Retained products of conception in hysteroscopy in a patient with breast cancer on tamoxifen

Abstract

Tamoxifen is a selective oestrogen receptor modulator widely used in breast cancer treatment, with good survival rates. Its partial agonist action on other tissues such as the uterus, however, promotes the development of endometrial hyperplasia and cancer. It appears that tamoxifen does not alter the age of menopause and women may still get pregnant while on tamoxifen. We present the case of a 47-year-old Chinese woman with breast cancer on tamoxifen, who presented with one episode of heavy per vaginal bleeding after 2 years of amenorrhoea. Her urine pregnancy test was negative and the ultrasound scan was suspicious for malignancy. She underwent a hysteroscopic evaluation for abnormal bleeding on tamoxifen. Histopathology confirmed products of conception. This case illustrates the importance of understanding the rise and decline of human chorionic gonadotropin in pregnancy, as well as the pivotal role of contraception despite having amenorrhoea on tamoxifen.

Background

Tamoxifen is a selective oestrogen receptor modulator (SERM) widely used in breast cancer treatment with good survival rates, its use now extended to 10 years. However, its partial agonist action on other tissues such as the uterus promotes the development of endometrial hyperplasia and cancer.^1–5 It appears that tamoxifen does not alter the age of menopause and despite the change in menstrual pattern (amenorrhoea and oligomenorrhoea) it induces, women must be aware of the possibility of pregnancy while on tamoxifen. Premenopausal women on tamoxifen are advised to use reliable contraception and evaluation is recommended in the presence of abnormal vaginal bleeding.

Case presentation

We present the case of a 47-year-old Chinese woman with intraductal carcinoma of her right breast, who had undergone a right mastectomy, sentinel lymph node biopsy and breast reconstruction in 2012. She was on tamoxifen for 4 years and her most recent left breast ultrasound and mammogram were normal. She presented with one episode of heavy per vaginal bleeding after 2 years of amenorrhoea. She was assumed to have been menopausal.

On examination, she had a moderate amount of bleeding. However, her cervix and vaginal examination were both unremarkable. The urine pregnancy test was negative and ultrasound scan showed thickened endometrium with septations, cystic spaces and internal vascularity. She underwent a dilatation and curettage hysteroscopy for evaluation of abnormal bleeding on tamoxifen. Histopathology confirmed products of conception.

Investigations

She underwent an ultrasound scan of her pelvis which showed that the endometrium was thickened at 36 mm, and heterogeneous with cystic spaces as well as septations (figure 1). Internal vascularity was seen within the endometrium (figure 2). Apart from that, the scan showed a right ovarian cyst measuring 0.8 cm and two left ovarian cysts measuring 0.7 and 1.4 cm.

Figure 1.

Ultrasound pelvis showing thickened endometrium with cystic spaces and septations.

Figure 2.

Ultrasound pelvis showing increased vascularity in the endometrium.

A urine pregnancy test done at the time was negative.

She underwent a dilatation and curettage hysteroscopy under general anaesthesia for her abnormal bleeding on tamoxifen as well as suspicious findings on ultrasound scan.

Intraoperatively, a suspicious endometrial mass was seen to be arising from lower uterine cavity measuring about 2 cm. This appeared to be of a malignant nature (figure 3). Hysteroscopic scissors were used to partially excise the lesion. Thereafter, a systematic curettage was done and the specimen was sent for urgent histology.

Figure 3.

Pictures taken during hysteroscopy, showing a 2 cm mass arising from the lower uterine cavity, appearing malignant.

Differential diagnosis

The clinical suspicion for malignancy was high in view of her abnormal uterine bleeding after 2 years of amenorrhoea, on the background of tamoxifen use. In addition, both the ultrasound scan of her pelvis as well as dilatation and curettage hysteroscopy added to the high likelihood of malignancy.

However, the histology returned as products of conception. The histology specimen consisted of hypersecretory endometrium, focally necrotic decidua with placental site reaction and chorionic villi showing hydropic changes and focal fibrosis (figure 4). Nucleated fetal red blood cells and fetal tissue were not identified, with no evidence of trophoblastic disease.

Figure 4.

Histology specimen consisting of chorionic villi showing hydropic changes and focal fibrosis.

Treatment

She required no further treatment after the dilatation and curettage hysteroscopy and remained well. She had no further episodes of vaginal bleeding thereafter.

Outcome and follow-up

The patient was informed that she had been pregnant and miscarried. The vaginal bleeding from the miscarriage presented itself as abnormal bleeding with tamoxifen use. She was informed that although tamoxifen may alter menstrual patterns and induce amenorrhoea, this does not necessarily equate to being menopausal. She was also counselled on the importance of contraception to prevent future unintended pregnancies.

Discussion

In pregnancy, the urine pregnancy test is a reliable diagnostic tool. It measures urinary levels of the human chorionic gonadotropin (hCG). It is able to detect hCG in urine about 2 weeks after pregnancy conception. It is usually highly accurate; however, false negatives may occur. This is most commonly due to early measurement soon after conception, when hCG levels are low and below the detection threshold of test kits. The hCG is detected in serum earlier than in urine, typically 2 to 3 days earlier.

