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Safety of ovarian conservation and fertility preservation in advanced borderline ovarian tumors

      Objective

      To assess the impact of a fertility-sparing approach on disease recurrence in women with advanced borderline ovarian tumors.

      Design

      Historic cohort study.

      Setting

      A tertiary referral center for gynecological oncology patients and a university teaching hospital.

      Patient(s)

      Consecutive patients with advanced borderline ovarian tumors defined as stage IC and above, treated at a single institution during a span of 30 years.

      Intervention(s)

      Data on surgical approach (e.g., fertility sparing, ovarian conserving) as well as histopathology, disease stage, CA-125 level, and use of chemotherapy were collected from the medical records, and their impact on disease recurrence was assessed.

      Main Outcome Measure(s)

      Recurrence-free interval. Its association with the type of surgery and with other clinical and pathological features was assessed using the Kaplan Meier and Cox proportional hazards methods.

      Result(s)

      Fifty-nine patients with advanced disease were identified. Median follow-up was 55.3 months. Mean age at diagnosis was 35 years. Most of the tumors (51, 84.4%) had serous histology. Twenty-seven patients (45.8%) developed recurrences and 6 (10%) died of their disease. Mean time to recurrence was 30.6 months. Of 44 women ≤40 years, 33 (75%) had a fertility-sparing procedure. Fertility preservation was not associated with disease recurrence. A total of 34 pregnancies and 26 live births were documented among 21 patients attempting conception.

      Conclusion(s)

      Borderline ovarian tumors carry a favorable prognosis, even at an advanced stage. Fertility preservation was not found to be associated with an increased risk of relapse in young patients with advanced disease, and may be reasonably considered.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/helpmanl-fertility-preservation-advanced-borderline-tumors/
      Borderline ovarian tumors (BOT) account for 10%–20% of all epithelial ovarian cancer (
      • Skirnisdottir I.
      • Garmo H.
      • Wilander E.
      • Holmberg L.
      Borderline ovarian tumors in Sweden 1960–2005: trends in incidence and age at diagnosis compared to ovarian cancer.
      ,
      • Morris C.R.
      • Liu L.
      • Rodriguez A.O.
      • Cress R.D.
      • Snipes K.
      Epidemiologic features of borderline ovarian tumors in California: a population-based study.
      ), and are typically indolent neoplasms (
      • Morris C.R.
      • Liu L.
      • Rodriguez A.O.
      • Cress R.D.
      • Snipes K.
      Epidemiologic features of borderline ovarian tumors in California: a population-based study.
      ,
      • Kurman R.J.
      • Trimble C.L.
      The behavior of serous tumors of low malignant potential: are they ever malignant?.
      ,
      • Leake J.F.
      • Currie J.L.
      • Rosenshein N.B.
      • Woodruff J.D.
      Long-term follow-up of serous ovarian tumors of low malignant potential.
      ,
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ). A minority of patients present at an advanced stage, and even those who do may expect extended survival (
      • Leake J.F.
      • Currie J.L.
      • Rosenshein N.B.
      • Woodruff J.D.
      Long-term follow-up of serous ovarian tumors of low malignant potential.
      ,
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ,
      • Prat J.
      • de Nictolis M.
      Serous borderline tumors of the ovary: a long-term follow-up study of 137 cases, including 18 with a micropapillary pattern and 20 with microinvasion.
      ,
      • Zanetta G.
      • Rota S.
      • Chiari S.
      • Bonazzi C.
      • Bratina G.
      • Mangioni C.
      Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.
      ). Disease extent at diagnosis, as well as histologic subtype and other characteristics have been shown to be important prognostic factors (
      • Ren J.
      • Peng Z.
      • Yang K.
      A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors.
      ,
      • Shih K.K.
      • Zhou Q.
      • Huh J.
      • Morgan J.C.
      • Iasonos A.
      • Aghajanian C.
      • et al.
      Risk factors for recurrence of ovarian borderline tumors.
      ).
      Median age at diagnosis is 40–55 years in different reports (
      • Skirnisdottir I.
      • Garmo H.
      • Wilander E.
      • Holmberg L.
      Borderline ovarian tumors in Sweden 1960–2005: trends in incidence and age at diagnosis compared to ovarian cancer.
      ,
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ,
      • Wong H.F.
      • Low J.J.
      • Chua Y.
      • Busmanis I.
      • Tay E.H.
      • Ho T.H.
      Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004.
      ,
      • Hannibal C.G.
      • Huusom L.D.
      • Kjaerbye-Thygesen A.
      • Tabor A.
      • Kjaer S.K.
      Trends in incidence of borderline ovarian tumors in Denmark 1978–2006.
      ). Because BOT are often diagnosed in women of childbearing age, fertility is an important consideration in planning treatment. Traditionally, fertility-sparing surgery had only been offered to patients with tumors limited to the ovary (
      • Kaern J.
      • Trope C.G.
      • Abeler V.M.
      A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review of clinicopathologic features and treatment modalities.
      ). However, more recent reports suggest that fertility preservation may be safely offered to appropriately selected patients with advanced disease (
      • Zanetta G.
      • Rota S.
      • Chiari S.
      • Bonazzi C.
      • Bratina G.
      • Mangioni C.
      Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.
      ,
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary.
      ). Because most published series are heterogeneous with a preponderance of cases with early stage disease, data on the safety of ovarian conservation in advanced borderline tumors are lacking.
      The primary objective of this study was to establish the safety of fertility preservation and specifically, ovarian conservation in young women with advanced BOT. A secondary objective was to investigate the impact of previously described prognostic features on disease outcome in this cohort of advanced tumors.

