Nishimoto Koshiro, Seki Tsugio, Kurihara Isao, Yokota Kenichi, Omura Masao, Nishikawa Tetsuo, Shibata Hirotaka, Kosaka Takeo, Oya Mototsugu, Suematsu Makoto, Mukai Kuniaki
Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
J Clin Endocrinol Metab. 2016 Jan;101(1):6-9. doi: 10.1210/jc.2015-3285. Epub 2015 Nov 18.
We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs). Some APCCs were recently found to carry aldosterone-producing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion.
A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. Genomic DNA samples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322_Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin.
A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.
我们之前报道过，人类肾上腺皮质会重塑形成包膜下醛固酮生成细胞簇（APCCs）。最近发现一些APCCs在离子通道/泵基因中携带与醛固酮瘤（APA）相关的体细胞突变，这意味着APCCs能自主产生醛固酮，是APA的起源。然而，尚无关于APCC到APA过渡性病变的报道。
组织学检查显示，两名原发性醛固酮增多症（PA）患者的肾上腺存在单侧多发性肾上腺皮质微结节。基于醛固酮合酶的免疫组化，部分微结节被鉴定为可能的APCC到APA过渡性病变（pAATLs；本文中使用的暂定术语），其由包膜下APCC样部分和内部微APA样（mAPA样）部分组成，两者之间无明显组织学边界。从pAATL组织切片制备的基因组DNA样本通过下一代测序分析已知的APA相关突变。在检查的三个大pAATLs中的两个，其mAPA样部分存在突变（pAATL 3中的KCNJ5 [p.G151R]和pAATL 7中的ATP1A1 [p.L337M]），而其相应的APCC样部分没有，提示它们在mAPA形成中的作用。另一个病变在mAPA样和APCC样部分均携带ATP1A1的新突变（p.Ile322_Ile325del和p.Ile327Ser），从而支持这些部分具有克隆起源。
在两名患者的肾上腺中检测到一种导致单侧PA的新型醛固酮生成病理，即pAATL。对大pAATLs的下一代测序分析表明，离子通道/泵基因中APA相关突变的引入可能参与了从现有APCCs发展为mAPA的过程。