In a case series discussed by Griffey et al,⁶ 40 cases were identified in which urine hCG testing was negative and serum quantitative hCG tested subsequently was positive, giving an overall false-negative rate of 0.34%. In 18 of these cases, the quantitative serum hCG level was actually below the threshold for detection for urine hCG assessment (25 IU/mL). Restriction of these results to a negative urine pregnancy test when serum hCG was within the detection range of the test kit would yield a lower false-negative rate of 0.19%. It is important to note nearly all of these patients asserted that they were pregnant or reported a recent positive urine pregnancy test—this was the factor which prompted further testing with serum hCG levels.

In the case discussed, a urine pregnancy test was performed in accordance to our hospital protocol, which mandates that all women with amenorrhoea of ≤3 years should have a preoperative urine pregnancy test to rule out pregnancy. The patient reported being amenorrhoeic for 2 years with no recent sexual activity, hence, the clinical suspicion of pregnancy was low. As such, a serum hCG level was not performed.

In a failed pregnancy, both urine and serum hCG will decline. This may take between 9 and 35 days with a median of 19 days.⁷ Urine hCG level in a failed pregnancy may be undetectable on a urine pregnancy test even if a complete miscarriage has not occurred. The exact timeframe for when an hCG result will be negative is dependent on what the hCG level was at the time of the miscarriage. In this unique case, it is likely that pregnancy had occurred and then failed, and the patient remained asymptomatic initially. However, when she started to bleed from the miscarriage, urine hCG had already fallen below detectable limits for the urine pregnancy test. With a negative urine pregnancy test, the patient was deemed to have abnormal uterine bleeding on tamoxifen.

Tamoxifen is a SERM. It exerts competitive antagonism on oestrogen receptors in breast tissues, causing inhibition. It is therefore used in breast cancer treatment. In contrast, tamoxifen also exerts partial agonist action on other tissues such as the vagina and uterus. This may promote the development of fibroids, endometrial polyps, sarcoma, hyperplasia and increases the risk of endometrial cancer.^8–11 There is an increased relative risk of endometrial cancer, up to two to three times higher than an age-matched population. However, survival from breast cancer was 38% higher in one study. Hence, where the benefits outweigh the risks, tamoxifen is used to improve outcomes for patients with breast cancer. Its use has also been extended to 10 years.

It is important to know that tamoxifen also has effects on the menstrual cycle. Menstrual pattern may change with tamoxifen, ranging from oligomenorrhoea to amenorrhoea. It appears that tamoxifen does not alter the age of menopause.¹² In this case discussed, the 47-year-old woman had not yet reached menopause despite 2 years of amenorrhoea induced by tamoxifen.

Tamoxifen induces subepithelial stromal hypertrophy and this is difficult to correlate with a thickened endometrium on ultrasound scan.¹³ In asymptomatic women on tamoxifen, screening for endometrial cancer with routine ultrasound scans or biopsy has not proven to be effective.^14–16 Routine surveillance is not recommended as it may lead to unnecessary costs and invasive procedures.

Women taking tamoxifen should be appropriately counselled about the risks of endometrial hyperplasia, proliferation and cancer. They should be empowered to report any abnormal vaginal bleeding immediately. Any abnormal vaginal bleeding, including staining or spotting, should be investigated. The risk of endometrial hyperplasia or cancer is higher for postmenopausal women on tamoxifen, as compared with premenopausal women. Hence, the former should be closely monitored for abnormal symptoms.

Patient’s perspective.

‘Two words alone can summarise the entire experience for me—anxiety and relief. After not having had my menstruation for two years, I had assumed I was menopausal. I was also very satisfied with tamoxifen and had no side effects from it. I was horrified when I had vaginal bleeding, and went to see the gynaecologist as soon as I could. Throughout this process, I was feeling immense anxiety. What if this was cancer? I want to live and I was not ready for another diagnosis of cancer. The ultrasound report was worrying, and the findings from the hysteroscopy did not help me feel better. I was so anxious for two weeks after my discharge, thinking about the possibility that I might have cancer.

I received the results of the biopsy the day before my birthday. It was a miscarriage! Not cancer. I was overwhelmed with relief. Needless to say, it was the biggest and best birthday celebration I have ever had. I am very thankful how this turned out, but I have never forgotten to use contraception since’.

Learning points.

• Tamoxifen may promote the development of endometrial hyperplasia, polyps and increases the risk of endometrial cancer. Any abnormal bleeding on tamoxifen should be investigated.

• The human chorionic gonadotropin declines in a failed pregnancy and this may take between 9 and 35 days. Bleeding from a failed pregnancy may present after hCG decline and urine pregnancy test at this time will be negative.

• Tamoxifen does not induce or alter the age of menopause. Despite amenorrhoea, reliable contraception should be mandated.