Abstract
Aldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension. Aldosterone-producing cell clusters (APCCs) comprise tight nests of zona glomerulosa cells, strongly positive for CYP11B2 (aldosterone synthase) in immunohistochemistry. APCCs have been suggested as possible precursors of APAs because they frequently carry driver mutations for constitutive aldosterone production, and a few adrenal lesions with histopathologic features of both APCCs and APAs have been identified. Our objective was to investigate the metabolic phenotypes of APCCs (n=27) compared with APAs (n=6) using in situ matrix-assisted laser desorption/ionization mass spectrometry imaging of formalin-fixed paraffin-embedded adrenals from patients with unilateral primary aldosteronism. Specific distribution patterns of metabolites were associated with APCCs and classified 2 separate APCC subgroups (subgroups 1 and 2) indistinguishable by CYP11B2 immunohistochemistry. Metabolic profiles of APCCs in subgroup 1 were tightly clustered and distinct from subgroup 2 and APAs. Multiple APCCs from the same adrenal displayed metabolic profiles of the same subgroup. Metabolites of APCC subgroup 2 were highly similar to the APA group and indicated enhanced metabolic pathways favoring cell proliferation compared with APCC subgroup 1. In conclusion, we demonstrate specific subgroups of APCCs with strikingly divergent distribution patterns of metabolites. One subgroup displays a metabolic phenotype convergent with APAs and may represent the progression of APCCs to APAs.
Highlights
Aldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension
This proposal is seemingly supported by the description of a few adrenal lesions with histological features characteristic of both Aldosterone-producing cell clusters (APCCs) and APAs, interpreted as APCCs transitioning to APAs.[17]
We have developed a protocol for high throughput in situ metabolic profiling from formalin‐fixed paraffin‐embedded (FFPE) samples using a high mass resolution matrix-assisted laser desorption/ionization Fouriertransform ion cyclotron resonance mass spectrometry imaging (MALDI-FT-ICR-MSI) platform for the detection of over 1700 metabolites within the mass range of m/z 50 to 1000.21,22 This technique has been recently used in several metabolic profiling studies of endocrine tissues and successfully applied to visualize the distribution of hormones and metabolites in the normal and diseased adrenal.[23,24,25,26]
Summary
Aldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension. Primary aldosteronism (PA) is a common but underdiagnosed cause of secondary hypertension characterized by the overproduction of aldosterone relative to suppressed plasma renin levels.[1,2] Unilateral aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia ( called idiopathic hyperaldosteronism) are the main subtypes of PA, which together account for >80% of all diagnosed cases of the disease.[3] Specific monoclonal antibodies to the highly homologous adrenal steroidogenic enzymes CYP11B2 (aldosterone synthase) and CYP11B1 (11β-hydroxylase) have proven valuable for immunohistochemistry studies and have established the broad spectrum of histological abnormality associated with PA.[4,5] In some cases, adrenals from patients with unilateral PA do not show evidence of a well circumscribed APA but display micronodular or diffuse hyperplasia.[4,5,6] Small nests of CYP11B2-positive cells located beneath the adrenal capsule, referred to as aldosterone-producing cell clusters (APCCs), have been described in normal adrenals and in adrenals from patients with PA.[7,8,9]. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) acquires molecular images based on the spatially resolved, label-free semiquantitative detection of thousands of different molecules in biological specimens.[18,19,20] We have developed a protocol for high throughput in situ metabolic profiling from formalin‐fixed paraffin‐embedded (FFPE) samples using a high mass resolution matrix-assisted laser desorption/ionization Fouriertransform ion cyclotron resonance mass spectrometry imaging (MALDI-FT-ICR-MSI) platform for the detection of over 1700 metabolites within the mass range of m/z 50 to 1000.21,22 This technique has been recently used in several metabolic profiling studies of endocrine tissues and successfully applied to visualize the distribution of hormones and metabolites in the normal and diseased adrenal.[23,24,25,26]
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