You are here

Article Text

Article menu

Download PDFPDF

Review
Fertility preservation in rare ovarian tumors
  1. Anca Chelariu-Raicu1,
  2. Lauren P Cobb2 and
  3. David M Gershenson2
  1. 1 Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
  2. 2 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr David M Gershenson, Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX 77230, USA; dgershen{at}mdanderson.org

Abstract

Although gynecologic cancers usually affect older women, a significant proportion of patients with rare ovarian tumors are of reproductive age. In a young patient who presents with a pelvic mass, a primary consideration should be the probability of a malignancy. If there is any suspicion of a cancer diagnosis, the patient should be referred to a gynecologic oncologist. Key factors in clinical management include assessment of preoperative studies (physical examination, tumor markers, and imaging) to determine the likelihood of a malignancy, appropriate preoperative counseling (including discussion of fertility preservation), choice of surgical approach (minimally invasive vs open), frozen section examination by a gynecologic pathologist, and intraoperative decision making. Fortunately, the clinical features of several rare ovarian tumors are compatible with fertility preservation. These characteristics include a high proportion of stage I disease and unilateral ovarian involvement for most rare histotypes. Once a final diagnosis of a rare ovarian tumor is determined, further clinical management may include the need for further studies, possible referral to a fertility expert, consideration of further surgery (if the initial surgery was incomplete), and recommendations for postoperative therapy. This article reviews the literature on fertility preservation in the context of the treatment of several rare ovarian tumor subtypes, including malignant germ cell tumors, sex cord-stromal tumors, borderline tumors, low grade serous carcinoma, clear cell carcinoma, mucinous carcinoma, and small cell carcinoma of the hypercalcemic type.

  • ovarian cancer
  • surgery

https://doi.org/10.1136/ijgc-2020-001775

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Our knowledge base on fertility preservation for patients with gynecologic malignancies has expanded significantly over the past two decades. Although gynecologic cancers usually affect older women, a significant proportion of patients with rare ovarian tumors are of reproductive age. There are several key factors in the approach to a young patient who presents with a pelvic mass. A primary consideration, based on diagnostic studies, is the probability of a malignancy. If there is any suspicion of a cancer diagnosis, the patient should be referred to a gynecologic oncologist. All too frequently, obstetricians and gynecologists operate on a child or young woman only to be surprised by a final pathologic diagnosis of cancer when, in retrospect, there were indicators predicting this outcome. Out of these missteps arise several potential adverse outcomes. For instance, an error in judgment may result in the patient requiring a second surgery to resect metastatic tumor or to adequately stage the patient to determine recommendations for postoperative management. In addition, with the increased practice of minimally invasive surgery, the operative procedure may result in rupture of an ovarian malignancy, upstaging the tumor, which could have been prevented had an open approach been selected based on the size of the ovarian mass or the results of preoperative diagnostic studies.

    For any child or woman of childbearing age who presents with an ovarian mass, especially bilateral ovarian masses, preoperative counseling regarding the operative procedure, possible complications, and the possibility or lack thereof of fertility preservation is essential. Whenever possible, a physician must discuss standard of care, either preoperatively or postoperatively, for the patient’s condition. Any deviation from the standard of care with the objective of preserving fertility must be discussed in the context of associated risk. In some instances, preoperative referral to a reproductive endocrine infertility expert for fertility preservation counseling is appropriate. In others, postoperative referral should occur. In an ideal situation, fertility potential can be preserved without compromising cure. Common options for fertility preservation include controlled ovarian hyperstimulation, followed by either embryo cryopreservation or oocyte cryopreservation, and ovarian tissue cryopreservation.

    In addition to the patient’s primary attending physician and the fertility preservation expert or team, the other important individual in optimizing the potential for fertility preservation is the gynecologic pathologist. Errors in frozen section diagnosis or final diagnosis may result in inappropriate treatment recommendations, intraoperatively or postoperatively. There are many cases where even the most expert gynecologic pathologist cannot render a precise frozen section diagnosis, distinguishing benign from malignant. In such instances, conservative management should generally be employed with the understanding that subsequent surgery may be necessary if the final diagnosis is cancer. In certain circumstances, a second opinion on the pathologic diagnosis should be sought. Whatever the circumstances that lead to a final diagnosis of an ovarian malignancy, the oncologist must have a complete understanding of the biologic behavior of each subtype in order to optimize recommendations for subsequent clinical management, including surveillance and, in consultation with a reproductive medicine expert, to determine how best to integrate fertility preservation strategies, when appropriate.

    This article will address the topic of rare ovarian tumors, with emphasis on the role of fertility sparing surgery for several specific subtypes. In addition, a brief discussion of the role of assisted reproductive technology options and the potential effects of adjuvant postoperative therapy, where applicable, will be included.

    Malignant Ovarian Germ Cell Tumors

    One of the greatest success stories in the chronicles of gynecologic oncology is that of malignant ovarian germ cell tumors, which comprise approximately 5% of all ovarian malignancies. From early case series providing details of operative findings, contemporary surgical principles evolved.1–10 From these reports, we learned that ovarian germ cell tumors occur primarily in girls and young women, tend to be quite large, and approximately 60% are confined to the ovary. The majority are unilateral, with bilateral ovarian involvement occurring in 10–15% of pure dysgerminomas, in some mixed germ cell tumors in which the dysgerminoma component predominates, and in occasional cases of advanced stage disease. In addition, mature cystic teratomas may occur in 5–10% of ovarian germ cell tumors, underscoring the fact that bilateral ovarian masses do not automatically indicate a malignant process.

    These host factors and tumor characteristics converge to form an ideal opportunity for fertility sparing surgery. Evidence to support such an approach initially emerged not from randomized clinical trials but rather from observational studies. Kurman and Norris observed no worse prognosis associated with fertility sparing surgery compared with bilateral salpingo-oophorectomy in 182 patients whose tumor was grossly confined to the ovary.5 Thus except in rare circumstances, fertility sparing surgery with unilateral salpingo-oophorectomy has become the standard of care for patients with ovarian germ cell tumors, even in most patients with metastatic disease. The presence of bilateral ovarian masses usually indicates either a contralateral ovarian mature cystic teratoma or a bilateral dysgerminoma component. In the former case, ovarian cystectomy is recommended. In the case of bilateral dysgerminoma, even unilateral salpingo-oophorectomy with ovarian cystectomy has been reported with excellent outcomes. A notable exception to the opportunity for fertility sparing surgery is the presence of dysgenetic gonads, in which case bilateral adnexectomy is recommended.

    Subsequent reports of ovarian germ cell tumor series demonstrated fertility sparing surgery rates in the range of 54–87%.11–14 As noted, fertility sparing surgery is frequently feasible even in patients with stage II–IV disease. Nasioudis and colleagues reported 526 patients with stage II–IV ovarian germ cell tumors from the National Cancer Database.15 The rate of uterine preservation in this cohort was 79.8%. Rates of uterine preservation were similar among histologic subtypes and across stages. Importantly, uterine preservation was not associated with decreased overall survival. In a recent report, Morrison and Nasioudis reviewed 47 studies in which 2189 patients underwent fertility sparing surgery for ovarian germ cell tumors.16 Data on the type of adnexal surgery performed was available for 1354 patients; 1219 had unilateral salpingo-oophorectomy or oophorectomy, 81 had unilateral cystectomy, 4 had bilateral cystectomy, and 50 had unilateral salpingo-oophorectomy or oophorectomy and contralateral cystectomy.

    In the United States, standard postoperative therapy is chemotherapy with the combination of bleomycin, etoposide, and cisplatin for all patients with ovarian germ cell tumors, except for stage IA dysgerminoma and stage IA, grade 1 immature teratoma. In parts of Europe and for US children under the care of pediatric oncologists, observation has been recommended for all stage I ovarian germ cell tumors. In a trial of the Children’s Oncology Group, 25 patients with stage I yolk sac tumor or mixed germ cell tumor underwent observation following primary surgery.17 Twelve (48%) patients relapsed and were treated with chemotherapy, and all but one was salvaged. This experience served as background for the AGCT1531 trial, which is currently recruiting. In this trial, a low risk cohort consisting of patients with stage IA or IB ovarian germ cell tumors, with the exception of dysgerminoma, undergo observation and receive chemotherapy only if they relapse. In addition, a standard risk cohort (stages IC–III) are randomized to either four cycles of standard bleomycin, etoposide, and cisplatin, or four cycles of bleomycin, etoposide, and carboplatin.

