{"paper_id":"2adb8701-1af5-402c-8a3f-895f6a17a73f","body_text":"Vol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nDiscover Oncology\nResearch\nOvarian clear cell carcinoma with or without endometriosis origin \nin a single institution cohort\nMingming Sun1,2 · Wei Jiang1,2\nReceived: 14 February 2023 / Accepted: 30 March 2023\n© The Author(s) 2023  OPEN\nAbstract\nBackground As ovarian clear cell carcinoma (OCCC) has distinct clinical features, biology, genetic characteristics and \nmechanisms of pathogenesis, and whether the origin of endometriosis or not affects the prognosis of OCCC remains \ncontroversial.\nMethods We retrospectively collected medical records and follow-up data of patients with OCCC treated at the Obstetrics \nand Gynecology Hospital of Fudan University from January 2009 to December 2019. Further, we divided patients into \n2 groups. Group 1: non-endometriosis origin; Group 2: endometriosis origin. Clinicopathological characteristics and \nsurvival outcomes were compared between the 2 groups.\nResults A total of one hundred and twenty-five patients with ovarian clear cell carcinoma were identified and included. \nIn the overall patients’ population, the 5 year overall survival was 84.8%, the mean overall survival was 85.9 months. The \nresults of the stratified analysis showed that early stage (FIGO stage I/II) OCCC had a good prognosis. The results of uni-\nvariate analyses indicated that a statistically significant relationship between overall survival (OS) and FIGO stage, lymph \nnode metastasis, peritoneum metastasis, chemotherapy administration methods, Chinese herbal treatment, molecular \ntarget therapy. As for progression-free survival (PFS), a significant relationship between PFS and child-bearing history, \nlargest residual tumor size, FIGO stage, tumor maximum diameter, lymph node metastasis was found, respectively. FIGO \nstage and lymph node metastasis are common poor prognostic factors affecting OS and PFS. The multivariate regression \nanalysis revealed that FIGO stage (p  = 0.028; HR, 1.944; 95% CI 1.073–3.52) and treatment by Chinese herbs (p = 0.018; \nHR, 0.141; 95% CI 0.028–0.716) were identified as influencing factors with regard to survival. The presence or absence of \nlymphadenectomy did not affect OS of 125 OCCC patients (p = 0.851; HR, 0.825; 95% CI 0.111–6.153).\nThere was a trend towards a better prognosis for patients with OCCC of endometriosis origin than those with OCCC of \nnon-endometriosis origin (p = 0.062; HR, 0.432; 95% CI 0.179–1.045). The two groups differed with respect to several \nclinicopathological factors. And the proportion of patients with disease relapse was higher in Group 1 (46.9%) than in \nGroup 2 (25.0%), with a statistically significant difference (p = 0.048).\nConclusions Surgical staging and treatment by Chinese herbs postoperatively are two independent prognostic factors \naffecting the OS of OCCC, early detection and Chinese herbal medicine combined with chemotherapy postoperatively \nmay be a good choice. Tumor with endometriosis-origin was found less likely to relapse. While the non-necessity of lym-\nphadenectomy in advanced ovarian cancer has been proven, the need for lymphadenectomy in the early stage ovarian \ncancer, including early stage OCCC, still deserved to be explored.\n * Wei Jiang, jw52317@126.com | 1Department Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, \nShanghai 200011, People’s Republic of China. 2Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, \nPeople’s Republic of China.\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nKeywords Ovarian clear cell carcinoma (OCCC) · Endometriosis-origin · Clinical characteristics · Overall survival (OS) · \nProgression-free survival (PFS) · Lymphadenectomy\nAbbrevations\nOCCC   Ovarian clear cell carcinoma\nFIGO  The International Federation of Obstetrics and Gynecology\nOS  Overall survival\nPFS  Progression-free survival\nEOCs  Epithelial ovarian cancers\nHGSOC  High-grade serous ovarian cancer\nWHO  World Health Organization\nCNV  Copy number variation\nPD-L1  Programmed cell death-ligand 1\nBMI  Body mass index\nMRI  Magnetic resonance imaging\nPET-CT  Positron emission tomography-computed tomography\nCA-125  Carbohydrate antigen 125\nSPSS  Statistical Program for Social Sciences\nHR  Hazard ratio\nCI  Confidence interval\nOB/GYN  Obstetrics and gynecology\nPARP  Poly(ADP-ribose) polymerase\n1 Introduction\nEpithelial ovarian cancers (EOCs) is one of the most common gynecologic malignancies with a high mortality rate. \nBRCA1/2 germline mutations are the strongest known genetic risk factors for EOCs and are found in 6–15% of women \nwith EOC. The BRCA1/2 status can be used for patients’ counselling regarding expected survival, as BRCA1/2 carriers \nwith EOC respond better than non-carriers to platinum-based chemotherapies. This yields greater survival, even though \nthe disease is generally diagnosed at a later stage and higher grade [1 ]. EOCs are classified into type I and type II [2 ]; Of \nthese, ovarian clear cell carcinoma (OCCC), endometrioid ovarian carcinoma, mucinous ovarian carcinoma and low-grade \nserous ovarian carcinoma are classified as type I, while type II is represented by high-grade serous ovarian cancer (HGSOC) \n[3]. The tumor that is currently classified as ovarian clear cell carcinoma was most likely originally described in 1899 by \nPeham as “hypernephroma of the ovary” , based on the striking similarity of the reported case to renal clear cell carcinoma \n[4]. Scully and Barlow’s seminal report [5] was also significant to detail a strong association between endometriosis and \nOCCC, and introduce the term clear cell carcinoma for these tumor. In 1973, ovarian clear cell carcinoma was included \nin the World Health Organization (WHO) classification of ovarian tumors [6 ].\nOvarian clear cell carcinoma (OCCC) is the second most common histological subtype, accounting for 5–25% of all \nEOCs [7, 8]. The prevalence of OCCC is largely region and ethnicity specific, it accounts for approximately 10% of EOCs \nin Europe and the United States with a higher incidence of about 10%-25% in Asian populations [9 –11]. Compared to \nHGSOC, the most common type of EOC, OCCC has a younger onset, is more likely to be diagnosed in the early stage, is \nclosely associated with endometriosis, and is characterized microscopically by a typical glycogen-filled clear cytoplasm \nand the presence of hobnail cells with a typical immunohistochemical phenotype [12– 15]. OCCC has a unique genetic \nprofile with a lower p53 mutation rate (25%) and a lower BRCA1/2 mutation rate (6.3%) but higher mutation rates in \nARID1A, PIK3CA and PTEN compared to HGSOC [ 16–20]. Since inflammatory and epigenetic processes seem to play a \npredominant role in the pathogenesis of OCCC, immune checkpoint inhibitors and targeting the PI3K pathway as well \nas epigenetic treatment approaches may play an important role in the treatment of these tumor entities [21]. Current \ntreatment recommendation for OCCC is based on data collected from cohort studies based on HGSOC, and surgery \ncombined with postoperative platinum-based chemotherapy is the recommended option [22]. Moreover, we noticed \nthat when mutations occur within DNA repair pathways, there is an increased risk of chemotherapy resistance. Given \nthat a significant proportion of OCCC shows homologous recombination deficiency, they should be susceptible to PARP \ninhibitor therapy. Among PARP inhibitors, olaparib, rucaparib, and niraparib have been approved by the FDA and/or the \n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nEMA in EOC in different settings. Olaparib, rucaparib, and niraparib trap PARP approximately 100-fold more efficiently \nthan veliparib [23]. Early stage OCCC has a better prognosis, while advanced/recurrent patients have a poor prognosis, \nwhich is related to their insensitivity to chemotherapy and chemoresistance [24, 25].