Clinical and Prognostic Relevance of Histologic Transition in Endometriosis- Associated Ovarian carcinoma

Clinical and Prognostic Relevance of Histologic Transition in Endometriosis- Associated Ovarian carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical and Prognostic Relevance of Histologic Transition in Endometriosis- Associated Ovarian carcinoma Anna Myriam Perrone, Elisa Scarpelli, Francesco Mezzapesa, Antonio De Leo, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-10176151/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Objective To evaluate the clinical and prognostic significance of histologic transition from endometriosis to carcinoma in epithelial ovarian cancer and to determine whether ovarian carcinomas associated with incidental endometriosis differ from those arising from endometriosis. Methods This retrospective single-center cohort study included 1,069 consecutive patients with epithelial ovarian cancer treated between 2014 and 2024. Patients were classified according to the presence of endometriosis and histologic evidence of transition from endometriosis to carcinoma. Progression-free survival was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Survival analyses were performed according to FIGO stage. Results Of the 1,069 patients included, 766 had ovarian carcinoma without endometriosis, 190 had ovarian carcinoma with incidental endometriosis, and 113 had ovarian carcinoma arising from endometriosis with histologic transition. Ovarian carcinomas with incidental endometriosis showed clinicopathologic characteristics comparable to those of ovarian carcinomas without endometriosis, including stage distribution, histologic subtype, tumor grade, and survival outcomes. In contrast, tumors with histologic transition were more frequently diagnosed at an early stage and were enriched for endometrioid and clear-cell histology. A significant difference in progression-free survival was observed only in FIGO stage I disease (log-rank p = 0.009). In multivariable analysis adjusted for histologic subtype and adjuvant treatment, ovarian carcinomas arising from endometriosis with histologic transition remained independently associated with improved progression-free survival compared with ovarian carcinomas without endometriosis (HR 0.30, 95% CI 0.10–0.91; p = 0.034), whereas ovarian carcinomas with incidental endometriosis did not differ significantly from ovarian carcinomas without endometriosis (HR 0.25, 95% CI 0.06–1.10; p = 0.066). No significant differences were observed in FIGO stage II–IV disease. Conclusions The prognostic relevance of endometriosis in epithelial ovarian carcinoma appears to depend on histologic evidence of malignant transition rather than on the mere coexistence of endometriosis. Distinguishing ovarian carcinomas arising from endometriosis from those with incidental endometriosis may improve the clinicopathologic characterization of endometriosis-associated ovarian carcinoma. Epithelial ovarian carcinoma Endometriosis Histologic transition Incidental endometriosis Prognosis Early-stage disease Figures Figure 1 Highlights What is already known on this topic The prognostic significance of endometriosis in ovarian cancer remains controversial. Most previous studies have considered endometriosis as a binary variable without distinguishing ovarian cancers arising from endometriosis from those in which endometriosis is an incidental finding, potentially contributing to inconsistent survival results. What this study adds This study demonstrates that ovarian cancers with incidental endometriosis share clinicopathologic characteristics and survival outcomes comparable to ovarian cancers without endometriosis. In contrast, ovarian cancers arising from endometriosis with histologic evidence of transition were independently associated with improved progression-free survival in FIGO stage I disease. How this study might affect research, practice or policy These findings support the routine pathological assessment and reporting of histologic transition from endometriosis to carcinoma. Distinguishing ovarian cancers arising from endometriosis from those with incidental endometriosis may improve the clinicopathologic characterization and prognostic stratification of early-stage epithelial ovarian cancer. Introduction The relationship between endometriosis and ovarian carcinoma remains a longstanding and unresolved clinical issue. Endometriosis is identified in up to 40% of ovarian clear cell and endometrioid carcinomas [ 1 – 3 ]. However, it is also frequently observed in association with other histologic subtypes (15%), raising the question of whether coexistence alone reflects a meaningful biological link or merely an incidental finding [ 4 ]. Since Sampson first proposed malignant transformation of endometriosis as a mechanism of ovarian carcinogenesis, later refined by Scott’s requirement of histologic continuity between benign endometriosis and adjacent carcinoma, the concept of “ovarian carcinoma arising from endometriosis” has been primarily grounded in morphologic transition [ 5 , 6 ]. Nevertheless, most contemporary clinical studies considered endometriosis as a binary variable, (present or absent), without systematically distinguishing tumors that arise through histologic transition from those in which endometriosis is detected incidentally and without evidence of malignant evolution [ 7 , 8 ]. This methodological limitation has likely contributed to the inconsistent survival data reported in endometriosis-associated ovarian carcinoma. While several retrospective series have suggested improved outcomes in patients with concomitant endometriosis, these findings have often been attributed to confounding factors such as earlier stage at diagnosis, favorable histologic subtypes, and higher rates of complete cytoreduction [ 9 – 11 ]. Importantly, even large studies focusing on endometrioid and clear cell ovarian carcinomas have rarely assessed the presence of histologic transition lesions, limiting the ability to determine whether endometriosis itself, or rather its specific relationship with the tumor, carries independent prognostic significance [ 12 ]. Recently, a prospective study from our institution proposed a conceptual refinement of endometriosis-associated ovarian carcinoma by distinguishing two clinicopathologically distinct entities: tumors arising from endometriosis with histologic evidence of transition (endometriosis-correlated ovarian carcinoma) and tumors in which endometriosis is present without transitional features (endometriosis-incidental ovarian carcinoma) [ 8 ]. This classification demonstrated that endometriosis-incidental ovarian carcinoma shares clinicopathologic characteristics more closely with non–endometriosis-associated ovarian carcinoma than with endometriosis-correlated ovarian carcinoma, challenging the assumption that all endometriosis-associated ovarian carcinomas constitute a homogeneous group. However, the relatively short follow-up of that cohort precluded evaluation of long-term oncologic outcomes, leaving the prognostic significance of endometriosis-incidental ovarian carcinoma unresolved. Against this background, the present study aimed to evaluate the clinical and prognostic relevance of this endometriosis-based classification in a large retrospective cohort of patients with epithelial ovarian carcinoma and long-term follow-up. Specifically, we sought to determine whether endometriosis-incidental ovarian carcinoma exhibits a clinicopathologic and prognostic profile more closely resembling non-endometriosis-associated ovarian carcinoma than endometriosis-correlated ovarian carcinoma, and to assess whether the prognostic significance of histologic transition differs according to disease stage. Materials and Methods Study design and population This retrospective single-center cohort study was conducted at the Division of Oncologic Gynecology, IRCCS Azienda Ospedaliero-Universitaria di Bologna. Ethical approval was obtained from the local Ethics Committee (reference number 34/2026/Oss/AOUBo). Consecutive patients treated for epithelial ovarian carcinoma (EOC) between January 2014 and June 2024 were included. Eligibility criteria were age ≥ 18 years, histologically confirmed epithelial ovarian carcinoma, and both surgical management and pathological assessment performed at our institution. Patients who did not undergo surgery or whose surgery and/or pathological evaluation had been performed elsewhere were excluded. Cases of synchronous ovarian and endometrial cancer were also excluded. The primary endpoint was progression-free survival. Secondary endpoints included the association between endometriosis-based classification and clinicopathologic characteristics. Data collection and variables Clinical, surgical, oncologic, and follow-up data were retrieved from electronic medical records. Variables collected included age at diagnosis, menopausal status, parity, body mass index (BMI), preoperative CA-125 levels, timing and type of surgery (primary debulking surgery or interval debulking surgery following neoadjuvant chemotherapy), surgical approach, Peritoneal Cancer Index [ 13 ], Predictive Index Value [ 14 ], and Completeness of Cytoreduction [ 15 ]. Pathological variables included FIGO stage [ 16 ], histologic subtype, tumor grade, and the presence or absence of endometriosis. When present, endometriosis was further classified according to the presence or absence of histologic evidence of malignant transition, including atypical endometriosis or borderline lesions [ 5 , 8 ]. Endometriosis-based classification Patients were classified into three mutually exclusive groups according to predefined morphologic criteria and our previously published classification framework: non-endometriosis-associated ovarian carcinoma: no histologic evidence of endometriosis. endometriosis-incidental ovarian carcinoma: presence of endometriosis without histologic evidence of transition to carcinoma. endometriosis-correlated ovarian carcinoma: presence of endometriosis with histologic evidence of transition to carcinoma, including atypical