    For patients with ovarian germ cell tumors who receive adjuvant chemotherapy, several studies have reported reproductive outcomes and estimated rates of chemotherapy induced ovarian failure.18–22 The evidence suggests that based on resumption of menstrual function, chemotherapy effects on the ovary are no greater than 10–15%.20 However, we now understand the anti-Mullerian hormone seems to be the most sensitive measure of ovarian reserve in cancer survivors, at times combined with antral follicle counts, luteinizing hormone, or follicle stimulating hormone.21 In the report by Morrison and Nasioudis, 28 of 796 patients (3.5%) who underwent adjuvant chemotherapy had premature ovarian failure.16 Of 710 patients from 19 studies who received chemotherapy, 239 (33.7%) had achieved at least one pregnancy. Based on 594 patients from 13 studies, 152 (25.6%) patients had at least one live birth.

    For those young patients with ovarian germ cell tumors who do undergo chemotherapy following fertility sparing surgery, the question arises as to whether the use of gonadotropin releasing hormone analogs can achieve ovarian protection from chemotherapeutic damage. In women undergoing chemotherapy for breast cancer, the findings have been conflicting. However, randomized trials that used quantitative measures of ovarian reserve, such as anti-Mullerian hormone with or without antral follicle counts, demonstrated no benefit from gonadotropin releasing hormone analogs.23 24

    Ovarian Sex Cord-Stromal Tumors

    Ovarian sex cord-stromal tumors account for less than 5% of all ovarian malignancies. Approximately 90% are stage I, and 95% are confined to one ovary. Thus fertility sparing surgery for ovarian sex cord-stromal tumors is also feasible in young patients. Granulosa cell tumors may occur at any age, although they are most commonly observed in postmenopausal women. In addition, approximately 25–30% are associated with endometrial pathology—hyperplasia or cancer.25 Sertoli–Leydig cell tumors also may occur at any age, but the majority are diagnosed in women in their twenties or thirties. Given the age range for these subtypes, particularly granulosa cell tumors, fertility sparing surgery is not nearly as common as for ovarian germ cell tumors.

    In a French National Network study of 460 patients with granulosa cell tumors who had adequate data, the authors evaluated the surgical procedure in two periods: before 2012 and after 2012.26 Before 2012, the surgical approach was minimally invasive in 43.7% and open in 55.5%, whereas after 2012, the figures were 48.9% and 47.8%, respectively. Fertility sparing surgery was practiced in 37.3% before 2012 and in 26.9% after 2012. In other reports from China, Sweden, and Italy, the rate of fertility sparing surgery in stage I granulosa cell tumors was 54%, 76%, and 33%, respectively.14 27 28 Of 229 patients in the Italian study, 32.6% underwent fertility sparing surgery and 67.4% underwent radical surgery.28 Of those who underwent fertility sparing surgery, 62.8% underwent unilateral salpingo-oophorectomy, 16.7% underwent ovarian cystectomy, and 20.5% underwent cystectomy followed by unilateral salpingo-oophorectomy. The median disease free survival was significantly worse in the fertility sparing surgery group compared with the radical surgery group (50% vs 74%). However, there was no significant difference between the unilateral salpingo-oophorectomy versus the radical surgery group (70% vs 75%); there were significant differences in disease free survival between the unilateral salpingo-oophorectomy group compared with the cystectomy group, and the unilateral salpingo-oophorectomy versus cystectomy followed by unilateral salpingo-oophorectomy groups (70% vs 16% and 70% vs 41%, respectively). Of the 113 patients in the Chinese report, 54% underwent fertility sparing surgery and 46% underwent radical surgery.27 There was no difference in disease free survival between the two groups. In addition, of 22 patients who attempted to conceive following fertility sparing surgery, 29 (86.4%) succeeded in achieving 20 singleton pregnancies. Of 19 patients in the Swedish study, three (16%) had given birth at the time of the report.14

    Studies of the much less common Sertoli–Leydig cell tumors are fewer. Sertoli–Leydig cell tumors are classified as well differentiated, with intermediate differentiation, or poorly differentiated. In addition, tumors may include heterologous elements or a retiform pattern, which are associated with an increased risk of relapse. In general, patients with stage I well differentiated tumors or intermediate differentiation are treated with surgery alone. Patients with stage I poorly differentiated tumors or stage II–IV tumors are generally treated with adjuvant chemotherapy. The presence of heterologous elements or a retiform pattern may also prompt a recommendation for chemotherapy. Thus just as in ovarian germ cell tumors, adjuvant chemotherapy may compromise fertility in some patients. Johansen et al reported nine patients with Sertoli–Leydig cell tumors, seven of whom underwent fertility sparing surgery.14 Two patients gave birth following fertility sparing surgery. In a study from the Italian MITO group, Sigismondi et al reported on 21 patients with Sertoli–Leydig cell tumors treated in 11 MITO centers.29 Median age was 37 years (range 16–76). Eighty-one per cent had stage I tumors. Eleven (53%) women underwent fertility sparing surgery, and 47% had hysterectomy and bilateral salpingo-oophorectomy. Five patients received adjuvant chemotherapy.

    Borderline Ovarian Tumors

    Borderline ovarian tumors account for approximately 10–15% of epithelial tumors. Histological types include serous, mucinous, endometrioid, clear cell, and Brenner (or transitional cell). The most common type is serous followed by mucinous, the two types discussed here. The primary surgical approach may be either minimally invasive or open, depending on several factors, not the least of which is tumor size. Since the average age of patients with borderline ovarian tumors is younger than those with invasive ovarian cancers, fertility sparing surgery is an important consideration in this population.

    Approximately 60–70% of serous borderline tumors are stage I, and 50% are bilateral. Approximately 90% of mucinous borderline tumors are stage I, and 80–90% are confined to one ovary at diagnosis. Options for fertility sparing surgery in the surgical management of borderline ovarian tumors, depending on surgical findings, include unilateral salpingo-oophorectomy, unilateral salpingo-oophorectomy with ovarian cystectomy, unilateral ovarian cystectomy, or bilateral ovarian cystectomy.

    Surgical Approach: Laparoscopy Versus Laparotomy (Open Approach)

    Over the past two decades, minimally invasive surgery has assumed a more prominent role in the surgical approach to women with adnexal masses. Table 1 shows details of studies of laparoscopy versus laparotomy, as well as comparison of outcomes in women with borderline ovarian tumors.30–39 Several studies have reported no difference in relapse rates, disease free survival, progression free survival, or overall survival between laparoscopic and open approaches.30–36 38 39 Vancraeynest et al reported a higher risk of recurrence after fertility sparing surgery compared with radical surgery; however, no effect on overall survival was observed.37 Two reports observed a higher rate of tumor rupture associated with laparoscopy compared with laparotomy.30 32

    View this table:
    Table 1

    Comparison of patients with borderline ovarian tumors who underwent laparoscopy versus laparotomy

    Park et al reported 360 patients who underwent surgical management for serous or mucinous borderline tumors.33 Eighty per cent underwent laparotomy and 20% underwent laparoscopy. They found no differences in relapse rates or disease free survival based on the surgical approach. Du Bois and colleagues described a cohort study of 1236 patients with stage I–III serous or mucinous borderline tumors who underwent surgery.35 Laparotomy was performed in 62% and laparoscopy in 38%, and they found no difference in relapse rates or overall survival based on surgical approach. Song and associates reported on 687 patients from the Korean registry who underwent surgery for serous or mucinous borderline tumors.38 Approximately 55% underwent laparotomy and 45% underwent laparoscopy; there was no difference in relapse free survival between the two groups.