\nMore and more studies have confirmed that OCCC and ovarian endometrioid carcinoma are all have close relation-\nships with ovarian endometriotic cysts, which originate from atypical endometrial cells and or possibly endometriotic \ncells [26– 28]. Common mutations in OCCC are frequently found in benign endometriosis without malignant lesions, \nincluding ARID1A, PIK3CA, PPP2R1A and KRAS. In particular, deletion of ARID1A gene (BAF250a) frequently occurs in \natypical endometriosis, which indicates an early role in carcinogenesis [17, 18, 29]. It indicated that endometriosis as \nthe tissue origin of OCCC, they have shared genomic abnormalities and monoclonal relationships (most likely atypical \novarian endometriotic cysts), that OCCC may be caused by malignant transformation of endometriosis with a common \ngenetic pedigree, that known oncogenes cause malignant transformation of ovarian endometriotic epithelium, and the \nmicroenvironment of endometriosis also promotes carcinogenesis [30, 31]. In addition, it has been suggested that over-\nexpression of HNF-1β was detected in OCCC and 40% of benign endometriotic cysts [28, 32, 33]. And biological properties \nsuch as PD-L1 overexpression and copy number variation (CNV) may promote the cancerous transformation in ovarian \nendometriosis from a non-invasive precursor lesion to OCCC [34– 36]. As OCCC has distinct clinical features, biology, \ngenetic characteristics and mechanisms of pathogenesis, as well as the dilemma of insensitivity to chemotherapy, and \nthe exact pathogenesis of ovarian endometriosis to OCCC has not been fully elucidated, further research and exploration \nare still needed. In this study, we retrospectively collected medical records and follow-up data of patients with OCCC \nfrom a single center, particularly those with OCCC of endometriosis and non-endometriosis origin, try to trigger more \nthinking about the future management of OCCC.\n2  Materials and methods\n2.1  Patients\nBetween January 2009 and December 2019, 139 patients were diagnosed with ovarian clear cell carcinoma and treated \nat Obstetrics and Gynecological Hospital of Fudan University, China. This study was approved by the ethics committee \nof OB/GYN Hospital of Fudan University. Data were collected from electronic medical records and outpatient visits. All \neligible patients had a pathological diagnosis of ovarian clear cell carcinoma in various stages, women with a concurrent \nmalignancy were excluded. In all, 125 women were enrolled in this study.\n2.2  Data collection\nData collected included demographic information, clinical, surgical and pathological information, chemotherapy infor-\nmation and follow-up information. Following a electronic medical records search, baseline data were obtained from the \ndatabase of patients’ medical records and included age at diagnosis, BMI, menopause, parity, personal medical history, \ncomorbid medical disease; Clinical data were also obtained from the patients and included symptom, preoperative \ntumor markers level, presence or absence of endometriosis, manifestations of endometriosis, duration of endometrio -\nsis, whether there is ascites, imaging findings; Surgical and pathological details included surgery mode, complete or \nincomplete surgery (complete surgical procedure consisted of total hysterectomy, bilateral salpingo-oophorectomy, \nomentectomy, pelvic and para-aortic lymphadenectomy, and debulking procedures such as colon resection), fertility-\nsparing surgery (the preservation of the uterus and one adnexa), largest residual tumor size, surgical staging (the Inter-\nnational Federation of Obstetrics and Gynecology, FIGO staging system), tumor maximum diameter, peritoneal cytology, \nlymph node metastasis (preoperative evaluation of retroperitoneal swollen lymph nodes was confirmed by computed \ntomography and MRI and/or PET-CT), omentum metastasis, peritoneum metastasis, tumor origin (histologically con-\nfirmed), postoperative pathological and immunohistochemical results (The pathologic diagnosis was performed and \nsupervised independently by 2 pathologists). Adjuvant therapy (observation or adjuvant chemotherapy, treatment by \nChinese herbs, molecular target therapy), chemotherapy circles (adjuvant chemotherapy regimen was a platinum based \ndoublet: carboplatin (AUC = 5–6) and paclitaxel (135–175 mg/m 2) every 3 weeks, for 3–6 cycles). Platinum-sensitivity \nwas defined as relapse occurring ≥ 6 months after the completion of last regimen or lack of recurrence and platinum-\nresistance was defined as relapse occurring within 6 months of the completion of last regimen. Patients came back to \nour hospital for follow-up evaluation with the interval of 3 months for the first 2 years, with the interval of 6 months for \n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nthe next 3 years, and annually thereafter. We also collected date of disease progression or death, disease progression \ndetails, adjuvant therapy after disease progression, status of the patient at the most recent follow-up. Overall survival \n(OS) and progression-free survival (PFS) was calculated from the date of primary surgery to death and disease progres-\nsion/recurrence, respectively, or the last disease-free visit.\n2.3  Analysis\nThe survival analysis was based on the Kaplan–Meier method, and the results were compared using the log-rank test. \nCox regression analysis was used to determine factors affecting survival and recurrence, and results are presented as \nHRs with 95% CIs. The distributions of clinicopathological factors were evaluated using the Student’s t-test or the χ2-test \nas appropriate. Spearman’s correlation analysis was used to assess the correlation between endometriosis origin and \nclinicopathological characteristics of OCCC patients. Multivariate survival analysis was performed using Cox regression \nmodel including prognostic factors that were significant in univariate analysis. all p values reported are two-tailed and a \np < 0.05 was considered significant. All statistical analyses were performed using Statistical Program for Social Sciences \n(SPSS) (version 19.0).