Inter- and intratumoral heterogeneity of aldosterone-producing adenomas: recent advances and clinical implications

Primary aldosteronism is the most common form of secondary hypertension, and aldosterone-producing adenoma (APA) is the most prevalent surgically curable subtype of primary aldosteronism. Over the past decade, the identification of recurrent somatic mutations, most notably in KCNJ5, has transformed the molecular understanding of APA and has revealed substantial heterogeneity across tumors. In parallel, advances in transcriptomic, epigenomic, and metabolomic profiling have further expanded insights into genotype-dependent differences in steroidogenic activity, cellular morphology, and clinical presentation. More recently, the application of single-cell, single-nucleus, and spatial transcriptomics technologies has revealed an additional layer of complexity, demonstrating marked heterogeneity within individual APA tissues. These studies show that APAs are composed of transcriptionally and functionally diverse cell populations with variable steroidogenic capacities, extending beyond what can be explained by the somatic mutation status alone. This review summarizes the current evidence for both intertumoral and intratumoral heterogeneity in APA, integrating findings from genomic, epigenomic, metabolomic, and single-cell-based studies. By highlighting how mutation-driven differences intersect with cell-state diversity and differentiation processes, this review aimed to provide a comprehensive framework for understanding the pathophysiology of APA and discuss the potential implications for disease classification, biomarker development, and future therapeutic strategies.