    Fertility Sparing Surgery Versus Complete or Radical Surgery

    There are also several reports of fertility sparing surgery compared with complete or radical surgery (terms used as a surrogate for bilateral salpingo-oophorectomy with or without other procedures) for borderline ovarian tumors.33 35 37 39–46 For serous borderline tumors, studies reveal fertility sparing surgery rates of 12–66% and radical surgery rates of 34–88%.33 37 40–44 For mucinous borderline tumors, reports indicate fertility sparing surgery rates of 26–60% and radical surgery rates of 40–74%.33 41 42 44–46 For studies that include both serous and mucinous borderline tumors, fertility sparing surgery rates are 26–35% and radical surgery rates 65–75%.35 39

    For serous borderline tumors, risk factors for relapse include: (1) histologic factors—micropapillary pattern within the ovary (non-invasive low grade serous carcinoma), microinvasion in the ovary, and presence of peritoneal implants; and (2) clinical factors—age at diagnosis, baseline serum CA125, conservative surgery, International Federation of Gynecology and Obstetrics (FIGO) stage, and residual disease. In addition, several studies showed that the type of fertility sparing surgery influences the risk of relapse, with a higher rate after ovarian cystectomy than following unilateral salpingo-oophorectomy. The majority of recurrences of serous borderline tumors occur in the ipsilateral or contralateral ovary following fertility sparing surgery, but a small number of cases can be associated with peritoneal implants. Rarely, relapses may be in the form of invasive low grade serous carcinoma and, even more rarely, in the form of high grade serous carcinoma.

    Barnhill et al reported 146 patients with stage I serous borderline tumors, of whom 23 (16%) underwent fertility sparing surgery; no patients had recurrence of disease.40 On the other hand, Uzan et al described 119 patients with stage I serous borderline tumors who underwent fertility sparing surgery, and 38 (32%) relapsed.36 All but one recurrence involved an ovary, and in 10 cases there were associated non-invasive peritoneal implants. In a study of 132 patients with serous borderline tumors, Vancraeynest et al reported that 42 (32%) patients underwent fertility sparing surgery and 90 (68%) underwent radical surgery.37 Although the risk of relapse was higher in the former group, no difference in overall survival was observed.

    For mucinous borderline tumors, risk factors for relapse include: (1) histologic factors—microinvasion and intraepithelial carcinoma; and (2) clinical factors—age at diagnosis, conservative surgery, and FIGO stage (although most experts believe all mucinous borderline tumors are stage I and only seromucinous tumors may be stage II or III). Practically speaking, essentially all recurrences of mucinous borderline tumors occur in the ipsilateral or contralateral ovary following fertility sparing surgery.

    Khunamornpong et al reported 171 patients with mucinous borderline tumors, 60 (35%) of whom underwent fertility sparing surgery and 111 (65%) had bilateral salpingo-oophorectomy.45 Six of 144 patients (4%) relapsed, with no difference between the fertility sparing surgery and radical surgery groups. In the study by De Decker et al, 2/74 (3%) patients with mucinous borderline tumors relapsed.46

    Relapse rates of 5–16% have occurred in studies comparing fertility sparing surgery with radical surgery in cohorts of both serous and mucinous borderline tumors.33 35 40 41 44 Two studies have reported a significantly higher risk of relapse for fertility sparing surgery versus radical surgery,35 44 while two studies did not show a difference in relapse rates based on type of surgery.33 41 Details of studies comparing fertility sparing surgery and radical surgery are shown in Table 2. 33 35 37 39–46

    View this table:
    Table 2

    Comparison of patients with borderline ovarian tumors who underwent fertility sparing surgery versus radical surgery (complete resection)

    Reproductive Outcomes Following Fertility Sparing Surgery for Borderline Tumors

    Reproductive outcomes have been reported in several cohorts of women following fertility sparing surgery for borderline tumors.32–34 36 39 42 47–50 In one of the earliest reports, Morris et al described 43 patients who underwent fertility sparing surgery for borderline tumors.47 Twenty-four women attempted pregnancy, and 12 conceived 25 pregnancies (16 live births, 4 spontaneous abortions, 3 ectopic pregnancies, and 2 ongoing pregnancies). In a cohort of 184 patients who underwent fertility sparing surgery, 130 were contacted for a telephone survey.33 Thirty-one patients attempted to conceive and 27 patients became pregnant. Three of these patients had received platinum based chemotherapy and all three had term pregnancies. Song et al reported 155 patients who underwent fertility sparing surgery, of whom 116 were contacted for a telephone interview.42 Fifty-one attempted to conceive and 45 patients had 48 singleton pregnancies, 3 twin pregnancies, 3 miscarriages, and 4 ongoing pregnancies, for a total of 54 full term infants. Following fertility sparing surgery in 119 patients with borderline tumors, 50 pregnancies were observed in 33 patients.36 Seven infertile patients achieved pregnancy following ovulation stimulation or an in vitro fertilization procedure.

    The use of assisted reproductive technology has also been reported in patients with borderline tumors. Fain-Kahn et al reported 17 patients with borderline tumors on frozen section examination were planned for ovarian tissue cryopreservation.51 Fifteen of these patients had previously been treated conservatively for borderline tumors. At the time of surgery, ovarian tissue cryopreservation was aborted for various reasons, and nine patients underwent successful cryopreservation. Fortin et al described 30 patients treated for borderline tumors of whom ovarian induction was performed in 25 for infertility after conservative surgery for borderline tumors.52 Five patients with a single ovary underwent ovarian induction before surgery for recurrent disease. Three of the 30 patients were treated with clomiphene and 27 patients underwent an in vitro fertilization procedure with hyperstimulation. Thirteen (43%) patients became pregnant. The mean interval between the assisted reproductive technology and pregnancy was 28 months. Three of the five patients treated with ovarian induction before surgery for recurrent disease had three normal pregnancies. Among 10 pregnancies in patients treated for infertility, outcomes included a single miscarriage, one premature delivery at 24 weeks, and eight normal pregnancies.

    Low Grade Serous Carcinoma

    Low grade serous carcinoma accounts for approximately 10% of all serous ovarian carcinomas. It is characterized by younger age at diagnosis, relative insensitivity to chemotherapy, responsiveness to endocrine therapy, and prolonged overall survival compared with high grade serous ovarian carcinoma.53–57 Similar to high grade serous carcinoma, most patients present with advanced stage disease, and over 70% relapse. In addition, low grade serous carcinoma has a high frequency of estrogen and progesterone receptor expression, and the mitogen activated protein kinase (MAPK) signaling pathway plays a prominent role in its pathogenesis, with frequent KRAS mutations as well as BRAF and NRAS mutations.55 58–65

    The frequency of bilaterality is 74–85%.53 57 66–70 In addition, only 2–27% of cases are stage I.57 67–70 Thus the opportunity for fertility sparing surgery in low grade serous carcinoma is somewhat limited. In addition, for those patients who undergo fertility sparing surgery but require adjuvant therapy (generally stages IC–IV), treatment with an aromatase inhibitor, either as primary or maintenance therapy, will require the addition of a gonadotropin releasing hormone analog to suppress ovarian function.

    Although we understand that fertility sparing surgery is feasible in a small proportion of women with low grade serous carcinoma, mostly stage I but also in rare patients with stages II–IV, there is almost no information in the literature regarding reproductive outcomes. Yin and colleagues reported one patient with stage IC low grade serous carcinoma who underwent primary surgery following six cycles of paclitaxel/carboplatin.71 She delivered by cesarean section at 37 weeks.

    Clear Cell Carcinoma

    Ovarian clear cell carcinoma is regarded as an aggressive histological subtype of cancer; women who develop such tumors are considered high risk patients. In accordance with this classification, clear cell carcinoma proved to have the poorest prognosis among epithelial ovarian cancer histological subtypes.72 Furthermore, the response rate to platinum based chemotherapy in patients with ovarian cancer was significantly lower in clear cell carcinoma compared with serous carcinoma.73 Currently, both the National Comprehensive Cancer Network (NCCN) and the European Society of Gynecologic Oncology (ESGO) guidelines do not recommend fertility sparing surgery as an option for the management of clear cell carcinoma patients with childbearing potential.74 75 Therefore, the available data on clear cell carcinoma are limited due to a small proportion of patients who were included in retrospective studies along with mucinous, endometrioid, and serous subtypes76 (Table 3).77–83

    View this table:
    Table 3

    Studies evaluating fertility sparing surgery in early stage (International Federation of Gynecology and Obstetrics stages IA–IC) mucinous and clear cell carcinomas

    Kajiyama et al were among the first to retrospectively compare the prognosis between patients with or without stage IA and IC clear cell carcinoma who underwent fertility sparing surgery.77 Considering the limitations of the analysis, including small number of cases (n=16) and no statistical significance, the study failed to demonstrate that fertility sparing surgery is safe for stage I clear cell carcinoma. However, given the lower rate of recurrence in the stage IA clear cell carcinoma group (4.3%), the authors concluded that patients with stage IA may benefit from fertility sparing surgery.

