Update of Laparoscopic Surgery in Borderline Ovarian Tumor: Systematic Review

Background : Borderline ovarian tumor (BOT) predominantly affects young women and is often diagnosed at an early stage. BOT accounts for 15% of all epithelial tumors. In this regard, a minimally invasive surgical approach and the ability to preserve fertility, without increasing the incidence of recurrences or worsening the prognosis, are crucial. This review aims to provide an update on the role and indications of laparoscopic surgery in BOTs. Methods : The electronic research was performed on Pubmed, Medline, and Embase. Articles published in the last 20 years (2004–2023) were included, and the following keywords were used: ‘borderline ovarian tumor’ and ‘laparoscopic surgery’, ‘borderline ovarian tumor’ and ‘minimally invasive surgery’, ‘borderline ovarian tumor’ and ‘fertility sparing’, ‘borderline ovarian tumor’ and ‘recurrence’ and ‘Borderline ovarian tumor’ and ‘relapse’. The agreement about potential relevance was reached by consensus of the researchers and according to PRISMA statement guidelines. We thoroughly reviewed all bibliographies to assess the inclusion of any further eligible studies. We excluded studies that did not align with the study’s objectives. Results : The electronic database search yielded 767 total studies. Of whom, 188 were published before 2004, 84 were case reports, and 45 were not in the English language. Of the remaining 450 studies, 148 were considered eligible for the study. We included 20 studies in this review. Conclusions : Despite the latest guidelines recommending an open approach for the treatment of BOT, the laparoscopic approach has gained popularity as a feasible and safe alternative. The use of an endo-bag, along with advanced laparoscopic skills, has made the minimally invasive approach increasingly safe, with oncological outcomes almost comparable to those of reference. Moreover, in the context of fertility-sparing surgery (FSS), laparoscopy seems to be associated with improved obstetrical outcomes, without detrimental effects on overall survival and disease-free survival. Therefore, the laparoscopic approach in the treatment of BOT appears to be a safe and effective option, especially in the case of FSS.


Introduction
Borderline ovarian tumors (BOTs) are a group of epithelial tumors characterized by uncontrolled hyperproliferation, and mild nuclear atypia without stromal invasion [1].BOT accounts for 15% of all epithelial tumors and it can be diagnosed as an adnexal mass with aspecific symptoms (dyspareunia, abdominal pain, or abdominal swelling), or incidentally during routine gynecological examinations.The ultrasound findings should be accompanied by serum tumor markers (usually elevated but nonspecific) [2].BOT can be associated with stromal micro invasion, intraepithelial carcinoma, and non-invasive peritoneal implants.Nevertheless, BOTs are mostly limited to the ovaries at the time of diagnosis with the International Federation of Gynecology and Obstetrics (FIGO) stage I or II (75% stage I).They have a good prognosis with a 5-10 year overall survival (OS) rate of 95-97%, and surgery is curative [3][4][5].
As stated by the European Society for Medical Oncology (ESMO) and European Society of Gynaecological Oncology (ESGO) 2019 guidelines, the treatment consists of ipsilateral salpingo-oophorectomy, and peritoneal staging after careful exploration of the peritoneal cavity to detect potentially suspicious implants.Peritoneal surgical staging is based on peritoneal washing, peritoneal biopsies (pelvic peritoneum, paracolic gutters, diaphragm), and omentectomy (at least infracolic) [7][8][9].
The recommended surgical approach is laparotomy (LPT) since it allows better macroscopic visualization and lower risk of cyst rupture during dissection, which would negatively impact FIGO staging, compared to minimally invasive surgery (MIS) [7,[10][11][12].
Nowadays, with the advent of accurate and innovative instrumentation, MIS in expert hands has taken more widespread in surgical BOT treatment [13,14].Since BOT often occurs in young patients [15], both minimally invasive surgical approaches and fertility-sparing surgery (FSS) are essential aspects to reduce postoperative complications and preserve childbearing desire.Several studies report excellent long-term survival rates among stage I patients treated with conservative surgery.This underscores the safety and efficacy of fertility-sparing and ultrafertility-sparing procedures, which involve either unilateral salpingo-oophorectomy or cystectomy, respectively [16][17][18].However, several concerns are still unresolved in the BOT treatment.When to perform fertility-sparing vs. ultra fertility-sparing surgery, the risk of intraoperative cyst rupture, or which adnexal mass sizes can be treated laparoscopically remain open questions [19][20][21].
In this manuscript, a systematic review of the literature of the last 20 years regarding the minimally invasive laparoscopic approach in BOT was performed.
We evaluated tumor diameter, cyst rupture, fertilitysparing approach, pregnancy rate, and oncological outcome in terms of recurrence rate, disease-free survival (DFS), and OS in patients treated by laparoscopy vs. open laparotomy.