      Materials and methods

       Study Population

      Consecutive patients with advanced BOT treated at our institution between 1981 and 2011 were identified from a prospectively maintained database. Advanced disease was defined as tumors not confined to the ovaries at diagnosis (i.e., stage IC and above).

       Data Collection

      Medical records, including patient charts, operative and pathology reports, and chemotherapy records were reviewed. Data were extracted from patient records and included clinical and demographic variables at presentation: patients' age, disease stage, and CA-125 level at diagnosis. Data were generally complete on medical history, pathological and surgical data. Missing data on fertility and gestational outcome were completed by telephone interview. This was done for all patients who had fertility-preserving surgery and were alive at the time of data collection (30 patients), as recording of fertility and gestational information in the gynecological oncology follow-up record was poor. The FIGO 2009 staging system for epithelial ovarian tumors was used for determining disease stage. This study was approved by the Institutional Review Board at Chaim Sheba Medical Center in adherence with Helsinki Convention principles.

       Pathology

      Histopathological features included tumor type (serous, mucinous, or endometrioid), ovarian surface involvement, and implant type (invasive vs. noninvasive) in patients with peritoneal disease. The histologic criteria used for the diagnosis of BOT included proliferation of the epithelial cells lining the ovarian cysts with the formation of papillary projections present in more than 10% of the lining epithelium, mild-to-moderate nuclear atypia, minimal mitotic activity, and the absence of destructive stromal invasion. A micropapillary pattern was reported when complex micropapillary structures in a filigree pattern were present in a serous borderline tumor. Intraepithelial carcinoma was diagnosed when borderline tumor showed severe nuclear atypia but no stromal invasion was identified. Microinvasion was diagnosed when a focus of stromal invasion was limited to an area of no more than 10 mm2. No pathological review of the specimens was undertaken for this series. Sheba Medical Center is a major referral center and the largest gynecological oncology practice in the country, thus the original pathology reporting was done by pathologists with significant expertise.

       Surgical Information

      Data were also collected on the completeness of surgical staging and on surgical approach used. Many patients had initial cystectomy and were referred to our center after the diagnosis of BOT had been made. These patients may have had a second, definitive surgical procedure after referral. The extent of surgery was determined by combining primary and completion surgery. Fertility preservation was defined as surgery sparing the uterus and some ovarian tissue to allow spontaneous conception in the future. Conservation of an involved ovary was defined as the removal of tumor from an ovary with macroscopic disease yet leaving apparently healthy ovarian tissue in situ. Surgical staging was defined as either [1] incomplete: peritoneal, including visual inspection of peritoneal surfaces, omentectomy, or omental biopsy and removal of any visible tumor; or [2] complete, including lymph node sampling. Use of adjuvant chemotherapy and follow-up data, including disease recurrence, treatment of recurrence(s), and survival were also collected.

       Statistical Analyses

      Primary outcome was defined as the disease-free interval, calculated as the interval of time from definitive surgery to first recurrence or last follow-up. Overall survival was also investigated as a secondary outcome. Recurrence-free interval and overall survival were assessed using the Kaplan Meier method and the log-rank test. The associations of clinical, pathological, and surgical variables with the disease-free interval were assessed using the Cox proportional hazards methods. The association between disease recurrence and the following variables was evaluated: patients' age, disease stage (stage IC vs. stage II-III), CA-125 level at diagnosis; tumor histology (serous vs. mucinous) and pathological characteristics such as a micropapillary pattern, intraepithelial carcinoma, and microinvasion; implant type (invasive vs. noninvasive) and use of chemotherapy in patients with peritoneal disease (n = 34); fertility preservation, and conservation of an involved ovary in women 40 years old and younger (n = 44). All statistical analyses were performed on SPSS software.

