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Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Corresponding author. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuai Fu Yuan, Eastern District, Beijing, 100730, China.
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
To investigate the clinicopathological features and prognostic value of endometriosis in young patients with ovarian endometrioid carcinoma (OEC) and ovarian clear cell carcinoma (OCCC).
Methods
The medical files and clinical follow-up data of patients aged 40 years or younger with OEC or OCCC between January 2006 and December 2017 who had undergone complete surgical staging followed by systemic chemotherapy were retrospectively reviewed.
Results
A total of 94 women were included in this study. Univariate analysis revealed that the progression-free survival (PFS) and overall survival (OS) rates of patients with endometriosis-associated ovarian carcinoma (EAOC) did not improve compared with those of patients without EAOC (5-year PFS: 80.0% vs. 75.9% and 5-year OS: 85.0% vs. 86.0%, respectively). Multivariate analyses confirmed that FIGO stage (II–IV), cytology-positive ascites or peritoneal washes and residual disease > 1 cm were independent predictors of PFS and that residual disease > 1 cm was the only predictor of OS.
Conclusions
Endometriosis is not independently associated with the prognosis of OEC and OCCC among young patients. The intrinsic relationship between endometriosis and ovarian cancer warrants further investigation.
Globally, there are 239,000 new cases and 152,000 deaths annually due to ovarian cancer, making this cancer the second most common cause of gynaecological cancer mortality [
]. Risk factors for EOC include the number of lifetime ovulations (early age of menarche, late age at menopause, and absence of pregnancy), smoking, family history of EOC, and benign gynaecological conditions (endometriosis, pelvic inflammatory disease, and polycystic ovary syndrome) [
]. In a large international collaborative study, self-reported endometriosis was found to be associated with an overall risk increase of nearly 50% (OR 1.46, 95% CI 1.31–1.63), especially for clear cell (OR 3.05, 95% CI 2.43–3.84) and endometrioid (OR 2.04, 95% CI 1.67–2.48) cancers [
]. However, it remains highly controversial whether EAOC is a different disease from or similar to non-endometriosis-associated ovarian cancer (non-EAOC). Many studies have evaluated clinical and prognostic differences between EAOC or non-EAOC according to specific histological types and the International Federation of Gynaecology and Obstetrics (FIGO) stage [
], very few have evaluated clinical and prognostic differences between EAOC and non-EAOC according to age, especially a young age. As some reports have indicated that younger age is an independent prognostic factor for improved survival [
], whether EAOC is a distinct clinical entity among young patients deserves investigation. Most ovarian cancer is diagnosed in women of nonreproductive age, yet 12.1% of ovarian cancer patients are ≤44 years of age [
], the number of young patients with EAOC is expected to be noteworthy.
In this study, we focused on cases of EAOC comprising ovarian endometrioid carcinoma (OEC) or ovarian clear cell carcinoma (OCCC) and compared them to those of non-EAOC among women of reproductive age (40 years or younger) at Peking Union Medical College Hospital, one of the largest endometriosis medical centres in China. We aimed to explore the association between endometriosis and EOC in young patients based on our data.
Materials and methods
The medical files and clinical follow-up data for patients with OEC or OCCC between January 2006 and December 2017 and aged 40 years or younger were reviewed. All patients received complete surgical staging or cytoreductive surgery (CRS) at the Division of Gynaecological Oncology of the Department of Obstetrics and Gynaecology at Peking Union Medical College Hospital (PUMCH). None of the patients had a history of any other cancer or a family history of breast or ovarian or colorectal cancer. This was a retrospective study, and University Institutional Review Board approval was obtained. All patients provided informed. Consent on admission to PUMCH.