Materials and Methods
From May to July 2023, an electronic research was performed on Pubmed, Medline, and Embase.For study purposes, articles published in the last 20 years (2004-2023) were included and the following keywords were used: 'borderline ovarian tumor' and 'laparoscopic surgery', 'borderline ovarian tumor' and 'minimally invasive surgery', 'borderline ovarian tumor' and 'fertility sparing', 'Borderline ovarian tumor' and 'recurrent' and 'Borderline ovarian tumor' and 'relapse'.
The consensus on potential relevance was achieved through the collective agreement of the researchers and according to PRISMA statement guidelines (see Fig. 1) [22].Two double-blind authors (IR and GM) read all abstracts.After the initial selection, the researchers assessed the complete texts of the chosen papers and independently extracted pertinent data concerning study design and outcomes.The present review encompasses systematic reviews, meta-analyses, clinical trials, and original articles.Studies deemed incompatible with the study's objectives, case reports and duplicate studies were excluded.More-over, only articles written in English were included.
All references were examined to assess the inclusion of any additional eligible studies.Redundant studies were excluded from the analysis.In the case of doubtful articles, further opinion was asked to a third author (VAC).

Results
The electronic database search yielded 767 total studies.Of whom, 188 were published before 2004, 84 were case reports, and 45 were not in the English language.Of the remaining 450 studies, 148 met the eligibility criteria for the study.One-hundred-twenty-eight studies not fitting the review scope were excluded.The studies' selection flowchart is shown in Fig. 1.
To better illustrate the results of the research and describe scientific evidence about laparoscopy and BOT surgical treatment, the main findings are reported in chapters: tumor diameter, cyst rupture and surgical approach; laparoscopic approach in fertility sparing surgery; oncological outcomes and surgical approach.