      Results

      A total of 246 patients with BOT were treated in the Sheba Medical Center between 1981 and 2011; 59 of these had advanced disease at presentation and are the subject of this report. Twenty-three of the patients (39%) had stage IC disease, 8 patients (13.5%) had stage II disease, and 28 patients (47.5%) had stage III disease. Mean CA-125 level before surgery was 406 (range, 5–2,150). Staging was incomplete for 10 patients; 17 patients had peritoneal staging without lymph node sampling and 33 patients had complete surgical staging. The principal factor appearing to determine the extent of surgical staging was the date of surgery. Only three patients with complete surgical staging (including lymph node sampling) had their procedure after 2006. Microscopic nodal metastases were diagnosed in six patients (18% of those who had complete staging).
      Most tumors (51, 84.4%) were of serous histology, and 14 (27.5%) of these had a micropapillary pattern. Of eight mucinous tumors, three (37.5%) had features of intraepithelial carcinoma. All cases of mucinous tumors were diagnosed at stage IC. Microinvasion was reported in 11 patients (18.6%) with BOT in this study. Of 34 patients with peritoneal disease, 7 (20.5%) had invasive implants. Thirteen patient received chemotherapy: 7 with invasive implants, 1 with noninvasive implants, 3 with nodal involvement, and 2 with stage IC disease.
      Mean age at diagnosis was 35 years (range, 19–81 years). Of 44 women aged ≤40 years at diagnosis, 33 (75%) had a fertility-sparing procedure, leaving the uterus and some intact ovarian tissue in situ. Of these, 17 patients (39%) retained the involved ovary, having cystectomy only and/or resection of ovarian surface metastases. Patients undergoing fertility-sparing surgery were younger and tended to have earlier disease (P = not significant [NS]). Baseline characteristics of patients undergoing fertility-sparing surgery and those whose fertility was compromised at surgery are presented in Table 1.
      Table 1Characteristics of study groups.
      CharacteristicFertility-sparing surgery (n = 33)No fertility-sparing surgery (n = 26)
      Age at diagnosis (y), mean2845
      Tumor histology
       Serous2823
       Mucinous53
      Disease stage
       IC176
       II-III1620
      Invasive implants16
      Chemotherapy310
      CA-125 before surgery, mean183636

       Disease Outcome

      Median follow-up was 55 months (range, 1–281 months). Twenty-seven patients (45.8%) developed recurrences and 6 (10%) died of their disease. Mean time to recurrence was 30.6 months (range, 2.6–92 months). Eleven cases recurred as metastatic disease with noninvasive (1/11) or invasive (9/11) implants. One patient was lost to follow-up after recurrence, and one other was not treated surgically, therefore the histology of her metastatic recurrence is unknown. Fifteen patients had isolated ovarian recurrences; 7 of these occurred in an ovary that had been conserved despite involvement at initial surgery. Only two metastatic recurrences occurred in patients who had ovarian conservation for disease confined to an ovary (stage IC). Both these patients had complete surgical staging at initial surgery. Metastatic recurrences similarly occurred in two patients with stage IC disease who did not have ovarian conservation at primary surgery.
      Most (25/27) initial recurrences were treated surgically. Half (14/27) of the patients who had an initial recurrence, including all patients who recurred with invasive implants, recurred again. At the second relapse, 7 of 14 patients were treated with chemotherapy and only 6 of 14 had surgery (1 patient succumbed to her disease before receiving treatment for a second recurrence).
      Kaplan Meier survival curves for the interval to first disease recurrence are presented in Figure 1. None of the variables assessed were found to be associated with an increased hazard ratio for recurrence (Table 2). Although patients whose fertility was preserved showed a tendency for earlier recurrence (27 vs. 39 months; P = NS), Cox proportional hazards modeling found no association between fertility preservation, the conservation of an involved ovary and an increased hazard ratio for recurrence (Table 2), or with significantly earlier recurrence (Fig. 1). Overall survival was similar, as well, with three patients succumbing to disease in each group, although numbers are too small for definitive conclusions.
      Figure thumbnail gr1
      Figure 1Kaplan Meier survival curves for interval to first disease recurrence. (A) Disease-free survival in patients undergoing fertility-preserving surgery (black) versus those whose fertility was compromised (gray). (B) Disease-free survival in patients in whom an involved ovary was conserved (black) versus those whose involved ovary was sacrificed (gray).
      Table 2Hazard ratios for disease recurrence.
      VariableHRCIP value
      Age at diagnosis (y)0.960.93–1.00.06
      Fertility preservation (in patients <40 y)1.690.61–4.68.31
      Ovarian conservation (in patients <40 y)1.410.59–3.32.44
      Tumor histology
       SerousReference
       Mucinous0.970.29–3.25.96
      Micropapillary pattern (in serous tumors only)1.200.47–3.00.7
      Disease stage
       ICReference
       II-III0.780.35–1.71.53
      Invasive implants (tumors with peritoneal spread only)0.650.19–2.26.5
      Chemotherapy (in advanced disease)0.520.17–1.63.26
      CA-125 before surgery0.990.99–1.00.22
      Note: CI = confidence interval; HR = hazard ratio.
      Among the six patients who eventually succumbed to their disease, the time to death was between 28 and 165 months. Five of the six died of disease after a second recurrence. Half of these patients had fertility-sparing surgery at disease presentation. Two of the six had mucinous borderline tumors. Detailed information on these six patients is presented in Table 3.
      Table 3Six cases of deaths in patients with recurrent borderline ovarian tumor.
      HistologyStageImplantsFertility preservationTime to recurrence (mo)Histology of recurrenceTreatment of recurrence2nd recurrence (mo)Time to death (mo)
      Mucinous1CNoneNo14Invasive implantsSurgical1328
      Mucinous1CNoneYes17Noninvasive implantsSurgical1770
      Serous1CNoneYes10LocalSurgical1331
      Serous3aInvasiveNo92UnknownChemotherapy165
      Serous3bInvasiveNo26Invasive implantsSurgical938
      Serous3bNoninvasiveYes40LocalSurgical1575

