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

Abstract

Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

“…The 2022 WHO classification no longer endorses the use of "nodular adrenal cortical hyperplasia" for incidentally discovered sporadic non-functional adrenal cortical nodules. The latter stems from recognition of the clonal/neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules [1][2][3][4][5]. The new classification endorses the term sporadic nodular adrenocortical disease for such manifestations (Fig.…”

KDM1A inactivation causes hereditary food-dependent Cushing syndrome

“…This correlation further supports the hypothesis of different clinicopathological groups of PBMAH as recent progress in other type of adrenal tumors have suggested. 21 This study identified the lysine-specific demethylase 1 gene KDM1A (also known as lysine-specific histone demethylase 1A gene LSD1) as a tumor suppressor gene responsible for the genetic predisposition to PBMAH associated with FDCS. A germline KDM1A variant was observed in 9 of 10 index cases of the patients with FDCS investigated in this study (in 5 of 6 patients of the 36 patients investigated in the integrated genomics study and in 4 of 4 additional index patients subsequently investigated specifically for KDM1A alteration).…”

Dermatological and endocrine elements in Carney complex (Review)

“…In individuals with CND, one in 10 adults has a tumor at the level of the adrenal cortex, mostly an age-dependent, so called 'adrenal incidentaloma' (44). Adrenal tumor-related genetic backup is identified with regard to channel anomalies as found in some cases of primary hyperaldosteronism; in TP53 mutations (such as Li-Fraumeni syndrome) causing adrenocortical carcinoma, especially in pediatric individuals, or pigmented adrenal lesions induced by CNC (45,46). Other syndromic circumstances associated with an adrenal tumor involves multiple endocrine neoplasia type 2A, neurofibromatosis type 1, McCune-Albright syndrome, Beckwith-Wiedemann syndrome, and von Hipple-Lindau disease (47).…”