endometriosis and/or borderline components. All pathological assessments were performed at our institution by the same dedicated gynecologic pathologist with specific expertise in endometriosis-associated ovarian neoplasms. Cases were reviewed according to predefined morphologic criteria based on Scott’s definition of histologic transition. Endometriosis-correlated ovarian carcinoma classification required direct morphologic continuity between endometriosis and carcinoma and/or the presence of atypical endometriosis or borderline lesions adjacent to the invasive tumor. Treatment and follow-up All patients were treated according to international guidelines for epithelial ovarian carcinoma [ 17 , 18 ]. Follow-up was performed every 6 or 12 months according to institutional practice and included physical examination, transvaginal and transabdominal ultrasound, serum CA-125 assessment, and contrast-enhanced computed tomography when clinically indicated. Additional evaluations and diagnostic investigations were performed at the discretion of the treating physician based on individual clinical circumstances. Statistical analysis Continuous variables were summarized as median and interquartile range (IQR) or mean and standard deviation, as appropriate, and compared using Student’s t test or the Mann–Whitney U test. Categorical variables were reported as frequencies and percentages and compared using the χ² test or Fisher’s exact test. When global comparisons among the three endometriosis groups were significant, pairwise post hoc comparisons were performed with Bonferroni correction. Progression-free survival was defined as the interval from diagnosis to disease recurrence or death, whichever occurred first, or last follow-up. Overall survival was defined as the interval from diagnosis to death or last follow-up. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Median follow-up was calculated using the reverse Kaplan–Meier method. Given the strong prognostic impact of disease stage and the substantial differences in FIGO stage distribution among non-endometriosis-associated ovarian carcinoma, endometriosis-incidental ovarian carcinoma, and endometriosis-correlated ovarian carcinoma, survival analyses were performed in a stage-stratified manner to reduce residual confounding and allow a more clinically meaningful comparison among groups. Variables with p < 0.10 in univariable analysis or deemed clinically relevant were considered for inclusion in multivariable Cox proportional hazards models. To avoid model overfitting given the limited number of progression events in FIGO stage I disease, only variables considered clinically relevant and supported by univariable analyses were retained in the final model. Categories with sparse data or no events were excluded to ensure model stability. The proportional hazards assumption was assessed using Schoenfeld residuals. All tests were two-sided, and a p value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 28.0.1.1. Results Study population and endometriosis-based classification A total of 1,069 patients with epithelial ovarian carcinoma were included in the analysis. Of these, 766 (71.6%) were classified as non-endometriosis-associated ovarian carcinoma, 190 (17.8%) as endometriosis-incidental ovarian carcinoma, and 113 (10.6%) as endometriosis-correlated ovarian carcinoma. Baseline clinicopathologic characteristics are summarized in Table 1. Baseline clinicopathologic characteristics Median age at diagnosis differed significantly across the three groups, decreasing from 62.0 years in non-endometriosis-associated ovarian carcinoma to 57.5 years in endometriosis-incidental ovarian carcinoma and 54.2 years in endometriosis-correlated ovarian carcinoma (p < 0.001). BMI did not differ significantly among groups (p = 0.626). Significant differences were observed in disease stage distribution (p < 0.001). Endometriosis-correlated ovarian carcinoma was more frequently diagnosed at an early stage, with FIGO stage I–II disease observed in 79.6% of cases, whereas advanced-stage disease (FIGO III–IV) predominated in both non-endometriosis-associated ovarian carcinoma (79.4%) and endometriosis-incidental ovarian carcinoma (68.9%). Histologic subtype distribution also differed significantly among groups (p < 0.001). High-grade serous carcinoma was the predominant subtype in both non-endometriosis-associated ovarian carcinoma (82.0%) and endometriosis-incidental ovarian carcinoma (77.3%), whereas endometriosis-correlated ovarian carcinoma was characterized by a higher prevalence of endometrioid (54.9%) and clear cell (27.4%) carcinomas. Tumor grade showed a similar pattern (p < 0.001). Grade 3 tumors were prevalent in non-endometriosis-associated ovarian carcinoma (87.7%) and endometriosis-incidental ovarian carcinoma (82.1%), whereas endometriosis-correlated ovarian carcinoma showed a lower proportion of grade 3 tumors (46.9%) and a higher proportion of low- and intermediate-grade lesions. BRCA testing results were available for 540 patients. The prevalence of BRCA mutations was comparable in non-endometriosis-associated ovarian carcinoma and endometriosis-incidental ovarian carcinoma (39.3% and 38.9%, respectively) and significantly lower in endometriosis-correlated ovarian carcinoma (15.6%; p = 0.005). Pairwise post hoc comparisons are reported in Supplementary Table S1. Primary treatment and surgical outcomes Primary treatment strategy differed significantly among groups (p < 0.001). Neoadjuvant chemotherapy followed by interval debulking surgery was more frequently administered in non-endometriosis-associated ovarian carcinoma and endometriosis-incidental ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma was more commonly managed with primary debulking surgery. Rates of complete cytoreduction (CC0) were high across all groups and increased progressively from non-endometriosis-associated ovarian carcinoma (81.0%) to endometriosis-incidental ovarian carcinoma (89.5%) and endometriosis-correlated ovarian carcinoma (96.5%) (p = 0.001). Survival analysis and stage-stratified analysis The median follow-up was 79.9 months (95% CI, 71.3–92.7) for the overall cohort. Progression-free survival was analyzed according to FIGO stage to account for stage-related prognostic heterogeneity. A statistically significant difference in PROGRESSION-FREE SURVIVAL among non-endometriosis-associated ovarian carcinoma, endometriosis-incidental ovarian carcinoma, and endometriosis-correlated ovarian carcinoma was observed only in patients with FIGO stage I disease (log-rank p = 0.009) (Figure 1). At 2 years, progression-free survival rates were 92.6% for non-endometriosis-associated ovarian carcinoma, 93.1% for endometriosis-incidental ovarian carcinoma, and 95.2% for endometriosis-correlated ovarian carcinoma. In this subgroup, progression events occurred in 24/101 non-endometriosis-associated ovarian carcinoma patients (23.8%), 2/37 endometriosis-incidental ovarian carcinoma patients (5.4%), and 5/73 endometriosis-correlated ovarian carcinoma patients (6.8%) (Supplementary Table S2). The distribution of progression events across all FIGO stages is reported in Supplementary Table S3. No significant differences in progression-free survival were observed among the three groups in FIGO stage II, III, or IV disease (log-rank p = 0.189, p = 0.825, and p = 0.117, respectively) (Supplementary Figures S1-S3). Based on these findings, subsequent analyses focused on patients with FIGO stage I ovarian carcinoma (Table 2). In this subgroup, the median follow-up was 72.4 months (95% CI, 63.2–81.7). Cox regression analysis in FIGO stage I disease In univariable Cox regression analysis, the presence of endometriosis was associated with a significantly reduced risk of disease progression (HR 0.29, 95% CI 0.13–0.68; p = 0.004). Histologic subtype was also significantly associated with progression-free survival (global p < 0.001). Compared with high-grade serous carcinoma, expansile-type mucinous carcinoma (HR 0.32, 95% CI 0.10–0.97; p = 0.044) and low-grade endometrioid carcinoma (HR 0.06, 95% CI 0.01–0.26; p < 0.001) were associated with a lower risk of progression. When stratified according to endometriosis-based classification, endometriosis-correlated ovarian carcinoma was associated with a significantly lower hazard of progression compared with non-endometriosis-associated ovarian carcinoma (HR 0.30, 95% CI 0.12–0.79; p = 0.015). No significant difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma (HR 0.27, 95% CI 0.06–1.13; p = 0.073). In multivariable Cox regression analysis including histologic subtype and adjuvant therapy, histologic subtype remained independently associated with progression-free survival (global p = 0.005). Compared with high-grade serous carcinoma, expansile-type mucinous carcinoma (HR 0.13, 95% CI 0.03–0.51; p = 0.004) and low-grade endometrioid carcinoma (HR 0.13, 95% CI 0.03–0.61; p = 0.010) retained a significantly lower risk of progression. Endometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival compared with non-endometriosis-associated ovarian carcinoma (HR 0.30, 95% CI 0.10–0.91; p = 0.034), whereas no significant difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma (HR 0.25, 95% CI 0.06–1.10; p = 0.066). Adjuvant therapy was not independently associated with progression risk (HR 0.75, 95% CI 0.25–2.24; p = 0.609). No violation of the proportional hazards assumption was observed (Supplementary Table S4). Sensitivity analyses Sensitivity analyses restricted to endometrioid and clear cell carcinomas are presented in Supplementary Figure S4. Within this subgroup, the direction of the association between endometriosis-based classification and progression-free survival remained consistent with that observed in the overall cohort, although no statistically significant differences were detected in stage-stratified analyses. Additional analyses restricted to patients diagnosed from 2019 onward are reported in Supplementary Table S5 and Supplementary Figure S5. Clinicopathologic characteristics were comparable to those observed in the overall study population. Similarly, the