{"paper_id":"6949e1db-3b85-4ffc-8929-bbd5025ce339","body_text":"Wang et al. BMC Cancer         (2023) 23:1210  \nhttps://doi.org/10.1186/s12885-023-11641-4\nRESEARCH\nCorrelation of clinicopathological \nand prognostic characteristics \nbetween endometriosis-associated and primary \novarian cancer\nHuimin Wang1†, Cong Chen1†, Danbo Wang1*, Yanmei Zhu2* and Peng Chen1 \nAbstract \nBackground The main aim of this study was to establish the clinicopathological and prognostic correlations \nbetween endometriosis-associated and non-endometriosis-associated primary ovarian cancer, with a view to provid-\ning a reference guide for revision of diagnostic criteria for malignant transformation of endometriosis.\nMethods Clinicopathological and follow-up data of 174 patients with clear cell and endometrial ovarian cancer \nwere retrospectively extracted. Cases were divided into endometriosis-associated and non-endometriosis-associated \nprimary ovarian cancer for comparative analysis of clinicopathological characteristics and prognosis.\nResults Average age and post-menopausal rate in the endometriosis-associated ovarian cancer group were lower \nrelative to the primary ovarian cancer group (P < 0.05). Body mass index, age at menopause, operation history, \ndysmenorrhea, complications, tumor size, tumor side, ascites, CA125, HE4, CA19.9, stage, differentiation, expression \nof ER, PR, P53, P16, Ki67, MMR, HNF-1β and Napsin A were not significantly different between the groups (P > 0.05). \nFurthermore, rates of resistance to platinum chemotherapy, relapse, progression-free survival and overall survival were \ncomparable between the two groups (P > 0.05).\nConclusion Endometriosis-associated and primary ovarian cancers of the same pathological type are speculated \nto be homologous in terms of origin from malignant transformation of endometriosis. It may therefore be necessary \nto revise the diagnostic criteria for ovarian endometriosis malignancy.\nKeywords Endometriosis-associated ovarian cancer, Ovarian clear cell carcinoma, Ovarian endometrioid carcinoma, \nDiagnostic criteria\nOpen Access\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom-\nmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBMC Cancer\n†Huimin Wang and Cong Chen are co-first authors.\n*Correspondence:\nDanbo Wang\nwangdanbo@cancerhosp-ln-cmu.com\nYanmei Zhu\nzhuyanmei1979@hotmail.com\nFull list of author information is available at the end of the article\n\nPage 2 of 11Wang et al. BMC Cancer         (2023) 23:1210 \nBackground\nEndometriosis is a common disease in women of child -\nbearing age, with an incidence of 15–20% [1]. Stud -\nies to date have shown that endometriosis has the same \nmolecular biological and genetic background as ovarian \ncancer and presents a high risk factor for ovarian cancer \ndevelopment [2]. According to the current internation -\nally recognized Sampson and Scott diagnostic criteria: \n(1) there must be a clear example of endometriosis in \nassociation with or close proximity to the cancer, (2) no \nother primary tumor site must exist and the histology of \nthe tumor should be consistent with an endometrial ori -\ngin, (3) endometriosis associated with cancers must show \nmorphologic progression from benign to malignant in a \ncontiguous fashion [3, 4], with a malignant transforma -\ntion rate of 0.5–1.0% [5]. However, due to the significant \nheterogeneity of endometriosis and atypical hyperplasia, \nhigh rates of missed pathological diagnosis are inevita -\nble and the actual incidence of malignant transformation \nof endometriosis may be higher [6, 7], which presents a \nchallenge in establishing accurate diagnostic criteria.