{"paper_id":"1cedce4d-1f45-4ada-a6b6-76b764225156","body_text":"155\n© 2016 The Korean Society of Pathologists/The Korean Society for Cytopathology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ \nby-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\npISSN 2383-7837\neISSN 2383-7845\nClear Cell Adenocarcinoma Arising from Adenofibroma in a Patient  \nwith Endometriosis of the Ovary\nInju Cho · Sung-Chul Lim\nDepartment of Pathology, Chosun University \nSchool of Medicine, Gwangju, Korea\nOvarian clear cell adenocarcinomas (CCACs) are frequently associated with endometriosis and, \nless often with clear cell adenofibromas (CCAFs). We encountered a case of ovarian CCAC aris-\ning from benign and borderline adenofibromas of the clear cell and endometrioid types with en-\ndometriosis in a 53-year-old woman. Regions of the adenofibromas showed transformation to \nCCAC and regions of the endometriosis showed atypical endometriotic cysts. This case demon-\nstrates that CCAC can arise from CCAF or endometriosis.\nKey Words: Adenocarcinoma, clear cell; Adenofibroma; Endometriosis; Ovary\nReceived: April 9, 2015\nRevised: July 23, 2015\nAccepted: August 7, 2015\nCorresponding Author\nSung-Chul Lim, MD, PhD\nDepartment of Pathology, Chosun University \nHospital, 365 Pilmun-daero, Dong-gu, Gwangju \n61453, Korea \nTel: +82-62-230-6343\nFax: +82-62-226-5860\nE-mail: sclim@chosun.ac.kr\nJournal of Pathology and Translational Medicine 2016; 50: 155-159\nhttp://dx.doi.org/10.4132/jptm.2015.08.07\n▒ CASE STUDY ▒\nHistological and epidemiological analyses have demonstrated \na close relationship between endometriosis and ovarian clear cell \nadenocarcinoma (CCAC).1-3 Clear cell adenofibroma (CCAF) is \na major benign or borderline type of ovarian clear cell tumor.4 \nHowever, benign CCAF is extremely rare.5,6 One study demon-\nstrated the coexistence of CCAF components (14 cases) in 21% \nof surgically resected ovarian CCACs. Of these 14 CCAF (+) \ncases, CCAF with atypia were found adjacent to CCAF without \natypia in 10, and adjacent to obvious CCACs in 13 cases.7 There-\nfore, we can speculate that both CCAF and endometriosis may \nbe precursors of CCAC. Several studies have demonstrated that \nthere is a genetic linkage between CCAF and CCAC,8 as well as \nbetween endometriosis and CCAC.9-11 \nHere, we report a case of CCAC in a 53-year-old woman with \nboth benign and borderline ovarian adenofibromas of the clear \ncell and endometrioid types, in addition to endometriosis. \nCASE REPORT\nA 53-year-old woman visited a local obstetrics and gynecolo-\ngy clinic for a routine examination. Ultrasonography demon-\nstrated a right ovarian cystic mass. The patient was referred to \nthe Department of Obstetrics and Gynecology at Chosun Uni-\nversity Hospital for further evaluation and treatment. The pa-\ntient had a history of laparoscopic left salpingo-oophorectomy \nand adhesiolysis due to left ovarian teratoma and intestinal ad-\nhesion seven years earlier. She had also experienced an intracra-\nnial hemorrhage 3 years earlier, and had suffered from medica-\ntion-controlled hypothyroidism for 5 years. \nAbdominal computed tomography revealed a 5.5-cm cystic \nmass in her right ovary (Fig. 1A). The cyst was unilocular with \nfluid attenuation, and there was no contrast-enhancing solid \nmass. Laparoscopy findings revealed a fluid-containing cystic \nmass that had a smooth surface with focal hemorrhage (Fig. 1B). \nLaparoscopic right salpingo-oophorectomy and adhesiolysis was \nundertaken under the clinical impression of benign cystadenoma. \nGross findings revealed a previously collapsed cystic mass \nmeasuring 5 cm × 4.5 cm × 2.5 cm. The mass showed a 2.3 cm × \n1.2 cm solid part on one side. Histologic examination revealed \nbenign and borderline CCAFs, endometriosis, atypical endome-\ntriotic cysts, and CCAC. The solid portion consisted of benign \nand borderline CCAF, CCAC, and endometriosis in descending \norder of prevalence. The cystic portion was merged into the solid \nportion of CCAF and CCAC, and consisted of benign and atyp-\nical endometriotic cysts. \nThe benign CCAF constituted a major portion of the tumor \n\n\nhttp://jpatholtm.org/ http://dx.doi.org/10.4132/jptm.2015.08.07\n156     •  Cho I, et al.