Background
Borderline ovarian tumors (BOT), indolent neoplasms characterized by the presence of cellular proliferation and nuclear atypia in the absence of destructive stromal invasion, account for 10-20% of all epithelial ovarian cancers [
1,
2]. Over the past two decades, considerable work has been performed to investigate the clinicopathologic features of serous and mucinous BOTs, as well as the oncological and fertility outcomes of patients with BOTs [
3‐
5]. However, due to its rare incidence, endometrioid BOTs (EBOTs), the third most common BOT, have been poorly studied [
6]. Most studies on EBOTs have focused mainly on the pathological characteristics and included only brief descriptions of management and follow-up [
6‐
10]. Additionally, only a few cases that were treated with conservative surgery have been reported; therefore, the fertility outcomes of these patients are unknown [
6,
9].
Although approximately one-third of patients with EBOT have endometrial hyperplasia and/or carcinoma, to the best of our knowledge, no specific data are available that identify groups at high risk for EBOT [
10]. Furthermore, staging surgery without endometrial biopsy remains the cornerstone for women with EBOT who hope to become pregnant. Thus, to better understand the course of EBOT and to improve the surveillance of these patients, a thorough exploration of the prevalence of synchronous endometrial disorders in women with EBOT and identification of potential risk factors is urgently needed.
The primary objective of our study was to investigate the risk of synchronous endometrial disorders among women with EBOT and to identify their risk factors. We also evaluated the oncological and fertility outcomes in these EBOT patients.
Discussion
EBOT is a rare tumor that represents 0.2% of all epithelial ovarian tumors. To our knowledge, this is the first study to evaluate risk factors for synchronous endometrial disorders in women with EBOT. Our results indicated that synchronous endometrial disorders are highly prevalent in women with EBOT, especially in those who are younger, nulliparous, and have AVB. Our study also demonstrated that, although women with EBOT have a favorable prognosis, their fertility outcomes are poor.
When treating EBOT patients, physicians must decide whether to include endometrial curettage as a therapeutic approach. Although few studies have evaluated the incidence of endometrial disorders in women with EBOT, studies by Bell and Kurman and Snyder et al. found that 12.5% (3/24) and 68.4% (13/19), respectively, of EBOT patients also had endometrial disorders [
7,
9]. However, our study revealed that the prevalence of synchronous endometrial disorders was 52%; this incidence remained high (41.4%) following systematic analysis. Thus, as recommended by Uzan et al., endometrial sampling should be performed in women with EBOT undergoing conservative surgery; in addition, a hysterectomy should be performed in cases requiring radical treatment [
6,
12].
The mechanisms underlying endometrial disorders in EBOT patients remain unclear. Although one study indicated that stromal luteinizations were more common in EBOT patients with concurrent endometrial disorders, to our knowledge, no other study has confirmed this result [
8]. Analyses of our data showed that EBOT patients who were younger, nulliparous, and had AVB were more likely to experience endometrial disorders. To our knowledge, this is the first study to demonstrate this relationship.
Endometrioid carcinomas of the ovary tend to coexist with various forms of endometrial neoplasia, whereas mutations in several genes, including β-catenin and PTEN, have been demonstrated to occur concurrently with endometrial cancers and endometrioid ovarian cancers [
13]. Furthermore, distinct clinical characteristics, including younger age, obesity, premenopausal status, and nulliparity were demonstrated in women with synchronous primary cancers of the endometrium and ovary [
14].
The finding that women with AVB were more likely to have concurrent endometrial disorders was not surprising. Endometrial cancer or atypical hyperplasia occurs in 1.31% of premenopausal women with AVB, and this incidence can increase to 17.3% in menopausal women [
15,
16]. However, 88.9% (
n = 10/11) of women with EBOT and AVB also had endometrial disorders, and this incidence was significantly higher than that of the general population. Furthermore, uterine endometrioid adenocarcinomas can also be found in women who do not show uterine symptoms [
6]. More than 60% (8/13) of our study participants were nulliparous, which is consistent with a study by Eifel et al., wherein 50% of the study participants who had synchronous endometrioid/endometrioid tumors were nulliparous [
17]. Similarly, Herrinton et al. reported a lower than expected mean parity in women with synchronous endometrial and ovarian cancers [
18].