\n3  Result\nIn all, 125 women were surgically diagnosed with OCCC at Obstetrics and Gynecology Hospital of Fudan University dur-\ning the study period. The characteristics of patients with OCCC involved are shown in Tables  1, 2. Besides, information \non the clinical characteristics of the relapsed patients among all OCCC patients is presented in Table 3.\nTable 1 shows us the clinical baseline information of the OCCC patients. The mean age at diagnosis was 50 years \n(range, 29–79 years). 68% of them had a BMI of less than or equal to 24.0 kg/m 2. About half of the patients are meno -\npausal (53.6%). 87.2% patients had history of delivery. There were only 2 (1.6%) patients had ovarian cancer family \nhistory and only 4 (3.2%) patients had breast cancer history. The most common clinical symptom of OCCC in our study \nwas pelvic mass (56.8%). Pelvic masses are adnexal masses of undetermined origin, benign or malignant, found by \nthe patient or by clinical examination or by imaging tests such as ultrasound, CT, MRI, PET/CT. Of these patients, 52 \n(41.6%) had a previous history of endometriosis disease. Followed by the most common ovarian endometriotic cyst, \n4 patients had peritoneal endometriosis and no one had deep infiltrating endometriosis in the series. Preoperative \nCA-125 values elevated (≥ 35U/ml) in 83 (66.4%) cases. And among them, 38 cases had normal levels of CA-125. Neu-\ntrophil and lymphocyte percentages in pretreatment blood tests were in the normal range in most patients, but the \nneutrophil percentage tended to rise and the lymphocyte percentage tended to decline. Positive imaging findings \naccount for almost all cases (99.2%). Further, a detailed description of the surgical and pathological characteristics \nis shown in Table 2. 102 (81.6%) patients with OCCC undergone the primary surgery at our institution and only 23 of \nthem referred after incomplete surgery. Most cases (88.8%) had gone through complete surgical staging procedures \nand only 2 of them had fertility sparing surgery in hopes of preserving fertility, other patients underwent conserva-\ntive surgery due to severe complications that excluded them from complete surgical staging. Lymphadenectomy \nwas omitted or replaced by lymph node biopsy in 6 cases because of advanced stage or patient morbidity, and in \naddition, those who only undergone lymph node biopsy or para-aortic lymphadenectomy without undergoing \npelvic lymphadenectomy were not included in the lymphadenectomy group, but a negative biopsy was considered \nas no lymph node metastasis, a positive para-aortic lymph node was regarded as positive lymph node metastasis. \nSeventy-four women were treated by laparoscopy, fifty had laparotomy. Upon the surgery, ascites were present in \n46 cases and peritoneal cytology was positive in 25 (20.0%) cases while 56 (44.8%) records were unavailable. Tumor \ndiameter with ≤ 50 mm took up 12.8%, 50–100 mm in 46 (36.8%) and > 100 mm in 60 (48.0%) cases. Debulking surgery \nwith residual tumor ≤ 1.0 cm (R0) was achieved in 98.4% of cases. During the procedure, 78.4% of patients received \nintraoperative chemotherapy, mainly cisplatin. Early-stage disease predominated, the surgical stage was I/II in 100 \n(80.0%) and III/IV in 23 (18.4%) patients. Among stage I patients, stage IC accounted for the majority (69/89). After \nreviewing the pathological records of these patients, a total of 70 (56.0%) tumors arose from endometriosis based on \nthe criteria of Sampson and Scott [37] [the criteria include: (1) the coexistence of benign and malignant tissue in the \nsame ovary which have the same histologic relationship to each other as in endometrial carcinoma of the uterine cor -\npus; (2) the carcinoma must actually be seen to arise in this tissue, and not to be invading it from some other source; \n(3) and additional supportive evidence includes the finding of tissue resembling endometrial stroma surrounding \n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nTable 1  Patients’ characteristics in 125 ovarian clear cell carcinoma women and Univariate analyses of impact of various prognostic parameters on overall survival (OS) (p1) and recurrence \n(Progression-free survival, PFS) (p2)\nCharacteristics Number of cases (%) Univariate analysis\nAge, median (range), year 50 (29–79) p1 Hazard Ratio 95% confidence interval p2 Hazard Ratio 95% \nconfidence \ninterval\n ≤ 60 y, n (%) 98 (78.4) 0.586 1.323 0.484–3.618 0.425 0.706 0.300–1.661\n > 60 y, n(%) 27 (21.6)\nBMI (Kg/m2)\n  ≤ 24.0 85 (68.0) 0.781 0.874 0.339–2.254 0.761 0.885 0.404–1.939\n  > 24.0 40 (32.0)\nMenopause\n Yes 67 (53.6) 0.521 1.328 0.559–3.156 0.998 1.001 0.493–2.032\n No 58 (46.4)\nParity\n Parous 109 (87.2) 0.224 0.508 0.170–1.513 0.024 0.313 0.114–0.855\n Nulliparous 16 (12.8)\nOvarian cancer family history\n Yes 2 (1.6) 0.763 0.049 0.000–16,550,195.08 / / /\n No 123 (98.4)\nBreast cancer history\n Yes 4 (3.2) 0.531 1.904 0.253–14.317 0.563 0.553 0.074–4.116\n No 121 (96.8)\nSymptom\n Vaginal bleeding 6 (4.8) 0.834 1.027 0.801–1.317 0.436 0.913 0.726–1.148\n Menstrual change 3 (2.4)\n Abdominal pain/bloating 19 (15.2)\n Pelvic mass 71 (56.8)\n Combination 1 (0.8)\n None 1 (0.8)\n Others 24 (19.2)\nComorbid medical disease\n Yes 50 (40.0) 0.334 0.627 0.243–1.616 0.32 1.496 0.676–3.311\n No 75 (60.0)\nEndomotriosis disease history\n Yes 52 (41.6) 0.457 0.708 0.285–1.758 0.511 1.274 0.619–2.622\n No 73 (58.4)\nManifestations (Types) of endometriosis\n Ovarian endometriotic cyst 57 (45.6) 0.132 1.268 0.931–1.727 0.888 0.983 0.775–1.247\n Peritoneal endometriosis 4 (3.2)\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nTable 1  (continued)\nCharacteristics Number of cases (%) Univariate analysis\nAge, median (range), year 50 (29–79) p1 Hazard Ratio 95% confidence interval p2 Hazard Ratio 95% \nconfidence \ninterval\n Deep infiltrating endometriosis (DIE) 0\n None 64 (51.2)\nPretreatment CA-125 (U/mL)\n  < 35 38 (30.4) 0.114 2.405 0.809–7.152 0.301 1.61 0.654–3.966\n  ≥ 35 83 (66.4)\nUnknown 4 (3.2)\nPretreatment neutrophil percentage\n Rise 40 (32.0) 0.621 0.827 0.390–1.755 0.434 0.784 0.426–1.443\n Normal 78 (62.4)\n Decrease 7 (5.6)\nPretreatment lymphocyte percentage\n Rise 2 (1.6) 0.908 1.052 0.446–2.480 0.916 0.959 0.440–2.091\n Normal 83 (66.4)\n Decrease 40 (32.0)\nImaging findings\n Positive 124 (99.2) 0.722 20.589 0.000–3.519E8 / / /\n Negative 1 (0.8)\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nTable 2  Surgical and pathological characteristics in 125 ovarian clear cell carcinoma women and univariate analyses of impact of various prognostic parameters on overall survival (OS) \n(p1) and recurrence (Progression-free Survival, PFS) (p2)\nCharacteristics Number of cases (%) Univariate analysis\nReferred after incomplete surgery p1 Hazard Ratio 95% confidence interval p2 Hazard Ratio 95% confidence interval\nYes 23 (18.4) 0.167 0.243 0.033–1.808 0.48 