{"paper_id":"276641ef-e9fc-487c-8afa-11f8e9697902","body_text":"Vol.:(0123456789)\nArchives of Gynecology and Obstetrics (2025) 312:273–286 \nhttps://doi.org/10.1007/s00404-025-08025-3\nRESEARCH\nDistinct endometriosis involvement confers divergent oncologic \noutcomes in ovarian clear cell carcinoma\nJie Deng1,2 · Jiayuan Li3 · Lian Xu4 · Tianjin Yi1 \nReceived: 4 November 2024 / Accepted: 31 March 2025 / Published online: 24 April 2025 \n© The Author(s) 2025\nAbstract\nObjective To evaluate the clinicopathologic characteristics and survival outcomes of ovarian clear cell carcinoma (OCCC) \npatients with different endometriosis statuses.\nMethods This retrospective study included OCCC patients diagnosed between 2012 and 2021, classified into three groups \nbased on the Sampson and Scott criteria: Without (no endometriosis), Arising (OCCC arising from endometriosis), and \nCoexisting (OCCC coexisting with endometriosis). Clinical and pathological characteristics were compared across groups, \nand survival outcomes were analyzed using Kaplan–Meier methods. Prognostic factors for progression-free survival (PFS) \nand overall survival (OS) were identified through univariate and multivariate analyses.\nResults Among 242 patients, 53.7% were in the Without group, 29.3% in the Arising group, and 16.9% in the Coexisting \ngroup. The Arising group had the highest prevalence of early FIGO stage disease (91.6%) compared to the Coexisting \n(75.6%, p = 0.041) and Without (67.7%, p  = 0.000) groups. Lymph-node metastasis was significantly lower in the Arising \ngroup (2.8%) than in the Coexisting (19.5%, p = 0.010) and Without (10%, p = 0.011) groups. Notably, the Arising group \ndemonstrated unique atypical endometriosis features. In univariate analysis, the presence of endometriosis (either arising \nfrom or coexisting with endometriosis) was associated with improved PFS (p = 0.004 and p = 0.009, respectively); however, \nmultivariate analysis confirms only coexisting with endometriosis as an independent factor (HR: 0.11, 95% CI: 0.01–0.84). \nFor OS, the Arising group demonstrated the most significant benefit, with a 5-year OS of 92.4% compared to the Coexist-\ning group (83.9%, p  = 0.293) and the Without group (62.6%, p  = 0.023). Multivariate analysis identified only FIGO stage \n(HR: 5.89, 95% CI: 2.06–16.82) as an independent prognostic factor for OS, while endometriosis did not reach statistical \nsignificance (HR: 0.62, 95% CI: 0.26–1.53).\nConclusions Classifying OCCC with endometriosis statuses reveals distinct prognostic patterns. Coexisting with endome-\ntriosis positively impacts PFS, while the Arising subgroup shows the most significant OS benefit but may be confounded \nwith other factors.\nKeywords Clinicopathologic · Sampson and Scott criteria · Atypical endometriosis · Survival outcomes · Prognostic \nfactors\nFirst author: Jie Deng.\n * Tianjin Yi \n ytj989@126.com\n1 Department of Obstetrics and Gynecology, Key Laboratory \nof Birth Defects and Related Diseases of Women \nand Children of Ministry of Education, West China Second \nUniversity Hospital, Sichuan University, Chengdu 610041, \nPeople’s Republic of China\n2 The Third People’s Hospital of Xindu District, \nChengdu 610041, People’s Republic of China\n3 West China School of Medicine, Sichuan University, \nChengdu 610041, People’s Republic of China\n4 Department of Pathology, West China Second University \nHospital, Sichuan University, Chengdu 610041, \nPeople’s Republic of China\n\n274 Archives of Gynecology and Obstetrics (2025) 312:273–286\nWhat does this study add to the clinical work? \nApplying the Sampson and Scott criteria to classify \novarian clear cell carcinoma patients by types of \nendometriosis involvement reveals distinct clinico-\npathologic characteristics and survival outcomes. \nEndometriosis presence, particularly in the coex-\nisting subgroup, is an independent favorable fac-\ntor for progression-free survival, while the arising \nsubgroup shows improved 5-year overall survival, \nemphasizing the prognostic value of detailed endo-\nmetriosis classification in patient management.\nIntroduction\nEndometriosis is a chronic, estrogen-dependent, inflamma-\ntory disorder characterized by ectopic endometrial glands \nand stroma, affecting approximately 10% of reproductive-\naged women [1 ]. Despite its benign nature, the chronic \ninflammation and immune dysregulation in endometriosis \nmay increase the risk of infertility and cancer [2 , 3]. Epi-\ndemiological evidence strongly links endometriosis with \nepithelial ovarian cancer (EOC), with particularly ovarian \nclear cell carcinoma (OCCC; OR = 3.05) and ovarian endo-\nmetrioid carcinoma (OR = 2.04) [4]. OCCC, a histological \nsubtype of EOC, is distinct in its clinical presentation, histo-\npathology, and genetics [5]. Although relatively uncommon, \nOCCC accounts for approximately 5% to 12% of all EOC \ncases and up to 30% in Asian populations [6]. Although early \nstage OCCC patients have favorable outcomes, advanced or \nrecurrent disease responds poorly to chemotherapy, resulting \nin worse prognoses compared to high-grade serous carci-\nnoma [7, 8]. This highlights the urgent need for improved \netiological understanding and prognostic markers.\nEndometriosis has been reported in 25–58% of OCCC \ncases [9 –11]. Some studies suggest better prognoses in \nendometriosis-associated OCCC, potentially due to younger \nage and earlier disease stage at diagnosis [12–14]. However, \nother studies have failed to demonstrate significant survival \ndifferences between these groups [15, 16] or to establish \nendometriosis as an independent prognostic factor [17–19]. \nThese inconsistencies leave the prognostic role of endome-\ntriosis in OCCC patients open to debate.