\nThe major pathological types of endometriosis-associ -\nated ovarian cancer are endometrioid and clear cell can -\ncer, accounting for 75–90% cases [8]. However, according \nto the diagnostic criteria of Sampson and Scott, only \n50–70% ovarian clear cell and endometrioid carcinoma \ncases are diagnosed as endometriosis-associated ovarian \ncancer (EAOC). Based on the theory of external origin \nof ovarian cancer, clear cell and endometrioid carcinoma \ntypes are closely related to endometriosis, potentially \nresulting from endometriosis-associated malignancy [9]. \nOur research is focused on the malignant transforma -\ntion of endometriosis. Previous studies have reported \ncomparable abnormal expression of EAOC-related genes, \nsuch as mismatch repair gene human mutL homolog \n1 (hLMH1) and runt-related transcription factor3 \n(RUNX3), between EAOC and non-endometriosis-asso -\nciated primary ovarian cancer (non-EAOC) groups [10, \n11], giving rise to the speculation that all clear cell and \nendometrioid carcinomas of the ovary originate from \nmalignant transformation of endometriosis. Since the \npathological changes of endometriosis are heterogene -\nous, particularly after malignant transformation, tumor \ntissues grow vigorously and destroy the original tissues, \nand the histological basis of endometriosis thus remains \nunclear. Pathological sampling has a number of limita -\ntions. For instance, cancer and endometriosis lesions are \nnot obtained at the same time and concurrent endome -\ntriosis is often overlooked, resulting in a low diagnostic \nrate of malignant transformation of endometriosis using \nthe standard criteria of Sampson and Scott. Further rele -\nvant clinical and basic research is thus warranted to vali -\ndate this theory.\nMaterials and methods\nResearch objects\nIn total, 174 cases of ovarian clear cell carcinoma and \novarian endometrioid carcinoma were diagnosed and \ntreated in China Medical University Cancer Hospital \nand Affiliated Shengjing Hospital from January 2008 to \nNovember 2018. Participants were divided into EAOC \n(74 patients) and non-EAOC (100 patients) groups \naccording to the standards of Sampson and Scott, as \nfollows: (1) coexistence of cancer and endometriosis \nin the same ovary, (2) a similar histological pattern, (3) \nexclusion of secondary tumors metastatic to the ovary, \nand (4) histopathological evidence demonstrating the \ntransition from benign endometriosis to malignancy. \nPatients that met the above criteria were classified \nas EAOC and the remaining patients as non-EAOC. \nAccording to the different pathological types, endome -\ntriosis-associated ovarian clear cell carcinoma (EOCC) \nand endometriosis-associated ovarian endometrioid \ncarcinoma (EOEC) groups were further defined. Non-\nendometrium-related primary ovarian cancer was \nfurther grouped into clear cell carcinoma (OCC) and \nendometrioid carcinoma (OEC) groups. Our patient \npopulation included 39 EOCC, 35 EOECC, 35 OCC \nand 65 OECC cases. Samples were fully encoded to \nprotect patient confidentiality.\nInclusion criteria were as follows: (1) definitive patho -\nlogical diagnosis, limited to clear cell carcinoma and \nendometrioid carcinoma, (2) complete case data, and \n(3) completion of the initial treatment plan (surgery and \nchemotherapy). Exclusion criteria were as follows: (1) the \npresence of other histological types of ovarian malignan -\ncies and borderline tumors of non-clear cell carcinoma \nand endometrioid carcinoma, (2) other primary malig -\nnant tumors, and (3) metastatic ovarian cancer. Sam -\nples of the selected cases were re-assessed by the same \ngynecological pathologist to further confirm diagnosis.\nData collection\nClinicopathological data of all patients were collected. \nClinical parameters included age, body mass index \n(BMI), dysmenorrhea or not, menopausal status, age of \nmenopause, endometriosis history, operation or not (for \ninstance, cesarean section, hysterectomy, endometriosis), \ncomplications (for instance, diabetes, heart disease, high \nblood pressure), related serum tumor markers (CA125, \nCA19.9, HE4), type of surgery (complete, suboptimal, \nand optimal), and endometriosis lesions during surgery. \nPathological parameters included tumor size, tumor \nside, ascites, FIGO stage, histological classification, and \nimmunohistochemical results (ER, PR, P53, P16, Ki67, \nMMR, HNF-1, Napsin A).\n\nPage 3 of 11\nWang et al. BMC Cancer         (2023) 23:1210 \n \nTreatments\nAll the included patients received standard surgi -\ncal treatment. Patients in the early stage (FIGO I-II) \nreceived comprehensive staging surgery while those in \nthe advanced stage (FIGO III-IV) received tumor cell \nreduction surgery. Postoperative chemotherapy regi -\nmens containing platinum were adopted according to \ninternational guidelines as follows: paclitaxel and car -\nboplatin (TC regimen), docetaxel and carboplatin (DC \nregimen), 6–8 cycles of chemotherapy, with an interval \nof 21 days.