{"paper_id":"de193c7e-7874-4af5-9044-948ac2bd20d7","body_text":"www.ogscience.org 27\nOriginal Article\nObstet Gynecol Sci 2019;62(1):27-34\nhttps://doi.org/10.5468/ogs.2019.62.1.27\npISSN 2287-8572 · eISSN 2287-8580\nIntroduction\nEndometriosis is a common disease entity affecting around \n10% of reproductive-age women [1]. It has a wide variety \nof clinical consequences ranging from benign lesions to ma\n-\nlignant transformation [2-4]. In a pooled analysis of case-\ncontrol studies, endometriosis was found to be significantly \ncorrelated with increased risk of epithelial ovarian cancer,                              \nClinicopathologic characteristics of ovarian clear cell \ncarcinoma in the background of endometrioma:  \na surveillance strategy for an early detection of malignant  \ntransformation in patients with asymptomatic endometrioma\nJoo-Hyuk Son\n1,2\n, Seokyoung Yoon\n2\n, Seokyung Kim\n2\n, Tae-Wook Kong\n1,2\n, Jiheum Paek\n1,2\n, Suk-Joon Chang\n1,2\n,  \nHee-Sug Ryu\n1,2\n1\nDivision of Gynecologic Oncology, \n2\nDepartment of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, Korea\nObjective\nThis study aimed to analyze the clinical features of clear cell carcinoma in relation to endometriosis and to determine \nan appropriate surveillance strategy for the early detection of malignant transformation of endometrioma in \nasymptomatic patients.\nMethods\nWe retrospectively reviewed the clinicopathologic data of 50 patients with ovarian clear cell carcinoma. \nClinicopathologic characteristics, treatment outcomes, and the association between endometriosis and the risk of \nmalignant transformation were analyzed.\nResults\nTen (20%) patients had been diagnosed with endometrioma before the diagnosis of clear cell carcinoma. The median \nperiod from the diagnosis of endometrioma to clear cell carcinoma diagnosis was 50 months (range, 12–213 months). \nAfter complete staging surgery, histological confirmation of endometriosis was possible in 35 (70%) patients. Of the \n50 patients, 39 (78%) had not undergone any gynecologic surveillance until the onset of symptoms, at which time \nmany of them presented with a rapidly growing pelvic mass (median 10 cm, range 4.6–25 cm). With the exception of \n2 patients, all cancer diagnoses were made when the patients were in their late thirties, and median tumor size was \nfound to increase along with age. Asymptomatic patients (n=11) who had regular gynecologic examinations were \nfound to have a relatively smaller tumor size, lesser extent of tumor spread, and lower recurrence rate (\nP=0.011, 0.283, \nand 0.064, respectively). The presence of endometriosis was not related to the prognosis.\nConclusion\nConsidering the duration of malignant transformation and the timing of cancer diagnosis, active surveillance might be \nconsidered from the age of the mid-thirties, with at least a 1-year interval, in patients with asymptomatic endometrioma. \nKeywords: Endometrioma; Neoplastic cell transformation; Epithelial ovarian cancer; Prognosis\nReceived: 2017.12.06.   Revised: 2018.07.03.   Accepted: 2018.07.17.\nCorresponding author: Suk-Joon Chang\nDivison of Gynecologic Oncology, Department of Obstetrics and \nGynecology, Ajou University School of Medicine, 164 World cup-\nro, Y eongtong-gu, Suwon 16499, Korea\nE-mail: drchang@ajou.ac.kr\nhttps://orcid.org/0000-0002-0558-0038\nArticles published in Obstet Gynecol Sci are open-access, distributed under the terms of \nthe Creative Commons Attribution Non-Commercial License (http://creativecommons.\norg/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, \nand reproduction in any medium, provided the original work is properly cited.