Clear Cell Adenocarcinoma Arising from Adenofibroma in a Patient with Endometriosis of the Ovary

Sampson12 was the first to report malignant transformation of ovarian endometriosis. Endometrioid adenocarcinoma and CCAC are the most common types of malignancy arising from ovarian endometriosis.13 Ovarian endometriosis is therefore con- sidered a precursor lesion to endometrioid adenocarcinoma and CCAC of the ovary. Sampson12 and Scott14 suggested the follow- ing criteria for determining whether a tumor has arisen from en- dometriosis: the presence of both malignant and benign endo- metrial tissue in the same ovary; cancer arising from ovarian endometriosis without other invasion; tissue resembling endo- metrial stroma surrounding characteristic epithelial glands; and a transition between benign endometriosis and malignant epi- thelium. In the present case, we found typical endometriosis, be- nign and atypical endometriotic cysts, and possible intraepithe- lial carcinomatous areas in the same ovary. CCAC arising in ovarian endometriosis or CCAF without other invasion was also found. Malignant transformation of ovarian endometriosis occurs in more than 1% of the cases.12 CCAC is the most common type of malignant transformation of ovarian endometriosis, and endo- metrioid adenocarcinoma is the second most common.13 Adenofibromas are also usually associated with ovarian endo- metriosis.5,15 In the present case, we identified benign and bor- B A Fig. 1. Abdominal computed tomography (CT) and laparoscopic findings. (A) Abdominal computed tomography showing a 5.5-cm cystic mass in the right ovary. (B) Laparoscopy findings reveal a fluid containing cystic mass with a smooth surface and focal hem- orrhage. http://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2015.08.07 Clear Cell Adenocarcinoma from Adenofibroma of the Ovary • 157 A C F H B ED G I Fig. 2. Histopathologic findings of the solid part of the mass. (A) The compact arrangement of variably-sized tubulocystic structures in the stroma is consistent with adenofibroma. The cell lining consisted of flattened indiscernible cells or flat cuboidal cells (B) and polygonal cells with abundant clear cytoplasm (C). (D, E) In some areas, stratified epithelium shows tiny buds with atypical nuclei. (F) The transitional zone from benign (white arrows) to borderline (black open arrows) clear cell adenofibromas to clear cell adenocarcinoma (black arrows). (G) Higher magnification shows benign (left) and atypical (right) adenofibromas. (H, I) Area of clear cell adenocarcinoma shows a tubulocystic pattern with hobnail, cuboidal, or flat atypical lining cells characterized by nuclear enlargement and hyperchromasia, and foci of altered stromal re- sponses. http://jpatholtm.org/ http://dx.doi.org/10.4132/jptm.2015.08.07 158 • Cho I, et al. derline adenofibromas, and the borderline adenofibromas dem- onstrated a transition to CCAC. Slow and progressive transform- ation of CCAC from benign to borderline to a microinvasive pattern has been suggested.5 In addition, patients with ovarian CCAF are younger than those with CCAC.5,6 This supports the suggestion of transformation of CCAC from benign to malig- nant tumors. CCAC containing CCAFs are occasionally found.6,16,17 Accord- ing to the classification of CCAC into groups with and without CCAF components, the CCAF (+) group showed a higher fre- quency of histologically low-grade tumors, a lower Ki-67 label- ing index, less frequent endometriosis, and better patient prog- nosis than the CCAF (–) group.7 There are two types of ovarian carcinogenesis, type I and type II. Type I tumors are usually low grade and in low stage, behave in an indolent fashion, and develop slowly from precursor le- sions. However, type II tumors are highly aggressive high grade tumors characterized by frequent TP53 mutations. They are not associated with the usual precursor lesions. CCAC is associated with precursor lesions such as endometriosis, adenofibromas, bor- derline/atypical adenofibromas and endometriotic cysts. It is also found in a low stage, showing a low frequency of TP53 muta- tions. However, CCAC is high grade and associated with poor prognosis when it is found in high stage.18 Zhao et al.18 speculat- ed that ovarian CCAC have two pathways. In one, epithelial atypia arises in an endometriotic cyst and then evolves into CCAC, and in the other, non-cystic endometriosis induces a fi- bromatous reaction resulting in the formation of an adenofibro- ma, which then develops into borderline adenofibroma and sub- sequently CCAC. Therefore, CCACs with or without adenofi- bromas are more closely related to type I tumors. Adenofi- bromatous and cystic types of CCAC appear to be derived from endometriosis. Adenofibromatous CCAC develops from non- cystic endometriosis and is associated with an adenofibromatous background, while the cystic type of CCAC develops from an endometriotic cyst and is not associated with an adenofibroma- tous background.18 The two pathways may overlap in some cases. The present case showed benign and borderline CCAFs, border- line CCAF with microinvasion, CCAC, endometriosis, and be- nign and atypical endometriotic cysts. Thus, the two pathways Fig. 3. Histopathologic findings of adenofibroma, endometriotic cyst, and endometriosis (A). Higher magnification of the inset shows endo- metriosis (B). (C) Endometriotic cyst with tubal-type epithelium overlying scant endometrial-type stroma. (D) Endometriotic cyst with simple cuboidal epithelium overlying endometrial stroma with hemosiderin pigmentation (upper) and gradual transition to nuclear atypia demonstrat- ing stratification with hyperchromatic, enlarged, and irregular nuclei with prominent nucleoli (middle and lower). A C B D http://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2015.08.07 Clear Cell Adenocarcinoma from Adenofibroma of the Ovary • 159 overlapped in the present case. ARID1A mutation and loss of the corresponding protein, BAF250a, are common in CCAC. However, loss of BAF250a expression is significantly more com- mon in CCAC with endometriosis than in cases with adenofi- broma.19 There is a common genetic linkage between endometriosis and ovarian cancers such as CCAC, including losses of heterozy- gosity (LOHs) and alleles at the PTEN locus.9-11 Moreover, there is also a common genetic linkage between CCAF and ovarian CCAC, such as LOHs on 5q, 10q, and 22q.7 Therefore, possible alternative ovarian clear cell carcinogenic pathways are endome- triosis to CCAC, CCAF to CCAC, or endometriosis to CCAF/ adenofibroma to CCAC. The present case demonstrates that both CCAF and endome- triosis should be regarded as precursors to CCAC. Conflicts of Interest No potential conflict of interest relevant to this article was reported. Acknowledgments This study was supported by research fund from Chosun Uni- versity, 2014.

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