\nImmunohistochemistry (IHC) plays a crucial role in \naccurately diagnosing OCCC and distinguishing it from \nother ovarian or metastatic carcinomas [20, 21]. OCCC \ntypically demonstrates high expression of Paired box gene \n8 (PAX-8) (approximately 95%), a reliable marker for \novarian origin, along with strong positivity for Hepato -\ncyte nuclear factor-1 beta (HNF-1β) (92–100%) and \nNapsin A (83–100%), making these markers particularly \nuseful for accurate diagnosis. Cytokeratin 7 (CK7) is \nconsistently positive in nearly all cases (close to 100%), \nwhereas Cytokeratin 20 (CK20) is usually negative, effec-\ntively differentiating OCCC from metastatic colorectal \ncarcinoma, which typically expresses CK20. Wilms' \ntumor 1 (WT1) negativity (0–5% positivity) distinguishes \nOCCC from high-grade serous carcinoma, which strongly \nexpresses WT1. Estrogen receptor (ER) and progesterone \nreceptor (PR) are predominantly negative in OCCC, with \nER positivity reported in approximately 10% of cases \nand PR positivity even less frequently (approximately \n5%). The p53 protein usually exhibits wild-type expres-\nsion patterns in OCCC; however, aberrant p53 staining \noccurs in approximately 10–24% of cases. In contrast, \nendometriosis tissues exhibit significantly elevated estro-\ngen receptor beta (ER-β)—over 100-fold higher compared \nto normal endometrial tissue—and reduced PR expres-\nsion [22]. These distinct hormonal receptor patterns in \nendometriosis likely contribute to its pathogenesis and \nresistance to treatment.\nSince Sampson's first description of malignancy aris-\ning from endometriosis in 1925 [23]and Scott's subse-\nquent histological criteria [24], studies have broadly \ncategorized OCCC into cases with or without endome-\ntriosis. In prior studies, OCCC patients were typically \ncategorized into two broad groups: those with and without \nendometriosis. In these studies, endometriosis-associated \nOCCC included the following conditions [14, 24–26]: (1) \nhistological identification of ovarian cancer and endo-\nmetriosis in the same ovary, with evidence of malignant \ntransition from endometriosis [e.g., atypical endometrio -\nsis (A-EMS)]; (2) endometriosis in one ovary and ovarian \ncancer in the contralateral ovary; and (3) coincidental \nidentification of ovarian cancer in any ovary or pelvic \nendometriosis. The first condition adheres to the Samp-\nson and Scott’s criteria and is defined as “OCCC aris -\ning from endometriosis”, while the latter two conditions \nrepresent the concurrent existence of endometriosis and \nOCCC in the same patient (“OCCC coexisting with endo -\nmetriosis”). Recent histological evidence suggests that \n“Arising” and “Coexisting” cases may represent different \nstages along a malignant continuum [27].\nTo better understand this relationship, we refined the \nclassification of OCCC into three distinct groups: OCCC \narising from endometriosis (“Arising”), OCCC coex -\nisting with endometriosis (“Coexisting”), and OCCC \nwithout endometriosis (\"Without\"). To date, no studies \n\n275Archives of Gynecology and Obstetrics (2025) 312:273–286 \nhave simultaneously analyzed the histological and clini-\ncal characteristics and outcomes of these three groups. \nOur study aims to elucidate how distinct endometriosis \ninvolvement patterns influence clinicopathological fea-\ntures and long-term oncological outcomes in OCCC.\nMethods\nStudy design and patient population\nThis retrospective study analyzed consecutive patients \nnewly diagnosed with OCCC and treated at our institu-\ntion from February 2012 to February 2021. Clinical data \nwere systematically collected and reviewed for all eligible \npatients. Demographic, clinical, and pathological data col-\nlected included age at diagnosis, height, weight, age at \nmenarche, FIGO stage, serum tumor markers, tumor grade, \nhistological findings, and treatment details.\nInclusion and exclusion criteria\nInclusion criteria were as follows: (1) Patients who under -\nwent comprehensive staging and debulking surgery at our \ninstitution. (2) OCCC diagnosis confirmed by histological \nslide reexamination by two experienced pathologists. (3) \nComplete clinicopathological data and follow-up informa-\ntion available.\nExclusion criteria included patients with histologically \nconfirmed invasive epithelial ovarian cancers other than \nOCCC, cases of OCCC mixed with other histology sub-\ntypes, treated with fertility preservation surgery and those \nwith incomplete clinical data.\nHistopathological assessment\nOCCC and endometriosis diagnoses were confirmed by two \ngynecological pathologists. Endometriosis was identified \nbased on the presence of ectopic endometrial glands and \nstroma. According to Sampson and Scott’s criteria [23, 24], \npatients were categorized into three groups: (1) Coexisting \ngroup: Patients with histologically confirmed endometriosis \nconcurrent with OCCC (in the same or contralateral ovary \nor other sites) but without evidence of malignant transition. \n(2) Arising group: To accurately define OCCC arising from \nendometriosis, cases in the Arising group were required to \nmeet four criteria: A. Histopathological analysis confirmed \nthe presence of both benign and neoplastic endometrial \ntissues within the tumors. B. Histological findings were \ncompatible with an endometrial origin. C. Comprehensive \nclinical and imaging assessments ensured the exclusion of \nother primary tumor sites. D. A morphologic demonstra-\ntion of a continuum between benign and malignant epithe-\nlium [with atypical endometriosis (A-EMS) identified as the \nprecancerous lesion [28]]. (3) Without group: Patients with \nOCCC and no endometriosis on final histological examina-\ntion or prior history of endometriosis.