Risk Factors for Postoperative Recurrence of Ovarian Endometrioma in Young Women

Background: Ovarian endometroma seriously affects women's health, and is susceptible to recurrence after surgery. However, only a few studies have been conducted to asses the risk factors for postoperative recurrence of ovarian endometrioma in young women, and no risk factors associated with recurrence have been found. The purpose of this study is to analyse the risk factors for postoperative recurrence of ovarian endometrioma in young women. Materials and Methods: We retrospectively analysed 196 young women who underwent ovarian endometrioma resection in Peking Union Medical College Hospital and Shengjing Hospital from January 2008 to January 2018 and were followed-up for at least 3 years postoperatively. The patients were divided into a recurrence group or a non-recurrence group. Their preoperative histories, laboratory indexes, intraoperative manifestations, and follow-up symptoms were analysed. Results: The cumulative recurrence rate of ovarian endometrioma in young women 3 and 5 years after surgery was 8.0%, and 20.3%, respectively. Univariate analysis showed signicant differences in cancer antigen-125 levels (hazard ratio [HR]: 3.207, 95% condence interval [CI]: 1.126–9.135, P = 0.029), the revised American Fertility Society (rAFS) disease stage (HR: 4.588, 95%CI: 1.422–14.805, P =0.011), postoperative pregnancy (HR: 0.28, 95%CI: 0.109–0.723, P = 0.008), and postoperative dysmenorrhoea (HR: 2.465, 95%CI :1.320–4.604, P = 0.005) between the two groups. Cox multivariate proportional risk analysis showed that rAFS disease stage (HR:3.783, 95%CI: 1.162–12.311, P=0.027) and postoperative dysmenorrhoea (HR: 2.291, 95%CI :1.222–4.296, P = 0.01) were risk factors for postoperative recurrence of ovarian endometrioma, whereas postoperative pregnancy (HR: 0.361, 95%CI: 0.138–0.944, P=0.038) was a protective factor for postoperative recurrence. There was no signicant correlation between recurrence of ovarian endometrioma and age at surgery, age at the time of menarche, body mass index, duration of dysmenorrhoea, degree of dysmenorrhoea, genital malformation, surgical approach, maximum diameter of the cyst, and postoperative medication. Conclusion: rAFS disease stage and postoperative dysmenorrhoea are risk factors for the recurrence of ovarian endometrioma during long-term follow-up, whereas postoperative pregnancy is a protective factor.


Introduction
Endometriosis is a disease caused by the presence of endometrial tissue outside the uterine body.
Although it is an oestrogen-dependent benign disease, it is characterised by implantation, invasion, and distant metastasis, which are features similar to those of malignant tumours.Patients with mild endometriosis can be treated with prophylactic therapy or medication.However, if the patient does not experience symptomatic relief after medication and the local lesion exacerbates, surgery is needed.Since this disease mostly occurs in women of childbearing age who have fertility requirements, conservative surgery is the rst choice of treatment.However, postoperative recurrence has become one of the challenges in the clinical treatment of this disease.In a comprehensive analysis of 23 studies, author estimated the recurrence rate of endometriosis in adult women after primary surgery to be 21.5% within 2 years and 40.0-50.0% within 5 years [1].In a multicentre retrospective cohort study of 105 adolescent women younger than 20 years old, Lee reported cumulative recurrence rates of 10% and 19.9% at 3 and 5 years, respectively; however, the analysis of the results did not identify risk factors for recurrence [2].Only a few studies have been conducted to analyse the risk factors for postoperative recurrence of ovarian endometrioma in young women.Therefore, the purpose of this study was to evaluate the frequency of clinical recurrence in young women who underwent conservative surgery for ovarian endometrioma, and to explore the risk factors for postoperative recurrence of the disease.

Study population
We retrospectively evaluated 196 young female patients who underwent ovarian endometrioma resection in Peking Union Medical College Hospital and Shengjing Hospital between January 2008 and January 2018.They were followed-up for at least 3 years, from the date of surgery to the date of last follow-up and the follow-up time was measured in months; the study ended in January 2021.The inclusion criteria were as follows: (1) ovarian endometriosis con rmed through pathological assessment, (2) age ≤ 21years old, and (3) follow-up duration of at least 3 years.The exclusion criteria were as follows: (1) prior surgery for ovarian endometriosis, (2) incomplete preoperative data, and (3) ovarian endometriosis complicated with malignant or borderline tumours.All patients provided informed consent prior to surgery.This study was approved by the Ethics Committee of Peking Union Medical College Hospital and Shengjing Hospital.