\nFollow‑up\nAll cases were followed up until the end of recurrence, \ndeath or the end of follow-up (up to 31/3/2019). The \nfollow-up time was 6-132 months, with median of 67 \nmonths. Cases requiring reoperation to obtain histo -\npathological and/or imaging evidence of new develop -\nments and/or continued abnormal elevation of tumor \nmarkers were considered tumor recurrence.\nStatistical analysis\nData were analyzed using SPSS 25.0 software. Enu -\nmeration data are expressed in terms of rates and \nmeasurement data as mean ± standard deviation (± sd). \nStudent’s T test was used for comparison between \ngroups. The enumeration data were compared using the \nChi-square test and Fisher’s exact test. Survival analysis \nwas performed using Kaplan-Meier curves and differ -\nences were assessed with the log-rank test. Differences \nwere considered significant at P  < 0.05.\nResults\nGeneral data analysis\nAnalysis of epidemiological data revealed a lower aver -\nage age and proportion of menopause of patients in the \nEAOC than non-EAOC group (P  < 0.05). No significant \ndifferences in BMI, dysmenorrhea history, menopausal \nage, endometriosis history, operation history, and com -\nplications were observed between the two groups (all \nP > 0.05), as shown in Table 1 .\nFurther intra-group and inter-group analyses of the \nsame pathological types showed a significantly lower \naverage age of onset and proportion of menopause in \nthe EOCC than OCC group (P  < 0.05). We observed \nno marked differences in the remaining parameters \nbetween the groups (P  > 0.05; Table 2).\nAnalysis of clinical features\nNo significant differences were evident between the two \ngroups in terms of tumor size, tumor side, ascites, type \nof surgery, CA125, HE4 and CA19.9 levels (all P  > 0.05). \nThe collective data are presented in Table 3 .\nFurther intra-group and inter-group analyses dis -\nclosed significantly higher incidence of bilateral tumors \nin the EOEC than EOCC group (40.0% vs. 17.9%, \nP < 0.05). Moreover, the HE4 level in the EOEC group \nwas higher than that in the EOCC group to a significant \nextent (355.4 vs. 89.4 pmol/L, P  < 0.05). No significant \ndifferences were found in the remaining parameters, \nincluding tumor size, tumor side, ascites and type of \nsurgery (Table 4).\nPathological characteristics\nPathological characteristics were comparable between \nthe two groups in terms of FIGO stage, differentiation \ndegree, ER, PR, P53, P16, Ki67, MMR, HNF-1, and Nap -\nsin A-positive expression (all P > 0.05; Table 5; Fig. 1).\nThe rates of ER and PR positivity in the EOEC group \nwere significantly higher than those in the EOCC group \n(71.4% vs. 17.9%, 60.0% vs. 7.7%; P < 0.05). Conversely, \nthe rates of HNF-1 and Napsin A positivity in the EOCC \ngroup were markedly higher relative to the EOEC group \n(28.2% vs. 20.0%, 30.8% vs. 7.7%; P < 0.05).\nHNF-1- and Napsin A-positive rates in the OCC group \nwere significantly higher than those in the OEC group \n(74.2% vs. 16.9%, 80.0% vs. 4.6%; P < 0.05), as shown in \nTable 6.\nTable 1 Comparative analysis of the epidemiological data of \nEAOC and non-EAOC patients (n, x ± s)\nCharacteristics EAOC Non‑EAOC P\n74 100\nAge(year) 49.4 ± 7.7 54.0 ± 10.0 0.001\nBMI 23.6 ± 3.3 23.5 ± 3.7 0.731\nHistory of dysmenorrhea 0.064\n Yes 29 26\n No 55 74\nMenopausal status 0.001\n Yes 32 68\n No 42 32\nAge of menopause 49.1 ± 4.3 49.3 ± 3.9 0.815\nEndometriosis history 0.980\n Yes 11 15\n No 63 85\nHistory of surgery 0.115\n Yes 19 16\n Caesarean section 11 6\n Hysterectomy 4 7\n Endometriosis 4 3\n No 65 84\nComplications 0.683\n Yes 31 45\n No 43 55\n\nPage 4 of 11Wang et al. BMC Cancer         (2023) 23:1210 \nPrognostic characteristics\nOverall, 74 patients in the EAOC group were subjected \nto initial analyses, 64 of whom were followed up (follow-\nup rate of 86.5%). Rates of platinum therapy resistance, \nrecurrence and mortality were determined as 6.25%, \n39.1%, and 28.1%, respectively. Among the 100 patients in \nthe non-EAOC group, 85 were followed up (85.0%). The \nplatinum resistance rate was determined as 9.41%, recur -\nrence rate as 54.1%, and mortality rate as 40.0%, which \nwere not significantly different between the two groups \n(all P > 0.05; Table 7).