Intratumoral heterogeneity of the tumor cells based on in situ cortisol excess in cortisol-producing adenomas; ∼An association among morphometry, genotype and cellular senescence∼

Gao, Xin; Yamazaki, Yuto; Tezuka, Yuta; Pieroni, Jacopo; Ishii, Keiichiro; Atsumi, Nanako; Ono, Yoshikiyo; Omata, Kei; Morimoto, Ryo; Nakamura, Yasuhiro; Satoh, Fumitoshi; Sasano, Hironobu

doi:10.1016/j.jsbmb.2020.105764

Cited by 14 publications

(30 citation statements)

References 29 publications

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“…These observations were also validated in a recent study that compared steroidogenic biomarker expression profile in PRKACA -, GNAS-and CTNNB1-mutant cortisol-producing adrenal cortical adenomas [116]. In terms of steroidogenic biomarker expression profile, PRKACA -mutant adrenal cortical adenomas displayed increased immunohistochemical reactivity for CYP11B1, CYP17A1, and 3βHSD compared with PRKACA -wild type (GNAS and CTNNB1 mutant) adenomas [116]. The same study also reported for the first time that cytomorphological heterogeneity was reflected in steroidogenic biomarker expression profile as the compact cell component of cortisol-producing adenomas had the highest expression.…”

Section: Genotype-phenotype Correlations In Benign Lesions Of Adrenal Cushing Syndromesupporting

confidence: 59%

“…Several lines of evidence showed that CTNNB1driven adenomas were preferably large, non-functional tumors as well as lesions with mild autonomous cortisol secretion [47]. These observations were also validated in a recent study that compared steroidogenic biomarker expression profile in PRKACA -, GNAS-and CTNNB1-mutant cortisol-producing adrenal cortical adenomas [116]. In terms of steroidogenic biomarker expression profile, PRKACA -mutant adrenal cortical adenomas displayed increased immunohistochemical reactivity for CYP11B1, CYP17A1, and 3βHSD compared with PRKACA -wild type (GNAS and CTNNB1 mutant) adenomas [116].…”

Section: Genotype-phenotype Correlations In Benign Lesions Of Adrenal Cushing Syndromementioning

confidence: 58%

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What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

et al. 2021

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Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.

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Section: Genotype-phenotype Correlations In Benign Lesions Of Adrenal Cushing Syndromesupporting

confidence: 59%

Section: Genotype-phenotype Correlations In Benign Lesions Of Adrenal Cushing Syndromementioning

confidence: 58%

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

et al. 2021

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“…mRNA expression levels of both CYP17A1 and CYP11B1 were also reported to be significantly higher in compact tumor cells than in clear ones, whereas that of CY-P11B2 tended to be higher in clear tumor cells regardless of genotype [43]. This is consistent with results of our previous study that the immunoreactivity of CYP11B1 and CYP17A1 was significantly higher in compact tumor cells of CPAs [39]. Therefore, the hybrid steroidogenesis or simultaneous biosynthesis of both glucocorticoids and mineralocorticoids in the same tumor cells of APAs represented the zonation-deviated phenotype and compact or ZG-like cells had higher cortisolproducing ability, whereas clear or ZF-like cells harbored higher aldosterone-producing ability.…”

Section: Aldosterone-producing Adenomassupporting

confidence: 92%

“…Adrenocortical cells are basically classified into compact and clear cells, also termed ZG/ZF-like cells from the standpoint of histology [38][39][40][41]. Compact cells have a high nuclear to cytoplasm ratio with an eosinophilic lipid-poor cytoplasm containing relatively abundant cell organelles, including mitochondria.…”

Section: Histopathology and Cellular Morphology Of Pamentioning

confidence: 99%

The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging

et al. 2021

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Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosteroneproducing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.

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“…Normal adrenal cortex was composed of ZG, ZF and zona reticularis (ZR) from outer to inner part but when normal adrenocortical cells differentiate or develop into nodules or tumors including aldosterone-producing lesions, the cells of these lesion were usually rather complex mixture of those simulating normal cortical cells, especially of ZF and ZR cells (Tsuchiyama et al 1980;Yamazaki et al 2018;Gao et al 2020). We recently termed these cells simulating ZF and ZG/ZR cells as clear and compact cells instead of ZG or ZF-like cells in order to avoid potential confusions, possibly alluding the functional features of those designated terms above (Williams et al 2021).…”

Section: Morphology Of Aldosterone-producing Adenomamentioning

confidence: 99%

Pathology of Aldosterone Biosynthesis and its Action

Gao

Yamazaki

Tezuka

et al. 2021

Tohoku J. Exp. Med.

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Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosteroneproducing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.

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Intratumoral heterogeneity of the tumor cells based on in situ cortisol excess in cortisol-producing adenomas; ∼An association among morphometry, genotype and cellular senescence∼

Cited by 14 publications

References 29 publications

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging

Pathology of Aldosterone Biosynthesis and its Action

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