Methods
This was a retrospective case control study.Consultation, pathography, telephone follow-up, and outpatient appointments were conducted for each patient and the following clinical data were collected: age at the time of surgery, body mass index (BMI), age at the time of menarche, dysmenorrhoea score, duration of dysmenorrhoea, serum cancer antigen 125 (CA125) level, surgical approach, the revised American Fertility Society (rAFS) disease stage, genital malformation, maximum diameter of ovarian endometrioma, postoperative pregnancy, postoperative dysmenorrhoea, postoperative medication, and duration from time of surgery to recurrence.Each surgery was performed by an experienced gynaecologist with expertise in the assessment and treatment of endometriosis.Pain was scored based on the 10 cm visual analogue scale, and pain intensity was classi ed as none (0), mild (1-4), moderate (5-7), or severe (8-10).The threshold points for de ning the severity of pain were chosen based on previous correlation analyses [3].Disease stages were classi ed according to the rAFS classi cation system (1996) [4].Recurrent endometrioma was de ned as the presence of a persistent ovarian cyst with a minimum diameter of 2 cm, thick walls, regular margins, and a homogenous low echogenic uid content with scattered internal echoes [5].If the cyst is indistinguishable from a transient luteal cyst or a haemorrhagic cyst, recurrence may be diagnosed only if the cyst persists after several successive menstrual cycles.

Statistical analysis
Statistical analysis was performed using the Statistic Package for Social Sciences 26.0 (SPSS Inc., Chicago, IL, USA).The Shapiro-Wilk test was used to test whether the measurement data complied with the normal distribution.The measurement data that conformed to the normal distribution were expressed as means ± standard deviations; the independent t-test was used for comparison between groups.The measurement data that did not follow the normal distribution were represented as medians ( rst quartile to third quartile); the comparison between groups was performed using the Wilcoxon rank sum test.
Enumeration data were presented as cases (percentages) using either Fisher's exact test or the chi-square test.The Kaplan-Meier curve was used to describe the survival changes, and log-rank test was used to compare the differences between survival curves.Univariate analysis was used to identify potential risk factors (P < 0.1).In multivariate analysis, if the assumption of equal proportional risk was satis ed, Cox proportional hazard regression model was used to study the in uence of factors on survival; if the equal proportional risk assumption was not satis ed, the strati ed variable control was used.Hazard ratio (HR) and 95% con dence intervals (CI) were calculated as measures of recurrence risk in each study.Signi cance was de ned as P < 0.05.
After at least 3 years of postoperative follow-up (median, 55 months [40-81 months]), the cumulative recurrence rate of ovarian endometrioma was 8.0% at 3 years and 20.3% at 5 years.The clinical characteristics of the patients with ovarian endometrioma in the non-recurrence and the recurrence groups are shown in Table 1.There were signi cant differences in rAFS disease stage and postoperative dysmenorrhoea between the two groups.

