{"paper_id":"0a6cd5c9-9349-4d2f-bca0-2298b116f669","body_text":"Research Article\nClinical Obstetrics, Gynecology and Reproductive Medicine\nClin Obstet Gynecol Reprod Med, 2017        doi: 10.15761/COGRM.1000178\n Volume 3(2): 1-3\nUltrasound monitoring of endometriomas—is there \nevidence of benefit for ovarian cancer detection?\nElizabeth Suh-Burgmann1* and Yun-Yi Hung2\n1Division of Gynecologic Oncology, The Permanente Medical Group, California, USA\n2Division of Research, Kaiser Permanente Northern California, California, USA\nAbstract\nObjective: To evaluate the potential impact of ultrasound monitoring of detected endometriomas on stage at diagnosis of clear cell and endometrioid type ovarian \ncancer.   \nMethods: Retrospective observational study of women diagnosed with clear cell or endometrioid type ovarian cancer between 1/1/2007 and10/15/2015 within a closed \nintegrated health system. Electronic medical records were reviewed to determine the proportion of women with these cancers who had a suspected endometrioma \ndescribed on ultrasound prior to their cancer diagnosis, the time interval between the report and diagnosis of cancer, whether follow-up imaging was done, and stage \nat diagnosis.    \nResults: Among 335 women diagnosed with clear cell or endometrioid ovarian cancer, 11 women (3.3%, 95%CI: 1.65% -5.8%) had a suspected endometrioma \nreported more than 1 year prior to cancer diagnosis with no intervening evidence of removal or resolution.  The median time interval from first report of an \nendometrioma to diagnosis was 15 years (range: 5-18 years).  In no cases, did monitoring in the absence of new symptoms lead to diagnosis of cancer.  At surgery, 8 \nwomen were found to have stage 1 disease, two women had stage 2 disease, and one woman had stage 3 disease.  \nConclusions: Prolonged ultrasound monitoring of suspected endometriomas is unlikely to significantly affect ovarian cancer stage at diagnosis.\nCorrespondence to: Elizabeth Suh-Burgmann, MD, Division of Gynecologic \nOncology, The Permanente Medical Group, California, USA; E-mail: Betty.Suh-\nBurgmann@kp.org\nReceived: March 20, 2017; Accepted: April 04, 2017; Published: April 07, 2017\nIntroduction\nClear cell and endometrioid ovarian carcinomas account for \napproximately 10-20% of ovarian cancers and, in contrast to high \ngrade serous cancers, are frequently diagnosed at early stage [1].  The \ndistinct clinical behavior and biology of these subtypes supports a \ndualistic model of ovarian carcinogenesis in which Type 1 cancers, \nwhich include clear cell and endometrioid histologies, are thought to \narise from benign ovarian precursor lesions, whereas Type 2 cancers \nsuch as high grade serous carcinoma arise primarily from fallopian \ntube dysplasia [2].\n Strong observational as well as molecular data \nsupport the notion that endometriomas and endometriotic implants \ncan act as precursors for clear cell and endometrioid ovarian cancers \n[3-7].\n Given this paradigm, the question arises whether long-term \nultrasound monitoring of endometriomas, which are common benign \novarian lesions, leads to meaningful benefit in terms of early detection \nof clear cell or endometrioid adenocarcinoma.  In order to assess the \npotential benefit of prolonged monitoring of suspected endometriomas \non cancer stage at diagnosis, we determined the proportion of women \ndiagnosed with clear cell or endometrioid ovarian cancer who had a \ndocumented history of a suspected endometrioma remote from their \ndiagnosis, and evaluated the clinical presentation leading to diagnosis. \nMethods\nStudy design, setting, and study cohort\nRetrospective observational cohort study. Following approval \nfrom the Kaiser Permanente Northern California Institutional Review \nBoard for Health Services,  all women diagnosed with clear cell and \nendometrioid ovarian cancer between January 1, 2007 and October \n15, 2015 within Kaiser Permanente Northern California (KPNC) were \nidentified via the institution’s tumor registry and confirmed by manual \nelectronic medical record (EMR) review.  