1.69 0.394–7.255\nNo 102 (81.6)\nComplete staging surgery\n Yes 111 (88.8) 0.426 2.26 0.303–16.850 0.967 1.044 0.140–7.798\n No 14 (11.2)\nLymphadenectomy\n Yes 118 (94.4) 0.851 0.825 0.111–6.153 / / /\n No 6 (4.8)\n Unknown 1 (0.8)\nSurgery mode\n Laparoscopy 74 (59.2) 0.854 1.085 0.455–2.584 0.461 0.762 0.370–1.570\n Laparotomy 50 (40.0)\n Unknown 1 (0.8)\nFertility-sparing surgery\n Yes 2 (1.6) 0.715 0.048 0–549,846.541 / / /\n No 123 (98.4)\nLargest residual tumor size\n Residual mass ≤ 1.0 cm 123 (98.4) 0.715 20.745 0–2.366E8 0.014 32 2.002–511.602\n Residual mass > 1.0 cm 1 (0.8)\nUnknown 1 (0.8)\nFIGO stage\n I 89 (71.2) 0.001 2.013 1.334–3.038 0.001 2.186 1.382–3.459\n IA 19 (15.2)\n IB 1 (0.8)\n IC 69 (55.2)\n53 (42.4)\n13 (10.4)\n3 (2.4)\n II 11 (8.8)\n III 21 (16.8)\n IV 2 (1.6)\n Unknown 2 (1.6)\nTumor maximum diameter (mm)\n  ≤ 50 16 (12.8) 0.122 1.682 0.870–3.251 0.029 0.559 0.332–0.943\n 50–100 46 (36.8)\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nTable 2  (continued)\nCharacteristics Number of cases (%) Univariate analysis\nReferred after incomplete surgery p1 Hazard Ratio 95% confidence interval p2 Hazard Ratio 95% confidence interval\n  > 100 60 (48.0)\n Unknown 3 (2.4)\nAscites\n Presense 46 (36.8) 0.25 1.618 0.712–3.674 0.698 0.874 0.443–1.724\n Absence 74 (59.2)\n Unknown 5 (4.0)\nPeritoneal cytology\n Positive 25 (20.0) 0.058 1.725 0.982–3.031 0.449 0.844 0.545–1.308\n Negative 44 (35.2)\n Unknown/unexamined 56 (44.8)\nLymph node metastasis\n Yes 12 (9.6) 0.002 5.454 1.830–16.251 0.01 3.312 1.336–8.210\n No 109 (87.2)\n Unknown 4 (3.2)\nOmentum metastasis\n Yes 12 (9.6) 0.907 1.111 0.189–6.536 0.145 3.436 0.653–18.084\n No 111 (88.8)\n Unknown 2 (1.6)\nPeritoneum metastasis\n Yes 20 (16.0) 0.01 3.453 1.343–8.877 0.214 1.641 0.751–3.586\n No 103 (82.4)\nUnknown 2 (1.6)\nTumor origin\n Endometriosis 70 (56.0) 0.062 0.432 0.179–1.045 0.341 1.413 0.694–2.880\n Non-endometriosis origin 55 (44.0)\nProgression time (endometriosis to OCCC), year\n  ≤ 5 21 (30.0) 0.127 0.194 0.026–1.474 0.258 2.511 0.827–7.624\n 5–10 16 (22.9)\n  > 10 12 (17.1)\nUnknown 21 (30.0)\nNeoadjuvant chemotherapy\n Yes 9 (7.2) 0.943 0.929 0.124–6.950 0.646 1.333 0.391–4.549\n No 116 (92.8)\nIntraoperative chemotherapy use\n Yes 98 (78.4) 0.193 0.379 0.088–1.632 0.53 0.713 0.248–2.047\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nTable 2  (continued)\nCharacteristics Number of cases (%) Univariate analysis\nReferred after incomplete surgery p1 Hazard Ratio 95% confidence interval p2 Hazard Ratio 95% confidence interval\n No 25 (20.0)\nUnknown 2 (1.6)\nAdjuvant chemotherapy\n Yes 119 (95.2) 0.551 21.376 0.001–496,996.629 / / /\n No 6 (4.8)\nAdjuvant chemotherapy cycles\n  < 6 courses 47 (37.6) 0.986 1.006 0.501–2.022 0.097 2.015 0.882–4.606\n  ≥ 6 courses 73 (58.4)\n Unknown 5 (4.0)\nChemotherapy administration methods\n Intravenous 60 (48.0) 0.044 2.381 1.025–5.533 0.193 0.624 0.307–1.268\n Intravenous + Intraperitoneal 55 (44.0)\n Unknown 10 (8.0)\nChemotherapy-related side-effects\n Yes 97 (77.6) 0.173 1.4 0.863–2.274 0.777 0.929 0.558–1.546\n No 4 (3.2)\n Unknown 24 (19.2)\nTreatment by Chinese herbs\n Yes 38 (30.4) 0.012 0.154 0.036–0.663 0.538 1.29 0.574–2.899\n No 66 (52.8)\n Unknown 21 (16.8)\nMolecular target therapy*\n Yes 11 (8.8) 0.001 4.819 1.862–12.477 0.161 0.57 0.259–1.252\n No 114 (91.2)\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\ncharacteristic epithelial glands, and the finding of old hemorrhage rather than fresh, since the latter can be the result \nof trauma resulting from surgical manipulation. (4) a microscopic section must show the benign endometriosis run-\nning into and continuous with the malignant epithelium]. 12 (9.6%) patients had positive lymph node metastases. \nTwelve of 125 women had omentum metastasis. Peritoneum metastasis occurred in 20 (16.0%) patients. Endometrio -\nsis progressed to OCCC within 5 years in 21 patients, representing 30% of the total number. Only 9 patients received \nneoadjuvant chemotherapy as assessed by their general condition and preoperative Suidan’s CT score [38]. After \nsurgery, 119 (95.2%) patients received a first-line combined chemotherapy with a platinum-based regimen. 58.4% \nof patients received at least 6 courses of chemotherapy, while 47 (37.6%) patients received lesser courses because \nof intolerance of side effects or uncomplaisance. Intravenous chemotherapy alone or intravenous combined with \nintraperitoneal chemotherapy each accounts for approximately half of the postoperative chemotherapy population. \nThe main chemotherapy-related side-effects were manifested as different degrees of myelosuppression (77.6% of the \npatients). Through our follow-up, we found that 30.4% of the patients received post-operative herbal treatments to \nregulate their bodies and achieved certain results. Of all patients, only 11 (8.8%) patients received molecular target \ntherapy (mainly with bevacizumab treatment), and they were mainly patients with advanced and relapsed disease. \nOnly one patient received immunotherapy by joining the clinical trial, but stopped the therapy due to the serious \nside effects and is still alive. None underwent postoperative radiotherapy.\nTable 3  Relapsed patients’ \ncharacteristics and Univariate \nanalyses of impact of various \nrelapse-related prognostic \nparameters on overall survival\nCharacteristics Number of cases (%) Univariate analysis\nDisease relapse p Hazard Ratio 95% \nconfidence \ninterval\nYes 38 (30.4) / / /\nNo 71 (56.8)\nUnknown 16 (12.8)\nProgression/ Relapse time*, months\n  ≤ 6 11 (28.9) 0.829 1.047 0.691–1.586\n  > 6 22 (57.90)\n Unknown 5 (13.2)\nTumor Origin\n Non-endometriosis Origin 23(60.5) 0.581 0.785 0.333–1.852\n Endometriosis Origin 15(39.5)\nProgression/ Relapse manifestations\n Elevated tumor markers 10 (26.3) 0.71 1.074 0.738–1.561\n Local mass based on imaging 9 (23.7)\n Metastasis based on imaging or pathology 12 (31.6)\n Others 1 (2.6)\n Unknown 6 (15.8)\nChemo-resistance\n Yes 12 (31.6) 0.18 0.636 0.328–1.233\n No 22 (57.9)\n Unknown 4 (10.5)\nTreatment after progression/ relapse**\n Chemotherapy 23 (60.5) 0.256 0.811 0.566–1.164\n Surgery 6 (15.8)\n Molecular target therapy 1 (2.6)\n Treatment by Chinese herbs 1 (2.6)\n Alleviative/palliative treatment 3 (7.9)\n Unknown 4 (10.5)\nMolecular target therapy\n Yes 11 (28.9) 0.082 2.22 0.903–5.456\n No 27 (71.1)\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nAs is shown in Table 3, of the women with follow-up, 38 (30.4%) OCCC patients presented with disease relapse. And \namong them, 11 (28.9%) had refractory disease, 12 (31.6%) had chemo-resistant disease, and 22 (57.9%) met the criteria \nfor chemo-sensitive disease. 