title: Disorganized Steroidogenesis in Adrenocortical Carcinoma, a Case Study.
abstract: Most adrenocortical carcinomas (ACCs) produce excessive amounts of steroid hormones including aldosterone, cortisol, and steroid precursors. However, aldosterone- and cortisol-producing cells in ACCs have not yet been immunohistochemically described. We present a case of ACC causing mild primary aldosteronism and subclinical Cushing's syndrome. Removal of the tumor cured both conditions. In order to examine the expression patterns of the steroidogenic enzymes responsible for adrenocortical hormone production, 10 tumor portions were immunohistochemically analyzed for aldosterone synthase (CYP11B2), 11β-hydroxylase (CYP11B1, cortisol-synthesizing enzyme), 3β-hydroxysteroid dehydrogenase (3βHSD, upstream enzyme for both CYP11B2 and CYP11B1), and 17α-hydroxylase/C17-20 lyase (CYP17, upstream enzyme for CYP11B1, but not for CYP11B1). CYP11B2, CYP11B1, and 3βHSD were expressed sporadically, and their expression patterns varied significantly among the different tumor portions examined. The expression of these enzymes was random and not associated with each other. CYP17 was expressed throughout the tumor, even in CYP11B2-positive cells. Small tumor cell populations were aldosterone- or cortisol-producing cells, as judged by 3βHSD coinciding with either CYP11B2 or CYP11B1, respectively. These results suggest that the tumor produced limited amounts of aldosterone and cortisol due to the lack of the coordinated expression of steroidogenic enzymes, which led to mild clinical expression in this case. We delineated the expression patterns of steroidogenic enzymes in ACC. The coordinated expression of steroidogenic enzymes in normal and adenoma cells was disturbed in ACC cells, resulting in the inefficient production of steroid hormones in relation to the large tumor volume.
authors.affiliation: Departments of Metabolism & Endocrinology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. uchitoyo@juntendo.ac.jp.
authors.forename: Toyoyoshi
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Japan. k.nishimoto@keio.jp.|Department of Biochemistry, School of Medicine, Keio University, Tokyo, 160-8582, Japan. k.nishimoto@keio.jp.
authors.forename: Koshiro
authors.initials: K
authors.lastname: Nishimoto
authors.affiliation: Department of Human Pathology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fukumura
authors.affiliation: Department of Human Pathology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Asahina
authors.affiliation: Departments of Metabolism & Endocrinology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Goto
authors.affiliation: Departments of Metabolism & Endocrinology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Urology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Department of Urology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujimura
authors.affiliation: Department of Medical Education, College of Medicine, California University of Science and Medicine, 1405 West Valley Blvd #101, Colton, CA, 92324, USA.
authors.forename: Tsugio
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, 160-8582, Japan.|Medical Education Center, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Mukai
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Endocrinology Section, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS, 39216, USA.
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: Department of Human Pathology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Urology, Juntendo University, Graduate School, Tokyo, 113-8421, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horie
authors.affiliation: Departments of Metabolism & Endocrinology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D003480:Cushing Syndrome / Q000209:etiology; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D006929:Hyperaldosteronism / Q000209:etiology; D007150:Immunohistochemistry; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D006854:Hydrocortisone
keywords: 11β-hydroxylase; Adrenocortical carcinoma; Aldosterone synthase; Primary aldosteronism; Subclinical Cushing’s syndrome