\nPrognostic analysis\nThe primary endpoints were overall survival (OS) and \nprogression-free survival (PFS) of OCCC patients, strati-\nfied by endometriosis involvement. Subgroup analysis was \nperformed according to the Coexisting, Arising, and Without \ngroups. Chemotherapy resistance was defined as tumor pro-\ngression or recurrence within six months of the last chemo-\ntherapy. OS was defined as the time from initial treatment to \ndeath or last follow-up, while PFS was defined as the time \nfrom initial treatment to tumor recurrence, determined by \nhistopathological evidence or new imaging.\nSurgical procedures\nAll patients underwent surgical treatment at our institution \nfollowing FIGO staging guidelines. Comprehensive stag -\ning surgery was conducted for stage I–II, while debulking \nsurgery was performed for stage III–IV cases. Main pro-\ncedures included total hysterectomy, bilateral salpingo-\noophorectomy, pelvic and para-aortic lymphadenectomy or \nlymph-node sampling, omentum resection, and peritoneal \nbiopsies as necessary. R0 was defined as no residual tumor \nor complete remission of the tumor, based on a combination \nof clinical and pathological findings.\nChemotherapy and maintenance therapy\nFirst-line chemotherapy consisted of platinum-based regi-\nmens combined with paclitaxel, including TC (paclitaxel/\ncarboplatin) and TP (paclitaxel/cisplatin), administered \nintravenously or intraperitoneally. Maintenance therapy with \nanti-angiogenic agents, such as bevacizumab, was offered \nbased on treatment protocols and availability. Platinum \nresistance was defined based on the widely accepted clini-\ncal criterion: disease progression within 6 months following \nthe completion of platinum-based chemotherapy.\nFollow‑up\nPatients were followed up from the date of surgical or patho-\nlogical diagnosis through outpatient visits, re-admission for \n\n276 Archives of Gynecology and Obstetrics (2025) 312:273–286\ntreatment, or telephone follow-ups. There was no loss to \nfollow-up, and the cutoff was September 2021. Follow-up \nincluded patient-reported complaints, pelvic exams, CA125 \nlevels, and imaging (ultrasound, CT, MRI, or PET-CT, as \nneeded).\nStatistical analysis\nStatistical analyses were performed using R version 3.6.2. \nCategorical variables were summarized as frequencies and \npercentages, while continuous variables were expressed as \nmeans ± standard deviations or medians with interquartile \nranges, as appropriate. For comparisons between two groups, \nthe Chi-square test was used to analyze categorical variables, \nensuring appropriate statistical evaluation of relationships. \nTo compare variables among the three groups (Coexisting, \nArising, and Without groups), the Chi-square test was also \napplied. Kaplan–Meier method estimated survival curves \nfor OS and PFS, compared with log-rank tests (GraphPad \nPrism version 9.0 for macOS, San Diego, California USA). \nSurvival analysis was conducted using the Cox proportional \nhazards model (CoxPHFitter from lifelines python package) \nto evaluate factors influencing PFS and OS. Hazard ratios \n(HRs) with corresponding 95% confidence intervals (CIs) \nwere calculated to quantify the strength of associations. Sta-\ntistical significance was set at p < 0.05 (two-tailed).\nResults\nWe included a total of 242 eligible patients following the \nselection workflow detailed in Fig.  1. These patients were \nfurther classified into three groups using the Sampson and \nScott criteria: Without group (n = 130, 53.7%), Arising \ngroup (n = 71, 29.3%), and Coexisting group (n = 41, 16.9%).\nPatients characteristics\nPatients’ characteristics were summarized in Table  1. \nPatients in the Coexisting and Arising groups were younger \n(mean ages: 45.7 ± 8.9 years and 47.6 ± 8.6 years, respec-\ntively), compared to the Without group (52.3 ± 9.3 years; \np < 0.000 and p = 0.012). More patients in the Coexisting \nand Arising groups were pre-menopausal (p  < 0.000 and \np = 0.005). The Arising group had a higher proportion of \npatients with a BMI  < 24.0 (74.6%) than the Coexisting \ngroup (48.8%, p = 0.01) and a higher percentage of patients \nwith fewer than two gestations compared to the Without \ngroup (42.2% vs. 26.1%, p = 0.029). Early FIGO stage (I + II) \nwas more prevalent in the Arising group (91.6%) compared \nto the Coexisting (75.6%, p  = 0.041) and Without (67.7%, \np = 0.000) groups. Lymph-node metastasis was least com-\nmon in the Arising group (2.8%) compared to Coexisting \n(19.5%, p = 0.010) and Without (10%, p  = 0.011) groups. \nThere were no significant differences in preoperative CA125 \nFig. 1  The flowchart of study selection and classification of OCCC \npatients based on Sampson and Scott criteria. A total of 275 patients \ndiagnosed with primary ovarian clear cell carcinoma (OCCC) from \n2012 to 2021 were initially identified. After excluding 30 patients \nwho underwent fertility-preserving surgery and 3 patients with insuf-\nficient data, 242 eligible patients were included. These patients were \nclassified using the Sampson and Scott criteria into three groups: the \nWithout group (patients with OCCC without endometriosis, n = 130), \nthe Arising group (patients with OCCC arising from endometriosis, \nn = 71), and the Coexisting group (patients with OCCC coexisting \nwith endometriosis, n = 41)\n\n277Archives of Gynecology and Obstetrics (2025) 312:273–286 \nlevels, ascites or peritoneal lavage fluid metastasis, or throm-\nbosis across groups.