Swanton et al. conducted a system review included 923 BOTs patients from 19 studies, the recurrence rate in the system review was 16% . In other literature, the recurrence rate of BOTs was 19% . Alvarez et al. reported that the recurrence rate of BOTs was 12%-58% . In this study, a total of 21 patients relapsed and the recurrence rate of BOTs patients was 12.4%, which was consistent with the literature reports.
Through retrospective analysis and literatures review, we found some recurrence factors, although our results do not confirm data from those previous studies. We found that FIGO stage, invasive implantation and chemotherapy were risk factors for recurrence of BOTs (P＜0.05). Many studies have demonstrated that higher FIGO stages are always accompanied by worse prognosis. While only 5% of patients initially diagnosed in FIGO stage I are confronted with relapse of the disease, patients with extended disease are faced with recurrence in up to 25% of cases [7-8]. Seong SJ et al.  reported that the 5-year survival for FIGO stage I BOT patients was approximately 95% to 97%, while stage II-III BOTs patients was only 65% to 87%. In the analysis of this study, the recurrence rate of FIGO stage I was 8.7% and FIGO stage II-III was 24.4% (P=0.035). The DFS between FIGO stage I group and FIGO stage II–III group had significant difference (P=0.021). However, the 5-year survival for FIGO stage I BOT patients was 95.2%, while stage II-III BOTs patients was 93.8% (P=0.086). Invasive implantation was one risk factor for the recurrence of BOTs in this study. Alvarez et al. showed the recurrence rate is higher in patients with invasive implantation . Shih et al. also demonstrated that the presence of invasive implantation was the independent risk factors for the recurrence of BOTs . Research have shown that the most important predictors of recurrence were the FIGO stage and the presence of invasive implantation . In this study, the recurrence rate of patients with invasive implantation was 40% and without invasive implantation was 10.7% (P=0.006). Through Kapan-Meier analysis, the DFS and OS were no significant difference between the two groups. In our study, chemotherapy as a treatment instead became a risk factor for recurrence. It is possible that the only patients with BOTs for whom chemotherapy is considered are those with advanced FIGO stage disease and invasive implants, because studies have found that this group of patients have a high recurrence rate. However, there is no proven benefit from chemotherapy, even in advanced disease stages or when there is presence of invasive implants. Longacre et al. Published a study of 276 patients with BOT. of 113 patients with advanced serous BOTs, 42 received chemotherapy. 71% of the patients in the chemotherapy group were still alive after a median follow-up of 126.5 months. In contrast, 87% of the patients without chemotherapy survived after 93 months of median follow-up . In our study, there were 36 patients received chemotherapy after surgery. The recurrence rate was 25%, which was significantly higher than patients without chemotherapy (9.1%), however, the DFS and OS had no significant difference between these group.
Previous studies showed that histology type was one of the controversial risk factors. Fang et al.  showed that the patients with serous borderline ovarian tumors had a higher recurrence rate (58% vs 12%, P=0.003), and a shorter recurrence interval (P=0.007) than patients with mucinous tumors. Uzan et al. reported that 140 mucinous BOTs and 114 serous BOTs, 43 patients had developed at least one recurrence, 26 among patients with SBOT and 17 among patients with MBOT (P=0.01) in the median follow-up of 45 (range 3-136) months . Loizzi et al. observed no difference in the survival rate between different histological types . Our data showed the recurrence rate was 10% in serous BOTs and was 16.2% in mucinous BOTs. There was no difference in the recurrence rate between different histological types. Many articles have reported that micropapillary pattern are always accompanied by higher recurrence rate. Shih et al. showed that of the 196 patients with borderline tumor of serous histology, those with a micropapillary pattern had a 3-year PFS of 75.9% compared with 94.3% for patients without micropapillary pattern (P＜0.001) . In silva’s study, micropapillary pattern was the only feature that was associated with a higher recurrence rate (26% vs. 4%, P =0.008) . On the controversy, Uzan et al. demonstrated that the recurrence rate was 71% in patients without micropapillary pattern and 51% in patients with micropapillary (P=0.1) . In this study, we found that the recurrence rate was 14.9% in patients without micropapillary pattern and 10.8% in patients with micropapillary pattern. There was no difference in the recurrence rate between patients with or without micropapillary pattern. Song et al. showed that a retrospective analysis was performed on 687 patients who underwent laparoscopy (n=312), or laparotomy (n=375) due to BOTs. After the median 41.8 months follow-up times, 21 patients in laparoscopy group, and 24 patients in laparotomy group had recurrence, and 4 patients in the laparoscopy group and 6 patients in the laparotomy group died of the disease. The rates of recurrence-free survival and overall survival did not differ between groups . In this study, we found that the recurrence rate was 14.4% in laparotomy group and 9.8% in laparoscopic group, the difference was no significant.
BOTs are typically present in reproductive age women, diagnosed at the early stage, and have a favorable prognosis. Median age at diagnosis is 45 years with 34% of patients being under 40 [18-20]. BOTs present more frequently as a disease limited to the ovaries compared with invasive carcinoma, as was reported in a systematic review of 6362 cases that 78.9% of the patients with BOTs are diagnosed at FIGO stage I . Therefore, a fertility sparing surgery is the preferred choice for young patients who desire to preserve fertility. In this study, the recurrence rate of FSS was 11.7%. Others studies have the similar conclusion. Seong et al. reported that recurrence rate of BOTs patients with fertility sparing is 10% to 20% . Qi et al also reported that the recurrence rate of BOT patients with FSS was 10.2% .
