Background: Sporadic aldosterone-producing adenomas (APA) are relevant cause of endocrine related hypertension in Primary Aldosteronism (PA). Next generation sequencing techniques have identified somatic mutations in APA harbored in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1 and PRKACA genes. Yet, a number of APA harbor no mutations in candidate genes (designated as wild type, WT) and little is known about genotype/phenotype correlation.
Objectives: We investigated the tissue-based molecular and histopathological characteristics of 132 APAs after laparoscopic unilateral adrenalectomy in PA-patients and studied genotype/morphometry and histopathology correlation.
Methods: Tumor-DNA was screened for somatic mutations in candidate genes by targeted (n=84) or whole-exome (n=48) sequencing. Accurate characterization of 179 morphometric parameters and of immunohistochemistry (IHC) results for steroidogenic enzymes CYP11B1, CYP11B2, CYP17, HSD3B1 and HSD3B2 was performed on tumor tissue microarrays from all samples by digital image analysis.
Results: Prevalence of WT APA in our cohort was 34% and affected men more frequently. In 8/48 APA, non-recurrent somatic mutations (NR) were identified. H&E analysis demonstrated that 6 morphometric parameters correlated negatively with WT status whereas those same parameters correlated positively with the presence of KCNJ5 or NR (P<0.01). The same reversed pattern between WT and KCNJ5 mutated APA was found in 10 cytoplasmic parameters, including mainly color-based features (P<0.01). KCNJ5 mutation status was negatively correlated with CYP11B1 and HSD3B1 expression (P<0.01). On the contrary, WT, CACNA1D and NR APA significantly correlated positively with CYP11B1. ATP1A1 mutated APA correlated positively with CYP11B2 (P<0.01) and not with CYP11B1 or HSD3B2.
Conclusion: Our findings in NR APA point towards a KCNJ5-like morphometric pattern associated with a WT-like steroidogenic enzymes expression pattern. WT APA presented an opposed morphometric pattern in comparison to mutated APA, indicating that in absence of detectable somatic mutations APA cells are driven towards a different cellular fate.
20 - 23 May 2017
European Society of Endocrinology