Megan A. Brady
History of present illness
A 40-year-old nulligravid Nigerian woman presented to the emergency room with two days of worsening abdominal pain.
She describes the pain as severe and crampy. She denies consti- pation, diarrhea, nausea, or vomiting. Four years ago, the patient was diagnosed with breast cancer in Nigeria and under- went a left radical mastectomy, radiation, and chemotherapy.
She has been on tamoxifen for the last three years. She has had three to four“periods”since chemotherapy. Her last episode of bleeding was two weeks ago. She often experiences hotflashes.
She is not using contraception. She also has hypertension, for which she takes hydrochlorothiazide.
Physical examination
General appearance:Alert woman who is not in distress Vital signs:
Temperature: 37.7°C Pulse: 110 beats/min
Blood pressure: 139/85 mmHg Respiratory rate: 14 breaths/min Oxygen saturation: 99% on room air Height: 165 cm
Weight: 180 lb BMI: 30 kg/m2
Cardiac:Tachycardic, no murmur Pulmonary:Lungs clear to auscultation bilaterally
Breast:Absent left breast with post-surgical scarring Abdomen:Soft, obese, diffusely tender to palpation, no rebound tenderness, normoactive bowel
sounds
Genitourinary:Normal appearing external genitalia; vagina with scant clear discharge; cervix appears normal; bimanual examination significant for 12-week size, smooth, mobile, nontender uterus; adnexa nontender without appreciable masses
Laboratory studies:
Urine pregnancy test: Negative
WBCs: 4100/àL (normal 3900–11 700/àL) Hb: 11.5 g/dL (normal 12–15 g/dL)
Imaging:The patient underwent a CT scan (Fig. 38.1a) which showed complex heterogenousfluid and soft tissue masses within the endometrial canal and uterus. An MRI
was recommended given the CTfindings (Fig. 38.1b). It showed a 9.6 × 5.7 × 4.9 cm multicystic mass protruding from the posterior fundus with lattice-like bandsfilling the entire endometrial canal. This was interpreted as consistent with endometrial hyperplasia, but mass with myometrial invasion cannot be ruled out
How would you manage this patient?
Since this finding was not a surgical emergency, the patient was discharged from the emergency room with narcotic analgesia and gynecology follow-up two days later. Office endometrial biopsy was attempted, but difficulty was encoun- tered introducing the biopsy instrument through the cervix.
False tracts were created during the attempted biopsy. Path- ology of the specimen revealed no cervical or endometrial tissue.
The patient was scheduled for the operating room. Des- pite her age and likely ovarian insufficiency from her prior chemotherapy, she and her husband hoped for pregnancy, planning in-vitro fertilization with donor eggs if necessary.
Fertility-sparing surgery was planned unless malignancy was diagnosed. She was consented for hysteroscopy with removal of the polypoid tissue and endometrial sampling, as well as possible diagnostic laparoscopy.
Hysteroscopy (Fig. 38.2) revealed a large mass of cystic appearing polyps, which were removed with multiple passes of uterine polyp forceps and a sharp curette. Laparoscopy was not performed as the intraoperative pathology from hystero- scopy provided an adequate diagnosis.
Pathology showed benign endometrial polyps with changes consistent with tamoxifen.
Gynecologic oncology consultants recommended that the patient stop tamoxifen and instead take anastrozole, an aro- matase inhibitor. Anastrozole has not been associated with pathologic changes to the endometrium. Since her medication change, she has not had recurrence of bleeding and her breast cancer remains in remission.
Tamoxifen-induced changes of the endometrium
Tamoxifen use increases the risk of endometrial adenocarci- noma, as well as several other types of uterine pathology, particularly uterine polyps. Tamoxifen is a selective estrogen receptor modulator (SERM) used as adjuvant therapy for
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
patients with estrogen receptor-positive breast cancer because of its anti-estrogen effects on breast tissue.
Effects on the endometrium are dependent on the pres- ences or absence of endogenous estrogen. In postmenopausal women, tamoxifen has an agonist effect on the endometrium, while in premenopausal women, it acts as an antagonist.
Although not well studied, adverse effects on premenopausal endometrium have not been documented [1]. The patient described, although age 40, has ovarian insufficiency from her prior chemotherapy, and is likely effectively menopausal as suggested by her hot flashes. The patient’s bleeding epi- sodes are probably from the uterine mass and unlikely to be menses.
Tamoxifen can stimulate proliferation of the postmeno- pausal endometrium, increasing risk for polyps, hyperplasia,
carcinoma, and sarcoma. The exact mechanism leading to these tissue changes is not well understood. Ten percent of women on tamoxifen will develop uterine pathology within five years leading to surgical evaluation [1]. Transvaginal ultrasound may show a thickened endometrium. However, no standard cutoff exists to define abnormal endometrial thickness in women on this medication [2]. Postmenopausal women on tamoxifen have a 2–3 times higher relative risk of developing endometrial cancer. This risk increases with treat- ment duration and dosage [3].
