaginal ultrasound alone in tamoxifen users—ultrasound screening may not be suitable for women taking tamoxifen due to tamoxifen-induced endometrial changes that reduce specificity. 6

• Do not perform empiric treatment without histologic diagnosis—the differential includes benign polyps, hyperplasia, and malignancy, each requiring different management. 3, 2

• Do not delay evaluation—abnormal uterine bleeding is present in 90% of endometrial cancer cases, particularly in postmenopausal women. 1