survival pattern identified in FIGO stage I disease was maintained, although statistical significance was not reached. Discussion This study suggests that the prognostic role of endometriosis in epithelial ovarian carcinoma may be limited to the presence of histologic evidence of malignant transition: endometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival in FIGO stage I disease, while no difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma. This prognostic concordance parallels the similarity in clinicopathologic characteristics, including stage distribution, histologic subtype, tumor grade, treatment strategy, and BRCA mutation prevalence, suggesting the endometriosis alone may represent an incidental finding without an active role in tumor development. Results in the context of the literature Previous studies evaluating the prognostic impact of endometriosis in ovarian carcinoma have reported conflicting results, ranging from improved survival to no independent effect after adjustment for stage and histology [ 19 ]. A major limitation shared by most of these studies is the lack of distinction between ovarian carcinomas arising from endometriosis and those merely coexisting with it. Our findings provide a possible explanation for these inconsistencies. By considering endometriosis-correlated ovarian carcinoma and endometriosis-incidental ovarian carcinoma as a single category of endometriosis-associated ovarian carcinoma, previous studies may have obscured clinically relevant differences between these two groups. This issue may be particularly relevant in cohorts enriched for high-grade serous carcinomas, as large epidemiologic studies have shown that the association between endometriosis and ovarian carcinoma is strongest for endometrioid and clear cell histologies rather than across all ovarian carcinoma subtypes [ 20 ]. Consistent with this interpretation, recent systematic reviews have reported substantial overlap in histologic subtype distribution between endometriosis-incidental ovarian carcinoma and endometriosis-correlated ovarian carcinoma, suggesting that histology alone may not adequately capture clinically relevant heterogeneity within endometriosis-associated ovarian carcinoma [ 21 ]. Our stage-stratified analysis further refines this concept. Even in early-stage disease, endometriosis-incidental ovarian carcinoma did not differ prognostically from non-endometriosis-associated ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival in FIGO stage I disease after adjustment for histologic subtype. Nevertheless, histologic subtype itself remained an important determinant of outcome, indicating that the prognostic contribution of histologic transition should be interpreted within the broader clinicopathologic context. Although endometriosis-correlated ovarian carcinoma was enriched in endometrioid and clear cell histologies, the association between endometriosis-correlated ovarian carcinoma and improved progression-free survival persisted after adjustment for histologic subtype. Furthermore, sensitivity analyses restricted to endometrioid and clear-cell carcinomas showed a similar direction of effect, suggesting that histologic transition may capture biologic information beyond histotype alone. The absence of a measurable prognostic effect in endometriosis-incidental ovarian carcinoma suggests that incidental endometriosis, by itself, is insufficient to identify a clinically distinct subgroup of ovarian carcinoma. In these cases, endometriosis may represent a concomitant condition without a measurable impact on prognosis. This interpretation is further supported by the BRCA mutation profile observed across groups. Endometriosis-incidental ovarian carcinoma showed a prevalence of BRCA mutations nearly identical to that of non-endometriosis-associated ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma was characterized by a substantially lower prevalence of BRCA alterations. Although BRCA status was not available for all patients, this finding suggests that endometriosis-correlated ovarian carcinoma may arise through biological pathways distinct from those typically associated with BRCA-driven ovarian carcinogenesis. In contrast, endometriosis-correlated ovarian carcinoma may represent the clinical counterpart of a continuum from benign endometriosis to carcinoma, a concept supported by studies describing progressive molecular alterations during malignant transformation [ 22 , 23 ]. Within this framework, our findings support the clinical relevance of histologic transition as a marker of ovarian carcinomas arising through endometriosis-associated pathways. Strengths and limitations The main strength of this study lies in the consistent pathological assessment performed at a single institution by a dedicated gynecologic pathologist with specific expertise in the identification of endometriosis and histologic transition. This approach enabled a reliable distinction between ovarian carcinomas arising from endometriosis and cases of incidental endometriosis. Conducted in a high-volume tertiary referral center, the study also benefited from homogeneous surgical management, standardized pathology reporting, and long-term follow-up. Furthermore, stage-stratified analyses allowed evaluation of the prognostic relevance of histologic transition across different disease stages and identified a significant association restricted to FIGO stage I disease. Nevertheless, several limitations should be acknowledged. First, the retrospective design entails the possibility of selection bias and residual confounding. Second, the distinction between ovarian carcinomas arising from endometriosis and cases of incidental endometriosis may be subject to interobserver variability, as histopathologic criteria for defining malignant transition are not uniformly applied in routine clinical practice. Consequently, external reproducibility of this classification remains to be established. Finally, BRCA testing was not available for all patients because genetic assessment was progressively implemented during the study period. In addition, the study period spans a decade during which the therapeutic landscape of ovarian carcinoma evolved substantially, particularly with the introduction of PARP inhibitors and other maintenance strategies that have improved progression-free survival [ 24 , 25 ]. Although sensitivity analyses restricted to more recently diagnosed patients showed results consistent with the primary analysis, we cannot exclude the possibility that temporal changes in treatment may have influenced survival outcomes. Furthermore, despite the large overall cohort, the limited number of progression events in FIGO stage I disease reduced statistical power and constrained multivariable modeling. Nevertheless, the consistency of the findings across univariable and multivariable analyses supports the relative robustness of the observed association, although confirmation in larger multicenter cohorts is warranted. Histologic transition may also be underestimated, particularly in advanced-stage tumors, where extensive tumor overgrowth can obscure precursor lesions. Finally, as a single-center study, our findings require external validation in independent multicenter cohorts. Implications for practice and future research Our findings suggest that histologic evidence of transition from endometriosis to carcinoma may provide clinically relevant prognostic information in FIGO stage I epithelial ovarian carcinoma and therefore deserves systematic assessment and reporting in pathological practice. When considered alongside established clinicopathologic factors, histologic transition may contribute to a more refined characterization of early-stage disease. Notably, the prognostic effect of histologic transition was confined to FIGO stage I disease and was not observed in more advanced stages. This finding suggests that any biological advantage associated with endometriosis-related carcinogenesis may be most relevant during the early phases of tumor development and may become progressively overshadowed by disease burden as stage advances. In contrast, our results do not support any modification of treatment strategies in advanced-stage ovarian carcinoma based solely on the presence of endometriosis or histologic transition. In this setting, disease stage, tumor histology, and other established prognostic factors remain the primary determinants of outcome. Future multicenter studies incorporating standardized pathological assessment together with molecular and imaging-based profiling are needed to validate these findings, further characterize the relationship between endometriosis-correlated ovarian carcinoma and endometriosis-incidental ovarian carcinoma, and determine whether histologic transition can improve prognostic stratification beyond currently available clinicopathologic parameters. Conclusions Our findings suggest that the prognostic relevance of endometriosis in epithelial ovarian carcinoma may depend on the presence of histologic evidence of transition to carcinoma. Ovarian carcinomas arising from endometriosis with histologic transition were associated with improved progression-free survival in FIGO stage I disease, independent of histologic subtype. In contrast, endometriosis-incidental ovarian carcinoma did not differ prognostically from non–endometriosis-associated ovarian carcinoma and was not associated with a distinct clinicopathologic profile. Taken together, these findings support the interpretation that endometriosis-incidental ovarian carcinoma shares clinicopathologic and prognostic characteristics more closely with non-endometriosis-associated ovarian carcinoma than with endometriosis-correlated ovarian carcinoma. Our results further highlight the importance of distinguishing histologic transition from the mere coexistence of endometriosis when evaluating endometriosis-associated ovarian carcinoma. Declarations Ethics approval and Consent to Participate This retrospective observational study was approved by the Ethics Committee of Area Vasta Emilia Centro (AVEC) (approval number 34/2026/Oss/AOUBo ). The study was conducted in accordance with the Declaration of Helsinki and applicable national regulations. Written informed consent to participate in the study and for the processing of personal data for research purposes was obtained from all participants. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Clinical trial number: not applicable. Authors' contributions A.M.P. conceived the study, contributed to the study design, supervised the project, drafted and critically revised the manuscript. E.S. contributed to data analysis and interpretation, drafted the manuscript, and coordinated manuscript preparation. F.M. participated in the interpretation of the results and critically revised the manuscript. A.D.L. contributed to pathological interpretation and critically revised the manuscript. C.A.C. contributed to statistical analysis and interpretation of the data. E.M. contributed to data curation and database management. G.M., E.F., El.F., and C.R. contributed to data collection. G.R. contributed to data interpretation and critically revised the manuscript. P.D.I. supervised the study and critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors gratefully acknowledge Stefano Friso for his valuable support in data management and database organization. References Heidemann LN, Hartwell D, Heidemann CH, Jochumsen KM. The relation between endometriosis and ovarian carcinoma – a review. Acta Obstet Gynecol Scand 2014;93:20–31. https://doi.org/10.1111/aogs.12255. Jimbo H, Yoshikawa H, Onda T, Yasugi T, Sakamoto A, Taketani Y. Prevalence of ovarian endometriosis in epithelial ovarian carcinoma. 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Ravegnini G, Coadă CA, Mantovani G, De Leo A, de Biase D, Costantino A, et al. MicroRNA profiling reveals potential biomarkers for the early transformation of endometriosis towards endometriosis-correlated ovarian carcinoma. Transl Oncol 2025;55:102367. https://doi.org/10.1016/j.tranon.2025.102367. Petousis S, Kahramanoglu I, Appenzeller-Herzog C, Angeles MA, Margioula-Siarkou C, Kacperczyk-Bartnik J, et al. PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian carcinoma. JAMA Netw Open 2025;8:e2541648. https://doi.org/10.1001/jamanetworkopen.2025.41648. Hwang S, Kim JH, Kim U, Ha HI, Park S-Y, Lim MC. Influence of Residual Disease on the Efficacy of PARP Inhibitors in Advanced Epithelial Ovarian carcinoma: A Systematic Review and Meta Analysis. Cancers (Basel) 2025;17:3365. https://doi.org/10.3390/cancers17203365. Tables Tables 1 and 2 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.jpg SupplementaryFigure2.jpg SupplementaryFigure3.jpg SupplementaryFigure4.jpg SupplementaryFigure5.jpg SupplementaryTable1.docx SupplementaryTable2.docx SupplementaryTable3.docx SupplementaryTable4.docx SupplementaryTable5.docx Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 30 Jul, 2026 Reviewers agreed at journal 26 Jul, 2026 Reviewers agreed at journal 26 Jul, 2026 Reviews received at journal 26 Jul, 2026 Reviewers agreed at journal 26 Jul, 2026 Reviewers agreed at journal 24 Jul, 2026 Reviewers agreed at journal 24 Jul, 2026 Reviewers agreed at journal 24 Jul, 2026 Reviewers agreed at journal 24 Jul, 2026 Reviewers invited by journal 24 Jul, 2026 Editor assigned by journal 10 Jul, 2026 Submission checks completed at journal 10 Jul, 2026 First submitted to journal 27 Jun, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-10176151","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":685691227,"identity":"3fcac75f-1ec0-458d-87d6-a455a3ecad43","order_by":0,"name":"Anna Myriam Perrone","email":"","orcid":"","institution":"University of Bologna","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Myriam","lastName":"Perrone","suffix":""},{"id":685691229,"identity":"59c2f42d-61a1-41e1-a133-04f7d6e309da","order_by":1,"name":"Elisa 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Bologna","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pierandrea","middleName":"","lastName":"De Iaco","suffix":""}],"badges":[],"createdAt":"2026-06-28 01:35:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-10176151/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-10176151/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":115946668,"identity":"d87e8866-09f2-47a3-93b3-ddb0386a57fd","added_by":"auto","created_at":"2026-07-29 07:35:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":178082,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier estimates of progression–free survival in patients with FIGO stage I epithelial ovarian cancer according to endometriosis-based classification.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePFS progression-free survival; NEOC, non–endometriosis-associated ovarian cancer; EIOC, incidental endometriosis-associated ovarian cancer; ECOC, endometriosis-correlated ovarian cancer.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1HROpen.jpg","url":"https://assets-eu.researchsquare.com/files/rs-10176151/v1/c106638aa73bc837ccddcfb6.jpg"},{"id":115946950,"identity":"f367aad5-6d34-4c0f-ad82-376b6b3a38a8","added_by":"auto","created_at":"2026-07-29 07:35:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":366806,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-10176151/v1/463762c2-53b5-49bb-b294-b4a798d58e9f.pdf"},{"id":115946702,"identity":"0f9f81cb-738b-4f59-82f2-0c8740eed4f5","added_by":"auto","created_at":"2026-07-29 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07:35:24","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":22144,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-10176151/v1/71a1f4db072ca361c47de3d2.docx"},{"id":115946670,"identity":"fb834f11-d8ae-4fa0-b22a-a5b61557ec5f","added_by":"auto","created_at":"2026-07-29 07:35:04","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":30336,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable5.docx","url":"https://assets-eu.researchsquare.com/files/rs-10176151/v1/09bd5440ff76b983a675707f.docx"},{"id":115946712,"identity":"d9aaeb51-9bb3-41fa-ba13-b1cb224d890c","added_by":"auto","created_at":"2026-07-29 07:35:14","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":22559,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-10176151/v1/8850fa5a5a789391964d1ad1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and Prognostic Relevance of Histologic Transition in Endometriosis- Associated Ovarian carcinoma","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u003cstrong\u003eWhat is already known on this topic\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prognostic significance of endometriosis in ovarian cancer remains controversial. Most previous studies have considered endometriosis as a binary variable without distinguishing ovarian cancers arising from endometriosis from those in which endometriosis is an incidental finding, potentially contributing to inconsistent survival results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat this study adds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study demonstrates that ovarian cancers with incidental endometriosis share clinicopathologic characteristics and survival outcomes comparable to ovarian cancers without endometriosis. In contrast, ovarian cancers arising from endometriosis with histologic evidence of transition were independently associated with improved progression-free survival in FIGO stage I disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHow this study might affect research, practice or policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese findings support the routine pathological assessment and reporting of histologic transition from endometriosis to carcinoma. Distinguishing ovarian cancers arising from endometriosis from those with incidental endometriosis may improve the clinicopathologic characterization and prognostic stratification of early-stage epithelial ovarian cancer.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe relationship between endometriosis and ovarian carcinoma remains a longstanding and unresolved clinical issue. Endometriosis is identified in up to 40% of ovarian clear cell and endometrioid carcinomas [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, it is also frequently observed in association with other histologic subtypes (15%), raising the question of whether coexistence alone reflects a meaningful biological link or merely an incidental finding [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Since Sampson first proposed malignant transformation of endometriosis as a mechanism of ovarian carcinogenesis, later refined by Scott\u0026rsquo;s requirement of histologic continuity between benign endometriosis and adjacent carcinoma, the concept of \u0026ldquo;ovarian carcinoma arising from endometriosis\u0026rdquo; has been primarily grounded in morphologic transition [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Nevertheless, most contemporary clinical studies considered endometriosis as a binary variable, (present or absent), without systematically distinguishing tumors that arise through histologic transition from those in which endometriosis is detected incidentally and without evidence of malignant evolution [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This methodological limitation has likely contributed to the inconsistent survival data reported in endometriosis-associated ovarian carcinoma. While several retrospective series have suggested improved outcomes in patients with concomitant endometriosis, these findings have often been attributed to confounding factors such as earlier stage at diagnosis, favorable histologic subtypes, and higher rates of complete cytoreduction [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Importantly, even large studies focusing on endometrioid and clear cell ovarian carcinomas have rarely assessed the presence of histologic transition lesions, limiting the ability to determine whether endometriosis itself, or rather its specific relationship with the tumor, carries independent prognostic significance [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Recently, a prospective study from our institution proposed a conceptual refinement of endometriosis-associated ovarian carcinoma by distinguishing two clinicopathologically distinct entities: tumors arising from endometriosis with histologic evidence of transition (endometriosis-correlated ovarian carcinoma) and tumors in which endometriosis is present without transitional features (endometriosis-incidental ovarian carcinoma) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis classification demonstrated that endometriosis-incidental ovarian carcinoma shares clinicopathologic characteristics more closely with non\u0026ndash;endometriosis-associated ovarian carcinoma than with endometriosis-correlated ovarian carcinoma, challenging the assumption that all endometriosis-associated ovarian carcinomas constitute a homogeneous group.