\nPatterns of care\nPatterns of care were outlined in Table  2. Most patients \nunderwent laparotomy, though laparoscopy was more \nfrequent in the Arising group than in the Without group \n(40.9% vs. 23.9%, p  = 0.018). Staging surgery was per -\nformed most frequently in the Arising group (91.6%), \ncompared to the Coexisting (75.6%) and Without (67.7%) \ngroups (p  < 0.001). Lymphadenectomy was performed in \n97.6% of Coexisting and 94.4% of Arising patients, com-\npared to 83.8% in the Without group (p  = 0.043). Para-\naortic lymphadenectomy was also more common in the \nCoexisting (65.9%) and Arising (66.2%) groups than in \nthe Without group (49.2%, p  = 0.031). While there were \nno significant differences in the number of lymph nodes \nresected, a higher percentage of patients in the Coexisting \n(80.5%) and Arising (81.7%) groups had ≥ 20 lymph nodes \nremoved compared to the Without group (63.9%) ( p = \n0.011). The percentage of patients with no residual tumor \n(R0) was significantly higher in the Arising group (97.2%) \ncompared to the Without group (83.1%, p = 0.007).\nRegarding chemotherapy, TC (paclitaxel + carboplatin) \nremained the most commonly used regimen across all \ngroups, with no significant differences (p  = 0.652). How-\never, chemotherapy with Bevacizumab was significantly \nless frequent in the Arising group (8.5%) compared to the \nWithout group (21.5%, p = 0.030). Most patients in the \nArising group (91.6%) received ≤ 6 cycles of chemother -\napy, significantly more than in the Without group (66.4%, \np < 0.001).\nTable 1  Clinicopathologic characteristics of ovarian clear cell carcinoma patients with different endometriosis involvement\n*Lymph-node metastasis was diagnosed through pathological examination\nCharacteristics Without Coexisting Arising p value\nn = 130 % n = 41 % n = 71 % Three-group \ncomparison\nWithout vs. \nCoexisting\nWithout \nvs. Arising\nCoexisting \nvs. Arising\nAge (years, mean ± SD) 52.3 ± 9.2 45.7 ± 8.8 47.6 ± 8.6\n  < 50 48 36.9 29 70.7 40 56.3  < 0.001  < 0.001 0.012 0.190\n  ≥ 50 82 63.1 12 29.3 31 43.7\nMenopause\n No 44 33.9 27 65.9 39 54.9  < 0.001  < 0.001 0.005 0.351\n Yes 86 66.2 14 34.2 32 45.1\nBMI (kg/m2, mean ± SD) 23.0 ± 2.9 23.0 ± 2.9 23.3 ± 4.6\n  < 24.0 82 63.1 20 48.8 53 74.6 0.022 0.140 0.130 0.010\n  ≥ 24.0 48 36.9 21 51.2 18 25.4\nGestation\n  ≥ 2 96 73.9 28 68.3 41 57.8 0.064 0.621 0.029 1.000\n  < 2 34 26.1 13 31.7 30 42.2\nFIGO stage\n I + II 88 67.7 31 75.6 65 91.6  < 0.001 0.436 0.000 0.041\n III + IV 42 32.3 10 24.4 6 8.4\nPresent with thrombosis\n Yes 28 21.5 5 12.2 7 9.9 0.074 0.274 0.058 0.946\n No 102 78.5 36 87.8 64 90.1\nPreoperative CA125(U/ml)\n  < 35 47 36.2 14 34.2 33 46.5 0.289 0.981 0.203 0.292\n  ≥ 35 71 54.6 23 56.1 32 45.1\nAscites or peritoneal lavage fluid\n Positive 24 18.5 5 12.2 12 16.9 0.682 0.548 0.951 0.653\n Negative 100 76.9 33 80.5 56 78.9\nLymph-node status*\n Negative 96 73.8 32 78 65 91.6 0.018 0.031 0.011 0.010\n Positive 13 10 8 19.5 2 2.8\n\n278 Archives of Gynecology and Obstetrics (2025) 312:273–286\nTable 2  Patterns of care and prognosis of ovarian clear cell carcinoma patients with different endometriosis involvement\nPFS progression-free survival, OS overall survival\nVariables Without Coexisting Arising p value\nn = 130 % n = 41 % n = 71 % Three-group comparison Without vs. \nCoexisting\nWithout vs. \nArising\nCoexisting vs. \nArising\nSurgical approach\n Laparotomy 99 76.2 31 75.6 42 59.2 0.031 1 0.018 0.119\n Laparoscopy 31 23.9 10 24.4 29 40.9\nSurgical procedure\n Staging surgery 88 67.7 31 75.6 65 91.6  < 0.001 0.444  < 0.001 0.041\n Total hysterectomy 119 91.5 40 97.6 69 97.2 0.157 0.334 0.209 1.000\n Bilateral salpingo-\noophorectomy\n130 100.0 41 100.0 71 100.0 1.000 1.000 1.000 1.000\n Omentum resection 118 90.8 40 97.6 68 95.8 0.146 0.274 0.313 1.000\n Pelvic lymphadenectomy 82 63.1 30 73.2 55 77.5 0.089 0.319 0.053 0.778\n Para-aortic lymphad-\nenectomy\n64 49.2 27 65.9 47 66.2 0.031 0.093 0.030 1.000\n Debulking surgery 42 32.3 10 24.4 6 8.5  < 0.001 0.444  < 0.001 0.041\nLymphadenectomy\n Yes 109 83.8 40 97.6 67 94.4 0.012 0.043 0.053 0.754\n No 21 16.2 1 2.4 4 5.6\nNo. of lymph nodes resected\n  < 20 47 36.2 8 19.5 13 18.3 0.011 0.221 0.323 1.766\n  ≥ 20 83 63.9 33 80.5 58 81.7\nResidual tumor\n No residual tumor (R0) 108 83.1 36 87.8 69 97.2 0.013 0.632 0.007 0.116\n  > R0 22 16.9 5 12.2 2 2.8\n Chemothrapy\n TC (paclitaxel + carbo-\nplatin)\n59 45.4 22 53.7 34 47.9 0.652 0.455 0.848 0.695\n TP (paclitaxel + cis-\nplatin)\n8 6.2 1 2.4 1 1.4 0.227 0.598 0.231 1.000\n TC/P(paclitaxel + cispl-\natin/carboplatin)\n45 34.6 12 29.3 21 29.6 0.694 0.658 0.569 1.000\n With bevacizumab 28 21.5 5 12.2 6 8.5 0.041 0.273 0.030 0.755\nNumber of chemotherapy\n  ≤ 6 87 66.4 30 73.2 65 91.6 0.001 0.013 <0.001 0.564\n  > 6 43 32.9 11 26.8 6 8.5\n Follow-up: median \n(range) (months)\n23.3 (0.9–110) 25.3 (0.4–111.9) 21.5 (1.1–95.0)\n 5-year PFS rate (%) 50.5 91.8 85.3  < 0.005 0.006 0.006 0.731\n 5-year OS rate (%) 62.6 83.9 92.4 0.01 0.17 0.023 0.293\n\n279Archives of Gynecology and Obstetrics (2025) 312:273–286 \nPathological characteristics\nFigure  2 illustrates the pathological characteristics of OCCC \nwith different status. The Arising group displayed carcinoma \nwith continuous atypical endometriosis (A-EMS), marked \nby moderate-to-severe cytologic atypia and a crowded or \nmicropapillary appearance. IHC analysis (Table  3) showed \nconsistent expression patterns across groups: HNF-1β was \npositive in nearly all cases (98.6%), and Napsin A in 84.9%. \nCK7 was expressed universally, and WT1 was largely nega-\ntive (positive in 21.1%). The expression rates of ER and PR \nwere low (18.2% and 9.5% positivity, respectively). Wild-\ntype p53 was positive in 77.7% of cases, while PAX-8 was \npositive in 89.3%. CK20 was negative in nearly all cases \n(2% positive).