Improving Diagnosis in Primary Aldosteronism Using HISTALDO and Nodule Size Metrics

Background Primary aldosteronism (PA) is the leading cause of secondary hypertension. The 2022 WHO classification introduced the HISTALDO system, separating solitary aldosterone-producing adenomas/nodules (APA/APN; classical histology) from multiple nodules/micronodules (MAPN/MAPM; non-classical histology). Surgery often cures classical cases, while non-classical cases frequently recur. HISTALDO uses CYP11B2 immunohistochemistry, but interpretation is challenged by background nodules. A “B2 ratio” (size ratio of largest to second-largest CYP11B2-positive nodule) has been proposed to aid diagnosis. Objective To assess whether standardized tissue sampling and the B2 ratio improve PA diagnosis and correlate with outcomes. Methods A prospective study of 75 unilateral PA patients undergoing adrenalectomy (2017–2022) at Karolinska University Hospital. CYP11B2 immunohistochemistry was performed using a standardized protocol, and the B2 ratio was calculated in cases with multiple CYP11B2-positive nodules (HISTALDO B2R). Outcomes were assessed using PASO criteria. Results HISTALDO classified 20 cases as classical and 55 as non-classical (median B2 ratio 9). Using a B2 ratio cut-off ≥8.1 reclassified 29/55 non-classical cases, yielding 49 classical and 26 non-classical cases under HISTALDO B2R. Higher B2 ratios correlated with complete clinical response (p=0.0038) and fewer antihypertensive medications postoperatively (R = -0.4, p = 0.0022). A trend for B2 ratio as an independent predictor of complete response was observed (OR = 1.07, p = 0.058). Conclusions HISTALDO may overreport non-classical histology. Adding the B2 ratio improves diagnostic accuracy, distinguishing APA with background zona glomerulosa activity from true multinodular disease, facilitating patient management and follow-up.