The effect of concurrent endometriosis on the prognosis of women with ovarian clear cell or endometrioid carcinoma

To evaluate features of ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC) by presence of endometriosis among women with endometriosis‐associated ovarian cancer (EAOC).


| INTRODUCTION
Endometriosis is a benign gynecologic disorder that is characterized by endometrial glands and stroma occurring outside the uterus. Since the first report of a malignant transformation in endometriosis in 1925, 1 an association between endometriosis and ovarian cancer has continued be documented. [2][3][4] The overall rate of malignant transformation in endometriosis has been estimated as 0.3%-0.8%, with relative risk ranging from 1.3 to 1.9. 2 The relationship between endometriosis and ovarian cancer has been classified as either a transition from endometriotic lesions to invasive ovarian carcinoma, or the coexistence of ovarian cancer with endometriosis without a transition. 5,6 Because the criteria for these types are poorly defined, they may be collectively called endometriosisassociated ovarian cancer (EAOC).
As compared with ovarian cancer without endometriosis, EAOC has been diagnosed in younger women and at an earlier stage. [7][8][9] Some studies have also reported a stronger association of endometriosis with ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC) types of cancer. 2,5,8,10 However, whether endometriosis is a prognostic factor for women with ovarian CCC or EC remains unclear. 6,7,[9][10][11][12] The aim of the present study was therefore to evaluate the clinical and prognostic features of ovarian CCC and EC, according to the presence of pathologically confirmed concurrent endometriosis, among women with EAOC. Hospital. Due to the retrospective nature of the study, patient consent was not required.

| MATERIALS AND METHODS
All study women had their initial treatment at the study hospital or were referred for complementary treatment after their initial surgery. The women underwent surgery and most received postoperative therapy. Surgical staging included total abdominal hysterectomy with bilateral salpingo-oophorectomy or unilateral salpingo-oophorectomy without hysterectomy, lymph node (LN) dissection, omentectomy, and removal of all macroscopic lesions. 13 All pathologic analyses were confirmed by a single gynecologic pathologist at the study institution. Stages were adjusted in accordance with the revised 2014 FIGO classification. 14 For the current study, EAOC was defined as any of the following: ovarian cancer with endometriosis identified histologically in the same ovary, endometriosis in one ovary and ovarian cancer in the contralateral ovary, or ovarian cancer with extra-ovarian pelvic endometriosis. Data were analyzed by using SPSS version 23.0 (IBM, Armonk, NY, USA). Clinical and prognostic features of ovarian CCC or EC, the most common histologic subtypes of the EAOC group, were compared between the presence and absence of endometriosis. Variables were compared between the two groups by using χ 2 or Fisher exact test.
Disease-free survival (DFS) was calculated as the number of months from the date of initial treatment to the date of disease progression and/or recurrence. Overall survival (OS) was defined in months from the date of initial treatment to the date of death or date at last contact. Survival comparisons were obtained by using the Kaplan-Meier log-rank test. To account for the potential confounding factors, the Cox proportional-hazards regression model was used to determine the hazard ratios (HR) and corresponding 95% confidence intervals (CIs). All reported P values were two-tailed, and a P value of 0.05 or less was considered to be statistically significant.

| RESULTS
During the study period, 578 women were diagnosed treated for ovarian cancer at the study institution. Of these, 40 (6.9%) women were found to have EAOC; the remaining 538 women had no pathologic evidence of endometriosis (non-EAOC group).
The clinical and pathologic characteristics of the 40 women with EAOC are summarized in Table 1. The mean age at diagnosis was 47.2 years (range, 28-77 years) and 26 (65%) women were premenopausal. Stage I disease was the most common stage at the time of diagnosis. The mean tumor size was 12.2 cm (range, 4-38 cm). Grade 3 tumors accounted for more than 50% of the cases. Most of the women had a unilateral tumor, no LN metastasis, and either no residual tumor or a tumor of 1 cm or smaller. One woman had synchronous endometrial cancer. All women underwent primary surgery. Of these, 35 (88%) received adjuvant chemotherapy (platinum-based regimens combined with taxanes). After their initial treatment, 36 (90%) women showed a complete or partial response, and 4 (10%) showed progressive disease.
During the follow-up period, nine women had a recurrence, and eight of them died owing to disease progression.
The features of ovarian CCC and EC compared were compared between the presence and absence of endometriosis ( Table 2). The mean age at diagnosis was approximately 4 years younger for women with endometriosis than for women without endometriosis; however, the difference was not significant. The proportion of premenopausal women was higher in the endometriosis group, although again the difference was not significant. Parity, pre-operative serum CA-125, prevalence of CA125 in normal range, tumor size, distribution of histologic subtypes and tumor grade, laterality of tumor, presence of LN metastasis, residual tumor greater than 1 cm, and presence of synchronous endometrial cancer did not differ between the two groups.
In addition, no difference was observed in the initial treatment protocol or the response to treatment, or in the rate of relapse or death.

