Fertility preservation in women with borderline ovarian tumours

Accepted Manuscript Fertility preservation in women with Borderline Ovarian Tumours Giorgia Mangili, Edgardo Somigliana, Veronica Giorgione, Fabio Martinelli, Francesca Filippi, Maria Cristina Petrella, Massimo Candiani, Fedro Peccatori PII: DOI: Reference:

S0305-7372(16)30049-4 http://dx.doi.org/10.1016/j.ctrv.2016.06.010 YCTRV 1520

To appear in:

Cancer Treatment Reviews Cancer Treatment Reviews

Received Date: Revised Date: Accepted Date:

7 March 2016 29 June 2016 30 June 2016

Please cite this article as: Mangili, G., Somigliana, E., Giorgione, V., Martinelli, F., Filippi, F., Petrella, M.C., Candiani, M., Peccatori, F., Fertility preservation in women with Borderline Ovarian Tumours, Cancer Treatment Reviews Cancer Treatment Reviews (2016), doi: http://dx.doi.org/10.1016/j.ctrv.2016.06.010

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Fertility preservation in women with Borderline Ovarian Tumours.

Giorgia MANGILI a, Edgardo SOMIGLIANA b, Veronica GIORGIONE a, Fabio MARTINELLIc, Francesca FILIPPIb, Maria Cristina PETRELLAd, Massimo CANDIANI a, Fedro PECCATORI d

a

Department of Obstetrics and Gynaecology, San Raffaele Scientific Institute, Via Olgettina 60,

20132 Milan, Italy. E-mail address: [email protected], [email protected], [email protected]. b Infertility Unit, Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Via Manfredo Fanti 6, 20122, Milan, Italy. E-mail address: [email protected], [email protected]. c

GynaecologicOncology Unit, Fondazione National Cancer Institute, Via Venezian 1, 20133 Milan,

Italy. E-mail address: [email protected]. d

Fertility and Procreation Unit, Division of Gynaecologic Oncology, European Institute of Oncology,

Via Giuseppe Ripamonti 435, 20141, Milan, Italy. E-mail address: [email protected], [email protected].

Corresponding author: MangiliGiorgia Department of Obstetrics and Gynaecology San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Phone number: +39 0226433770; Fax number: +39 0226432759; E-mail address: [email protected]

1

Fertility preservation in women with Borderline Ovarian Tumours.

Abstract Borderline ovarian tumours (BOT) may occur in young women and have an excellent survival rate. Therefore, there is the obligation to put emphasis on fertility preservation in affected women. On the other hand, it has also been underlined that the disease should be managed with caution because these tumours can relapse and, albeit rare, malignant transformation can also occur. Unfortunately, evidence on fertility preservation in women with BOT is scanty. In this opinion paper, we tried to draw some clinical indications based on the few available studies on the clinical management of BOT and their possible relation with controlled ovarian hyper-stimulation (COH). We ultimately came to the following conclusions: 1) Fertility counselling should become an integral part of the clinical management of women with BOT. Conservative management without pre-surgical counselling may expose women without reasonable chances of future conceptions to undue risks. 2) Despite some epidemiological concerns on the possible relation between COH and BOT, the conservative surgical treatment should be associated to oocyte cryopreservation considering the high risk of recurrence of the disease. 3) Letrozole during COH should be considered to temper the theoretical risk of increased recurrences. 4) Pregnancy should not be delayed in women at low-moderate risk of recurrences. Fertility preservation may be avoided in these women provided that they start active pregnancy seeking early. 5) Albeit experimental, oocytes retrieval from affected ovaries removed at the time of surgery can be considered. Conversely, ovarian cortex cryopreservation is not justified given the possible risks of malignant reseeding.

Key words Borderline ovarian tumours; fertility preservation; oocyte cryopreservation; ovulation induction; infertility

2

Introduction Borderline ovarian tumours (BOT) have been recognized as a separate diagnostic category of epithelial ovarian tumours [1, 2]. They are characterized by features of malignant tumours, including cellular proliferation, stratification of the epithelial lining of the papillae, nuclear atypia, and mitotic activity, but without destructive stromal invasion [3]. They represent about 10-20% of all ovarian epithelial tumours with an estimated incidence ranging from 1.8 to 5.5 per 100,000 women per year [4]. One-third of BOT are observed in patients younger than 40 years of age [5]. BOT are diagnosed at stage I in 82% of cases and have a 5-year survival rate of more than 90% across all tumour stages, with a considerable number of patients cured [6]. However, BOT may relapse and, albeit rare, malignant transformation can occur. FIGO stage, younger age, the presence of peritoneal implants, especially invasive implants, and the type of surgery are the most significant predictive factors of relapse [5, 7]. Overall, given the peculiar epidemiological profile of BOT, there is the indisputable obligation to put emphasis on ovarian function and fertility preservation in affected women.

Fertility-sparing surgery, conservative treatment of BOT The basic treatment of BOT is surgery. In most cases, this is the exclusive treatment. The intervention aims at complete resection of the tumour, besides full surgical staging. In postmenopausal or in women who do not wish to preserve fertility the complete staging procedure includes: peritoneal washing, bilateral salpingo-oophorectomy, multiple peritoneal biopsies, omentectomy, resection of grossly visible metastases and inspection and palpation of the abdominal cavity. Conversely, there is no rationale for systematic lymphadenectomy and hysterectomy [5, 8]. Considering the good prognosis of BOT, fertility-sparing surgery can be considered for young women who desire to preserve fertility. Fertility-sparing surgery is defined as preservation of the uterus and a least part of one ovary. Thus, in patients desiring fertility preservation and with tumour

3

confined to one ovary, surgical management may be limited to unilateral salpingo-oophorectomy or ovarian cystectomy with complete surgical staging [9]. In this case, the contralateral normalappearing ovary should be carefully inspected but biopsy is not required since it may cause unnecessary damage to the ovarian reserve and/or peritoneal adhesions [10, 11]. If there is bilateral ovarian involvement and complete resection can be achieved, unilateral or bilateral ovarian cystectomy may be considered, even if patients should be informed about the higher recurrence rate [12]. In all stages and disease extension, the uterus should be preserved because of the increasingly used egg donation option [13]. The most common histotypes are serous (65%) and mucinous (35%). Serous borderline tumours are unilateral in 50% of cases and bilateral in 30%; extraovarian diffusion may occur in 35% of cases in the form of peritoneal implants which may be non invasive (75%) or invasive (25%) [14-15]. Mucinous BOT represent a peculiar situation. In these tumours, benign, borderline and invasive lesions can coexist [16] and there is thus the necessity for an in-depth histological evaluation of the lesions. Moreover, mucinous BOT tend to recur as invasive ovarian carcinoma more frequently than serous BOT after conservative treatment [17, 18]. Appendectomy for mucinous type BOT is also strongly recommended. Therefore, the mere excision of the tumour is not feasible in women with mucinous BOT and at least unilateral salpingo-oophorectomy is required regardless of the dimension of the lesion [19]. The laparoscopic approach in stage I BOT seems to be safe and it is now commonly accepted. The development of laparoscopic techniques with the use of Endo-Bag, which allows the confinement of the tumour within a plastic bag during laparoscopy, gives less risk of spillage and less port-side metastases [20, 21]. Indications of adjuvant platinum-based chemotherapy remain rare in this disease and are limited to patients with invasive peritoneal implants or with nodal spread located near the nodal sinus. Of note, no randomized studies have demonstrated any survival advantage of adjuvant chemotherapy [5, 22].

4

The risk of relapse after conservative treatment of BOT. The overall risk of recurrence after fertility-sparing surgery is higher (0-25%) than after bilateral salpingo-oophorectomy (0-5%) [23]. For women with stage I BOT treated with either unilateral salpingo-oophorectomy or ovarian cystectomy, after an average follow-up of three to six years, the borderline recurrence rate was 13%, recurrence with malignant disease was 1.6% and the death rate was 0.5% [23]. Comparing unilateral salpingo-oophorectomy or ovarian cystectomy, the recurrence rate was higher and recurrence occurred sooner with the latter [23, 24]. A recent meta-analysis based on clinical case series compared the oncological outcome between different surgical approaches in BOT. The authors defined fertility sparing surgery as uni-or bilateral cystectomy or unilateral salpingo-oophorectomy with or without contralateral cystectomy while radical surgery was defined as bilateral salpingo-oophorectomy. Interestingly, based on their analyses, in patients with unilateral BOT, unilateral salpingo-oophorectomy was significantly favoured over cystectomy in terms of reduction of recurrences (OR=2.20, 95%CI:0.79-2.84; p<0.0001), namely the recurrence rates were 12% and 25% respectively. No other significant results emerged. Noteworthy, the survival rates did not differ. Pooled mortality estimates for fertility sparing surgery and radical treatment were 1.6% (95%CI:1.1-2.3%) and 2.0% (95%CI: 1.4-2.9%), respectively [25]. Unfortunately, only one small RCT on conservative management of BOT is available [26]. Thirtytwo women with bilateral BOTs were randomized to unilateral salpingo-oophorectomy with controlateral cystectomy versus bilateral cystectomy. After a follow-up period of 81 months, there were no differences in terms of cumulative rate of recurrences between the two groups but the pregnancy rate was higher in women allocated to bilateral cystectomy. However, in this latter group, the time to first recurrence was shorter and the rate of radical treatment of the recurrence was higher [26]. The above-mentioned recent meta-analyses also showed a similar rate of recurrence between the two approaches (28% vs 26%) [25]. Hence, if indicated, a more conservative approach could be chosen also in bilateral BOT. Stage is an important factor to be considered when conservative surgery is planned because this