Electronic medical record \nsystems were implemented throughout KPNC during 2006. The study \ninterval was selected in order to capture the maximum number of clear \ncell and endometrioid ovarian cancer cases during the time frame in \nwhich ultrasound reports and clinical notes would be reliably captured \nin the EMR. Demographic characteristics as well as the length of time \nthat women had been members of the health plan prior to cancer \ndiagnoses were determined from health plan enrollment records. \nUsing electronic database searches of pelvic ultrasound transcripts and \nconfirmatory chart review, all non-obstetric pelvic ultrasounds > 12 \nmonths prior to the diagnosis of cancer for each patient were identified \nin which a mass was described as a possible or probable endometrioma. \nWomen with at least one such ultrasound report were considered to \nbe those for whom long-term monitoring of an endometrioma could \npotentially have facilitated diagnosis of cancer.  Women were excluded \nfrom this group if subsequent to the report, there was documented \nsurgical removal or resolution of the lesion on follow-up imaging prior \nto cancer diagnosis. \nThe clinical presentation that led to cancer diagnosis was assessed \nfrom the medical records, reviewing outpatient or emergency room \nvisit notes as well as the indications for ultrasound or other imaging \n\nSuh-Burgmann E (2017) Ultrasound monitoring of endometriomas—is there evidence of benefit for ovarian cancer detection?\nClin Obstet Gynecol Reprod Med, 2017        doi: 10.15761/COGRM.1000178\n Volume 3(2): 2-3\nthat was ordered. The time from the first ultrasound description of the \nendometrioma to cancer diagnosis was determined. Surgical pathology \nreports were reviewed for histology and stage at diagnosis. Staging \nwas considered complete if both omental and retroperitoneal nodal \nevaluation were performed in addition to removal of the tumor. \nStatistical analysis\nComparisons involving categorical variables were performed using \nChi-square or Fisher’s exact test.  Normally distributed continuous \nvariables were compared using Student’s t-test.  Comparisons of \nnon-normally distributed continuous variables were conducted using \nthe Wilcoxon rank-sum test.  All analyses were performed using \nStatistical Analysis Systems (SAS) version 9.3 (SAS Institute, Cary, \nNorth Carolina). We considered a 2-sided P value less than 0.05 to be \nstatistically significant. \nResults\nWe identified 335 women diagnosed with primary clear cell/\nendometrioid ovarian cancer between January 1, 2007 and October \n15, 2015. Prior to cancer diagnosis, women had been members in \nthe health plan for an average of 10 years (median 11 years’ range: 0 \n- 18 years).  The average age at cancer diagnosis was 57 years old.  Of \nthe 335 women, 104 had at least one pelvic ultrasound done at least \n1 year prior to cancer diagnosis and in 11 cases (3.3%, 95%CI: 1.65% \n-5.8%), the report described a possible or probable endometrioma. The \naverage age at first detection of the endometrioma was 46 years old. The \ndemographic characteristics of women with and without a history of \nreported endometrioma are shown in Table 1. \nThe median time interval from initial report of an endometrioma \nto diagnosis for 10 of the 11 women was 15 years (range: 5-18 years). \nFor one woman, an endometrioma was reported in May 2005, she \ndiscontinued membership between Aug 2005 and March 2014, and \ncancer was diagnosed shortly after resumption of membership.  \nThe clinical presentation leading to diagnosis of cancer is shown \nin Table 2. Three women had a history of previous surgery for \nendometriosis and/or endometrioma. Pain was the most common \npresenting complaint (8/11).  All women underwent staging with \nassessment of retroperitoneal lymph nodes and omentum in addition \nto total hysterectomy and bilateral salpingooophorectomy. At surgery, \n8 women were found to have stage 1 disease, two women had stage 2 \ndisease, and one woman had stage 3 disease.\nDiscussion\nSeveral observational studies have reported an association between \nendometrioma, endometriosis and ovarian cancer [3-7]. An increased \nincidence of ovarian cancer was reported among women who were \nentered into a registry of women with clinical endometriomas in Japan \n[8]. With a median ot 12.8 years of follow-up, 0.72% of women developed \novarian cancer, 74% of which were either clear cell or endometrioid \nhistology.  The investigators found that older age as well as large size \nof the endometrioma  increased the risk of subsequent cancer [9].