       Fertility Outcome

      Among 33 young women treated conservatively with a fertility-sparing procedure, 4 were lost to follow-up and 8 have not attempted to conceive. Of 21 patients who had attempted to conceive at the time of data extraction, there were 34 pregnancies among 18 patients. Fifteen patients underwent fertility treatments, including three of the younger patients who had no immediate plans for conception and elected to have ovarian stimulation with cryopreservation of embryos or oocytes. Pregnancy outcome was excellent with 5 of 34 miscarriages, 1 extrauterine pregnancy, 2 pregnancy terminations, and 26 of 34 live births.

      Discussion

      Borderline ovarian tumors—or tumors with low malignant potential—were classified as a separate entity in the early 1970s, when it was recognized that this subset of epithelial ovarian tumors are set apart by pathological features and clinical behavior. They have a typically indolent course, and are infrequently fatal. Population-based studies report an incidence of 1.5–2.5 in 100,000 (
      • Skirnisdottir I.
      • Garmo H.
      • Wilander E.
      • Holmberg L.
      Borderline ovarian tumors in Sweden 1960–2005: trends in incidence and age at diagnosis compared to ovarian cancer.
      ,
      • Morris C.R.
      • Liu L.
      • Rodriguez A.O.
      • Cress R.D.
      • Snipes K.
      Epidemiologic features of borderline ovarian tumors in California: a population-based study.
      ,
      • Hannibal C.G.
      • Huusom L.D.
      • Kjaerbye-Thygesen A.
      • Tabor A.
      • Kjaer S.K.
      Trends in incidence of borderline ovarian tumors in Denmark 1978–2006.
      ,
      • Mink P.J.
      • Sherman M.E.
      • Devesa S.S.
      Incidence patterns of invasive and borderline ovarian tumors among white women and black women in the United States. Results from the SEER Program, 1978–1998.
      ).
      Because of the rarity of these tumors, there is a paucity of statistically robust data on their natural history and prognosis. One Surveillance, Epidemiology, and End Results (SEER) population-based report describes survival rates of 95% overall, and approximately 90% in patients with advanced disease (
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ). Other studies have corroborated this difference in prognosis across stages (
      • Morris C.R.
      • Liu L.
      • Rodriguez A.O.
      • Cress R.D.
      • Snipes K.
      Epidemiologic features of borderline ovarian tumors in California: a population-based study.
      ,
      • Shih K.K.
      • Zhou Q.
      • Huh J.
      • Morgan J.C.
      • Iasonos A.
      • Aghajanian C.
      • et al.
      Risk factors for recurrence of ovarian borderline tumors.
      ,
      • Longacre T.A.
      • McKenney J.K.
      • Tazelaar H.D.
      • Kempson R.L.
      • Hendrickson M.R.
      Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up.
      ), although the reports on survival in patients with advanced BOT vary (
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ,
      • Ren J.
      • Peng Z.
      • Yang K.
      A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors.
      ,
      • Shih K.K.
      • Zhou Q.
      • Huh J.
      • Morgan J.C.
      • Iasonos A.
      • Aghajanian C.
      • et al.
      Risk factors for recurrence of ovarian borderline tumors.
      ,
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary.
      ,
      • Longacre T.A.
      • McKenney J.K.
      • Tazelaar H.D.
      • Kempson R.L.
      • Hendrickson M.R.
      Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up.
      ,
      • Lenhard M.S.
      • Mitterer S.
      • Kumper C.
      • Stieber P.
      • Mayr D.
      • Ditsch N.
      • et al.
      Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort.
      ,
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Pautier P.
      • Lhomme C.
      • et al.
      How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a large series stage II-III serous borderline tumours of the ovary.
      ).
      Although the prognosis of most patients with BOT is excellent, these are tumors with a concerning recurrence rate—30% overall, and up to 50% when patients present with advanced disease. Several prognostic factors have been reported to increase the risk of recurrence. These include advanced stage disease at diagnosis, invasive peritoneal implants, and pathological features such as intraepithelial carcinoma and a micropapillary pattern of growth (
      • Ren J.
      • Peng Z.
      • Yang K.
      A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors.
      ,
      • Shih K.K.
      • Zhou Q.
      • Huh J.
      • Morgan J.C.
      • Iasonos A.
      • Aghajanian C.
      • et al.
      Risk factors for recurrence of ovarian borderline tumors.
      ,
      • Lenhard M.S.
      • Mitterer S.
      • Kumper C.
      • Stieber P.
      • Mayr D.