5

variable is significantly associated with the risk of progression to invasive disease. In a recent study investigating clinical outcome after conservative surgery for stage II to IV serous BOT, the recurrence rate was 38% and, among recurrences, eight (6%) were invasive [23]. In another study on 59 women with advanced disease (≥ IC FIGO stage), 33 (75%) patients were treated conservatively and the rate of recurrence was similar to those receiving radical treatment [27]. Conservative management may be an option also for patients with peritoneal implants if the implants can be entirely removed [28, 29], while it should be used with more caution in the presence of invasive implants considering the aggressiveness of these lesions and the association with a poorer prognosis [29, 30]. About 70% of recurrent lesions shows borderline histology and can be effectively cured by surgery without any impact on the long-term survival [6, 28, 31]. If technically feasible, conservative management thus represents a valuable alternative also in patients with recurrent BOT [32]. In all kind of BOT, malignant transformation to invasive ovarian cancer occurs in about 30% (29/74) of relapses (74/950), i.e. in 2.3% of cases [6]. However, in patients younger than 40 years who underwent conservative management that risk seems to be lower [7, 25]. Table 1a and 1b report patients’ outcome in early and advanced stages BOT after fertility-sparing surgery [33-65].

Tailoring fertility-sparing surgical treatment. Overall, fertility-sparing management exposes women to a higher risk of recurrences. Clinical monitoring should be more intensive and a considerable proportion of women require additional surgeries. This situation may cause supplementary risks, more patients’ stress and increased costs. Therefore, conservative management should always be carefully balanced and should not be thoroughly advocated exclusively based on women age. A comprehensive evaluation of the clinical situation and an in-depth counselling is mandatory. A shared decision should be reached. Surprisingly, scanty attention to the evaluation of the fertility potential prior to an intervention for BOT is given in the literature. Fertility-sparing surgery in young women is commonly presented as a

6

dogma rather than a therapeutic option to be tailored to the woman. In our opinion, conservative surgery should be mainly aimed at future pregnancies and should not be considered if the woman has already fulfilled her reproductive wishes or if future pregnancies are implausible (such as in women older than 40 and in those with infertility and concomitant compromised ovarian reserve prior to surgery). Prevention of early menopause and its associated detrimental effects may also play a role in the decision-making process in particular in younger women. An exhaustive oncofertility counselling is thus mandatory in all young women with a diagnosis of BOT. If possible, this should take place before the intervention and then amended after it. Obviously, if BOT is an unexpected finding only post-surgical counselling can be done. More specifically, affected women should undergo a fertility work-up through the collection of a complete clinical history (focusing on menstrual cycles characteristics, parity and history of infertility), transvaginal ultrasound to evaluate the antral follicle count (AFC) and hormonal assessments (anti-mullerian hormone-AMH regardless of the menstrual phase and, if temporally possible serum FSH and E2 at day 2-5 of the cycle). Noteworthy, infertility is observed in 10-35% of patients with BOT before treatment [37, 66-68]. Moreover, these patients can suffer from infertility even after conservative surgery because of the possible surgery-related reduction of ovarian reserve [69, 70] and the occurrence of adhesions that might interfere with fallopian tube function [71]. In women with bilateral lesions, the surgery-related reduction of the ovarian reserve may ultimately reduce the duration of the fertile period [72, 73]. Moreover, the presence of post-surgical adnexal adhesions is associated with a 20-30% reduction of pregnancy rate [74]. Recent evidences showed that AFC might be reliable also in the presence of ovarian cysts [75, 76] and that serum AMH is not also markedly affected by these lesions [77, 78]. Ideally, this evaluation should precede surgery but important insights could emerge also after the intervention and may guide future decisions. Of particular relevance is the monitoring of ovarian reserve over time after the intervention. Importantly, this information should be collected at least 6 months after surgery since re-equilibrium of the ovarian function needs time [79, 80].

7

Beyond fertility-sparing surgical management: fertility preservation. Fertility preservation has received growing consideration during the last decades and it is now advocated for a number of malignant conditions [81]. Noteworthy, indications to preserve gametes should be considered also in conditions not requiring chemotherapy because of the necessity to delay pregnancy for several years for close follow-up or hormonal treatments (such as early breast cancer). Women who are diagnosed with BOT are also amenable to fertility preservation considerations. Although they do not require chemotherapy, they can be young and face a risk of fertility impairment after surgery. Adhesions may develop and interfere with natural conception and, most importantly, ovarian reserve may be directly injured by surgery. The common attitude to warn against pregnancies for 2-5 years to consent accurate follow-up, further worsens the situation because affected women are also exposed to the deleterious effects of aging (in particular if they are in the late thirties). Preserving gametes at the time of diagnosis could open the possibility to have children also in women who may result infertile after the end of the treatments and follow-up. However, fertility preservation in women with BOT has some peculiarities that deserve in-depth considerations.

Association between controlled ovarian hyper-stimulation, ovarian cancer and BOT. Several fertility preservation options have emerged during the last decade. They include oocytes cryopreservation following controlled ovarian hyper-stimulation (COH), oocytes cryopreservation after in vitro maturation (IVM) of oocytes collected without pharmacological stimulation and ovarian cortex freezing. In adult women, the former option should be the first choice since it is no longer considered experimental and is easily accessible because the expertise is diffuse and growing. However, this option strongly contrasts with the diffuse albeit poorly supported view that ovarian COH may increase the risk of ovarian cancer. This issue deserves some clarifications as it assumes crucial relevance in the decision-making process of women with BOT. The worrying alarm linking COH with cancer switched on with a paper published in 1994 in the New

8

England Journal of Medicine that showed a statistically significant association between clomiphene assumption and ovarian cancer [82]. A plethora of studies were subsequently published on the relation between COH and ovarian cancer and overall lessened this alarmism. According to the most recent meta-analysis, the OR of ovarian cancer for COH aimed at in vitro fertilization (IVF) was 1.06 (95%CI: 0.85-1.32)[83]. The previously available meta-analysis showed different figures, but was anyhow reassuring. Even if a statistically significant association between COH and ovarian cancer emerged (RR=1.50, 95%CI: 1.17-1.92) it vanished when the risk was related to the infertile rather than the general population (RR=1.26, 95%CI: 0.62-2.55) [84]. Specific data on BOT are scantier [85]. Most epidemiological studies showed an increased risk of BOT in women receiving infertility drugs [67, 82, 86-95]. Most of these studies were methodologically debatable and results could be due to confounders. A crucial point to be reemphasized here is the intriguing but neglected association between BOT and infertility. As discussed above, infertility is reported in approximately 10-35% of patients with BOT [66-68] and this may markedly distort epidemiological findings. The point here is discerning whether the association between infertility drugs and BOT is due to the confounding effect of infertility. To disentangle this issue, only studies selecting both cases and controls from infertile women can be informative (Table 2). Moreover, in the context of the present review, the most helpful studies are those reporting on the use of IVF, the procedure that more properly mimic oocytes cryopreservation. This evidence would allow to evaluate both the impact of the use of gonadotropins but also to assess the possible concomitant insult of the oocytes retrieval procedure. Two studies fulfil these requirements [92, 94]. Both are large retrospective cohort studies designed with the use of national registers. Van Leeuwen et al. linked the Dutch registries of IVF and cancer and ultimately selected 19,146 women undergoing IVF and 6,006 infertile women who did not undergo IVF. The number of BOT cases diagnosed during the follow-up (excluding the first year after inclusion) was 27 and 4, respectively corresponding to an Hazard Ratio (HR) adjusted for age, tubal problems and parity before referral to an infertility unit of BOT for IVF users of 4.23 (95%CI: 1.25-14.33) [92]. Stewart

9

et al. linked the Australian databases of infertility and cancer and obtained data on 21,639 infertile women, of whom 7,544 underwent IVF and 14,095 did not. The number of women diagnosed with BOT in the two cohorts was 17 and 14, respectively, corresponding to an HR adjusted for age, calendar period and socio-economic status of BOT for IVF users of 2.46 (95%CI: 1.20-5.04) [94]. In general, extreme caution is warranted when evaluating epidemiological studies on the association between COH and BOT. The available evidence does not consent to draw inferences on causality. Indeed, available studies are mathematically weak (ovarian cancer is uncommon) and exposed to significant confounders. Of utmost relevance here is that risk factors for ovarian cancer mostly relate to reproductive events [85]. Parity, tubal sterilization and oral contraceptive use that are obviously negatively associated with infertility have conversely strong protective effects on ovarian cancer. Noteworthy, the two previously discussed cohort studies focussing on BOT in infertile women did not properly control for these confounders [92, 94]. Infertile women from both exposed and unexposed cases may have conceived and/or assumed oral contraceptive before and after inclusion. In addition, the risk profile of BOT differs from ovarian cancer in general and remains to be clarified [94]. In general, the magnitude of these confounding associations is relevant and can markedly distort results from epidemiological studies. Study designs and mathematical models cannot properly overcome these limitations and one should thus accept that epidemiological evidence would never definitely disentangle this issue [96, 97]. It is finally worthwhile noting that the main biological rational for claiming a causal relation is currently losing consensus. The “incessant ovulation” theory is indeed being replaced with other hypotheses [85, 98]. Indeed, the ovulation as a causal mechanism in the development of cancer has lost credibility. This theory was a crucial point in supporting causality between COH, IVF and ovarian cancer. The view that one cycle would represent several oncologic insults corresponding to the number of ovulations is strictly related to the incessant ovulation hypothesis. If this hypothesis is not valid, the rational for a link between COH and ovarian cancer gets lost. Noteworthy, biological credibility is crucial according to the criteria proposed by Hill AB in 1965 for causal inferences [99].

