Human Reproduction, Vol. 14, No. 7, 1908-1911,
July 1999
© 1999 European Society of Human Reproduction and Embryology
Successful pregnancy in an infertile patient with conservatively treated endometrial adenocarcinoma after transfer of embryos obtained by intracytoplasmic sperm injection: Case report
Department of Obstetrics and Gynecology, Hyogo College of Medicine,1–1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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Abstract |
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A rare case of successful pregnancy in a woman with early-stage endometrial adenocarcinoma conservatively treated is presented. The patient, having polycystic ovaries, was initially diagnosed with hyperplasia of the endometrium and treated with several cycles of ovulation induction following intrauterine insemination. Then dilatation and curettage were carried out when hysteroscopy was performed. The histology report identified a well-differentiated adenocarcinoma of the endometrium. After repeated endometrial curettage, in-vitro fertilization and embryo transfer were introduced for immediate treatment of the patient's infertility in order to avoid the risk of recurrence of neoplastic endometrial lesions by oestrogens. A single pregnancy was achieved after transfer of the embryos obtained after intracytoplasmic sperm injection. This was performed due to the poor semen characteristics (asthenozoospermia). The patient delivered a healthy normal male infant at term. A transvaginal ultrasound examination 2 months after delivery showed a smooth, linear endometrium. Moreover, the histology report after endometrial biopsy was free of any malignancies. The patient now desires another pregnancy. We conclude that conservative treatment of early-stage endometrial adenocarcinoma in young women wishing to preserve fertility should be considered in carefully selected cases. Assisted reproductive technologies may be helpful for immediate achievement of pregnancy in such patients.
Key words: endometrial adenocarcinoma/infertility/intracytoplasmic sperm injection/IVF/polycystic ovarian syndrome
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Introduction |
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Endometrial carcinoma remains uncommon in women under 40 years of age even though the incidence of the disease has recently increased (Parazzini et al., 1991
). Approximately 1–5% of all cases of endometrial carcinoma have been reported to occur in women aged 40 years and younger (Dockerty et al., 1951; Peterson, 1968; Kempson and Pokorny, 1968; Gallup and Stock, 1984). Endometrial carcinoma in young women are well known to be associated with Stein–Leventhal syndrome, polycystic ovaries, and the unopposed oestrogen effect (Dockerty et al., 1951; Jackson and Dockerty, 1957; Peterson, 1968; Kempson and Pokorny, 1968; Fechner and Kaufman, 1974; Henderson et al., 1983; Gallup and Stock, 1984). It has been shown that although 60–70% of endometrial adenocarcinoma in young women are indeed associated with the Stein–Leventhal syndrome, 30–40% of them are oestrogen independent and have a poorer prognosis (Christopherson et al., 1982; Bokhman, 1983; Colafrancheschi et al., 1983; Mencaglia et al., 1990; Gordon and Ireland, 1994). In general, the prognosis in young women with endometrial carcinoma has been shown to be better than that in women older than 40 years because of high differentiation of the tumour and early-stage disease. Thus, conservative therapy such as hormonal therapy, chemotherapy and endometrial curettage might be recommended to preserve fertility. Moreover, a few cases of successful pregnancy have been reported after conservative therapies (O'Neill, 1970; Eddy, 1978; Farhi et al., 1986; Muechler et al., 1986; Lai et al., 1994; Niwa et al., 1994; Kimmig et al., 1995). We present the case report of a patient with conservatively treated endometrial carcinoma who conceived and took home a baby after a transfer of embryos fertilized by intracytoplasmic sperm injection (ICSI). To our knowledge, this is the first demonstration of a successful application of ICSI in an infertile couple with both conservatively treated endometrial carcinoma and male factor infertility.
