{"paper_id":"ab813a0b-f2a1-46d6-8393-c1acc21d6941","body_text":"Endometriosis is a benign estrogen-dependent gynecologic disease that occurs mainly among women of reproductive age, and the prevalence rate is estimated to be 5–10 % [ 1 , 2 ]. A defining feature of endometriosis is the presence of endometrial gland and/or stroma outside the uterine cavity, generally on the pelvic peritoneum and ovaries [ 3 ]. Taniguchi et al. reported that approximately 1% of endometriosis cases undergo malignant transformation [ 4 ]. In addition, Wilbur et al. reported that women with endometriosis have a two- to three-fold increase in the absolute risk of developing epithelial ovarian cancer [ 5 ]. Among the histologic types of ovarian endometriosis, atypical endometriosis (AE) is known to be a precursor lesion of endometriosis-associated ovarian cancer (EAOC) characterized by cytologic atypia and architectural atypia or hyperplasia [ 6 ]. “Cytologic atypia” describes the presence of nuclear atypia within the epithelial lining of endometriotic cysts, whereas ‘architectural atypia or hyperplasia’ refers to the same spectrum of hyperplasia discovered in the endometrium [ 7 ]. Tanase et al. emphasized the importance of considering the possibility of malignant change, and strongly recommended carefully following patients in cases when AE is observed [ 8 ]. Because of the risk of malignant transformation, most studies regarding atypical endometriosis focused on EAOC. However, other data, such as clinical characteristics, risk factors, and recurrence of AE are limited. Therefore, the aims of this study were to evaluate the clinical characteristics and recurrence rates of AE compared to typical endometriosis (TE) in addition to the malignant transformation rate of AE.\n\nA retrospective cohort study was performed in a single gynecological surgery center using data collected between January 2008 and September 2019. During the study period, a total of 3957 patients were surgically treated and displayed pathologically confirmed ovarian endometriosis. Patients were excluded if they had (1) gynecologic malignancy in addition to ovarian endometriosis (n = 87) and underwent bilateral oophorectomy (n = 17), (2) menopause (n = 15), (3) revised American Society of Reproductive Medicine (rASRM) stage of I or II (n = 18) at initial surgery [ 9 ], or (4) follow-up duration of <6 months (n = 1109). The definition of atypical endometriosis included cytologic atypia, architectural atypia, or hyperplasia. According to McCluggage, reactive change of ovarian endometrioma can occur secondary to repeated episodes of hemorrhage and may be confused with atypical endometriosis [ 10 ]. Therefore, we excluded those patients who were also diagnosed with cytological atypia or hyperplasia associated with reactive change (n = 30). Thus, a total of 2681 patients were included and their data analyzed in the current study. The recurrence of endometrioma was considered when transvaginal or transrectal sonography indicated the presence of a round-shaped cystic mass with a minimum diameter of 20 mm, thick walls, regular margins, homogenous low echogenic fluid content with scattered internal echoes, and the absence of papillary proliferation [ 11 ]. If a patient had two endometriomas that were <20 mm and the sum of their diameters was >20 mm, the patient was considered to have endometrioma recurrence. Reoperations were performed when (1) the size of endometrioma was more than 5 cm despite medical treatments, (2) the