Borderline Ovarian Tumors: Recurrence Patterns and Management

doi:10.21203/rs.3.rs-4627979/v1

Purpose: We aimed to evaluate the factors associated with disease recurrence, recurrence patterns, and obstetric outcomes of borderline ovarian tumors. The main outcome was prognostic factors for disease recurrence. The secondary outcomes were recurrence sites and obstetric results.

Methods: This study included patients diagnosed with BOT in Başkent University. Data was obtained from patient files and hospital records. Histopathological results were re-evaluated based on the new 2020 WHO classification. Risk factors for disease recurrence were evaluated for early-stage and advanced-stage diseases. Survival was measured from the time of diagnosis.

Results: A total of 142 patients were included. The median follow-up time was 100.5 months. Recurrence occurred in 24(16.9%) patients and the 5-year RFS 86.3% and no deaths were recorded. The main recurrence site of the tumor was the same ovary (12/24, 50%). In multivariate analysis, cystectomy was found as a risk factor for recurrence in the early stage (HR:4.28; 95%CI: 1.40 – 13.08, p:0.011). One patient’s tumor showed malignant transformation (1/24, 4.17%). The pregnancy rate was 76.7% among 43 patients who attempted to conceive. There was no difference in obstetric outcomes between USO and cystectomy (p:0.223).

Conclusion: The risk of recurrence in patients with BOT was higher in patients who underwent cystectomy and obstetric outcomes were similar between cystectomy and USO. In this study, most recurrences occurred in the ovaries. Therefore, fertility-sparing appears to be an appropriate choice for young women with satisfactory obstetric outcomes even in the advanced stage.

Borderline Ovarian Tumor

Disease-Free Survival

Fertility Sparing Surgery

Obstetric Outcomes

Recurrence site

The risk of recurrence in patients with BOT was higher in patients who underwent cystectomy and obstetric outcomes were similar between cystectomy and USO. Fertility-sparing appears to be an appropriate choice for young women with satisfactory obstetric outcomes even in the advanced stage.

Borderline ovarian tumors (BOT) are rare and it’s incidence varies from 1.5 to 4.8 in 100,000 per year [1, 2] and constitutes 10-20% of all ovarian malignancies[3]. BOTs do not have aggressive behavior, with about 90% disease-free and overall survival rates [4]. Surgery is the cornerstone of treatment for BOTs and varies from cystectomy to non-aggressive debulking based on the age and fertility status of the patient, and the extent of the tumor. Approximately one-third of the patients with BOTs are diagnosed before 40 years of age and the mean age of presentation is approximately 10–20 years earlier than its invasive counterpart [5-7]. The high frequency of the disease at a younger age is associated with almost excellent oncologic outcomes because of management in favor of conservative surgery in this group of patients [4]. Hence, results concerning fertility have been reported revealing a pregnancy rate between 32% and 63% after fertility-sparing surgery (FSS) [8-10]. However, comprehensive surgery and surgical staging remain the standard treatment in case of extended disease and older age [11].Management may vary between centers or clinicians [12]. For that reason, we aimed to evaluate possible risk factors for disease recurrence, recurrence patterns and obstetric outcomes after FSS in BOTs and share the experience of a single institution with a standard approach over 13 years.

This retrospective study was conducted at Başkent University Ankara Hospital, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, per the principles of the Declaration of Helsinki. The study was approved by the Institutional Review Board (KA 23/233). A written informed consent was obtained from the patients with guarantees of confidentiality.

This study involved patients with BOTs and treated between March 2007 and June 2023. Age, fertility status, histopathological reports, recurrence, and pregnancy rates were obtained from the patient records. The stages of the disease were evaluated following the International Federation of Gynecology and Obstetrics (FIGO) 2014 Ovarian Cancer Staging System[13]. Stage I or II disease is defined as early-stage disease, while stage III disease is labeled as advanced disease. All histopathological results were reviewed and re-evaluated based on the new 2020 WHO classification of ovarian tumors by the co-author pathologist (NH)[14].