\nCopyright © 2019 Korean Society of Obstetrics and Gynecology \n\nwww.ogscience.org28\nVol. 62, No. 1, 2019\nespecially clear cell adenocarcinoma [5]. In addition, a recent \nstudy has provided significant evidence of an association \nbetween endometriosis-related genetic variation and ovarian \ncancer risk, especially in those with clear cell histotypes [6]. In \nspite of these risks, there are still debates and disagreements \nas to the optimal treatment and follow-up strategies for pa -\ntients with endometriosis. Although several guidelines have \nbeen developed to provide information on the diagnosis, \ntreatment, and prevention of endometriosis, there is still a \nlack of evidence regarding follow-up intervals and the timing \nof surgical intervention especially in patients with asymp\n-\ntomatic endometriosis [7-10]. Surgical treatment of endome-\ntriomas may confer the benefit of histological confirmation \nalong with a protective effect against later development of \novarian cancer [7,11]. On the other hand, universal surgical \nresection of endometriomas may cause operative risk and \ndecreased ovarian reserve [12,13]. Previous studies suggested \nthat the risk of malignant transformation of endometrio -\nsis was approximately 1% for premenopausal women and \n1–2.5% for postmenopausal women [14,15]. In a Japanese \nprospective study, malignant transformation was reported in \nabout 46 (0.72%) of 6,398 patients with endometriosis after \na median follow-up period of 12.8 years [16].\nDespite the low potential for malignant transformation of \nendometriosis and the relatively long latent period, studies \ninvestigating the management strategies for endometriosis, \nespecially in asymptomatic patients, are urgently needed. The \naim of this study was to examine the treatment outcomes of \nclear cell carcinoma of the ovary in relation to endometriosis \nand to determine an appropriate management strategy for \nasymptomatic patients with endometrioma.\nMaterials and methods\nA retrospective review of medical records was performed \nin patients with clear cell carcinoma of the ovary who were \ndiagnosed and treated between 2001 and 2017 at Ajou \nUniversity Hospital, Suwon, Korea. A total of 50 consecutive \npatients with ovarian clear cell carcinoma were identified. \nAll the patients were evaluated with Siemens Acuson S2000 \nUltrasound system (Siemens Healthcare, Ultrasound Business \nUnit, Mountain View, CA, USA) and computed tomographic \n(CT) scans to inspect the characteristics of the adnexal mass\n-\nes before surgery. Forty-nine patients underwent complete \nstaging surgery, while one patient refused to undergo sur -\ngery.\nAfter the surgery, patients received adjuvant systemic che -\nmotherapy with paclitaxel (175 mg/m\n2\n) plus 3 to 6 cycles \nof carboplatin (area under the curve [AUC] of 6). Clinico -\npathologic characteristics including age at diagnosis, parity, \nbody mass index (BMI), initial symptoms, maximum tumor \ndiameter, and ovarian involvement (laterality) were analyzed. \nTreatment outcomes including the type of treatment, Inter\n-\nnational Federation of Gynecology and Obstetrics (FIGO) \nstage, status of residual disease, and disease recurrences \nwere analyzed. Recurrence was defined based on Gyneco\n-\nlogic Cancer Intergroup criteria after evaluation using the \nResponse Evaluation Criteria in Solid Tumors guidelines [17]. \nIf a patient was diagnosed with endometrioma prior to sur -\ngery, the associations between endometriosis and clear cell \ncarcinoma were analyzed, including a previous diagnosis of \nendometriosis and the latent period until the diagnosis of \nclear cell carcinoma. Statistical analysis was performed using \nIBM SPSS Statistics for windows (version 20.0, IBM Corp., \nArmonk, NY, USA). Risk factors were compared according to \nrecurrence status using the Mann-Whitney \nU test for con -\ntinuous data and Pearson’s χ\n2\n test or Fisher’s exact test for \ncategorical data. P-values less than 0.05 were considered \nstatistically significant.