Successful transfer of frozen–thawed embryos obtained immediately before radical surgery for stage IIIa serous borderline ovarian tumour: Case report

D. Gallot1,2, J.L. Pouly1, L. Janny1, G. Mage1, M. Canis1, A. Wattiez1 and M.A. Bruhat1

1 Department of Obstetrics, Gynaecology and Reproductive Medicine, Polyclinique de l'Hôtel-Dieu, 13 Boulevard Charles de Gaulle, 63033 Clermont-Ferrand Cédex 1, France


    Abstract
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
A stage IIIA borderline serous ovarian tumour was treated conservatively by laparoscopy to preserve the fertility of a 21 year old nulligravid woman. Six months later, recurrent lesions were resected. An `urgent' IVF was performed to obtain frozen embryos. Oncological treatment was then completed by radical surgery with uterine conservation. Fifteen months later, two thawed embryos were successfully transferred and the patient delivered one baby. From this observation, the authors discuss an alternative to oocyte donation in cases of bilateral ovariectomy for stage IIIA borderline serous ovarian tumour.

Key words: borderline ovarian tumour/IVF/radical surgery


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Serous low malignant potential tumours (LMPT) of the ovary occur in women who, on average, are 10 years younger than those who present with malignant ovarian cancers (median age 44 years) (Miller et al., 1997Go). Consequently, these tumours may occur during the childbearing years. Approximately 80% of borderline tumours will present as stage I and II disease (Bristow and Karlan, 1996Go). Survival is also significantly better in cases of LMPT. However, the survival rate is the subject of disagreement. According to most authors, the prognosis is good at any stage. The 7-year survival rate is >90% for stage I (Michel et al., 1996Go) and ~90% for stages II and III (Bristow and Karlan, 1996Go). According to one report (Massad et al., 1991Go), the absence of residual tumour after surgery is associated with a 100% 5-year survival rate independent of the stage. A compilation of 1100 cases of LMPT revealed a mortality of 1.8, 5 and 19% for stages I, II and III respectively and a recurrence rate of 2, 6 and 14% for stages I, II and III respectively (Massad et al., 1991Go). On the other hand, a review of the occurrence, morbidity and mortality of borderline and invasive epithelial ovarian tumours in young women (age <40 years) for 15 years (Carter et al., 1993Go) showed that the median survival was 36 months for LMPT and 21 months for invasive tumours. Histologically, LMPT are characterized by a high degree of cellular proliferation (stratification of the epithelial lining of the papillae, nuclear atypia, mitotic activity) in the absence of stromal invasion (Tropé and Kaern, 1996Go). Despite the term `borderline`, it was generally thought that such tumours are associated with considerable morbidity and mortality, but this opinion is nowadays widely criticized (Carter et al., 1993Go). These opposing views indicate that there is no consensus on the histopathological classification of LMPT. LMPT have epidemiological risk factors similar to their more malignant counterparts, yet they are distinctly different with respect to biological and clinical behaviour (Bristow and Karlan, 1996Go). Independent prognostic factors in patients with epithelial ovarian borderline tumours without residual tumour after primary surgery are DNA ploidy, International Federation of Gynecology and Obstetrics stage (FIGO), histological type and patient age (Tropé and Kaern, 1996Go). The favourable factors are age <40 years, a low level stage, serous (or mucinous) histology and the absence of aneuploidy. When this entire pattern exists, the survival rate seems to be 100%. Patients with aneuploid tumours have a 19-fold increased risk of mortality compared with patients with diploid tumours (Tropé and Kaern, 1996Go).