      • Ditsch N.
      • et al.
      Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort.
      ,
      • Du Bois A.
      • Ewald-Riegler N.
      • de Gregorio N.
      • Reuss A.
      • Mahner S.
      • Fotopoulou C.
      • et al.
      Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group.
      ).
      The prognostic significance of a micropapillary pattern is especially controversial, and evidence exists suggesting that it is a surrogate marker for disease with a penchant for peritoneal spread, rather than an independent prognosticator (
      • Park J.Y.
      • Kim D.Y.
      • Kim J.H.
      • Kim Y.M.
      • Kim K.R.
      • Kim Y.T.
      • et al.
      Micropapillary pattern in serous borderline ovarian tumors: does it matter?.
      ,
      • Fauvet R.
      • Demblocque E.
      • Morice P.
      • Querleu D.
      • Darai E.
      Behavior of serous borderline ovarian tumors with and without micropapillary patterns: results of a French multicenter study.
      ). Data presented here on advanced disease found no significant association between recurrence and histologic subtype (serous vs. mucinous histology), a micropapillary pattern in patients with serous BOT, implant type (invasive vs. noninvasive), use of chemotherapy for patients with peritoneal disease, or with the extent of disease spread as reflected by stage and CA-125 level at diagnosis. Although we found it concerning that 2 of 8 patients with mucinous BOT died of their disease, the sample size was too small to establish a statistically significant association. Other investigators have reported on the prognostic significance of mucinous histology, and their findings have been inconsistent (
      • Ren J.
      • Peng Z.
      • Yang K.
      A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors.
      ,
      • Shih K.K.
      • Zhou Q.
      • Huh J.
      • Morgan J.C.
      • Iasonos A.
      • Aghajanian C.
      • et al.
      Risk factors for recurrence of ovarian borderline tumors.
      ,
      • Lenhard M.S.
      • Mitterer S.
      • Kumper C.
      • Stieber P.
      • Mayr D.
      • Ditsch N.
      • et al.
      Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort.
      ,
      • Du Bois A.
      • Ewald-Riegler N.
      • de Gregorio N.
      • Reuss A.
      • Mahner S.
      • Fotopoulou C.
      • et al.
      Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group.
      ,
      • Uzan C.
      • Nikpayam M.
      • Ribassin-Majed L.
      • Gouy S.
      • Bendifallah S.
      • Cortez A.
      • et al.
      Influence of histological subtypes on the risk of an invasive recurrence in a large series of stage I borderline ovarian tumor including 191 conservative treatments.
      ).
      Interestingly, a report from Uzan and colleagues (
      • Uzan C.
      • Muller E.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Bendiffallah S.
      • et al.
      Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary.
      ) on conservatively managed early serous BOT also found no association between recurrences and previously recognized pathological features such as microinvasion and a micropapillary pattern. In this study, only age remained a statistically significant prognostic factor on multivariate analysis. Another recent report on advanced disease (
      • Leary A.
      • Petrella M.C.
      • Pautier P.
      • Duvillard P.
      • Uzan C.
      • Tazi Y.
      • et al.
      Adjuvant platinum-based chemotherapy for borderline serous ovarian tumors with invasive implants.
      ) also suggests that recognized pathological prognosticators may have no impact on the outcome of this subgroup of patients. Only 8% of patients in this series were managed conservatively.
      Disease stage has certainly been a consistently validated predictor of outcome in BOT, as in other diseases. As this research targets a population with advanced disease, we did not expect to find a prognostic impact for disease stage. It is important to emphasize that most BOT series define stages IA–IC, or sometimes stages I–II, as early disease (
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary.
      ,
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Pautier P.
      • Lhomme C.
      • et al.
      How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a large series stage II-III serous borderline tumours of the ovary.
      ,
      • Song T.
      • Choi C.H.
      • Kim H.J.
      • Lee W.
      • Lee Y.Y.
      • Kim T.J.
      • et al.
      Oncologic and reproductive outcomes in patients with advanced-stage borderline ovarian tumors.
      ). We chose to group stages IC and higher together in this series, similarly to other reports (
      • Lenhard M.S.
      • Mitterer S.
      • Kumper C.
      • Stieber P.
      • Mayr D.
      • Ditsch N.
      • et al.
      Long-term follow-up after ovarian borderline tumor: relapse and survival in a large patient cohort.
