Clinical comparison and genetic analysis in pheochromocytoma with primary aldosteronism

Abstract

Pheochromocytoma is a rare form of adrenal hypertension. This study aimed to investigate the clinical characteristics and associated genetic mutations in patients with pheochromocytoma and primary aldosteronism. We retrospectively analyzed data from 23 patients with pheochromocytoma diagnosed and treated between 2011 and 2022. Three cases were complicated by primary aldosteronism. Compared to 15 other patients without primary aldosteronism complications, these three patients had a greater suppression of plasma renin activity (0.2 vs. 2.3 ng/mL/h, p < 0.01) and a higher aldosterone-to-renin ratio (p < 0.01). No significant differences were found in blood pressure, serum potassium levels, or plasma aldosterone concentrations between the two groups. In genetic analysis, among the three patients with pheochromocytoma and primary aldosteronism, two had a KCNJ5 (G151R) mutation in the pheochromocytoma tumor tissues. However, no CYP11B2- or CYP11B1-positive cells were detected via immunostaining in the pheochromocytoma tissues of these three patients. To our knowledge, this is the first study to reveal the presence of the KCNJ5 mutation, commonly considered specific to primary aldosteronism, in pheochromocytoma cases clinically complicated by primary aldosteronism. The findings suggest that patients with pheochromocytoma and suppressed plasma renin activity should be assessed for primary aldosteronism.

Keywords: KCNJ5; Next-generation sequencing; Pheochromocytoma; Primary aldosteronism.

Fig. 1. Genetic analysis of the 23 patients with pheochromocytoma

Gene mutations, defined as those of uncertain significance, included APC p.E1645K, APC p.E1663K, GNAS p.A436D, MEN1 p.T456A, VHL p.T124K, and RET p.V292M. Gene mutations defined as pathogenic or likely pathogenic included RET p.M918T, RET p.C634G, KCNJ5 p.G151R, NF1 p.S1063X, and VHL p.N78S. Gene mutations defined as other included CYP11B1 p.R374R, PRKACA p.P62P, and ATP2B3 p.G491G.

Fig. 2. Radiological, histopathological, and genetic findings in Case 3

A, abdominal computed tomography; B, I-123 metaiodobenzylguanidine (MIBG); C, hematoxylin and eosin staining (HE); D, gene analysis of KCNJ5 using the Sanger DNA sequencing technique; the yellow arrow in A indicates a tumor with a diameter of 26 mm in the right adrenal gland; the red arrow in B indicates an uptake of MIBG in the right adrenal gland, which is not inconsistent with pheochromocytoma; a mutation was detected in KCNJ5, and the change in the corresponding amino acid was confirmed (c.451C).

Fig. 3. Immunohistochemistry findings in the three cases of PHEO coexistence with PA

Case 1: A–C; Case 2: D–F; Case 3: G–I. Cases 2 and 3 involved PHEO with a KCNJ5 mutation. A, D, and G, hematoxylin and eosin staining (HE); B, E, and H, immunostaining for CYP11B1; C, F, and I, immunostaining for CYP11B2; t, tumor; a, adjacent adrenal gland; APCC, black arrow in I. PHEO, pheochromocytoma; PA, primary aldosteronism; APCC, aldosterone-producing cell cluster.

Graphical Abstract