Tumor Diameter, Cyst Rupture and Surgical Approach
Cyst diameter is crucial in surgical approach selection.The risk of cyst rupture during the procedure and the inherent difficulty in its extraction may limit the use of MIS.Undoubtedly, the use of endo-bag for tumor extraction is mandatory, since port-site metastasis occurrence is reported also in the case of BOT [39].
In any case, there is no real established cut-off for opting for open surgery vs. laparoscopy.In 2004 Maneo et al. [13] conducted a retrospective study on 62 patients with BOT.The authors found that a tumor diameter larger than 5 cm in the laparoscopy group was associated with a higher risk of tumor relapse compared to patients with smaller cysts (odds ratio (OR): 9.7, p = 0.02).The authors concluded that laparoscopy should be discouraged for tumors larger than 5 cm, however, subsequent analysis showed laparoscopic safety and feasibility also for larger masses [13].
Romagnolo et al. [20] in a case series on 113 patients showed that a tumor diameter >10 cm was significantly associated with a preference for the laparotomic approach.Cyst rupture with tumor spillage was significantly higher in the laparoscopy group than in the open laparotomy group (34.6% vs. 6.6%, p < 0.0001).However, the recurrence rate was similar between the two groups (13.5% in the laparoscopy groups vs. 9.8% in the open laparotomy group, p > 0.05), and only the use of cystectomy was associated with reduced progression-free survival (PFS) [20].
In line with these results, Fauvet et al. [21] reported a significantly higher median diameter of the cyst in the laparotomy compared to the laparoscopic group (13.5 vs. 7.5 cm, respectively, p < 0.0001), and cyst rupture was significantly higher in the laparoscopy group (p < 0.001).On the other hand, the authors found that the conservative surgery was the only factor affecting the recurrence rate [21].
Song et al. [19] compared single-port laparoscopy, multi-port laparoscopy, and laparotomy.The median diameter was significantly different between the three groups (p < 0.001): 9 cm, 8 cm, and 14 cm, respectively.The maximal diameter treated by laparoscopy was 17 cm, and the cyst rupture occurrence rate was not reported in these studies.
According to Ødegaard et al. [23], when considering a maximal diameter of 10 cm, tumor spillage is significantly higher with a laparoscopic approach than with open laparotomy.
On the contrary, in 2020 Kang et al. [24] conducted a retrospective study considering only patients with suspected BOT treated by single-port laparoscopy (n = 105) or open laparotomy (n = 73).The mean tumor diameter was 20 cm in both groups, and no significant difference was registered in intraoperative tumor rupture (11.4% vs. 6.8%,p = 0.307).Remarkably, a technique involving controlled cyst rupture has been described.This method utilizes a wound retractor and aspiration of the cyst's contents, without compromising the continuation of the procedure through laparoscopy [24].In line with these results Desfeux et al. [25] in a retrospective series on 118 patients with BOT, found an incidence of intraoperative tumor rupture of 9%, without differences between laparoscopy and laparotomy (p = 0.1).
In summary, current literature does not establish a unanimous maximal cut-off to favor laparotomy over laparoscopy or vice versa.Some authors have reported a hig- Laparoscopic treatment in BOTs should be reserved to masses smaller than 5 cm.When conservative therapy is desired, a salpingo-oophorectomy should be performed.In case of bilateral disease, cystectomy could be an option in women who wish to preserve fertility, although they are at high risk of relapse.Laparoscopic surgery and open surgery showed similar survival outcomes in BOTs.The surgical outcomes of laparoscopic surgery were more favorable.
In the multivariate analysis, age less than 40 years, nonmucinous histologic type, and extraovarian tumor implants were independent risk factors for decreased DFS.
Abbreviations: BOT, borderline ovarian tumor; LPS, laparoscopy; LPT, laparotomy; SPA-LPS, single-port access laparoscopy; MP-LPS, multi-port laparoscopy; FSS, fertility sparing surgery; DFS, disease free survival; FU, follow-up.The ultra-conservative approach (BC) has superior reproductive outcomes compared with the standard approach, albeit with an increased oncological risk.One died for recurrent low-grade ovarian carcinoma A very low recurrence rate was observed.Neither advanced FIGO stage, nor incomplete staging, nor peritoneal implants were associated with a higher recurrence rate, contrary to findings in other studies.Further studies are necessary to investigate additional recurrence risks.
her risk of cyst rupture during laparoscopy [20,21,23]; however, this association is not consistently confirmed in all available case series, even for large masses [24][25][26].Furthermore, when considering the oncological outcome, cyst rupture does not necessarily affect the prognosis, and the use of an endo-bag provides additional assistance to the surgeon in preventing tumor spillage into the abdominal cavity [40,41].In conclusion, when deciding the optimal surgical approach for BOT treatment, tumor dimension should not be the sole parameter to consider.Instead, the surgeon's laparoscopic skills and the risk of malignancy at the final histology should also be taken into account [42].