In our study population, women with EBOT and synchronous endometrial disorders were approximately 12 years younger than those with EBOT alone. Similar findings were also reported in women with coexisting endometrial and ovarian carcinomas [
19]. The combination of younger age, AVB, and nulliparity, as well as other characteristics, including obesity, in women with synchronous endometrioid/endometrial carcinomas suggests the involvement of a hormonal “field effect” in the development of these simultaneous tumors, particularly endometrioid cell-type tumors [
14,
19]. In recent years, accumulating evidence has suggested that ovarian cancer arises from the pleiotropic interactions of the committed stem cells within the ovary, the surrounding microenvironment, and the infiltrating immune cells [
20,
21]. Thus, whether these interactions may contribute to the development of synchronous endometrial and ovarian disorders needs further exploration.
With respect to oncological outcomes, over the past decade several studies have demonstrated the safety of fertility-sparing surgery in early stage epithelial ovarian cancer patients whose preservation of reproductive potential is pivotal to their quality of life [
22‐
24]. Previous studies have found that women with EBOT have a favorable prognosis, with minimal recurrence and no EBOT-associated deaths [
6‐
9]. However, in this study, three patients experienced recurrences, of which two recurred on the contralateral ovary and one relapsed as a bilateral recurrence. All three women were young (23, 30, and 30 years old, respectively), nulliparous, and had synchronous endometrial disorders. Uzan et al. reported a malignant transformation, wherein a 37-year old woman suffered an invasive relapse as endometrioid carcinoma after radical treatment for her first recurrence [
6]. This unusual case, in combination with our three recurrences, emphasizes the importance of endometrial biopsy in women with EBOT and the need for an intensive post-operative follow-up, especially in younger patients.
Promising data have been reported for fertility outcomes in women with serous/mucinous BOTs after conservative management. One study reported a pooled estimated spontaneous pregnancy rate of 54% that increased to 80% after fertility treatment [
4]. In women with advanced-stage serous BOTs, a long-term follow-up study reported a pregnancy rate of 57.1% [
25]. For BOTs, conservative treatment, patient age, and BOT histologic subtype have been reported to influence fertility outcomes; however, for patients with EBOT, there is limited information about fertility outcomes [
26‐
28].
In this study, we demonstrated for the first time that women with EBOT have poor fertility outcomes. Of the nine women who attempted conception, only one (11.1%) pregnancy was achieved that resulted in a live birth. We should note that five of these nine women developed endometrial disorders after their initial EBOT surgery, including two women with endometrial cancer. Only two women experienced AVB but endometrial sampling was not performed during the initial surgery (unpublished data). Thus, whether nulliparity itself contributes to the development of endometrial disorders or vice versa awaits further study. In addition, adherence and alterations in ovarian function following surgery could also contribute to poor fertility outcomes.
This study has several limitations. First, the present study is inherently limited by its retrospective design and small sample size; in addition, the data were collected from a single institution. As a result, the data in this study did not include all factors that could contribute to the etiology of EBOT tumors, such as body mass index. Women with obesity are at increased risk of endometrial disorders due to excess peripheral conversion of androstenedione to estrone in adipose tissue. However, to the best of our knowledge, due the rare incidence of this condition, this is the largest study to focus on endometrial sampling in women with EBOT. Second, pathological review of the specimens was not performed. The Peking Union Medical College Hospital is a major referral center and has the best gynecology and pathology department in the country. In addition, two gynecological pathologists reviewed original pathology reports. Finally, not all women included in this study underwent endometrial biopsies during their initial surgery (endometrial disorders were observed in six women during follow-up), which may have resulted in overestimation of the incidence of synchronous endometrial disorders. However, this incidence of was 41.4% following after systematic analysis.