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Promotion, ovarian adenomas leads to Promotion, Ovarian Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia||non-adjacent||Moderate||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Ovarian tumors are abnormal mass of tissues grows on or in the ovaries of the aged females. Ovarian adenomas / cystadenomas are very common and benign type of tumors, which are found in epithelial tissues of the ovaries. Almost 60% of the ovarian tumors are due to the epithelial neoplasm (abnormal growth of tissue) of the ovary (Limaiem et al. 2022). Ovarian adenomas are classified into different categories such as serous cystadenoma, mucinous cystadenoma, endometrioid cystadenoma, clear cell cystadenoma and seromucinous systadenoma. Reports have shown that ovarian serous cystadenoma can turn progress to serous carcinoma (Cheng et al. 2004). Frequent mutations of two genes (BRAF and KRAS) are identified as the cause of the serous carcinoma.
Evidence Collection Strategy
Morphological features of the different ovarian adenomas in the epithelium tissue of adult female ovaries are distinct from the each other. Endometrial hyperplasia in the ovaries of the aged female frequently observed as a consequence of the high level of the estrogen activity in the stroma cells.
MacDonald et al., had shown androstenedione production rate and estrogen level in the postmenopausal woman are five-fold higher than the normally expected level. Increased androstenedione production rate leads towards the formation of mucinous cystadenocarcinoma in the stromal cells of the ovary (MacDonald et al. 1976). Pascal et al., had reported ovarian mucinous cystadenoma with distinct feature of luteinization of the stroma cells in a 32 year old female patient (Pascal and Grecco 1988). Epithelial neoplasma of the ovary classified as borderline ovarian tumors (BOT), which have separate distinguishing features than the carcinoma. Ovarian cystadenomas are benign neoplasms present in the epithelial tissues of the patients are also categorised as borderline ovarian tumors.
Evidence Supporting this KER
Nishida et al., had reported the development of adenoma malignum of the uterine cervix associated with the mucinous carcinoma in a female patient (Nishida et al. 1991).
Goedhals et al., had reported development of ovarian mucinous carcinoma arising from the mucinous cystadenoma of the ovary in a 68 yr old female patient (Goedhals et al. 2008).
Smith et al., had shown with the help of immunohistochemistry the development of sebaceous adenoma arising within a benign ovarian mature cystic teratoma in a 52 yr old female patient (Smith et al. 2011).
Cheng et al., had reported the sub-classification of Ovarian adenomas / cystadenoma based on the cell types such as serous cystadenoma, mucinous cystadenoma and endometrioid cystadenoma (Cheng et al. 2004). Possible molecular genetic alteration associated with the high grade serous and endometrioid cystadenoma are mutation in TP53 gene and dysfunction of BRCA1 and/or BRCA 2 gene. Whereas, low grade serous carcinoma or borderline serous cystadenoma occurred via activation of the RAS-RAF signaling pathway and frequent mutations in BRAF or KRAS genes. Mucinous cystadenoma is originated in germ cells and often related with mutation in KRES gene (Beroukhim et al. 2021). Only 2-4% of the ovarian tumors are accounted for the endometrioid cystadenoma (Tsukahara et al. 1982). Endometrioid cystadenoma is related to the mutations in CTNNB1 and PTEN gene (Bell 2005, Sanseverino et al. 2005, Wei et al. 2012).
Uncertainties and Inconsistencies
Balat et al., had reported the detection of unthreatened late pregnancy with a large mucinous cyst adenoma of the ovary in a female patient (Balat et al. 2002). Vidhale et al., had reported the detection of serous cystadenoma in the ovary, which is benign in nature (Vidhale et al. 2022). Mittal, et al., had reported the detection of benign type of mucinous cystadenoma in the ovary (Mittal et al. 2008).
Known modulating factors
|Modulating Factor (MF)||MF Specification||Effect(s) on the KER||Reference(s)|
Horn et al., had evaluated the 74 cases of borderline ovarian tumors and shown that majority of the cases are belongs to the serous borderline ovarian tumors (60.8%), followed by the mucinous borderline ovarian tumors (25.7%). Adenoma in the borderline ovarian tumors was found in 86.5% cases. The report had suggested that the association of papillary tubal hyperplasia and salpingoliths with the borderline ovarian tumors (Horn et al. 2017).
Observed in months to years
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Observed in adult female (human) also in rodents.
Balat, O., Kutlar, I., Erkilic, S., Sirikci, A., Aksoy, F. and Aydin, A. (2002) Unthreatened late pregnancy with a huge mucinous cyst adenoma of the left ovary: report of an unusual case. Eur J Gynaecol Oncol 23(1), 84-85.
Bell, D.A. (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18 Suppl 2, S19-32.