10

It is safe to perform COH in patients already diagnosed with BOT? Even if there is insufficient evidence to claim a causal relationship between COH and BOT, one may claim a potential detrimental effect in women with active lesions at the time of COH. In other words, COH may accelerate tumour growth [100]. This concern is supported by epidemiological and biological evidence. Van Leeuwen et al. highlighted that the risk of BOT was particularly high during the first year after IVF [92]. Constitutive oestrogen and progesterone receptors expression has previously been reported for serous BOT [101, 102] with higher expression in low grade compared to high-grade carcinomas [103], reflecting their more differentiated nature. The level of oestrogen and progesterone receptors expression in BOT was significantly higher in serous than in mucinous BOT [104]. However, in vitro studies showed no proliferation effect of FSH or oestradiol on primary cultures of cells from serous BOT at different stages, despite the presence of their receptors [105, 106]. No data is available for the mucinous subtype. In conclusion, even if not supported by clear data, a detrimental effect of COH on BOT growth is plausible and COH should not be offered when BOT is still present. A distinct situation is COH in women with a history of BOT who may require COH for infertility treatment or oocytes cryopreservation. If the tumour is no more present, the issue should be reconducted to the relation between COH and BOT recurrence or new occurrence, and not BOT growth. However, this population is peculiar and cannot be considered completely equal to the general population in terms of basal risk of new tumour arise. Moreover, as discussed above, BOT is associated with a high risk of recurrences and one may always consider the presence of undetected initial lesions. Data about the feasibility and safety of COH in women with previously diagnosed BOT is scanty but reassuring. Darai et al. revised the literature on this specific issue and identified a total of 126 women with a history of BOT who subsequently underwent COH to treat infertility. Specifically, 104 of them were previously operated on for early stage disease while the remaining 22 were operated on

11

for advanced stages. The pooled estimate of pregnancy was 80% and the rate of recurrences was 23% (45/126). One case of progression to an invasive carcinoma was documented [64] but no deaths were observed. If we consider only patients with a stage I and we exclude bilateral tumours (69/104), the rate of recurrence dropped at 15% (9/59) [23]. Overall, the magnitude of the reported frequency of recurrences is very similar to what reported in the literature for BOT not exposed to COH. In other words, women opting for a conservative approach of BOT face a significant risk of recurrence and COH does not appear to significantly modify this risk. On these bases, one can consider the possibility of oocytes cryopreservation, in particular in women who cannot seek pregnancy after treatment. Banking oocytes at this time would consent to have chances of pregnancy even if a recurrence and the need for radical surgery will occur. On the other hand, it has to be highlighted that this conclusion cannot be considered definite and further evidence is warranted, in particular for more advanced cases.

When and how to perform COH in patients with BOT. Theoretically, oocytes cryopreservation following COH may be considered either before or after surgery. However, the former situation is clinically unacceptable and, to our knowledge, it has never been reported. Reasons to ban this approach are the following: Firstly, ovarian responsiveness to COH could be better but the accuracy of a pre-surgical diagnosis of BOT is mandatory. Sonography has done impressive progresses in recent years and in some cases the pre-surgical diagnosis of BOT is highly reliable [107-109]. However, performing pre-surgical oocytes collection in a woman with ovarian cancer is unacceptable because the accidental spillage may ultimately affect prognosis. Secondly, the above-mentioned concern regarding a possible COH mediated acceleration of the growth of BOT cannot be dismissed. Thirdly, surgery may be more demanding after a recent COH and the surgical related damage to ovarian reserve may be increased. On one side, the challenging discerning between BOT and corpora

12

lutea may cause the removal of functional lesions while the presence of corpora lutea can cause significant bleeding that may require extensive coagulation. Postponing surgery consenting regression of the corpora lutea may obviously overcome these latter difficulties but this delay may have a clinical impact since it would mean delaying surgery for at least two more weeks (though six weeks would be more appropriate). Thus, overall, surgery would have to be postponed for one or two months. On the whole, there are thus disproportionate concerns to consider oocytes cryopreservation prior to surgery. Post-surgical oocytes cryopreservation is conversely clinically safer. The histopathological diagnosis is definite and concerns are only related to the possible COH-mediated increased risk of BOT recurrences or new occurrences. As already discussed, clear evidence is lacking and the magnitude of the presumed risk is quite limited. Actually, a 3-4 folds increased risk of a rare (<1%) and curable condition is of debatable relevance considering that affected women already face a consistent risk (20%) of recurrence of this disease. Regarding the fear that COH might accelerate the growth of residual tumour, one could argue that relapse would anyway occur in these women and COH would only anticipate it. Moreover, it is unlikely that an anticipated relapse may have an impact on survival. Regardless of these reassuring considerations, we advocate the concomitant use of letrozole during COH for oocyte cryopreservation. Letrozole is an aromatase inhibitor that can be employed in the COH protocols to avoid high oestrogen levels. It has already been used for fertility preservation in breast cancer patients to maintain reduced oestrogen levels while concomitantly consenting to harvest several mature oocytes [110, 111]. Even if the lack of strong evidence cannot justify this safety measure, it may have certain legal and psychological benefits. Letrozole assumption may indeed be important to ensure adherence to treatment because women with gynaecological cancers are typically concerned about the use of hormonal treatments. In case of recurrence, its use may also protect physicians from potential litigations fuelled by poorly adjourned colleagues. In addition, it is noteworthy that given the non-urgent setting, women can undergo multiple cycles of COH if necessary. The aim here is not to collect the highest number of oocytes in the shortest period

13

of time as for classic fertility preservation programs that apply to urgent situations of women scheduled for oncological treatments. Up to three cycles can be considered. The goal is storing at least 20 mature oocytes [112]. As a final point, there is insufficient evidence to indicate whether COH cycles can be started immediately after surgery or, conversely, whether it may be more appropriate to wait some months to allow complete normalization of the folliculogenesis in the operated gonads.

“Natural” fertility preservation in patients diagnosed with BOT When the diagnosis of BOT is established after conservative surgery, all young patients should be referred to an oncofertility team to have an extensive counselling. A neglected but important issue here is the possibility to consider natural pregnancy. This would allow achieving the pregnancy without exposing the woman to the potential risks of oocytes cryopreservation. Therefore, if the woman has a partner and she is interested in having a pregnancy, she should be encouraged to have regular intercourses starting as soon as possible. If she has a history of infertility, Assisted Reproductive Techniques (ARTs) should be immediately considered. IVF in particular should be favoured since it may abbreviate time to pregnancy. Moreover, if pregnancy is obtained, it may consent in some cases to store some supernumerary embryos for future additional pregnancies (a kind of “unplanned fertility preservation”). In women who have not yet attempted to seek natural pregnancy, an active management is advisable. Basic infertility tests should be performed soon, couples should be educated on the best time for sexual intercourses and treatments should be envisaged earlier. The underlying view is to obtain a pregnancy prior to BOT recurrence. Our position in advising immediate pregnancy seeking after the diagnosis may be a matter of concern and deserves some explanations. This indication sharply contrasts with the conventional oncological attitude to advise a period of close follow-up (2 to 5 years) before seeking pregnancy. This policy is mainly dictated by the potential interferences that pregnancy may cause on the diagnostic and therapeutic processes. Imaging techniques are limited by pregnancy, abdominal surgery is more

14

complicated and chemotherapy during the first trimester is contra-indicated. BOT however represents a peculiar situation for several reasons. Recurrences are common, they can occur even after several years and, overall, they rarely affect survival. There is actually no consensus on the best timing for conception seeking. Some authors suggested waiting 1-2 years after the initial treatment of BOT mainly because the risk of recurrence after conservative treatment is higher in the first two years [68, 113]. However, the median time to recurrence was very variable among different studies with cases of relapse and death occurring after more than 10-15 years [6]. Women estimated at elevated risk of recurrence may represent an exception and should be discouraged from pregnancy seeking. Occurrence of BOT during early pregnancy may expose the woman and the foetus to clinical challenges. Sonographic follow-up is complicated and surgery in pregnancy is feasible but risky. However, concomitantly, these women should be offered cryopreservation of oocytes. Obviously, also women who cannot seek pregnancy after the operation because of social constraints should be scheduled for oocytes cryopreservation.

