Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism

Area of Science:

• Endocrinology
• Molecular Biology
• Pathology

Background:

• The human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs).
• APCCs may be an origin of aldosterone-producing adenomas (APAs) due to somatic mutations in ion channel/pump genes.
• No transitional lesions between APCCs and APAs have been previously described.

Observation:

• Histological examination of adrenal glands from two primary aldosteronism (PA) patients revealed unilateral multiple adrenocortical micronodules.
• Immunohistochemistry identified some micronodules as possible APCC-to-APA transitional lesions (pAATLs), featuring both APCC-like and micro-APA-like portions.
• These pAATLs lacked a distinct histological border between the APCC-like and mAPA-like components.

Findings:

• Next-generation sequencing of pAATL histological sections identified APA-associated mutations.
• Micro-APA-like portions of large pAATLs harbored mutations (KCNJ5, ATP1A1), while their APCC-like portions did not, indicating mutation acquisition during development.
• Another pAATL showed novel ATP1A1 mutations in both portions, supporting a clonal origin for the lesion.

Implications:

• A novel aldosterone-producing pathology, pAATL, causing unilateral PA has been identified.
• These findings suggest that APA-associated mutations in ion channel/pump genes contribute to the development of micro-APAs from existing APCCs.
• pAATLs represent a potential transitional stage in the pathogenesis of aldosterone-producing adenomas.