Download Sertoli–Leydig cell tumour in an infertile patient after stimulated

Human Reproduction vol.12 no.5 pp.1021–1023, 1997
CASE REPORT
Sertoli–Leydig cell tumour in an infertile patient after
stimulated ovulation
Hung-Hsueh Chou1,3, Ying-Ming Lai1,
Chyong-Huey Lai1, Swei Hsueh2 and
Yung-Kuei Soong1
1Department
of Obstetrics and Gynecology 2Department of
Pathology, Chang Gung Memorial Hospital, Linkou Medical Center
and Chang Gung Medical College, Taipei, Taiwan, Republic of
China
3To
whom correspondence should be addressed at: Department of
Obstetrics and Gynecology, Chang Gung Memorial Hospital and
Medical School, Linkou Medical Center, 5 Fu-Hsing Street, KweiShan, Tao-Yuan, Taiwan 10591, Republic of China
A 36 year-old infertile female developed a stage IV (FIGO)
ovarian carcinoma consisting of a poorly differentiated
Sertoli–Leydig cell tumour after receiving one course of
ovulation induction with follicle stimulating hormone
(FSH), human menopausal gonadotrophin (HMG) and
human chorionic gonadotrophin (HCG) followed by gonadotrophin-releasing hormone analogue (GnRHa). The
patient died of liver metastasis and hepatic failure 412
months after first diagnosis, despite aggressive treatment
consisting of debulking surgery and aggressive adjuvant
chemotherapy.
Key words: ART/infertility/Sertoli–Leydig cell tumour/stimulated ovulation
Introduction
Ovarian stimulation is the preliminary procedure of all assisted
reproductive techniques (ART) in infertility treatment. Several
articles have reported the presence of ovarian cancers in infertile
females receiving clomiphene citrate and gonadotrophin. There
has been much debate on the ‘incessant-ovulation and ovarian
cancer of epithelial origin’ hypothesis. Nevertheless, the relationship between ovarian cancer and stimulated ovulation still
remains uncertain. In literature reports concerning association
between ovarian carcinomas and stimulated ovulation, serous
adenocarcinoma has been the second most common histological
type (Atlas et al., 1982; Carter et al., 1987; Kulkami et al., 1989;
Dietl, 1991; Goldberg et al., 1992; Lopes et al., 1992; Balasch
et al., 1993). Willemsen (1993) described 12 granulosa-cell
tumours, this being the second most common type. Other investigators have presented cases of mucous cystadenoma (Grimbizis
et al., 1995) and endometroid ovarian carcinoma (Bamford
et al., 1982). To our knowledge, this is the first report of a
Sertoli–Leydig cell tumour in an infertile female receiving ART.
© European Society for Human Reproduction and Embryology
Case report
A 36 year old female entered our protocol of ART following the
diagnosis of primary infertility for 15 years. Due to anovulation
and asthenozoospermia (motility 27.8%) and consideration of
her age, she received one cycle of ovulation induction with
follicle stimulating hormone (FSH; Metrodin, Serono Laboratories, Rome, Italy), human menopausal gonadotrophin (HMG;
Pergonal, Serono) and gonadotrophin-releasing hormone analogue (GnRHa; leuprolide acetate, LA, Lupron, Abbott
Australasia PTY Ltd., Kurnell, NSW, Australia) (long protocol,
1 mg/day 3 10 days in the mid-luteal phase). Two oocytes
were retrieved from the left ovary and inseminated in vitro.
Unfortunately, the oocytes did not show two pronuclei 24 h
after insemination. Intracytoplasmic sperm injection (ISCI) was
performed to re-inseminate the unfertilized oocytes, but in vain.
During the course of stimulated ovulation, an ovarian cyst,
3.232.5 cm, was observed in the right ovary. During oocyte
retrieval, a chocolate-like fluid was drained from the right
ovarian cyst, which confirmed the diagnosis of endometrioma.
Danazol 800 mg was administered daily to treat the endometriosis for 1 month. The regimen was changed to leuplin depot
3.75 mg s.c. injection once a month in the following 2 months.
Ten days after the second dose of leuplin depot, she was admitted
and operated for a right adnexal solid tumour and massive ascites,
associated with multiple liver nodules and pleural effusion. During the laparotomy, we found massive ascites and a right side
solid ovarian tumour entrapping the sigmoid colon, posterior
aspect of uterus and left side ovary presenting as a frozen pelvis.
The size of the right ovarian tumour was 15 cm in diameter.