The management of recurrent cases From an oncofertility perspective, recurrent cases pose a clinical challenge. Theoretically, all the considerations made for primary cases can be valid for recurrences with some worthy differences. The pre-surgical diagnosis of recurrences is facilitated compared to primary cases [114]. However, the increased accuracy of the diagnosis does not change the scenario and pre-surgical cryoconservation of oocytes remains unfeasible. Entirely ruling out malignancy is not possible and the procedure would expose women to the risk of spillage and thus modification of the stage of disease. Noteworthy, this procedure would also be expected to retrieve less oocytes compared to primary cases because of the previous surgery that may have injured the ovarian reserve. As for primary cases, a pre-surgical comprehensive evaluation of the fertility potential of the woman including tests of ovarian reserve is required.

15

Surgery for recurrent cases can be either conservative or radical. Compared to first line surgery, conservative interventions are less indicated and most cases actually underwent castration. For instance it is not justified if the reproductive prognosis of the woman is deemed compromised. However, in selected cases, a conservative approach might be done. In these last event, a postsurgical counselling and, if possible, oocytes cryopreservation are indicated.

Do alternative options to egg banking exist? In recent years, there is cumulative evidence documenting the feasibility and effectiveness of cryopreserving ovarian tissue. The technique consists in surgical excision of a fragment of ovarian cortex and its cryopreservation. When needed, even several years later, the fragment can be thawed and re-implanted, mainly into the pelvic cavity)[115, 116]. Albeit still considered experimental, the use of ovarian tissue cryopreservation for young girls with malignancies is growing. Not surprisingly, it has been claimed to potentially play a role also for BOT [112]. Theoretically, this approach would have here the advantage to consent fertility preservation without exposing the woman to additional risks at the time of first diagnosis and treatment. Indeed, ovarian cortex can be collected during surgery for BOT and the woman would not be exposed to the risks of oocytes cryopreservation, i.e. the need to receive medications of potential harmful effect on BOT or to undergo one or more oocytes retrievals. However, ovarian tissue cryopreservation raises some safety concerns in this context. BOT is a tumour located in the organ where the biopsy is taken. Since to date, the ultimate aim of ovarian cortex biopsy is to eventually re-implant the fragment, if needed, one has to be confident that this second intervention will not also re-implant BOT cells. In fact, this was a concern for all malignant indications in the early days of ovarian cortex biopsy [81]. However, subsequent biological and clinical evidence tended to lessen the relevance of this concern with the exception of leukaemia [117]. Data on the safety for BOT is lacking but based on clinical common sense, we thus recommend extreme caution in considering this option. Noteworthy, women requiring the use of the re-implantation of frozen biopsy would be those requiring at first intervention or at the

16

time of recurrence, radical surgery. In fact, the concern of reseeding BOT cells in these cases is consequently even higher. Moreover, even if reseeding could be excluded, one should consider that this same tissue has already undergone malignant transformation and that this may occur again. Reimplanting a tissue carrying this risk is at least debatable. Despite these concerns, there is some preliminary data on this option in the literature. They refer to removed affected ovaries. Specifically, Fain-Kahn et al. proposed ovarian cortex cryopreservation in women with BOT recurrence in a single ovary (previous history of BOT) and in women with bilateral ovarian involvement when the conservative management was not technically feasible [118]. In their experience, the procedure was feasible in 9 out 17 women (53%). In the remaining eight cases, the procedure was not performed because: 1) conservative management was finally carried out (n=4) 2) a malignant recurrence was identified (n=1) 3) no macroscopic healthy ovarian tissue could be found (n=3). None of the frozen samples was re-implanted. Noteworthy, the challenge in finding healthy parenchyma on gross histological inspection of BOT is an additional difficulty that actually occurred in 3 out of the 12 (25%) women who were estimated to potentially benefit from the procedure. The concern about the potential risk of malignant cell transmission from ovarian tissue in BOT could be avoided by IVM of immature oocytes retrieved from the visible antral follicles of ovarian specimen immediately after surgical removal [119]. This option is fascinating but IVM is an investigational technology, which consents to retrieve few oocytes of lower quality in terms of chances to achieve pregnancy. On the other hand, this technique does not expose the woman to risks. Interestingly, two recent live births were described following IVM of oocytes retrieved from extracorporeal ovarian tissue aspiration. Both occurred in women with ovarian tumour [120, 121]. This evidence represents a valuable proof of concept. Even if the effectiveness of the technique is presumably modest, this option can thus be considered.

17

Conclusions Fertility counselling should become an integral part of the clinical management of women with BOT (Figure 1, Table 3). It should precede and follow surgery and, most importantly, it should become an integral part of the concept of conservative management. Fertility-sparing surgery without fertility pre-surgical counselling is meaningless and may expose women to undue risks. Despite the concerns on the possible relationship between COH and BOT, oocyte cryopreservation should be considered after surgery in young women treated conservatively. Given the high risk of recurrence of the disease, the conservative approach may loose its sense if it is not associated to fertility preservation procedures after surgery. Women may actually have to face a recurrence prior to have achieved pregnancy. Letrozole during COH should be considered to temper the theoretical risk of increased recurrences. In addition, pregnancy should not be delayed in women who are in the social condition to seek conception. Fertility preservation may be avoided in these women provided that they start active pregnancy seeking early. In addition, albeit experimental and presumably poorly effective, oocytes retrieval from removed affected ovaries can be considered. Conversely, ovarian cortex freezing is not currently justified given the possible risks of reseeding. Finally, available options and related pros and cons have to be in-depth discussed with the woman. She should receive a comprehensive this information by a multidisciplinary team that should at least include an oncologist and an expert in reproductive medicine.

18

Conflicts of interest: none

19

References [1] Taylor HC. Malignant and semi malignant tumours of the ovary. Surg Gynecol Obstet 1929;48:240-38. [2] Scully RE. World Health Organization classification and nomenclature of ovarian cancer. Natl Cancer Inst Monogr 1975;42:5-7. [3] Asc G. Serous and mucinous borderline (low malignant potential) tumors of the ovary Am J Clin Pathol 2005;123: S13 -57. [4] Skirnisdottir I, Garmo H, Wilander E, Holmberg L. Borderline ovarian tumors in Sweden 1960-2005: trends in incidence and age at diagnosis compared to ovarian cancer. Int J Cancer 2008;123:1897-901. [5] Harter P, Gershenson D, Lhomme C, Lecuru F, Ledermann J, Provencher DM et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian tumors of low malignant potential (borderline ovarian tumors). Int J Gynecol Cancer 2014;24:S5-S8. [6] du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C et al. Borderline

tumours

of

the

ovary:

A

cohort

study

of

the

ArbeitsgmeinschaftGynäkologischeOnkologie (AGO) Study Group. Eur J Cancer 2013;49:1905-14. [7] Trillsch F, Mahner S, Woelber L, Vettorazzi E, Reuss A, Ewald-Riegler N et al. Agedependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics

and

outcome:

results

from

a

sub-analysis

of

the

ArbeitsgemeinschaftGynaekologischeOnkologie (AGO) ROBOT study. Ann Oncol 2014;25:1320-7. [8] Lesieur B, Kane A, Duvillard P, Gouy S, Pautier P, Lhommé C et al. Prognostic value of lymph node involvement in ovarian serous borderline tumors. Am J Obstet Gynecol 2011;204:438.e1-438.e7. [9] National Comprehensive Cancer Network NCCN. Guidelines Version 2.2011 epithelial ovarian cancer fallopian tube cancer primary peritoneal cancer 12, 2011. [10] Weinstein D, Polishuk WZ. The role of wedge resection of the ovary as a cause for mechanical sterility. Surg Gynecol Obstet 1975;141:417-8. [11] Morice P, Camatte S, El Hassan J, Pautier P, Duvillard P, Castaigne D. Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril 2001;75:92-6.

20

[12] Palomba S, Zupi E, Russo T, Falbo A, Del Negro S, Manguso F et al. Comparison of two fertility-sparing approaches for bilateral borderline ovarian tumours: a randomized controlled study. Hum Reprod 2007;22:578-85. [13] Luke B, Brown MB, Missmer SA, Spector LG, Leach RE, Williams M et al. Assisted reproductive technology use and outcomes among women with a history of cancer. Hum Reprod 2016;31:183-9. [14] Aure JC, Hoeg K, Kolstad P. Clinical and histologic studies of ovarian carcinoma. Obstet Gynecol 1971;37:1. [15] Fox H. The concept of borderline malignancy in ovarian tumours: a reappraisal. Curr Top Pathol 1989;78:111-34. [16] Hart WR. Mucinous tumors of the ovary: a review. Int J GynecolPathol 2005;24:4-25. [17] Koskas M, Uzan C, Gouy S, Pautier P, Lhommé C, Haie-Meder C et al. Fertility determinants after conservative surgery for mucinous borderline tumours of the ovary (excluding peritoneal pseudomyxoma). Hum Reprod 2011;26:808-14. [18] Morice P, Uzan C, Fauvet R, Gouy S, Duvillard P, Darai E. Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol 2012;13:e103-15. [19] Tropé CG, Kaern J, Davidson B. Borderline ovarian tumours. Best Pract Res Clin Obstet Gynaecol 2012;26:325-36. [20] Deffieux X, Morice P, Camatte S, Fourchotte V, Duvillard P, Castaigne D. Results after laparoscopic management of serous borderline tumor of the ovary with peritoneal implants. GynecolOncol 2005;97:84-9. [21] Fauvet R, Boccara J, Dufournet C, Poncelet C, Daraï E. Laparoscopic management of borderline ovarian tumors: results of a French multicenter study. Ann Oncol 2005;16:40310. [22] Leary A, Petrella MC, Pautier P, Duvillard P, Uzan C, Tazi Y et al. Adjuvant platinumbased chemotherapy for borderline serous ovarian tumors with invasive implants. Gynecol Oncol 2014;132:23-7. [23] Daraï E, Fauvet R, Uzan C, Gouy S, Duvillard P, Morice, P. Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options. Hum Reprod Update 2013;19:151-66. [24] Suh-Burgmann E. Long-term outcomes following conservative surgery for borderline tumor of the ovary: a large population-based study. GynecolOncol 2006;103:841-7.