    A more recent retrospective study of Nasioudis et al included a cohort of 741 premenopausal women (age <50 years) from 18 cancer registries, diagnosed between 1988 and 2013 with a primary ovarian tumor, clear cell histology, stage IA and IC.84 In this study, the rate of uterine preservation was 14.5% and the rate of ovarian preservation was 28.1%. After controlling for disease substage (IA vs IC), neither uterine nor ovarian preservation was associated with a worse cancer specific or overall mortality. Among the uterine preservation group, the authors reported a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.36 to 1.56) for overall mortality and a HR of 0.84 (95% CI 0.44 to 1.62) for cancer specific mortality. In addition, the results for the ovarian preservation group were HR 0.36 (95% CI 0.13 to 1.02) for cancer specific mortality and HR 0.44 (95% CI 0.17 to 1.13) for overall mortality.

    Lastly, Park et al designed a case-control study and compared the oncologic outcomes of 22 premenopausal women (mean age 36.5 years) with clear cell carcinoma, stage IA and IC, who underwent fertility sparing surgery, with a group of 25 patients who had radical surgery (mean age 40.9 years).85 In all of the above mentioned studies, no difference was noted in disease free survival or overall survival between the two groups after a median follow-up of 72 months, even when stratification by disease substage was applied.

    The majority of studies reporting obstetric outcome after fertility sparing surgery in patients with stage I epithelial ovarian cancer are limited due the low number of subjects who benefit from fertility sparing surgery.86 One recent study reported one pregnancy in a patient with stage IA clear cell carcinoma who had a successful vaginal delivery at 39 weeks.71 The overall consensus is that planning a pregnancy in clear cell carcinoma patients should be carefully considered, given the risk of recurrences in extraovarian locations within the first 2 years following initial surgical staging. This is especially important for patients with stage IC, where recurrences were much higher when compared with stage IA.87

    Taken together, fertility sparing surgery management should be carefully discussed with clear cell carcinoma patients, based on the limited data on clinical and obstetric outcome. However, given the low recurrence rate reported by several retrospective studies in patients with stage IA, fertility sparing surgery could still be an opportunity to consider.

    Mucinous Carcinoma

    In 2004,Hess et al reported a case-control study in which they suggested reduced platinum sensitivity for mucinous carcinomas compared with other histological subtypes of epithelial ovarian cancer.88 In addition, 83% of mucinous carcinomas are stage I and approximately 80% are unilateral.89 The recurrence rate for stage I mucinous carcinoma is only 5.8%, and 5 year survival is 91%.90 Thus NCCN guidelines recommend observation for stages IA-B and either observation or consideration of adjuvant chemotherapy for stage IC mucinous carcinoma.74

    Therefore, fertility sparing surgery represents a reasonable option for patients with stage I mucinous carcinoma. Given the good prognosis of these patients, several studies evaluating the safety of fertility sparing surgery in epithelial ovarian cancer enrolled mostly patients with this histological subtype (Table 3).77–83 In view of these observations, both NCCN and ESGO guidelines included fertility sparing surgery management for stage IA–B mucinous carcinoma and considered it an option for high risk patients with stage IC.74 75 In addition, a more recent study reporting more granularity regarding mucinous carcinoma subtypes compared fertility sparing surgery results for expansile with infiltrative subtypes.90 Even though infiltrative type tumors are considered to be more aggressive than expansile, the authors of the study reported no difference in oncologic outcomes between the two subtypes and also recommended fertility sparing surgery for early stage infiltrative type tumors.

    Data on obstetric outcome were reported for five patients who underwent fertility sparing surgery for mucinous carcinoma.71 Among the patients evaluable for obstetric outcome, one patient with stage IA and four patients with stage IC received at least three cycles of an adjuvant platinum based chemotherapy. Three patients delivered vaginally at 33, 36, and 38 weeks. The other two patients had fetal anomalies at 23 and 24 weeks, which resulted in pregnancy termination. In addition, other studies, including a large cohort of patients with mucinous histology, reported good obstetric outcome, reaching 80% pregnancy rates.86 91 However, data from these studies are reported for all patients with epithelial ovarian cancer (serous, mucinous, endometrioid, and clear cell) and not specifically for patients with mucinous carcinoma.

    In summary, stage I mucinous carcinoma has the best clinical outcome within epithelial ovarian cancer, and fertility sparing surgery is a safe option for young women with stages IA–B and for selected patients with stage IC with childbearing potential. Consequently, fertility sparing surgery is currently included in the international guidelines for the treatment of ovarian cancer.74 75 Women with stage IA–B mucinous carcinoma could consider initiating pregnancy planning shortly after staging surgery, given the fact that adjuvant therapy is not recommended. However, for stage IC mucinous carcinoma patients, adjuvant chemotherapy may be recommended, in which case pregnancy planning should be delayed.

    Small Cell Carcinoma of the Ovary, Hypercalcemic Type

    Small cell carcinoma of the ovary, hypercalcemic type, is a rare aggressive malignancy characterized by an average age of diagnosis at 24 years.92 Prognosis is poor with median overall survival of 14.9 months.93 Given the rarity of this disease, with fewer than 300 cases reported in the literature, there is no consensus on the optimal treatment strategy or consideration of fertility preservation.

    In the largest clinicopathologic analysis to date, Young and colleagues reviewed the features of 150 patients with small cell carcinoma of the ovary, hypercalcemic type.92 Almost all cases documented unilateral ovarian involvement. Even so, they suggested that bilateral salpingo-oophorectomy might lead to better survival outcomes. In a subset analysis of 50 patients with stage 1A disease, 14 (33%) were alive without disease. They reported that 8/14 (57%) of stage 1A patients who underwent bilateral salpingo-oophorectomy were disease free, whereas only 5/21 (23%) who underwent unilateral salpingo-oophorectomy were disease free.

    In contrast, in a Gynecologic Cancer InterGroup study of 17 patients with small cell carcinoma of the ovary, hypercalcemic type, Harrison and colleagues concluded that given the young average age at diagnosis and unilaterality in 99% of cases, unilateral salpingo-oophorectomy is reasonable.94 However, they did not specifically address the outcomes of their patients undergoing unilateral salpingo-oophorectomy. Of the 10 patients with stage I disease, six initially underwent either unilateral oophorectomy or unilateral salpingo-oophorectomy. Three of these six patients were alive without disease (although two of three of these patients received radiation as part of their treatment). One of six who did not receive radiation died of disease, and two of six were alive with disease. These findings may speak more to the role of radiation in the treatment rather than to the feasibility of fertility preservation.

    In a retrospective study by Callegaro-Filho et al, the clinical characteristics, treatment modalities, and outcomes of 47 patients with small cell carcinoma of the ovary, hypercalcemic type, were reviewed.93 Consistent with other case series, the tumor was unilateral in the majority of cases (96.3%). All patients underwent cytoreductive surgery, with 26 patients (55%) undergoing unilateral salpingo-oophorectomy and 21 patients (44.7%) undergoing a total abdominal hysterectomy with bilateral salpingo-oophorectomy as part of their cytoreductive effort. Most patients received chemotherapy, with only four patients receiving chemotherapy and radiation. Thirty-five patients (74.5%) developed recurrent disease, with the most common sites of recurrence including the pelvis, retroperitoneal lymph nodes, and contralateral ovary. In a subset analysis of patients with stage I disease (n=16), eight (50%) underwent fertility sparing unilateral salpingo-oophorectomy. Of those eight patients, only two (25%) were alive without evidence of disease (median follow-up of 13.2 months) with no reported pregnancies.