60.5% of recurrent patients were of non-endometriosis origin. The most common manifes-\ntation of recurrent disease was imaging-indicated metastases lesions or pathological evidence of metastases (31.6%), \nfollowed by elevated tumor markers (26.3%) and local mass based on imaging (23.7%). These patients were also followed \nfor treatment after relapse, chemotherapy remained the mainstay of treatment after relapse (60.5%). A significant number \nof women (15.8%) had undergone surgical procedure again, primarily to relieve tumor load and remove isolated lesions. \nIt was noted that among the relapsed patients, 11 of them received chemotherapy and molecular target therapy (mainly \nwith bevacizumab treatment) at the same time.\nSurvival analysis was retrospectively performed to identify the significant outcome predictors that affect disease \nrelapse and survival in patients with OCCC. In the overall patients’ population, the 5 year overall survival was 84.8%, \nthe mean overall survival was 85.9 months (95% CI 79.7–92.1). The median follow-up time from the initial surgery was \n58.0 months (range, 10–102 months) (Fig. 1a). We also performed survival analysis for early (stage I-II) and advanced (stage \nIII-IV) stage OCCC respectively, and the results are shown in Fig. 1b and Fig. 1c. Early stage OCCC had a good prognosis, \nthe mean overall survival was 91.9 months (95% CI 86.5–97.2). In comparison, the mean overall survival of advanced \nOCCC was 51.8 months (95% CI 32.7–71.0), the median overall survival for advanced OCCC was 48 months. A detailed \ndescription of the results of univariate analyses on overall survival (p1) and progression-free survival (p2) is shown in \nTables 1, 2, it indicated that a statistically significant relationship between survival probability and FIGO stage (p = 0.001), \nlymph node metastasis (p = 0.002), peritoneum metastasis (p = 0.01), chemotherapy administration methods (p = 0.044), \nChinese herbal treatment (p = 0.012), molecular target therapy (p = 0.001), the survival curves of these factors affecting \nOS are shown in Fig. 2(a, b, c, d, e, f ). Among the many characteristics, peritoneal cytology, tumor origin are two clinical \nfactors, which had p values less than 0.1 for univariate analysis of OS, then, we also included these two clinical data in the \nsubsequent multivariate analyses. For analysis of the correlation between clinical data and PFS, a significant relationship \nbetween PFS and child-bearing history (p = 0.024), largest residual tumor size (p = 0.014), FIGO stage (p = 0.001), tumor \nmaximum diameter (p = 0.029), lymph node metastasis (p = 0.01) was found, respectively (Fig. 3a, b, c, d, e). The results of \nmultivariate analyses carried out to determine the effect of demographic characteristics and clinical features on overall \nsurvival are provided in Table 4\nThrough our analyses, it revealed that FIGO stage and lymph node metastasis are common poor prognostic factors \naffecting OS and PFS. Overall survival decreased in patients who developed peritoneum metastases (p = 0.01; HR, 3.453; \n95% CI 1.343–8.877), but there was no significant difference in the effect on PFS. Patients treated with intravenous com-\nbined with intraperitoneal chemotherapy have a worse prognosis than those treated with intravenous chemotherapy \nalone (p = 0.044; HR, 2.381; 95% CI 1.025–5.533). Interestingly, in terms of treatment, in addition to post-operative chemo-\ntherapy, patients treated with herbal remedies have a better OS (p = 0.012; HR, 0.154; 95% CI 0.036–0.663). However, \npatients receiving bevacizumab-based molecular target therapy have a poorer prognosis (p = 0.001; HR, 4.819; 95% CI \n1.862–12.477). In our analysis, women who have given birth to offspring have a lower risk of disease recurrence (p = 0.024; \nHR, 0.313; 95% CI 0.114–0.855). Larger tumor diameter was associated with prolonged PFS (p = 0.029; HR, 0.559; 95% CI \n0.332–0.943). Whether surgery achieved R0 was associated with recurrence and did not affect OS. A subsequent multivari-\nate regression analysis revealed that FIGO stage (p = 0.028; HR, 1.944; 95% CI 1.073–3.52) and treatment by Chinese herbs \n(p = 0.018; HR, 0.141; 95% CI 0.028–0.716) were identified as risk factors with regard to survival. Patients who received \nFig. 1  a. Survival curves of overall survival; b. Survival curves of overall survival in early stage OCCC (FIGO stage I and II); c. Survival curves of \noverall survival in advanced stage OCCC (FIGO stage III and IV)\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nmolecular target therapy were mainly patients with advanced and relapsed disease as mentioned above, so we ignored \nthis factor even though the p value is less than 0.05.\nBesides, as is shown in Fig.  4a, we can see that even there was no significant difference between tumor origin and \nOS, a trend towards a better prognosis for patients with OCCC of endometriosis origin than those with OCCC of non-\nendometriosis origin (p = 0.062; HR, 0.432; 95% CI 0.179–1.045). To further evaluate the significance of endometriosis \norigin on the recurrence and prognosis of ovarian clear cell carcinoma (OCCC) and its relationship with other clinical \nparameters, we divided patients into 2 groups according to the association between ovarian endometriosis and OCCC \non pathology. The patients were classified as Group 1 (non-endometriosis origin) if the tumor was not originated from \nendometriosis. The patients were classified as Group 2 (endometriosis origin) if clear cell carcinoma arose from ovarian \nendometriosis or if ovarian endometriosis was present and found elsewhere in the ovary. Clinicopathological charac -\nteristics and survival outcomes were compared between the 2 groups. The two groups differed with respect to clinico -\npathological factors, such as age, menopause status, endometriosis disease history, manifestations of endometriosis, \npretreatment CA-125 level, referred after incomplete surgery, peritoneal cytology and disease relapse. Of 125 OCCC \npatients at OB/GYN Hospital of Fudan University during the study period, 70 (56%) patients had OCCC arising from \novarian endometriosis or coexisting ovarian endometriosis elsewhere in the ovary, and 55 (44%) of these patients had \nOCCC of non-endometriosis origin. The patients’ baseline characteristics and clinico-surgical pathological characteris-\ntics between the two groups are presented in Table  5. Group 1 patients were older than Group 2 (p < 0.001), and most \nOCCC in postmenopausal patients did not have endometriosis origin (Group1), while those with endometriosis origin \n(Group 2) often appear before menopause (p < 0.001). Having analyzed our data, we have concluded that the major -\nity of patients in Group 2 (70%, p < 0.001) have a history of endometriosis and their presentation mainly appeared as \novarian endometriotic cysts (75.7%, p < 0.001). There were more abnormal CA-125 levels in Group 1 patients than in \nGroup 2 patients prior to surgery (80% vs 55.7%). No differences were found between the two groups in the number \nof patients underwent complete staging surgery. However, more patients in Group 2 referred after incomplete surgery \n(p = 0.004). Optimal debulking surgery, which was defined as the size of the largest residual tumor