\u003c/p\u003e \u003cp\u003eHowever, the relatively short follow-up of that cohort precluded evaluation of long-term oncologic outcomes, leaving the prognostic significance of endometriosis-incidental ovarian carcinoma unresolved.\u003c/p\u003e \u003cp\u003eAgainst this background, the present study aimed to evaluate the clinical and prognostic relevance of this endometriosis-based classification in a large retrospective cohort of patients with epithelial ovarian carcinoma and long-term follow-up. Specifically, we sought to determine whether endometriosis-incidental ovarian carcinoma exhibits a clinicopathologic and prognostic profile more closely resembling non-endometriosis-associated ovarian carcinoma than endometriosis-correlated ovarian carcinoma, and to assess whether the prognostic significance of histologic transition differs according to disease stage.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis retrospective single-center cohort study was conducted at the Division of Oncologic Gynecology, IRCCS Azienda Ospedaliero-Universitaria di Bologna. Ethical approval was obtained from the local Ethics Committee (reference number 34/2026/Oss/AOUBo).\u003c/p\u003e \u003cp\u003eConsecutive patients treated for epithelial ovarian carcinoma (EOC) between January 2014 and June 2024 were included. Eligibility criteria were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, histologically confirmed epithelial ovarian carcinoma, and both surgical management and pathological assessment performed at our institution. Patients who did not undergo surgery or whose surgery and/or pathological evaluation had been performed elsewhere were excluded. Cases of synchronous ovarian and endometrial cancer were also excluded.\u003c/p\u003e \u003cp\u003eThe primary endpoint was progression-free survival. Secondary endpoints included the association between endometriosis-based classification and clinicopathologic characteristics.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and variables\u003c/h3\u003e\n\u003cp\u003eClinical, surgical, oncologic, and follow-up data were retrieved from electronic medical records. Variables collected included age at diagnosis, menopausal status, parity, body mass index (BMI), preoperative CA-125 levels, timing and type of surgery (primary debulking surgery or interval debulking surgery following neoadjuvant chemotherapy), surgical approach, Peritoneal Cancer Index [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], Predictive Index Value [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and Completeness of Cytoreduction [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePathological variables included FIGO stage [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], histologic subtype, tumor grade, and the presence or absence of endometriosis. When present, endometriosis was further classified according to the presence or absence of histologic evidence of malignant transition, including atypical endometriosis or borderline lesions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eEndometriosis-based classification\u003c/h3\u003e\n\u003cp\u003ePatients were classified into three mutually exclusive groups according to predefined morphologic criteria and our previously published classification framework:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003enon-endometriosis-associated ovarian carcinoma: no histologic evidence of endometriosis.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eendometriosis-incidental ovarian carcinoma: presence of endometriosis without histologic evidence of transition to carcinoma.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eendometriosis-correlated ovarian carcinoma: presence of endometriosis with histologic evidence of transition to carcinoma, including atypical endometriosis and/or borderline components.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eAll pathological assessments were performed at our institution by the same dedicated gynecologic pathologist with specific expertise in endometriosis-associated ovarian neoplasms. Cases were reviewed according to predefined morphologic criteria based on Scott\u0026rsquo;s definition of histologic transition. Endometriosis-correlated ovarian carcinoma classification required direct morphologic continuity between endometriosis and carcinoma and/or the presence of atypical endometriosis or borderline lesions adjacent to the invasive tumor.\u003c/p\u003e\n\u003ch3\u003eTreatment and follow-up\u003c/h3\u003e\n\u003cp\u003eAll patients were treated according to international guidelines for epithelial ovarian carcinoma [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Follow-up was performed every 6 or 12 months according to institutional practice and included physical examination, transvaginal and transabdominal ultrasound, serum CA-125 assessment, and contrast-enhanced computed tomography when clinically indicated. Additional evaluations and diagnostic investigations were performed at the discretion of the treating physician based on individual clinical circumstances.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were summarized as median and interquartile range (IQR) or mean and standard deviation, as appropriate, and compared using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test or the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test. Categorical variables were reported as frequencies and percentages and compared using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test. When global comparisons among the three endometriosis groups were significant, pairwise post hoc comparisons were performed with Bonferroni correction.\u003c/p\u003e \u003cp\u003eProgression-free survival was defined as the interval from diagnosis to disease recurrence or death, whichever occurred first, or last follow-up. Overall survival was defined as the interval from diagnosis to death or last follow-up. Survival curves were estimated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Median follow-up was calculated using the reverse Kaplan\u0026ndash;Meier method.\u003c/p\u003e \u003cp\u003eGiven the strong prognostic impact of disease stage and the substantial differences in FIGO stage distribution among non-endometriosis-associated ovarian carcinoma, endometriosis-incidental ovarian carcinoma, and endometriosis-correlated ovarian carcinoma, survival analyses were performed in a stage-stratified manner to reduce residual confounding and allow a more clinically meaningful comparison among groups. Variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in univariable analysis or deemed clinically relevant were considered for inclusion in multivariable Cox proportional hazards models. To avoid model overfitting given the limited number of progression events in FIGO stage I disease, only variables considered clinically relevant and supported by univariable analyses were retained in the final model. Categories with sparse data or no events were excluded to ensure model stability. The proportional hazards assumption was assessed using Schoenfeld residuals. All tests were two-sided, and a \u003cem\u003ep\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 28.0.1.1.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy population and endometriosis-based classification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 1,069 patients with epithelial ovarian carcinoma were included in the analysis. Of these, 766 (71.6%) were classified as non-endometriosis-associated ovarian carcinoma, 190 (17.8%) as endometriosis-incidental ovarian carcinoma, and 113 (10.6%) as endometriosis-correlated ovarian carcinoma. Baseline clinicopathologic characteristics are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline clinicopathologic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedian age at diagnosis differed significantly across the three groups, decreasing from 62.0 years in non-endometriosis-associated ovarian carcinoma to 57.5 years in endometriosis-incidental ovarian carcinoma and 54.2 years in endometriosis-correlated ovarian carcinoma (p \u0026lt; 0.001). BMI did not differ significantly among groups (p = 0.626).\u003c/p\u003e\n\u003cp\u003eSignificant differences were observed in disease stage distribution (p \u0026lt; 0.001). Endometriosis-correlated ovarian carcinoma was more frequently diagnosed at an early stage, with FIGO stage I\u0026ndash;II disease observed in 79.6% of cases, whereas advanced-stage disease (FIGO III\u0026ndash;IV) predominated in both non-endometriosis-associated ovarian carcinoma (79.4%) and endometriosis-incidental ovarian carcinoma (68.9%).\u003c/p\u003e\n\u003cp\u003eHistologic subtype distribution also differed significantly among groups (p \u0026lt; 0.001). High-grade serous carcinoma was the predominant subtype in both non-endometriosis-associated ovarian carcinoma (82.0%) and endometriosis-incidental ovarian carcinoma (77.3%), whereas endometriosis-correlated ovarian carcinoma was characterized by a higher prevalence of endometrioid (54.9%) and clear cell (27.4%) carcinomas.\u003c/p\u003e\n\u003cp\u003eTumor grade showed a similar pattern (p \u0026lt; 0.001). Grade 3 tumors were prevalent in non-endometriosis-associated ovarian carcinoma (87.7%) and endometriosis-incidental ovarian carcinoma (82.1%), whereas endometriosis-correlated ovarian carcinoma showed a lower proportion of grade 3 tumors (46.9%) and a higher proportion of low- and intermediate-grade lesions.