    There are additional small case series and case reports that have reported good outcomes in patients who received fertility preserving treatment.95–98 In a review of four patients (two stage 1A, one stage 2B, and one stage IIIC) who underwent cytoreductive or staging surgery (including unilateral salpingo-oophorectomy in three patients) followed by chemotherapy, only the patient with stage IIIC disease relapsed and died.96 The authors concluded that stage appears to play a significant role in outcome, and that fertility preservation may be considered in early stages. In a case report from our group, a 26-year-old woman with stage IA disease underwent unilateral salpingo-oophorectomy followed by chemotherapy with vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide; 6 years later she conceived naturally.98 This is the first reported case of pregnancy after treatment for small cell carcinoma of the ovary, hypercalcemic type. Because fertility preservation in this highly aggressive malignancy remains controversial, further experience is necessary to determine if this is a feasible approach.

    Summary

    In summary, fertility sparing surgery is feasible in several rare ovarian tumors, including all stages of malignant ovarian germ cell tumors, all stages of borderline ovarian tumors, stage I ovarian sex cord-stromal tumors, and stage I invasive epithelial ovarian cancer. Table 4 presents the international guidelines regarding fertility sparing surgery for rare ovarian tumors by the NCCN and ESMO-ESGO.74 99

    View this table:
    Table 4

    International guidelines for fertility sparing surgery in patients with rare ovarian tumors

