Epithelial Borderline Ovarian Tumor: Clinicopathological Features, Outcome and Prognostic Factors

Borderline ovarian tumors (BOT) are non-invasive neoplasms with atypical epithelial cell proliferation without destructive stromal invasion. The pathological severity is greater than benign tumor but less than their malignant ovarian tumors [1]. Taylor has first described these type of ovarian tumor in 1929 that was different from both benign and malignant epithelial ovarian tumors [2]. Then, in 1973, the name ‘borderline’ was assigned by the World Health Organization (WHO) with morphological criteria with the absence of stromal invasion [3]. The WHO Classification in 2014 of Tumors of the Female Genital Organs used the term “borderline tumor” interchangeable with “atypical proliferative tumor”—a terminology that was discouraged in the previous WHO classification [4], while the term “tumor of low malignant potential” is no longer use [3]. BOTs have seven types include serous, mucinous, Abstract


Introduction
Cancer antigen 125 (CA-125) might help in advanced stage cases [10]. Regarding the controversy in the surgical management and staging of BOTs, some surgeons prefer to do the surgical staging whereas the others do not perform lymphadenectomy [8][9][10][11]. Women who have completed childbearing and those with advanced stage disease are treated with complete surgical staging that includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymphadenectomy and resection of visible peritoneal lesions. Appendectomy may be considered in mucinous BOT subtype [12]. Conservative procedure is preserved for fertility needed patients. The procedure consisting of unilateral salpingo-oophorectomy or ovarian cystectomy in cases of bilateral ovarian involvement [12][13].
In the present study, we reviewed the clinic-pathological characteristics, surgical management, and surgical outcomes, and assessed factors affecting survival in patients with borderline ovarian tumors who were had been treated in our institute.

Materials and Methods
After the Ethics Committee for Human Research were approved under protocol number HE581436, the retrospective study was performed in Srinagarind Hospital, Department of Obstetrics and Gynecology, Khon Kaen University, Thailand. All patients with BOTs diagnosed between 1 January 2001 and 31 October 2016 were included. The patient age, gravidity, menopausal status, pre-operative serum CA-125 level, clinical symptoms were collected. Moreover, surgical technique, mean tumor diameter, lymph node status, stage at diagnosis, chemotherapy after surgery and postoperative follow-up periods were evaluated. The histopathological results were re-evaluated and interpreted by only one gynecologic pathologist of Srinagarind Hospital (Kleebkaow P.). Patients with incomplete data were excluded from the analysis.
The International Federation of Gynecology and Obstetrics (FIGO) 2009 staging scheme for epithelial ovarian carcinomas was staged in all patients [14]. Although the FIGO ovarian staging classification was revised on 1 January 2014, we used the previous staging classification for 2014 patients for consistency. Surgical procedures were categorized into two groups: the first group was conservative surgery that for those fertility function is needed. The procedures consisted of unilateral salpingo-oophorectomy (USO) or bilateral salpingo-oophorectomy (BSO) and/or infracolic omentectomy and/or pelvic and/or para-aortic lymphadenectomy (sampling or complete). While the second group was radical surgery that for those with finished childbearing and those with advanced stage disease. It comprised of total hysterectomy and bilateral salpingo-oophorectomy (TAH+BSO) and/or infracolic omentectomy and/or pelvic and/or para-aortic lymphadenectomy (sampling or complete). Additionally, an appendectomy was often performed in case of mucinous BOT. After underwent the surgical procedure, postoperative adjuvant chemotherapy (CT) was administered for FIGO stage IC and more advanced stages or recurrent disease. The postoperative chemotherapy (CT) regimens consisted of carboplatin (AUC5) and paclitaxel (175 mg/m 2 ) every 3 weeks for 6 cycles.
After complete primary treatment (surgery or adjuvant chemotherapy), all patients were followed every 3 months for first 24 months and every 6 months up to 5 years. Long-term outcome evaluated at 5 and 10 years was obtained. At each follow-up visit, a patients' history taking, physical and pelvic examinations were performed.
Survival analysis was based on the Kaplan-Meier method and results were compared using the log-rank test. Disease-free survival (DFS) was defined as the time from the date of primary surgery to the detection of recurrence or the latest observation. Overall survival (OS) was defined as the time from the date of primary surgery to death or the latest follow up. The χ2 test and Student's t-test for unpaired data were used for statistical analyses. For predictors with a p-value of less than 0.20 in univariate analysis (log-rank test), Cox proportional hazards regression would be used to determine the independent predictor (s) of survival. All statistical analyses were performed using the SPSS version 22.0. A p-value < 0.05 was considered to indicate statistical significance.

Results
A total of 52 patients having a final diagnosis of BOTs between January 1, 2001, and October 31, 2016, in our institution were identified. The mean age+ SD was  (Table 2). Mucinous type is the most common followed by serous type (75% and 25%, respectively) Only one patient (1.9%) had the serous type with the micro-invasive lesion. Endometriosis and pseudomyxoma peritonei lesions were found as co-incidental findings in patients with the mucinous group (3.8% and 5.5%, respectively). The surgical procedures are shown in Table 3. Twenty patients (38.5%) underwent conservative surgery. Twenty-one patients (40.3%) underwent lymphadenectomy. An appendectomy was performed in 19 (36.5 %) cases. Only one case (1.9%) with mucinous type had appendiceal involvement. After underwent the surgical procedure, twelve patients received postoperative adjuvant chemotherapy (CT).
The median follow-up period was 67.5 months (range, 7 to 180 months). The 5-year and 10-year overall survival rates for all stages was 90% and 85%, respectively. The 5-year and 10-year disease-free survival rates for all stages were 87% and 87%, respectively. Seven patients (13.5 %) had disease recurrence. Most recurrent patients were the mucinous type (71.4%) and in advanced stage (57.1%). Moreover, of the 7 recurrence patients, 6 patients (85.7%) underwent radical surgery and 5 patients (71.4%) received CT for recurrent disease. No one died during the follow-up period.

