Oncologic and obstetric outcomes of fertility-sparing surgery for borderline ovarian tumors in women of reproductive age: a retrospective cohort study

Objective To retrospectively evaluate the oncologic and obstetric outcomes of fertility-sparing surgery (FSS) for borderline ovarian tumors(BOT). Methods 132 patients with borderline ovarian tumors were divided into the incompletely staging surgery (ISS) group and the completely staging surgery (CSS) group. The overall survival and disease-free survival curves were determined using the Kaplan–Meier method. The Cox proportional hazards method was used to assess the association between the variables and live birth and multivariate analysis to identify the independent associations. Continuous variables mean ± standard deviation (SD) and tested by T-test, or Whitney U test (for variables with an abnormal distribution). The overall survival (OS) and disease-free survival (DFS) curves were determined using the Kaplan–Meier method and compared using the Log-rank test. The associations of the variables with live birth and intervals after the initial surgery were assessed using the Cox proportional hazards method; multivariate analysis was used to identify independent associations. A p-value of ≤ 0.05 in a two-sided test was statistically signicant. All statistical analyses using IBM

Oncologic and obstetric outcomes of fertilitysparing surgery for borderline ovarian tumors in women of reproductive age: a retrospective cohort study Rui  Introduction Borderline ovarian tumours (BOTs) are characterised by complex papillary architecture, multilayered epithelium with tufting, mild nuclear atypia, and modestly increased mitotic activity. They do not exert destructive stromal invasion [1] and account for approximately 10-15% of all ovarian epithelial tumors [2,3] .
The incidence of BOTs has been rising over the past decades [4] . Epidemiologic data indicate that onethird of BOT patients are younger than 40 years [5,6] . Nearly 70% of the cases are generally diagnosed as International Federation of Gynecology and Obstetrics (IFGO) stage I with a 5-year survival rate of 95-97% [7] .Given the young age and the good prognosis of BOTs, fertility-sparing surgery (FSS) is normally performed under fully informed consent for young women who desire fertility [8] to preserve the uterus and at least one ovary with or without staging surgery. However, it remains unclear that the increased risk exposes patients with FSS, especially those who undergo ISS, to a potential effect on survival state and live birth.
The aim of this study was to evaluate the oncologic and obstetric outcomes in women of reproductive age who were treated for BOTs with staging fertility-sparing surgery and to assess the role of staging surgery in fertility-sparing surgery.

Material And Methods
The medical records of all consecutive patients treated with FSS for BOTs from January 2000 to August 2017 at the First A liated Hospital of Nanjing Medical University were retrospectively reviewed. Excluded were patients suffering from a primary malignant tumor in another part of the body or of other malignant ovarian cell types, older than 40 years or lost to follow-up within one month after the initial surgery.
FSS preserved the uterus and minimally one ovary, with or without staging surgery. For ovary preservation, the patient underwent one of the following surgical procedures: unilateral adnexectomy (UA), unilateral cystectomy (UC), unilateral adnexectomy with contralateral cystectomy (UA + CC), and bilateral cystectomy (BC). The procedure of CSS included careful inspection of the peritoneal surfaces, peritoneal washing, random or oriented multiple biopsies and infracolic omentectomy. Systematic appendectomy was also a criterion for complete staging of mucinous BOT.
The pathology images were reviewed by two independent pathologists. Staging of the disease was retrospectively performed according to IFGO staging system for ovarian carcinoma (2014). The stage of ISS was evaluated based on the patients' operative records and the available pathologic ndings, with the unevaluated areas negative for metastatic lesions. Early disease was de ned as IFGO stages IA-IB, and advanced disease as IFGO stages IC and above.
The decision of adjuvant chemotherapy was made based on the ovarian cyst rupture, positive pelvic washing data, lymph node metastasis status, invasive implants, and the extent of disease.
The time of overall survival was calculated from the date of the initial operation to the last follow-up or until death. The time of disease-free survival was calculated from the date of the initial operation to the date of recurrence.
After the initial treatment, patients were followed up once a month for the rst six months, every three months for the next six months, every six months for the next two to ve years, and every year thereafter.
Recurrence was de ned by clinical and/or imaging evidence and con rmed pathologically. Telephone interviews were also conducted to assess obstetric outcomes such as pregnancy attempts, delivery, and the use of assisted reproductive technology.

