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 the 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 Primary Aldosteronism Surgical Outcome 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, 29/55 non-classical cases were reclassified, yielding 49 classical and 26 non-classical cases under HISTALDO B2R. Higher B2 ratios correlated with complete clinical response (P = .0038) and fewer antihypertensive medications postoperatively (R = -0.4, P = .0022). A trend for B2 ratio as an independent predictor of complete response was observed (OR = 1.07, P = .058).

Conclusions: HISTALDO may over-report 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.