Ectopic adrenal adenoma causing gross hematuria: Steroidogenic enzyme profiling and literature review

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149375/1/iju512068.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149375/2/iju512068_am.pd

Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults

Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

金沢大学医薬保健研究域医学系Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. © 2017 The Author(s)

Supplemental Figure 1.pdf

<div><b>Supplemental Figure 1</b>. All images. Scanned images of CYP11B2 staining (left columns), H&E (middle columns), and HSD3B2 staining (right columns). Case number, block number, staining methods, and section numbers (5 digits) are labeled below each image. Bars indicate 5 mm.</div><div><br></div

Supplemental Figure 3

<div><b>Supplemental Figure 3</b>. Correlations between 3 examiners. Correlations of NOA (/mm2) between KN vs KM (A), KN vs GAE (B), and KM vs GAE (C), as well as those of AA/WAA (%) between KN vs KM (D), KN vs GAE (E), and KM vs GAE (F). r and p values were calculated by Pearson’s product moment correlation analysis.</div

Supplemental Figure 2

<div><b>Supplemental Fig. 2</b>. A: An example (A-5847) of tracing an adrenal section. An arrowhead indicates the portion of the enlarged image in panel B. The area of the section was measured in a similar manner to tracing using CYP11B2-stained sections. C: Weakly positive cells, positive cells, and strongly positive cells were colored in yellow, orange, and red, respectively, in the example image in panel A. Their areas were used to measure positivity, which was automatically performed using the algorithm “Positive Pixel Count 2004-08-11” in ImageScope software (version12.2.1.5005, Aperio). The arrowhead shows the enlarged image in Panel D. E: An example of tracing APCCs (black lined areas), which was performed by KM on a CYP11B2-stained section of sample A-5797.</div><div><br></div><div><br></div><div><br></div><div><br></div><div><br></div

Supplemental Table 1

Data of analyzed sections

A case of intraepithelial squamous cell carcinoma arising from urethral caruncle

A 62-year-old female patient had occasional bleeding from a mass in the urethral meatus. She had been conservatively treated with steroid ointment at another hospital for 1 year, but the bleeding had persisted. The patient was therefore referred for further treatment. A reddish mass, measuring 5 mm in diameter was noted at the posterior lip of the urethral meatus. The mass was diagnosed to be a urethral caruncle and was removed. Microscopically, the squamous epithelium, which covered the urethral caruncle, was found to be keratinized, with the proliferation of atypical cells with swollen nuclei in the entire mucosal layer. The mass was finally diagnosed to be intraepithelial squamous cell carcinoma arising from the urethral caruncle