Unilateral forms of primary aldosteronism are usually surgically treated to remove the source of aldosterone excess. After adrenalectomy, aldosteronism persists in some patients indicating abnormal aldosterone production from the unresected gland. Our objective was to investigate histopathology, genotype, and postsurgical outcomes in a 3-year prospective cohort of surgically treated patients for primary aldosteronism (from 2016 to 2018). The cohort comprised 60 consecutively operated patients categorized with classical or nonclassical histopathologic findings of unilateral primary aldosteronism. In the classical group were 45 solitary aldosterone-producing adenomas or dominant aldosterone-producing nodules; in the nonclassical group were 15 cases of multiple aldosterone-producing micronodules or nodules (12 cases) or aldosterone-producing diffuse hyperplasia (3 cases). The classical group displayed higher baseline plasma aldosterone concentrations (262 versus 155 pg/mL, P =0.008) and an increased aldosterone-to-renin ratio (81 versus 42, P =0.002). A high proportion of the classical group achieved complete biochemical success (97.6% versus 66.7% in the nonclassical group, P =0.002). The nonclassical versus classical group displayed an increased ratio of absolute aldosterone concentration in the contralateral adrenal vein to peripheral vein at adrenal venous sampling (3.8 versus 2.0, P =0.004). Variants in aldosterone-driver genes were identified in 85% of 41 aldosterone-producing adenomas and were excluded in the remaining 15% by CYP11B2 guided next-generation sequencing. There were no differences in clinical or biochemical outcomes in patients with a solitary aldosterone-producing adenoma categorized by KCNJ5 mutation status. In conclusion, adrenals with a nonclassical histopathology of unilateral primary aldosteronism are associated with a higher incidence of postsurgical disease persistence and increased aldosterone production from the unresected adrenal.

Unilateral primary aldosteronism (PA) is the most common surgically curable form of hypertension that must be accurately differentiated from bilateral PA for therapeutic management (surgical versus medical). Adrenalectomy results in biochemical cure (complete biochemical success) in almost all patients diagnosed with unilateral PA; the remaining patients with partial or absent biochemical success comprise those with persisting aldosteronism who were misdiagnosed as unilateral PA preoperatively. To identify determinants of postsurgical biochemical outcomes, we compared the adrenal histopathology and the peripheral venous steroid profiles of patients with partial and absent or complete biochemical success after adrenalectomy for unilateral PA. A large multicenter cohort of adrenals from patients with absent and partial biochemical success (n=43) displayed a higher prevalence of hyperplasia (49% versus 21%; P=0.004) and a lower prevalence of solitary functional adenoma (44% versus 79%; P<0.001) compared with adrenals from age- and sex-matched patients with PA with complete biochemical success (n=52). We measured the peripheral plasma steroid concentrations in a subgroup of these patients (n=43) and in a group of patients with bilateral PA (n=27). Steroid profiling was associated with histopathologic phenotypes (solitary functional adenoma, hyperplasia, and aldosterone-producing cell clusters) and classified patients according to biochemical outcome or diagnosis of bilateral PA. If validated, peripheral venous steroid profiling may be a useful tool to guide the decision to perform surgery based on expectations of biochemical outcome after the procedure.

Aldosterone-producing adenomas (APAs) are one of the main causes of primary aldosteronism and the most prevalent surgically correctable form of hypertension. Aldosterone-producing cell clusters (APCCs) comprise tight nests of zona glomerulosa cells, strongly positive for CYP11B2 (aldosterone synthase) in immunohistochemistry. APCCs have been suggested as possible precursors of APAs because they frequently carry driver mutations for constitutive aldosterone production, and a few adrenal lesions with histopathologic features of both APCCs and APAs have been identified. Our objective was to investigate the metabolic phenotypes of APCCs (n=27) compared with APAs (n=6) using in situ matrix-assisted laser desorption/ionization mass spectrometry imaging of formalin-fixed paraffin-embedded adrenals from patients with unilateral primary aldosteronism. Specific distribution patterns of metabolites were associated with APCCs and classified 2 separate APCC subgroups (subgroups 1 and 2) indistinguishable by CYP11B2 immunohistochemistry. Metabolic profiles of APCCs in subgroup 1 were tightly clustered and distinct from subgroup 2 and APAs. Multiple APCCs from the same adrenal displayed metabolic profiles of the same subgroup. Metabolites of APCC subgroup 2 were highly similar to the APA group and indicated enhanced metabolic pathways favoring cell proliferation compared with APCC subgroup 1. In conclusion, we demonstrate specific subgroups of APCCs with strikingly divergent distribution patterns of metabolites. One subgroup displays a metabolic phenotype convergent with APAs and may represent the progression of APCCs to APAs.

Ambrosia artemisiifolia L., (common ragweed), is an annual invasive and highly troublesome plant species originating from North America that has become widespread across Europe. New sets of genomic and expressed sequence tag (EST) based simple sequence repeats (SSRs) markers were developed in this species using three approaches. After validation, 13 genomic SSRs and 13 EST-SSRs were retained and used to characterize the genetic diversity and population genetic structure of Ambrosia artemisiifolia populations from the native (North America) and invasive (Europe) ranges of the species. Analysing the mating system based on maternal families did not reveal any departure from complete allogamy and excess homozygosity was mostly due the presence of null alleles. High genetic diversity and patterns of genetic structure in Europe suggest two main introduction events followed by secondary colonization events. Cross-species transferability of the newly developed markers to other invasive species of the Ambrosia genus was assessed. Sixty-five percent and 75% of markers, respectively, were transferable from A. artemisiifolia to Ambrosia psilostachya and Ambrosia tenuifolia. 40% were transferable to Ambrosia trifida, this latter species being seemingly more phylogenetically distantly related to A. artemisiifolia than the former two.