\nSurvival analysis\nThe median follow-up was 31.09  months (range: \n6–112 months). Among 242 patients, there were 45 recur -\nrences: 27.69% in the Without group (36/130), 7.32% in \nCoexisting (3/41), and 8.45% in Arising (6/71). Mortality \nrates were 23.08% (30/130) in Without, 12.20% (5/41) in \nCoexisting, and 5.63% (4/71) in Arising. The 5-year PFS \nrates were significantly higher in Coexisting (91.8%) and \nArising (85.3%) compared to Without (50.5%, p  = 0.006) \n(Fig.  3A). The 5-year OS rate was highest in Arising \n(92.4%), which was significantly greater than in the Without \ngroup (62.6%, p = 0.023) but not significantly different from \nCoexisting (83.9%, p = 0.293) (Fig. 3B).\nPrognostic factors of PFS in univariate and multivariate \nanalyses\nUnivariate and multivariate analyses for PFS (Table 4) iden-\ntified several factors as significant prognostic indicators. In \nunivariate analysis, significant factors included FIGO stage \n(p < 0.001), no residual tumor (R0) (p  = 0.029), platinum \nresistance (p = 0.017), lymph-node involvement (p = 0.036), \nascites or peritoneal lavage fluid metastasis (p  = 0.003), \nand the presence of endometriosis (p  < 0.001). Subgroup \nanalyses revealed that tumors coexisting with ( p = 0.009) \nand arising from (p = 0.004) endometriosis were correlated \nwith longer PFS. In multivariate analysis, the presence of \nendometriosis remained an independent favorable factor for \nPFS (HR: 0.24, 95% CI: 0.09–0.66, p = 0.006). Specifically, \ntumors coexisting with endometriosis (HR: 0.11, 95% CI: \n0.01–0.84, p = 0.033) were associated with significantly \nbetter PFS outcomes. Tumors arising from endometrio-\nsis showed a trend toward improved PFS (HR: 0.34, 95% \nCI: 0.11–1.05, p  = 0.061), though not reaching statistical \nsignificance.\nPrognostic factors of OS in univariate and multivariate \nanalyses\nUnivariate and multivariate analyses for OS (Table  5) iden-\ntified several factors as significant indicators. In univariate \nanalysis, significant factors included FIGO stage (p < 0.001), \nresidual tumor status (R0) (p  < 0.001), platinum resistance \n(p < 0.001), lymph-node involvement (p = 0.008), ascites or \nperitoneal lavage fluid metastasis (p  < 0.001), thrombosis \n(p < 0.005), and the presence of endometriosis (p  = 0.006). \nSubgroup analyses revealed that only carcinoma arising \nfrom endometriosis (p = 0.012) correlated significantly with \nimproved OS. In multivariate analysis, FIGO stage (HR: 5.89, \n95% CI: 2.06–16.82, p < 0.001) was identified as an independ-\nent factor affecting OS, while residual tumor status (HR: 1.82, \n95% CI: 0.78–4.29, p = 0.168), platinum resistance (HR: 2.39, \n95% CI: 0.86–6.67, p = 0.096), and endometriosis presence \n(HR: 0.62, 95% CI: 0.26–1.53, p = 0.302) did not reach statisti-\ncal significance.\nDiscussion\nUnlike prior studies that primarily categorized patients \nbased solely on the presence or absence of endometriosis, \nour research employs the Sampson and Scott criteria [23, \n24] to rigorously classify endometriosis subtypes. Nearly \nhalf (46.3%) had cancer associated with endometriosis, \nwith one-third (29.3%) having cancer arising from endo-\nmetriosis and a smaller yet significant proportion (16.9%) \nhaving cancer coexisting with endometriosis.\nUnderstanding the role of endometriosis in OCCC pro-\ngression is crucial for guiding treatment and predicting \nprognosis. A key question remains whether OCCC coexist-\ning with endometriosis behaves more like OCCC arising \nfrom endometriosis or OCCC without endometriosis. In \nour cohort, we observed significant clinical and prognos -\ntic differences between these groups. Both the Arising and \nCoexisting groups were younger at diagnosis, more likely \npre-menopausal, received less intense chemotherapy, and \nhad higher 5-year PFS rates than the Without group, consist-\nent with studies demonstrating favorable prognosis in OCCC \nwith endometriosis [10, 12, 13, 18, 19, 29]. Notably, only the \nArising group demonstrated significantly higher 5-year OS \nrates, with no significant OS difference observed between \nthe Coexisting and Without groups.\nTo evaluate whether differences in treatment approaches \ninfluenced survival outcomes, we systematically analyzed \nsurgical and chemotherapeutic interventions across the \nthree groups (Table  2). Our analysis revealed both consist-\nencies and variations that help contextualize the observed \nsurvival patterns. Notably, five key treatment variables \nshowed no significant differences across groups: total \n\n280 Archives of Gynecology and Obstetrics (2025) 312:273–286\nhysterectomy (91.5–97.6%, p = 0.157), bilateral salpingo-\noophorectomy (100% across groups, p  = 1.000), omentum \nresection (90.8–97.6%, p  = 0.146), pelvic lymphadenec-\ntomy (63.1–77.5%, p = 0.089), and chemotherapy regimens, \nincluding TC/P (78.9–86.2%, p = 0.227–0.694). This uni-\nformity in radical cytoreduction and first-line chemotherapy \nsuggests comparable baseline treatment intensity across \ngroups, minimizing potential confounding effects related to \ntreatment variability.