    References

    1. ↵
      2. Norris HJ ,
      3. Zirkin HJ ,
      4. Benson WL
      . Immature (malignant) teratoma of the ovary. A clinical and pathologic study of 58 cases. Cancer 1976;37:2359–72.doi:10.1002/1097-0142(197605)37:5<2359::AID-CNCR2820370528>3.0.CO;2-Q pmid:1260722
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      2. Kurman RJ ,
      3. Norris HJ
      . Malignant mixed germ cell tumors of the ovary: a clinical and pathologic analysis of 30 cases. Obstet Gynecol 1976;48:579–89.pmid:http://www.ncbi.nlm.nih.gov/pubmed/185553
      OpenUrlPubMedWeb of Science
    3. ↵
      2. Kurman RJ ,
      3. Norris HJ
      . Embryonal carcinoma of the ovary. A clinicopathologic entity distinct from endodermal sinus tumor resembling embryonal carcinoma of the adult testis. Cancer 1976;38:2420–33.doi:10.1002/1097-0142(197612)38:6<2420::AID-CNCR2820380630>3.0.CO;2-2 pmid:63319
      OpenUrlCrossRefPubMed
    4. ↵
      2. Kurman RJ ,
      3. Norris HJ
      . Endodermal sinus tumor of the ovary. A clinical and pathologic analysis of 71 cases. Cancer 1976;38:2404–19.doi:10.1002/1097-0142(197612)38:6<2404::AID-CNCR2820380629>3.0.CO;2-3 pmid:63318
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      2. Kurman RJ ,
      3. Norris HJ
      . Malignant germ cell tumors of the ovary. Hum Pathol 1977;8:551–64.doi:10.1016/S0046-8177(77)80115-9 pmid:http://www.ncbi.nlm.nih.gov/pubmed/198350
      OpenUrlPubMed
    6. ↵
      2. Jimerson GK ,
      3. Woodruff JD
      . Ovarian extraembryonal teratoma. Am J Obstet Gynecol 1977;127:73–9.doi:10.1016/0002-9378(77)90317-9
      OpenUrlPubMed
    7. ↵
      2. Jimerson GK ,
      3. Woodruff JD
      . Ovarian extraembryonal teratoma. II. Endodermal sinus tumor mixed with other germ cell tumors. Am J Obstet Gynecol 1977;127:302–5.doi:10.1016/0002-9378(77)90474-4 pmid:189611
      OpenUrlPubMed
    8. ↵
      2. Gershenson DM ,
      3. Del Junco G ,
      4. Herson J , et al
      . Endodermal sinus tumor of the ovary: the M.D. Anderson experience. Obstet Gynecol 1983;61:194–202.pmid:6185892
      OpenUrlPubMedWeb of Science
    9. ↵
      2. Gershenson DM ,
      3. Del Junco G ,
      4. Copeland LJ , et al
      . Mixed germ cell tumors of the ovary. Obstet Gynecol 1984;64:200–6.pmid:http://www.ncbi.nlm.nih.gov/pubmed/6204258
      OpenUrlPubMed
    10. ↵
      2. Gershenson DM ,
      3. Del Junco G ,
      4. Silva EG , et al
      . Immature teratoma of the ovary. Obstet Gynecol 1986;68:624–9.pmid:http://www.ncbi.nlm.nih.gov/pubmed/3763073
      OpenUrlPubMedWeb of Science
    11. ↵
      2. Gershenson DM ,
      3. Morris M ,
      4. Cangir A , et al
      . Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 1990;8:715–20.doi:10.1200/JCO.1990.8.4.715 pmid:http://www.ncbi.nlm.nih.gov/pubmed/1690272
      OpenUrlAbstract
    12. ↵
      2. Williams S ,
      3. Blessing JA ,
      4. Liao SY , et al
      . Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 1994;12:701–6.doi:10.1200/JCO.1994.12.4.701 pmid:7512129
      OpenUrlAbstract
    13. ↵
      2. Mangili G ,
      3. Sigismondi C ,
      4. Lorusso D , et al
      . The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study. Ann Oncol 2017;28:333–8.doi:10.1093/annonc/mdw563 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27803008
      OpenUrlPubMed
    14. ↵
      2. Johansen G ,
      3. Dahm-Kähler P ,
      4. Staf C , et al
      . Fertility-sparing surgery for treatment of non-epithelial ovarian cancer: oncological and reproductive outcomes in a prospective nationwide population-based cohort study. Gynecol Oncol 2019;155:287–93.doi:10.1016/j.ygyno.2019.08.017 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31493900
      OpenUrlPubMed
    15. ↵
      2. Nasioudis D ,
      3. Frey MK ,
      4. Chapman-Davis E , et al
      . Fertility-preserving surgery for advanced stage ovarian germ cell tumors. Gynecol Oncol 2017;147:493–6.doi:10.1016/j.ygyno.2017.10.010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29021083
      OpenUrlPubMed
    16. ↵
      2. Morrison A ,
      3. Nasioudis D
      . Reproductive outcomes following fertility-sparing surgery for malignant ovarian germ cell tumors: a systematic review of the literature. Gynecol Oncol 2020;158:476–83.doi:10.1016/j.ygyno.2020.05.036 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32513565
      OpenUrlPubMed
    17. ↵
      2. Billmire DF ,
      3. Cullen JW ,
      4. Rescorla FJ , et al
      . Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group. JCO 2014;32:465–70.doi:10.1200/JCO.2013.51.1006
      OpenUrlAbstract/FREE Full Text
    18. ↵
      2. Gershenson DM
      . Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270–5.doi:10.1200/JCO.1988.6.2.270 pmid:http://www.ncbi.nlm.nih.gov/pubmed/2828558
      OpenUrlAbstract
    19. ↵
      2. Zanetta G ,
      3. Bonazzi C ,
      4. Cantù M , et al
      . Survival and reproductive function after treatment of malignant germ cell ovarian tumors. J Clin Oncol 2001;19:1015–20.doi:10.1200/JCO.2001.19.4.1015 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11181664
      OpenUrlAbstract/FREE Full Text
    20. ↵
      2. Gershenson DM ,
      3. Miller AM ,
      4. Champion VL , et al
      . Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group study. J Clin Oncol 2007;25:2792–7.doi:10.1200/JCO.2006.08.4590 pmid:17602084
      OpenUrlAbstract/FREE Full Text
    21. ↵
      2. Ottolina J ,
      3. Mangili G ,
      4. Sigismondi C , et al
      . Reproductive function assessment after surgery plus chemotherapy for germ cell ovarian tumors (MOGCT): novel clues deriving from the field of fertility preservation. Gynecol Endocrinol 2014;30:778–80.doi:10.3109/09513590.2014.943724 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25034573
      OpenUrlPubMed
    22. ↵
      2. Park J-Y ,
      3. Kim D-Y ,
      4. Suh D-S , et al
      . Analysis of outcomes and prognostic factors after fertility-sparing surgery in malignant ovarian germ cell tumors. Gynecol Oncol 2017;145:513–8.doi:10.1016/j.ygyno.2017.03.023 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28372870
      OpenUrlPubMed
    23. ↵
      2. Demeestere I ,
      3. Brice P ,
      4. Peccatori FA , et al
      . No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial. J Clin Oncol 2016;34:2568–74.doi:10.1200/JCO.2015.65.8864 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27217453
      OpenUrlAbstract/FREE Full Text
    24. ↵
      2. Munster PN ,
      3. Moore AP ,
      4. Ismail-Khan R , et al
      . Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 2012;30:533–8.doi:10.1200/JCO.2011.34.6890 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22231041
      OpenUrlAbstract/FREE Full Text
    25. ↵
      2. van Meurs HS ,
      3. Bleeker MCG ,
      4. van der Velden J , et al
      . The incidence of endometrial hyperplasia and cancer in 1031 patients with a granulosa cell tumor of the ovary. Int J Gynecol Cancer 2013;23:1417–22.doi:10.1097/IGC.0b013e3182a57fb4
      OpenUrlAbstract/FREE Full Text
    26. ↵
      2. Lenck C ,
      3. Chopin N ,
      4. Gouy S , et al
      . The French National Network dedicated to rare gynecological cancers diagnosis and management could improve the quality of surgery in daily practice of granulosa cell tumors. A TMRG and GINECO group study. Gynecol Oncol 2020;157:78–84.doi:10.1016/j.ygyno.2020.02.012 pmid:32131977
      OpenUrlPubMed
    27. ↵
      2. Wang D ,
      3. Cao D ,
      4. Jia C , et al
      . Analysis of oncologic and reproductive outcomes after fertility-sparing surgery in apparent stage I adult ovarian granulosa cell tumors. Gynecol Oncol 2018;151:275–81.doi:10.1016/j.ygyno.2018.09.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30219238
      OpenUrlPubMed
    28. ↵
      2. Bergamini A ,
      3. Cormio G ,
      4. Ferrandina G , et al
      . Conservative surgery in stage I adult type granulosa cells tumors of the ovary: results from the MITO-9 study. Gynecol Oncol 2019;154:323–7.doi:10.1016/j.ygyno.2019.05.029 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31189500
      OpenUrlPubMed
    29. ↵
      2. Sigismondi C ,
      3. Gadducci A ,
      4. Lorusso D , et al
      . Ovarian Sertoli-Leydig cell tumors. A retrospective MITO study. Gynecol Oncol 2012;125:673–6.doi:10.1016/j.ygyno.2012.03.024 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22446621
      OpenUrlPubMed
    30. ↵
      2. Fauvet R ,
      3. Boccara J ,
      4. Dufournet C , et al
      . Laparoscopic management of borderline ovarian tumors: results of a French multicenter study. Ann Oncol 2005;16:403–10.doi:10.1093/annonc/mdi083 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15653700
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      2. Desfeux P ,
      3. Camatte S ,
      4. Chatellier G , et al
      . Impact of surgical approach on the management of macroscopic early ovarian borderline tumors. Gynecol Oncol 2005;98:390–5.doi:10.1016/j.ygyno.2005.04.043 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16043215
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      2. Romagnolo C ,
      3. Gadducci A ,
      4. Sartori E , et al
      . Management of borderline ovarian tumors: results of an Italian multicenter study. Gynecol Oncol 2006;101:255–60.doi:10.1016/j.ygyno.2005.10.014 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16307793
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      2. Park J-Y ,
      3. Kim D-Y ,
      4. Kim J-H , et al
      . Surgical management of borderline ovarian tumors: the role of fertility-sparing surgery. Gynecol Oncol 2009;113:75–82.doi:10.1016/j.ygyno.2008.12.034 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19171373
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      2. Uzan C ,
      3. Kane A ,
      4. Rey A , et al
      . Outcomes after conservative treatment of advanced-stage serous borderline tumors of the ovary. Ann Oncol 2010;21:55–60.doi:10.1093/annonc/mdp267 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19608617
      OpenUrlCrossRefPubMed
    35. ↵
      2. du Bois A ,
      3. Ewald-Riegler N ,
      4. de Gregorio N , et al
      . Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynäkologische Onkologie (ago) Study Group. Eur J Cancer 2013;49:1905–14.doi:10.1016/j.ejca.2013.01.035 pmid:http://www.ncbi.nlm.nih.gov/pubmed/23490647
      OpenUrlPubMed
    36. ↵
      2. Uzan C ,
      3. Muller E ,
      4. Kane A , et al
      . Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary. Ann Oncol 2014;25:166–71.doi:10.1093/annonc/mdt430 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24287939
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      2. Vancraeynest E ,
      3. Moerman P ,
      4. Leunen K , et al
      . Fertility preservation is safe for serous borderline ovarian tumors. Int J Gynecol Cancer 2016;26:1399–406.doi:10.1097/IGC.0000000000000782 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27465897
      OpenUrlAbstract/FREE Full Text
    38. ↵
      2. Song T ,
      3. Kim MK ,
      4. Jung YW , et al
      . Minimally invasive compared with open surgery in patients with borderline ovarian tumors. Gynecol Oncol 2017;145:508–12.doi:10.1016/j.ygyno.2017.03.019 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28381342
      OpenUrlPubMed
    39. ↵
      2. Zhao J ,
      3. Liu C ,
      4. Liu J , et al
      . Short-term outcomes and pregnancy rate after laparoscopic fertility-sparing surgery for borderline ovarian tumors: a Single-Institute experience. Int J Gynecol Cancer 2018;28:274–8.doi:10.1097/IGC.0000000000001170 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29324543
      OpenUrlAbstract/FREE Full Text
    40. ↵
      2. Barnhill DR ,
      3. Kurman RJ ,
      4. Brady MF , et al
      . Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: a Gynecologic Oncology Group study. J Clin Oncol 1995;13:2752–6.doi:10.1200/JCO.1995.13.11.2752 pmid:7595734
      OpenUrlAbstract
    41. ↵
      2. Rao GG ,
      3. Skinner EN ,
      4. Gehrig PA , et al
      . Fertility-sparing surgery for ovarian low malignant potential tumors. Gynecol Oncol 2005;98:263–6.doi:10.1016/j.ygyno.2005.04.025 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15964063
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      2. Song T ,
      3. Choi CH ,
      4. Park HS , et al
      . Fertility-sparing surgery for borderline ovarian tumors. Int J Gynecol Cancer 2011;21:640–6.
      OpenUrlAbstract/FREE Full Text
    43. ↵
      2. Hannibal CG ,
      3. Vang R ,
      4. Junge J , et al
      . A nationwide study of serous "borderline" ovarian tumors in Denmark 1978-2002: centralized pathology review and overall survival compared with the general population. Gynecol Oncol 2014;134:267–73.doi:10.1016/j.ygyno.2014.06.002 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24924123
      OpenUrlPubMed
    44. ↵
      2. Plett H ,
      3. Harter P ,
      4. Ataseven B , et al
      . Fertility-sparing surgery and reproductive-outcomes in patients with borderline ovarian tumors. Gynecol Oncol 2020;157:411–7.doi:10.1016/j.ygyno.2020.02.007 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32115229
      OpenUrlPubMed
    45. ↵
      2. Khunamornpong S ,
      3. Settakorn J ,
      4. Sukpan K , et al
      . Mucinous tumor of low malignant potential ("borderline" or "atypical proliferative" tumor) of the ovary: a study of 171 cases with the assessment of intraepithelial carcinoma and microinvasion. Int J Gynecol Pathol 2011;30:218–30.doi:10.1097/PGP.0b013e3181fcf01a pmid:http://www.ncbi.nlm.nih.gov/pubmed/21464732
      OpenUrlPubMed
    46. ↵
      2. De Decker K ,
      3. Speth S ,
      4. Ter Brugge HG , et al
      . Staging procedures in patients with mucinous borderline tumors of the ovary do not reveal peritoneal or omental disease. Gynecol Oncol 2017;144:285–9.doi:10.1016/j.ygyno.2016.11.035 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27889017
      OpenUrlPubMed
    47. ↵
      2. Morris RT ,
      3. Gershenson DM ,
      4. Silva EG , et al
      . Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol 2000;95:541–7.doi:10.1016/s0029-7844(99)00619-5 pmid:http://www.ncbi.nlm.nih.gov/pubmed/10725486
      OpenUrlCrossRefPubMedWeb of Science
    48. ↵
      2. Morice P ,
      3. Camatte S ,
      4. El Hassan J , et al
      . Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril 2001;75:92–6.doi:10.1016/S0015-0282(00)01633-2 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11163822
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      2. Boran N ,
      3. Cil AP ,
      4. Tulunay G , et al
      . Fertility and recurrence results of conservative surgery for borderline ovarian tumors. Gynecol Oncol 2005;97:845–51.doi:10.1016/j.ygyno.2005.03.010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15896834
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      2. Chevrot A ,
      3. Pouget N ,
      4. Bats A-S , et al
      . Fertility and prognosis of borderline ovarian tumor after conservative management: Results of the multicentric OPTIBOT study by the GINECO & TMRG group. Gynecol Oncol 2020;157:29–35.doi:10.1016/j.ygyno.2019.12.046 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32241341
      OpenUrlPubMed
    51. ↵
      2. Fain-Kahn V ,
      3. Poirot C ,
      4. Uzan C , et al
      . Feasibility of ovarian cryopreservation in borderline ovarian tumours. Hum Reprod 2009;24:850–5.doi:10.1093/humrep/den459 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19098070
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      2. Fortin A ,
      3. Morice P ,
      4. Thoury A , et al
      . Impact of infertility drugs after treatment of borderline ovarian tumors: results of a retrospective multicenter study. Fertil Steril 2007;87:591–6.doi:10.1016/j.fertnstert.2006.07.1503 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17113086
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      2. Gershenson DM ,
      3. Sun CC ,
      4. Lu KH , et al
      . Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary. Obstet Gynecol 2006;108:361–8.doi:10.1097/01.AOG.0000227787.24587.d1 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16880307
      OpenUrlCrossRefPubMedWeb of Science
    54. ↵
      2. Gershenson DM ,
      3. Sun CC ,
      4. Bodurka D , et al
      . Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol 2009;114:48–52.doi:10.1016/j.ygyno.2009.03.001 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19361839
      OpenUrlCrossRefPubMed
    55. ↵
      2. Gershenson DM ,
      3. Sun CC ,
      4. Iyer RB , et al
      . Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol 2012;125:661–6.doi:10.1016/j.ygyno.2012.02.037 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22406638
      OpenUrlCrossRefPubMed
    56. ↵
      2. Schmeler KM ,
      3. Sun CC ,
      4. Bodurka DC , et al
      . Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol 2008;108:510–4.doi:10.1016/j.ygyno.2007.11.013 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18155273
      OpenUrlCrossRefPubMed
    57. ↵
      2. Gershenson DM ,
      3. Bodurka DC ,
      4. Lu KH , et al
      . Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum: results of a large single-institution registry of a rare tumor. J Clin Oncol 2015;33:2675–82.doi:10.1200/JCO.2015.61.0873 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26195696
      OpenUrlAbstract/FREE Full Text
    58. ↵
      2. Wong K-K ,
      3. Lu KH ,
      4. Malpica A , et al
      . Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis. Int J Gynecol Pathol 2007;26:404–9.doi:10.1097/pgp.0b013e31803025cd pmid:http://www.ncbi.nlm.nih.gov/pubmed/17885490
      OpenUrlCrossRefPubMed
    59. ↵
      2. Gershenson DM ,
      3. Bodurka DC ,
      4. Coleman RL , et al
      . Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. JCO 2017;35:1103–11.doi:10.1200/JCO.2016.71.0632
      OpenUrlPubMed
    60. ↵
      2. Wong K-K ,
      3. Tsang YTM ,
      4. Deavers MT , et al
      . BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol 2010;177:1611–7.doi:10.2353/ajpath.2010.100212 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20802181
      OpenUrlCrossRefPubMedWeb of Science
    61. ↵
      2. Grisham RN ,
      3. Iyer G ,
      4. Garg K , et al
      . Braf mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. Cancer 2013;119:548–54.doi:10.1002/cncr.27782 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22930283
      OpenUrlCrossRefPubMedWeb of Science
    62. ↵
      2. Jones S ,
      3. Wang T-L ,
      4. Kurman RJ , et al
      . Low‐grade serous carcinomas of the ovary contain very few point mutations. J Pathol 2012;226:413–20.doi:10.1002/path.3967 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22102435
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      2. Emmanuel C ,
      3. Chiew Y-E ,
      4. George J , et al
      . Genomic classification of serous ovarian cancer with adjacent borderline differentiates Ras pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver. Clin Cancer Res 2014;20:6618–30.doi:10.1158/1078-0432.CCR-14-1292 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25316818
      OpenUrlAbstract/FREE Full Text
    64. ↵
      2. Hunter SM ,
      3. Anglesio MS ,
      4. Ryland GL , et al
      . Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget 2015;6:37663–77.doi:10.18632/oncotarget.5438 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26506417
      OpenUrlCrossRefPubMed
    65. ↵
      2. Gershenson DM ,
      3. Sun CC ,
      4. Wong K-K
      . Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum. Br J Cancer 2015;113:1254–8.doi:10.1038/bjc.2015.364 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26484411
      OpenUrlCrossRefPubMed
    66. ↵
      2. Malpica A ,
      3. Deavers MT ,
      4. Lu K , et al
      . Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004;28:496–504.doi:10.1097/00000478-200404000-00009 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15087669
      OpenUrlCrossRefPubMedWeb of Science
    67. ↵
      2. Vang R ,
      3. Shih I-M ,
      4. Kurman RJ
      . Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 2009;16:267–82.doi:10.1097/PAP.0b013e3181b4fffa pmid:http://www.ncbi.nlm.nih.gov/pubmed/19700937
      OpenUrlCrossRefPubMedWeb of Science
    68. ↵
      2. Ali RH ,
      3. Kalloger SE ,
      4. Santos JL , et al
