Human Reproduction vol.15 no.11 pp.
2347–2350, 2000
CASE REPORT
Successful transfer of frozen–thawed embryos obtained
immediately before radical surgery for stage IIIa serous
borderline ovarian tumour
D.Gallot1,2, J.L.Pouly1, L.Janny1, G.Mage1,
M.Canis1, A.Wattiez1 and M.A.Bruhat1
1Department
of Obstetrics, Gynaecology and Reproductive
Medicine, Polyclinique de l’Hôtel-Dieu, 13 Boulevard Charles de
Gaulle, 63033 Clermont-Ferrand Cédex 1, France
2To
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
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
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., 1997). 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, 1996). 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., 1996) and ~90% for stages II and III (Bristow
and Karlan, 1996). According to one report (Massad et al.,
1991), 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., 1991). 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., 1993) showed that the median
© European Society of Human Reproduction and Embryology
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, 1996). Despite
the term ‘borderline‘, it was generally thought that such
tumours are associated with considerable morbidity and mortal-
ity, but this opinion is nowadays widely criticized (Carter
et al., 1993). 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, 1996). 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, 1996). 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, 1996).
Case report
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 cystadenocarcin-
oma 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,
1987). Two months later, a second-look laparoscopy revealed
an involved granulation on the left ovary. Only the granulation
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D.Gallot et al.
was resected. Peritoneal cytology was positive. No dissemina-
tion was visible in the peritoneum and CA 125 was normal.
Four months later, a third look laparoscopy revealed dissemina-
tion 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,
1994). 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 (Deca-
peptyl 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 recommenda-
tions (Toth et al., 1994). 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
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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
The recommended primary surgical treatment for patients
with LMPT includes bilateral adnexectomy and omentectomy.
Peritoneal washing should be done. However, there is reason-
able 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., 1997). 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, 1996).
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 vegeta-
tions 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, 1994). 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., 1995). 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 laparos-
copy 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., 1997). 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 abdom-
inal 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.,
1995; Perrin et al., 1999). 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., 1999).
Indeed, neither pregnancy status at time of diagnosis nor
occurrence of subsequent term pregnancy have been found to
alter the prognosis (Trimble and Trimble, 1994). A pregnancy
obtained by IVF 2 years after conservative surgery has been
reported for serous LMPT (Hoffman et al., 1999). In addition,
11 patients receiving ovulation induction have been shown to
have no apparent effect on their prognosis (Gottleib et al.,
1998). In fact, the use of both IVF and donor oocytes
has been reported in patients treated for borderline tumour
(Mantzavinos et al., 1994; Lawal and Lynch, 1996). 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 gonado-
trophins play a central role in the development or proliferation
of these tumours (Bandera et al., 1995). It has been proposed
that the pattern of excessive hormonal stimulation is also
applicable to human epithelial ovarian cancer (Cramer and
Welch, 1983). 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., 1992). In 1996, of the 15 published
reports of ovarian carcinoma associated with fertility drug use,
nine were of borderline histology (Bristow and Karlen, 1996).
The ovarian cancer risk was 2.8-fold higher for the patients
treated for infertility (Whittemore et al., 1992). 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., 1995). 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
Embryo transfer before ovarian cancer surgery
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., 1997). 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, 1971). 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., 1992). 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 recur-
rence 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 collabora-
tion 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.
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Received on February 16, 2000; accepted on July 11, 2000

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