Beroukhim, G., Ozgediz, D., Cohen, P.J., Hui, P., Morotti, R., Schwartz, P.E., Yang, H. and Vash-Margita, A. (2021) Progression of Cystadenoma to Mucinous Borderline Ovarian Tumor in Young Females: Case Series and Literature Review. J Pediatr Adolesc Gynecol 35(3), 359-367.
Cheng, E.J., Kurman, R.J., Wang, M., Oldt, R., Wang, B.G., Berman, D.M. and Shih, I.-M. (2004) Molecular genetic analysis of ovarian serous cystadenomas. Laboratory Investigation 84(6), 778-784.
Chodankar, R., Kwang, S., Sangiorgi, F., Hong, H., Yen, H.Y., Deng, C., Pike, M.C., Shuler, C.F., Maxson, R. and Dubeau, L. (2005) Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells. Curr Biol 15(6), 561-565.
Dey, P., Nakayama, K., Razia, S., Ishikawa, M., Ishibashi, T., Yamashita, H., Kanno, K., Sato, S., Kiyono, T. and Kyo, S. (2022) Development of Low-Grade Serous Ovarian Carcinoma from Benign Ovarian Serous Cystadenoma Cells. Cancers (Basel) 14(6).
Goad, J., Ko, Y.-A., Kumar, M., Jamaluddin, M.F.B. and Tanwar, P.S. (2018) Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling. Carcinogenesis 39(9), 1105-1116.
Goedhals, J., van der Merwe, J., Yazbek, V.A. and Beukes, C.A. (2008) Adenoma malignum-like mucinous ovarian carcinoma. Histopathology 53(3), 352-354.
Horn, L.C., Angermann, K., Hentschel, B., Einenkel, J. and Hohn, A.K. (2017) Frequency of papillary tubal hyperplasia (PTH), salpingoliths and transition from adenoma to borderline ovarian tumors (BOT): A systematic analysis of 74 BOT with different histologic types. Pathol Res Pract 213(4), 305-309.
Limaiem, F., Lekkala, M.R. and Mlika, M. (2022) Ovarian Cystadenoma.
MacDonald, P.C., Grodin, J.M., Edman, C.D., Vellios, F. and Siiteri, P.K. (1976) Origin of estrogen in a postmenopausal woman with a nonendocrine tumor of the ovary and endometrial hyperplasia. Obstet Gynecol 47(6), 644-650.
Mittal, S., Gupta, N., Sharma, A.K. and Dadhwal, V. (2008) Laparoscopic management of a large recurrent benign mucinous cystadenoma of the ovary. Arch Gynecol Obstet 277(4), 379-380.
Nishida, T., Ushijima, K., Oda, T., Sugiyama, T., Tsuji, Y., Imaishi, K. and Yakushiji, M. (1991) Minimal deviation adenocarcinoma (adenoma malignum) of the uterine cervix associated with mucinous ovarian carcinoma. Kurume Med J 38(4), 265-269.
Pascal, R.R. and Grecco, L.A. (1988) Mucinous cystadenoma of the ovary with stromal luteinization and hilar cell hyperplasia during pregnancy. Hum Pathol 19(2), 179-180.
Saloniemi, T., Lamminen, T., Huhtinen, K., Welsh, M., Saunders, P., Kujari, H. and Poutanen, M. (2007) Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas. Mol Endocrinol 21(11), 2627-2636.
Sanseverino, F., D'Andrilli, G., Petraglia, F. and Giordano, A. (2005) Molecular pathology of ovarian cancer. Anal Quant Cytol Histol 27(3), 121-124.
Smith, J., Crowe, K., McGaughran, J. and Robertson, T. (2011) Sebaceous adenoma arising within an ovarian mature cystic teratoma in Muir-Torre syndrome. Ann Diagn Pathol 16(6), 485-488.
Tsukahara, Y., Shiozawa, I., Sakai, Y., Ishii, J., Iwai, S. and Fukuta, T. (1982) Study on the histogenesis of ovarian tumors--with special reference to five clinical cases with common epithelial tumors detected during the preclinical stage. Nihon Sanka Fujinka Gakkai Zasshi 34(7), 959-965.
Vidhale, S.A., Chavarkar, S.P., Sudhamani, S. and Rao, R. (2022) Cholesterolosis of ovary associated with benign serous cystadenoma. Indian J Pathol Microbiol 65(2), 496-498.
Wei, X., Lu, Q.J., Sun, H.X., Qi, Y.F., Wang, J.O. and Cao, C.C. (2012) [Expression and significance of p-AKT, p-GSK3beta and beta-catenin in epithelial carcinoma of ovary]. Zhonghua Bing Li Xue Za Zhi 41(2), 86-90.
Yamagata, S., Yamamoto, K., Tsuchida, S., Kawamura, N., Matsumoto, Y., Ueki, S. and Sugawa, T. (1989) Estrogen production in epithelial tumors of the ovary--clinical and endocrinological study in postmenopausal women. Nihon Sanka Fujinka Gakkai zasshi 41(11), 1761-1768.