size of endometrioma was more than 5 cm and medical treatment was unavailable, (3) malignancy was suspected in the recurred cyst, or (4) a procedure was needed for cesarean section or co-existing gynecologic diseases such as myoma or dermoid cyst. In cases of reoperation during the study period, the initial surgery was analyzed. However, if the pathologic results indicated AE in a later surgery, the later surgery was analyzed in the AE group. The study protocol was approved by the Institutional Review Boards and ethics committee of CHA Gangnam Medical Center on the Use of Human Subjects in Research (GCI-20−04); informed consent requirements for the study were waived given its retrospective nature.\nStatistical analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA) and R for Windows, ver. 4.0.2. Chi-square and Fisher’s exact tests were used for the analysis of categorical variables. Quantitative variables were compared using the Mann-Whitney  U  test The Kaplan-Meier method was required for calculation of the cumulative probability of recurrence, and the comparison between the curves was performed using the long-rank test. P-values <0.05 were considered statistically significant. In addition, the inverse probability of treatment weighting (IPTW) method based on the propensity score was used to reduce the effect of selection/allocation bias between the with recurrence and without recurrence groups.\n\nA total of 2681 patients were included in this study. The median follow-up duration was 26.0 months (range, 6−138 months). Baseline characteristics of the patients are shown in  Table 1 \n. The mean age was 33.2 ± 6.7 years and 77.4 % of the patients were nulliparous. The median duration of postoperative hormonal treatments was 9.0 months (range, 0−126 months). Of the 2681 patients, 86 (3.2 %) were pathologically diagnosed with atypical endometriosis. A total of 362 (13.5 %) patients experienced recurrent ovarian endometrioma with 32.8 ± 26.8 months of mean time to recurrence. Among the 362 patients, 66 (18.2 %) underwent reoperation. Table 1 Baseline characteristics of patients. Table 1 Clinical characteristics Patients (n = 2681) Age (years) 33.2 ± 6.7 (32.0, 16−64) Parity  No 2074 (77.4 %)  Yes 607 (22.6 %) BMI (kg/m2) 21.1 ± 3.0 (20.5, 14.7−37.9) Size of ovarian cyst(s) (cm) 6.7 ± 3.4 (6.0, 0.5−36.4) Duration of follow-up (months) 36.7 ± 29.2 (26.0, 6−138) Preoperative CA125 (n = 2358) 81.1 ± 167.0 (48.0, 1.0−5203) Preoperative AMH (n = 1117) 3.40 ± 2.99 (2.62, 0.01−21.14) Previous history of endometrioma operation  No 2449 (91.3 %)  Yes 232 (8.7 %) Preoperative symptoms  Pain 1645 (61.4 %)  Bleeding 158 (5.9 %)  Compression symptom 34 (1.3 %)  Infertility 72 (2.7 %)  Growing ovarian cyst 186 (6.9 %)  Incidentally detected 586 (21.9 %) Laterality  Unilateral 1931 (72.0 %)  Bilateral 750 (28.0 %) Cyst nature  Unilocular 1613 (60.2 %)  Multilocular 1068 (39.8 %) Cul-de-sac obliteration  None 922 (34.4 %)  Partial 728 (27.2 %)  Complete 1031 (38.5 %) ASRM stage  Stage III 1369 (51.1 %)  Stage IV 1312 (48.9 %) Medication duration  None 468 (17.5 %)  <6Mo 323 (12.0 %)  ≥6-<12Mo 653 (24.4 %)  ≥12Mo-<24Mo 650 (24.2 %)  ≥24Mo 587 (21.9 %) Duration of hormonal treatment (months) 16.1 ± 18.9 (9.0, 0−126) Atypical endometriosis  No 2595 (96.8 %)  Yes 86 (3.2 %) Subsequent pregnancy  No plan to pregnancy 1755 (65.5 %)  No pregnancy 425 (15.9 %)  Confirmed pregnancy 501 (18.7 %) Recurrence after previous operation 362 (13.5 %) Time to recurrence (months) (n = 362) 32.8 ± 26.8 (26, 1−126) Reoperation after recurrence 66 (18.2 % of recurrent cases/ 2.5 % of total) Data presented with mean ± standard deviation (median, range) or number (%).BMI. Body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; ASRM, American society of reproductive medicine.