\nKaplan-Meier analysis and log-rank test showed that \nthe average overall survival (OS) of the EAOC group was \n91.6 months (95% CI: 76.9–106.5 months) while that of \nthe non-EAOC group was 77.8 months (95% CI: 66.1–\n90.0 months), with no significant differences (P = 0.068, \n> 0.05). The median progression-free survival (PFS) of \nthe EAOC group was 78.4 months (95% CI: 62.2–94.5 \nmonths), which was not significantly different from \nthe non-EAOC group (64.0 months; 95% CI: 50.7–77.1 \nmonths) (P = 0.216, > 0.05), as shown in Fig. 2.\nIntra-group and inter-group analyses of the same \npathological types via Kaplan-Meier and log-rank tests \nTable 2 Intra-group and inter-group analyses of EAOC and non-EAOC patients (n, x ± s)\na :EOEC vs. EOCC, b:EOEC vs. OEC, c:EOCC vs. OCC\nCharacteristics EOEC EOCC OEC OCC P\n35 39 65 35\nAge(year) 50.6 ± 8.4 48.2 ± 6.7 54.3 ± 10.7 53.3 ± 8.6 0.177a/0.060b/<0.01c\nBMI 23.9 ± 2.9 23.3 ± 3.6 23.7 ± 3.8 22.8 ± 3.1 0.430a/0.782b/0.570c\nHistory of dysmenorrhea 0.076a/0.667b/0.075c\n Yes 10 19 16 10\n No 25 20 49 25\nPostmenopausal status 0.178a/0.199b/<0.01c\n Yes 18 14 42 26\n No 17 25 23 9\nAge of menopause 48.8 ± 4.7 49.2 ± 3.8 49.9 ± 4.1 48.2 ± 3.2 0.802a/0.408b/0.363c\nEndometriosis history 0.894a/0.883b/0.894c\n Yes 5 6 10 5\n No 30 33 55 30\nHistory of surgery 0.599a/0.106b/0.810c\n Yes 8 11 7 9\n Caesarean section 3 8 2 4 0.149a/0.340b/0.290c\n Hysterectomy 3 1 3 4 0.339a/0.420b/0.183c\n Endometriosis 2 2 2 1 0.911a/0.610b/0.475c\n No 27 28 58 26\nComplications 0.528a/0.916b/0.892c\n Yes 16 15 29 14\n No 19 24 36 21\nTable 3 Comparative analysis of clinical features of EAOC and \nnon-EAOC patients (n, x ± s)\nR0: no residual lesions; R1: residual lesions < 1 cm; R2: residual lesions > 1 cm\nCharacteristics EAOC Non‑EAOC P\n74 100\nAscites 0.666\n Yes 39 56\n No 35 44\nTumor size 0.769\n ≥ 10 cm 45 63\n <10 cm 29 37\nTumor side 0.355\n Unilateral 53 65\n Bilateral 21 35\nType of surgery 0.804\n R0 66 87\n R1 9 10\n R2 2 3\nBiomaker\n CA125(U/ml) 448.9 ± 980.0 739.8 ± 1141.4 0.080\n HE4(pmol/L) 203.4 ± 240.0 264.5 ± 217.5 0.620\n CA19.9(U/ml) 194.0 ± 460.4 274.2 ± 546.7 0.465\n\nPage 5 of 11\nWang et al. BMC Cancer         (2023) 23:1210 \n \nshowed that OS of the EOCC group was 90.8 months \n(95% CI, 69.9–111.8 months), EOEC group was 96.8 \nmonths (95% CI, 76.8–116.8 months), OCC group was \n77.4 months (95% CI, 51.49–103.30 months), and OEC \ngroup was 81.10 months (95% CI, 68.0–94.2 months). \nWe observed no significant differences in OS in EOCC \nvs. EOEC, EOCC vs. OCC, and EOEC vs. OEC groups \n(P = 0.290, 0.262, 0.070, all P > 0.05). PFS of patients in \nthe EOCC group was 80.9 months (95% CI, 61.2–100.6 \nmonths), EOEC group was 82.3 months (95% CI, 59.4–\n105.2 months), OCC group was 85.9 months (95% CI, \n68.4–108.3 months), and OEC group was 60.0 months \n(95% CI, 45.50–74.6 months). We observed no significant \ndifferences in PFS in EOCC vs. EOEC, EOCC vs. OCC, \nand EOEC vs. OEC groups (P = 0.222, 0.675, 0.071, all \nP > 0.05; Fig. 3).\nDiscussion\nSeveral recent studies have highlighted a significantly \nincreased risk of ovarian cancer in endometriosis \npatients [12]. As a precancerous lesion, endometriosis is \nclosely related to ovarian clear cell and endometrioid car-\ncinomas. The theory of external origin of ovarian cancer \nhypothesizes that both clear cell and endometrioid car -\ncinoma of the ovary originate from malignant transfor -\nmation of endometriosis, which poses a challenge to the \ncurrent diagnostic criteria for endometriosis-associated \nmalignant transformation. However, further clinical and \nbasic research evidence is needed to substantiate this \ntheory. In the current study, the two ovarian cancer types \n(clear cell and endometrioid carcinomas) most closely \nassociated with endometriosis were examined as a whole. \nAccording to the diagnostic criteria of Sampson and \nTable 4 Intra-group and inter-group clinical features analyses of EAOC and non-EAOC patients (n, x ± s)\na :EOEC vs. EOCC, b:EOEC vs. OEC, c:EOCC vs. OCC.