Discussion
In the present study, we analysed the risk factors for postoperative recurrence of ovarian endometrioma in young women.Endometriosis is a common gynaecological disease.Recently, the high postoperative recurrence rate of endometriosis and its related risk factors have been analysed and reported in an increasing number of retrospective and prospective studies.Ovarian endometrioma is the most common type of endometriosis.However, only a few studies have been conducted to asses the risk factors for postoperative recurrence of ovarian endometrioma in young women, and no risk factors associated with recurrence have been found.The present study focused on the risk factors associated with recurrence of ovarian endometrioma in young women.
Owing to the different criteria used to de ne postoperative recurrence endometrioma, its actual recurrence rate is not clear.Some authors consider the recurrence of symptoms as the recurrence of the disease.However, in most studies, the diagnosis of endometrioma was based on the results of ultrasound imaging.In addition, the recurrence rate was also affected by factors such as the severity of the disease, surgical technique used, duration of postoperative follow-up, postoperative intervention, and statistical methods used.The cumulative rate of postoperative recurrence of ovarian endometrioma over 5 years varies widely from 6.1-50% [2,[6][7][8][9].In the present study, the cumulative ve-year postoperative recurrence rate was 20.3%.
Numerous previous studies have investigated risk factors for recurrence of ovarian endometrioma.Busacca et al. reported that rAFS disease stage was a risk factor for recurrence of ovarian endometrioma [10].Chon et al. reported that dysmenorrhoea and inner cyst septation signi cantly affects the postoperative recurrence rate of ovarian endometrioma [11].Selcuk et al. reported that the depth of endometrial tissue penetration into the ovarian cyst wall is an independent risk factor for recurrence [12].Guzel et al. reported that CA125 levels, ovarian cyst size, and history of pelvic surgery affect the recurrence rate [13].Moini et al. reported that large ovarian endometrioma is a high risk factor for postoperative recurrence [14].However, it is di cult to compare the results of these studies due to differences in study population, duration of follow-up, and de nition of recurrent ovarian endometrioma.
Most gynaecologists use the rAFS staging to describe the extent, depth, degree, and location of lesions in endometrioma.Tobiume et al. suggested that the rAFS disease stage is an independent risk factor for postoperative recurrence [8], whereas Porpora et al. believed that the rate of recurrence is higher in patients with late rAFS stage-disease [3].Similar to the results of previous studies, we found that the rAFS disease stage was a risk factor for postoperative recurrence in the present study(Fig.1A).The rAFS stage represents the extent of invasion by lesions and the severity of adhesions.The later the disease stage, the more di cult it is to completely eliminate the lesions, and the more prone the patient is to postoperative recurrence.Therefore, the postoperative recurrence of endometrioma can be predicted using the rAFS staging system.
Dysmenorrhoea is one of the most typical symptoms of ovarian endometrioma.The cause of dysmenorrhoea in ovarian endometrioma is not completely understood; however, it may occur in several ways.When abnormal endometrial tissue is present outside the uterus, periodic microbleeding within the endometrioma may cause severe dysmenorrhoea.The lesion activates a cascade of macrophages and cytokines that leads to a chronic in ammatory process that causes dysmenorrhoea [15].The overexpression of local oestrogen receptors may also be a key factor in the severity of dysmenorrhoea [16].Furthermore, endometrial lesions may in ltrate deeply into the intestines [17] and cause pelvic oor nerve entrapment and dysmenorrhoea [18].The incidence of preoperative dysmenorrhoea in the present study was 83.2% and the median duration of dysmenorrhoea was ve months.However, the duration and intensity of preoperative dysmenorrhoea had no effect on postoperative recurrence in the present study.
Owing to the high incidence rate of dysmenorrhoea among young women with endometriosis, and given that some previous studies have demonstrated that the severity of preoperative dysmenorrhoea is a risk factor for postoperative recurrence [6], it is therefore recommended that if a patient experiences pain for 3-6 months, a more comprehensive assessment of chronic pelvic pain, including history taking and thorough physical examination, should be performed to assess the underlying cause of the pain.In the present study, postoperative dysmenorrhoea was a risk factor for postoperative recurrence of ovarian endometriosis(Fig.1B), which is consistent with those of previous studies [19].This suggests that close attention should be paid to dysmenorrhoea during postoperative follow-up.If dysmenorrhoea persists or worsens, further examination using ultrasound or pelvic magnetic resonance imaging is recommended to evaluate the potential causes of dysmenorrhoea.
Some previous studies have suggested that women who get pregnant postoperatively have a low recurrence rate of ovarian endometrioma, suggesting that postoperative pregnancy may have a protective effect on the recurrence of endometrioma [6, [20][21][22].Concordantly, the univariate analysis in our study shows that the postoperative pregnancy is signi cantly associated with endometrioma recurrence(Fig.1C).Another study revealed a higher rate of spontaneous pregnancy in the rst year after laparoscopic resection of the ovarian endometrioma [23].Therefore, gynaecologists should provide active guidance for young women according to the patient's current and future pregnancy wishes.If the patient has a need for fertility after surgery, it is recommended that she try to get pregnant as early as possible after cystectomy.
The results of several multivariate analyses in previous studies have suggested that being too young at the time of surgery is a risk factor for recurrence of ovarian endometrioma [14,22,24].A meta-analysis of 10 studies suggested that younger age might be a high-risk factor for the recurrence of ovarian endometrioma after conservative surgery [25].In contrast, Parazzini suggested that older age is a risk factor for the recurrence of ovarian endometriosis [26].The results of the present study suggest that the age at the time of surgery has no signi cant effect on the risk of recurrence.This may be related to the fact that all the patients enrolled in this study were young women.
We assessed the size of ovarian endometrioma in this study, and the results showed that cyst size has no effect on the recurrence of ovarian endometrioma.This nding is also consistent with those of previous studies [3,6].However, in a multivariate analysis of women aged 40-49 years, ovarian endometrioma larger than 5.5 cm was the only risk factor for postoperative recurrence [27].The ndings of some previous studies suggest that cyst size is a risk factor for recurrence of the disease [14,20].These differences may be related to surgical experience, age of patients, and whether the tumour can be completely resected.
Serum CA125 level is currently the most commonly used marker for the assessment of endometrioma.However, only a few researchers have suggested that CA125 level is a risk factor for the recurrence of ovarian endometrioma [13].In our series, log-rank test suggests women with preoperative serum CA125 over35U/ml had higher endometrioma recurrence rate(Fig.1D), however, the result of Cox proportional hazard regression model, which suggests that preoperative serum CA125 level is not an independent risk factor for postoperative ectopic recurrence, is consistent with those of most studies(Fig.1F).Due to the limited diagnostic accuracy and low sensitivity of CA125, its accuracy in predicting recurrence of endometrioma is limited.
In the present study, GnRH-a was administered for 3-6 months after surgery.We found that postoperative GnRH-a treatment did not signi cantly reduce the recurrence rate of endometrioma, which is consistent with those of previous studies [27,28], Muzii reported that preoperative administration of GnRH-a for three months did not signi cantly reduce the postoperative recurrence rate of ovarian endometrioma [29].
The results of the present study did not indicate that perioperative use of GnRH-a is bene cial for the prevention of postoperative recurrence.Due to the high cost of GnRH-a drugs and a series of side effects such as osteoporosis and perimenopause-related symptoms caused by long-term use, other effective drugs have been promoted instead.Takamura found that oral contraceptive treatment for 24 months after laparoscopic resection of ovarian endometrioma is effective in preventing postoperative recurrence of ovarian endometrioma [30].A retrospective study of 362 women of reproductive age who underwent laparoscopic surgery for endometrioma showed that postoperative GnRH-a combined with cyclic oral contraceptives signi cantly reduced the ve-year postoperative recurrence rate of endometrioma compared with GnRH-a alone [9].Another meta-analysis revealed that patients who received dienogest after conservative surgery for endometriosis had a signi cantly lower risk of postoperative disease recurrence than those who were expectantly managed [31].However, the results of the present study did not show that oral contraceptives alone or combined with GnRH-a could reduce the postoperative recurrence rate of endometrioma.This may be related to the small number of patients who took oral drugs in this study.Future studies with larger sample sizes are necessary to verify this nding.
The recommended treatment for endometriosis in adolescents is conservative surgical therapy in combination with continuous suppressive medication [32].Surgical treatment for endometriosis includes laparotomy and laparoscopy.However, laparoscopy has become the preferred surgical method for the treatment of endometriosis due to its advantages, including prevention of adhesion, less intraoperative blood loss, early postoperative exhaust, short duration of postoperative fever, and quick recovery.The proportion of laparoscopy cases in the present study was 90.3%.
The advantages of this study are that the follow-up duration was more than three years, the clinical data was documented in detail, and the sample size is large.However, the study contains some limitations.
First, this was a retrospective case-control study, patients from two regional medical center hospitals were selected as subjects, due to the high proportion of combined genital malformation, there may be bias in selection.Second, patients with severe endometriosis may be more inclined to receive preoperative medication, but this study failed to collect preoperative medication data, which may have a potential impact on the study results.Finally, determination of disease recurrence was based on an ultrasound diagnosis, which depends on the sonographer's skill and experience.These limitations can cause correlations to be underestimated or overestimated.
In conclusion, we conducted a long-term follow-up study for more than 3 years to investigate the risk factors for postoperative recurrence of ovarian endometrioma in young women.Our results showed that the rAFS disease stage and postoperative dysmenorrhoea are independent risk factors for recurrence of ovarian endometrioma, whereas postoperative pregnancy is a protective factor for recurrence.For young patients who have severe disease or who still have dysmenorrhoea after surgery, greater attention should be paid to the risk of postoperative recurrence.Those who are willing to get pregnant should be guided to actively prepare for pregnancy and undergo individualised treatment to obtain better curative effects.