\nBaseline characteristics of patients.\nData presented with mean ± standard deviation (median, range) or number (%).BMI. Body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; ASRM, American society of reproductive medicine.\nBaseline characteristics of the two groups (TE and AE) are shown in  Table 2 \n. The mean size of ovarian cysts was significantly smaller in the TE than the AE group (6.7 ± 3.3 vs. 7.6 ± 3.5 cm, p = 0.01) and the proportion of nulliparous women was significantly higher in the TE group than the AE group (77.8 % vs. 65.1 %, p = 0.008). Otherwise, there were no statistically significant differences between the two groups. Table 2 Baseline characteristics of two groups. Table 2 Characteristics Typical endometriosis (TE) (n = 2595) Atypical endometriosis (AE) (n = 86) p-value Age (years)  1 33.2 ± 6.7 (32.0, 16−64) 34.3 ± 6.3 (33.0, 16−49) 0.083 Parity 2 0.008  No 2018 (77.8 %) 56 (65.1 %)  Yes 577 (22.2 %) 30 (34.9 %) BMI (kg/m2)  1 21.1 ± 3.0 (20.6, 14.7−37.9) 21.2 ± 3.2(20.3,15.1−28.9) 0.860 Size of ovarian cyst(s) (cm)  1 6.7 ± 3.3 (6.0, 0.5−36.4) 7.6 ± 3.5 (6.7, 2.0−23.6) 0.010 Duration of follow-up (months) 1 36.8 ± 29.3 (26.0, 6−138) 34.2 ± 26.5 (24.0, 6−106) 0.530 Preoperative CA125 (n = 2358)  1 80.7 ± 165.9 (48.0, 1.0−5203)(n = 2277) 91.1 ± 196.4 (52.5, 3.6−1704)(n = 81) 0.895 Preoperative AMH (n = 1117)  1 3.40 ± 2.99 (2.62, 0.01−21.14) (n = 1070) 3.52 ± 3.15 (2.81,0.11−10.38) (n = 47) 0.913 Previous history of endometrioma operation 2 0.327  No 2373 (91.4 %) 76 (88.4 %)  Yes 222 (8.6 %) 10 (11.6 %) Preoperative symptoms 3 0.672  Pain 1590 (61.3 %) 55 (64.0 %)  Bleeding 154 (5.9 %) 4 (4.7 %)  Compression symptom 32 (1.2 %) 2 (2.3 %)  Infertility 68 (2.6 %) 4 (4.7 %)  Growing ovarian cyst 180 (6.9 %) 6 (7.0 %)  Incidentally detected 571 (22.0 %) 15 (17.4 %) Laterality 2 0.224  Unilateral 1874 (72.2 %) 57 (66.3 %)  Bilateral 721 (27.8 %) 29 (33.7 %) Cyst nature 2 0.655  Unilocular 1559 (60.1 %) 54 (62.8 %)  Multilocular 1036 (39.9 %) 32 (37.2 %) Cul-De-Sac obliteration 3 0.169  None 896 (34.5 %) 26 (30.2 %)  Partial 697 (26.9 %) 31 (36.0 %)  Complete 1002 (38.6 %) 29 (33.7 %) ASRM stage 2 0.827  Stage III 1324 (51.0 %) 45 (52.3 %)  Stage IV 1271 (49.0 %) 41 (47.7 %) Medication duration 3 0.949  None 451 (17.4 %) 17 (19.8 %)  <6Mo 312 (12.0 %) 11 (12.8 %)  ≥6-<12Mo 632 (24.4 %) 21 (24.4 %)  ≥12Mo-<24Mo 632 (24.4 %) 18 (20.9 %)  ≥24Mo 568 (21.9 %) 19 (22.1 %) 0.468 Duration of hormonal treatment (months)  1 16.2 ± 18.9 (9.0, 0−126) 14.3 ± 17.5 (7.5, 0−106) Subsequent pregnancy 3 0.235  No plan to pregnancy 1695 (65.3 %) 60 (69.8 %)  No pregnancy 417 (16.1 %) 8 (9.3 %)  Confirmed pregnancy 483 (18.6 %) 18 (20.9 %) Time to recurrence (months) (n = 362)  1 33.1 ± 26.9 (27, 1−126)(n = 344) 26.8 ± 24.9 (18, 6−94)(n = 18) 0.347 Data presented with mean ± standard deviation (median, range) or number (%). BMI. Body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; ASRM, American society of reproductive medicine. 1 Mann-Whitney  U  test. 2 Fisher’s exact tests. 3 Chi-square test.\nBaseline characteristics of two groups.\nData presented with mean ± standard deviation (median, range) or number (%).\nBMI. Body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; ASRM, American society of reproductive medicine.