      ). We believe that stages IC and II actually represent disease that is no longer confined to the ovary and has been exposed to the peritoneal cavity, which, some would argue, may be limited anatomically but not oncologically. Data on invasive epithelial ovarian cancer demonstrate that positive cytology in apparently early disease (as exemplified in stage IC) impacts on outcome and carries a worse prognosis. This has also been shown for BOT. In a series (
      • Longacre T.A.
      • McKenney J.K.
      • Tazelaar H.D.
      • Kempson R.L.
      • Hendrickson M.R.
      Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up.
      ) that investigated outcome for separate substages, the mortality rate for stage IC was actually similar to that of stages II and III disease (9%, 7%, and 9%, respectively) and three times higher than for stage IA-IB disease. Our own data showed similar survival curves for stage IC disease compared with stages II–III (not shown), and this was also reflected in similar hazards ratio for recurrence (Table 2).
      Another important disparity between BOT and invasive epithelial ovarian cancer is their age distribution. Whereas epithelial ovarian cancer is primarily a postmenopausal disease, BOT are often diagnosed in women of childbearing age. In fact, more than one-third of these tumors are diagnosed in women less than age 40 years (
      • Skirnisdottir I.
      • Garmo H.
      • Wilander E.
      • Holmberg L.
      Borderline ovarian tumors in Sweden 1960–2005: trends in incidence and age at diagnosis compared to ovarian cancer.
      ,
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ). Because many BOT are diagnosed in young women, fertility becomes an important consideration in planning surgical treatment. A fertility-sparing approach has been considered safe for most BOT cases because of limited disease extent at diagnosis, a typically indolent course, and the ability to salvage recurrences with repeat surgery (
      • Zanetta G.
      • Rota S.
      • Chiari S.
      • Bonazzi C.
      • Bratina G.
      • Mangioni C.
      Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.
      ,
      • Song T.
      • Choi C.H.
      • Park H.S.
      • Kim M.K.
      • Lee Y.Y.
      • Kim T.J.
      • et al.
      Fertility-sparing surgery for borderline ovarian tumors: oncologic safety and reproductive outcomes.
      ,
      • Darai E.
      • Fauvet R.
      • Uzan C.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options.
      ). Fertility-sparing surgery is commonly practiced in early disease (
      • Uzan C.
      • Muller E.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Bendiffallah S.
      • et al.
      Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary.
      ,
      • Gotlieb W.H.
      • Flikker S.
      • Davidson B.
      • Korach Y.
      • Kopolovic J.
      • Ben-Baruch G.
      Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome.
      ,
      • Schilder J.M.
      • Thompson A.M.
      • DePriest P.D.
      • Ueland F.R.
      • Cibull M.L.
      • Kryscio R.J.
      • et al.
      Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy.
      ,
      • Poncelet C.
      • Fauvet R.
      • Boccara J.
      • Darai E.
      Recurrence after cystectomy for borderline ovarian tumors: results of a French multicenter study.
      ,
      • Yinon Y.
      • Beiner M.E.
      • Gotlieb W.H.
      • Korach Y.
      • Perri T.
      • Ben-Baruch G.
      Clinical outcome of cystectomy compared with unilateral salpingo-oophorectomy as fertility-sparing treatment of borderline ovarian tumors.
      ,
      • Palomba S.
      • Falbo A.
      • Del Negro S.
      • Rocca M.
      • Russo T.
      • Cariati F.
      • et al.
      Ultra-conservative fertility-sparing strategy for bilateral borderline ovarian tumours: an 11-year follow-up.
      ,
      • Song T.
      • Hun Choi C.
      • Lee Y.Y.
      • Kim T.J.
      • Lee J.W.
      • Bae D.S.
      • et al.
      Oncologic and reproductive outcomes of cystectomy compared with oophorectomy as a treatment for borderline ovarian tumours.
      ,
      • Donnez J.
      • Munschke A.
      • Berliere M.
      • Pirard C.
      • Jadoul P.
      • Smets M.
      • et al.
      Safety of conservative management and fertility outcome in women with borderline tumors of the ovary.
      ). However, although an argument could be made that in disease that has metastasized outside of the ovary, removing the ovary itself may be of even of less benefit than in disease limited to the ovary, little information is available on the outcome of a conservative surgical approach in patients with advanced disease. Most published series are heterogeneous and comprised of a majority of early BOT.
      A large prospective cohort study by Zanetta et al. (
      • Zanetta G.
      • Rota S.
      • Chiari S.
