Clinicopathological heterogeneity in ovarian clear cell adenocarcinoma: a study on individual therapy practice

Ovarian clear cell adenocarcinoma (CCA) has been believed to be a lethal histological subtype of an epithelial ovarian adenocarcinoma (EOA); its precursor has been assumed to be endometriosis. However, it has been reported that CCAs occasionally exhibit different clinical behaviors, suggesting that CCAs might not belong to a single category. We focused on CCAs combined with other histological types of EOAs; we re-evaluated the pathology of 46 CCAs and divided them into two subgroups: 35 CCAs alone (pure-type CCAs); and 11 CCAs with other histological types, endometrioid adenocarcinomas (EAs) or/and serous adenocarcinomas (SAs) (mixed-type CCAs). Immunohistochemical analysis for expression of ARID1A, p53, PTEN, Annexin 4, hepatocyte nuclear factor-1β (HNF-1β), and WT-1 was employed. We identified that patients with endometriosis were younger than those without endometriosis in pure-type CCAs (P < 0.005). In mixed-type CCAs, the immunohistochemical-staining patterns revealed internal transition of each histological component. In pure-type CCAs, expressions of ARID1A and p53 were mutually altered, and altered expression of p53 was associated with worse prognosis than that of ARID1A (P < 0.001). Our results provide evidence that CCAs would have clinicopathological heterogeneity, determining the patient’s prognosis. Furthermore, immunohistochemical analysis may shed light on the selection of appropriate treatment, including chemotherapy. Similar content being viewed by others

Peham H (1899) Aus accessorischen nebennieren-anlage entstandene ovarial-tumore. Monatschr Geburtsch Gynäk 10:685–687 Schiller W (1939) Mesonephroma ovarii. Am J Cancer 35:1–21 Scully RE, Barlow JF (1967) ‘‘Mesonephroma’’ of the ovary: tumor of Müllerian nature related to endometrioid carcinoma. Cancer 20:1405–1412 Serov SF, Scully RE, Jobin LH (1973) Histologic typing of ovarian tumors. In: Scully RE ed World Health Organization. International Histological Classification of Tumours. Geneva: Springer, p37–42 Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, Suzuki M, Sato I, Taguchi K (2000) Clinical characteristics of clear cell carcinoma of the Ovary. Cancer 11:2584–2589 del Carmen MG, Birrer M, Schorge JO (2012) Clear cell carcinoma of the ovary: a review of the literature. Gynecol Oncol 126:481–490 Takano M, Kikuchi Y, Yaegashi N, Kuzuya K, Ueki M, Tsuda H, Kigawa J, Takeuchi S, Tsuda H, Moriya T, Sugiyama T (2006) Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer 94:1369–1374 Pectasides D, Fountzilas G, Aravantinos G, Kalofonos C, Efstathiou H, Farmakis D, Skarlos D, Pavlidis N, Economopoulos T, Dimopoulos MA (2006) Advanced stage clear-cell ovarian cancer: the Hellenic cooperative oncology group experience. Gynecol Oncol 102:285–291 Ho CM, Huang YJ, Chen TC, Huang SH, Liu FS, Chang Chien CC, Yu MH, Mao TL, Wang TY, Hsieh CY (2004) Pure-type clear cell carcinoma of the ovary as a distinct histologic type and improved survival in patients treated with paclitaxel-platinum-based chemotherapy in pure-type advanced disease. Gynecol Oncol 94:197–203 Utsunomiya H, Akahira J, Tanno S, Moriya T, Toyoshima M, Niikura H, Ito K, Morimura Y, Watanabe Y, Yaegashi N (2006) Paclitaxel-platinum combination chemotherapy for advanced or recurrent ovarian clear cell adenocarcinoma: a multicenter trial. Int J Gynecol Cancer 16:52–56 Recio FO, Piver MS, Hempling RE, Driscol DL (1996) Lack of improved survival plus increase in thromboembolic complications in patients with clear cell carcinoma of the ovary treated with platinum versus nonplatinum-based chemotherapy. Cancer 78:2157–2163 Rauh-Hain JA, Winograd D, Growdon WB, Goodman AK, Boruta DM 2nd, Schorge JO, del Carmen MG (2012) Prognostic determinants in patients with uterine and ovarian clear cell carcinoma. Gynecol Oncol 125:376–380 Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, Shih Ie M, Kurman RJ (2009) Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Pathol 33:844–853 Kurman RJ, Shih Ie M (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Pathol 34:433–443 Yamamoto S, Tsuda H, Shimazaki H, Takano M, Yoshikawa T, Kuzuya K, Tsuda H, Kurachi H, Kigawa J, Kikuchi Y, Sugiyama