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Case report |
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A 32 year old woman, having a normal body mass index (19.0 kg/m2), with a four year history of primary infertility, was referred to our hospital for further investigation and treatment in July 1991. She had been treated with several cycles of unsuccessful ovarian stimulation following intrauterine insemination (IUI) by a local gynaecologist. Her menarche had been at the age of 14 years and her menstrual cycle was infrequent and irregular. She was not hirsute and an abdomino-pelvic examination found her to be normal. A cervical smear test was performed and was negative. A laboratory analysis at the early follicular phase yielded the following data: follicle stimulating hormone (FSH) 9.0 mIU/ml (normal, 3.1–23.7 mIU/ml), luteinizing hormone (LH) 21.4 mIU/ml (normal, 0.9–15.5 mIU/ml), prolactin 5.7 ng/ml (normal, <15.0 ng/ml), testosterone 82.9 ng/dl (normal <80.0 ng/dl). A transvaginal ultrasound showed ovaries with `pearl necklace' appearance and a normal-looking endometrium. Thus the diagnosis of polycystic ovarian syndrome was confirmed. Hysterosalpingography demonstrated normal bilateral tubal patency but an irregular surface in the endometrial cavity. A hysteroscopic examination was performed, revealing a cluster of multiple endometrial polyps, which were biopsied. The histology report identified simple hyperplasia of the endometrium (Figure 1
). Her partner's semen characteristics were normal at that time, according to the criteria of the World Health Organization (1992).
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Ovulation was induced with clomiphene citrate and gonadotrophin followed by IUI for several cycles. However, conception was unsuccessful. One year after the initial examination, hysteroscopy was repeated with laparoscopy under general anaesthesia. Dilatation and curettage was carried out after multiple abnormal polypoid structures were identified. Laparoscopy with a dye test showed a normal pelvis with patent tubes, but with bilateral polycystic ovaries. The histology report identified a well differentiated adenocarcinoma of the endometrium (Figure 2
). The endometrial glands showed a confluent pattern with anisonucleosis and prominent nucleoli in some nuclei. Desmoplasia appeared in some stroma of the endometrium, indicating there was stromal invasion of the adenocarcinoma. However, no invasion of the adenocarcinoma was identified in the myometrium (Figure 2). The oestrogen receptor and the progesterone receptor were positive. The p53 expression was found to be negative in the endometrial carcinoma specimen using immunohistochemical staining, which was carried out by using standard immunoperoxidase techniques. Monoclonal antibodies to the p53 suppressor gene product, the oestrogen receptor-related protein (p29) and the progesterone receptor were commercially obtained from BioGenex (San Ramon, CA, USA) and used according to the manufacturer's instructions. A chest X-ray was found to be normal. Magnetic resonance imaging (MRI) showed an intact junctional zone. Pelvic and abdominal computerised tomography (CT) scan showed normal lymph nodes and normal intra-abdominal and pelvic organs. After these investigations, and approximately 3 weeks after the first dilatation and curettage, this procedure was repeated, but only a small amount of specimen was obtained. The endometrial histology did not show any residual malignancy. After consultation, the patient and her husband were committed to the conception of a child and strongly requested that their fertility be preserved. The patient was undergoing serial monitoring, including ultrasonography, MRI and dilatation and curettage repeated once a month.
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In-vitro fertilization (IVF) and embryo transfer were carried out, as previously reported (Shibahara et al., 1996
, 1997), 8 months after the diagnosis of endometrial carcinoma. IVF–embryo transfer treatment was repeated with periodic evaluation of the endometrium with ultrasound and endometrial curettage. However, there was no evidence of carcinoma. This led to the continuation of IVF–embryo transfer treatment. Semen characteristics and fertilization rates in each IVF–embryo transfer treatment are shown in Table I. Following three unsuccessful treatment cycles of IVF–embryo transfer, ICSI was attempted, as previously reported (Shibahara et al., 1998), because it was noticed that her partner's semen quality declined in the third IVF–embryo transfer treatment. On the day of egg collection, six oocytes were retrieved, of which four were in metaphase II suitable for ICSI. Spermatozoa with apparently normal morphology and motility were chosen for injection. The spermatozoon was inserted deeply into the cytoplasm of the oocyte using a microinjector (Narishige, Tokyo, Japan). On the morning following microinjection, four oocytes were found to be fertilized normally with 2PN, and cultured for another 24 h to allow for cleavage. Four oocytes cleaved and three 2- to 4-cell embryos with the highest morphology score were selected for transfer to the patient on the second day after oocyte retrieval. A urinary pregnancy test was positive 14 days after oocytes were collected and a singleton pregnancy was achieved. In November 1997, a healthy normal male infant with a birth weight of 2892 g was born by spontaneous vaginal delivery at 40 weeks gestation. No tumour could be identified in the placenta. A transvaginal ultrasound examination 2 months after delivery showed a smooth, linear endometrium. An endometrial biopsy was carried out and the histology report was free of any malignancies. This patient is now seeking another pregnancy.