In this study, “endometriosis-associated ovarian carcinoma (EAOC)” was defined as the presence of ovarian cancer and endometriosis identified histologically in the same ovary or the presence of ovarian cancer in one ovary with endometriosis in the contralateral ovary or extraovarian pelvic endometriosis. For statistical analysis, serum CA125 levels were divided into low (≤35 U/mL), middle (35–500 U/mL) and high (≥500 U/mL). Synchronous tumours of the ovary and endometrium were found and analysed in this series. The criteria of Young and Scully [
] were applied to differentiate between synchronous primary tumours of both organs and metastasis of a tumour from one organ to the other. The International FIGO [
] stage categories were classified into early stage (FIGO stage I) and late stage (FIGO stages II to IV). Pathology slides were all independently reviewed by two experienced pathologists at PUMCH. The histological cell type and tumour differentiation were assessed according to World Health Organization (WHO) criteria [
]. Most of the patients received carboplatin/cisplatin-based chemotherapy. In this study, the patient follow-up period ended in June 2019. Progression-free survival (PFS) was calculated as the period from the date of initial surgery to the date of disease progression. OS was calculated as the number of months from the date of initial surgery to the date of patient death from the disease. Patients who died from other conditions or who were survivors at the time of their last visit were censored. The pregnancy outcomes of the patients with fertility-sparing surgery (FSS) were also recorded. FSS is defined as the preservation of ovarian tissue in one or both adnexa and the uterus in patients of reproductive age. All of the patients were followed up every 3 months for the first 2 years, every 6 months for the next 3 years, and once per year thereafter. Statistical analysis was performed using SPSS. Between-group comparisons were performed using the chi-square or Fisher's exact test and the independent samples T-test. Survival analysis was conducted using the log-rank test and adjusted Kaplan–Meier model. Cox proportional hazards regression was used for multivariate analysis. The level of statistical significance was set at p < 0.05.
Results
During the study period, 592 patients with OEC and OCCC were admitted to PUMCH; of these, 110 (18.6%) were aged 40 years or younger. Ultimately, a total of 94 eligible patients were included in this study. According to the pathologic criteria listed above, we identified 40 (42.6%) of the 94 patients as having endometriosis (EAOC group). The remaining 54 (57.4%) patients had no pathologic evidence of endometriosis (non-EAOC group).
The patient clinicopathological characteristics and associated P-values between the two groups are shown in Table 1. The mean patient age at initial diagnosis was 33.10 ± 5.40, ranging from 18 to 40. The mean age of the patients was 34.42 ± 4.01 in the EAOC group, ranging from 27 to 40, and 32.11 ± 6.08 years in the non-EAOC group, ranging from 18 to 40 (P = 0.31). Three patients were 18–20 years old; 25 patients were 21–30 years old, and the remaining 66 were 31–40. Therefore, we divided the patients into two groups based on age, 18 to 30 and 31 to 40; although it appeared that the non-EAOC group had more than 18- to 30-year-old patients, there was no significant difference (P = 0.07). We observed significant differences in dysmenorrhoea (P < 0.01) between the two groups. In contrast, there was no obvious difference in parity number or other clinical symptoms. Nearly all of the patients (93/94, 98.9%) had a pelvic mass (measured by ultrasound). The mean tumour diameter was 10.75 ± 4.86 cm: 10.09 ± 3.74 in the EAOC group and 11.24 ± 5.53 in the non-EAOC group. The majority (83/94,88.3%) of the surgeries were performed using a laparotomy approach. Pathological examination showed that of the patients in the study, 44 (46.8%) had OCCC, 44 (46.8%) had OEC, 6 (6.4%) had a mixed pathology, 2 had mainly OCCC with a part of the tumour being OEC, and the other 4 had mainly OEC with a part of the tumour being OCCC. Unilateral tumours occurred in 74 (78.7%) patients. In addition, coexisting synchronous endometrial cancer was confirmed in 20 (21.3%) of the patients. There were 8 (8.5%) cases of residual disease (>1 cm) at the end of surgical staging. Carboplatin/cisplatin chemotherapy was administered to 87 (92.6%) patients; 39 (41.5%) of them received less than or equal to 4 chemical regimens, whereas 48 (51.1%) received more than 4 cycles. 4 patients with stage IA grade 1 (G1) OEC did not receive chemotherapy after surgery, and 1 patient with stage IC OCCC and 2 patients with stage IC OEC refused postoperative chemotherapy. The median follow-up time for all patients was 63.8 months, and 53.2% of the patients had a follow-up time of ≥60 months. A total of 21 (22.3%) patients experienced recurrence at least once during the follow-up period. The average PFS was 15.8 months, with a range of 1–92 months. The salvage treatments used for those with recurrences included repeated CRS, salvage chemotherapy, and radiotherapy. A total of 77 (81.9%) patients were alive with no evidence of residual tumour at the time of the last visit, 4 (4.3%) patients were alive with the recorded disease, and 13 (13.8%) were dead of the recorded disease. There were no obvious differences between the two groups in terms of these variables.