\nMann-Whitney  U  test.\nFisher’s exact tests.\nChi-square test.\nThe possible risk factors for recurrent endometrioma are presented in  Table 3 \n. There were significant differences between the without and with recurrence groups with respect to age, BMI, size of ovarian cysts, duration of follow-up, preoperative CA125 levels, previous history of endometrioma operation, laterality, surgical method, cyst nature, CDS obliteration, rASRM stage, duration of hormonal treatment, and subsequent pregnancy. The factor of atypical endometriosis showed marginal significance (p = 0.052). Table 3 Analysis of possible risk factors for recurrent ovarian endometriosis (n = 2681). Table 3 Characteristics No recurrence (n = 2319) Recurrence (n = 362) p-value Age (years)  1 33.4 ± 6.8 (33, 16−64) 32.1 ± 5.9 (32, 16−48) 0.003 Parity 2 0.251  No 1785 (77.0 %) 289 (79.8 %)  Yes 534 (23 %) 73 (20.2 %) BMI (kg/m 2 )  1 21.1 ± 3.0 (20.6, 14.7−37.9) 20.8 ± 3.0 (20.2, 16.3−34.4) 0.008 Size of ovarian cyst(s) (cm)  1 6.6 ± 3.2 (6.0, 0.5−36.4) 7.8 ± 3.9 (6.8, 0.8−23.6) <0.001 Duration of follow-up (months) 1 33.7 ± 27.5 (23, 6−138) 56.1 ± 32.3 (51, 6−133) <0.001 Preoperative CA125 (U/mL) (n = 2358)  1 78.9 ± 172.1 (46.4, 1.0−5203) (n = 2038) 95.2 ± 129.8 (60.7, 8.4−1718) (n = 320) <0.001 Preoperative AMH (ng/mL) (n = 1117)  1 3.39 ± 3.01 (2.6, 0.01−21.14) (n = 1011) 3.53 ± 2.84 (2.92, 0.06−13.14) (n = 106) 0.374 Previous history of endometrioma operation 2 0.005  No 2133 (92.0 %) 316 (87.3 %)  Yes 186 (8.0 %) 46 (12.7 %) Preoperative symptoms 3 0.353  Pain 1410 (60.8 %) 235 (64.9 %)  Bleeding 141 (6.1 %) 17 (4.7 %)  Compression symptom 28 (1.2 %) 6 (1.6 %)  Infertility 67 (2.9 %) 5 (1.4 %)  Growing ovarian cyst 164 (7.1 %) 22 (6.1 %)  Incidentally detected 509 (21.9 %) 77 (21.3 %) Laterality 2 0.008  Unilateral 1692 (73.0 %) 239 (66.0 %)  Bilateral 627 (27.0 %) 123 (34.0 %) Extent of surgery: ovary 2 0.727  Cyst enucleation only 2175 (93.8 %) 338 (93.4 %)  One oophorectomy 144 (6.2 %) 24 (6.6 %) Extent of surgery: uterus 2 0.473  Uterus preservation 2179 (94.0 %) 344 (95.0 %)  Hysterectomy 140 (6.0 %) 18 (0.5 %) Extent of surgery: tube 3 0.402  No 2032 (87.6 %) 325 (89.8 %)  One tube 159 (6.9 %) 23 (6.3 %)  Both tube 127 (5.5 %) 14 (3.9 %) Surgical method 2 <0.001  Explo-laparotomy 107 (4.6 %) 37 (10.2 %)  Laparoscopy or Robotic 2212 (95.4 %) 325 (89.8 %) Cyst nature 2 0.009  Unilocular 1418 (61.1 %) 195 (53.9 %)  Multilocular 901 (38.9 %) 167 (46.1 %) Typical vs. atypical 2 0.052  Typical 2251 (97.1 %) 344 (95.0 %)  Atypical 68 (2.9 %) 18 (5.0 %) Cul-De-Sac obliteration 3 <0.001  None 836 (36.0 %) 86 (23.7 %)  Partial 626 (27.0 %) 102 (28.2 %)  Complete 857 (37.0 %) 174 (48.1 %) rASRM stage 2 <0.001  Stage III 1225 (52.8 %) 144 (39.8 %)  Stage IV 1094 (47.2 %) 218 (60.2 %) Medication duration 3 <0.001  None 417 (18.0 %) 51 (14.1 %)  <6 Mo 271 (11.7 %) 52 (14.4 %)  ≥6-<12 Mo 571 (24.6 %) 82 (22.6 %)  ≥12 Mo-<24 Mo 583 (25.1 %) 67 (18.5 %)  ≥24 Mo 477 (20.6 %) 110 (30.4 %) Duration of hormonal treatment (months)  1 15.6 ± 18.3 (9.0, 0−126) 19.4 ± 22.3 (11.0, 0−124) 0.019 Subsequent pregnancy 3 0.01  No plan to pregnancy 1542 (66.5 %) 213 (58.8 %)  No pregnancy 351 (15.1 %) 74 (20.5 %)  Confirmed pregnancy 426 (18.4 %) 75 (20.7 %) Data are presented as mean ± standard deviation (median, range) or number (%). BMI, body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; rASRM, revised American Society of Reproductive Medicine. 