Laparoscopic Approach in Fertility Sparing Surgery
Fertility preservation is a crucial concern in the treatment of BOT, especially considering that one-third of patients are younger than 40 years at the time of diagnosis [43,44].In this specific group of patients, laparoscopy emerges as a preferable option compared to laparotomy offering improved cosmetic outcomes [45,46].Furthermore, some authors reported the feasibility of fertility-sparing surgery not only in early-stage disease but also in patients with peritoneal implants [47].
Chen et al. [27] analyzed the oncological and fertility outcomes of 122 patients undergoing FSS via laparotomy (n = 70) and laparoscopy (n = 52).Recurrence rate (RR) and DFS did not differ depending on the surgical approach (7.1% vs. 5.8% and 25.5 months vs. 26.3months, p > 0.05).The pregnancy rate was respectively 66.7% in the laparotomy group and 88.9% in the laparoscopy group, but this difference did not reach statistical significance (p = 0.16).
Looking at the feasibility of conservative treatment in advanced-stage borderline ovarian tumors, Uzan et al. [28] retrieved the outcomes of 39 patients affected by BOT and conservatively treated.The laparoscopic approach was used in 21 patients, the laparotomic approach in 10 patients, and in 8 cases the surgical approach was unknown [28].In their study, 22 patients (56%) relapsed, and no association with the type of surgical approach was observed.Five and ten-year overall survival (OS) rates were 100% and 92%, respectively.According to the authors, conservative surgery is feasible in advanced-stage patients with peritoneal implants.However, an adequate follow-up is necessary because of the higher recurrence rate.Moreover, the treatment of recurrence can once again involve a fertilitysparing approach if technically feasible.Eighteen pregnancies were observed in 14 patients, however, the pregnancy rate was not assessed because the desire for pregnancy was not registered.
A study conducted by Palomba et al. [29] in 2007, and then extended in 2010, compared the fertility outcomes in patients affected by bilateral stage I BOT treated by conservative surgery.In these studies, patients were divided into two groups: the experimental group underwent ultraconservative treatment (bilateral cystectomy) while the control group underwent conservative treatment (unilateral salpingo-oophorectomy plus contralateral cystectomy).Surgery in both groups was conducted with a laparoscopic approach and consisted of complete peritoneal staging.The study showed significantly higher serum folliclestimulating hormone (FSH) levels and a higher cumulative pregnancy rate, with a shorter time to conceive in the experimental group compared to the control group.Therefore, in the case of bilateral serous BOTs bilateral cystectomy should be performed if technically feasible.
In 2010 Palomba et al. [30] published the oncological and obstetrics outcomes, in the same group of patients, after an 11-year follow-up.There was no significant difference between the two groups in the recurrence rate, neither in the multiple recurrence rate, in age at first recurrence, nor in the age of patients who received non-conservative surgery.On the other hand, a much shorter progression free survival was observed in patients who underwent bilateral cystectomy compared with those who received unilateral salpingo-oophorectomy plus contralateral cystectomy (p < 0.01).
Trillsch et al. [31] in 2014 conducted a sub-analysis on 950 patients with BOT, comparing patients under 40 years of age and older than 40 years.The laparoscopic approach was significantly more frequently used in the younger group (p < 0.001).At multivariate analysis, advanced FIGO stage and FSS were associated with reduced PFS.However, the authors emphasize that in young patients the disease relapsed as BOT.Therefore, patients who wish to retain fertility should be counseled about the potential risk of recurrence without a detrimental effect on OS.
In 2018 Zhao et al. [32] compared short-term outcomes and pregnancy rates in 74 patients undergoing FSS for BOT.Out of the 74 patients, 44 underwent laparotomic treatment, while 30 received laparoscopic treatment.Interestingly, there was no statistically significant difference in the recurrence rate observed between these two groups.The overall pregnancy rate was 33.8% (25 out of 74 patients), with 30% (9 patients) in the laparotomy group and 36.4% (16 patients) in the laparoscopic group achieving pregnancy during the follow-up period.Interestingly, the pregnancy rate was significantly higher in the laparoscopy group when considering incomplete surgical staging (complete laparoscopic exploration with incomplete surgery).
In conclusion, laparoscopy is widely used for fertilitysparing surgery in BOT patients, with good oncological outcomes.However, a higher recurrence risk should be taken into account, especially in case of a higher FIGO stage and incomplete staging.A minimally invasive approach with limited surgical gestures seems also to be associated with a good impact on obstetric outcomes.Indeed, laparoscopic FSS is the preferable approach in young patients with BOT who wish to preserve fertility.