\nR0: no residual lesions; R1: residual lesions < 1 cm; R2: residual lesions > 1 cm\nCharacteristics EOEC EOCC OEC OCC P\n35 39 65 35\nAscites 0.469a/0.295b/0.209c\n Yes 20 19 44 12\n No 15 20 21 23\nTumor size 0.892a/0.881b/0.363c\n ≥ 10 cm 21 24 38 25\n <10 cm 14 15 27 10\nTumor side 0.036a/0.303b/0.316c\n Unilateral 21 32 33 32\n Bilateral 14 7 32 3\nType of surgery 0.894a/0.883b/0.590c\n R0 30 33 55 32\n R1 3 6 8 2\n R2 2 0 2 1\nBiomaker\n CA125(U/ml) 618.0 ± 1309.8 297.0 ± 509.6 870.3 ± 895.0 493.7 ± 1479.0 0.161a/0.255b/0.437c\n HE4(pmol/L) 355.4 ± 319.5 89.4 ± 69.1 498.9 ± 547.0 132.7 ± 259.0 0.039a/0.575b/0.651c\n CA19.9(U/ml) 248.1 ± 525.4 160.6 ± 423.0 276.9 ± 586.0 220.5 ± 547.0 0.556a/0.877b/0.663c\nTable 5 Comparative analysis of pathological characteristics of \nEAOC and non-EAOC patients(n, %)\nCharacteristics EAOC Non‑EAOC P\n74 100\nFIGO stage 0.417\n I/II 51 63\n III/IV 23 37\nDifferentiation 0.932\n Low 18 21\n Middle 34 52\n High 22 27\nBiomarker\n ER(+) 32 52 0.253\n PR(+) 24 45 0.094\n P53(+) 59 68 0.085\n P16(+) 41 54 0.854\n MMR(-) 19 37 0.114\n Ki67(%) 30.0 ± 18.0 30.8 ± 18.94 0.767\n Napsin A(+) 18 37 0.075\n HNF-1β(+) 15 31 0.113\n\nPage 6 of 11Wang et al. BMC Cancer         (2023) 23:1210 \nFig. 1 IHC expression of related molecules in ovarian tissues (SP 200X). a ER-positive; b ER-negative; c PR-positive; d PR-negative; e P53-positive; \nf P53-negative; g P16-positive; h P16-negative; i. Ki67-positive; j MLH1-positive; k MLH1-negative; l. MSH2-positive; m MSH2-negative; \nn MSH6-positive; o MSH6-negative; p PMS2-positive; q PMS2-negative; r HNF-1β-positive; s HNF-1β-negative; t Napsin A-positive; u Napsin \nA-negative\n\nPage 7 of 11\nWang et al. BMC Cancer         (2023) 23:1210 \n \nScott, samples were divided into EAOC and non-EAOC \ngroups for comparison of clinicopathologic features and \nprognosis. Our results showed no significant differences \nbetween the groups, supporting the theory that both \nnon-endometriosis-associated primary ovarian endome -\ntrial carcinoma and ovarian clear cell carcinoma poten -\ntially have the same origin as EAOC from endometriosis.\nWe retrospectively analyzed the clinical features of \n174 patients from EAOC and non-EAOC groups. The \naverage age and proportion of menopausal patients in \nTable 6 Intra-group and inter-group pathological characteristics of EAOC and non-EAOC patients(n, %)\na :EOEC vs. EOCC, b:EOEC vs. OEC, c:EOCC vs. OCC\nCharacteristics EOEC EOCC OEC OCC P\n35 39 65 35\nFIGO stage\n I/II 21 30 37 26 0.116a/0.767b/0.792c\n III/IV 14 9 28 9\nDifferentiation\n Low 11 7 18 3 0.177a/0.695b/0.239c\n Middle 17 17 40 12\n High 7 15 7 20\nBiomarker\n ER(+) 25 7 49 3 < 0.01a/0.667b/0.311c\n PR(+) 21 3 40 5 < 0.01a/0.880b/0.635c\n P53(+) 29 30 43 25 0.526a/0.076b/0.589c\n P16(+) 16 25 32 22 0.112a/0.710b/0.912c\n MMR(-) 8 11 22 15 0.072a/0.548b/0.291c\n Ki67(%) 29.1 ± 20 30.7 ± 14 29.6 ± 19 33.0 ± 16.5 0.718a/0.907b/0.564c\n Napsin A(+) 7 11 11 26 < 0.01a/0.459b/0.230c\n HNF-1β(+) 3 12 3 28 < 0.01a/0.317b/0.273c\nTable 7 Prognosis comparison between EAOC and non-EAOC \npatients(n)\nCharacteristics EAOC non‑EAOC P\n74 100\nPlatinum resistance 4 8 0.483\nRelapse 25 39 0.405\nDeath 19 34 0.193\nFig. 2 Differences in OS and PFS between EAOC and non-EAOC patients. a OS; b PFS\n\nPage 8 of 11Wang et al. BMC Cancer         (2023) 23:1210 \nthe EAOC group was lower relative to the non-EAOC \ngroup (P < 0.05). These differences may be attributed to \na potential decrease in postmenopausal hormone levels, \ngradual atrophic degradation of ectopic endometrium \n[13], limitations of pathological materials, and errors due \nto insufficient pathological evidence of endometriosis. \nFurther experiments on larger sample sizes are required \nto confirm these findings. No significant differences \nwere evident in BMI, dysmenorrhea history, endome -\ntriosis history, operation history, complications, ascites, \ntumor size, type of surgery and relevant serum tumor \nmarkers (CA125, HE4, CA19.9) between the two groups \nFig. 3 Differences in OS and