21

[25] Vasconcelos I, de Sousa Mendes M. Conservative surgery in ovarian borderline tumours: a meta-analysis with emphasis on recurrence risk. Eur J Cancer 2015;51:620-31. [26] Palomba S, Falbo A, Del Negro S, Rocca M, Russo T, Cariati F et al. Ultra-conservative fertility-sparingstrategy for bilateral borderline ovariantumours: an 11-year follow-up. Hum Reprod 2010;25:1966-72. [27] Helpman L, Beiner ME, Aviel-Ronen S, Perri T, Hogen L, Jakobson-Setton A et al. Safety of ovarian conservation and fertility preservation in advanced borderline ovarian tumors. FertilSteril 2015;104:138-44. [28] Zanetta G, Rota S, Chiari S, Bonazzi C, Bratina G, Mangioni C. Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study. J Clin Oncol 2001;19:2658-64. [29] Uzan C, Kane A, Rey A, Gouy S, Duvillard P, Morice P. Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary. Ann Oncol 2010;21:5560. [30] Viganò R, Petrone M, Pella F, Rabaiotti E, De Marzi P, Mangili G. Surgery in advanced borderline tumors. Fertil Steril 2010;94:1163-5. [31] Park JY, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. Surgical management of borderline ovarian tumors: The role of fertility-sparing surgery. Gynecol Oncol 2009;113:75-82. [32] Uzan C, Muller E, Kane A, Gouy S, Bendifallah S, Fauvet R et al. Fertility sparing treatment of recurrent stage I serous borderline ovarian tumours. Hum Reprod 2013;28:3222-6. [33] Rice LW, Berkowitz RS, Mark SD, Yavner DL, Lage JM. Epithelial ovarian tumors of borderline malignancy. Gynecol Oncol 1990;39:195–8. [34] Barnhill DR, Kurman RJ, Brady MF, Omura GA, Yordan E, Given FT, et al. Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: a Gynecologic Oncology Group study. J Clin Oncol 1995;13:2752–6. [35] Ji H, Yliskoski M, Anttila M, Syrjanen K, Saarikoski S. Management of stage-I borderline ovarian tumors. Int J Gynaecol Obstet 1996;54:37–44. [36] Tamakoshi K, Kikkawa F, Nakashima N, Tamakoshi A, Kawai M, Furuhashi Y, et al. Clinical behavior of borderline ovarian tumors: a study of 150 cases. J Surg Oncol 1997;64:147–52.

22

[37] Morris RT, Gershenson DM, Silva EG, Follen M, Morris M, Wharton JT. Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol. 2000;95:541-7. [38] Beiner ME, Gotlieb WH, Davidson B, Kopolovic J, Ben-Baruch G. Infertility treatment after conservative management of borderline ovarian tumors. Cancer 2001;92:320–5. [39] Seracchioli R, Venturoli S, Colombo FM, Govoni F, Missiroli S, Bagnoli A. Fertility and tumor recurrence rate after conservative laparoscopic management of young women with early-stage borderline ovarian tumors. Fertil Steril 2001;76:999–1004. [40] Camatte S, Rouzier R, Boccara-Dekeyser J, Pautier P, Pomel C, Lhomme C, et al. Prognosis and fertility after conservative treatment for ovarian tumors of limited malignity: review of 68 cases. Gynecol Obstet Fertil 2002;30:583–91. [41] Prat J, De Nictolis M. Serous borderline tumors of the ovary: a long-term follow-up study of 137 cases, including 18 with a micropapillary pattern and 20 with microinvasion. Am J Surg Pathol 2002;26:1111–28. [42] Donnez J, Munschke A, Berliere M, Pirard C, Jadoul P, Smets M, et al. Safety of conservative management and fertility outcome in women with borderline tumors of the ovary. Fertil Steril 2003;79:1216–21. [43] Maneo A, Vignali M, Chiari S, Colombo A, Mangioni C, Landoni F. Are borderline tumors of the ovary safely treated by laparoscopy? Gynecol Oncol 2004;94:387–92. [44] Boran N, Cil AP, Tulunay G, Ozturkoglu E, Koc S, Bulbul D, et al. Fertility and recurrence results of conservative surgery for borderline ovarian tumors. Gynecol Oncol 2005;97:845–51. [45] Rao GG, Skinner EN, Gehrig PA, Duska LR, Miller DS, Schorge JO. Fertility-sparing surgery for ovarian low malignant potential tumors. Gynecol Oncol 2005;98:263–6. [46] Langacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up. Am J Surg Pathol 2005;29:707–23. [47] Poncelet C, Fauvet R, Boccara J, Darai E. Recurrence after cystectomy for borderline ovarian tumors: results of a French multicenter study. Ann Surg Oncol 2006;13:565–71. [48] Yokoyama Y, Moriya T, Takano T, Shoji T, Takahashi O, Nakahara K, et al. Clinical outcome and risk factors for recurrence in borderline ovarian tumours. Br J Cancer 2006;94:1586–91.

23

[49] Tinelli FG, Tinelli R, La Grotta F, Tinelli A, Cicinelli E, Schonauer MM. Pregnancy outcome and recurrence after conservative laparoscopic surgery for borderline ovarian tumors. Acta Obstet Gynecol Scand 2007;86:81–7. [50] Wong HF, Low JJH, Chua Y, Busmanis I, Tay EH, Ho TH. Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer 2007;17:342–9. [51] Yinon Y, Beiner ME, Gotlieb WH, Korach Y, Perri T, Ben-Baruch G. Clinical outcome of cystectomy compared with unilateral salpingo-oophorectomy as fertility-sparing treatment of borderline ovarian tumors. Fertil Steril 2007;88:479–84. [52] De Iaco P, Ferrero A, Rosati F, Melpignano M, Biglia N, Rolla M, et al. Behaviour of ovarian tumors of low malignant potential treated with conservative surgery. Eur J Surg Oncol 2009;35:643–8. [53] Kokawa K, Mikami Y, Sakata H, Oki N, Tanakas T, Yamazaki M, et al. Clinical outcome and prognostic factors in borderline tumors of the ovary. Results from 17 years’ experience in the Kinki District of Japan (1990-2006). Eur J Gynaecol Oncol 2009;30:155–61. [54] Anfinan N, Sait K, Ghatage P, Nation J, Chu P. Ten years experience in the management of borderline ovarian tumors at Tom Baker Cancer Centre. Arch Gynecol Obstet 2011;284:731–5. [55] Kanat-Pektas M, Ozat M, Gungor T, Dikici T, Yilmaz B, Mollamahmutoglu L. Fertility outcome after conservative surgery for borderline ovarian tumors: a single center experience. Arch Gynecol Obstet 2011;284:1253–8. [56] Song T, Hun Choi C, Lee Y-Y, Kim T-J, Lee J-W, Bae D-S, et al. Oncologic and reproductive outcomes of cystectomy compared with oophorectomy as a treatment for borderline ovarian tumours. Hum Reprod 2011;26:2008–14. [57] Tsai H-W, Ko C-C, Yeh C-C, Chen Y-J, Twu N-F, Chao K-C, et al. Unilateral salpingooophorectomy as fertility-sparing surgery for borderline ovarian tumors. J Chin Med Assoc 2011;74:250–4. [58] Uzan C, Muller E, Kane A, Rey A, Gouy S, Bendiffallah S, et al. Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary. Ann Oncol 2014;25:166–71. [59] Gungor T, Cetinkaya N, Yalcin H, Ozdal B, Ozgu E, Baser E, et al. Retrospective evaluation of borderline ovarian tumors: single center experience of 183 cases. Arch Gynecol Obstet 2015;291:123–30.

