Case Report:The potential oncogenic effect of tamoxifen on the endometrium

M. Berlière1,3, C. Galant2 and J. Donnez1

1 Departments of Gynaecology, and 2 Pathology, St Luc's Hospital. Avenue Hippocrate, 10, 1200 Brussels, Belgium


    Abstract
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 Abstract
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 Case report
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We report the case of an in-situ endometrial adenocarcinoma with severe atypical hyperplasia which developed while the patient was on tamoxifen only 1 year after endometrial resection for benign pathology. A 55-year-old woman received tamoxifen as adjuvant therapy for breast cancer treated in 1994. At that time, a benign endometrial polyp was also removed before initiating tamoxifen treatment. In 1997, endometrial resection was performed for benign pathology (atrophic cystic endometrium). In 1998, an endometrial adenocarcinoma was diagnosed. This case illustrates that endometrial resection does not protect women taking tamoxifen against subsequent development of severe atypical lesions.

Key words: atypical endometrial lesions/endometrial resection/oncogenic potential of tamoxifen/patients at higher risk


    Introduction
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
The potential oncogenic effect of tamoxifen on the endometrium has been widely studied in recent years (Fisher et al., 1994Go; Rutqvist et al., 1995Go; Berlière et al., 1998Go). The exact modalities of treatment of endometrial lesions induced by the drug are still a matter of considerable debate (Assikis et al., 1996Go; Nephen et al., 1996Go; Berlière et al., 1998Go).

We present the case of an in-situ endometrial adenocarcinoma which developed while the postmenopausal breast cancer patient was on tamoxifen 1 year after endometrial resection for benign pathology.


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A 55-year-old woman, gravida 2, para 2, was hospitalized in May 1998 for the treatment of an endometrial adenocarcinoma discovered while on tamoxifen. Her oncological history began in 1994 when she was treated for breast cancer at our university hospital. At that time, she underwent a lumpectomy and axillary dissection for a tumour of the left breast. Histology showed an infiltrating ductal carcinoma (grade SBR III according to the classification of Scarff, Bloom and Richardson). Two of the 13 lymph nodes removed showed partial involvement. Dosage of hormonal receptors was performed by immunohisto-chemistry and revealed strong staining for oestrogen receptors (ER) (immunoreactive score >80% of cells with very strong staining) and for progesterone receptors (PR) (immunoreactive score >80 % of cells with moderate staining). The patient was postmenopausal and received radiotherapy as adjuvant therapy (5000 cGy to the breast and 4400 cGy to the axillary area). She also received 20 mg of tamoxifen daily. This hormonal treatment was planned to go on until 1999.

Before the operative breast procedure, the patient underwent a complete gynaecological examination with a Papanicolaou (PAP) smear and vaginal ultrasound. This showed a thick mucosa and a polyp was suspected. She underwent operative hysteroscopy and a benign endometrial polyp was resected. The pathological analysis revealed a benign proliferative polyp without atypia (Figure 1Go).



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Figure 1. A. Endometrial polyp resected in 1994 (scale bar = 10 mm). B. Atrophic cystic endometrium resected in 1997 (scale bar = 75 µm). C. In-situ endometrial adenocarcinoma with multiple foci of atypical hyperplasia (vaginal hysterectomy in 1998) (scale bar = 30 µm).

 
The patient underwent gynaecological follow-up based on annual gynaecological examinations with a PAP smear, vaginal ultrasound and, in the case of abnormal ultrasound (endometrial thickness >5 mm), hysteroscopy. She also underwent oncological follow-up.

The gynaecological follow-up was negative in 1995 and 1996, but in 1997 the patient, who was totally asymptomatic, had a vaginal ultrasound which revealed endometrial thickening of 11 mm.

Bilateral adnexal cysts were also observed: the right ovarian cyst measured 22x16 mm; it was heterogeneous and a dermoid cyst was suspected. The left adnexal cyst was homogeneous and measured 70x36 mm. A para-ovarian cyst was suspected.

The patient underwent laparoscopy with bilateral salpingo-oophorectomy and operative hysteroscopy using a resectoscope equipped with a 5 mm loop (electrodiathermy).

Histopathological examination revealed a right dermoid cyst and a left para-ovarian cyst (the two lesions were benign). The peritoneal cytology was normal and the endometrial examination showed atrophic cystic endometrium without atypia. According to our pathologist, burning damage was minimal in this particular case and it was obvious that the endometrial lesion was benign.

In March 1998 despite being devoid of any gynaecological symptoms, vaginal ultrasound demonstrated an endometrial thickening of 21 mm. Outpatient hysteroscopy with endometrial biopsy was carried out. The biopsy revealed an endometrial adenocarcinoma. It was not possible to confirm from the biopsy if it was in situ or infiltrating.

Vaginal hysterectomy was performed in May 1998 and the diagnosis of an in-situ endometrial adenocarcinoma with multiple foci of severe atypical hyperplasia was made. No myometrial invasion was observed. Immunohistochemical analysis revealed a very high ER and PR content (>80% of cells with very strong staining). The proliferation index measured by nuclear Ki 67 was 50%.

No further treatment, such as radiotherapy, was proposed because the lesion was an in-situ carcinoma. The patient now comes for regular follow-up to our outpatient clinic and her tamoxifen treatment will continue until 1999, as planned.


    Discussion
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 Abstract
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 Case report
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The reduced recurrence rates and overall survival benefits of tamoxifen treatment have made this drug the adjuvant treatment of choice for postmenopausal patients with breast cancer (Early Breast Cancer Trialists' Collaborative Group, 1998).