    Case report
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
A 21 year old nulligravid woman presented in July 1996 with a complaint of amenorrhoea associated with microprogestative contraception. Her past medical history was unremarkable. She was unaware of any family history of ovarian or breast cancer. Physical examination and ultrasound discovered a 5 cm bilateral heterogeneous adnexal mass without any ascites. A laparoscopic examination revealed bilateral extra-cortical ovarian vegetations, three granulations in the pouch of Douglas cul-de-sac and one granulation under the right round ligament. No lesions appeared on liver, omentum, parietocolic gull or diaphragm. The extra-ovarian vegetations, lower omentum and all visible granulations were resected. Frozen sections found a non-invasive bilateral borderline tumour. Permanent sections confirmed the diagnosis of borderline serous cystadenocarcinoma on ovaries, granulations and peritoneal cytology. CA 125 was elevated (101 IU/ml). The tumour cell population was diploid with a low proliferation index according to our cut-off values (fraction of phase S or M cells <4%) (Rodenburg, 1987Go). Two months later, a second-look laparoscopy revealed an involved granulation on the left ovary. Only the granulation was resected. Peritoneal cytology was positive. No dissemination was visible in the peritoneum and CA 125 was normal. Four months later, a third look laparoscopy revealed dissemination on diaphragm, liver, sigmoid and each posterior face of the broad ligament. Most of the lesions were resected during the laparoscopy, but no decision for immediate radical treatment was taken. Peritoneal cytology was negative. The tumour was classified as stage IIIA.

Post-operatively, the patient was informed of her oncological status and that extensive surgical treatment was required, including at least a bilateral oophorectomy. The different options to `preserve' her reproductive potential were discussed. Two options were presented to the patient. The first one was immediate surgical treatment with uterine conservation and subsequent oocyte donation. The second was to perform an `urgent' IVF in order to freeze embryos and to perform the surgical treatment after oocyte retrieval. The patient was advised that this second solution presented more oncological risks in theory than the first, but it was the only chance to obtain a baby with her own genetic material (Ovarian Cancer, 1994Go). She and her male partner finally opted for the second alternative after 2 days of reflection.

The patient was immediately treated with long-acting gonadotrophin-releasing hormone (GnRH) analogues (Decapeptyl retard 3 mg; Laboratoires Ipsen-Biotech, Paris, France) and then stimulated with human menopausal gonadotrophin (HMG; Neopergonal, Serono Laboratories, Boulogne, France). Fifteen days later, pituitary down-regulation was obtained, and a step-down ovarian stimulation protocol was started. After 10 days of HMG stimulation, 16 oocytes were harvested; 10 embryos were obtained and frozen (two at 2-cell stage, two at 3-cell stage, five at 4-cell stage and one at 5-cell stage). The cryopreserved embryos were frozen using propanediol as cryoprotectant. Two days later, radical surgery was performed that included bilateral oophorectomy, omentectomy, iliac and lomboaortic dissection. At the time of radical surgery, ovarian tissue was also frozen according to the Hogden recommendations (Toth et al., 1994Go). All the procedures were managed by laparoscopy. The pathologist found no lymph node metastasis and no lesions on ovaries. CA 125 was slightly elevated (49 IU/ml).

Regular marker evaluation and ultrasound check-up did not show any recurrence. One year later the patient asked for the transfer of the frozen embryos. As initially explained to the patient, a laparoscopic second-look was performed in order that embryos were not transferred without being as sure as possible that there was no recurrence. Thirteen months after radical surgery, a fifth laparoscopy confirmed the absence of any residual tumour. Peritoneal biopsies and cytology were negative. Two months later, two thawed embryos were replaced. The substitution treatment included 2 mg micronized oestradiol per day (Progynova 1 mg, Schering Laboratories, Lys-lez-Lannoy, France) from day 1 to day 28, and vaginal progesterone (Utrogestan, Laboratories Besins Iscovesco, Paris, France) at a dose of 200 mg per day from days 14 to 28. The embryos were transferred on day 17. One embryo implanted. The substitutive treatment was continued during 2 months. It included 4 mg of micronized oestradiol and 300 mg of oral progesterone. The patient had a normal monofetal pregnancy and delivered vaginally a healthy boy, 3830 g, 50 cm, Apgar 10/10/10, 36 weeks after transfer. Up to now (June 2000), this patient has had no clinical, biological or radiological sign indicative of a recurrence of her cancer.


