Histopathological stratification of primary aldosteronism using the CYP11B2 size ratio: first evaluation in clinical...

In primary aldosteronism (PA), the HISTALDO framework classifies aldosterone-producing lesions as 'classical' (solitary nodule) or 'non-classical' (multinodular or diffuse) based on CYP11B2 immunohistochemistry, but interpretation is complicated by frequent micronodules, even in patients without PA. The CYP11B2 size ratio (B2R), a quantitative measure of size disproportion between CYP11B2-positive nodules, offers an objective way to assess lesion architecture and has shown value in predicting cure versus relapse. In this study, diagnostic classification was intentionally B2R-guided, generating a modified HISTALDO B2R system in clinical routine.

Prospective evaluation of the prognostic value of B2R-guided classification in routine pathology and assessment of postoperative outcomes across B2R-defined subgroups.

Specimens of 70 adrenalectomies underwent multisection CYP11B2 staining; 61 patients had at least 6 months of follow-up (mean age 53 years, 54% were females). All had adrenal vein sampling and confirmatory testing before unilateral laparoscopic adrenalectomy. Imaging showed unilateral findings in 51%, bilateral in 8% and no detectable nodules in 41%. A B2R ≥8.1 defined classical lesions; B2R < 8.1 non-classical. Outcomes at 6-12 months were assessed using PASO criteria, which classify biochemical and clinical success as absent, partial or complete.

Biochemical cure was achieved in 95% of patients with classical B2R morphology, compared with 40% of those with non-classical B2R morphology (p < 0.001). Complete clinical success was also significantly more frequent in the classical B2R group than in the non-classical group (57% versus 25%, p = 0.0235). Medication-based measures supported these findings: patients with classic histology showed a trend towards reductions in antihypertensive medication expressed as defined daily doses (DDD) (median ΔDDD 2.83 versus 2.00, p = 0.1254), and a significantly greater reduction in potassium supplementation (median ΔDDD 1.25 versus 0.00, p < 0.001) compared to those with non-classical histology.

B2R-guided HISTALDO yields biologically distinct subgroups with clear prognostic separation. Earlier work using the original HISTALDO definition reported ~40%-45% persistent biochemical aldosteronism in non-classical cases. Our findings reproduce this poor non-classical outcome profile in a larger and more consistently defined B2R-classified cohort. Importantly, incorporating B2R reduces misclassification of tumours as non-classical when background nodularity is present despite a dominant CYP11B2-positive lesion.