PFS of EOCC vs. EOEC, EOCC vs. OCC and EOEC vs. OEC groups. a OS-EOCC vs. EOEC; b OS- EOCC vs. OCC; c OS- EOEC vs. \nOEC; d PFS- EOCC vs. EOEC; e PFS- EOCC vs. OCC; f PFS- EOEC vs. OEC\n\nPage 9 of 11\nWang et al. BMC Cancer         (2023) 23:1210 \n \n(all P > 0.05), consistent with earlier results. Our experi -\nments support similar characteristics of endometrio -\nsis- and non-endometriosis-associated primary ovarian \ncancers. Furthermore, upon stratified analysis according \nto pathological type into EOCC and EOEC, OCC and \nOEC groups, relevant epidemiological and clinical char -\nacteristics, such as BMI, dysmenorrhea history, endome -\ntriosis history, history of surgery, complications, ascites, \ntumor size, type of surgery and serum tumor marker \n(CA125, HE4, CA19.9) levels, were not significantly dif -\nferent (P > 0.05). Our findings present further evidence \nthat primary ovarian endometrial carcinoma and clear \ncell carcinoma are associated with corresponding patho -\nlogical types in endometriosis-associated ovarian cancer \nwith similar clinical features. These results provide pre -\nliminary confirmation that the two groups have compa -\nrable epidemiological and clinical characteristics and the \nage difference is potentially attributed to strict diagnostic \ncriteria.\nHistopathological evaluation is currently the gold \nstandard of ovarian cancer diagnosis and classification. \nImmunohistochemical analysis revealed high expression \nof ER and PR in endometrioid carcinoma of ovary and \nlow expression in clear cell carcinoma [14]. Compared \nwith other epithelial ovarian cancer types, increased \nHNF-1β, high expression of Napsin A and positivity for \nP53 were characteristic features of ovarian clear cell car -\ncinoma [15]. MMR expression in both ovarian endome -\ntrial and clear cell carcinoma types is abnormally high \nrelative to that in other subtypes of ovarian cancer [16]. \nThe above molecules may therefore serve as useful bio -\nmarkers to distinguish epithelial ovarian cancer subtypes. \nKi-67 is currently used as a positive nuclear proliferation \nmarker and its expression reflects the biological behavior \nof tumor cells [17]. For analysis of differences, similari -\nties and potential mechanisms of EAOC and non-EAOC, \nwe compared the pathologies of the two groups. Our data \nshowed no histological differences in terms of pathologic \ndifferentiation degree, ER, PR, P53, and P16, Ki67, MMR, \nHNF-1β and Napsin A-positive expression (P > 0.05) \nbetween EAOC and non-EAOC. The majority of previ -\nous reports have investigated the malignant transforma -\ntion of endometriosis, with limited studies focusing on \nthe characteristics of different pathological types of endo-\nmetrial carcinoma and clear cell carcinoma. However, a \nnumber of differences in clinicopathological characteris -\ntics exist between endometrioid and clear cell carcinoma \ntypes. Further grouping analysis revealed no significant \ndifferences in expression of relevant non-specific indi -\ncators, such as P53, P16, Ki67 and MMR, among the \ngroups. The positive expression rates of ER and PR were \nmarkedly different between endometrioid carcinoma and \nclear cell carcinoma groups, but not from the primary \novarian carcinoma of the same pathologic type. Differen -\ntiation of endometriosis into two tissue types is reported \nto occur in a dual mode regulated by sex hormones [18, \n19]: (1) estrogen and progesterone receptor-positive \nendometriosis lesions undergo malignant transformation \nto form hormone-dependent endometrioid carcinoma \nafter long-term stimulation without antagonistic estro -\ngen and (2) atrophic ectopic endometrial lesions negative \nfor estrogen and progesterone receptors are stimulated \nby oxidative stress for a long period of time, resulting \nin malignant transformation and formation of non-hor -\nmone-dependent clear cell carcinoma. Our results were \nconsistent with earlier literature, validating that clear \ncell carcinoma is a non-hormone-dependent tumor. The \npositive expression rates for HNF-1β and Napsin A were \nsignificantly higher in clear cell carcinoma than endome -\ntrioid carcinoma. Accordingly, we concluded that differ -\nent histological types undergo distinct mechanisms for \ndevelopment of endometriosis-associated ovarian can -\ncer, which will be the focus of follow-up investigations. \nThe above results further confirm similar expression of \npathology-related molecular indicators in EAOC and \nnon-EAOC with the same pathological subtype. Moreo -\nver, the differences in molecular expression indicated by \nthe results of stratified analysis based on pathological \nsubtype may be related to the pathogenesis of the differ -\nent types.