1 Mann-Whitney  U  test. 2 Fisher’s exact tests. 3 Chi-square test.\nAnalysis of possible risk factors for recurrent ovarian endometriosis (n = 2681).\nData are presented as mean ± standard deviation (median, range) or number (%).\nBMI, body mass index; CA125, cancer antigen 125; AMH, anti-Mullerian hormone; rASRM, revised American Society of Reproductive Medicine.\nMann-Whitney  U  test.\nFisher’s exact tests.\nChi-square test.\nResults of the univariate and multivariate analyses for independent risk factors of recurrent ovarian endometrioma, including atypical endometriosis, using the Cox regression method are listed in  Table 4 \n. In the univariate analysis, size of ovarian cysts >6 cm (hazard ratio [HR] = 1.418; 95 % confidence interval [CI] = 1.150−1.749; p = 0.001), preoperative CA125 level >48.0 U/mL (HR = 1.694; 95 % CI = 1.353−2.122; p < 0.001), previous history of endometrioma operation (HR = 1.542; 95 % CI = 1.132−2.102); p = 0.006), bilateral endometrioma (HR = 1.397; 95 % CI = 1.124−1.736; p = 0.003), multilocular cyst (HR = 1.392; 95 % CI = 1.131−1.711; p = 0.002), atypical endometriosis (HR = 1.927; 95 % CI = 1.199−3.096; p = 0.007), CDS obliteration (HR = 1.597; 95 % CI = 1.254−2.035; p < 0.001), rARSM stage IV (HR = 1.553; 95 % CI = 1.258−1.917; p < 0.001), and duration of medication >9 months (HR = 0.811; 95 % CI = 0.659−0.997; p = 0.047) were significant. Factors with p-values ≤0.20 in univariate analyses were included in the multivariate Cox regression analysis. In the multivariate analysis, preoperative CA125 level >48.0U/mL (HR = 1.485; 95 % CI = 1.176−1.876; p = 0.001), multilocular cyst (HR = 1.270; 95 % CI = 1.011−1.596; p = 0.040), atypical endometriosis (HR = 1.771; 95 % CI = 1.050−2.988); p = 0.032), CDS obliteration (HR = 1.474; 95 % CI = 1.073−2.025; p = 0.017), postoperative medication (HR = 1.749, 95 % CI = 1.226−2.496; p = 0.002), and duration of medication >9 months (HR = 0.592; 95 % CI = 0.463−0.756; p < 0.001) were statistical significant. Table 4 Univariate and multivariate analyses for independent risk factors of recurrent ovarian endometrioma using the Cox regression method. Table 4 Characteristics Univariate Multivariate Risk factors of recurrence HR (95 % CI) p-value HR (95 % CI) p-value Age >32 years (vs. ≤ 32 years) 0.913 (0.742−1.123) 0.390 BMI >20.5 kg/m 2  (vs. ≤20.5) 0.926 (0.752−1.139) 0.466 Size of ovarian cysts >6.0 cm (vs. ≤ 6.0) 1.418 (1.150−1.749) 0.001 1.083 (0.828−1.417) 0.561 1.694 (1.353−2.122) <0.001 1.485 (1.176−1.876) 0.001 Preoperative CA125 level >48.0 U/mL (vs. ≤ 48.0) (n = 2358) 1.542 (1.132−2.102) 0.006 1.201 (0.844−1.708) 0.308 Previous history of endometrioma operation (vs. no) Bilateral (vs. unilateral) 1.397 (1.124−1.736) 0.003 1.105 (0.813−1.501) 0.525 Explo-laparotomy (vs. laparoscopic or robotic) 0.725 (0.514−1.022) 0.067 0.889 (0.578−1.368) 0.593 Multilocular cyst (vs. unilocular) 1.392 (1.131−1.711) 0.002 1.270 (1.011−1.596) 0.040 Atypical endometriosis (vs. typical) 1.927 (1.199−3.096) 0.007 1.771 (1.050−2.988) 0.032 CDS obliteration (vs. no obliteration) 1.597 (1.254−2.035) <0.001 1.474 (1.073−2.025) 0.017 rASRM stage IV (vs. III) 1.553 (1.258−1.917) <0.001 1.069 (0.782−1.461) 0.675 Postoperative medication (vs. no) 1.345 (0.999−1.810) 0.051 1.749 (1.226−2.496) 0.002 Duration of medication >9 months 0.811 (0.659−0.997) 0.047 0.592 (0.463−0.756) <0.001 Subsequent pregnancy (vs. no) 0.861 (0.667−1.111) 0.249 HR, hazard ratio; CI, confidence interval; BMI, body mass index; CA125, cancer antigen 125; rASRM, revised American Society for Reproductive Medicine; CDS, cul-de-sac; d/t, due to; endo, endometriosis; Mo, month.