\nand demonstrated a compact arrangement of variably sized tu-\nbulocystic structures in the cellular stroma with no nuclear atyp-\nia. Flattened indiscernible, flat cuboidal, and polygonal cells with \nrelatively abundant cytoplasm and no nuclear atypia lined the \nmass (Fig. 2). The glands in the borderline CCAF showed a great-\ner degree of crowding and variation in size and shape compared \nwith the benign CCAF. Focal nuclear atypia was observed in the \nglandular linings. The glands were delineated with one to three \nlayers of cells with abundant cytoplasm and mildly pleomorphic, \nhyperchromatic nuclei. In some areas, stratified epithelium \nshowed tiny buds with atypical nuclei. However, the glands in \nmany areas were lined with non-atypical flat to cuboidal epithe-\nlium (Fig. 2). \nThe CCAC had a tubulocystic pattern with hobnail, cuboidal \nor flat atypical cell lining, characterized by nuclear enlargement \nand hyperchromasia. The glands were separated by fibrous stro-\nma, and foci of altered stromal responses were noted. There was \ncrowding of tubules with a slightly haphazard arrangement in \nsome areas. The borderline CCAF had microinvasion character-\nized by a few cells scattered haphazardly in the surrounding \nstroma. The borderline CCAF and CCAC were scattered, and a \nhistologic continuum between borderline CCAF and CCAC was \nfound within the same tumor (Fig. 2).\nThe benign endometriotic cysts had a predominantly cystic \ngross appearance. Typical endometriotic cysts showed minimally \nstratified tubal-type epithelium overlying the scant endometri-\nal-type stroma. This endometriotic epithelium gradually showed \ngreater nuclear atypia, demonstrating a multilayered epithelium \nwith hyperchromatic, enlarged and irregular nuclei with prom-\ninent nucleoli as it merged with possible intraepithelial carci-\nnomatous areas (Fig. 3).\nThe presence of benign and borderline CCAFs, borderline \nCCAF with microinvasion, CCAC, endometriosis, and benign \nand atypical endometriotic cysts within this single ovarian mass \nsuggests a histologic continuum among endometriosis, CCAF \nand CCAC.\nDISCUSSION\nSampson12 was the first to report malignant transformation \nof ovarian endometriosis. Endometrioid adenocarcinoma and \nCCAC are the most common types of malignancy arising from \novarian endometriosis.13 Ovarian endometriosis is therefore con-\nsidered a precursor lesion to endometrioid adenocarcinoma and \nCCAC of the ovary. Sampson12 and Scott14 suggested the follow-\ning criteria for determining whether a tumor has arisen from en-\ndometriosis: the presence of both malignant and benign endo-\nmetrial tissue in the same ovary; cancer arising from ovarian \nendometriosis without other invasion; tissue resembling endo-\nmetrial stroma surrounding characteristic epithelial glands; and \na transition between benign endometriosis and malignant epi-\nthelium. In the present case, we found typical endometriosis, be-\nnign and atypical endometriotic cysts, and possible intraepithe-\nlial carcinomatous areas in the same ovary. CCAC arising in \novarian endometriosis or CCAF without other invasion was also \nfound.\nMalignant transformation of ovarian endometriosis occurs in \nmore than 1% of the cases.12 CCAC is the most common type of \nmalignant transformation of ovarian endometriosis, and endo-\nmetrioid adenocarcinoma is the second most common.13 \nAdenofibromas are also usually associated with ovarian endo-\nmetriosis.5,15 In the present case, we identified benign and bor-\nB\nA\nFig. 1. Abdominal computed tomography (CT) and laparoscopic \nfindings. (A) Abdominal computed tomography showing a 5.5-cm \ncystic mass in the right ovary. (B) Laparoscopy findings reveal a \nfluid containing cystic mass with a smooth surface and focal hem-\norrhage.\n\nhttp://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2015.08.07\nClear Cell Adenocarcinoma from Adenofibroma of the Ovary  •     157\nA\nC\nF\nH\nB\nED\nG\nI\nFig. 2. Histopathologic findings of the solid part of the mass. (A) The compact arrangement of variably-sized tubulocystic structures in the \nstroma is consistent with adenofibroma. The cell lining consisted of flattened indiscernible cells or flat cuboidal cells (B) and polygonal cells \nwith abundant clear cytoplasm (C). (D, E) In some areas, stratified epithelium shows tiny buds with atypical nuclei. (F) The transitional zone \nfrom benign (white arrows) to borderline (black open arrows) clear cell adenofibromas to clear cell adenocarcinoma (black arrows). (G) Higher \nmagnification shows benign (left) and atypical (right) adenofibromas. (H, I) Area of clear cell adenocarcinoma shows a tubulocystic pattern \nwith hobnail, cuboidal, or flat atypical lining cells characterized by nuclear enlargement and hyperchromasia, and foci of altered stromal re-\nsponses.