1. Introduction
Ovarian cancer is a highly common malignancy [
1] and has the highest mortality rate among all cancers of the female genital tract [
2]. Most cases of ovarian cancer are of epithelial ovarian cancer (EOC), and over 70% of EOC diagnoses are made at an advanced stage [
3]. Approximately 15% of all patients with EOC present with localized early-stage cancer; in these patients, the cure rate after optimal treatment is 90% [
3]. Despite the predominance of EOC in older women, particularly postmenopausal women, approximately 10–13% of all EOC cases are diagnosed in women aged <40 years [
4,
5]. Borderline ovarian tumors (BOTs), a distinct condition from EOC, are characterized by epithelial proliferation and nuclear atypia without invasive stromal destruction [
6,
7]. Furthermore, BOTs typically occur in younger women and are often diagnosed at earlier stages. Approximately 75–80% of all BOT cases are detected in their early stage, with one-third of these cases occurring in women aged <40 years [
8]. The prognosis for BOTs is considerably more favorable than that for EOC with a 5-year overall survival (OS) rate of >90% [
9].
Many women in industrialized countries choose to delay childbirth, to their 30s and even 40s, as more participate in the workforce and pursue higher education [
10,
11]. Therefore, preserving the fertility of young patients with EOC or BOTs while ensuring optimal oncological outcomes through fertility-sparing surgery (FSS) is a crucial topic that warrants further investigation.
The guidelines of the European Society of Medical Oncology recommend comprehensive FSS (cFSS) for young patients with any stage IA histology or stage IC1/IC2 with favorable histology (i.e., low-grade tumors) [
12]. The recent National Comprehensive Cancer Network guidelines recommend FSS for patients who wish to preserve their fertility despite having apparent early-stage disease, low-risk tumors such as early-stage invasive epithelial tumors and low malignant potential tumors (ovarian borderline epithelial tumors), or a combination of both. For patients with stage IA or IB EOC who wish to preserve their fertility, a suitable treatment option may involve comprehensive surgical staging along with unilateral salpingo-oophorectomy (USO) for stage IA EOC or bilateral salpingo-oophorectomy (BSO) for stage IB EOC. For patients with BOTs who wish to sustain their fertility, either USO or BSO combined with residual disease resection may be considered.
This study evaluated several treatment outcomes, namely preserved fertility, menstrual regularity, and pregnancy outcomes, in patients undergoing FSS for EOC or BOT.
2. Methods
This retrospective study was conducted at a single tertiary hospital in Taiwan between January 2007 and September 2022. The study protocol was approved by the Research Ethics Committee of National Taiwan University Hospital before the initiation of data collection. The medical records of patients who underwent FSS at our hospital for EOC or BOTs were retrospectively reviewed. Patients were eligible for inclusion in this study if they (1) were aged between 18 and 45 years at the time of initial diagnosis and expressed a desire to preserve their fertility while having a comprehensive understanding of the risks and benefits of FSS, (2) were pathologically confirmed to have stage I disease (BOT or EOC), and (3) underwent initial FSS and regular follow-up and received adjuvant chemotherapy at our hospital. Patients were excluded if they (1) had nonepithelial histology (i.e., sex cord–stromal tumor and germ cell tumor), (2) had incomplete medical records, and (3) did not undergo regular follow-up.
All included patients had undergone either simple FSS (sFSS) or comprehensive FSS (cFSS). FSS is defined as any surgical procedure that preserves the uterus and at least one ovary; under this definition, FSS is still defined as such regardless of whether it is conducted for unilateral or bilateral disease. This can be accomplished by performing salpingo-oophorectomy or unilateral oophorocystectomy while preserving at least one ovary and the uterus.
sFSS refers to FSS performed without any additional surgical staging procedure. By contrast, cFSS includes not only FSS but also surgical staging procedures, such as peritoneal evaluation (peritoneal washing cytology, omentectomy/omental biopsy, and peritoneal biopsy if necessary) and lymph node evaluation, if deemed necessary. Lymph node evaluation involves the dissection or sampling of lymph nodes or the identification and removal of enlarged lymph nodes through palpation.
In this study, pathologic reviews were conducted by an gynecologic pathologist. Tumor stage was determined using the International Federation of Gynecology and Obstetrics (FIGO) classification framework. Patients with EOC included in this study may have had three to six postoperative cycles of platinum-based adjuvant chemotherapy based on their risk factor profiles.