\nUnivariate and multivariate analyses for independent risk factors of recurrent ovarian endometrioma using the Cox regression method.\nHR, hazard ratio; CI, confidence interval; BMI, body mass index; CA125, cancer antigen 125; rASRM, revised American Society for Reproductive Medicine; CDS, cul-de-sac; d/t, due to; endo, endometriosis; Mo, month.\nTo reduce the effect of selection/allocation bias, inverse probability of treatment weighting (IPTW)-adjusted multivariate Cox regression analyses were performed ( Table 5 \n). After adjusting for IPTW, the three dependent risk factors for recurrent ovarian endometrioma were preoperative CA125 level >48.0 U/mL (HR = 2.741; 95 % CI = 1.517−4.952; p < 0.001), multilocular cyst (HR = 1.909; 95 % CI = 1.128−3.230; p = 0.016), atypical endometriosis (HR = 2.666; 95 % CI = 1.659−4.284; p < 0.001). Table 5 Multivariate analysis of independent risk factors of recurrent ovarian endometrioma using the Cox regression method adjusted with inverse probability of treatment weighting (IPTW). Table 5 Characteristics Multivariate analysis (non-adjusted with IPTW) Multivariate adjusted with IPTW Risk factors of recurrence HR (95 % CI) p-value HR (95 % CI) p-value Preoperative CA125 level >48.0 U/mL (vs. ≤ 48.0) (n = 2358) 1.485 (1.176−1.876) 0.001 2.741 (1.517−4.952) <0.001 Multilocular cyst (vs. unilocular) 1.270 (1.011−1.596) 0.040 1.909 (1.128−3.230) 0.016 Atypical endometriosis (vs. typical) 1.771 (1.050−2.988) 0.032 2.666 (1.659−4.284) <0.001 CDS obliteration (vs. no obliteration) 1.474 (1.073−2.025) 0.017 0.854 (0.394−1.855) 0.691 Postoperative medication (vs. no) 1.749 (1.226−2.496) 0.002 1.711 (0.694−4.215) 0.243 Duration of medication >9 months 0.592 (0.463−0.756) <0.001 0.890 (0.460−1.721) 0.729 HR, hazard ratio; CI, confidence interval; BMI, body mass index; CA125, cancer antigen 125; rASRM, revised American Society for Reproductive Medicine; CDS, cul-de-sac; d/t, due to; endo, endometriosis; Mo, month.\nMultivariate analysis of independent risk factors of recurrent ovarian endometrioma using the Cox regression method adjusted with inverse probability of treatment weighting (IPTW).\nHR, hazard ratio; CI, confidence interval; BMI, body mass index; CA125, cancer antigen 125; rASRM, revised American Society for Reproductive Medicine; CDS, cul-de-sac; d/t, due to; endo, endometriosis; Mo, month.\nThe cumulative recurrence rates by Kaplan-Meier analysis at 12, 24, 36, and 60 months were 4.4 %, 8.3 %, 12.0 %, and 21.3 %, respectively ( Fig. 1 \n). The AE group had a significantly higher cumulative recurrence rate than the TE group according to the log-rank test (p = 0.0057) in the original cohort ( Fig. 2 \nA), and after adjusting with IPTW, the AE group showed a significantly higher cumulative recurrence rate (p = 0.003). ( Fig. 2 B) Fig. 1 Cumulative recurrence rate of ovarian endometrioma using the Kaplan-Meier analysis. Fig. 1 Fig. 2 Comparison of cumulative recurrence rate of typical and atypical endometriosis (log-rank test) in the original cohort (A) and IPTW-adjusted cohort (log-rank test) (B). Fig. 2\nCumulative recurrence rate of ovarian endometrioma using the Kaplan-Meier analysis.\nComparison of cumulative recurrence rate of typical and atypical endometriosis (log-rank test) in the original cohort (A) and IPTW-adjusted cohort (log-rank test) (B).