24

[60] Oh S, Kim R, Lee Y-K, Kim JW, Park N-H, Song Y-S. Clinicopathological aspects of patients with recurrence of borderline ovarian tumors. Obstet Gynecol Sci 2015;58:98– 105. [61] Chen R-F, Li J, Zhu T-T, Yu H-L, Lu X. Fertility-sparing surgery for young patients with borderline ovarian tumors (BOTs): single institution experience. J Ovarian Res 2016;9:16. [62] Ureyen I, Karalok A, Tasci T, Turkmen O, Boran N, Tulunay G, et al. The Factors Predicting Recurrence in Patients With Serous Borderline Ovarian Tumor. Int J Gynecol Cancer 2016;26:66–72. [63] Morice P, Camatte S, Rey A, Atallah D, Lhomme C, Pautier P, et al. Prognostic factors for patients with advanced stage serous borderline tumours of the ovary. Ann Oncol 2003;14:592–8. [64] Attar E, Berkman S, Topuz S, Baysal B, Akhan S, Chambers JT. Evolutive peritoneal disease after conservative management and the use of infertility drugs in a patient with stage IIIC borderline micro-papillary serous carcinoma (MPSC) of the ovary: case report. Hum Reprod 2004;19:1472-5. [65] Kane A, Uzan C, Gouy S, Pautier P, Duvillard P, Morice P. Fertility results and outcomes after pure laparoscopic management of advanced-stage serous borderline tumors of the ovary. Fertil Steril 2010;94:2891–4. [66] Gotlieb WH, Flikker S, Davidson B, Korach Y, Kopolovic J, Ben-Baruch G. Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome. Cancer 1998;82:141-66. [67] Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Ovarian stimulation and borderline ovarian tumors: a case-control study. Fertil Steril 1998;70:1049-55. [68] Fauvet R, Poncelet C, Boccara J, Descamps P, Fondrinier E, Daraï E. Fertility after conservative treatment for borderline ovarian tumors: a French multicenter study. Fertil Steril 2005;83:284-90. [69] Somigliana E, Ragni G, Infantino M, Benedetti F, Arnoldi M, Crosignani PG. Does laparoscopic removal of nonendometriotic benign ovarian cysts affect ovarian reserve? Acta Obstet Gynecol Scand 2006;85:74-7. [70] Kwon SK, Kim SH, Yun SC, Kim DY, Chae HD, Kim CH et al. Decline of serum antimüllerian hormone levels after laparoscopic ovarian cystectomy in endometrioma and other benign cysts: a prospective cohort study. Fertil Steril 2014;101:435-41. [71] Bolnick A, Bolnick J, Diamond MP. Postoperative adhesions as a consequence of pelvic surgery. J Minim Invasive Gynecol 2015;22:549-63.

25

[72] Busacca M, Riparini J, Somigliana E, Oggioni G, Izzo S, Vignali M et al. Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynecol 2006;195:421-5. [73] Coccia ME, Rizzello F, Mariani G, Bulletti C, Palagiano A, Scarselli G. Ovarian surgery for bilateral endometriomas influences age at menopause. Hum Reprod 2011;26:3000-7. [74] Practice Committee of the American Society for Reproductive Medicine: Society of Reproductive Surgeons. Pathogenesis, consequences and control of peritoneal adhesions in gynecologic surgery. Fertil Steril 2007;88:21–6. [75] Benaglia L, Candotti G, Busnelli A, Paffoni A, Vercellini P, Somigliana E. Antral follicle count as a predictor of ovarian responsiveness in women with endometriomas or with a history of surgery for endometriomas. Fertil Steril 2015;103:1544-1550.e1-3. [76] Lima ML, Martins WP, Coelho Neto MA, Nastri CO, Ferriani RA, Navarro PA. Assessment of ovarian reserve by antral follicle count in ovaries with endometrioma. Ultrasound Obstet Gynecol 2015;46:239-42. [77] Streuli I, de Ziegler D, Gayet V, Santulli P, Bijaoui G, de Mouzon J et al. In women with endometriosis anti-Müllerian hormone levels are decreased only in those with previous endometrioma surgery. Hum Reprod 2012;27:3294-303. [78] Somigliana E, Marchese MA, Frattaruolo MP, Berlanda N, Fedele L, Vercellini P. Serum anti-mullerianhormone in reproductiveagedwomen with benignovariancysts. Eur J Obstet Gynecol Reprod Biol 2014;180:142-7. [79] Chang HJ, Han SH, Lee JR, Jee BC, Lee BI, Suh CS, Kim SH. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-Mullerian hormone levels. Fertil Steril 2010;94:343–9. [80] Somigliana E, Berlanda N, Benaglia L, Viganò P, Vercellini P, Fedele L. Surgicalexcision of

endometriomas

and

ovarianreserve:

a

systematicreview

on

serumantimüllerianhormonelevelmodifications. Fertil Steril 2012;98:1531-8. [81] De Vos M, Smitz J, Woodruff TK. Fertility preservation in women with cancer. Lancet 2014;384:1302-10. [82] Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771-6. [83] Zhao J, Li Y, Zhang Q, Wang Y. Does ovarian stimulation for IVF increase gynaecological cancer risk? A systematic review and meta-analysis. Reprod Biomed Online 2015;31:20-9.

26

[84] Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M, Mavromatis I et al. Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer--a systematic review and meta-analysis. Hum Reprod Update 2013;19:105-23. [85] Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane Database Syst Rev 2013;8:CD008215. [86] Harris R, Whittemore AS, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:1204-11. [87] Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13-8. [88] Parazzini F, Negri E, La Vecchia C, Moroni S, Polatti A, Chiaffarino F et al. Treatment for fertility and risk of ovarian tumors of borderline malignancy. Gynecol Oncol 1998;68:2268. [89] Cusidó M, Fábregas R, Pere BS, Escayola C, Barri PN. Ovulation induction treatment and risk of borderline ovarian tumors. Gynecol Endocrinol 2007;23:373-6. [90] Sanner K, Conner P, Bergfeldt K, Dickman P, Sundfeldt K, Bergh T et al. Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden. Fertil Steril 2009;91:1152-8. [91] Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;1155:217-24. [92] van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AMG, Lambalk CB, Kortman M et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod 2011;26:3456-65. [93] Yli-Kuha AN, Gissler M, Klemetti R, Luoto R, Hemminki E. Cancer morbidity in a cohort of 9175 Finnish women treated for infertility. Hum Reprod 2012;27:1149-55. [94] Stewart LM, Holman CDJ, Finn JC, Preen DB, Hart R. In vitro fertilization is associated with an increased risk of borderline ovarian tumours. Gynecol Oncol 2013;129:372-6. [95] Bjørnholt SM, Kjaer SK, Nielsen TSS, Jensen A. Risk for borderline ovarian tumours after exposure to fertility drugs: results of a population-based cohort study. Hum Reprod 2015;30:222-31. [96] Grimes DA. Epidemiologic research with administrative databases: red herrings, false alarms and pseudo-epidemics. Hum Reprod 2015;30:1749-52.

27

[97] Evers JL, Sharpe RM, Somigliana E, Williams AC. The war on error. Hum Reprod 2015;30:1747-8. [98] Vercellini P, Crosignani P, Somigliana E, Viganò P, Buggio L, Bolis G, et al. The 'incessant menstruation' hypothesis: a mechanistic ovarian cancer model with implications for prevention. Hum Reprod 2011;26:2262-73. [99] Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–330. [100] Brinton LA, Moghissi KS, Scoccia B, Westhoff CL, Lamb EJ. Ovulation induction and cancer risk. Fertil Steril 2005;83:261-74. [101] Abu-Jawdeh GM, Jacobs TW, Niloff J, Cannistra SA. Estrogen receptor expression is a common feature of ovarian borderline tumors. Gynecol Oncol 1996;60:301-7. [102] Høgdall EVS, Christensen L, Høgdall CK, Blaakaer J, Gayther S, Jacobs IJ et al. Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: from the 'MALOVA' ovarian cancer study. Oncol Rep 2007;18:1051-9. [103] Escobar J, Klimowicz AC, Dean M, Chu P, Nation JG, Nelson GS et al. Quantification of ER/PR expression in ovarian low-grade serous carcinoma. Gynecol Oncol 2013;128:371-6. [104] Sallum LF, Sarian LO, Lucci De Angelo Andrade L, Vassallo J, Soares FA et al. Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status. J Gynecol Oncol 2013;24:167-76. [105] Tourgeman DE, Lu JJ, Boostanfar R, Amezcua C, Felix JC, Paulson RJ. Human chorionic gonadotropin suppresses ovarian epithelial neoplastic cell proliferation in vitro. Fertil Steril 2002;78:1096-9. [106] Basille C, Olivennes F, Le Calvez J, Beron-Gaillard N, Meduri G, Lhommé C et al. Impact of gonadotrophins and steroid hormones on tumour cells derived from borderline ovarian tumours. Hum Reprod 2006;21:3241-5. [107] Timmerman D, Ameye L, Fischerova D, Epstein E, Melis GB, Guerriero S et al. Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group. BMJ 2010;341:c6839. [108] Van Calster B, Timmerman D, Valentin L, McIndoe A, Ghaem-Maghami S, Testa AC, et al. Triaging women with ovarian masses for surgery: observational diagnostic study to compare RCOG guidelines with an International Ovarian Tumour Analysis (IOTA) group protocol. BJOG 2012;119:662-71.