      • Bonazzi C.
      • Bratina G.
      • Mangioni C.
      Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.
      ) reports on a mixed population that includes 56 advanced stage cases of BOT. Twenty-four of these patients underwent fertility-sparing surgery, with 11 recurrences documented almost exclusively in cases treated conservatively. However, because all but one of the recurrences was salvaged with surgery and chemotherapy, the investigators conclude that fertility preservation is safe in most cases with advanced disease.
      Longacre et al. (
      • Longacre T.A.
      • McKenney J.K.
      • Tazelaar H.D.
      • Kempson R.L.
      • Hendrickson M.R.
      Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up.
      ) report on 278 patients with BOT, of whom 113 had advanced disease. Twenty-one patients with advanced disease had fertility-sparing surgery in their series. The outcome for this patient group is not reported separately; however, 26% of patients receiving fertility-sparing treatment recurred overall and most recurrences were completely resected at repeat surgery.
      A more recent report from Korea (
      • Song T.
      • Choi C.H.
      • Park H.S.
      • Kim M.K.
      • Lee Y.Y.
      • Kim T.J.
      • et al.
      Fertility-sparing surgery for borderline ovarian tumors: oncologic safety and reproductive outcomes.
      ) on a heterogeneous series of 298 patients notes no significant differences in recurrence rates between patients treated conservatively with a fertility-sparing approach and those treated radically. In that series, only 25 patients had advanced disease. A separate report on these patients (
      • Song T.
      • Choi C.H.
      • Kim H.J.
      • Lee W.
      • Lee Y.Y.
      • Kim T.J.
      • et al.
      Oncologic and reproductive outcomes in patients with advanced-stage borderline ovarian tumors.
      ) details that five of them had a fertility-sparing procedure, with five resulting pregnancies. There were, however, four relapses (80%) during a mean 71-month follow-up.
      The largest report, from a dedicated group in Villejuif, France (
      • Uzan C.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary.
      ,
      • Kane A.
      • Uzan C.
      • Rey A.
      • Gouy S.
      • Camatte S.
      • Pautier P.
      • et al.
      Prognostic factors in patients with ovarian serous low malignant potential (borderline) tumors with peritoneal implants.
      ), describes 41 patients with advanced BOT treated conservatively. The 10-year recurrence rates were reported as 78% with 92% overall survival. Conservative management was, in fact, found to be the only significant prognostic factor in that series.
      A comprehensive review of fertility-sparing surgery in BOT (
      • Darai E.
      • Fauvet R.
      • Uzan C.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options.
      ) concluded that the risk of relapse for conservatively managed early disease is 13%, whereas in advanced disease, this risk increases to 38%. Our study focused exclusively on advanced BOT. Mean age at diagnosis was 35 years and 44 of 59 women were less than 40 years old—75% of whom had fertility-sparing surgery. In our study population 45% of patients developed a recurrence during the course of follow-up. Logistic regression analysis showed no difference in the hazard ratio for recurrence between patients having a fertility-sparing procedure as opposed to a more radical surgical approach.
      In addition, in the present report 39% of patients less than 40 years had surgery that spared an ovary involved with tumor, despite advanced disease at diagnosis. These women had a cystectomy or cytoreduction of tumor. A number of reports (
      • Uzan C.
      • Muller E.
      • Kane A.
      • Rey A.
      • Gouy S.
      • Bendiffallah S.
      • et al.
      Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary.
      ,
      • Gotlieb W.H.
      • Flikker S.
      • Davidson B.
      • Korach Y.
      • Kopolovic J.
      • Ben-Baruch G.
      Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome.
      ,
      • Schilder J.M.
      • Thompson A.M.
      • DePriest P.D.
      • Ueland F.R.
      • Cibull M.L.
      • Kryscio R.J.
      • et al.
      Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy.
      ,
      • Poncelet C.
      • Fauvet R.
      • Boccara J.
      • Darai E.
      Recurrence after cystectomy for borderline ovarian tumors: results of a French multicenter study.
      ,
      • Yinon Y.
      • Beiner M.E.
      • Gotlieb W.H.
      • Korach Y.
      • Perri T.
      • Ben-Baruch G.
      Clinical outcome of cystectomy compared with unilateral salpingo-oophorectomy as fertility-sparing treatment of borderline ovarian tumors.
      ,
      • Palomba S.
      • Falbo A.
      • Del Negro S.
      • Rocca M.
      • Russo T.
      • Cariati F.