    Discussion
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
The recommended primary surgical treatment for patients with LMPT includes bilateral adnexectomy and omentectomy. Peritoneal washing should be done. However, there is reasonable doubt as to the oncological efficacy of removing the uterus because, although serous metastatic microscopic implants may be present, the uterine peritoneum represents only a small part of all pelvic peritoneum. Moreover, metastasis at this point can be removed or destroyed easily, unlike those located on the intestinal peritoneum (Pouly et al., 1997Go). It is clear that preservation of reproductive potential must be proposed to young patients with diploid stage IA tumours that do not require any additional treatment (Tropé and Kaern, 1996Go). Treatment of such patients consists of unilateral oophorectomy and omentectomy. Patients with stage III disease, however, should normally undergo maximal debulking. Our case was unusual. The FIGO stage was IIIA during the first surgery but the main proliferation took the form of extra-ovarian vegetations and it was possible to obtain maximal debulking without bilateral oophorectomy. Moreover, histology was serous, the patient was <40 years old, and the cell population was diploid. Three out of four favourable patterns were present and the absence of aneuploidy was a major argument to propose a conservative approach. The absence of residual ovarian tumour during the second laparoscopy was an argument against radical surgery (oophorectomy) and for close monitoring. During the third laparoscopy, significant tumour spread was found but both ovaries were free of disease and that was confirmed by the final histology. The only option was to remove the ovaries, as it is well known that removal of the initial tumour is liable to induce regression of the metastasis and at least to reduce the risk of new ones occurring (Ovarian Cancer, 1994Go). No explanation exists for this fact, which is largely proven by this case. However, due to the absence of residual tumours on the ovaries, it was felt that a 1 month delay was acceptable before bilateral oophorectomy.

All the surgical procedures were performed by laparoscopy, which could be questioned because of the higher risk of crushing the lesions with peritoneal and parietal dissemination (Michel et al., 1995Go). Everything was carried out according to oncological rules. Tissue samples were extracted from the abdomen in endobags. The surgeons were highly experienced in oncological laparoscopic surgery. The advantage of laparoscopy in these circumstances is the possibility to repeat the procedures without major discomfort for the patient. It is very probable that without the ability to treat by laparoscopy this case would have been concluded earlier with radical treatment. Laparoscopy permits a therapeutic strategy to be defined with more accurate staging and without significant loss of time and opportunity (Pouly et al., 1997Go). Before each laparoscopy, the patient was advised that a second operation might be necessary a few days later according to the operative and histological findings. Using only laparotomy, such an accurate prediction is impossible. The risk of carcinomatous spread to the abdominal wall might be a point against the laparoscopic strategy. This risk seems to be increased in animal models, but the situation in this case was different in two ways: it was an LMPT about which no clinical data have ever been reported of an increased risk, and all precautions were taken to minimize this risk (low abdominal pressure, and extraction in endobags).