\n\nhttp://jpatholtm.org/ http://dx.doi.org/10.4132/jptm.2015.08.07\n158     •  Cho I, et al.\nderline adenofibromas, and the borderline adenofibromas dem-\nonstrated a transition to CCAC. Slow and progressive transform-\nation of CCAC from benign to borderline to a microinvasive \npattern has been suggested.5 In addition, patients with ovarian \nCCAF are younger than those with CCAC.5,6 This supports the \nsuggestion of transformation of CCAC from benign to malig-\nnant tumors. \nCCAC containing CCAFs are occasionally found.6,16,17 Accord-\ning to the classification of CCAC into groups with and without \nCCAF components, the CCAF (+) group showed a higher fre-\nquency of histologically low-grade tumors, a lower Ki-67 label-\ning index, less frequent endometriosis, and better patient prog-\nnosis than the CCAF (–) group.7 \nThere are two types of ovarian carcinogenesis, type I and type \nII. Type I tumors are usually low grade and in low stage, behave \nin an indolent fashion, and develop slowly from precursor le-\nsions. However, type II tumors are highly aggressive high grade \ntumors characterized by frequent TP53 mutations. They are not \nassociated with the usual precursor lesions. CCAC is associated \nwith precursor lesions such as endometriosis, adenofibromas, bor-\nderline/atypical adenofibromas and endometriotic cysts. It is also \nfound in a low stage, showing a low frequency of TP53 muta-\ntions. However, CCAC is high grade and associated with poor \nprognosis when it is found in high stage.18 Zhao et al.18 speculat-\ned that ovarian CCAC have two pathways. In one, epithelial \natypia arises in an endometriotic cyst and then evolves into \nCCAC, and in the other, non-cystic endometriosis induces a fi-\nbromatous reaction resulting in the formation of an adenofibro-\nma, which then develops into borderline adenofibroma and sub-\nsequently CCAC. Therefore, CCACs with or without adenofi-\nbromas are more closely related to type I tumors. Adenofi-\nbromatous and cystic types of CCAC appear to be derived from \nendometriosis. Adenofibromatous CCAC develops from non-\ncystic endometriosis and is associated with an adenofibromatous \nbackground, while the cystic type of CCAC develops from an \nendometriotic cyst and is not associated with an adenofibroma-\ntous background.18 The two pathways may overlap in some cases. \nThe present case showed benign and borderline CCAFs, border-\nline CCAF with microinvasion, CCAC, endometriosis, and be-\nnign and atypical endometriotic cysts. Thus, the two pathways \nFig. 3. Histopathologic findings of adenofibroma, endometriotic cyst, and endometriosis (A). Higher magnification of the inset shows endo-\nmetriosis (B). (C) Endometriotic cyst with tubal-type epithelium overlying scant endometrial-type stroma. (D) Endometriotic cyst with simple \ncuboidal epithelium overlying endometrial stroma with hemosiderin pigmentation (upper) and gradual transition to nuclear atypia demonstrat-\ning stratification with hyperchromatic, enlarged, and irregular nuclei with prominent nucleoli (middle and lower).\nA\nC\nB\nD\n\nhttp://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2015.08.07\nClear Cell Adenocarcinoma from Adenofibroma of the Ovary  •     159\noverlapped in the present case. ARID1A mutation and loss of \nthe corresponding protein, BAF250a, are common in CCAC. \nHowever, loss of BAF250a expression is significantly more com-\nmon in CCAC with endometriosis than in cases with adenofi-\nbroma.19\nThere is a common genetic linkage between endometriosis \nand ovarian cancers such as CCAC, including losses of heterozy-\ngosity (LOHs) and alleles at the PTEN locus.9-11 Moreover, there \nis also a common genetic linkage between CCAF and ovarian \nCCAC, such as LOHs on 5q, 10q, and 22q.7 Therefore, possible \nalternative ovarian clear cell carcinogenic pathways are endome-\ntriosis to CCAC, CCAF to CCAC, or endometriosis to CCAF/\nadenofibroma to CCAC. \nThe present case demonstrates that both CCAF and endome-\ntriosis should be regarded as precursors to CCAC.\nConflicts of Interest\nNo potential conflict of interest relevant to this article was \nreported.\nAcknowledgments\nThis study was supported by research fund from Chosun Uni-\nversity, 2014.\nREFERENCES\n1. 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