\nNo patients were diagnosed with atypical endometriosis to malignant transformation during the follow-up period. However, two typical endometriosis patients experienced recurrent disease with borderline malignancy and malignant ovarian cancer; one was diagnosed with a seromucinous borderline tumor associated with endometriosis on the same side of the ovary 7 years after initial surgery, and the other was diagnosed with ovarian serous carcinoma on the opposite side after 33 months.\n\nThe main finding of this study was that the AE group displayed higher recurrence in addition to the clinical characteristics of larger cyst size and higher proportion of multiparity than the TE group. During the 32.4 ± 26.5 months follow-up period, no patient was diagnosed with atypical endometriosis to malignant transformation. To the best of our knowledge, this is the first large cohort study to evaluate the recurrence rates of atypical endometriosis.\nAlthough it has been overlooked due to the more important issue of malignant transformation in atypical endometriosis, one of the important aspects of endometriosis is a high rate of recurrence. However, there is no published study on atypical endometriosis as a risk factor for recurrence. The mechanisms explaining recurrence are not clear. The hypothesis that explains the mechanism of recurrence is that recurrent lesions might originate from remnant lesions or de novo cells resulting from retrograde bleeding after surgery [ 12 ]. Our results indicate that AE displays a significantly higher cumulative recurrence rate than TE, along with higher CA125 level and multilocular cysts.\nWe assumed that the inherent characteristics of AE contribute to the recurrence. There is a biomarker called Ki-67 which is a nuclear protein observed in proliferating cells such as tumors and endometriosis [ [13] ,  [14] ,  [15] ]. Cells tend to have a more aggressive course with vascular invasion, proliferation, and metastasis if the Ki-67 proliferation rate is high [ 13 ]. Ogawa et al. found significantly higher Ki-67 index in AE than in TE but lower than in ovarian cancer [ 16 ]. We, therefore, assumed that AE tends to recur more frequently than TE.\nAs we hypothesized, AE was related to a higher recurrence rate than TE. We think that residual atypical endometriotic lesions that were not removed completely at initial surgery could aggressively proliferate. However, a remaining source of confusion was the difference in the mean size of ovarian cysts. Several studies have demonstrated that larger cyst size is related to higher recurrence [ [17] ,  [18] ,  [19] ]. In our results, the mean size of ovarian cysts of the AE group was larger than the TE group. (7.6 ± 3.5 vs. 6.7 ± 3.3 cm, p = 0.01). Although the degree of difference in size between the two groups was very tiny, this difference may lead to more frequent recurrence among patients with AE. Alternatively, it is possible that the tumor-like features of AE can induce increased size in cysts, as well as more frequent recurrence. Further, we observed that there were more parous women among the AE group and the reason for this is unclear. We postulate this may be because the mean age of the AE group was higher, although this age difference was not statistically significant.