\u003c/p\u003e\n\u003cp\u003eBRCA testing results were available for 540 patients. The prevalence of BRCA mutations was comparable in non-endometriosis-associated ovarian carcinoma and endometriosis-incidental ovarian carcinoma (39.3% and 38.9%, respectively) and significantly lower in endometriosis-correlated ovarian carcinoma (15.6%; p = 0.005). Pairwise post hoc comparisons are reported in Supplementary Table S1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary treatment and surgical outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary treatment strategy differed significantly among groups (p \u0026lt; 0.001). Neoadjuvant chemotherapy followed by interval debulking surgery was more frequently administered in non-endometriosis-associated ovarian carcinoma and endometriosis-incidental ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma was more commonly managed with primary debulking surgery.\u003c/p\u003e\n\u003cp\u003eRates of complete cytoreduction (CC0) were high across all groups and increased progressively from non-endometriosis-associated ovarian carcinoma (81.0%) to endometriosis-incidental ovarian carcinoma (89.5%) and endometriosis-correlated ovarian carcinoma (96.5%) (p = 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival analysis\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and stage-stratified analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up was 79.9 months (95% CI, 71.3\u0026ndash;92.7) for the overall cohort. Progression-free survival was analyzed according to FIGO stage to account for stage-related prognostic heterogeneity.\u003c/p\u003e\n\u003cp\u003eA statistically significant difference in PROGRESSION-FREE SURVIVAL among non-endometriosis-associated ovarian carcinoma, endometriosis-incidental ovarian carcinoma, and endometriosis-correlated ovarian carcinoma was observed only in patients with FIGO stage I disease (log-rank p = 0.009) (Figure 1). At 2 years, progression-free survival rates were 92.6% for non-endometriosis-associated ovarian carcinoma, 93.1% for endometriosis-incidental ovarian carcinoma, and 95.2% for endometriosis-correlated ovarian carcinoma. In this subgroup, progression events occurred in 24/101 non-endometriosis-associated ovarian carcinoma patients (23.8%), 2/37 endometriosis-incidental ovarian carcinoma patients (5.4%), and 5/73 endometriosis-correlated ovarian carcinoma patients (6.8%) (Supplementary Table S2). The distribution of progression events across all FIGO stages is reported in Supplementary Table S3.\u003c/p\u003e\n\u003cp\u003eNo significant differences in progression-free survival were observed among the three groups in FIGO stage II, III, or IV disease (log-rank p = 0.189, p = 0.825, and p = 0.117, respectively) (Supplementary Figures S1-S3). Based on these findings, subsequent analyses focused on patients with FIGO stage I ovarian carcinoma (Table 2). In this subgroup, the median follow-up was 72.4 months (95% CI, 63.2\u0026ndash;81.7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCox regression analysis\u003c/strong\u003e\u003cstrong\u003ein FIGO stage I disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn univariable Cox regression analysis, the presence of endometriosis was associated with a significantly reduced risk of disease progression (HR 0.29, 95% CI 0.13\u0026ndash;0.68; p = 0.004). Histologic subtype was also significantly associated with progression-free survival (global p \u0026lt; 0.001). Compared with high-grade serous carcinoma, expansile-type mucinous carcinoma (HR 0.32, 95% CI 0.10\u0026ndash;0.97; p = 0.044) and low-grade endometrioid carcinoma (HR 0.06, 95% CI 0.01\u0026ndash;0.26; p \u0026lt; 0.001) were associated with a lower risk of progression.\u003c/p\u003e\n\u003cp\u003eWhen stratified according to endometriosis-based classification, endometriosis-correlated ovarian carcinoma was associated with a significantly lower hazard of progression compared with non-endometriosis-associated ovarian carcinoma (HR 0.30, 95% CI 0.12\u0026ndash;0.79; p = 0.015). No significant difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma (HR 0.27, 95% CI 0.06\u0026ndash;1.13; p = 0.073).\u003c/p\u003e\n\u003cp\u003eIn multivariable Cox regression analysis including histologic subtype and adjuvant therapy, histologic subtype remained independently associated with progression-free survival (global p = 0.005). Compared with high-grade serous carcinoma, expansile-type mucinous carcinoma (HR 0.13, 95% CI 0.03\u0026ndash;0.51; p = 0.004) and low-grade endometrioid carcinoma (HR 0.13, 95% CI 0.03\u0026ndash;0.61; p = 0.010) retained a significantly lower risk of progression.\u003c/p\u003e\n\u003cp\u003eEndometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival compared with non-endometriosis-associated ovarian carcinoma (HR 0.30, 95% CI 0.10\u0026ndash;0.91; p = 0.034), whereas no significant difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma (HR 0.25, 95% CI 0.06\u0026ndash;1.10; p = 0.066). Adjuvant therapy was not independently associated with progression risk (HR 0.75, 95% CI 0.25\u0026ndash;2.24; p = 0.609). No violation of the proportional hazards assumption was observed (Supplementary Table S4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSensitivity analyses restricted to endometrioid and clear cell carcinomas are presented in Supplementary Figure S4. Within this subgroup, the direction of the association between endometriosis-based classification and progression-free survival remained consistent with that observed in the overall cohort, although no statistically significant differences were detected in stage-stratified analyses.\u003c/p\u003e\n\u003cp\u003eAdditional analyses restricted to patients diagnosed from 2019 onward are reported in Supplementary Table S5 and Supplementary Figure S5. Clinicopathologic characteristics were comparable to those observed in the overall study population. Similarly, the survival pattern identified in FIGO stage I disease was maintained, although statistical significance was not reached.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study suggests that the prognostic role of endometriosis in epithelial ovarian carcinoma may be limited to the presence of histologic evidence of malignant transition: endometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival in FIGO stage I disease, while no difference was observed between endometriosis-incidental ovarian carcinoma and non-endometriosis-associated ovarian carcinoma. This prognostic concordance parallels the similarity in clinicopathologic characteristics, including stage distribution, histologic subtype, tumor grade, treatment strategy, and BRCA mutation prevalence, suggesting the endometriosis alone may represent an incidental finding without an active role in tumor development.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eResults in the context of the literature\u003c/h2\u003e \u003cp\u003ePrevious studies evaluating the prognostic impact of endometriosis in ovarian carcinoma have reported conflicting results, ranging from improved survival to no independent effect after adjustment for stage and histology [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A major limitation shared by most of these studies is the lack of distinction between ovarian carcinomas arising from endometriosis and those merely coexisting with it. Our findings provide a possible explanation for these inconsistencies. By considering endometriosis-correlated ovarian carcinoma and endometriosis-incidental ovarian carcinoma as a single category of endometriosis-associated ovarian carcinoma, previous studies may have obscured clinically relevant differences between these two groups. This issue may be particularly relevant in cohorts enriched for high-grade serous carcinomas, as large epidemiologic studies have shown that the association between endometriosis and ovarian carcinoma is strongest for endometrioid and clear cell histologies rather than across all ovarian carcinoma subtypes [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Consistent with this interpretation, recent systematic reviews have reported substantial overlap in histologic subtype distribution between endometriosis-incidental ovarian carcinoma and endometriosis-correlated ovarian carcinoma, suggesting that histology alone may not adequately capture clinically relevant heterogeneity within endometriosis-associated ovarian carcinoma [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our stage-stratified analysis further refines this concept. Even in early-stage disease, endometriosis-incidental ovarian carcinoma did not differ prognostically from non-endometriosis-associated ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma remained independently associated with improved progression-free survival in FIGO stage I disease after adjustment for histologic subtype. Nevertheless, histologic subtype itself remained an important determinant of outcome, indicating that the prognostic contribution of histologic transition should be interpreted within the broader clinicopathologic context. Although endometriosis-correlated ovarian carcinoma was enriched in endometrioid and clear cell histologies, the association between endometriosis-correlated ovarian carcinoma and improved progression-free survival persisted after adjustment for histologic subtype. Furthermore, sensitivity analyses restricted to endometrioid and clear-cell carcinomas showed a similar direction of effect, suggesting that histologic transition may capture biologic information beyond histotype alone.