Ethics approval
The study was approved by the Ethics Committee of Peking Union Medical College Hospitalthe (JS-1804) and Shengjing Hospital of China Medical University (2019PS015F) and conducted in accordance with the Declaration of Helsinki.

Figures
Figure 1 1A Kaplan-Meier curves presenting the cumulative recurrence rate according to the rAFS stage.There were signi cant differences between the two groups according to the log-rank test analysis (χ2 = 7.915, p = 0.005).1B Kaplan-Meier curves presenting the cumulative recurrence rate according to the Postoperative dysmenorrhoea.There were signi cant differences between the two groups according to the log-rank test analysis (χ2 = 8.629, p = 0.003).1C Kaplan-Meier curves presenting the cumulative recurrence rate according to the Postoperative pregnancy.There were signi cant differences between the two groups according to the log-rank test analysis (χ2 = 7.857, p = 0.005).1D Kaplan-Meier curves presenting the cumulative recurrence rate according to the CA125.There were signi cant differences between the two groups according to the log-rank test analysis (χ2 = 5.77, p = 0.017).1E Cumulative recurrence rate in 196 young women who underwent conservative surgery for ovarian endometrioma.1F Multivariable predictor of postoperative recurrence of ovarian endometrioma.

Table 2
Univariate and multivariate analysis of risk factors in the ovarian endometrioma recurrence and nonrecurrence groups Abbreviations:CA-125 Cancer antigen 125, mm millimeter, m month, rAFS Revised American Fertility Society classi cation system