\nEndometriosis is considered a risk factor for ovarian cancer. The possible pathogenesis of the malignant transformation of endometriosis to EAOC is considered that cyclic hemorrhage into the endometriotic cyst leads to the accumulation of blood components and can induce inflammation by oxidative stress, which then potentiates DNA damage [ 20 ]. Additional molecular alterations were also noted; ARIDA1/BAF250a, PIK3CA, CTNNB1 and PTEN mutation, microsatellite instability, and loss of heterozygosity [ [21] ,  [22] ,  [23] ,  [24] ,  [25] ]. According to the meta-analysis by Wentzensen et al., relative risk (RR) of all invasive ovarian cancers along with endometriosis was 1.35 (95 % confidence interval (CI), 1.07–1.71), RR of endometrioid carcinoma was 2.32 (CI, 1.36–3.95), and clear cell carcinoma was 2.87 (CI, 1.53–5.39) [ 26 ]. Thomsen et al. reported in a systematic review of the risk factors for the development of EAOC among patients with endometriosis [ 27 ]. In their review, the risk factors included older age at the time of diagnosis, solid component, postmenopausal status, larger size (≥9 cm) of endometrioma, nuliparity, and hyperestrogenism [ 27 ]. In our study, atypical endometriosis was associated with a larger cyst size. However, parity displayed a different pattern; atypical endometriosis related to a higher rate of multiparity.\nAtypical endometriosis is considered a premalignant lesion of the subtype of endometrioid and clear cell carcinoma. This owing to the coexistence of AE and ovarian cancer had been reported several times. However, the cases of AE that transformed to cancer are rarely reported [ 8 , 28 ]. Tanase et al. reported a case of 33-year-old women whose disease progressed from a TE to AE and finally to endometrioid adenocarcinoma over 10 years and three laparoscopic surgeries [ 8 ]. Although no case recurred from AE to ovarian cancer in reoperation in our study, it will be helpful for AE patients to be followed up carefully.\nAs in other retrospective studies, our study has several limitations. First, we did not consider the types of postoperative medications. Although the exact mechanism is not clarified, postoperative medical treatment is known to delay recurrence [ 29 , 30 ]. However, there was no significant difference in the duration of medications between the AE and TE groups. Second, our study included women who conceived after their initial surgery. According to several previous studies, postoperative pregnancy prevents the recurrence of endometriosis [ 17 , 31 , 32 ]. Although there were no significant differences in the proportion of women who conceived after surgery between AE and TE groups, it may affect results. Third, we defined recurrence as the presence of cysts more than 20 mm in size as identified by ultrasonography, not by histological confirmation, and identification of cysts is therefore dependent upon the skill of the ultrasonography operator, which can vary. Additionally, we did not evaluate the recurrence of pain. In practice, the recurrence of pain is frequent and important regardless of ultrasonography findings. The strength of the present study, meanwhile, is that it is the first large cohort study to analyze the clinical characteristics of AE and its recurrence rate compared to TE, and to reduce the selection bias, we analyzed with the IPTW method.\nIn conclusion, AE appears to be related to higher recurrence rates compared to TE. Further prospective studies are needed to confirm our findings and close surveillance is needed for patients with AE, given not only the possibility of malignant change but also of recurrence.\n\nNo financial support was received for this study.\n\nThe authors report no declarations of interest.","source_license":"CC0","license_restricted":false}