Oncological Outcomes and Surgical Approach
BOT is typically diagnosed at an early stage, with a 5-year OS rate reaching 95-97% [48].However, the prognosis is primarily influenced by recurrences, even long after the primary treatment, therefore a long-term follow-up is suggested [47].
In a large retrospective analysis including 950 patients, du Bois et al. [33] analyzed risk factors for BOT recurrence.The surgical approach was laparoscopy in 38.3% of cases, and laparotomy in 61.6%.The recurrence rate was 7.8%.At multivariate analysis, the authors found that higher stage, residual tumor, and incomplete staging are independent prognostic factors for recurrence.On the contrary, recurrence rate and OS are not affected by the type of surgical approach.
In an important retrospective study conducted by Wu et al. [34] the outcomes of 233 patients affected by BOT at various stages and submitted to different methods of surgery were analyzed in terms of five-year and ten-year OS and PFS.16.7% of the patients were treated by laparoscopic approach and 83.3% by laparotomy, 30.9% underwent complete staging, while 62.2% received FSS.Fiveyear and ten-year OS were 97.6% and 96.4%, and PFS were 92.7% and 88.2% in the laparoscopic compared to the laparotomic group.Of the 21 patients who had a recurrence, 7 had an invasive carcinoma recurrence and 5 of them died from the disease.Four out of 5 patients who died were stage II or higher at first surgery, and only one had stage IC mucinous BOT with invasive relapse.The other 14 patients had recurrent borderline tumors or implants.Data showed no difference in recurrence-free survival (RFS) or OS between laparoscopic and laparotomic approaches and between fertility-sparing and non-sparing surgery.Higher stage, excisional type (cystectomy vs. adnexectomy), and higher serum CA125 level (≥144 U/mL) were independent prognostic factors for 5-year PFS.
Mucinous borderline tumor (mBOT) represents a particular condition since they often present as large masses and are associated with a higher recurrence risk even in the form of invasive disease [47].In a retrospective study by Koskas et al. [35], the management and outcome of 97 patients diagnosed with mBOT were analyzed to investigate prognostic factors for disease recurrence.43% of patients underwent laparoscopy, and 56% received open laparotomy.There were 14 recurrences in 13 patients, 6 in the form of recurrent borderline tumors and 6 in the form of invasive disease.5-year and 10-year DFS was, respectively, 81.6% and 77.3% in the laparoscopy compared to the laparotomic group.Of these 13 patients who relapsed, 8 had received unilateral cystectomy as initial surgery.Neither the surgical approach during surgery, perioperative tumor rupture, conservative surgery, nor incomplete staging were associated with an increased risk for recurrence.Cystectomy was the only factor significantly associated with the risk of recurrence.
A retrospective study conducted by Lenhard et al. [36] assessed long-term survival and relapse rate of 113 patients diagnosed with BOT.The surgical approach was laparoscopic in 15.9% of the patients and laparotomic in 84.1% of the patients.The mean follow-up time was 9.6 ± 6.6 years.The overall 5-year and 10-year survival rates were 98.0% and 92.9%, respectively.During the follow-up period, relapse occurred in 10 patients (10.1%, 10/99).Among the various factors analyzed, only a higher FIGO stage at diagnosis (above IA) was significantly associated with relapse occurrence.Neither the choice between laparoscopic and laparotomic approach, nor the type of surgery (conservative or ultraconservative) versus radical surgery, showed any significant impact on oncological outcomes.
Camatte et al. [37] reviewed the clinical outcome after laparoscopic treatment of 34 patients affected by BOT.Among the 34 patients, 23 underwent primary surgery, while 11 patients received laparoscopic treatment for a BOT recurrence.After a median follow-up time of 45 months, six patients experienced a relapse, with three cases observed in each group.The median time to recurrence was 29 months.Notably, all patients were treated laparoscopically, and none had recurrent invasive cancer.
A study published in 2023 by Kipp et al. [38] analyzed the data of 42 women with BOT.Among these patients, 29 (69%) underwent laparoscopic surgery, while 13 (31%) received laparotomic surgery.The majority of women were diagnosed at FIGO stage I (85.8%).Four patients (9.6%) received FSS.The study observed two cases of relapse (4.8%), and one patient succumbed to recurrent low-grade ovarian carcinoma, which occurred 44 months after the primary surgery for a mucinous BOT.Interestingly, the study found no significant associations between the surgical approach (laparoscopic vs. laparotomic), advanced FIGO stage, incomplete staging, or peritoneal implants with a higher recurrence rate.These findings highlight the need for further research to understand the factors influencing recurrence in BOT cases.
In conclusion, BOT has optimal long-term survival, but the prognosis can be affected by the long-term risk of recurrence [36,47].Therefore, a long follow-up is recommended for these patients.The relapse itself does not change the OS as it mostly recurs as BOT.Nevertheless, there's a risk of evolution to invasive carcinoma that appears to be higher in older patients [31] and in mucinous BOT [38].In the case of mBOT a salpingo-oophorectomy may be preferred to the cystectomy.Despite international guidelines favoring open surgery as the standard of care, laparoscopy remains a reasonable option, even in cases of relapsed disease, as there is no significant correlation between the laparoscopic approach and the recurrence rate based on the most updated literature [37].

