The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity

Abstract

Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype–phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5-mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3, and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (PRKACA, PRKAR1A, GNAS, PDE11A, and PDE8B) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

“…Very rare examples of aldosterone-producing adenomas with oncocytic change have also been reported [16]. However, most conventional adenomas leading to Conn syndrome have a characteristic golden-yellow color due to enrichment of lipidrich zona fasciculata (ZF)-type clear cells in the tumor; however, zona reticularis (ZR)-and zona glomerulosa (ZG)-like compact cells can be exclusively noted in some aldosteroneproducing adenomas [17]. In addition, some tumors can feature mixed ZF-and ZG/ZR-like cells [17].…”

“…However, most conventional adenomas leading to Conn syndrome have a characteristic golden-yellow color due to enrichment of lipidrich zona fasciculata (ZF)-type clear cells in the tumor; however, zona reticularis (ZR)-and zona glomerulosa (ZG)-like compact cells can be exclusively noted in some aldosteroneproducing adenomas [17]. In addition, some tumors can feature mixed ZF-and ZG/ZR-like cells [17]. The overall morphological heterogeneity is now better reflected in molecular genotypephenotype correlations of primary aldosteronism [17].…”

“…In addition, some tumors can feature mixed ZF-and ZG/ZR-like cells [17]. The overall morphological heterogeneity is now better reflected in molecular genotypephenotype correlations of primary aldosteronism [17].…”

“…Molecular studies of primary aldosteronism have helped develop genotype-phenotype correlations with respect to tumor characteristics (e.g., cytomorphology, size, and focality), degree of autonomous aldosterone secretion, patient demographics (age, gender, and ethnic background), higher risk of recurrence of postoperative hypertension, and expression of steroidogenic enzymes (ZG-related biomarkers: CYP11B2, ZF-related biomarkers: CYP11B1 and CYP17) in various aldosterone-producing adrenal cortical lesions (e.g., APAs, APM/APCCs, and APN) [17,24,33,[63][64][65].…”

“…KCNJ5-related phenotype is on a par with the original description of APA (4.0-cm clear-cell-rich APA in a young female) by Dr. J. Conn [11,12]. KCNJ5-wild type disease is more frequent in males (often later age of diseaseonset) and is likely to manifest with a smaller tumor size (often less than 1.0 cm) and/or multifocal disease including MAPM/APCCs and/or MAPNs, and frequent compact cell cytomorphology [17,33]. These observations are also in line with the fact that the classical histology designation of the HISTALDO classification is enriched in KCJN5-mutant aldosterone-producing lesions when compared with the nonclassical histology group [19].…”