\n \nA pooled analysis of 13 case-control studies found an increased risk \nof clear cell (OR, 3.05) and endometrioid (OR, 2.21) ovarian cancer \namong women who reported a history of endometriosis [3].\n In addition \nto observational data, recent studies provide molecular support for the \nhypothesis that endometrioid and clear cell carcinomas arise out of \nendometriotic implants and endometriomas.  Mutations in both PTEN \nand the tumor suppressor gene ARIDIA have been observed in up both \nclear cell and endometrioid cancers as well as adjacent endometrioitic \nepithelium [10-14]. \nThe failure of ovarian screening trials to demonstrate survival \nbenefit is partially explained by the heterogeneity of ovarian cancers.  It \nis now recognized that Type 2 cancers, which represent the majority of \novarian malignancies, arise primarily from fallopian tube precursors.  \nWhile the pathogenesis of Type I cancers would appear to make them \nmore amenable to detection by screening, as noted by Kurman “the \n Characteristics Total cohort (N=335)\nWomen with documented \nhistory of endometrioma \n(N=11)\nWomen without \ndocumented history of \nendometrioma (N=324)\nP-value\nRace/Ethnicity\nWhite/Caucasian, n (%) 176 (53) 4 (36) 172 (53)\nFisher exact test p-value=0.087 \nAfrican-American, n (%) 22 (7) 1 (9) 21 (7)\nHispanic, n (%) 40 (12) 4 (36) 36 (11)\nAsian Pacific Islander, n (%) 74 (22) 1 (9) 72 (23)\nNative American/other, n (%) 23 (7) 1 (9) 22 (7)\nAge at cancer diagnosis, median (interquartile range) 56 (49-64) 55 (44-60) 56 (50-64) Wilcoxon rank-sum testp-value=0.354\nTable 1.Demographic characteristics of women with and without a prior ultrasound reporting endometrioma.\n# Age at first detection of \nendometrioma Age at cancer diagnosis Hx of surgically documented \nendometriosis   endometrioma Presenting complaint Stage \n1 42 57 No Pain 1a\n2 54 68 No Pain and postmenopausal bleeding 2b\n3 59 69 No Pain 1a\n4 49 57 No Postmenopausal bleeding 1a\n5 36 39 No Pain 1c\n6 46 60 No Mass on exam 1c\n7 40 45 Yes Pain 1a\n8 44 53 No Right pleural effusion and \npostmenopausal bleeding 1a\n9 54 55 Yes Pain 1c \n10 41 44 No Pain 1a\n11 40 44 No pain 3c\nTable 2. Clinical presentation and stage at diagnosis for women with history of endometrioma.\n\nSuh-Burgmann E (2017) Ultrasound monitoring of endometriomas—is there evidence of benefit for ovarian cancer detection?\nClin Obstet Gynecol Reprod Med, 2017        doi: 10.15761/COGRM.1000178\n Volume 3(2): 3-3\nFunding\nFunding for the study was provided by the Community Benefits \nProgram of Kaiser Permanente Northern California.\nReferences\n1. Kosary CL (2007) Cancer of the ovary. In: Reis LAG, Young JL, Keel GE, Eisner \nMP, Lin YD, Horner MJ, editors. Seer Survival Monograph: Cancer Survival Among \nAdults: US SEER Program, 1988-2001, Patient and Tumor Characteristics. Publication \nNo. 07-6215. Bethesda, MD: National Cancer Institute, 133–44. \n2. Kurman RJ, Shih IeM (2010) The origin and pathogenesis of epithelial ovarian cancer: \na proposed unifying theory. Am J Surg Pathol 34: 433-443. [Crossref]\n3. Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, et al. (2012) Association \nbetween endometriosis and risk of histological subtypes of ovarian cancer: a pooled \nanalysis of case-control studies. Lancet Oncol 13: 385-394. [Crossref]\n4. King CM, Barbara C, Prentice A, Brenton JD, et al. (2016) Models of endometriosis \nand their utility in studying progression to ovarian clear cell carcinoma. J Pathol 238: \n185-196. [Crossref]\n5. Lu Y, Cuellar-Partida G, Painter JN, Nyholt DR, Australian Ovarian Cancer Study; \nInternational Endogene Consortium (IEC), Morris AP, et al. (2015) Shared genetics \nunderlying epidemiological association between endometriosis and ovarian cancer. \nHum Mol Genet 24: 5955-5964. [Crossref]\n6. Worley MJ Jr, Liu S, Hua Y, Kwok JS, Samuel A, et al. (2015) Molecular changes in \nendometriosis-associated ovarian clear cell carcinoma. Eur J Cancer 51: 1831-1842. \n[Crossref]\n7. Acién P, Velasco I, Acién M, Capello C, Vela P (2015) Epithelial ovarian cancers and \nendometriosis. Gynecol Obstet Invest 79: 126-135. [Crossref]\n8. Kobayashi H, Sumimoto K, Moniwa N, Imai M, Takakura K, et al. (2007) Risk of \ndeveloping ovarian cancer among women with ovarian endometrioma: a cohort study \nin Shizuoka, Japan. Int J Gynecol Cancer 17: 37-43. [Crossref]\n9. Kobayashi H, Sumimoto K, Kitanaka T, Yamada Y, Sado T, et al. (2008) Ovarian \nendometrioma--risks factors of ovarian cancer development. Eur J Obstet Gynecol \nReprod Biol 138: 187-193. [Crossref]\n10. Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, et al. (2010) ARID1A mutations in \nendometriosis-associated ovarian carcinomas. N Engl J Med 363: 1532-1543. [Crossref]\n11. Matsumoto T, Yamazaki M, Takahashi H, Kajita S, Suzuki E, et al. (2015) Distinct \nß-catenin and PIK3CA mutation profiles in endometriosis-associated ovarian \nendometrioid and clear cell carcinomas. Am J Clin Pathol 144: 452-463. \n12. Mao TL, Shih IeM (2013) The roles of ARID1A in gynecologic cancer. J Gynecol \nOncol 24: 376-381. [Crossref]\n13. Maeda D, Shih IeM (2013) Pathogenesis and the role of ARID1A mutation in \nendometriosis-related ovarian neoplasms. Adv Anat Pathol 20: 45-52. [Crossref]\n14. Jiang X, Morland SJ, Hitchcock A, Thomas EJ, Campbell IG (1998) Allelotyping of \nendometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. \nCancer Res 58: 1707-1712. [Crossref]\n15. Kurman RJ (2013) Origin and molecular pathogenesis of ovarian high-grade serous \ncarcinoma. Ann Oncol 24 Suppl 10: x16-21. [Crossref]\ntumors that present in stage I are type I neoplasms, which account for \n10% of deaths from ovarian cancer,” [15] underscoring the fact that \nscreening is only beneficial if it detects a cancer earlier than it would \notherwise be detected.  The main potential benefit of monitoring an \nasymptomatic adnexal mass is the possibility that the mass represents \neither an early cancer or a cancer precursor and that monitoring will \nlead to earlier stage at diagnosis. Since women with symptomatic \nendometriomas are generally offered surgical removal, the clinical \nquestion is whether monitoring asymptomatic endometriomas can be \njustified based on potential benefit. \nThe strengths of this study are the population-based nature \nof the cohort, the length of observation, and the completeness of \ndata regarding prior imaging, clinical presentation and treatment. \nIdentification of patients did not rely on referral and draws on a \nracial and ethnically diverse population.  Limitations of the study \ninclude those inherent to retrospective review. The duration of time \nthat women had been within the health plan prior to cancer diagnosis \nwas variable. It is possible that women may have had ultrasounds \ndone prior to becoming health plan members. The study identified \nwomen whose ultrasound reports specifically described a mass as a \npossible or probable endometrioma. It did not identify women based \non ultrasound characteristics themselves. There may have been some \nwomen with prior endometriomas who were not recognized either due \nto the inherent limitations of ultrasound and/or variability in radiology \nreporting, or due to the fact that they never had an ultrasound or \nother imaging study prior to cancer diagnosis. Because it is impossible \nfor any study to accurately identify all women with endometriomas \nindependent of imaging, the absolute risk of clear cell or endometrioid \ncancer arising from an endometrioma cannot be determined, and was \nnot the goal of the study. Rather, we sought to assess the potential yield \nof prolonged ultrasound monitoring of known endometriomas on \ncancer detection and stage at diagnosis.\nWe found that the proportion of women with clear cell and \nendometrioid ovarian cancer who had a prior ultrasound reporting \nan endometrioma is small at 3.3%, the average time interval between \nendometrioma detection and cancer was 15 years, and that among these \nwomen, evaluation prompted by clinical symptoms led to early stage \ndiagnosis in 10/11 cases. These findings suggest that although a history \nof endometrioma and endometriosis is a risk factor for development \nof clear cell or endometrioid ovarian cancer, long-term ultrasound \nmonitoring of suspected endometriomas is unlikely to significantly \naffect ovarian cancer stage at diagnosis.\nCopyright: ©2017 Suh-Burgmann E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits \nunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.","source_license":"CC0","license_restricted":false}