Follow-up assessments comprised physical examinations, ultrasonography, and serum cancer antigen (CA)-125 level measurements. These assessments were conducted every 1–3 months during the first 2 years following primary treatment, every 3–6 months during the subsequent 3 years, and then annually thereafter. In patients with suspected disease recurrence, computed tomography or magnetic resonance imaging was performed to detect potential local recurrence, pelvic lymphadenopathy, or distant metastasis. The total follow-up duration was recorded for each patient.
The following patient characteristics were analyzed: age, body mass index, preoperative serum CA-125 level, tumor histological type, tumor size, FSS comprehensiveness, FIGO stage, adjuvant chemotherapy history, obstetric and gynecological history, underlying medical conditions, marital status, menstrual regularity, development of persistent amenorrhea (defined as secondary amenorrhea lasting for a minimum of 6 months after primary treatment), numbers of pregnancies and deliveries after FSS, type of conception (namely, natural conception or assisted reproductive technology (ART)-assisted conception), and adverse pregnancy events (e.g., preterm delivery). In addition, data regarding the interval between primary treatment and recurrence, recurrence site, management strategies for recurrence, pathologic findings pertaining to recurrent lesions, and mortality were analyzed.
Statistical Analysis
Statistical analyses were performed using SAS (SAS software for Windows version 9.4, SAS Institute, Cary, NC, USA). Demographic data were summarized using descriptive statistics. Pearson’s chi-square tests and Fisher’s exact tests were performed to identify significant differences between various subgroups in terms of disease recurrence and menstrual irregularity due to disease. A p value of <0.05 indicated statistical significance.
4. Discussion
A previous study reported that the rate of first childbirth among women aged >35 years increased by 23% between 2000 and 2014 [
13]. Because delayed childbirth has become a global trend [
10,
11], FSS should be considered for patients with early-stage EOC or BOTs who wish to preserve their fertility. Thus, the safety of FSS as a treatment for early-stage EOC and BOTs is a crucial topic.
Kajiyama et al. reported no significant difference in OS or recurrence-free survival between patients with early-stage EOC undergoing FSS and those undergoing radical surgery [
14]. Watanabe et al. indicated that FSS is an acceptable treatment option for stage IA and IC1 EOC, highlighting the favorable reproductive outcomes associated with this treatment [
15]. A meta-analysis revealed no difference in OS or recurrence-free survival between patients with stage I EOC who underwent FSS and those who underwent radical surgery [
16]. In a multi-institutional study, laparoscopic FSS was proposed as a viable option for stage I EOC [
17]. In their study involving patients with stage IC2/IC3 EOC, Nasioudis et al. concluded that FSS was not associated with poor OS [
18]. In our study, only one patient experienced disease recurrence, which occurred after 21 months of regular follow-up. No significant correlation was noted between recurrence and the patient characteristics analyzed in the present study. Although our EOC study group had a similar patient composition in terms of stage IC group percentage (54.5% vs. 57.5%), histology distribution, and adjuvant chemotherapy percentage (60.6% vs. 63.4%), the rate of tumor recurrence (3% vs. 14.7%) in our EOC study group was lower than that reported in a previous study by Kajiyama et al. [
14]. This difference in recurrence rates may be attributed to our relatively small sample size.
FSS is currently a widely accepted strategy for the treatment of patients with BOTs who wish to preserve their fertility. This procedure is typically performed for early-stage BOTs. However, the feasibility of FSS in advanced BOTs remains a topic of debate. An analysis of data retrieved from a Danish national database revealed a 5-year DFS rate of 97.6% for patients with stage I BOTs who underwent FSS; this rate is similar to the 5-year DFS rate for patients with BOTs who underwent conventional surgery [
19]. One study indicated FSS to be a feasible option even for patients with advanced BOTs, reporting that FSS was not associated with an increased risk of relapse in young patients [
20]. Lu et al. also reported findings supporting the efficacy of FSS in terms of fertility outcomes and overall prognosis in advanced BOTs [
21]. However, whether minimal invasive surgery should be used in FSS remains controversial. In a study conducted in France, laparoscopic FSS for BOTs was found to be associated with an elevated cyst rupture risk, incomplete staging, and an increased recurrence rate [
22]. However, Kasaven et al. determined no significant difference in the recurrence rate among the types or routes of FSS [
23].