\u003c/p\u003e \u003cp\u003eThe absence of a measurable prognostic effect in endometriosis-incidental ovarian carcinoma suggests that incidental endometriosis, by itself, is insufficient to identify a clinically distinct subgroup of ovarian carcinoma. In these cases, endometriosis may represent a concomitant condition without a measurable impact on prognosis. This interpretation is further supported by the BRCA mutation profile observed across groups. Endometriosis-incidental ovarian carcinoma showed a prevalence of BRCA mutations nearly identical to that of non-endometriosis-associated ovarian carcinoma, whereas endometriosis-correlated ovarian carcinoma was characterized by a substantially lower prevalence of BRCA alterations. Although BRCA status was not available for all patients, this finding suggests that endometriosis-correlated ovarian carcinoma may arise through biological pathways distinct from those typically associated with BRCA-driven ovarian carcinogenesis.\u003c/p\u003e \u003cp\u003eIn contrast, endometriosis-correlated ovarian carcinoma may represent the clinical counterpart of a continuum from benign endometriosis to carcinoma, a concept supported by studies describing progressive molecular alterations during malignant transformation [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Within this framework, our findings support the clinical relevance of histologic transition as a marker of ovarian carcinomas arising through endometriosis-associated pathways.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe main strength of this study lies in the consistent pathological assessment performed at a single institution by a dedicated gynecologic pathologist with specific expertise in the identification of endometriosis and histologic transition. This approach enabled a reliable distinction between ovarian carcinomas arising from endometriosis and cases of incidental endometriosis. Conducted in a high-volume tertiary referral center, the study also benefited from homogeneous surgical management, standardized pathology reporting, and long-term follow-up. Furthermore, stage-stratified analyses allowed evaluation of the prognostic relevance of histologic transition across different disease stages and identified a significant association restricted to FIGO stage I disease.\u003c/p\u003e \u003cp\u003eNevertheless, several limitations should be acknowledged. First, the retrospective design entails the possibility of selection bias and residual confounding. Second, the distinction between ovarian carcinomas arising from endometriosis and cases of incidental endometriosis may be subject to interobserver variability, as histopathologic criteria for defining malignant transition are not uniformly applied in routine clinical practice. Consequently, external reproducibility of this classification remains to be established. Finally, BRCA testing was not available for all patients because genetic assessment was progressively implemented during the study period.\u003c/p\u003e \u003cp\u003eIn addition, the study period spans a decade during which the therapeutic landscape of ovarian carcinoma evolved substantially, particularly with the introduction of PARP inhibitors and other maintenance strategies that have improved progression-free survival [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Although sensitivity analyses restricted to more recently diagnosed patients showed results consistent with the primary analysis, we cannot exclude the possibility that temporal changes in treatment may have influenced survival outcomes.\u003c/p\u003e \u003cp\u003eFurthermore, despite the large overall cohort, the limited number of progression events in FIGO stage I disease reduced statistical power and constrained multivariable modeling. Nevertheless, the consistency of the findings across univariable and multivariable analyses supports the relative robustness of the observed association, although confirmation in larger multicenter cohorts is warranted. Histologic transition may also be underestimated, particularly in advanced-stage tumors, where extensive tumor overgrowth can obscure precursor lesions. Finally, as a single-center study, our findings require external validation in independent multicenter cohorts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eImplications for practice and future research\u003c/h2\u003e \u003cp\u003eOur findings suggest that histologic evidence of transition from endometriosis to carcinoma may provide clinically relevant prognostic information in FIGO stage I epithelial ovarian carcinoma and therefore deserves systematic assessment and reporting in pathological practice. When considered alongside established clinicopathologic factors, histologic transition may contribute to a more refined characterization of early-stage disease. Notably, the prognostic effect of histologic transition was confined to FIGO stage I disease and was not observed in more advanced stages. This finding suggests that any biological advantage associated with endometriosis-related carcinogenesis may be most relevant during the early phases of tumor development and may become progressively overshadowed by disease burden as stage advances.\u003c/p\u003e \u003cp\u003eIn contrast, our results do not support any modification of treatment strategies in advanced-stage ovarian carcinoma based solely on the presence of endometriosis or histologic transition. In this setting, disease stage, tumor histology, and other established prognostic factors remain the primary determinants of outcome.\u003c/p\u003e \u003cp\u003eFuture multicenter studies incorporating standardized pathological assessment together with molecular and imaging-based profiling are needed to validate these findings, further characterize the relationship between endometriosis-correlated ovarian carcinoma and endometriosis-incidental ovarian carcinoma, and determine whether histologic transition can improve prognostic stratification beyond currently available clinicopathologic parameters.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur findings suggest that the prognostic relevance of endometriosis in epithelial ovarian carcinoma may depend on the presence of histologic evidence of transition to carcinoma. Ovarian carcinomas arising from endometriosis with histologic transition were associated with improved progression-free survival in FIGO stage I disease, independent of histologic subtype. In contrast, endometriosis-incidental ovarian carcinoma did not differ prognostically from non\u0026ndash;endometriosis-associated ovarian carcinoma and was not associated with a distinct clinicopathologic profile.\u003c/p\u003e \u003cp\u003eTaken together, these findings support the interpretation that endometriosis-incidental ovarian carcinoma shares clinicopathologic and prognostic characteristics more closely with non-endometriosis-associated ovarian carcinoma than with endometriosis-correlated ovarian carcinoma. Our results further highlight the importance of distinguishing histologic transition from the mere coexistence of endometriosis when evaluating endometriosis-associated ovarian carcinoma.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study was approved by the Ethics Committee of Area Vasta Emilia Centro (AVEC) (approval number \u003cstrong\u003e34/2026/Oss/AOUBo\u003c/strong\u003e). The study was conducted in accordance with the Declaration of Helsinki and applicable national regulations. Written informed consent to participate in the study and for the processing of personal data for research purposes was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.M.P. conceived the study, contributed to the study design, supervised the project, drafted and critically revised the manuscript. E.S. contributed to data analysis and interpretation, drafted the manuscript, and coordinated manuscript preparation. F.M. participated in the interpretation of the results and critically revised the manuscript. A.D.L. contributed to pathological interpretation and critically revised the manuscript. C.A.C. contributed to statistical analysis and interpretation of the data. E.M. contributed to data curation and database management. G.M., E.F., El.F., and C.R. contributed to data collection. G.R. contributed to data interpretation and critically revised the manuscript. P.D.I. supervised the study and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge Stefano Friso for his valuable support in data management and database organization.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHeidemann LN, Hartwell D, Heidemann CH, Jochumsen KM. The relation between endometriosis and ovarian carcinoma \u0026ndash; a review. Acta Obstet Gynecol Scand 2014;93:20\u0026ndash;31. https://doi.org/10.1111/aogs.12255.\u003c/li\u003e\n\u003cli\u003eJimbo H, Yoshikawa H, Onda T, Yasugi T, Sakamoto A, Taketani Y. Prevalence of ovarian endometriosis in epithelial ovarian carcinoma. International Journal of Gynecology \u0026amp; Obstetrics 1997;59:245\u0026ndash;50. https://doi.org/10.1016/S0020-7292(97)00238-5.\u003c/li\u003e\n\u003cli\u003eBizzarri N, Imterat M, Fruscio R, Giannarelli D, Perrone AM, Mancari R, et al. 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Best Pract Res Clin Obstet Gynaecol 2004;18:349\u0026ndash;71. https://doi.org/10.1016/j.bpobgyn.2003.03.001.\u003c/li\u003e\n\u003cli\u003eMezzapesa F, Dondi G, Coada CA, De Leo A, De Terlizzi F, Strigari L, et al. Two possible entities of endometriosis-associated ovarian carcinoma: correlated or incidental? International Journal of Gynecological Cancer 2025;35:101634. https://doi.org/10.1016/j.ijgc.2025.101634.\u003c/li\u003e\n\u003cli\u003eAskari E, Keshtvarz Hesam Abadi AM. ENDOMETRIOSIS-ASSOCIATED OVARIAN CARCINOMA, FROM RISK FACTORS TO SURVIVAL RATE: A SYSTEMATIC REVIEW AND META-ANALYSIS. Fertil Steril 2025;124:e42. https://doi.org/10.1016/j.fertnstert.2025.07.172.\u003c/li\u003e\n\u003cli\u003eNoli S, Cipriani S, Scarfone G, Villa A, Grossi E, Monti E, et al. Long Term Survival of Ovarian Endometriosis Associated Clear Cell and Endometrioid Ovarian carcinomas. International Journal of Gynecological Cancer 2013;23:244\u0026ndash;8. https://doi.org/10.1097/IGC.0b013e31827aa0bb.\u003c/li\u003e\n\u003cli\u003eJu UC, Kang WD, Kim SM. The effect of concurrent endometriosis on the prognosis of women with ovarian clear cell or endometrioid carcinoma. International Journal of Gynecology \u0026amp; Obstetrics 2019;146:177\u0026ndash;83. https://doi.org/10.1002/ijgo.12861.