Before the surgical intervention, patients with suspicious ovarian cysts were informed about the possibility of ovarian cancer or borderline tumor of the ovary and if patients had a desire to preserve fertility, they were well briefed that FSS is not the standard surgery for ovarian cancer and all patients had given informed consent. Fertility-sparing is defined as preserving at least one ovary and uterus. Unilateral salpingo-oophorectomy (USO) or cystectomy was performed as the FSS procedure in the patients who had informed consent previously. The decision for the type of surgical procedure was based on the current approaches.

Rutine follow-up protocol in our clinic for this patient group was control visits every 3 months in the first 2 years, twice annually during the following 3 years, and once a year thereafter until any finding or sign of disease recurrence. A gynecologic examination, pelvic ultrasound, testing of disease-related serum tumor marker (cancer antigen 125, etc.), and a thoracoabdominal CT scan (every 6 months in the first 2 years) were the components of the follow-up visits. A debulking surgery was applied in case of disease recurrence.

Recurrence-free survival (RFS) was defined as the time between the surgery and the time of detection of disease recurrence. Overall survival (OS) was defined as the time between the surgery and the time of death related to the disease. Age≤35, FIGO stage, histology, surgical procedure (USO vs cystectomy vs Bilateral salpingo-oophorectomy (BSO)±Total abdominal hysterectomy (TAH)), FSS, lymphadenectomy, and presence of micro invasion were evaluated as possible risk factors for disease recurrence. The obstetric outcome was evaluated by collecting data up until the patient's last follow-up visit from the hospital records and patient files. The components of obstetric data were marital status at the time of diagnosis, current marital status (or having a partner), history of gravida and parity, the current status of gravida and parity, desire for pregnancy to date, and pregnancy method (spontaneous or assisted).

Survival analyses were performed in early-stage and advanced-stage patients. Obstetric outcomes of the FSS patients were also evaluated.

Statistical analyses were performed by using IBM SPSS Statistics for Windows 25.0 (IBM Corp., Armonk, NY, USA). The data were expressed as the median and range for the continuous variables. Binary variables were reported as the number and percentage. The Kaplan-Meier test was used to identify differences between the curves for recurrence-free survival (RFS). An overall survival (OS) analysis was not performed due to the lack of any death events. The multivariate analysis was calculated using the Cox regression test. Survival was measured from the time of diagnosis. P-value < 0.05 was accepted as statistically significant.

The median age of the patients was 34.0 (range: 17-76). The median follow-up time was 100.5 (range: 20–266) months. Of the 142 patients, 94 (66.2%) had serous histology and 48 (33.8%) patient’s tumor histology was non-serous. One hundred and twenty-three (86.6%) patients had early-stage disease while 19 patients had advanced-stage disease, 13 (68.4%) of whom were under 35 years of age. Characteristics of the patients are summarized in Table 1.

Median follow-up time was 100.5 months (range:20-266). Recurrence occurred in 24 (16.9%) patients and the 5-year RFS 86.3% and no deaths observed. One of the patient’s tumor showed malignant transformation (1/24, 4.17%). The mean RFS time was 199.9 months, median RFS was not reached in follow-up time. In univariate analysis; age≤35 (p:0.000), FSS (p:0.000), and advanced-stage disease (p:0.000) were associated with decreased 5-year RFS. The multivariate analysis showed early-stage disease was the only prognostic factor for RFS in whole cohort (HR:0.42; 95%CI; 0.27-0.66, p:0.002) and age≤35, and fertility preservation showed no significant difference (p:0.098 and 0.935, respectively).

In univariate analysis of early-stage patients age≤35 (p:0.008), cystectomy (p:0.000), and FSS (0.005) were associated with shorter recurrence-free survival time. In multivariate analysis of early-stage patients cystectomy was found as a risk factor for disease recurrence. Table 2 shows the RFS analysis of early-stage patients. Figure 1 shows the survival plot of surgical procedures on disease recurrence in early-stage patients. In univariate analysis of the advanced-stage patients, age≤35 (p:0.011) and FSS (p:0.028) were found as possible risk factors for disease. A flowchart of recurrence patterns is given in table 3.