\nHowever, significant differences were observed in the \nArising group, which demonstrated higher rates of laparos-\ncopy (40.9%, p = 0.031), staging surgery (91.6%, p < 0.001), \npara-aortic lymphadenectomy (66.2%, p = 0.031), and com-\nplete tumor resection (R0) (97.2%, p = 0.013), while under-\ngoing less debulking surgery (8.5%, p < 0.001) and receiving \nbevacizumab less frequently (8.5%, p = 0.041). This distinct \nsurgical paradigm—characterized by minimally invasive \ntechniques, systematic nodal evaluation, and optimal cytore-\nduction—likely contributed to the improved OS observed in \nthe Arising group. The higher rate of complete tumor resec-\ntion (97.2% R0) in the Arising group may have reduced the \nneed for adjuvant biologics, as reflected in the lower rates \nof debulking surgery and bevacizumab use. Consistent with \nlandmark studies in ovarian cancer [30], R0 has been identi-\nfied as a pivotal determinant of survival.\nTo further explore potential confounding factors that \nmay influence the results, we analyzed the impact of sur -\ngical approach (laparotomy or laparoscopy), lymph-node \nstatus, and residual tumor status (R0 or > R0) on PFS and \nOS using univariate and multivariate analyses (Table  4 and \nTable  5). In univariate analysis, R0 was a significant factor \nfor both PFS and OS, because it was analyzed in isolation. \nFig. 2  Pathological character-\nistics of OCCC with different \nendometriosis involvement. (A) \nHematoxylin and eosin (HE) \nstained section of ovarian clear \ncell carcinoma (OCCC) arising \nfrom endometriosis. The yellow \narrow indicates a region of clear \ncell carcinoma, characterized \nby its typical clear cytoplasm \nand distinct cell borders. The \ngray arrow points to con-\ntiguous atypical endometriosis \n(A-EMS), which shows cellular \natypia, suggesting its role as \na precursor lesion to malig-\nnancy. Higher magnification \nviews of these areas highlight \nthe transition between atypical \nendometriosis and invasive \ncarcinoma. Additionally, a \ndistant endometriotic lesion is \nshown. (B) HE and immuno-\nhistochemical (IHC) staining of \nOCCC specimens categorized \nbased on their association with \nendometriosis: without, aris-\ning from, or coexisting with \nendometriosis. The first column \nshows HE staining of carcinoma \ntissue, displaying the typical \npolyhedral clear cells of OCCC, \nseparated by delicate fibrovas-\ncular or hyalinized stroma. The \nother columns show consistent \nIHC staining patterns across \nall three subtypes for HNF-1β \n(nuclear staining), Napsin A \n(cytoplasmic staining), and \nCK-7 (membranous/cytoplasmic \nstaining)\n\n\n281Archives of Gynecology and Obstetrics (2025) 312:273–286 \nThis indicates that achieving complete tumor resection (R0) \nis associated with better survival outcomes when considered \nindependently. However, in multivariate analysis, R0 was \nnot a significant factor. Its lack of significance suggests that \nits effect is confounded or mediated by other variables, such \nas FIGO stage, platinum resistance, lymph-node status, or \nothers. These findings underscore the importance of consid-\nering the broader clinicopathological context when inter -\npreting the results. The improved outcomes in the Arising \ngroup likely reflect the combined benefits of optimal cytore-\nduction and other biological characteristics, rather than the \neffect of R0 alone. These findings challenge the prevailing \nnotion that all OCCC cases associated with endometriosis \nexhibit uniform clinical characteristics and prognoses. A \nmore nuanced understanding of the role of endometriosis in \nOCCC is essential for guiding personalized treatment strate-\ngies and improving patient outcomes.\nPrevious studies have often treated OCCC “arising from” \nand “coexisting with” endometriosis as one entity, endome-\ntriosis-associated ovarian cancer (EAOC) [ 11, 13, 18, 25, \n26], despite unclear pathological distinctions. According \nto Sampson and Scott criteria, “arising from” cases exhibit \nmalignant transformation, with A-EMS as the precancer -\nous lesion for OCCC [ 31]. A-EMS is rare, found in 1.7% \nto 4.4% of all endometriotic lesions [31– 33], though pre-\nsent in 12–35% of ovarian endometriosis cases [34]. In our \nstudy, all “arising from” cases showed continuous A-EMS, \naccounting for nearly 30% of all OCCC cases. The World \nHealth Organization defines A-EMS by atypical epithelium \nresembling endometrial neoplasia or cyst lining changes \nwith stratification and cytologic atypia [35]. Apart from \nA-EMS, no significant histologic and immunophenotypic \ndifferences were observed in the carcinoma between the \nCoexisting, Arising, and Without groups.\nA-EMS is associated with increased malignant progres-\nsion risk [ 31, 32], frequently positive for ER and PR, with \nwild-type p53 staining and a low proliferation index [28, 36]. \nThis differs from OCCC, which is often hormone receptor-\nnegative and may exhibit abnormal p53/Ki67 expression. \nMolecularly, both OCCC and A-EMS lack ARID1A expres-\nsion, but ARID1A remains intact in distant endometriotic \n[37]. HNF-1β is expressed in OCCC but not in contiguous or \ndistant endometriosis, and estrogen receptor is expressed in \nboth contiguous and distant endometriosis but not in OCCC, \nsupporting the progression from benign to malignant.