28

[109] Sayasneh A, Wynants L, Preisler J, Kaijser J, Johnson S, Stalder C et al. Multicentre external validation of IOTA prediction models and RMI by operators with varied training. Br J Cancer 2013;108:2448-54. [110] Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006;91:3885–90. [111] Reddy J, Oktay K. Ovarian stimulation and fertility preservation with the use of aromatase inhibitors in women with breast cancer. Fertil Steril 2012;98:1363-9. [112] Schattman GL.CLINICAL PRACTICE. Cryopreservation of Oocytes. N Engl J Med 2015;373:1755-60. [113] Fortin A, Morice P, Thoury A, Camatte S, Dhainaut C, Madelenat P. Impact of infertility drugs after treatment of borderline ovarian tumors: results of a retrospective multicenterstudy. Fertil Steril 2007;87:591-6. [114] Franchi D, Boveri S, Fruscio R, Fischerova D, Guerriero S, Moruzzi MC et al. Imaging in gynecological disease(8): ultrasound characteristics of recurrent borderline ovarian tumors. Ultrasound Obstet Gynecol 2013;41:452-8. [115] Donnez J, Dolmans MM, Pellicer A, Diaz-Garcia C, Sanchez Serrano M, Schmidt KT et al. Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertil Steril 2013;99:1503-13. [116] Donnez J, Dolmans MM, Pellicer A, Diaz-Garcia C, Ernst E, Macklon KT et al. Fertility preservation for age-related fertility decline. Lancet 2015;385:506-7. [117] Bastings L, Beerendonk CCM, Westphal JR, Massuger LFAG, Kaal SEJ, van Leeuwen FE et al. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review. Hum Reprod Update 2013;19:483-506. [118] Fain-Kahn V, Poirot C, Uzan C, Prades M, Gouy S, Genestie C et al. Feasibility of ovarian cryopreservation in borderline ovarian tumours. Hum Reprod 2009;24:850-5. [119] Huang JY, Buckett WM, Gilbert L, Tan SL, Chian RC. Retrieval of immature oocytes followed by in vitro maturation and vitrification: a case report on a new strategy of fertility preservation in women with borderline ovarian malignancy. Gynecol Oncol 2007;105:5424. [120] Prasath EB, Chan ML, Wong WH, Lim CJ, Tharmalingam MD, Hendricks M et al. First pregnancy and live birth resulting from cryopreserved embryos obtained from in vitro matured oocytes after oophorectomy in an ovarian cancer patient. Hum Reprod 2014;29:276–8.

29

[121] Uzelac PS, Delaney AA, Christensen GL, Bohler HC, Nakajima ST. Live birth following in vitro maturation of oocytes retrieved from extracorporeal ovarian tissue aspiration and embryo cryopreservation for 5 years. Fertil Steril 2015;104:1258-60.

30

Figure 1 Title The flow-chart of fertility preservation in young women affected by borderline ovarian tumour (BOT). Caption The figure shows when the oncofertility counselling should be performed during treatment and the existing modalities to preserve fertility in patients with BOT. Legend BOT: borderline ovarian tumours, COH: controlled ovarian hyper-stimulation, IVM: in vitro maturation.

31

Table 1a. Oncological outcome of early-stage BOT after fertility-sparing surgery. Authors

N° Patients

Rice et al., 1990 [33]

32

Histology: Serous (n°), Mucinous (n°) S (15), M (18)

Stage (n°)

Surgical procedure (n°)

Recurrence (n°)

> 90% I

NS

0

Invasive recurrenc e (n°) //

//

Interval to recurrence (months) //

//

//

//

4

0

1

Mean 16 (range 7- 35)

USO (48), OC (4)

0

//

//

//

I (15) Unstaged (25)

USO (35), OC (8)

2 10

0 0

0 1

S (28), M (15)

I (39)

USO (30), OC (12)

6

0

0

Median 39 (range 3-147) Mean 35 (range 9-89)

Mean 49 Median 42.4 (range 1.6-108) Mean 88 (range 9-256) Mean 61 (range 2-140) Median 68 (range 17-300) Mean 75 (range 25-93)

Barnhill et al., 1995 [34]

28

S (28)

I (28)

USO (21), OC (7)

0

Ji et al., 1996 [35]

25

S (8), M (16)

I (25)

USO (15), OC (3), USO+CC (7)

Tamakoshi et al., 1997 [36] #

48

NS

I (48)

Morris et al., 2000 [37] #

40

S (26), M (17)

Beiner et al., 2001 [38] #

39

Morice et al., 2001 [11]

44

NS

I (32), II-III (12)

USO (38), OC (5), USO+CC (5), BC(1)

9

0

0

Mean 38 (range 1-243)

Mean 109 (range 24-300)

Seracchioli et al., 2001 [39]

19

0

0

164

I (19) IA (95), IB (14), I C (55)

1

Zanetta et al., 2001 [28]

S (16), M (3) S (88), M (55), other (1)

24

5

1

6 Median 34 (range 14-141)

Mean 42 Median 71 (range 27-221)

Camatte et al., 2002 [40] #

50

S (46), M (16), others (6)

I (50)

7

0

0

Mean 19 (range 5-240)

Median 71.5

21

NS

I (21)

NS

2

0

0

NS

Mean 84 (range 24-216)

Donnez et al., 2003 [42]

14

NS

I (14), II (2)

NS

3*

0

0

Mean 18 (range 12-30)

Mean 43.4 (range 9-141)

Maneo et al., 2004 [43]

62

S (18), M (42), others (2)

I (62)

USO (28), OC (34)

17

0

0

NS

Median 61

Boran et al., 2005 [44]

62

S (27), M (33), others (2)

I (30), IIIA (1), unstaged (31)

USO (42),OC (13), USO+CC (5), BC (2)

4*

0

0

Mean 42

Mean 44 (range 3 – 128)

Prat and De Nictolis 2002 [41]

#

USO (8), OC (11) USO (102), OC (62) US0 (47), OC (2), USO+CC (17),BC (7)

Deaths (n°)

Follow-up (months)

Rao et al., 2005 [45] #

34

S (21), M (16), other (1)

I (34)

USO (27), OC (5), USO+CC (6)

5

0

0

Langacre et al., 2005 [46] #

53

NS

I (53)

NS

9

2

0

Poncelet et al., 2006 [47]

133

S (63), M (60), others (10)

I (133)

USO (100), OC (33)

21

0

0

Mean 28

Mean 39

Suh-Burgmann 2006 [24]

193

S (109), M (81), others (3)

I (189), II-III (5)

USO (143), OC (47)

23

2

1

Mean 4.7 years

Mean 6.9 years (range 6 to 19.2 years)

Yokoyama et al., 2006 [48]

53

NS

> 90% I

NS

6

1

0

Tinelli et al., 2007 [49]

43

S (36), M (7)

0

0

116

NS

USO (31), OC (6), USO+CC (6) USO (78), OC (38)

3

Wong et al., 2007 [50]

IA (37), IB (5), IC (1) > 90% I

4

2

1

Yinon et al., 2007 [51]

62

S (38), M (24)

> 90% I

USO (40), OC (22)

16*

1

0

De Iaco et al., 2009 [52] #

74

S (54), M 22

I (74)

19

0

0

Park et al., 2009 [31] #

181

S (43), M 139), others (2)

I A (153), IB (10), IC (18)

USO (43), OC (31) USO (128), OC (12), USO+CC (40), BC (4)

8

1

1

Kokawa et al., 2009 [53] #

84

NS

I (84)

USO (52), OC (34)

1

0

1

Palomba et al., 2010 [26]

32

S (29), M (3)

I (32, bilateral)

20

0

0

Anfinan et al., 2011 [54]

43

NS

> 90% I

6

0

0

S (29), M (24), other (1)

0

//

0

52

unstaged (24)

USO+CC (17), BC (15) USO (38), OC (2), USO+CC (3) USO (36), OC (12), USO+CC (5), BC (2)

2

0

Koskas et al., 2011 [17]

69

M (69)

> 90% I

USO (49), OC (20)

6*

Song et al., 2011 [56] #

150

S (37), M (106), others (12)

I (150)

USO (112), OC (38)

Tsai et al., 2011 [57]

31

NS

> 90% I

Uzan et al., 2014 [58]

119

S (119)

IA (70), IB

Kanat-Pektas et al., 2011 [55]

#

I (28)

Mean 66 (range 11-122) Mean 90 (range 24–480)

Mean 44 (range 14-107) Mean 39 (range 32-60) Mean 82 Mean 36 (range 7-81) NS Mean 45 (range 10-82)

Mean 26 > 5 years

Median 57 Mean 57

Mean 21 Mean 83 (6-180) Mean 61 Mean 70 (range 3-216)

Mean 9.5 (range 3-16) Mean 32 (range 3-72)

Mean 128 (range 115-150)

NS

Median 37

0

Mean 23 (range 18-30 )

Mean 61.0 (range 22–120)

4

3

NS

Median 59 (range 12-182)

11

1

0

Median 40

Median 56 (range 26-83)

USO (24), OC (7)

7

2

0

USO (50),

38**

2

1

Median 25 (range 10-56) NS

Mean 56.5 (range 12-103) Median 45 (range

Mean 39

(18), IC (22)

USO+CC (15), OC (43), BC (11) USO (38), USO+CC (30), OC (15), BC (6)

12-120)

4

NS

NS

Mean 22 (range 18-30)

NS

USO (51), OC (19)

8

5

4

Mean 29 (range 1-79)

Mean 66 (range 1- 241)

I (111)

USO (47), OC (75)

7

1

0

Mean 26

NS

> 90% I

USO (48), OC (12), USO+CC (7), BC (4)

8

1

0

Median 47 (range 23-173)

Median 57 (range 3-270)

321

30

15

Gungor et al., 2015 [59]

89

NS

> 90% I

Oh et al., 2015 [60]

70

NS

> 90% I

Chen et al., 2016 [61] #

111

S(64), M (51), others (7)

Ureyen et al., 2016 [62]

72

S (72)

Total

2612

%

12%

BOT borderline ovarian tumor; S serous, M mucinous; NS not stated; USO unilateral salpingo-oophorectomy, OC ovarian cystectomy, CC contralateral cystectomy, BC bilateral cystectomy; * one patient developed two recurrences; ** 11 patients had 2 recurrence and 4 patients had > 2 recurrence; # patients with BOT at II-III stage were excluded

Table 1b. Oncological outcome of advanced-stage BOT after fertility-sparing surgery.