Numerous studies (many retrospective and a few prospective) have suggested an association between the use of tamoxifen in breast carcinoma patients and the subsequent development of endometrial carcinomas (Fornander et al., 1989Go; Fisher et al., 1994Go and Rutqvist et al., 1995Go).

However, a study published recently (Katase et al., 1998Go) did not show any increase in the relative risk of endometrial carcinoma development from tamoxifen exposure, but this study was retrospective without any exploration of the endometrial cavity before initiation of tamoxifen treatment.

Our case report highlights the importance of the evaluation of the uterine cavity before starting tamoxifen. It confirms the results of our recently published prospective study (Berlière et al., 1998Go) in which this patient was also included. This study revealed that women with endometrial lesions (such as polyps) diagnosed before tamoxifen treatment are at higher risk of developing atypical endometrial lesions on tamoxifen.

Consequently, these patients require annual gynaecological examination with vaginal ultrasound and, if necessary, hysteroscopy. This follow-up must be performed even in the absence of symptoms.

Some authors do not recommend regular gynaecological follow-up for asymptomatic patients on tamoxifen. They also claim that lesions discovered while on tamoxifen could be diagnosed earlier because patients are more likely to have symptoms such as abnormal bleeding (Katase et al., 1998Go). Our case provides an argument against this view.

Because of their initial endo-uterine pathology, these patients may be more sensitive to the carcinogenic effect of tamoxifen. Currently, the exact mechanisms of tamoxifen-associated carcinogenesis are not known (Barakat, 1996Go; Carmichael et al., 1996Go, Nephen et al., 1996Go). Some authors (Hochner-Celnikier et al., 1997Go) believe that the oestrogenic agonistic effects of tamoxifen on the human uterus may play an important role. For others (Nephen et al., 1996Go), overexpression of oncogenes induced by the drug may contribute to uterine toxicity.

In an attempt to identify the prognostic indicators that could be used to predict and explain the behaviour of endometrial lesions induced by tamoxifen, we initiated an immunohistochemical study of these lesions. The very high ER and PR content and proliferative activity observed seem to argue in favour of the oestrogenic agonistic effect of tamoxifen.

In this case and in other atypical lesions, we found a very high ER and PR content and proliferation index (unpublished data) .

One question which still remains unanswered is the optimal surgical management of endometrial lesions diagnosed while on tamoxifen. In the case presented here, endometrial resection performed one year earlier did not offer any protection against subsequent endometrial cancer. The very short interval between the conservative surgical procedure and the development of cancer must be emphasized. Not only did the endometrial resection fail to prevent the appearance of endometrial cancer, but the disease developed only one year after the surgical procedure, a much shorter interval than has been considered the risk period in the literature.The debate is open but perhaps more aggressive surgical procedures need to be proposed for patients considered to be at higher risk, defined in one of our prospective studies (Berlière et al., 1998Go) as the group of women with benign intrauterine lesions before starting tamoxifen.


    Notes
 
3 To whom correspondence should be addressed at: Department of Gynaecology, Catholic University of Louvain, Cliniques Universitaires St Luc, Avenue Hippocrate, 10 – 1200 Bruxelles, Belgium Back


    References
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Assikis, V.J., Neven, P., Jordan, V.C. et al. (1996) A realistic clinical perspective of tamoxifen and endometrial carcinogenesis. Eur. J. Cancer, 32, 1464–1476.

Barakat, R.R. (1996) Tamoxifen and endometrial neoplasia. Clin. Obstet. Gynaecol., 93, 629–640.

Berlière, M. and Donnez, J. (1997) Tamoxifène: à prescrire ou à proscrire? Références en Gynécologie Obstétrique, 1, 5–7.

Berlière, M., Charles, A., Galant, C. et al. (1998) Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet. Gynecol., 91, 40–44.[Abstract/Free Full Text]

Carmichael, P.L., Ugwumadu, A.H., Neven, P. et al. (1996) Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res., 56, 1475–1479.[Abstract]

Early Breast Cancer Trialists' Collaborative Group. (1998) Tamoxifen for early breast cancer : an overview of the randomized trials. Lancet, 351, 1451–1467.[ISI][Medline]

Fisher, B., Constantino, J.P., Redmond, C.K. et al. (1994) Endometrial cancer in tamoxifen treated breast cancer patients; findings from the NSABP B 14. J. Natl. Cancer Inst., 86, 527–537.[Abstract]

Fornander, T., Rutqvist, L.E., Cedermark, B. et al. (1989) Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet, i, 117–120.

Hochner-Celnikier, D., Greenfield, C., Finci-Yeheskel, Z. et al. (1997) Tamoxifen exerts estrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glucogen metabolism and p53 protein expression, in cultures of estrogen-responsive human endometrial adenocarcinoma cells. Mol. Hum Reprod., 3, 1019–1027.[Abstract]

Katase, K., Sugiyama, Y., Hasumi, K. et al. (1998) The incidence of subsequent endometrial carcinoma with tamoxifen use in patients with primary breast carcinoma. Cancer, 82, 1698–1703.[ISI][Medline]

Nephen, K.P., Polek, T.C. and Khan, S.A.. (1996) Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium. Endocrinology, 137, 219–224.[Abstract]

Rutqvist, L.E., Johansson, H., Signomklao, T. et al. (1995) Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J. Natl. Cancer Inst., 87, 645–651.[Abstract]

Submitted on September 2, 1998; accepted on January 5, 1999.