Diffuse multiple metastatic nodules were seen in the liver. A
solitary tumour of irregular surface was also found in the area
of the junction of the caecum and appendix. Optimal debulking
surgery (residual tumour ,1 cm) was performed. Pathological
examination showed the tumour to be mainly composed of
Sertoli tubules which had arisen from the gonadal stromal cells
with rare Leydig cell clusters (Figure 1). The Sertoli cells focally
had pleomorphic and anaplastic nuclei. Immunochemical study
showed that the Sertoli tubular cells were positive for αfetoprotein and focally for carcinoembryonic antigen (CEA),
rarely for vimentin and negative for epithelial membrane antigen
(EMA). The gonadal stromal cells and Leydig cell clusters were
positive for vimentin only. These findings established the diagnosis of Sertoli–Leydig cell tumour of intermediate
grade. Despite two courses of chemotherapy with cisplatin (100
mg/m2), etoposide (100 mg/m2, D2,3,4) and bleomycin (25
mg/m2, D2,3,4), the patient died of hepatic failure.
1021
H.-H.Chou et al.
Figure 1. The tumour is mainly composed of Sertoli cell tubules with rare Leydig cell clusters.
Discussion
Fathalla (1967) and Stevenson (1970) first reported that patients
with endometriosis had a higher incidence of ovarian cancer.
Despite extensive study of ovarian cancers, no definite aetiology
has been established. However, several risk factors and protecting factors for ovarian cancer have been found in previous
research. Patients with infertility have a higher incidence of
epithelial ovarian cancer (Lingeman, 1983; Negri et al., 1991).
In contrast, pregnancy and the use of oral contraceptives are
thought to have protective roles (Heintz et al., 1985; Wu et al.,
1988). Fathalla (1971) proposed the hypothesis that ovarian
cancer was related to incessant ovulation. Zajicek (1977) also
observed the association between ovarian cystomas and ovulation. This supported the possibility of the malignant transformation of ovarian surface epithelium and follicle lining epithelium
during repeated trauma and repairing. Meanwhile, oral contraceptive pills and pregnancy can protect the ovary by suppression
of ovulation (Scott, 1984).
Whittemore et al. (1992) reported that infertile females using
fertility drugs were 27 times more likely to develop ovarian
cancer than a fertile female. These results were reappraised by
Balasch et al. (1993), who disputed the relationship between
ovarian cancer and fertility treatment. The cause of increased
risk of ovarian cancer in infertile patients may be the underlying
disorder, rather than the use of fertility drugs. In the current case,
the long protocol of GnRHa plus FSH (metrodin, 150 IU38
days), HMG (Pergonal, two ampoules39 days) followed by
HCG (10 000 IU) was used for one cycle. Before initiating
ovulation induction, a small cyst diagnosed as endometrioma
was noted and persisted through stimulated ovulation to oocyte
retrieval. During oocyte retrieval, transvaginal sonographic
examination demonstrated an endometrioma in the right ovary,
the diagnosis being proved by the chocolate-like content. No
abnormal mass implying ovarian tumour or Sertoli–Leydig cell
tumour was found in the same scan. The relationship between
fertility drugs and Sertoli–Leydig cell tumour was not definite.
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Leuplin depot is a type of GnRHa which reduces the
release of luteinizing hormone (LH) and FSH by downregulation. Immediately after administration of GnRHa, a
period of up-regulation occurs which usually lasts 4–6 days.
Feldberg et al. (1989) reported ovarian cyst formation in
five of the 22 patients in the period of up-regulation after
buserelin (900 mg, days 1–3; Superfact, Hoechst A.G.,
Frankfurt, Germany) administration. Whether or not the
repeated up-regulation of GnRHa is one of the factors
inducing the malignant transformation of a silent tumour
remains uncertain.
Reviewing the case reports, ovarian cancers associated
with infertility were predominantly serous adenocarcinoma
or granulosa cell carcinoma. To our knowledge, no case of
Sertoli–Leydig cell tumour has been reported similar to the
current one. Sertoli–Leydig cell tumours are usually divided
into three groups based on the differentiation: good,
intermediate and poor. The survival rate is significantly
higher in patients in the good differentiation category, as
compared to patients in the moderate and poor differentiation
categories (Scully, 1979; Roth et al., 1981; Zaloudek et al.,
1984; Young et al., 1985). The current case was a poorly
differentiated stage IV disease. The interval between diagnosis
to mortality was 412 months despite aggressive adjuvant
chemotherapy following debulking surgery.
Although no direct connection can be found between
fertility drugs and ovarian cancer, a tumour of rapid growth
is noteworthy. It should be kept in mind that ascites occurring
in patients receiving ovulation induction may indicate a
diagnosis of ovarian cancer other than ovarian hyperstimulation syndrome. Patients with endometrioma should be closely
followed up with CA-125 measurement and sonography
performed through the course of ovulation induction and
even after oocyte retrieval. Moreover, cells retrieved during
oocyte retrieval should be subjected to cytological examination to rule out the possibility of malignant change.
Sertoli–Leydig cell tumour after stimulated ovulation
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Received on November 22, 1996; accepted on February 5, 1997
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