Several case reports are available about successful pregnancy after conservative surgery for early-stage cancer (Niwa et al., 1995Go; Perrin et al., 1999Go). At present, there is no evidence of any adverse effect of pregnancy on the course of advanced stage borderline tumour of the ovary (Hoffman et al., 1999Go). Indeed, neither pregnancy status at time of diagnosis nor occurrence of subsequent term pregnancy have been found to alter the prognosis (Trimble and Trimble, 1994Go). A pregnancy obtained by IVF 2 years after conservative surgery has been reported for serous LMPT (Hoffman et al., 1999Go). In addition, 11 patients receiving ovulation induction have been shown to have no apparent effect on their prognosis (Gottleib et al., 1998Go). In fact, the use of both IVF and donor oocytes has been reported in patients treated for borderline tumour (Mantzavinos et al., 1994Go; Lawal and Lynch, 1996Go). In our case, the impossibility of natural fertility preservation led us to propose an IVF with embryo cryopreservation before radical surgery. This strategy enabled oocyte donation to be avoided but imposed a 1 month delay and ovum retrieval, while two laparoscopies revealed recurrent lesions of LMPT. The absence of invasion and the almost complete treatment for macroscopic lesions during the third laparoscopy support the view that this delay was acceptable without dramatically decreasing the vital prognosis of this patient. A single cycle of ovulation induction preparing for IVF can be equivalent to 2 years of normal menstrual cycles in terms of the number of follicles produced and oestrogen concentration achieved (Fishel and Jackson, 1986). Animal models of ovarian tumours suggest that gonadotrophins play a central role in the development or proliferation of these tumours (Bandera et al., 1995Go). It has been proposed that the pattern of excessive hormonal stimulation is also applicable to human epithelial ovarian cancer (Cramer and Welch, 1983Go). Furthermore, FSH binding sites have been identified in epithelial ovarian cancer cell lines and FSH has been shown to stimulate papillary serous ovarian cancer cell division (Wimalasena et al., 1992Go). In 1996, of the 15 published reports of ovarian carcinoma associated with fertility drug use, nine were of borderline histology (Bristow and Karlan, 1996Go). The ovarian cancer risk was 2.8-fold higher for the patients treated for infertility (Whittemore et al., 1992Go). In fact, the risk is not higher if the patient becomes pregnant after the stimulation. Inversely, unsuccessful embryo transfer after stimulation leads to a higher risk. Currently available data in the literature suggest that an association between ovulation induction and ovarian cancer does not necessarily indicate a causal effect (Tarlatzis et al., 1995Go). For all these reasons, we thought that to delay the radical surgery did not represent a significant reduction in the chance to survive, and also that the high concentration of oestrogen induced by stimulation would not incur a major increase in risk of spread of the tumour. No data except ours are available concerning this opinion (Pouly et al., 1997Go). Nevertheless, the patient was advised of the uncertainty concerning this point and accepted it.

The duration of the interval prior to uterine transfer of thawed embryos is debatable. In case of invasive cancer, we thought that the delay should be 2 years because most recurrences occur during this period even if some have been reported to occur as much as 6 years later (Lansac, 1971Go). In the case of LMPT, the situation is different. The delay for recurrence is generally much longer and it can occur up to 20 years later (Leake et al., 1992Go). We felt that before trying to obtain a pregnancy, it was ethically necessary to ascertain a non-recurrence status. Laparoscopy with peritoneal cytology and biopsy was therefore mandatory because metastasis of <1 cm can be missed by radiological imaging or marker evaluation. Therefore, a fifth laparoscopy, including peritoneal cytology and biopsies, was performed. The absence of recurrence authorized the transfer of two thawed embryos leading to a monofetal normal pregnancy. This couple still have eight frozen embryos, and 3.5 years after the initial diagnosis, this patient is free of recurrence.

In conclusion, even if a stage IIIA serous borderline tumour needs a bilateral oophorectomy, it is possible to perform conservative maximal debulking, ovum retrieval for IVF and embryo cryopreservation before radical surgery. Secondly, an embryo transfer can successfully avoid oocyte donation. This observation underlines the great advantage of close collaboration between oncological and reproductive units in the treatment of cancers. In our opinion, this strategy should preferably be reserved for women <30 years old but may be extended to those aged 35 years.


    Notes
 
2 To whom correspondence should be addressed at: Department of Obstetrics, Gynaecology and Reproductive Medicine, Polyclinique de l'Hôtel-Dieu, 13 Boulevard Charles de Gaulle, 63033 Clermont-Ferrand Cédex 1, France Back


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 Introduction
 Case report
 Discussion
 References
 
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Submitted on February 16, 2000; accepted on July 11, 2000.