T, Matsubara O (2011) Clear cell adenocarcinoma with a component of poorly differentiated histology: a poor prognostic subgroup of ovarian clear cell adenocarcinoma. Int J Gynecol Pathol 30:431–441 Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, Shih Ie M, Kurman RJ (2009) Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 33:844–853 Kurman RJ, Craig JM (1972) Endometrioid and clear cell carcinoma of the ovary. Cancer 29:1653–1664 Han G, Gilks CH, Leung S, Ewanowich CA, Irving JA, Longacre TA, Soslow RA (2008) Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma: an interobserver correlative and immunohistochemical study of 32 cases. Am J Surg Pathol 32:955–964 Köbel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, Gilks CB, Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency, Vancouver BC (2010) Differences in tumor type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol 29:203–211 Jones S, Wang TL, Shih Ie M, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA Jr, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N (2010) Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 8:228–231 Wiegand KC, Shah SP, AI-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih Ie M, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG (2010) ARID1A mutations in endometriosis-associated ovarian carcinoma. N Engl J Med 363:1532–1543 Guan B, Wang TL, Shih Ie M (2011) ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res 71:6718–6727 Guan B, Gao M, Wu CH, Wang TL, Shih Ie M (2012) Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions. Neoplasia 14:986–993 Wu CH, Mao TL, Vang R, Ayhan A, Wang TL, Kurman RJ, Shie Ie M (2012) Endocervical-type mucinous borderline tumors are related to endometrioid tumors based on mutation and loss of expression of ARID1A. Int J Gynecol Pathol 31:297–303 Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L (1997) p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 150:177–185 Sato N, Tsunoda H, Nishida H, Morishita Y, Takimoto Y, Kubo T, Noguchi M (2000) Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 60:7052–7056 An HJ, Lee NH, Shim JY, Kim JY, Lee C, Kim SJ (2002) Alteration of PTEN expression in endometrial carcinoma is associated with down-regulation of cyclin-dependent kinase inhibitor, p27. Histopathology 41:437–445 Miao Y, Cai B, Liu L, Yang Y, Wan X (2009) Annexin 4 is differentially expressed in clear cell carcinoma of the ovary. Int J Gynecol Cancer 19:1545–1549 Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sado T, Oi H, Kobayashi H (2010) Clear cell carcinoma of the ovary: potential pathologic mechanisms (Review). Oncol Rep 23:1193–1203 Köbel M, Turbin D, Kalloger SE, Gao D, Huntsman DG, Gilks CB (2011) Biomarker expression in pelvic high-grade serous carcinoma: comparison of ovarian and omental sites. Int J Gynecol Pathol 30:366–371 DeLair D, Oliva E, Köbel M, Macias A, Gilks CB, Soslow RA (2011) Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases. Am J Pathol 35:36–44 Jiang X, Morland SJ, Hitchcock A, Thomas EJ, Campbell IG (1998) Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res 58:1707–1712 Ichikawa A, Kinoshita T, Watanabe T, Kato H, Nagai H, Tsushita K, Saito H, Hotta T (1997) Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N Engle J Med 337:529–534 Ayhan A, Mao TL, Seckin T, Wu Ch, Guan B, Ogawa H, Futagami M, Mizukami H, Yokoyama Y, Kurman RJ, Shih Ie M (2012) Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Int J Gynecol Cancer 22:1310–1315 Acknowledgments We thank Dr. Ken-ichi Iyama (Department of Surgical Pathology, Kumamoto University Hospital) for his help with the diagnosis of the 46 cases. We also thank Ms. Ai Aoki (Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University) for her technical assistance. This research was supported by a grant from Grants-in-Aid for Scientific Research (B) 21390454. Conflict of interest The authors have no conflict of interest. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Matsuo, Y., Tashiro, H., Yanai, H. et al. Clinicopathological heterogeneity in ovarian clear cell adenocarcinoma: a study on individual therapy practice. Med Mol Morphol 48, 146–154 (2015). https://doi.org/10.1007/s00795-014-0090-z Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00795-014-0090-z