Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139975/1/cen13442.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139975/2/cen13442_am.pd

Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11β-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated β-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11-mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause

Comparison of the acceptability and safety of molnupiravir in COVID-19 patients aged over and under 80 years

Background: Molnupiravir is being widely used as a treatment for coronavirus disease 2019 (COVID-19); however, its acceptability and safety in older patients aged ≥ 80 years in real-world clinical practice is not well understood. Methods: We conducted a single-centre retrospective study and assessed the outcome of patients with COVID-19 treated with molnupiravir according to the following criteria: (A) discontinuation rate of molnupiravir; (B) type, frequency, and severity of adverse events; (C) all-cause mortality within 30 days of the diagnosis of COVID-19. Results: Forty-seven patients (46.1%) were aged ≥ 80 years (older patients) and 55 (53.9%) were aged < 80 years (younger patients). There were no significant differences in coexisting diseases and history of vaccination for COVID-19 between older and younger patients. Older patients were significantly more likely to have moderate disease (moderate 1 and 2) according to the Japanese Ministry of Health, Labour and Welfare classification than younger patients. During treatment, 8.5% of older patients and 1.8% of younger patients stopped taking molnupiravir, but the difference was not significant. Adverse events were observed in 39/102 (38.2%) patients. The most common adverse events were diarrhoea (9.8%), exacerbation of coexisting diseases (6.9%), bone marrow suppression (6.9%), liver dysfunction (5.9%), and loss of appetite (4.9%). Most adverse events were minor, ranging from grades 1 to 3. The all-cause mortality rate was 10.8%, and no molnupiravir-related deaths were observed. Conclusions: Molnupiravir treatment is acceptable and safe in older patients with COVID-19 aged ≥ 80 years

Biochemical, histopathological and genetic characterization of posture responsive and unresponsive APAs

Context and Objective: Posture-responsive and -unresponsive aldosterone-producing adenomas (APAs) account for approximately 40% and 60% of APAs, respectively. Somatic gene mutations have been recently reported to exist in approximately 90% of APAs. This study was designed to characterize the biochemical, histopathologic, and genetic properties of these two types of APA. Methods: Plasma levels of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) were measured by LC-MS/MS. Immunohistochemistry (IHC) for CYP11B2 (aldosterone synthase) and CYP17A1 (17α-hydroxylase) and DNA sequencing (Sanger and next-generation sequencing) were performed on APA tissue collected from 23 posture-unresponsive and 17 posture-responsive APA patients. Results: Patients with posture-unresponsive APA displayed higher (P < 0.01) levels of hybrid steroids, recumbent aldosterone and cortisol, larger (P < 0.01) zona fasciculata (ZF)-like tumors with higher (P < 0.01) expression of CYP17A1 (but not of CYP11B2) than patients with posture-responsive APA (most of which were not ZF-like). Of 40 studied APAs, 37 (92.5%) were found to harbour aldosterone-driving somatic mutations (KCNJ5 = 14, 35.0%; CACNA1D = 13, 32.5%; ATP1A1 = 8, 20.0%; and ATP2B3 = 2, 5.0%), including 5 previously unreported mutations (3 in CACNA1D and 2 in ATP1A1). Notably, 64.7% (11/17) of posture-responsive APAs carried CACNA1D mutations, whereas 56.5% (13/23) of posture-unresponsive APAs harboured KCNJ5 mutations. Conclusions: The elevated production of hybrid steroids by posture-unresponsive APAs may relate to their ZF-like tumor cell composition, resulting in expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol which acts as the substrate for CYP11B2-generated hybrid steroids

High resolution tissue mass spectrometry imaging reveals a refined functional anatomy of the human adult adrenal gland.

In the adrenal gland, neuroendocrine cells that synthesize catecholamines and epithelial cells that produce steroid hormones are united beneath a common organ capsule to function as a single stress-responsive organ. The functional anatomy of the steroid hormone producing adrenal cortex and the catecholamine producing medulla is ill defined at the level of small molecules. Here, we report the first comprehensive high-resolution mass spectrometry imaging (MSI) map of the normal human adrenal gland. A large variety of biomolecules was accessible by matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance (MALDI-FT-ICR) MSI, including nucleoside phosphates indicative of oxidative phosphorylation, sterol and steroid metabolites, intermediates of glycolysis and the tricarboxylic acid (TCA) cycle, lipids and fatty acids. Statistical clustering analyses yielded a molecular defined adrenal anatomy of ten distinct molecular zones including a highly structured corticomedullary interface. By incorporating pathway information, activities of carbohydrate, amino acid and lipid metabolism as well as endocrine bioactivity were revealed to be highly spatially organized which could be visualized as different molecularly defined zones. Together, these findings provide a molecular definition of human adult adrenal gland structure beyond classical histological anatomy

Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma

International audienceAldosterone-producing adenoma (APA) cause primary aldosteronism—the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated β-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5 -mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development