\nThe majority of previous studies focused on comparing \nclinicopathological and prognostic differences between \nintrauterine endometriosis-associated ovarian cancers of \na single pathologic type. However, sample sizes in earlier \nreports were usually small and the results obtained were \ninconsistent. Some studies suggest that ovarian endome -\ntrial carcinoma and clear cell carcinoma are early phases \nwith better prognosis than the two pathological types of \nprimary ovarian cancer [20, 21], while other researchers \nreport no obvious differences [22, 23]. Here, we exam -\nined 174 cases of ovarian endometrial carcinoma and \nclear cell carcinoma, with a median follow-up period of \n67 months. Our data showed no significant differences \nbetween platinum resistance, recurrence and mortal -\nity rates between the EAOC and non-EAOC groups \n(P > 0.05). PFS and OS were comparable between the \ntwo groups (P  > 0.05), supporting similar prognosis. In \n2020, Hermens et al. [24] analyzed 32,419 patients with \novarian cancer and found synchronous endometriosis of \novarian cancer staging of early, higher progression-free \nsurvival and overall survival is longer, perhaps because \nof more frequent hospital visits of patients with endome -\ntriosis due to simultaneous treatment with the appropri -\nate drugs and long-term state of endometriosis-induced \ninflammation, which activates immune function, in turn, \nfacilitating early detection and better prognosis, giving \n\nPage 10 of 11Wang et al. BMC Cancer         (2023) 23:1210 \nrise to the theory that ovarian cancer with endometriosis \nmay have different pathophysiological features relative \nto other ovarian cancer types. Earlier studies have estab -\nlished a low early incidence of epithelial ovarian cancer. \nIn this research, the early incidence rates of EAOC and \nnon-EAOC were 68.9% and 63.0%, respectively, which \nwere significantly higher than the average early inci -\ndence of ovarian cancer (30.0%). Overall survival rates \nof the EAOC and non-EAOC groups were 71.9% and \n60.0%, which were markedly higher than the average \nfive-year survival rate of ovarian epithelial carcinoma \n(44- 50%) [25]. Considerable evidence suggests that \novarian clear cell carcinoma and endometrioid carci -\nnoma are sources of malignant transformation of endo -\nmetriosis and can therefore be detected earlier. However, \naccelerated growth of tumor tissue destroys the tissue of \norigin owing to malignant transformation. Pathological \nsampling cannot remove cancer and ectopic foci lesions \nat the same time. Consequently, a proportion of clear cell \nand endometrioid carcinomas of the ovary are not diag -\nnosed as endometriosis-associated ovarian cancer. Our \nresults indicate similar rates of recurrence and survival \nin EAOC and non-EAOC groups.\nIn summary, this study found no significant differ -\nences in epidemiological or pathological features and \ncomparable prognosis between endometriosis- and \nnon-endometriosis-associated ovarian cancer diag -\nnosed according to the Sampson and Scott criteria, \nleading to the speculation that primary ovarian endo -\nmetrial and clear cell carcinomas have the same origin \nas EAOC. Our findings support the theory of dualism \nof ovarian cancer suggesting that both endometrial \ncarcinoma and clear cell carcinoma originate from \nprogression of endometriosis. Based on our findings, \nwe propose that the Sampson and Scott diagnostic \ncriteria for endometriosis malignancy are too strict \nand the actual incidence of malignant transformation \nof endometriosis may be higher. Therefore, it is worth \nexploring whether the stringent diagnostic criteria for \nmalignant transformation of endometriosis require fur -\nther revision. In view of the collective data, the diag -\nnostic criteria for endometriosis malignancy could \ninclude the following guidelines: (1) no other primary \ntumor site must exist, (2) the histology of the tumor \nshould be consistent with an endometrial origin, and \nexclude: there must be a clear example of endometrio -\nsis in association with or close proximity to the cancer \nand endometriosis associated with cancers must show \nmorphologic progression from benign to malignant in a \ncontiguous manner.