      . Stage II to IV low-grade serous carcinoma of the ovary is associated with a poor prognosis: a clinicopathologic study of 32 patients from a population-based tumor registry. Int J Gynecol Pathol 2013;32:529–35.doi:10.1097/PGP.0b013e31827630eb pmid:http://www.ncbi.nlm.nih.gov/pubmed/24071867
      OpenUrlCrossRefPubMed
    69. ↵
      2. Ahn G ,
      3. Folkins AK ,
      4. McKenney JK , et al
      . Low-grade serous carcinoma of the ovary: clinicopathologic analysis of 52 invasive cases and identification of a possible noninvasive intermediate lesion. Am J Surg Pathol 2016;40:1165–76.doi:10.1097/PAS.0000000000000693 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27487741
      OpenUrlPubMed
    70. ↵
      2. Scott SA ,
      3. Llaurado Fernandez M ,
      4. Kim H , et al
      . Low-grade serous carcinoma (LGSC): a Canadian multicenter review of practice patterns and patient outcomes. Gynecol Oncol 2020;157:36–45.doi:10.1016/j.ygyno.2020.01.021 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32001076
      OpenUrlPubMed
    71. ↵
      2. Yin J ,
      3. Wang Y ,
      4. Shan Y , et al
      . Pregnancy and oncologic outcomes of early stage low grade epithelial ovarian cancer after fertility sparing surgery: a retrospective study in one tertiary hospital of China. J Ovarian Res 2019;12:1–5.doi:10.1186/s13048-019-0520-6
      OpenUrlPubMed
    72. ↵
      2. Lee Y-Y ,
      3. Kim T-J ,
      4. Kim M-J , et al
      . Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis. Gynecol Oncol 2011;122:541–7.doi:10.1016/j.ygyno.2011.05.009 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21640372
      OpenUrlCrossRefPubMed
    73. ↵
      2. Sugiyama T ,
      3. Kamura T ,
      4. Kigawa J , et al
      . Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 2000;88:2584–9.pmid:http://www.ncbi.nlm.nih.gov/pubmed/10861437
      OpenUrlCrossRefPubMedWeb of Science
    74. ↵
      1. NCCN
      . Clinical practice guidelines in oncology. ovarian cancer including fallopian tube cancer and primary peritoneal cancer version 1, 2020. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
    75. ↵
      2. Morice P ,
      3. Denschlag D ,
      4. Rodolakis A , et al
      . Recommendations of the fertility task force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant tumors. Int J Gynecol Cancer 2011;21:951–63.doi:10.1097/IGC.0b013e31821bec6b pmid:21697684
      OpenUrlAbstract/FREE Full Text
    76. ↵
      2. Liu D ,
      3. Cai J ,
      4. Gao A , et al
      . Fertility sparing surgery vs radical surgery for epithelial ovarian cancer: a meta-analysis of overall survival and disease-free survival. BMC Cancer 2020;20:320. doi:10.1186/s12885-020-06828-y pmid:http://www.ncbi.nlm.nih.gov/pubmed/32293358
      OpenUrlPubMed
    77. ↵
      2. Kajiyama H ,
      3. Shibata K ,
      4. Mizuno M , et al
      . Fertility-sparing surgery in patients with clear-cell carcinoma of the ovary: is it possible? Hum Reprod 2011;26:3297–302.doi:10.1093/humrep/der342 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22016417
      OpenUrlCrossRefPubMed
    78. ↵
      2. Crafton SM ,
      3. Cohn DE ,
      4. Llamocca EN , et al
      . Fertility‐sparing surgery and survival among reproductive-age women with epithelial ovarian cancer in 2 cancer registries. Cancer 2020;126:1217–24.doi:10.1002/cncr.32620 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31774553
      OpenUrlPubMed
    79. ↵
      2. Jiang X ,
      3. Yang J ,
      4. Yu M , et al
      . Oncofertility in patients with stage I epithelial ovarian cancer: fertility-sparing surgery in young women of reproductive age. World J Surg Oncol 2017;15:154. doi:10.1186/s12957-017-1222-4 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28806962
      OpenUrlPubMed
    80. ↵
      2. Fruscio R ,
      3. Ceppi L ,
      4. Corso S , et al
      . Long-term results of fertility-sparing treatment compared with standard radical surgery for early-stage epithelial ovarian cancer. Br J Cancer 2016;115:641–8.doi:10.1038/bjc.2016.254 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27537385
      OpenUrlPubMed
    81. ↵
      2. Lee J-Y ,
      3. Jo YR ,
      4. Kim TH , et al
      . Safety of fertility-sparing surgery in primary mucinous carcinoma of the ovary. Cancer Res Treat 2015;47:290–305.doi:10.4143/crt.2014.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25287480
      OpenUrlPubMed
    82. ↵
      2. Ditto A ,
      3. Martinelli F ,
      4. Bogani G , et al
      . Long-term safety of fertility sparing surgery in early stage ovarian cancer: comparison to standard radical surgical procedures. Gynecol Oncol 2015;138:78–82.doi:10.1016/j.ygyno.2015.05.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25969349
      OpenUrlCrossRefPubMed
    83. ↵
      2. Wright JD ,
      3. Shah M ,
      4. Mathew L , et al
      . Fertility preservation in young women with epithelial ovarian cancer. Cancer 2009;115:4118–26.doi:10.1002/cncr.24461 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19670446
      OpenUrlCrossRefPubMed
    84. ↵
      2. Nasioudis D ,
      3. Chapman-Davis E ,
      4. Frey MK , et al
      . Could fertility-sparing surgery be considered for women with early stage ovarian clear cell carcinoma? J Gynecol Oncol 2017;28:e71. doi:10.3802/jgo.2017.28.e71 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28758377
      OpenUrlPubMed
    85. ↵
      2. Park J-Y ,
      3. Suh D-S ,
      4. Kim J-H , et al
      . Outcomes of fertility-sparing surgery among young women with FIGO stage I clear cell carcinoma of the ovary. Int J Gynaecol Obstet 2016;134:49–52.doi:10.1016/j.ijgo.2015.10.022 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27039052
      OpenUrlPubMed
    86. ↵
      2. Watanabe T ,
      3. Soeda S ,
      4. Nishiyama H , et al
      . Clinical and reproductive outcomes of fertility-sparing surgery in stage I epithelial ovarian cancer. Mol Clin Oncol 2020;12:44–50.doi:10.3892/mco.2019.1954 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31832189
      OpenUrlPubMed
    87. ↵
      2. Satoh T ,
      3. Yoshikawa H
      . Fertility-sparing surgery for early stage epithelial ovarian cancer. Jpn J Clin Oncol 2016;46:703–10.doi:10.1093/jjco/hyw069 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27284094
      OpenUrlCrossRefPubMed
    88. ↵
      2. Hess V ,
      3. A'Hern R ,
      4. Nasiri N , et al
      . Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004;22:1040–4.doi:10.1200/JCO.2004.08.078 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15020606
      OpenUrlAbstract/FREE Full Text
    89. ↵
      2. Brown J ,
      3. Frumovitz M
      . Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep 2014;16:389. doi:10.1007/s11912-014-0389-x pmid:http://www.ncbi.nlm.nih.gov/pubmed/24777667
      OpenUrlCrossRefPubMed
    90. ↵
      2. Gouy S ,
      3. Saidani M ,
      4. Maulard A , et al
      . Results of fertility-sparing surgery for expansile and infiltrative mucinous ovarian cancers. Oncologist 2018;23:324–7.doi:10.1634/theoncologist.2017-0310 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29242280
      OpenUrlAbstract/FREE Full Text
    91. ↵
      2. Fruscio R ,
      3. Corso S ,
      4. Ceppi L , et al
      . Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series. Ann Oncol 2013;24:138–44.doi:10.1093/annonc/mds241 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22945381
      OpenUrlCrossRefPubMedWeb of Science
    92. ↵
      2. Young RH ,
      3. Oliva E ,
      4. Scully RE
      . Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol 1994;18:1102–16.doi:10.1097/00000478-199411000-00004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/7943531
      OpenUrlCrossRefPubMedWeb of Science
    93. ↵
      2. Callegaro-Filho D ,
      3. Gershenson DM ,
      4. Nick AM , et al
      . Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): a review of 47 cases. Gynecol Oncol 2016;140:53–7.doi:10.1016/j.ygyno.2015.11.004 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26546963
      OpenUrlPubMed
    94. ↵
      2. Harrison ML ,
      3. Hoskins P ,
      4. du Bois A , et al
      . Small cell of the ovary, hypercalcemic type -- analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol 2006;100:233–8.doi:10.1016/j.ygyno.2005.10.024 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16321429
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      2. Woopen H ,
      3. Sehouli J ,
      4. Pietzner K , et al
      . Clinical experience of young patients with small cell ovarian carcinoma of the hypercalcemic type (OSCCHT). Eur J Obstet Gynecol Reprod Biol 2012;165:313–7.doi:10.1016/j.ejogrb.2012.07.034 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22906684
      OpenUrlPubMed
    96. ↵
      2. Dykgraaf RHM ,
      3. de Jong D ,
      4. van Veen M , et al
      . Clinical management of ovarian small-cell carcinoma of the hypercalcemic type: a proposal for conservative surgery in an advanced stage of disease. Int J Gynecol Cancer 2009;19:348–53.doi:10.1111/IGC.0b013e3181a1a116 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19407558
      OpenUrlAbstract/FREE Full Text
    97. ↵
      2. Qin Q ,
      3. Ajewole VB ,
      4. Sheu TG , et al
      . Successful treatment of a stage IIIC small-cell carcinoma of the ovary hypercalcemic subtype using multi-modality therapeutic approach. Ecancermedicalscience 2018;12:832. doi:10.3332/ecancer.2018.832 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29910829
      OpenUrlPubMed
    98. ↵
      2. Phoolcharoen N ,
      3. Woodard T ,
      4. James D , et al
      . Successful pregnancy following chemotherapy in a survivor of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): a case report and review of literature. Gynecol Oncol Rep 2020;32.doi:10.1016/j.gore.2020.100576 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32405521
    99. ↵
      2. Colombo N ,
      3. Sessa C ,
      4. du Bois A , et al
      . ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†. Ann Oncol 2019;30:672–705.doi:10.1093/annonc/mdz062 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31046081
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors All authors contributed to writing and review of final version.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.