Histological and biochemical distinctiveness of atypical aldosterone‐producing adenomas responsive to upright posture and angiotensin

Abstract

Fifteen patients with primary aldosteronism were classified as angiotensin II-unresponsive aldosterone-producing adenoma (AII-U APA, n = 9), or angiotensin II-responsive aldosterone-producing adenoma (AII-R APA, n = 6), based on the responsiveness of aldosterone to upright posture and to angiotensin II infusion. Lack of aldosterone response to angiotensin II infusion immediately postoperatively in the AII-R APA subtype was consistent with previous responsiveness residing solely within the adenoma. Cortisol levels in five of the six patients with AII-R APA failed to suppress normally with dexamethasone consistent with some autonomous production of cortisol by the adenoma. In contrast, cortisol levels suppressed normally during dexamethasone administration in all patients with AII-U APA. This biochemical distinction can be added to the previously described overproduction of 18-oxo cortisol in AII-U APA but not in AII-R APA. Histological examination of adenoma sections revealed predominantly (greater than or equal to 50%) zona fasciculata type cells in AII-U APA. In contrast, AII-R APA contained less than 20% zona fasciculata type. Thus, biochemical differences between AII-U APA and AII-R APA subtypes of primary aldosteronism may be due to underlying differences in cellular composition of the aldosterone-producing adenomas.

Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas

“…Several studies have shown distinct biochemical characteristics of patients with primary aldosteronism due to APA, based on different aldosterone responses to upright posture (7, 29 -31) and dexamethasone administration (12, 13, 32 -34). Responsiveness to endogenous angiotensin II and ACTH inhibition may reflect a different prevalence of zona fasciculata-like cells within the tumor (30,35). No relationship was found in our patients with APA between CYP11B1 and CYP11B2 transcript levels and aldosterone secretion, either basal or in response to dynamic testing.…”

Combined Primary Aldosteronism and Cushing's Syndrome Due to a Single Adrenocortical Adenoma Complicated by Hashimoto's Thyroiditis.

“…Another possibility is that APAis composed of both aldosterone-producing cells and cortisol-producing cells. The reports describing the APAcontaining zona glomerulosa, zona fasciculate and their hybrid cells (9,18,19) support this possibility. In our case, the latter possibility is more likely considering the result of immunohistochemical studies.…”

Somatic Mutations Affecting the Selectivity Filter of KCNJ5 Are Frequent in 2 Large Unselected Collections of Adrenal Aldosteronomas

“…It was subsequently shown that this lack of response to posture or the infusion of angiotensin (Ang) II was not shared by all of the APAs and appeared restricted to those with ZF morphology and the production of excessive "hybrid" steroids18-hydroxyand 18-oxo-cortisol. 9,10 This makes our observation that our APAs with mutations lacked an aldosterone response to posture all the more intriguing, because it represents the response of the APA cells to Ang II generated in vivo by the renin-Ang system on standing. 9,10,24 Possibly, APA cells depolarized by KCNJ5 mutations cannot respond to Ang II receptor activation by further depolarization and aldosterone release.…”

“…9,10 This makes our observation that our APAs with mutations lacked an aldosterone response to posture all the more intriguing, because it represents the response of the APA cells to Ang II generated in vivo by the renin-Ang system on standing. 9,10,24 Possibly, APA cells depolarized by KCNJ5 mutations cannot respond to Ang II receptor activation by further depolarization and aldosterone release. Alternatively, the histology of APAs that are unresponsive to posture and secrete excess amounts of the hybrid 18-oxo steroids may be relevant.…”

“…We explored other genotype-phenotype associations in this data set and found a significant association of genotype with the aldosterone response to upright posture (calculated as the percentage rise in plasma aldosterone from 7:00 AM or 8:00 AM after overnight recumbency to 10:00 AM after 2 to 3 hours of standing, sitting, or walking, with "responsiveness" defined as a rise of Ն50% over basal. 9,10 We only had these data for the Australian APAs, but in this collection 10 of 10 with the mutation were unresponsive versus 6 of 16 without a mutation (1 Australian patient did not undergo posture studies). This was significant (PϽ0.02, Fisher's exact test), as was the change in aldosterone on standing when compared in the 2 genotypes ( Figure 3 and Figure S2 in the online-only Data Supplement).…”