After debulking surgery for recurrent disease, a total of 6 recurrences (27.3%) occurred. In cystectomy and USO subgroups, recurrence rates (30% vs 25%, respectively) and mean recurrence-free time (140.8 vs 89.7 months, respectively) were similar after debulking surgery (p:0.891 and p:0.306, respectively).

Forty-three patients (34/43, 79.1% were nulliparous) attempted to conceive, in posttreatment. During the follow-up, 37 pregnancies occurred among 33 patients, with 34 live births and 3 miscarriages. Of the patients who had a livebirth, 23 were nulliparous at the time of disease treatment. Moreover, 13 pregnancies occurred after intracytoplasmic sperm injection (ICSI), while 20 patients conceived spontaneously. There was no effect of the surgical procedure (cystectomy or USO) in obstetric outcomes (p:0.223).The obstetric outcomes of the patients are summarized in table 4 as a flowchart.

This study revealed remarkable results regarding BOTs from a single gynecologic oncology department. Firstly, the recurrence site after conservative surgery is mostly observed in the same ovary and the management of recurrent disease is easy and consists of debulking of mass. Secondly, all the recurrences were observed in the patients who underwent FSS, while there was no disease recurrence in the BSO±TAH patients. The advanced-stage disease was significantly associated with disease recurrence. In early-stage patients, cystectomy resulted in lower RFS than USO in the patients.

It is known that BOTs have a good prognosis and the 10-year survival rate is between 70–95%, depending on the stage of the disease [15]. In this study, the 5-year OS rate was 100% for all patients during follow-up and this was higher than expected. The follow-up in the upcoming years will be more directive for a better evaluation of OS. The recurrence rate in this study was 16.9%, which was concordant with recently published studies (recurrence rates between 10–35%) [8, 9, 16]. Invasive implants, micropapillary architecture, and cystectomy during FSS rather than USO were associated with recurrence and a relatively worse prognosis in various studies [16–18]. Cystectomy was a significant factor for decreased 5-year RFS in early-stage and advanced-stage patients in this study. Moreover, USO seemed to be superior to cystectomy in terms of recurrence. Similarly, a higher recurrence risk after cystectomy has been reported in 2 recent studies [17, 18]. Tal et al. reported that the contralateral ovary was the main recurrence site in USO-treated patients and it was the same ovary in the patients who underwent cystectomy [19]. In the current study, the same ovary was the main recurrence localization for cystectomy patients while the contralateral ovary was the main localization for USO patients. Both locations are easily manageable when recurrence occurs. In addition to these findings, no disease recurrence occurred in patients who had undergone BSO±TAH, even in advanced-stage disease.

Limitations for the surgical management of BOTs were also considered. These considerations predominantly focus on the abandonment of hysterectomy or BSO at younger ages. At this point, it is important to state that in this study, no recurrences occurred in the BSO±TAH group and all of the recurrences were observed in FSS patients with an acceptable rate, which was similar to the literature [20]. On the other hand, there have been many studies reporting similar PFS and OS results for FSS when compared with standard surgery [6, 16, 21]. Good overall survival results promote the FSS approaches, despite the higher risk of recurrence. Thus, patient-based evaluation, including the selection of FSS candidates and the selection of the surgical approach, plays an important role in the management of patients of reproductive age with BOTs. Moreover, the experience of the centers regarding gynecologic cancer surgery, intraoperative observation, and FSS approaches would affect these results. Increased risk of recurrence for FSS should be emphasized during patient counseling and patients should be well-informed that the recurrence risk is very low in patients undergone BSO.

Lymphadenectomy is another arguable issue in the management of BOTs. Although there are studies that have suggested the avoidance of LND in apparent stage I disease [22], lymphadenectomy has not been completely excluded in the management of BOTs [23]. Lymphadenectomy did not affect RFS in this study. The retrospective nature of the current study was an obstacle to making recommendations but may constitute a kernel point for a larger prospective series for the re-evaluation of lymphadenectomy in the management of BOTs.