Table 1Clinicopathologic features and associated P-values.
The 5-year PFS rate was 77.9% and the 5-year OS rate 85.5% for the entire study population. Univariate analysis revealed that endometriosis had no significant influence on PFS and OS (Table 2, Fig. 1). According to multivariate analysis, FIGO stage, cytology and residual disease were independent predictors for relapse in these patients (P = 0.03, 0.01 and 0.002, respectively), though only residual disease was identified as an independent predictor for death (P = 0.04).
Figure 1The 5-year PFS and OS curves of patients under 40 years old with ovarian endometrioid and clear cell carcinoma arising from endometriosis or not.
The clinical characteristics and pregnancy outcomes of 22 patients after FSS are shown in Table 3. Twenty-two (90.9%) patients had early-stage (FIGO stage IA or IC) OEC or OCCC. Two of the 22 (9.1%) patients were upstaged after surgical staging according to the FIGO criteria. One had stage IIA OCCC (bilateral salpingo-oopherectomy, uterus preserved), and the other had stage IIIA1(i) G1 OEC with para-aortic lymph node micrometastasis. Both patients underwent staging laparotomy, rejected additional surgery and received chemotherapy with paclitaxel and carboplatin for 6 cycles. No disease recurrence was found after 5 years of follow-up for these two patients. Four of the 22 patients (18.2%) did not receive adjuvant chemotherapy, 2 patients had stage IA G1 OEC, 1 had stage IC G1 OEC, and 1 had stage IC OCCC; the two IC patients rejected advised adjuvant chemotherapy. Only 2 (9.1%) patients had disease recurrence, and none died. The two patients with recurrence had G1 OEC and received staging laparotomy; neither of them received chemotherapy. One had stage IA disease and relapsed at 92 months after the initial surgery; the other had stage IC disease and relapsed after 10 months. These two patients received CRS and chemotherapy with paclitaxel and carboplatin for 4 cycles. Seventeen patients (77.3%) had no desire to have a child. Five patients (22.7%) had successfully conceived spontaneously; three (13.6%) patients had foetal loss, and 2 (9.1%) had live births. No tumour recurrence occurred during or after pregnancy.
Table 3Clinical characteristics and pregnancy outcomes of 22 patients after fertility-sparing surgery.
Histologically, EOC is classified into 5 major subtypes: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous ovarian cancers. OCCC represents approximately 5% of EOCs in North America and Europe, and endometrioid cancer of the ovary represents approximately 10% of EOCs [
]. High rates of endometrioid and clear cell carcinoma in Asian women have been previously documented in the United States and Eastern Asia, though the reasons remain unknown [
Recent trends in ovarian cancer incidence and relative survival in the United States by race/ethnicity and histologic subtypes. Cancer epidemiology, biomarkers & prevention : a publication of the American association for cancer research, cosponsored by the.