Statistical analysis
The clinical features of the two groups, including age at diagnosis, histological type, micro interstitial in ltrates, IFGO stage, infertility, postoperative chemotherapy, surgery procedure, were compared and analyzed. Categorical variables were expressed as number (%) and tested by Chi-square test or Fisher exact test. Continuous variables were presented as mean ± standard deviation (SD) and tested by T-test, or Whitney U test (for variables with an abnormal distribution). The overall survival (OS) and disease-free survival (DFS) curves were determined using the Kaplan-Meier method and compared using the Log-rank test. The associations of the variables with live birth and intervals after the initial surgery were assessed using the Cox proportional hazards method; multivariate analysis was used to identify independent associations. A p-value of ≤ 0.05 in a two-sided test was statistically signi cant. All statistical analyses were performed using IBM SPSS statistics 17.

Patient characteristics
During the study period, 147 women with BOTs who received primary fertility-sparing surgical treatment were documented (Fig. 1). Excluded were the women whose surgery details were missing and those who were lost to follow-up within one month after the initial surgery. Finally, 132 women were included in the study (Table 1). Of the 132 patients, 54 undergone CSS and 78 undergone ISS. There were no signi cant differences in terms of age, histological type, peritoneal implantation, IFGO stage and postoperative chemotherapy between the two groups. There were signi cant differences in surgery procedure (p < 0.001).  Fig. 2a). The recurrence rate was signi cantly higher in the ISS group than the CSS group (51.3%% vs. 13.0%, p < 0.001). The Kaplan-Meier analysis revealed that the CSS group suffered fewer relapses and longer disease-free survival time than the ISS group (p = 0.003) (Fig. 2b).

Obstetric outcomes
Telephone interviews were conducted with all 132 patients (including the family members of the two dead patients) after FSS. Among them, 70 attempted to conceive were included in this part of the study (Table 2) and 62 women who did not try to conceive were removed. There were no signi cant differences in terms of staging surgery, IFGO stage, histological type, peritoneal implantation, postoperative menstruation, chemotherapy and infertility between the live birth group and the non-live-birth group. The two groups had signi cant differences in age and surgery procedure (p = 0.047 and 0.032, respectively). To nd out the factors affecting the live birth intervals after FSS, all the listed covariates in Table 3 were entered into the initial Cox proportional hazard model with backward logistic stepwise regression method.
The nal hazard regression model (Table 3) showed that age, surgery procedure and chemotherapy was statistically related to live birth intervals after FSS. Yet only age was identi ed as the independent risk factor for patients' live births in the multivariate analysis (adjusted odds ratio = 0.902, 95%CI 0.823-0.988, p = 0.027). Adjusted analysis was not possible for BC because no cases were observed in the BC group.