\nThe retrospective nature of this study is a major limi -\ntation. Moreover, the results represent single-center \ndata and the number of included cases is relatively low. \nFurther large-scale, prospective multicenter clinical \nand molecular biology studies are therefore required to \nvalidate the associations of malignant transformation \nof endometriosis with ovarian clear cell and endome -\ntrial carcinomas, which should aid in clarification of the \nunderlying biological mechanisms and development of \nindividualized treatments for patients with endometri -\nosis-associated ovarian cancer.\nAbbreviations\nEAOC  Endometriosis-associated ovarian cancer\nnon-EAOC  Non-endometriosis-associated primary ovarian cancer\nEOCC  Endometriosis associated ovarian clear cell carcinoma\nEOEC  Endometriosis associated ovarian endometrioid carcinoma\nOCC  Clear cell carcinoma\nOEC  Endometrioid carcinoma\nBMI  Gody Mass Index\nOS  Overall survival\nPFS  Progression-free survival\nAcknowledgements\nNot applicable.\nAuthors’ contributions\nHW and CC carried out most parts of the experiment; YZ participated in \nthe experiment; DW participated in the design of the study; HW, CC and PC \nperformed the statistical analysis. All authors read and approved the final \nmanuscript.\nFunding\nThis work was supported by grants from The National Natural Science Founda-\ntion of China (Grant Number 81771556) and the Natural Fund of Liaoning \nProvince (2020-ZLLH-36).\nAvailability of data and materials\nThe datasets generated and/or analyzed in the current study are not publicly \navailable due to the data also forming part of an ongoing study, but can be \nmade available by the corresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nSamples were fully encoded to protect patient confidentiality. All methods \nwere carried out in accordance with the relevant guidelines and regulations. \nDue to the retrospective nature of this study and preserved anonymity of \npatients, a waiver of informed consent was obtained from the Research Ethics \ncommittees of Liaoning Cancer Hospital & Institute. The study and associated \nprotocols were approved by the Research Ethics committees of Liaoning \nCancer Hospital & Institute (2020G0322).\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAuthor details\n1 Department of Gynecology, Liaoning Cancer Hospital & Institute, 44 Xiao-\nheyan Road, Dadong District, Shenyang, Liaoning 110004, China. 2 Department \nof Pathology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China. \nReceived: 23 April 2023   Accepted: 14 November 2023\n\n\nPage 11 of 11\nWang et al. BMC Cancer         (2023) 23:1210 \n \n•\n \nfast, convenient online submission\n •\n  \nthorough peer review by experienced researchers in your field\n• \n \nrapid publication on acceptance\n• \n \nsupport for research data, including large and complex data types\n•\n  \ngold Open Access which fosters wider collaboration and increased citations \n \nmaximum visibility for your research: over 100M website views per year •\n  At BMC, research is always in progress.\nLearn more biomedcentral.com/submissions\nReady to submit y our researc hReady to submit y our researc h  ?  Choose BMC and benefit fr om: ?  Choose BMC and benefit fr om: \nReferences\n 1. Giudice LC. Endometriosis. N Engl J Med. 2010;362:2389–98.\n 2. Erzen M, Rakar S, Klancnik B, Syrjänen K. Endometriosis-associated ovarian \ncarcinoma (EAOC): an entity distinct from other ovarian carcinomas as \nsuggested by a nested case-control study. Gynecol Oncol. 2001;83:100–8.\n 3. Sampson J. 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