The rate of recurrence in our BOT cohort was 11.27% (8/71), which is similar to those reported in prior studies [
19,
23]. Recurrence in our BOT group was significantly associated with disease stage (
p = 0.0354), histology type (
p = 0.0179), and preoperative CA-125 level (
p = 0.0238) but not FSS comprehensiveness and the inclusion of cystectomy. In our study, two of the five patients with bilateral BOTs experienced recurrence; both patients presented with IC disease and underwent cFSS as primary treatment. A study focusing on bilateral disease revealed no difference in OS between patients undergoing FSS and those undergoing radical surgery, although the FSS group exhibited poorer DFS than did the radical surgery group; the study also reported similar recurrence and DFS rates between patients undergoing bilateral ovarian cystectomy and those undergoing USO with contralateral cystectomy in the FSS group [
24].
Because recurrence may occur in patients with BOTs while they are still young and wishing to conceive someday, a second FSS may be performed after thorough consultation. Wang et al. confirmed that a second FSS was as safe as radical surgery for recurrent BOTs with a pregnancy rate of 46.9% and a live birth rate of 81.3% [
25]. In our study group, 8 of 71 patients with BOTs experienced tumor recurrence. Of these, two received radical surgery: one as a result of choice and the other due to malignant transformation. Among the six patients who received a second FSS, four achieved six pregnancies, including four live births and two spontaneous abortions after the surgery.
Five (15.1%) of our patients with EOC experienced amenorrhea before 45 years of age after primary treatment, which is a higher rate compared with that reported in the study by Satoh et al., where only a 5% (6/121) persistent secondary amenorrhea rate in their EOC group was reported [
26]. Because we did not have data on antral follicle counts or anti-Mullerian hormone levels to evaluate the difference in baseline ovarian reserve, a younger median age in their patient group (29 vs. 34) may explain the difference in amenorrhea rates.
Because the act of conception is affected by not only biological determinants but also social and emotional ones, patients undergoing FSS may not necessarily desire to conceive. Studies have indicated that only 16–65.4% of all patients with early-stage EOC who underwent FSS reported active attempts to conceive [
27,
28], which may be explained by their fear of disease recurrence [
29] and marital status [
30]. Chen et al. observed the most common reasons for patients who did not attempt conception after FSS were either being unmarried (70%) or already having children (15%) [
31]. A review study reported that among patients with EOC who underwent FSS and actively attempted to conceive, the rate of pregnancy was 79% (242/307) and that of live births was 76–96% [
32]. In our study, 42.4% of the patients with EOC (14/33) were married, and 85.7% of these married patients (12/14) had at least one post-treatment pregnancy, resulting in a live birth rate of 93.3% (14/15). Unlike in patients with BOTs, patients with EOC had similar pregnancy rates (100% vs. 80%, respectively) regardless of whether they had prior live birth experience.
Among patients with BOTs who underwent FSS, the rate of pregnancy varied widely (17.9% to 100%) [
32]. Among patients with BOTs who expressed a desire to conceive, an overall pregnancy rate of 32–88% was reported for all stages [
33,
34]. Helpman et al. reported a pregnancy rate of 85.6% (18/21) among patients with advanced stage BOTs who underwent FSS and had at least one pregnancy; the rate of live births in these patients was 76.4% (26/34) [
19]. In our study, only 49.3% of the patients with BOTs were married (35/71). Among these married patients, 57.1% (20/35) had at least one pregnancy; the corresponding rate of live births was 88.5% (23/26). A subgroup analysis revealed a higher pregnancy rate in patients without prior live birth experience (82.4% (14/17)) than in those with prior live birth experience (33.3% (6/18)).
For patients with BOTs and EOC who underwent FSS, ART should be considered if persistent infertility is noted. A systematic review addressing this issue concluded that ART can be initiated in patients with stage I BOTs [
34] if required. A systematic review suggested that in EOC, ART may not be associated with an increased risk of relapse, and subsequent pregnancies do not lead to poor oncological outcomes [
35].
Marital status and prior childbirth are correlated with pregnancy rates and the desire to conceive after FSS, as demonstrated in this study and previous studies [
29,
30,
31]. Therefore, a thorough preoperative consultation is essential for confirming whether a patient has a strong desire to conceive. The patient’s age, ovarian reserves, marital status, marital plans, and live birth experience should be considered in the consultation. To help patients make informed surgical decisions, clinicians should provide information regarding the percentage of patients who attempted to conceive after treatment, the corresponding pregnancy rates, live birth rates, and recurrence risks after undergoing FSS relative to those in standard staging surgery, as reported in previous studies. This information can help patients understand the risks and the odds of success and make well-informed choices.