\nResults\nDuring the study period, a total of 533 patients with epithe-\nlial ovarian cancer (EOC) were identified. Clear cell carcinoma \nof the ovary comprised 9.3% (50/533) of the EOC. Median \nage at diagnosis was 49.5 (range, 25–75) years; 42 patients \n(42/50, 82%) were older than 40 years at the time of diag\n-\nnosis, and only 2 patients were younger than 37 years in this \npatient cohort. The median tumor size increased with in\n-\ncreasing patient age (Fig. 1). Most patients’ symptoms were \nrelated to the mass effect of the tumor. Frequent symptoms \nincluded palpable mass (32%), abdominal distention (20%), \nand abdominal pain (20%). Only 11 (22%) patients were di\n-\nagnosed during gynecologic evaluation and did not have any \nsymptoms. Of the 50 patients, 40 patients (80%) had a uni\n-\nlateral ovarian tumor with a size greater than 8 cm. Ten (20%) \npatients had been diagnosed with endometrioma before the \ndiagnosis of clear cell carcinoma. The initial diagnosis of en\n-\n\nwww.ogscience.org 29\nJoo-Hyuk Son, et al. Surveillance strategy of endometrioma\ndometrioma was made by ultrasonography. Nine of the pa -\ntients self-reported the previous diagnosis of endometrioma \nin a local clinic, and 1 patient was diagnosed in our institu -\ntion. However, not all patients had follow-up visits after the \ninitial diagnosis of endometrioma made by ultrasonography. \nHistologic confirmation of endometriosis was possible in 35 \n(70%) patients after complete staging surgery. The median \ntime period from the diagnosis of endometriosis to clear cell \ncarcinoma was 50 (range, 12–213) months in the 10 patients \n(Table 1).\nThe median tumor size in the patients without and with \nan endometriosis background was 9.7 cm (range, 5–20) and \n10.5 cm (range, 4.6–25), respectively. Presence of endome\n-\ntriosis on pathology was not associated with tumor size or \npatient age (\nP=0.519 and 0.451, respectively), nor was it \nrelated to the prognosis (FIGO stage, P=0.747; disease recur-\nrence, P=0.672) (Table 2). Interestingly, among patients who \nhad been diagnosed via routine gynecologic examination, \nonly 1 patient experienced disease recurrence (1/11, 6.7%). \nAsymptomatic patients (n=11) who had regular gynecologi\n-\ncal examinations were found to have a relatively smaller tu -\nmor size, lesser extent of tumor spread, and lower recurrence \nrate (\nP=0.011, 0.283, and 0.064, respectively) (Table 3).\nThirty-eight patients underwent primary debulking surgery, \n3 had neoadjuvant chemotherapy with interval debulking \nsurgery due to a comorbid condition or extensive disease \nburden, and 8 had re-staging surgery after unilateral ovarian \ncystectomy or unilateral salpingo-oophorectomy. Of the 50 \npatients, 35 (70%) were diagnosed with FIGO stage I or II \ndisease. Four patients (8%) were found to have concurrent \nthromboembolic disease during the follow-up period. Fifteen \npatients experienced disease recurrence (Table 4). Among the \nvarious clinicopathologic factors, FIGO stage and the status \nof residual disease were the only significant factors affecting \ndisease recurrence. A previous history of endometriosis was \nnot a significant factor for recurrence (\nP=0.654) (Table 5).\nDiscussion\nAccording to this study, nearly three-quarters of the clear cell \ncarcinoma cases were confirmed in the background of en -\ndometriosis. Most patients were diagnosed during their late \nthirties or forties with a median of 4 years until malignant \nchange. Yet, asymptomatic patients who were diagnosed \nduring regular gynecologic evaluations were more likely to \npresent with a smaller tumor size and early FIGO stage. More \nimportantly, they experienced a low rate of recurrent disease. \nConsidering the risk of malignant potential in endome\n-\ntriosis, appropriate follow-up strategies are indispensable. \nPrevious epidemiological and molecular studies have indi\n-\ncated that endometriosis is the most plausible precursor of \n20\n18\n16\n14\n12\n10\n8\n6\n4\n2\n0\n16\n14\n12\n10\n8\n6\n4\n2\n0\nNumber of patients\nTumor size (cm)\nAge group Age group\nSeventies\n1\nTwenties\n1\nThirties\n7\nThirties\n9.6\nFourties\n17\nFourties\n10\nFifties\n19\nFifties\n11\nSixties\n5\nSixties\n15\nA B\nFig. 1. (A) Number of patients diagnosed with clear cell carcinoma according to the age group. (B) Median tumor size according to the \nage at diagnosis of clear cell carcinoma.