Fertility preservation strategies in borderline ovarian tumor recurrences: different sides of the same coin

Borderline ovarian tumors (BOT) account for 10–20% of all ovarian epithelial tumors, with one-third of cases diagnosed under the age of 40 [1]. Fertility-sparing surgery (FSS) can be offered to patients who wish to spare their reproductive potential, even if the overall risk of recurrence after FSS is higher (0–25%) than after bilateral salpingo-oophorectomy (0–5%) [2, 3]. The management of patients who recur after FSS is challenging. Although a second FSS can be offered [4, 5], repeated surgery may reduce healthy ovarian parenchyma, increasing the risk of infertility [6]. Moreover, the occurrence of postoperative adhesions might interfere with fallopian tube function [7]. Thus, for a patient undergoing FSS and interested in having a pregnancy, the best option is to achieve pregnancy through spontaneous conception immediately after first surgery, acknowledging the higher recurrence rate during the first 2 years [8–10] and that pregnancy does not increase this risk [11–14]. In situations involving a personal history of infertility or when reproduction is not desired by patients yet, the most appropriate plan B is to rely on assisted reproductive techniques (ARTs), with oocyte harvesting and cryopreservation after FSS [15].

In this issue of Journal of Assisted Reproduction and Genetics, Filippi and colleagues report their experience in harvesting and cryopreserving oocytes before surgery as a novel strategy of fertility preservation for patients who had an ovarian relapse after FSS [16]. They describe two successful cases that underwent gonadotrophin administration with concomitant letrozole, apparently without an increase in tumor volume and conclude that “oocyte cryopreservation at the time of recurrence of BOT is feasible and may be considered in the decision-making process with the patients.”

Authors should be commended for exploring different options of fertility preservation in this challenging setting but several critical questions should be answered:

1. Is oocyte cryopreservation before surgery safe?

2. Is oocyte cryopreservation really feasible when the ovary harbors a BOT relapse?

3. Is fertility preservation always necessary?

Firstly, ovarian stimulation and subsequent oocyte pick-up are contraindicated in the presence of an invasive tumor given the potential risk of spillage of neoplastic cells and upstaging [15]. Even if we acknowledge that most BOT recurrences mimic the morphological features of the primary tumor [2, 17], invasive recurrences cannot be ruled out by transvaginal ultrasound (TVUS) in 100% of cases [17]. This holds true also when patients are followed in high volume centers with dedicated sonographers [2, 17] and with diagnostic accuracy probably lower in primary care centers. Thus, the need of centralized patient care is of utmost importance, as the authors underline too.

Among the two cases reported by Filippi et al., one patient had a recurrence after a primary diagnosis of seromucinous BOT with an area of invasive adenocarcinoma [16]. The only known prognostic factors for progression to invasive ovarian cancer after BOTs are residual disease after upfront surgery and the presence of invasive implants; micropapillary pattern/stromal micro-invasion and intra-epithelial carcinoma remain controversial factors for serous and mucinous BOTs, respectively [18]. In these high-risk cases, ovarian stimulation with the tumor onsite should probably be avoided. On the other hand, in vitro studies have not shown a proliferative effect of FSH or estradiol on primary cultures of BOT [19, 20]. The concomitant use of letrozole to reduce estrogen levels during controlled ovarian hyperstimulation (COH) is a potentially useful strategy, but strong evidence about its efficacy in this setting is lacking [15].

Secondly, not all women are good candidates for oocyte harvesting before surgery. An expert sonographer should describe the localization and size of the lesion within the ovary, the amount of healthy residual parenchyma, and the possible presence of extraovarian masses. Pelvic magnetic resonance (MRI) might be useful to exactly localize the tumor in some cases [3]. If TVUS or MRI shows a mass in the Pouch of Douglas or a BOT relapse involving almost completely the ovary, oocyte pick-up could not be performed without transfixing the lesions and the procedure should not be performed. Another critical issue could be the presence of abdomino-pelvic adhesions which can distort the pelvic anatomy and increase the complication rate. Hence, ovarian stimulation and oocyte pick-up after BOT relapse are not always feasible and easy, again calling for a centralization of these procedures.

Thirdly, should we perform fertility preservation even if there is no fertility to preserve or when the risk of losing the reproductive potential after surgery is low? The decision should be tailored on a case-by-case basis, carefully considering the estimated ovarian reserve at relapse. Furthermore, ovarian reserve should be contextualized in two different settings: spontaneous conception and/or ART. Noteworthy, anti-Müllerian hormone level is an acceptable marker of ovarian reserve and ovarian response in ARTs, but it does not appear to be a preconception marker of ovarian competence and fecundability in spontaneous conception [21, 22]. It is understood that in cases of unilateral salpingo-oophorectomy (USO), the ovarian reserve is reduced. Data demonstrate that women undergoing COH after USO have a lower number of developing follicles and retrieved oocytes than controls [23]. Nonetheless, two high-quality studies have shown that age at menopause after USO is reduced by 1.2–1.4 years only [24, 25], suggesting compensatory mechanisms in the residual ovary [26] and confirming the clinical observation that young patients after FSS may have fertility and pregnancy rates that are not significantly different from their peers harboring both ovaries [27, 28]. As demonstrated in numerous reports, young age remains the most robust factor of post-treatment fertility and pregnancy in these patients [29].

In conclusion, the management of fertility issues in patients diagnosed with BOT recurrence after FSS is still controversial; decisions should be individualized considering safety, feasibility, and appropriateness of each procedure. Available options should be discussed with the patient by a multidisciplinary team including the gynecologic oncologist and an expert in reproductive medicine, possibly in a referral center with high patient volumes. Well-designed prospective studies are needed to address the specific fertility issues of patients with BOT at diagnosis and at relapse.