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Discussion |
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For younger women with stage Ia, grade 1 endometrial carcinoma which is known to result in a good prognosis (International Federation of Obstetrics and Gynecology, 1989
), total hysterectomy and bilateral salpingo-oophorectomy has been thought to be too radical for some patients desiring a baby. However, conservative treatment with progestogens may not always succeed in achieving a remission or prolonging the patient's reproductive life. Even in patients with endometrial hyperplasia with atypia, progestogen-treated cases had a success rate of 70–100% after a 2 year follow-up (Kjorstad et al., 1978; Ferenczy and Gelfand, 1989). It was reported (Farhi et al., 1986) that four out of eight patients (50.0%) with grade 1 adenocarcinoma, limited to the endometrium, were successfully treated with progesterone and dilatation and curettage. There have also been a few pregnancies reported in patients who had been diagnosed with endometrial adenocarcinoma and treated conservatively (O'Neill, 1970; Eddy, 1978; Farhi et al., 1986; Muechler et al., 1986; Lai et al., 1994; Niwa et al., 1994; Kimmig et al., 1995). These results suggest that the preservation of fertility with primary hormone therapy and conservative curettage of the endometrium should be considered in carefully selected cases.
In our case, a well-differentiated endometrial adenocarcinoma was diagnosed when dilatation and curettage was repeatedly carried out, although the initial diagnosis was simple hyperplasia of the endometrium. When atypical hyperplasia is diagnosed in the endometrium obtained by a biopsy or curettage, 15–25% of the patients may also have a uterine carcinoma (King et al., 1984). Even although the initial diagnosis was simple hyperplasia of the endometrium, there is a possibility that the endometrial cancer was already present but not recognized at the first biopsy in this patient. Nevertheless, it is not unusual to carry out the formal fractional dilatation and curettage for patients in whom simple hyperplasia is diagnosed by standard outpatient procedures.
There was no evidence of myometrial invasion using MRI and ultrasonography, which is an important prognostic implication (Gordon et al., 1989). Lymph node metastasis was absent as shown by pelvic and abdominal CT scan examinations, which is also one of the important prognostic factors (Morrow et al., 1991). Immunohistochemical diagnosis revealed the presence of tumour hormone receptors which are associated with a favourable prognosis (Creasman et al., 1985; Mutch et al., 1987; Segreti et al., 1989). Over-expression of p53, a tumour suppressor gene, was also immunohistochemically estimated and was not identified in this patient. Recently, over-expression of p53 has been revealed to be associated with several poor prognostic factors in endometrial carcinoma (Bur et al., 1992; Kohler et al., 1992). The majority of these variables suggested a better prognosis for the early endometrial carcinoma arising in this patient, who wished to remain fertile.
We took a conservative approach in treating this patient, with periodic evaluation of the endometrium by ultrasound and endometrial curettage. In order to avoid the risk of recurrence of neoplastic endometrial lesions by oestrogens, IVF–embryo transfer was introduced for immediate treatment of the patient's infertility after diagnosis of malignancies. Compared with the general population, the incidence of endometrial cancer has been found to be significantly higher in infertile women with hormonal deficiency (Ron et al., 1987) and in those treated with IVF (Venn et al., 1995); this was why periodic evaluation of the endometrium with ultrasound and endometrial curettage was repeated in our patient. ICSI was finally applied because of the poor fertilization rate in the third attempt of IVF–embryo transfer. Following delivery, a transvaginal ultrasound examination and endometrial biopsy were carried out and there was no evidence of malignancies.
There are a few reports in which a hysterectomy was performed following delivery, with respect to the risk of recurrence of endometrial carcinoma (Farhi et al., 1986; Muechler et al., 1986; Kimmig et al., 1995). However, no evidence of residual or recurrent tumour was identified in any of these cases. Other reports in which patients were carefully followed-up after delivery found no evidence of recurrence (O'Neill, 1970; Eddy, 1978; Lai et al., 1994). These results suggest that elective hysterectomy following successful pregnancy should be considered to avoid a long stressful follow-up and possible morbidity or mortality due to a delay in detecting the recurrence.
We conclude that a conservative approach with careful observation might be possible in an early-stage endometrial adenocarcinoma in a young woman wishing to conceive. Assisted reproductive technologies may be helpful for immediate achievement of pregnancy in such patients.
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To whom correspondence should be addressed
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Submitted on September 21, 1998; accepted on March 16, 1999.
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