less than or equal to \n1.0 cm, was performed in both groups, with 98.2% of patients in Group 1 and 98.6% of patients in Group 2 (p = 0.357). \nFig. 2  (a, b, c, d, e, f). Survival curves of prognostic factors for overall survival by FIGO stage (a), lymph node metastasis (b), peritoneum \nmetastasis (c), chemotherapy administration methods (d), Chinese herbal treatment (e), molecular target therapy (f)\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nA higher percentage of patients in Group 1 had positive ascites cytology compared to Group 2 (42.1% vs 29.0%). More \npatients with OCCC of endometriosis origin (Group 2) were in the early stage of cancer (stage I and II, 87.1% vs 73.6%) \nthan patients with OCCC of non-endometriosis origin, advanced-stage diseases (stage III and IV) were more frequent in \nGroup 1 (26.4% vs 12.9%), but among stage I patients, stage IC patients accounted for a greater proportion of Group 2 \npatients (84.2% vs 65.6%). As for the data on other clinical-surgical pathological features, no differences were observed \nbetween the two groups in BMI, parity, symptom, pretreatment neutrophil and lymphocyte percentage, surgery mode, \ntumor maximum diameter, ascites presence, lymph node metastasis, omentum metastasis, peritoneal metastasis. After \nsurgery, 53 patients (96.4%) in Group 1 and 66 patients (94.3%) in Group 2 received adjuvant chemotherapy (p = 0.59). No \ndifferences in chemotherapy cycles, chemotherapy administration methods, chemotherapy-related side-effects, Chinese \nherbs’ treatment and molecular target therapy were observed between the two group. It is worth noting that the propor-\ntion of patients with disease relapse was higher in Group 1 (46.9%) than in Group 2 (25.0%), with a statistically significant \ndifference (p = 0.048), and as is depicted in Fig.  4b, this result is consistent with the previously mentioned the trend of \nFig. 3  (a, b, c, d, e). Survival curves of prognostic factors for progression-free survival by child-bearing history (a), largest residual tumor size \n(b), FIGO stage (c), tumor maximum diameter (d), lymph node metastasis (e)\nTable 4  Multivariate analyses \nof significant prognostic \nparameters on overall survival \nin patients with ovarian clear \ncell carcinoma cox-regression \nanalysis.\nCharacteristics Wald p Harzard ratio 95% confidence interval\nFIGO stage 4.809 0.028 1.944 1.073–3.52\nPeritoneal cytology 1.609 0.205 0.651 0.336–1.263\nLymph node metastasis 0.167 0.683 0.762 0.207–2.81\nPeritoneum metastasis 2.154 0.142 2.414 0.744–7.834\nTumor origin 1.26 0.262 0.54 0.184–1.584\nChemotherapy administration methods 3.555 0.059 2.402 0.966–5.974\nTreatment by Chinese herbs 5.587 0.018 0.141 0.028–0.716\nMolecular target therapy 6.275 0.012 4.009 1.353–11.880\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nhigher 5-year OS in endometriosis origin OCCC patients (Group 2) compared with non-endometriosis origin patients \n(Group 1) (Fig. 4a), even though there was no statistically significant difference between the two groups in terms of PFS \n(p = 0.341). And, there were no significant differences in progression/ relapse time, progression/relapse manifestations, \nchemo-resistance and treatment after progression/relapse demonstrates Table  6 the results of spearman correlation \nanalysis between endometriosis origin of OCCC and clinical indicators of each parameter.\n4  Discussion\nMany factors can influence and indicate the prognosis of OCCC. With the development of technologies of proteomics, \nsuch as mass spectrometry (MS) and protein array analysis, the available novel biomarkers, namely, targeted proteomics, \nis a key technique that enables the validation and verification of biomarkers that have been discovered. It works with \nuntargeted proteomics to complete the cycle of biomarker discovery and validation. Peptidomics, is the second new \nsub-division of proteomics and can, also, be used to shed light on new biomarkers. Further, exosomes, play a critical role \nin intercellular communication and they have emerged as a compelling diagnostic and prognostic biomarkers for OCCC, \nas they may transport some tumour-associated proteins [39]. And many studies have shown that the clinicopathological \nstage of the tumor is the most important prognostic factor for OCCC [10, 40]. Other poor prognostic factors include lym-\nphatic vascular invasion, blocked p16 expression, deletion of BAF250a expression, β-catenin nuclear expression, abnor -\nmal p53 staining patterns, expression of IMP3, CBX7, Emi1, CXCR4, HOXA10, Glypican 3, MET gene amplification, CCNE1 \ncopy number gain, MDM2 amplification in TP53 wild type cases and multiple somatic copy number variants [ 41–45].\nOur studies have suggested important roles of surgical staging and treatment by Chinese herbs postoperatively as two \nindependent prognostic factors. Efficacy and safety of Chinese herbal medicine on ovarian cancer after surgery have been \ndiscussed in these years [46]. Researchers found that Chinese herbal medicine treatments significantly improved symp-\ntoms and enhanced curative effects. It also showed the unique superior chemotherapy tolerance in quality of patient’s \nlife and minimal toxic and adverse effects due to chemotherapy [47]. Specifically, Chinese herbal medicine combined \nwith chemotherapy after surgery may reduce incidences of gastrointestinal reactions, marrow depression, urinary system \nsymptoms and regulate even boost the immune system [48, 49]. Therefore, when we are keep thinking ovarian cancer \nfor improving outcomes, we should consider proper treatments that are truly palliative and improve symptom control \n[50]. And treatment should be stratified in accordance not only to prognosis, but also with more emphasis being placed \non patients’ experience and on minimizing side effects, for all these reasons, Chinese herbal medicine combined with \nchemotherapy postoperatively may be a good choice.\nWhat deserved our attention is that among the early stage (FIGO stage I/II) OCCC patients in our study, 97% \n(97/100) of them underwent lymphadenectomy and 1 patient had lymph node biopsy. And after the confirmation \nFig. 4  a Survival curves of prognostic factors for overall survival by Tumor origin; b. The proportion of patients with disease relapse in Group \n1 (non-endometriosis origin) and Group 2 (endometriosis origin)\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nTable 5  Comparison of 125 \nOCCC with and without \nendometriosis origin\nCharacteristics Tumor Origin p-value\nGroup 1 (non-endo-\nmetriosis origin)\nGroup 2 (endome-\ntriosis origin)\nAge, median (range), y 57 (29–79) 47 (29–67)\n ≤ 60 y, n (%) 33 65  < 0.001\n  > 60 y, n(%) 22 5\nBMI (Kg/m2)\n ≤ 24.0 37 48 0.877\n  > 24.0 18 22\nMenopause\n Yes 44 23  < 0.001\n No 11 47\nParity\n Parous 50 59 0.271\n Nulliparous 5 11\nTubal ligation history\n Yes 2 0 0.108\n No 53 70\nOvarian cancer family history\n Yes 0 2 0.206\n No 55 68\nBreast cancer history\n Yes 2 2 0.806\n