]. In our study, 110 of 592 (18.6%) patients were under 40 years of age. It may be because the study enrolled patients with OEC or OCCC. Indeed, the incidence of each of these two subtypes peaks at a younger age than that of high-grade serous ovarian cancer [
], our study mainly focused on these two histological subtypes. When age was confined to less than 40 years, the proportion of EAOC was 40/94 (42.6%), which was equal to that in the study conducted by Ayhan et al. [
]. In their study, the overall rate of cancer originating from endometriotic cysts was 42.5% among patients with clear cell and endometrioid cancer. However, endometriosis was observed in 4–29% of patients in a group comprising all types of EOC [
] showed that younger age was an independent prognostic factor for improved survival among EOC patients. Additionally, a few studies have indicated that patients with EAOC tend to be younger than those with non-EAOC, and the early stage and lower grade are partially responsible for the improved survival of these young women [
]. In our study, which confined age to less than 40 years, no differences in clinicopathological or prognostic features were found between EAOC and non-EAOC, except for dysmenorrhoea (P < 0.01), which is a typical symptom of patients with endometriosis (Table-1). This means that the favourable characteristics of EAOC, such as early-stage and low-grade disease, are not observed among young patients. It is interesting that the mean age between the two groups did not differ, though the age range in the EAOC group was 27–40 years and that in the non-EAOC group was 18–40 years. The reason may be that EAOCs develop from extraovarian benign endometriosis lesions that embed into the ovary and that these lesions need time to undergo a series of mutations that result in malignant transformation. Nonetheless, as non-EAOC may exhibit rapid progression possibly through de novo carcinogenesis, it can occur at a very young age. The most common symptom experienced by the patients with OEC and OCCC was a pelvic mass (98.9%), with a mean tumour diameter of 10.8 ± 4.9 cm (measured by ultrasound). The patient without a pelvic mass was diagnosed with a normal ovary size by caesarean section, and the tumour was located on the surface of the ovary. This is in agreement with another study indicating that OECs are typically large with a mean size of 15–20 cm and that OCCCs are typically 10–15 cm in diameter [
], the preoperative serum level of CA125 was significantly lower than in those without endometriosis, and EAOC patients were more likely to have normal CA125 levels than were non-EAOC patients. We recorded no statistically significant difference in preoperative serum CA125 level between the young EAOC and non-EAOC groups (P = 0.88).
The difference in prognosis between EAOC and non-EAOC patients is still not clear. Some studies have shown better survival rates for patients with EAOC [
] conducted a 12-year cohort study that included 188 patients with OEC at the same institution as in our study, and 32 (17%) of these patients had endometriosis. The patients with endometriosis had a better OS rate (96.9% vs. 84%, P = 0.027) and lower recurrence and mortality rates (18.8% vs. 56.4%, P < 0.001). Regardless, multivariate analysis showed that menopausal status and FIGO stage are the only independent predictors of OS. A retrospective study conducted by Ju et al. [
] analysed clinical and prognostic features of 578 OCCC and OEC patients with endometriosis and those without, no association was found between the presence of endometriosis and the prognosis of OCCC or OEC. In our study, there were no significant differences in the 5-year PFS or OS based on endometriosis origin (Fig. 1). Moreover, Kaplan–Meier survival analysis showed FIGO stage (II–IV), cytology-positive ascites or peritoneal washes and residual disease >1 cm were to be factors for progression and overall survival (Table 2). Cox regression analysis further confirmed that these three factors were independent predictors of PFS and residual disease >1 cm was the only independent predictor of OS. These results suggest that endometriosis may not affect progression after the onset of ovarian cancer. Previous molecular profiling of OEC revealed that the most prevalent mutations are similar to those in OCCC, including PIK3CA (40%), ARID1A (30%), KRAS (30%), PTEN (16%), and PPP2R1A (16%) and suggesting a shared molecular pathogenesis [
] found a definitive link suggesting that endometrioid and clear cell carcinomas arise from endometriosis and that the mutation in ARID1A, which encodes AT-rich interactive domain-containing protein 1A that participates in chromatin remodelling, is important in this process. However, this conclusion was based on only two observations, and extensive validation involving endometriotic lesions from patients with ovarian cancer and patients without cancer is necessary. Furthermore, endometriotic lesions excised years before the development of cancer should be compared with the tissue obtained at the time of cancer diagnosis. In addition, endometrioid and clear cell histotypes appear to follow a dualistic developmental model, namely, a hormone-dependent pathway for the endometrioid histotype and a hormone-independent pathway for the clear cell histotype [
]. In fact, endometrioid cancers are predominantly positive for oestrogen and progesterone receptors, whereas clear cell carcinomas typically exhibit very low receptor expression. Therefore, endometriosis that can transform into clear cell ovarian cancer may become hormone independent during the transformation process. The precise steps in the malignant transformation of the ectopic endometrium still need to be understood.