Tamoxifen-related endometrial changes have not been well described. One study describes patterns in almost 300 postmenopausal women on tamoxifen during afive-year treatment period at four tertiary care centers in Europe.
Five dynamic patterns were characterized by transvaginal
Fig. 38.2 Hysteroscopyfindings. Note irregular, cystic appearing endometrium with scattered vascularities.
(a) (b)
Fig. 38.1 CT (a) and MRI (b) images of uterine mass. (a) CT showed enlarged uterus with complex heterogenousfluid and soft tissue within the endometrial canal, as well as focal thinning of the posterior myometrium. (b) MRI showed a 9.6 × 5.7 × 4.9 cm multicystic mass protruding from the posterior fundus with lattice-like bandsfilling the entire endometrial canal.
ultrasound, diagnostic hysteroscopy, and annual endometrial biopsy: atrophic, hypervascularized, cystic, endometrial polyp, and pattern suspicious for malignancy. The endometria of women in the study most commonly experienced the atrophic pattern in the first year, with the hypervascularized pattern seen most frequently in the second year of treatment. The cystic pattern was seen more frequently over time, mostly in the third and fourth years of treatment. Only eight of the patients in the study had a pattern suspicious for malignancy.
Three of these patients had endometrial adenocarcinomas and one had papillary serous carcinoma [2].
The patient described was menopausal on tamoxifen with symptoms of vaginal bleeding and pain. Given their large size, the pain was thought to be from the polyps. Tissue diagnosis was necessary to ensure cancer was not present and as long as cancer was not present, removal of the polyps was necessary to resolve the patient’s bleeding and pain. If the biopsy returned as a cancer, she would have undergone total hysterectomy and staging. Given the large mass on initial imaging, hysterectomy would have been a reasonable next step if she was not committed to preserving options for fertility. Given the benign pathology of the endometrial spe- cimen at time of surgery, she discontinued tamoxifen and began taking anastrozole.
The American College of Obstetricians and Gynecologists states that, “In asymptomatic women using tamoxifen, screening for endometrial cancer with routine transvaginal ultrasonography, endometrial biopsy, or both has not been shown to be effective” [4]. Patients with endometrial polyps prior to tamoxifen initiation may be at higher risk for develop- ing atypical hyperplasia so evaluation with transvaginal ultra- sound or hysteroscopy before initiation of therapy may be reasonable [4]. Postmenopausal women on tamoxifen should
have close follow-up. Although no routine surveillance should be performed, symptoms, especially vaginal bleeding, should be immediately evaluated. Premenopausal women on tamoxifen do not require additional surveillance besides rou- tine care as this group has no known increased risk of uterine cancer. Tamoxifen has an important role in increasing survival of women with breast cancer, but increases the risk of endo- metrial pathology. Providers caring for women taking tamoxi- fen need to be aware of these risks to appropriately maximize benefits to the breast while minimizing risk to the endometrium.
Key teaching points
Tamoxifen-induced endometrial changes are most often benign.
Postmenopausal tamoxifen users have a 2–3 times greater risk of developing endometrial cancer than women not taking tamoxifen.
The overall benefits from tamoxifen in patients with breast cancer outweigh the risks.
Asymptomatic women on tamoxifen should not be screened for endometrial abnormalities with transvaginal ultrasound, endometrial biopsy, or hysteroscopy. Such screening may lead to unnecessary costly and invasive procedures without benefiting the patient.
Postmenopausal women taking tamoxifen should be educated about the need for evaluation if they experience any vaginal bleeding or bloody vaginal discharge. These women should be fully evaluated with imaging,
visualization of the endometrium with hysteroscopy, and endometrial sampling as necessary.
References
1. Kim HS, Jeon YT, Kim YB. The effect of adjuvant hormonal therapy on the endometrium and ovary of breast cancer patients.J Gynecol Oncol 2008;19:256–60.
2. Perez-Medina T, Salazar FJ, San-Frutos L, et al. Hysteroscopic dynamic
assessment of the endometrium in patients treated with long-term tamoxifen.J Minim Invasive Gynecol 2010;18:349–54.
3. Dibi RP, Zettler CG, Pessini SA, et al.
Tamoxifen use and endometrial lesions:
hysteroscopic, histological, and immunohistochemicalfindings in
postmenopausal women with breast cancer.Menopause2009;16:
293–300.
4. American College of Obstetricians and Gynecologists. Tamoxifen use and uterine cancer. Committee Opinion No. 336.Obstet Gynecol2006;107:
1475–8.
Case 38: A 40-year-old woman on tamoxifen therapy with a uterine mass