Tumor cell subtypes based on the intracellular hormonal activity in KCNJ5-mutated aldosterone-producing adenoma

Yuto Yamazaki, Kei Omata, Yuta Tezuka, Yoshikiyo Ono, Ryo Morimoto, Yuzu Adachi, Kazue Ise, Yasuhiro Nakamura, Celso E. Gomez-Sanchez, Yukiko Shibahara, Takumi Kitamoto, Tetsuo Nishikawa, Sadayoshi Ito, Fumitoshi Satoh, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Aldosterone-producing adenomas (APAs) harbor marked intratumoral heterogeneity in terms of morphology, steroidogenesis, and genetics. However, an association of biological significance of morphologically identified tumor cell subtypes and genotypes is virtually unknown. KCNJ5 mutation is most frequently detected and generally considered a curable phenotype by adrenalectomy. Therefore, to explore the biological significance of KCNJ5 mutation in APA based on intracellular hormonal activities, 35 consecutively selected APAs (n=18; KCNJ5 mutated, n=17; wild type) were quantitatively examined in the whole tumor areas by newly developed digital image analysis incorporating their histological and ultrastructural features (14 cells from 2 KCNJ5-mutated APAs and 15 cells from 1 wild type) and CYP11B2 immunoreactivity. Results demonstrated that KCNJ5-mutated APAs had significantly lower nuclear/cytoplasm ratio and more abundant clear cells than wild type. CYP11B2 immunoreactivity was not significantly different between these genotypes, but a significant correlation was detected between the proportion of clear cells and CYP11B2 immunoreactivity in all of the APAs examined. CYP11B2 was predominantly immunolocalized in clear cells in KCNJ5-mutated APAs. Quantitative ultrastructural analysis revealed that KCNJ5-mutated APAs had significantly more abundant and smaller-sized mitochondria with well-developed cristae than wild type, whereas wild type had more abundant lipid droplets per unit area despite the small number of the cases examined. Our results did provide the novel insights into the morphological features of APA based on their biological significance. KCNJ5-mutated APAs were characterized by predominance of enlarged lipid-rich clear cells possibly resulting in increased neoplastic aldosterone biosynthesis.

Original languageEnglish
Pages (from-to)632-640
Number of pages9
JournalHypertension
Volume72
Issue number3
DOIs
Publication statusPublished - 2018

Keywords

  • Adrenocortical adenoma
  • Aldosterone
  • Cytochrome P-450 CYP11B2
  • Hyperaldosteronism
  • Immunohistochemistry
  • Mitochondria
  • Mutation

ASJC Scopus subject areas

  • Internal Medicine

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