Another important issue regarding FSS for BOTs is the pregnancy outcomes, and many studies have been presented with the increasing number of FSS approaches. The majority of women with a history of BOT surgery conceive spontaneously [10] and this study was also in agreement with this datum. Follow-up without intervention may be a feasible approach in these patients, with lower cost and applicability. Moreover, ART can also be used in the case of infertility, low ovarian reserve, or patient desire without compromising their prognosis [10]. Pre-conceptional counseling, co-decision with the patient, and a patient-based approach would constitute this management. Published literature on pregnancy outcomes has revealed a pregnancy rate between 32% and 63% after FSS for BOTs [8-10]. The pregnancy rate was 79% in the current study for the women who attempted to conceive.

There was no difference in obstetric outcomes of surgical intervention between cystectomy and USO in this study. In a recent study, pregnancy rates were similar among patients who underwent bilateral cystectomy vs unilateral adnexectomy plus contralateral cystectomy in patients with bilateral BOTs[24]. Bilateral cystectomy was associated with shorter RFS, in this study.

The substantial number of FSS patients, standard management of a tertiary institution, and long-term follow-up seemed to be the major strengths of the current study. The retrospective design, limited number of advanced-stage patients, and monocentric nature of this study were its notable limitations.

Fertility sparing was associated with an increased risk of recurrence and lower RFS in patients with BOTs. Patients should be informed in detail about the recurrence risk and survival issues. USO seems to be associated with a longer RFS when compared to cystectomy. Nevertheless, FSS seems to be a safe approach for women with BOTs of reproductive age, as it does not influence overall survival. There is limited data on fertility preservation and the new WHO ovarian cancer classification. Further studies may contribute to the literature.

ACKNOWLEDGEMENTS

None.

DISCLOSURE

No disclosures.

CONFLICT OF INTEREST

The authors declare there are no conflicts of interest, financial or otherwise, related to the material presented herein.

FUNDING

None.

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Table 1

Characteristics of the Patients
	n	%
Age Group ≤ 35 > 35	76 66	53.5 46.5
Tumor Histology Serous Mucinous Seromucinous Endometrioid	94 34 13 1	66.2 23.9 9.2 0.7
Stage Early Advanced	123 19	86.6 13.4
Surgical Procedure Cystectomy USO BSO ± TAH	37 61 44	26.0 43.0 31.0
Fertility Sparing Yes No	94 48	66.2 33.8
Lymphadenectomy Yes No	106 36	74.6 25.4
Microinvasion Yes No	42 100	29.6 70.4
Abbreviations: USO: Unilateral salpingo-oophorectomy, BSO: Bilateral salpingo-oophorectomy, TAH: Total abdominal hysterectomy

Table 2

Univariate and Multivariate Analyses of the Prognostic Factors for RFS in Early-Stage Patients
Factor	n	Univariate Survival Analysis	Multivariate Survival Analysis
Factor	n	p-value	HR	95% CI	p-value
Age Group ≤ 35 > 35	63 60	0.008	0.70	0.15–3.23	0.643
Histology Serous Non-Serous	76 47	0.455
Surgical Procedure Cystectomy USO BSO ± TAH	31 53 39	0.000	4.28	1.40–13.08*	0.011* 0.039
Fertility Sparing Yes No	80 43	0.005	0.00	0.00-3.15	0.951
Lymphadenectomy Yes No	88 35	0.162
Microinvasion Yes No	32 91	0.269
Abbreviations: HR: Hazard ratio, CI: Confidence interval, USO: Unilateral salpingo-oophorectomy, BSO: Bilateral salpingo-oophorectomy, TAH: Total abdominal hysterectomy.
*Cystectomy vs USO

Table 3. Recurrence Patterns

Abbreviations: FSS: Fertility-sparing surgery

Table 4. Obstetric outcomes

Abbreviations: FSS: Fertility-sparing surgery

Borderline Ovarian Tumors: Recurrence Patterns and Management

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Abstract

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TAKE HOME MESSAGE

1. Introduction

2. Materials and Methods

3. Results

4. Discussion

Declarations

References

Tables

Supplementary Files

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