Discussion
Surgical staging of BOTs is controversial. Some people suggest that re-staging surgery and full staging surgery is not necessary for all BOTs. Kimio [9] believed that there was no signi cant difference in patients' survival between those who underwent re-staging surgery and those who did not. A French multi-centered study [10] found no difference in recurrence rates between patients who received restaging operations and those who did not. For patients who underwent restaging, the mean recurrence time was 40 ± 19.9 months after surgery, compared with 30.9 ± 36.3 months for those who did not undergo restaging (no signi cant difference). Similarly, in a series of 233 BOT patients without re-staging procedures, the patients who had undergone complete staging suffered fewer relapses than those with incomplete staging (5.1% vs 12.3%), but this difference was not statistically signi cant according to the multivariate analysis [11] . Margarita suggested that the bene ts of complete staging in BOT patients could be limited because: a) it might not affect the decision of adjuvant treatment as this was not a standard care; and b) most recurrences could be salvaged [12,13] . However, other people hold a different point of view. A metaanalysis of 2770 BOT cases from 18 observational studies showed that CSS signi cantly reduced recurrence (the pooled odds ratio for CSS and recurrence: 0.64, 95% con dence interval: 0.47-0.87, p < 0.05) [14] . A large cohort study on BOT of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO ROBOT study) con rmed ISS as an independent negative prognostic factor for disease recurrence, apart from other factors such as higher IFGO stage, residual tumour, and fertility preservation [15] . Generally, fertility preservation for BOT patients carries a good prognosis [16][17][18][19] . But few studies have discussed the safety and necessity of CSS for BOTs in FSS. As for ISS, we found that despite the high recurrence rate, the overall survival and prognosis were not affected. Chi-square analysis and Kaplan-Meier analysis showed no signi cant differences in survival between CSS and ISS (p = 1.000 and 0.716, respectively), and CSS signi cantly increased the disease-free survival time of BOT (p = 0.000) and reduced the risk of relapse (51.3% vs. 13.0%, p = 0.000).
Many studies were conducted regarding the pregnancy rates of BOT patients after FSS, but few addressed live birth rates. Zhao [20] reported a total pregnant rate of 33.8%. Lee also reported that 26 of the 32 patients (81.3%) had successful pregnancies [16]. A systematic review of 230 articles on conservative management of BOTs reported the pregnancy rates ranged from 32-88%, and the pooled estimate for spontaneous pregnancies was 54% (95% CI: 38-70%, I 2 = 91%) [21] . Higher pregnancy rates were reported in Asian series where the proportion of conservatively treated mucinous tumor was higher: pregnancy rates were 88% according to Song et al [22] , and 73% according to Park et al [23] . In our series, 48.5% (34/70) of the cases had live births after FSS. The birth intervals after FSS was 31.86 ± 19.325 (range: 4.93-82.17) months. Fauvet [24] reported that the median interval from surgery to pregnancy was 28.6 ± 24.6 (range: 4-89) months. The results in our study corresponded with the literatures. In general, positive reproductive treatment is needed for fertility-sparing patients of older age to help them conceive as early as possible. For those who want to conceive naturally, fertility guidelines can be introduced at 31.86 ± 19.325 months after surgery.
A nomogram developed to predict live birth for BOT women after FSS found factors such as FIGO stage, age at diagnosis, histological subtype and surgery type could impact live birth and fertility [25] . The in uence of age on live birth cannot be ignored. Fauvet [26] reported that on average, the women who conceived were younger than those who did not conceive (26.7 ± 5.6 years vs. 32.3 ± 6.5 years; p = 0.001), yet the two subgroups did not differ signi cantly in terms of nulliparity proportion, the history of infertility or ovarian surgery, preoperative tumor marker levels, tumor size, or the type of conservative treatment.
Previous studies [26] showed that age at initial treatment was the only determinant of fertility. In patients aged 35 years, the pregnancy rate was 42%, which was signi cantly higher (by 20%) than that of patients aged 35 to 40 years. In our study, the nal COX model showed that age, surgery procedure and chemotherapy was statistically related to live birth and intervals after FSS during follow-up. But only age was identi ed as an independent risk factor for live birth, which was similar to previous studies. Furthermore, we nd that the live birth rate of women with ISS was higher than that of women with CSS, but the difference was not statistically signi cant.

Strengths And Limitations
Our study is limited by the inherent aws of a retrospective design, as well as a referral bias of patients who received treatment and follow-up at a single tertiary cancer center. Another limitation dictated by the rarity of these tumors is an extended study period, which exposes the study cohort to shifts in classi cation and management. One should consider these limitations in assessing our ndings.

Conclusion
FSS with CSS or ISS both seemed safe and feasible for young women who desire fertility preservation.
CSS could signi cantly increase the disease-free survival time of BOT and reduce the risk of relapse, while there was no signi cant difference in overall survival between CSS and ISS. Besides, CSS had slightly negative and statistically insigni cant association with live birth. For young patients who required to conceive naturally, assisted reproductive technology could be introduced until 31.86 ± 19.325 months after surgery. However, positive reproductive treatment should be used for fertility-sparing patients of older age to help them conceive as early as possible. Availability of data and materials The datasets analysed during the current study are not publicly available due to further study but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The study was approved by the ethics committee of the First A liated Hospital, Nanjing Medical University, Jiangsu Province Hospital. Approval number No. 2018-SRFA-052. All participants provided an informed written consent after explaining the aim of the study, the procedure & the potential hazards.

Consent for publication
Not applicable Competing interests Figure 1 Study ow diagram of the paper