\n\nwww.ogscience.org30\nVol. 62, No. 1, 2019\nTable 1. Clinicopathologic characteristics of patients with ovarian clear cell carcinoma (n=50)\nCharacteristics Values\nAge at diagnosis 49 (25–75)\nParity 2 (0–4)\nBMI (kg/m\n2\n) 22.2 (17.9–36.1)\nMenopause patients 17 (34)\nAge of menopause 48 (46–55)\nInitial symptoms and median tumor size (cm)\nPalpable mass 16 (32), 11.5 (9–25)\nIncidental diagnosis during follow-up 11 (22), 8.5 (4.6–10.8)\nAbdominal distension 10 (20), 11.4 (5–16)\nAbdominal pain 10 (20), 10.0 (7.3–15)\nUrinary symptom 2 (4), 17 (15–19)\nVaginal discharge 1 (2), 5\nMaximum diameter of tumor by pelvic ultrasound (cm)\n4–8 10 (20)\n8–12 25 (50)\n>12 15 (30)\nMedian diameter (cm) 10 (4.6–25)\nOvarian involvement\nUnilateral 40 (80)\nRight 17 (46)\nLeft 23 (34)\nBilateral 10 (20)\nDiagnosis of endometrioma or endometriosis\nBefore staging surgery for clear cell carcinoma (based on ultrasonographic diagnosis) 10/50 (20)\nAfter staging surgery for clear cell carcinoma (based on histologic diagnosis) 35/50 (70)\nLatent period (month) 50 (12–213)\nData are presented as median (range) or number (%).\nBMI, body mass index.\nTable 2. Characteristics of the patients with or without endometriosis background\nCharacteristics Patients with endometriosis  \nbackground (n=35)\nPatients without endometriosis  \nbackground (n=15) P-value\nTumor size (cm) 9.7 (5–20) 10.5 (4.6–25) 0.519\nAge at diagnosis 47 (33–60) 50 (25–65) 0.451\nFIGO stage \nI or II 25 (71.4) 10 (66.7) 0.747\nIII or IV 10 (28.6) 5 (33.3)\nRecurrence event 11 (31.4) 4 (26.6) 0.572\nData are presented as median (range) or number (%).\nFIGO, International Federation of Gynecology and Obstetrics.\n\nwww.ogscience.org 31\nJoo-Hyuk Son, et al. Surveillance strategy of endometrioma\novarian clear cell carcinoma [5,6,18-20]. In a meta-analysis \nof 13 case-control studies including 7,911 women with EOC, \nwomen with a self-reported history of endometriosis had \nthree times the risk of clear cell carcinoma (odds ratio [OR], \n3.05; 95% confidence interval [CI], 2.43–3.84; \nP<0.0001) \nand double the risk of endometrioid (OR, 2.04; 95% CI, \n1.67–2.48; P<0.0001) and low-grade serous carcinoma (OR, \n2.11, 95% CI, 1.39–3.20) [5]. In previous studies, the mech-\nanisms of malignant transformation were suggested to be \nrelated to the activation of oncogenic \nKRAS and PI3K path-\nways and inactivation of tumor suppressor genes PTEN and \nARID1A [19,20]. Menopause status has also been indicated \nas a potential risk factor [14]. In premenopausal woman, \nthe risk of malignant transformation of endometriosis has \nbeen estimated at around 1 percent [15]. However, there \nhave been no age-specific guidelines for the timing of active \nsurveillance in asymptomatic patients. Current guidelines rec\n-\nommend that endometriomas be removed only if they have \nan atypical appearance on imaging studies or other concern\n-\ning features such as enlarged size in asymptomatic patients, \nthough no information as to the timing or interval of surveil\n-\nlance has been provided [21].\nIn this patient cohort, many patients were asymptomatic \nuntil the median tumor size was about 10 cm. In addition, \n80% of the patients did not receive any surveillance until the \nonset of symptoms, and many of them characteristically pre\n-\nsented with a rapidly growing pelvic mass in a background of \nendometriosis. In a Japanese study of 33 patients with clear \ncell carcinoma, tumor size was found to have doubled in the \n6 months prior to the diagnosis of malignant transformation \nin 30 patients. These patients had been followed for at least \n2 years after the diagnosis of ovarian endometrioma and \ncontinued to be followed after the identification of malig\n-\nnant transformation [22]. In the current study, asymptomatic \npatients who had regular gynecologic examinations were \nfound to have a relatively smaller tumor size with less tu\n-\nmor spreading. In light of the median duration (50 months; \nrange, 12–123 months) of malignant transformation and the \nage of cancer incidence, surveillance should be started from \nthe age of the mid-thirties, with at least 1-year interval sur\n-\nTable 3. Clinical stages and recurrence events during the follow-up periods in patients with ovarian clear cell carcinoma\nCharacteristics Incidental diagnosis during gynecologic \nfollow-up (n=11) Symptomatic diagnosis (n=39) P-value\nTumor size 9.6 (4.6–10.8) 11 (5–25) 0.011\nFIGO stage 0.283\nI, II 9 (9/11, 81.8) 26 (26/39, 66.7)\nIII, IV 2 (2/11, 18.2) 13 (13/39, 33.3)\nRecurrence event 1 (1/11, 9.1) 14 (14/39, 35.8) 0.064\nData are presented as median (range) or number (%).