| DISCUSSION
In the current study, approximately 7% of all ovarian cancers were associated with endometriosis, and three-quarters of EAOC cases were histologically CCC or EC. Previous studies have reported the presence of endometriosis in 10%-18% of ovarian cancers. 11,15 The mechanisms underlying the malignant transformation of endometriosis remain unclear. Among women of reproductive age, an immune imbalance and an hormonal environment marked by an excess of estrogen and a deficiency of progesterone might trigger a transition from benign endometriosis toward malignancy. 5,16 In particular, some studies have focused on a link between endometriosis and CCC or EC histology. 5,17 Recently, on the basis of 13 case-control studies including more than 23 000 women, endometriosis was found to be significantly associated with an increased risk of ovarian CCC or EC. 18 That finding, as well as those from other studies, suggests that endometriosis increases the risk of ovarian CCC and EC, despite the overall low incidence of ovarian cancer among women with endometriosis.
The role of concurrent endometriosis is controversial in the prognosis of ovarian cancer. In general, ovarian cancer is diagnosed at an advanced stage, whereas EAOC is diagnosed at an early stage; in addition, longer survival times have been reported for women with EAOC than for women with non-EAOC types of ovarian cancer. 7,8,11 However, other studies have found no clear association between the presence of endometriosis and ovarian cancer survival. 6,9,10,12 The current study showed that ovarian CCC and EC cases with endometriosis were associated with better survival rates as compared with cases without endometriosis. The favorable prognostic role of endometriosis might be explained by the different distribution of stages between the two groups, because stage I disease was significantly more common in the EAOC group than in the non-EAOC group. No difference was found between the two groups in age at diagnosis, tumor features (size, grade, and laterality), LN metastasis status, residual tumor greater than 1 cm, or incidence of synchronous endometrial cancers. The only difference between the groups was disease detection at an earlier stage in the EAOC group.
It is known that CCC and EC with endometriosis are diagnosed earlier because endometriosis is frequently associated with specific symptoms, such as pelvic pain, dysmenorrhea, and dyspareunia. 16,19 In addition, women with endometriosis tend to have more continual medical care for their disorder, whereas ovarian cancers are frequently asymptomatic until an advanced stage. 2  The present study has some limitations. It was a retrospective analysis of data obtained from clinical records. During the long-term follow-up period, it is possible that the pathologic diagnoses and treatment protocols might have changed; however, a single pathologist and two gynecologic oncologists conducted all diagnoses and treatments.
Furthermore, there was no significant difference in therapeutic regimens between the two groups. All study women underwent surgical procedures and more than 90% of them received platinum-based chemotherapies combined with taxanes. Another limitation relates to the inability to compare cases of ovarian cancer originating in endometriosis and cases in which endometriosis was not contiguous with the tumor but was detected incidentally in surgical specimens, owing to the small proportion of women with EAOC.
In conclusion, endometriosis was most frequently associated with CCC and EC histologic types among epithelial ovarian cancers.
However, no clear association was observed between the presence of concurrent endometriosis and prognosis of ovarian CCC or EC.
Ovarian CCC and EC with endometriosis are often diagnosed at an earlier stage relative to cases without endometriosis, and therefore have a more favorable prognosis.

AUTHOR CONTRIBUTIONS
JUC, KWD, and KSM all contributed to study conception and design; data acquisition, analysis, and interpretation; and writing and revising the manuscript.

ACKNOWLEDGMENTS
The study was supported by a grant from the Chonnam National University Hwasun Hospital Institute for Biomedical Science (no. HCRI 18006-1).