\nThe association between endometriosis and OCCC \nhas been increasingly recognized, with molecular studies \nshedding light on the mechanisms driving this progression \n[38]. Endometriosis creates a pro-tumorigenic microenvi-\nronment characterized by cyclic hemorrhage-induced iron \noverload and reactive oxygen species (ROS) accumulation \n[39]. Chronic inflammation upregulates pro-inflammatory \ncytokines (e.g., IL-6 and TNF-α) and activates the NF-κB/\nTable 3  The expression of IHC markers in ovarian clear cell carcinoma patients with different endometriosis involvement\nComparisons: a. Without vs. Coexisting; b. Without vs. Arising; c. Coexisting vs. Arising\nIHC immunohistochemistry, HNF1β hepatocyte nuclear factor-1 beta (HNF1β), NA not available\nMarkers Total Positive (%) Negative (%) Without Coexisting Arising Comparisons\nPositive (%) Negative (%) Positive (%) Negative (%) Positive (%) Negative (%) a b c\nHNF1β 72 71 (98.6) 1 (1.4) 38 (97.4) 1 (2.6) 12 (100) 0 (0) 21 (100) 0 (0) 1 1 NA\nWT1 194 41 (21.1) 153 (78.8) 21 (20.2) 83 (79.8) 7 (23.3) 23 (76.7) 13 (21.7) 47 (78.3) 0.906 0.981 1\nER 192 35 (18.2) 157 (81.8) 16 (16.3) 82 (83.7) 4 (14.3) 24 (85.7) 15 (22.7) 51 (77.3) 1 0.981 1\nPR 189 18 (9.5) 171 (90.5) 12 (12.6) 83 (87.4) 1 (3.6) 27 (96.4) 5 (7.6) 61 (92.4) 0.307 0.410 0.515\nNapsin A 185 157 (84.9) 28 (15.1) 75 (81.5) 17 (18.5) 30 (96.8) 1 (3.2) 52 (83.9) 10 (16.1) 0.074 0.873 0.140\nCK7 187 187 (100) 0 (0) 99 (100) 0 (0) 28 (100) 0 (0) 60 (100) 0 (0) 1 1 1\nCK20 149 3 (2.0) 146 (98.0) 3 (3.8) 76 (96.2) 0 (0) 21 (100) 0 (0) 49 (100) 0.852 0.436 NA\nP53 202 157 (77.7) 45 (22.3) 85 (79.4) 22 (20.6) 27 (84.4) 5 (15.6) 45 (71.4) 18 (28.6) 0.715 0.316 0.255\nPAX-8 28 25 (89.3) 3 (10.7) 16 (84.2) 3 (15.8) 2 (100) 0 (0) 7 (100) 0 (0) 1 0.670 NA\n\n282 Archives of Gynecology and Obstetrics (2025) 312:273–286\nCOX-2/PGE2 signaling pathway [40], which not only \ninduces DNA damage but also suppresses mismatch repair \n(MMR) mechanisms, leading to genomic instability [41]. \nOver time, oxidative stress drives somatic mutations in key \nregulatory genes, including ARID1A (15–62% of OCCC \ncases) and PIK3CA (31.5–55%), which are hallmarks \nof malignant transformation [42, 43]. Loss of ARID1A \ndisrupts the SWI/SNF chromatin remodeling complex, \nimpairing DNA repair and promoting unchecked prolif-\neration in endometriosis-derived lesions. Concurrently, \nPIK3CA mutations constitutively activate the PI3K/AKT/\nmTOR pathway, enhancing cell survival and chemore-\nsistance through downstream effectors like eEF1A2 and \nPPP1R14B [44].\nThe dichotomy between “Arising” and “Coexisting” \nOCCC subgroups reflects distinct molecular trajectories. \nDespite their shared clinical characteristics, the Coexist-\ning group does not experience the same OS benefit as the \nArising group, suggesting key molecular differences that \ninfluence disease progression and treatment response. In \nthe Arising group, OCCC evolves directly from endome-\ntriosis, implying a continuous clonal progression. This may \nlead to a more homogeneous tumor population with spe-\ncific molecular vulnerabilities, potentially making it more \nresponsive to treatment. In contrast, the Coexisting group \ncomprises separate endometriosis and OCCC lesions, sug-\ngesting independent tumor origins or parallel evolution, \nwhich could lead to greater intratumoral heterogeneity. This \nheterogeneity may contribute to treatment resistance and a \nless favorable OS. Additionally, the Coexisting group may \ninclude cases that have already undergone malignant trans-\nformation from atypical endometriosis (A-EMS) and cases \noriginating from other pathological subtypes not directly \nassociated with endometriosis.\nBy applying the Sampson and Scott criteria, our study \nenhances understanding of the pathological and clinical con-\nnection between endometriosis and OCCC, showing that dif-\nferent types of endometriosis involvement may contribute to \nvaried outcomes. Recognizing these distinctions is essential \nfor elucidating the clinical behavior and prognosis of OCCC \nFig. 3  Kaplan–Meier survival \ncurves for Coexisting, Aris-\ning, and Without groups. (A) \nOverall Survival (OS) and \n(B) Progression-Free Survival \n(PFS) for patients in each \ngroup. The log-rank test showed \nsignificant differences in sur-\nvival among the three groups \nfor both OS (p = 0.0102) and \nPFS (p = 0.0002). Specifically, \npatients in the Arising group \nhad a more favorable 5-year OS \nthan those in the Without group \n(92.4% vs. 62.6%, p = 0.023). \nThe Arising and Coexisting \ngroups also had a more favora-\nble 5-year PFS than the Without \ngroup (85.3% and 91.8%, \nrespectively, p = 0.006). There \nwas no significant difference in \nthe 5-year OS and PFS between \nthe Arising and Coexisting \ngroups (p = 0.293 and p = 0.731, \nrespectively)\n\n\n283Archives of Gynecology and Obstetrics (2025) 312:273–286 \nassociated with endometriosis, potentially guiding tailor \nsurveillance and treatment decisions. Future studies should \ninvestigate the biological mechanisms underlying this dis -\ncrepancy, particularly differences in the tumor microenviron-\nment, immune landscape, and metabolic reprogramming. A \ndeeper molecular characterization of these subgroups could \nidentify novel therapeutic targets tailored to each distinct \nevolutionary pathway.