Through univariate analysis, we found that tumor size and tumor site were the risk factors for recurrence of patients receiving FSS. However, they do not affect the pregnancy rate. In our study, the recurrence rate of tumor size smaller than 10cm was 20.7% and of tumor size larger than 10cm was 3.2% (P=0.035), however, the pregnant rate of tumor size smaller than 10cm was 80% and larger than 10cm was 83.3% (P=0.282). Qi et al. reported that the recurrence rate was 10.3% in tumor size smaller than 10cm group and 10.1% in tumor size larger than 10cm group, the pregnant rate was 54.5% and 57.9%, respectively. The difference was not statistically significant . Fang et al. showed that the recurrence rate was 40.7% in tumor size smaller than 10cm group and 29.6% in tumor size larger than 10cm group (P=0.569) . In all of these studies, tumor size smaller than 10cm seem to be more likely to recur. We speculate that it may be because small tumors are more likely to be cystectomy rather than salpingo-oophorectomy, or it may be that small tumors are less likely to be removed completely. We also found that bilateral tumor was a risk factor for recurrence. In this study, the recurrence rate of bilateral BOTs was 30% and unilateral was 8%, the difference has statistically significant (P=0.048), however, it didn’t affect the pregnancy rate. Some researchers reported that the 5-year RFS was 74% and 48% in patients with unilateral and bilateral tumors, respectively . Fang et al. also showed that patients with bilateral tumors had a higher recurrence rate after FSS (27.9% vs 63.6%, P=0.038). The pregnancy rate was no significant difference between the two groups . Qi et al reported that there were 7.4% recurrence rate in unilateral group and 24.2% in bilateral group (P=0.009). The pregnancy rate was 59.6% in unilateral group and 43.7% in bilateral group, the difference was no significant(P=0.271) . Chen et al. reported that patients with bilateral tumors had a higher recurrence rate (4.7% vs 18.7%, P=0.07) and a shorter recurrence interval (33.2months vs 23months, P=0.00) after conservative treatment .
In our population, FSS includes the following surgical approach: unilateral cystectomy (UC), unilateral salpingo-oophorectomy (USO), bilateral cystectomy (BC), unilateral salpingo-oophorectomy combined with contralateral ovarian cystectomy (USO+CC). Through analysis, surgical approach did not influence recurrence or fertility. 10 patients recurred after UC with a recurrence rate of 10%, which was higher than that of 0% after USO. Compared with USO+CC, the recurrence rate of BC was lower (25% vs 33.3%). Qi et al. reported that regarding the comparison of USO with UC, 5 cases recurred after UC with a recurrence rate of 8.9%, which was higher than that of 6.5% after USO (P=0.812). 10 cases pregnant after UC with a pregnancy rate of 66.7%, which was higher than that of 56.2% after USO (P=0.498), but there were no significant differences between the two groups. Compared with USO+CC, the recurrence rate of BC was lower (18.7% vs 29.4%), the pregnancy rate of BC was also lower (40% vs50%), there were no significant differences between the two groups . There were 106 patients with unilateral BOTs in a study, 47 patients underwent unilateral adnexectomy and 59 underwent unilateral cystectomy. The study showed that more patients relapsed in shorter time in unilateral cystectomy group, though this difference was not statistically significant (6.8% vs 2.1%, P=0.38), and there was also no difference between these two group in pregnancy outcome .
Uzan et al. reported that surgery approach (laparoscopic or laparotomy) was not associate with recurrence for patients underwent FSS [14,23]. Chen et al. analyzed that, compared to laparotomy, laparoscopy had no disadvantage in terms of recurrence rate and pregnancy rate . In this study, surgery procedure was also not associate with recurrence rate and pregnancy rate for patients underwent FSS. Qi et al. showed that the recurrence rate of laparotomy in FSS patients is higher than in laparoscopic surgery (14.3% vs 4.3%, P=0.029). The pregnancy rate between laparotomy and laparoscopic has no significant difference (60.6% vs 50%, P=0.397) . Therefore, laparoscopy seems to be the most attractive surgical approach to BOT due to well-proven benefits such as faster recovery, lower perioperative complication rates and reduce pelvic adhesion that could possibly impair fertility.
In our study, there were 13 patients received chemotherapy after FSS. The recurrence rate was 15.4% and the pregnancy rate was 75%, compared to without chemotherapy patients, the difference was not statistically significant. Fang et al. Studied 12 patients underwent chemotherapy and concluded that there was no significant difference in recurrence rate and pregnancy rate . All the evidence demonstrated that the patients did not receive any benefit from chemotherapy, especially for patients underwent FSS. Chemotherapeutic agents which reach the ovaries lead to damage to the primordial follicles. The detrimental effect of cytotoxic agents on the ovary is thought to be caused by damage to peri-oocyte granulosa cells in the ovaries. Damage to ovarian tissue as a result of the use of cytotoxic agents is irreversible. Histological samples of ovarian tissue after chemotherapy have shown range of damage, from a reduction in follicle count to complete failure . Therefore, chemotherapy was not recommended for patients even with advanced BOT, especially of patients who have fertility desire.
There are some limitations in this study. It is a retrospective study and the nature of the study might be a source of bias. The number of included patients was limited, and the relatively small number of patients attempt to conceive might limit the statistical power of our findings.