No 53 68\nSymptom\n Vaginal bleeding 2 4 0.133\n Menstrual change 3 0\n Abdominal pain/bloating 10 9\n Pelvic mass 26 45\n Combination 0 1\n None 0 1\n Others 14 10\nEndomotriosis disease history\n Yes 3 49  < 0.001\n No 52 21\nManifestations (Types) of endometriosis\n Ovarian endometriotic cyst 4 53  < 0.001\n Peritoneal endometriosis 2 2\n Deep infiltrating endometriosis (DIE) 0 0\n None 49 15\nPretreatment CA-125 (U/mL)\n  < 35 11 27 0.009\n  ≥ 35 44 39\n Unknown 0 4\nPretreatment neutrophil percentage\n Rise 17 23 0.232\n Normal 37 41\n Decrease 1 6\nPretreatment lymphocyte percentage\n Rise 0 2 0.424\n Normal 38 45\n Decrease 17 23\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nTable 5  (continued) Characteristics Tumor Origin p-value\nGroup 1 (non-endo-\nmetriosis origin)\nGroup 2 (endome-\ntriosis origin)\nImaging findings\n Positive 55 69 0.373\n Negative 0 1\nReferred after incomplete surgery\n Yes 4 19 0.004\n No 51 51\nComplete staging surgery\n Yes 51 60 0.217\n No 4 10\nPelvic lymphadenectomy\n Yes 50 68 0.266\n No 4 2\n Unknown 1 0\nSurgery mode\n Laparoscopy 29 45 0.259\n Laparotomy 25 25\n Unknown 1 0\nLargest residual tumor size\n Residual mass ≤ 1.0 cm 54 69 0.357\n Residual mass > 1.0 cm 0 1\n Unknown 1 0\nFIGO stage\n I 32 57 0.053\n IA 10 9 0.297\n IB 1 0\n IC 21 48\n II 7 4\n III 13 8\n IV 1 1\n Unknown 2 0\nTumor maximum diameter (mm)\n  ≤ 50 4 12 0.058\n 50–100 16 30\n  > 100 33 27\n Unknown 2 1\nAscites\n Presense 26 20 0.098\n Absence 27 47\n Unknown 2 3\nPeritoneal cytology\n Positive 16 9 0.011\n Negative 22 22\n Unknown/unexamined 17 39\nLymph node metastasis\n Yes 8 4 0.236\n No 45 64\n Unknown 2 2\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nTable 5  (continued) Characteristics Tumor Origin p-value\nGroup 1 (non-endo-\nmetriosis origin)\nGroup 2 (endome-\ntriosis origin)\nOmentum metastasis\n Yes 8 4 0.061\n No 45 66\n Unknown 2 0\nPeritoneum metastasis\n Yes 11 9 0.542\n No 43 60\n Unknown 1 1\nProgression time (endometriosis to OCCC), year\n  ≤ 5 1 21  < 0.001\n  > 5 0 28\n Unknown 54 21\nNeoadjuvant chemotherapy\n Yes 5 4 0.468\n No 50 66\nIntraoperative chemotherapy use\n Yes 45 53 0.125\n No 8 17\n Unknown 2 0\nAdjuvant chemotherapy\n Yes 53 66 0.59\n No 2 4\nAdjuvant chemotherapy cycles\n  < 6 courses 20 27 0.756\n  ≥ 6 courses 32 41\n Unknown 3 2\nChemotherapy administration methods\n Intravenous 29 31 0.644\n Intravenous + Intraperitoneal 22 33\n Unknown 4 6\nChemotherapy-related side-effects\n Yes 40 57 0.101\n No 4 0\n Unknown 11 13\nTreatment by Chinese herbs\n Yes 14 24 0.512\n No 32 34\n Unknown 9 12\nMolecular target therapy*\n Yes 6 5 0.724\n No 38 52\n Unknown 11 13\nDisease relapse\n Yes 23 15 0.048\n No 26 45\n Unknown 6 10\nProgression/ Relapse time*, months\n  ≤ 6 6 5 0.881\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nof the final pathology report, we found that of the 23 recurrent patients in early stage, 22 patients who underwent \nlymphadenectomy did not develop lymph node metastasis. Moreover, the presence or absence of lymphadenectomy \ndid not affect OS of 125 OCCC patients (p = 0.851; HR, 0.825; 95% CI 0.111–6.153) by our data analysis. A prospec -\ntive randomized controlled study of the effect of lymphadenectomy on survival in early-stage ovarian cancer found \nthat although more positive lymph nodes were detected with systematic lymphadenectomy than with lymph node \nsampling, the study was not statistically valid enough to analyze the effect of systematic lymphadenectomy on \nPFS and OS in early-stage ovarian cancer due to the small sample size, and perioperative morbidity and postopera-\ntive complications were significantly higher in the systematic lymphadenectomy group than in the lymph node \nsampling group [ 51]. According to the previous literature [52 ], the complication rate of retroperitoneal systematic \nlymphadenectomy ranges from 5.9% to 24%, with the more serious recent complications occurring in 5.9% to 18.1% \nof these. Common recent complications include vascular injury, lymphatic cysts, small bowel obstruction and deep \nvein thrombosis, and possibly urinary fistula and postoperative infection, etc. The main long-term complication is \nlymphoedema of the lower limbs, which sometimes seriously affects the patient’s quality of life. In addition, lymph \nnodes are peripheral immune organs located on the way of lymphatic vessels, and their main function is to filter \nlymphatic fluid and produce immune cells, which participate in the immune response of the body. Although removal \nof regional lymph nodes blocks one of the metastatic pathways of tumors, it also weakens the anti-tumor immunity \nof the body. Besides, the functional protection of the immune organs contributes to the immunotherapy of tumors. \nThe role of regional lymph nodes in the tumor immune cycle is crucial, as it is the site of initiation and maintenance \nof the body’s anti-tumor immune response, and its lack of function will cause a disconnect in the tumor immune \ncycle, bringing about a failure of immune supervision [53]. Whether systematic lymphadenectomy provides a survival \nbenefit for patients with early-stage ovarian cancer, including those with early-stage OCCC, remains controversial. \nAs mentioned previously in this study, patients with early stage OCCC have a good prognosis which is consistent \nwith previous studies [ 7, 11, 13]. All these suggest that we may be able to omit lymphadenectomy in early stage \nOCCC patients, thereby reducing the risk of intraoperative injury, shortening the operative time and reducing the \nrisk of postoperative complications associated with lymphadenectomy itself, and ultimately improving the patients’  \npostoperative quality of life to some extent. As the results of the various retrospective studies were inconsistent \n[54– 57] and retrospective studies are vulnerable to the effects of bias from confounding factors, in China, there is an \nongoing prospective multicenter randomized controlled study on “the Exemption of early-stage epithelial ovarian \nTable 5  (continued) Characteristics Tumor Origin p-value\nGroup 1 (non-endo-\nmetriosis origin)\nGroup 2 (endome-\ntriosis origin)\n  > 6 14 8\n Unknown 3 2\nProgression/ Relapse manifestations\n Elevated tumor markers 3 7 0.202\n Local mass based on imaging 7 2\n Metastasis based on imaging or pathology 8 4\n Others 1 0\n Unknown 4 2\nChemo-resistance\n Yes 7 5 0.821\n No 13 9\n Unknown 3 1\nTreatment after progression/relapse\n Chemotherapy 13 10 0.726\n Surgery 4 2\n Molecular target therapy 1 0\n Treatment by Chinese herbs 0 1\n Alleviative/palliative treatment 2 1\n Unknown 3 1\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\ncancer from systemic lymphadenectomy” , and our institution, as one of the subcenters, is actively enrolling suitable \npatients for this clinical study. This multicenter clinical study aims to optimize treatment strategies in the future for \nearly-stage ovarian cancer (including early-stage OCCC) and to provide a