\nFIGO, International Federation of Gynecology and Obstetrics.\nTable 4. Treatment outcomes\nCharacteristics Values\nOperation type\nPDS 38 (76)\nIDS 3 (6)\nRe-staging operation 8 (16)\nBiopsy only 1 (2)\nFIGO stage\nI 30 (60)\nII 5 (10)\nIII 12 (24)\nIV 3 (6)\nSynchronous endometrial cancer 1 (2)\nConcurrent thromboembolic disease \nDVT 1 (2)\nPTE 3 (6)\nRecurrence event by stage (%)\nI 2 (6.7)\nII 2 (40)\nIII 9 (75)\nIV 2 (67)\nTotal 15 (30)\nTotal follow up period (month) 34.0 (2–164)\nData are presented as median (range) or number (%).\nPDS, primary debulking surgery; IDS, interval debulking surgery; \nFIGO, International Federation of Gynecology and Obstetrics; DVT, \ndeep vein thrombosis; PTE, pulmonary thromboembolism.\n\nwww.ogscience.org32\nVol. 62, No. 1, 2019\nveillance in asymptomatic patients with endometriosis. Ow -\ning to the rapid growth characteristics of clear cell carcino -\nma, patients should be also informed as to the risk of cancer \nand the necessity of regular gynecologic surveillance despite \na lack of symptoms. If the tumor size increases during regu\n-\nlar follow-up, surgical treatment should be considered, since \novarian clear cell carcinoma has been known to be chemo-\nresistant with an extremely low chemo-response rate [23,24].\nThe current study has some limitations. First, the retrospec\n-\ntive nature of the study might have inevitably led to a patient \nor treatment selection bias. Second, since the most patients \nwith endometriosis were diagnosed at a local clinic, we could \nnot confirm the effectiveness of various multimodal screen\n-\ning tools including CA-125 and sonography. Third, other \nthan age, the risk factors for malignant transformation were \nnot confirmed in this study. Further large studies focusing on \nthe risk factors and screening tools for malignant transfor\n-\nmation are necessary. Despite these limitations, the current \nstudy has proposed a surveillance strategy for asymptomatic \npatients with endometriosis. Despite the overall low inci\n-\ndence of ovarian clear cell carcinoma, the current study had \na relatively long follow-up period in a single institution. In \naddition, all patients were treated with the same quality of \nmedical and surgical treatment.\nIn summary, early detection of malignant transformation \nduring gynecologic evaluation and surgical intervention are \ndirectly associated with oncologic prognosis in asymptomatic \nendometriosis patients. For the timely detection of malignant \ntransformation of ovarian endometrioma, at least 1-year in\n-\nterval surveillance and counseling should be provided, com -\nmencing in the patients’ mid-thirties.\nConflict of Interest\nNo potential conflict of interest relevant to this article was \nTable 5. Risk factors for ovarian clear cell carcinoma recurrence\nCharacteristics No Recurrence (n=35) Recurrence (n=15) P-value\nAge 48.2 50.0 0.726\nParity 1.8 1.4 0.402\nBMI 22.8 23.1 0.426\nMenopause status 12 (34.3) 5 (33.3) 0.608\nMaximum diameter 10.8 12.14 0.451\nBilateral ovarian involvement 5 (14.3) 5 (33.3) 0.125\nOperation type 0.617\nPDS 27 (77.1) 11 (73.3)\nIDS 2 (5.7) 1 (6.7)\nRestaging 6 (17.1) 2 (13.3)\nUSO (n=5) 3 2\nUOC (n=3) 3 0\nNo gross residual disease 35 (100) 11 (73.3) 0.006\nFIGO stage 0.001\nI 28 (80) 2 (13.3)\nII 3 (8.6) 2 (13.3)\nIII 3 (8.6) 9 (60.0)\nIV 1 (2.9) 2 (13.3)\nConcurrent thromboembolic event 3 (8.6) 1 (6.7) 0.702\nPrevious endometriosis diagnosis 8 (22.9) 2 (13.3) 0.654\nData are presented as number (%).\nBMI, body mass index; PDS, primary debulking surgery; IDS, interval debulking surgery; USO, unilateral salpingo-oophoretomy; UOC, unilateral \novarian cystectomy; FIGO, International Federation of Gynecology and Obstetrics.\n\nwww.ogscience.org 33\nJoo-Hyuk Son, et al. 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