Authors

Tamakoshi et al., 1997 [36] Morris et al., 2000 [37] Beiner et al., 2001 [38] Zanetta et al., 2001 [28] Camatte et al., 2002 [40] Prat and De Nictolis [41] Morice et al., 2003 [63] Attar et al., 2004 [64] Rao et al., 2005 [45] Langacre et al., 2005 [46] De Iaco et al., 2009 [52] Park et al., 2009 [31] Kokawa et al., 2009 [53] Kane et al., 2010 [65] Uzan et al., 2010 [29] Viganò et al., 2010 [30] Kanat-Pektas et al., 2011[55] Song et al., 2011 [56] Helpman et al., 2015 [27] Chen et al., 2016 [61] Total %

Patie nts (n°) 4 3 4 25 18 10 15 1 4 21 11 3 2 13 41 10 3 5 33 11 237

Stage (n°)

II, III (4) III (3) II-III (4) II-III (25) II-III (18) II-III (10) II-III IIIC II-III (4) II-III (21) II-III (11) II-III (3) II-III (2) II-III (13) II-III (41) II-III (10) II-III (3) II-III (5) IC (17), II-III (16) II-III (11)

Presence of implants

NS NS NS 15 NI, 7 I, 2 unknown 15 NI, 3I 9 NI, 1 I 12 NI, 3 I NS NS NS 10 unknown 2 NI 1I NS 35 NI, 3 I, 1 unknown 10 NI NS 3NI, 2 I 1I NS

Recurrence (n°)

Invasive recurrence (n°)

Deaths (n°)

Interval to recurrence (months)

4 2 3 10 10 3 8 1 1 5 3 1 1 7 22 6 1 1 17* 1 90 45%

0 0 0 1 0 1 0 1 0 0 0 0 0 2 3 0 0 0 NS NS 8

2 0 0 0 0 1 0 0 0 0 0 0 1 1 1 0 0 0 3 0 9

NS Median 39 (range 3-147) Mean 35 (range 9-89) NS Mean 19 (range 5-240) NS Median 23 (range 5-84) 18 5 Mean 24.6 (range 11–36) NS Mean 45 (range 10-82) Mean 9.5 (range 3-16) Mean 29 (range 11-53) Mean 48 (range 4-115) Mean 96 (6-240) Mean 23 (range 18-30 ) 47 NS Mean 26

BOT borderline ovarian tumor; NS not stated; I invasive, NI non-invasive * half patients developed more than one recurrences

Table 2. Epidemiological studies on the relation between infertility drugs and BOT.

Reference

Study design

Population

Drug studied (n° case patients/n° control patients)

Association measurement

Result (95%CI)

Shushan et al., 1996 [87]

Casecontrol

200 women with ovarian cancer (164 IOC and 36 BOT) versus 408 controls

Any treatment (10/29)

OR

3.52 (1.23-10.09)

CC

OR

1.28 (0.25-6.87)

hMG

OR

9.38 (1.66-52.08)

CC and/or hMG

OR

3.08 (0.98-9.69)

Any treatment (17/58)

OR

Nulliparous 1.5 (0.51-4.39); Parous 1.46 (0.56-3.81)

CC

OR

Nulliparous 0.8 (0.19-3.38); Parous 1.93 (0.56-6.59)

CC and hCG

OR

Nulliparous 3.01 (0.73-12.33); Parous 1.54 (0.30-7.81)

hMG and hCG

OR

Nulliparous 0.91 (0.14-6.13); Parous 1.43 (0.28-7.19)

Mosgarrd et al., 1998 [67]

Casecontrol

231 women with BOT versus 1721 controls

Parazzini et al., 1998 [88]

Casecontrol

93 women with BOT versus 273 controls

NS

Fisher´s exact test

4 BOT cases (4.3%) and no controls reported fertility drug use (p= 0.004)

Cusido et al., 2007 [89]

Casecontrol

42 women with BOT versus 257 controls

Any treatment(5/34)

X2 or Fisher's exact test

Non significant

Gonadotrophins (3/26)

X2 or Fisher´s exact test X2 or Fisher´s exact test

Any treatment

SIR

CC (4/16)

Sanner et al., 2009 [90]

Cohort

Infertile women (n° 2768) → BOT (n° 12 including 7 women who had IVF and 5 women who did not)

Non significant

Adjusted for

Correlation between BOT and fertility drugs

Age, parity, BMI, region of birth, education, family history, and interviewer

Yes (+ hMG)

Age, residence, use of oral contraceptives, smoking

No

Yes

No

Non significant

3.61 (1.45-7.44) Yes (+CC)

CC Gonadotrophins

SIR SIR

4.59 (0.95-13.42) 1.88 (0.05-10.45)

van Leeuwen et al., 2011 [92] Yli-Kuha et al., 2012 [93] Stewart et al., 2013 [94] Bjornholt et al., 2015 [95]

Casecohort Casecohort Casecohort Casecohort

IVF group (n°19146) → Key messages BOT*(n° 27); non-IVF group (n°6006) → BOT* (n° 4) IVF group (n°9175)→BOT* (n°4); non-IVF group (n°9175) →BOT*(n°3) IVF group (n°7544) →BOT (n°17); non-IVF group (n°14095) → BOT (n°14) Infertile women (n°96545) →n° 142 BOT versus subcohort (n°1328)

CC and gonadotrophins

SIR

3.99 (0.82-11.67)

NS

HR

Explanation 4.23 (1.25-14.33)

NS

OR

2.25 (0.59-8.68)

NS

HR

2.46 (1.20-5.04)

Any treatment

RR

1.00 (0.67-1.15)

Gonadotrophins CC

RR RR

1.32 (0.81-2.14) 0.96 (0.64-1.44)

hCG

RR

0.91 (0.61-1.36)

GnRH analogues

RR

1.10 (0.66-1.81)

Progesterone

RR

1.82 (1.03-3.24)

Age at end of follow-up, tubal problems, parity

Yes

No Age, calendar period, socio-economic status

Yes

Parity

No

BOT borderline ovarian tumor; hCG human chorionic gonadotrophins; hMG human menopausal gonadotrophins; IOC invasive ovarian cancer; CC Clomiphene citrate; RR rate ratio; OD odd ratio; HR hazard ratios; SIR Standardized incidence ratio; NS not stated; *escluding BOT diagnosed during the first year after inclusion

Table 3. Key points for the conservative management of BOT

Pre-surgical fertility counselling

Comprehensive evaluation of the future probability of childbirth aimed at determining the validity of a conservative approach.

Avoid egg freezing prior to surgery

It delays surgery, it can cause iatrogenic spillage, it can stimulate tumour growth, it can complicate the intervention and may increase surgically-related damage to ovarian reserve.

Do not perform hysterectomy

The procedure adds risks without benefits. Moreover, egg donation is possible. Even women denying this option may change their opinion in the future.

Avoid diagnostic biopsy of the contralateral intact gonad

The procedure adds risks (adhesions, damage to the ovarian reserve) without benefits.

Do not perform ovarian cortex biopsy and freezing

It may damage ovarian reserve, the probability of requiring its use is low and there is the risk of re-seeding.

Oocytes retrieval and IVM for ovarian specimens

When the ovary is removed, aspiration of antral follicles from the obtained specimen can be considered. Albeit presumably poorly effective, live births have been reported and the procedure does not expose to risks.

Post-surgical counselling

Discuss pros and cons of natural conception and oocytes cryo-preservation. Wait 6 months prior to prescribe tests for estimate the residual ovarian reserve.

Do not delay pregnancy seeking

BOT have a high rate of recurrence but recurrence can be late and does not significantly affect survival. Pregnancy should be considered if possible without delays.

Consider oocytes cryopreservation after surgery

Data on a relation between ovarian hyper-stimulation and BOT are still inconclusive and do not justify restraining from egg banking. The woman should be informed on this possibility but concomitantly also reassured.

Letrozole for ovarian hyperstimulation

Some evidence suggests a potential detrimental effect of ovarian hyperstimulation on tumour growth. Letrozole, by reducing peripheral levels of sex steroids, may temper this theoretical risk without hampering its success.

BOT borderline ovarian tumor; IVM in vitro maturation.

Highlights • Fertility counselling should become fundamental in the conservative management of BOT. • Conservative surgery is the first step towards fertility preservation in patients with BOT. • The evidence on relation between infertility treatment and BOT is scanty. • Oocyte freezing should be considered after conservative surgery to preserve fertility.

33