new evidence-based basis for updating \nclinical guidelines. In our study, all 12 patients with positive lymph nodes were advanced stage (FIGO stage III/IV) \npatients. The rate of positive lymph node metastases is approximately 52.2% (12/23). Even though patients with \nlymph node metastases had shorter OS (Fig.  2b) and PFS (Fig.  3e) among the 125 OCCC patients. After our stratified \nTable 6  Spearman analysis \nof correlation between \nendimetriosis origin \nand clinicopathological \ncharacteristics of OCCC \npatients\nVariables With or without endometriosis \norigin\np-value\nSpearman correlation\nAge − 0.497  < 0.001\nBMI 0.005 0.956\nMenopause 0.469  < 0.001\nParity 0.098 0.275\nTubal ligation history 0.144 0.109\nOvarian cancer family history − 0.113 0.209\nBreast cancer history 0.022 0.808\nSymptom − 0.088 0.332\nEndomotriosis disease history − 0.65  < 0.001\nManifestations (Types) of endometriosis − 0.687  < 0.001\nPretreatment CA-125 0.224 0.013\nPretreatment neutrophil percentage 0.028 0.758\nPretreatment lymphocyte percentage  < 0.001 0.998\nImaging findings 0.08 0.378\nReferred after incomplete surgery 0.255 0.004\nComplete staging surgery 0.11 0.22\nPelvic lymphadenectomy − 0.105 0.245\nSurgery mode − 0.107 0.237\nLargest residual tumor size 0.079 0.382\nFIGO stage − 0.227 0.012\nTumor maximum diameter (mm) − 0.237 0.009\nAscites 0.183 0.041\nPeritoneal cytology 0.267 0.003\nLymph node metastasis 0.153 0.094\nOmentum metastasis 0.157 0.084\nPeritoneum metastasis 0.099 0.278\nProgression time (endometriosis to OCCC), y 0.228 0.111\nNeoadjuvant chemotherapy 0.065 0.472\nIntraoperative chemotherapy use 0.113 0.213\nAdjuvant chemotherapy − 0.048 0.593\nAdjuvant chemotherapy cycles − 0.036 0.693\nChemotherapy administration methods 0.084 0.373\nChemotherapy-related side-effects − 0.235 0.018\nTreatment by Chinese herbs 0.113 0.254\nMolecular target therapy* − 0.077 0.442\nDisease relapse − 0.229 0.017\nProgression/relapse time*, months − 0.179 0.318\nProgression/relapse manifestations − 0.354 0.043\nChemo-resistance − 0.017 0.921\nTreatment after Progression/relapse − 0.08 0.647\nSurvival State 0.2 0.039\n\nVol:.(1234567890)\nResearch Discover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8\n1 3\nanalysis of advanced stage OCCC, we found that lymph node metastasis had no significant effect on OS and PFS in \npatients with advanced disease, and the difference was not statistically significant (OS: p = 0.311; HR, 1.922; 95% CI \n0.544–6.792; PFS: p  = 0.937; HR, 1.058; 95% CI 0.261–4.287). We also analyzed whether lymphadenectomy affected OS \nin patients with advanced disease as well, and found that lymph node dissection did not affect OS in these advanced \nOCCC patients (p = 0.636; HR, 1.666; 95% CI 0.201–13.808). Here, our findings are consistent with those of the LION \nstudy [58] recently published in the New England Journal. The LION study suggested that lymphadenectomy did not \nresult in longer PFS or OS in patients with advanced ovarian cancer when there were no clinically suspicious abnormal \nlymph nodes. According to LION, systemic lymphadenectomy does not provide a survival benefit for patients with \nadvanced ovarian cancer whose lymph nodes are visual normal, but increases the risks and complications of surgery; \nSystematic lymphadenectomy should not be routinely performed in these patients and international guidelines have \nbeen rewritten as a result [22].\nPrevious studies have reported conflicting outcomes regarding the prognostic role of endometriosis in OCCC [40, \n59–63]. In our study, OCCC with endometriosis origin showed a trend toward improved survival outcomes. OCCC with \nendometriosis was found younger, more in early stage, more referred after incomplete surgery due to its unexpect -\nedly diagnosis during surgery for young women with presumed endometrioma, more presented with intraoperative \ntumor rupture while had a lower incidence of positive ascites cytology, which is in line with previous studies [ 30, 60]. \nThere may be a difference in the pathogenesis and underlying biology of OCCC in patients with endometriosis origin. \nTherefore, further studies are required to explore the molecular mechanisms of pathogenesis, molecular genetic \nfeatures of OCCC derived from endometriosis.\n5  Conclusions\nIn conclusion, patients with ovarian clear cell carcinoma are younger, tend to present at an early stage, tumors with \nor without endometriosis origin have different clinical features in many aspects. Genetic, epigenetic, metabolic \nand immunological factors interact or combine with each other and are induced or directly influenced by specific \nmicroenvironments to lead to the development of OCCC. The early stage and proper Chinese herbal medicine treat -\nment postoperatively are important independent factors to improve patients’ prognosis. While the non-necessity of \nlymphadenectomy in advanced ovarian cancer has been proven, we here again question the necessity of lymphad-\nenectomy in the early stage ovarian cancer. A multi-center clinical trial is currently underway in China and its results \nwill be used to guide gynecologic surgeon in deciding the scope of surgery and selecting proper regimen for their \npatients. Surely, our study in the present has several limitations, which include the potential inherited unmeasured \nbiases associated with its retrospective nature, the small sample size, single-institution study and variable follow-\nup length. Hence, larger-scale, prospective, randomized and well-controlled studies are required to confirmed the \nfindings presented herein.\nAcknowledgements The authors thank all the patients who voluntarily provided clinical information for research use.\nAuthor contributions Wei Jiang and Mingming Sun conceived the project and designed the study; Mingming Sun acquired data, performed \nstatistical analysis and wrote the first draft of the manuscript; Wei Jiang provided critical revisions. All authors read and approved the final \nmanuscript.\nFunding Not applicable.\nData availability The original contributions presented in the study are included in the article material. Further inquiries can be directed to \nthe corresponding author.\nDeclarations \nEthics approval and consent to participate This retrospective study was conducted following a protocol (2021–81) approved by the ethics \ncommittee of the Obstetrics and Gynecology Hospital of Fudan University in accordance with the 1964 Helsinki Declaration. Each participant \ngave a consent at enrolment.\nConsent for publication Not applicable.\n\nVol.:(0123456789)\nDiscover Oncology           (2023) 14:39  | https://doi.org/10.1007/s12672-023-00649-8 \n Research\n1 3\nCompeting interests The authors declare that they have no conflicts of interest.\nOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article \nare included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Gynecol Oncol. 2008;110(3):336–44.\nPublisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}