In addition, all patients in this study had a premenopausal status, and 48/94 (51.1%) of them had no child at the time of surgery (Table 3). Because many women tend to give birth to their first child when they are 35–40 years old [
], there is an increasing need for FSS in women with early-stage EOC. As a result of late childbearing, fertility preservation has become a major issue among young women with gynaecological cancer. Overall, the potential role of FSS in reproductive-aged women diagnosed with ovarian cancer requires more attention. In this study, 22 patients with apparent early-stage EOC received comprehensive FSS, including 5 with stage IC OCCC and 1 with stage IIA OCCC. Only 2 (9.1%) patients had disease recurrence, and none died. Regardless, the number of patients with FSS in this study may be too small for statistical analyses; we can, however, speculate that it is important to consider treatment approaches that incorporate both ovarian cancer treatment and fertility preservation for young women, even for stage IC OCCC patients. Cancer recurrences can be successfully managed with repeated surgery and very rarely lead to patient death. Good obstetrical results after FSS make the conservative treatment of early EOC a sensible option for women who desire it [
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.
]. Up to 20% of OECs coexisted with an endometrioid carcinoma of the endometrium, and a similar association occurred less commonly with OCCC. Therefore, patients with OEC and OCCC should undergo endometrial biopsy during FSS, as concomitant uterine cancer might be present. Because EAOCs are known to develop from endometriosis, de novo carcinogenesis is conceivable, and it is vital to ensure that no endometriotic lesions are left behind in the contralateral ovary during FSS.
This was a retrospective study in one tertiary hospital in China. The number of young patients enrolled in this study was relatively small, though any bias and deviation of data might be better eliminated compared with multicentre research. In addition, the patient clinicopathological and follow-up data in this study were relatively complete, which enabled us to perform a robust analysis to evaluate the prognostic implications of endometriosis in young patients with OEC or OCCC. More research is warranted to investigate the differences between EAOC and non-EAOC among young patients.
Conclusions
Endometriosis is not an independent prognostic predictor in patients with OCCC and OEC when age is confined to under 40 years. It is premature to consider ovarian cancers arising from endometriosis as a distinct entity. This analysis also suggests that reproductive-aged women with early-stage OEC and OCCC should be offered conservative treatment. Future research should focus on the identification of factors that are associated with the malignant transformation of endometriosis and how to identify women for whom more definitive endometriosis treatment would be appropriate to prevent ovarian cancer.
Role of the funding source
This study received financial support from the Chinese Academy of Medical Sciences Initiative for Innovative Medicine ( 2017-I2M-1–002 ) (No. CAMS-2017-I2M-1–002 ) and the National Key Research and Development Plan for Major Chronic Noncommunicable Diseases Prevention and Control Projects (No. 2016YFC1303701 ).
Declaration of competing interest
The authors declare no conflict of interest.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Recent trends in ovarian cancer incidence and relative survival in the United States by race/ethnicity and histologic subtypes. Cancer epidemiology, biomarkers & prevention : a publication of the American association for cancer research, cosponsored by the.
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.
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