\u003c/li\u003e\n\u003cli\u003eLeone Roberti Maggiore U, Bogani G, Paolini B, Martinelli F, Chiarello G, Span\u0026ograve; Bascio L, et al. Endometriosis-associated ovarian carcinoma: a different clinical entity. International Journal of Gynecological Cancer 2024;34:863\u0026ndash;70. https://doi.org/10.1136/ijgc-2023-005139.\u003c/li\u003e\n\u003cli\u003eSugarbaker PH, Jablonski KA. Prognostic Features of 51 Colorectal and 130 Appendiceal Cancer Patients with Peritoneal Carcinomatosis Treated by Cytoreductive Surgery and Intraperitoneal Chemotherapy. Ann Surg 1995;221:124\u0026ndash;32. https://doi.org/10.1097/00000658-199502000-00002.\u003c/li\u003e\n\u003cli\u003eFagotti A, Ferrandina G, Fanfani F, Ercoli A, Lorusso D, Rossi M, et al. A Laparoscopy-Based Score To Predict Surgical Outcome in Patients With Advanced Ovarian Carcinoma: A Pilot Study. Ann Surg Oncol 2006;13:1156\u0026ndash;61. https://doi.org/10.1245/ASO.2006.08.021.\u003c/li\u003e\n\u003cli\u003eSugarbaker PH. Successful management of microscopic residual disease in large bowel cancer. Cancer Chemother Pharmacol 1999;43:S15\u0026ndash;25. https://doi.org/10.1007/s002800051093.\u003c/li\u003e\n\u003cli\u003eMutch DG, Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer. Gynecol Oncol 2014;133:401\u0026ndash;4. https://doi.org/10.1016/j.ygyno.2014.04.013.\u003c/li\u003e\n\u003cli\u003eLedermann JA, Matias-Guiu X, Amant F, Concin N, Davidson B, Fotopoulou C, et al. ESGO\u0026ndash;ESMO\u0026ndash;ESP consensus conference recommendations on ovarian carcinoma: pathology and molecular biology and early, advanced and recurrent disease. Annals of Oncology 2024;35:248\u0026ndash;66. https://doi.org/10.1016/j.annonc.2023.11.015.\u003c/li\u003e\n\u003cli\u003eNational Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines\u0026reg;): Ovarian carcinoma. Version 4.2026. Plymouth Meeting, PA: National Comprehensive Cancer Network; 2026. n.d.\u003c/li\u003e\n\u003cli\u003eSun M, Jiang W. Ovarian clear cell carcinoma with or without endometriosis origin in a single institution cohort. Discover Oncology 2023;14:39. https://doi.org/10.1007/s12672-023-00649-8.\u003c/li\u003e\n\u003cli\u003eBarnard ME, Farland L V., Yan B, Wang J, Trabert B, Doherty JA, et al. Endometriosis Typology and Ovarian carcinoma Risk. JAMA 2024;332:482. https://doi.org/10.1001/jama.2024.9210.\u003c/li\u003e\n\u003cli\u003eChiaffarino F, Cipriani S, Ricci E, Esposito G, Parazzini F, Vercellini P. Histologic Subtypes in Endometriosis-Associated Ovarian carcinoma and Ovarian carcinoma Arising in Endometriosis: A Systematic Review and Meta-Analysis. Reproductive Sciences 2024;31:1642\u0026ndash;50. https://doi.org/10.1007/s43032-024-01489-9.\u003c/li\u003e\n\u003cli\u003eCoada CA, Perrone AM, Gorini F, De Leo A, de Biase D, Mantovani G, et al. MiRNome alterations drive the malignant transformation of endometriosis into endometriosis-correlated ovarian carcinoma. Sci Rep 2025;15:41434. https://doi.org/10.1038/s41598-025-26466-3.\u003c/li\u003e\n\u003cli\u003eRavegnini G, Coadă CA, Mantovani G, De Leo A, de Biase D, Costantino A, et al. MicroRNA profiling reveals potential biomarkers for the early transformation of endometriosis towards endometriosis-correlated ovarian carcinoma. Transl Oncol 2025;55:102367. https://doi.org/10.1016/j.tranon.2025.102367.\u003c/li\u003e\n\u003cli\u003ePetousis S, Kahramanoglu I, Appenzeller-Herzog C, Angeles MA, Margioula-Siarkou C, Kacperczyk-Bartnik J, et al. PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian carcinoma. JAMA Netw Open 2025;8:e2541648. https://doi.org/10.1001/jamanetworkopen.2025.41648.\u003c/li\u003e\n\u003cli\u003eHwang S, Kim JH, Kim U, Ha HI, Park S-Y, Lim MC. Influence of Residual Disease on the Efficacy of PARP Inhibitors in Advanced Epithelial Ovarian carcinoma: A Systematic Review and Meta Analysis. Cancers (Basel) 2025;17:3365. https://doi.org/10.3390/cancers17203365.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Epithelial ovarian carcinoma, Endometriosis, Histologic transition, Incidental endometriosis, Prognosis, Early-stage disease","lastPublishedDoi":"10.21203/rs.3.rs-10176151/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-10176151/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo evaluate the clinical and prognostic significance of histologic transition from endometriosis to carcinoma in epithelial ovarian cancer and to determine whether ovarian carcinomas associated with incidental endometriosis differ from those arising from endometriosis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis retrospective single-center cohort study included 1,069 consecutive patients with epithelial ovarian cancer treated between 2014 and 2024. Patients were classified according to the presence of endometriosis and histologic evidence of transition from endometriosis to carcinoma. Progression-free survival was assessed using Kaplan\u0026ndash;Meier analysis and Cox proportional hazards models. Survival analyses were performed according to FIGO stage.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOf the 1,069 patients included, 766 had ovarian carcinoma without endometriosis, 190 had ovarian carcinoma with incidental endometriosis, and 113 had ovarian carcinoma arising from endometriosis with histologic transition. Ovarian carcinomas with incidental endometriosis showed clinicopathologic characteristics comparable to those of ovarian carcinomas without endometriosis, including stage distribution, histologic subtype, tumor grade, and survival outcomes. In contrast, tumors with histologic transition were more frequently diagnosed at an early stage and were enriched for endometrioid and clear-cell histology. A significant difference in progression-free survival was observed only in FIGO stage I disease (log-rank p\u0026thinsp;=\u0026thinsp;0.009). In multivariable analysis adjusted for histologic subtype and adjuvant treatment, ovarian carcinomas arising from endometriosis with histologic transition remained independently associated with improved progression-free survival compared with ovarian carcinomas without endometriosis (HR 0.30, 95% CI 0.10\u0026ndash;0.91; p\u0026thinsp;=\u0026thinsp;0.034), whereas ovarian carcinomas with incidental endometriosis did not differ significantly from ovarian carcinomas without endometriosis (HR 0.25, 95% CI 0.06\u0026ndash;1.10; p\u0026thinsp;=\u0026thinsp;0.066). No significant differences were observed in FIGO stage II\u0026ndash;IV disease.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe prognostic relevance of endometriosis in epithelial ovarian carcinoma appears to depend on histologic evidence of malignant transition rather than on the mere coexistence of endometriosis. Distinguishing ovarian carcinomas arising from endometriosis from those with incidental endometriosis may improve the clinicopathologic characterization of endometriosis-associated ovarian carcinoma.\u003c/p\u003e","manuscriptTitle":"Clinical and Prognostic Relevance of Histologic Transition in Endometriosis- Associated Ovarian carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-07-28 17:33:21","doi":"10.21203/rs.3.rs-10176151/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"294734115653622202380475561208547167987","date":"2026-07-30T15:30:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44419748323416827491718919475866718409","date":"2026-07-26T18:58:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146381304809546192037059605349954709158","date":"2026-07-26T14:27:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-07-26T10:16:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251707900963109541671741553808364895078","date":"2026-07-26T08:56:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332796072987815892720104410730036103207","date":"2026-07-24T10:28:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284557824868764300185472133876223627260","date":"2026-07-24T09:34:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290585028202640658107323163924852462273","date":"2026-07-24T09:22:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110445561428557351237939283870108830369","date":"2026-07-24T08:41:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-07-24T08:32:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-07-10T04:38:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-07-10T04:38:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ovarian Research","date":"2026-06-27T17:42:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"31b845d6-e271-4a0b-90c6-06c4db2b6a82","owner":[],"postedDate":"July 28th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"294734115653622202380475561208547167987","date":"2026-07-30T15:30:46+00:00","index":121,"fulltext":""},{"type":"reviewerAgreed","content":"44419748323416827491718919475866718409","date":"2026-07-26T18:58:23+00:00","index":119,"fulltext":""},{"type":"reviewerAgreed","content":"146381304809546192037059605349954709158","date":"2026-07-26T14:27:47+00:00","index":118,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-07-26T10:16:24+00:00","index":117,"fulltext":""},{"type":"reviewerAgreed","content":"251707900963109541671741553808364895078","date":"2026-07-26T08:56:17+00:00","index":115,"fulltext":""},{"type":"reviewerAgreed","content":"332796072987815892720104410730036103207","date":"2026-07-24T10:28:32+00:00","index":110,"fulltext":""},{"type":"reviewerAgreed","content":"284557824868764300185472133876223627260","date":"2026-07-24T09:34:55+00:00","index":108,"fulltext":""},{"type":"reviewerAgreed","content":"290585028202640658107323163924852462273","date":"2026-07-24T09:22:35+00:00","index":106,"fulltext":""},{"type":"reviewerAgreed","content":"110445561428557351237939283870108830369","date":"2026-07-24T08:41:00+00:00","index":104,"fulltext":""},{"type":"reviewersInvited","content":"95","date":"2026-07-24T08:32:53+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-07-28T17:33:21+00:00","versionOfRecord":[],"versionCreatedAt":"2026-07-28 17:33:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-10176151","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-10176151","identity":"rs-10176151","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}