      • et al.
      Ultra-conservative fertility-sparing strategy for bilateral borderline ovarian tumours: an 11-year follow-up.
      ,
      • Song T.
      • Hun Choi C.
      • Lee Y.Y.
      • Kim T.J.
      • Lee J.W.
      • Bae D.S.
      • et al.
      Oncologic and reproductive outcomes of cystectomy compared with oophorectomy as a treatment for borderline ovarian tumours.
      ) advocate for the safety of cystectomy in the surgical management of BOT in early disease. In this scenario, the likelihood of local recurrence may be higher (
      • Darai E.
      • Fauvet R.
      • Uzan C.
      • Gouy S.
      • Duvillard P.
      • Morice P.
      Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options.
      ,
      • Poncelet C.
      • Fauvet R.
      • Boccara J.
      • Darai E.
      Recurrence after cystectomy for borderline ovarian tumors: results of a French multicenter study.
      ,
      • Palomba S.
      • Falbo A.
      • Del Negro S.
      • Rocca M.
      • Russo T.
      • Cariati F.
      • et al.
      Ultra-conservative fertility-sparing strategy for bilateral borderline ovarian tumours: an 11-year follow-up.
      ) but, as such recurrences are easily treated with repeat surgery, impact on patient survival is negligible (
      • Song T.
      • Hun Choi C.
      • Lee Y.Y.
      • Kim T.J.
      • Lee J.W.
      • Bae D.S.
      • et al.
      Oncologic and reproductive outcomes of cystectomy compared with oophorectomy as a treatment for borderline ovarian tumours.
      ). On the other hand, fertility outcomes have been reported to be improved when cystectomy rather than adnexectomy is performed (
      • Palomba S.
      • Falbo A.
      • Del Negro S.
      • Rocca M.
      • Russo T.
      • Cariati F.
      • et al.
      Ultra-conservative fertility-sparing strategy for bilateral borderline ovarian tumours: an 11-year follow-up.
      ). Little data are available on this type of conservative surgical management in patients with advanced disease. We would argue that when metastatic disease is present elsewhere, conserving apparently healthy ovarian tissue should not compromise outcome, even if it may harbor microscopic disease, as local ovarian recurrences are most amenable to surgical treatment. In our series of advanced stage BOT, the conservation of an involved ovary was not associated with a significantly higher risk of recurrence or with earlier recurrence. In fact, our recurrence and survival data are comparable to other reports in the literature on patients with advanced disease who were, for the most part, managed radically (
      • Morris C.R.
      • Liu L.
      • Rodriguez A.O.
      • Cress R.D.
      • Snipes K.
      Epidemiologic features of borderline ovarian tumors in California: a population-based study.
      ,
      • Sherman M.E.
      • Mink P.J.
      • Curtis R.
      • Cote T.R.
      • Brooks S.
      • Hartge P.
      • et al.
      Survival among women with borderline ovarian tumors and ovarian carcinoma: a population-based analysis.
      ,
      • Longacre T.A.
      • McKenney J.K.
      • Tazelaar H.D.
      • Kempson R.L.
      • Hendrickson M.R.
      Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up.
      ).
      The conservative approach to management of advanced BOT practiced by our group has enabled a number of our patients to realize their childbearing potential. Eighteen of 21 of our younger patient population who had attempted pregnancy at the time of this audit succeeded, with 34 pregnancies and 26 live births documented. Twelve of 21 patients attempting conception required fertility intervention.
      As is often the case in series of BOT, sample size is an important limitation. This is especially conspicuous in this series of advanced BOT, as most reports describe heterogeneous groups of patients with a preponderance of early disease. At present this is, however, one of the largest series focusing on advanced BOT, and specifically on conservatively managed advanced disease.
      In summary, borderline tumors of the ovary carry a favorable prognosis, even when diagnosed at an advanced stage, with a high recurrence rate but limited mortality. Pathological features, such as tumor histology, a micropapillary pattern, and invasive implants, which have been reported to be associated with worse outcome, seem to have less prognostic significance in patients with advanced disease at presentation. Although certainly limited by a small sample size, in our series conservative surgical management with fertility preservation and conservation of an ovary after removing macroscopically apparent disease was not found to be associated with an increased risk of recurrence or with earlier recurrence. We conclude that this approach may be reasonably offered to young women who have not completed their childbearing.

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