Conclusions
In conclusion, current guidelines recommend open laparotomy as the preferred approach for suspicious ovarian masses, but laparoscopy has gained popularity as a feasible and safe alternative for treating BOT.While some studies suggest a higher risk of cyst rupture during laparoscopy, it does not necessarily affect the oncological prognosis.Moreover, the use of an endo-bag, along with advanced laparoscopic skills, can help reduce the occurrence of tumor spillage.Laparoscopy is widely employed for FSS in BOT patients, demonstrating more favorable obstetric outcomes compared to open approach, without detrimental effect on OS and DFS.Although relapse does not significantly impact overall survival, a long-term risk of recurrence exists, but laparoscopic surgery does not appear to increase this risk.Finally, based on the existing retrospective evidence, laparoscopy emerges as a safe and viable choice for the management of BOT.However, additional confirmation through prospective studies is necessary to further establish laparoscopy efficacy and safety in BOT patients.

Table 1 .
± 41.1 months Laparoscopy in borderline ovarian tumors is associated with a higher rate of cyst rupture and incomplete staging.Moreover, a higher recurrence rate is observed.Continued.

Table 2 . Laparoscopic approach in fertility sparing surgery.
FSS is safe and beneficial for most young BOTs.USO through laparoscopy should be recommended as the first choice.To the patients with bilateral tumors, elevated CA125, extra-ovary tumor or mucinous type, conservative surgery should be carefully chosen and subsequent pregnancy should be attempted in short term.
implants) but there's a high risk of relapse.Nevertheless, this high recurrence rate has no impact on survival.Conservative surgery is feasible in patients with a borderline tumor of the ovary and noninvasive peritoneal implants.In case of persistent infertility following treatment of the BOT, an in vitro fertilization procedure can be cautiously proposed.

Table 3 . Oncological outcomes and surgical approach.
Although BOT has an excellent prognosis, they are not exempted from a risk of recurrence.Stage II/III (or invasive implants), cystectomy and higher pre-operative serum CA125 were independent variables predicting recurrence.