Discussion
In this study, we reviewed 52 patients with BOTs who were treated with surgery in Srinagarind Hospital, Khon Kaen, Thailand. BOTs represent approximately 10% of EOC. However, their prognosis is more favorable. These tumors are detected at the younger age and at lower stages [8] that is similar to our study. That is most patients in our review were in premenopausal status and presented in the early stage of the disease. The presenting symptoms varied between studies. Comert et al. [15] found that the most common symptoms were the pelvic pain (42.7%), and followed by bloating sensation (25.3%). While the adnexal mass is the most common leading symptoms that found in our study and followed by GI symptoms, abdominal pain, and abnormal vaginal bleeding.
Regarding histopathologic types of BOTs, Aure JC et al. [16] reported the most common histopathological types were serous (65%) and followed by the mucinous (35%). In addition, Link et al. [17] showed that 50% of the borderline ovarian tumors patients presented with serous histology, 46% were mucinous, and 3.9% were mixed, endometrioid, clear cell or Brenner tumors. Whereas our study found mucinous type was the predominant type (75%) and followed by serous type (25%). The differences might be the geographic and cultural variation.
BOTs are staged using the FIGO criteria that have been developed and applied to invasive ovarian carcinomas. Russell P et al. [18] reported that most BOTs presented at stage I (50% to 80%) that is similar to our findings. It was found 90.4% had the early stage of the disease. Furthermore, Massad et al. [19] showed the recurrence or persistence rate after surgery in each stage. The recurrent rates were 2.1% in stage I was 2.1%, 7.1% in stage II nd 14.4% in stage III/IV. These findings are in line with our study. The recurrent rates in stage I-II and III-IV BOTs in the present study were approximately 5.8% and 7.7%, respectively.
There is an important and controversial issue regarding surgical approaches in diagnosed BOT patients, especially in women who wish to preserve their reproductive status. As has already been mentioned, patients with borderline ovarian tumors tend to be younger than women with invasive ovarian cancer. Therefore, the fertility issue is taken to be the account in younger women [20]. In our study, more than half of patients were radical surgery similar to the ovarian cancer surgery situation. However, we found no difference between the survival rates of radical and conservative surgery patients. Many previous studies [21][22] have suggested that patients who had undergone conservative surgery had higher recurrence rates than the radical surgery group. Furthermore, Boran et al. [21] reported that no recurrence was found after

Risk factors
Hazard ratio 95%CI P-value  radical surgery, Whereas, the recurrent rate was 6.5% after conservative surgery. In contrast, we found that 7 patients (13.5%) experienced the recurrence of the disease. Six patients (85.7%) underwent radical surgery. Moreover, no difference was found between completely and incompletely staged patients. Thus, surgical procedural types not reduced the recurrence of the disease. Our data found that lymphadenectomy did not show statistically significant improvement in DFS and OS. These results were similar to those previously reported [23].
Furthermore, we found that radical surgery was not an independent prognostic factor for DFS or OS. These findings were similar to the previous studies [21][22]. We also demonstrated that hysterectomy had no impact on survival in BOT patients, that similar to Menczer et al.'s study [24].
Coincidental appendectomy to surgical staging procedures has been recommended for mucinous tumors [8].  [26] reached the same conclusion.
The use of adjuvant chemotherapy for BOTs remains controversial [27]. According to the last version of the National Comprehensive Cancer Network (NCCN), the treatment recommendation after comprehensive staging depends on the presence or absence of invasive implants. The initial therapeutic approach in patients with invasive implants may include observation as well as alternative to consider adjuvant chemotherapy (Category 2B) [28]. Trope et al. [29] and Gokcu et al. [27] reported that surgery followed by chemotherapy did not show a different survival rate compared to no adjuvant chemotherapy in advanced-stage BOTs. Contrast with our study that chemotherapy after surgical procedure given in FIGO stage IC and more advanced stages improved overall survival (OS) and disease-free survival (DFS) significantly.
The previous studies [22-27-30] noted that the age more than 40 years, menopausal status, FIGO stage, surgical staging, radical surgery, lymph node dissection, appendectomy and undergoing adjuvant chemotherapy for a tumor of stage ≥ IC were not independent prognostic factors for DFS or OS. While our study found that absent residual disease and adjuvant chemotherapy for tumor stage ≥ IC on disease-free survival (DFS) were the significant associated prognostic factors for DFS (HR = 0.33; 95 %CI 0.11 -0.96; p = 0.04, HR = 0.22; 95 %CI 0.08 -0.65; p = 0.006, respectively). This is a retrospective study to evaluate the clinicopathological features, outcomes and prognostic factors affecting the overall survival and disease-free survival in women with borderline ovarian tumors with only one gynecologic pathologist interpreted histopathology. Therefore, this is the strength of the study. However, due to the rarity of these tumors and limitation of sample size with retrospective data in only one institute so this is the weakness of our study. For more promising data, multicenter prospective randomized controlled trials data should be conducted.
In Conclusion, the majority of patients with BOTs presented in young age and early stage. Residual disease and postoperative adjuvant chemotherapy were associated factors for DFS.

Funding Statement
None