\nHowever, our study has limitations. As a retrospective \nanalysis from a single specialized center, selection bias may \nimpact the generalizability of our findings. One limitation of \nour study is the potential underdiagnosis of endometriosis, \nas routine Douglas pouch peritoneal biopsy was not univer-\nsally performed. Future prospective studies may consider \nsystematic peritoneal biopsies to classify endometriosis \nstatus more accurately. Additionally, while we identified \nclinical differences among subgroups, further studies on bio-\nlogical mechanisms, such as microenvironmental or immune \nfactors driving these prognostic differences, should be taken \ninto consideration. Multi-center prospective cohorts will be \ncrucial for validating our findings and uncovering molecu-\nlar pathways distinguishing OCCC subtypes associated with \nendometriosis.\nTable 4  Factors associated with \nprogression-free survival in \npatients with OCCC \nRisk factors N Univariate analysis Multivariate analysis\nHR 95% CI  p value  Adjusted HR 95% CI p value\nAge (years)\n  < 50 117 1 (Ref) – –\n  ≥ 50 125 1.35 0.59–1.47 0.303\nBMI (kg/m2)\n  < 24.0 155 1 (Ref) – –\n  ≥ 24.0 87 0.97 0.38—1.86 0.417\nSurgery approach\n Laparotomy 172 1 (Ref) – –\n Laparoscopy 70 0.89 0.45–1.74 0.642\nFIGO stage\n I–II 184 1 (Ref) – – 1 (Ref) – –\n III–IV 58 3.52 1.91–6.50  < 0.001 2.49 0.49–4.93 0.459\nResidual tumor\n No residual tumor (R0) 213 1 (Ref) – – 1 (Ref) – –\n  > R0 29  2.19  1.08–4.42  0.029  1.42 0.58–3.48   0.444\nResistant to platinum\n No 214 1 (Ref) – – 1 (Ref) – –\n Yes 16 3.25 1.23–8.55 0.017 0.84 0.19–3.67 0.82\nLymph nodes\n Negative 192 1 (Ref) – – 1 (Ref) – –\n Positive 23 2.41 1.06–5.47 0.036 1.88 0.51–6.95 0.342\nAscites or peritoneal lavage fluid\n Negative 189 1 (Ref) – – 1 (Ref) – –\n Positive 41 2.86 1.44–5.68 0.003 2.49 0.87–7.13 0.089\nPresent with thrombosis\n No 202 1 (Ref) – –\n Yes 40 1.01 0.98–3.77 0.081\nEndometriosis\n No 130 1 (Ref) – – 1 (Ref) – –\n Yes 112 0.25 0.12–0.52  < 0.001 0.24 0.09–0.66 0.006\nEndometriosis involvement\n Without 130 1 (Ref) – – 1 (Ref) – –\n Coexisting 41 0.21 0.06–0.68 0.009 0.11 0.01–0.84 0.033\n Arising 71 0.28 0.12–0.67 0.004 0.34 0.11–1.05 0.061\n\n284 Archives of Gynecology and Obstetrics (2025) 312:273–286\nSupplementary Information The online version contains supplemen-\ntary material available at https:// doi. org/ 10. 1007/ s00404- 025- 08025-3.\nAuthor contributions Project development: JD and TY; data collection: \nJD and JL; data analysis: LX and TY; manuscript writing: JD and TY; \nmanuscript editing: JD, LX, JL and TY. All authors approved the final \nsubmitted draft.\nFunding This work was supported by National Natural Science Foun-\ndation of China (Grant No. 82002756).\nData availability The patients’ clinicopathological data used to gener-\nate the results are presented in Supplemental Table.\nDeclarations \nConflicts of interest The authors declare no competing interests.\nEthics approval This study was performed in line with the principles \nof the Declaration of Helsinki. Since the retrospective study utilized \nanonymous patient information, the Research Ethics Committee of \nWest China Second Hospital, Sichuan University, confirmed that no \nethical approval was required.\nOpen Access  This article is licensed under a Creative Commons \nAttribution-NonCommercial-NoDerivatives 4.0 International License, \nwhich permits any non-commercial use, sharing, distribution and repro-\nduction in any medium or format, as long as you give appropriate credit \nto the original author(s) and the source, provide a link to the Creative \nCommons licence, and indicate if you modified the licensed material. \nYou do not have permission under this licence to share adapted material \nderived from this article or parts of it. The images or other third party \nmaterial in this article are included in the article’s Creative Commons \nlicence, unless indicated otherwise in a credit line to the material. If \nmaterial is not included in the article’s Creative Commons licence and \nTable 5  Factors associated with \noverall survival in patients with \nOCCC \nRisk factors N Univariate analysis Multivariate analysis\nHR 95% CI p value Adjusted HR 95% CI p value\nAge (years)\n  < 50 117 1 (Ref) – –\n  ≥ 50 125 1.26 0.60–2.68 0.401\nBMI (kg/m2)\n  < 24.0 155 1 (Ref) – –\n  ≥ 24.0 87 0.88 0.38–1.93 0.211\nSurgery approach\n Laparotomy 172 1 (Ref) – –\n Laparoscopy 70 0.41 0.13–1.02 0.112\nFIGO stage\n I–II 184 1 (Ref) – – 1 (Ref) – –\n III–IV 58 7.12 3.71–13.59  < 0.001 5.89 2.06–16.82  < 0.001\nResidual tumor\n No residual tumor (R0) 213 1 (Ref) –  – 1 (Ref) – –\n  > R0 29  3.68  1.88–7.22  < 0.001  1.82  0.78–4.29  0.168\nResistant to platinum\n No 214 1 (Ref) – – 1 (Ref) – –\n Yes 16 14.46 6.69–31.24  < 0.001 2.39 0.86–6.67 0.096\nLymph nodes\n Negative 192 1 (Ref) – – 1 (Ref) – –\n Positive 23 3.05 1.33–6.99 0.008 0.87 0.32–2.40 0.789\nAscites or peritoneal lavage fluid\n Negative 189 1 (Ref) – – 1 (Ref) – –\n Positive 41 5.11 2.67–9.73  < 0.001 2.18 0.84–5.67 0.111\nPresent with thrombosis\n No 202 1 (Ref) – – 1 (Ref) – –\n Yes 40 3.6383 1.62–8.08  < 0.005 2.544 0.83–7.27 0.105\nEndometriosis\n No 130 1 (Ref) – – 1 (Ref) – –\n Yes 112 0.35 0.17—0.74 0.006 0.62 0.26–1.53 0.302\nEndometriosis involvement status\n Without 130 1 (Ref) – – 1 (Ref) – –\n Coexisting 41 0.48 0.18–1.22 0.125 0.62 0.22–1.96 0.415\n Arising 71 0.26 0.09–0.75 0.012 0.63 0.21–1.98 0.429\n\n285Archives of Gynecology and Obstetrics (2025) 312:273–286 \nyour intended use is not permitted by statutory regulation or exceeds \nthe permitted use, you will need to obtain permission directly from the \ncopyright holder. 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