Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

Abstract

Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal.

Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal

“…These observations could support a role of mast cells in the setting and/or regulation of aldosterone biosynthesis, as formerly described in the adult adrenal and aldosterone-producing adenomas Lefebvre et al, 2001). They thus also provide an additional example of the similarities of the mechanisms involved respectively in tumor formation and normal human fetal development Lalli and Figueiredo, 2015). The mechanisms by which mast cells may regulate aldosterone secretion during fetal development need to be now determined.…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…Pediatric ACTs differ from adult tumors under several aspects related to their pathogenesis, clinical presentation, molecular signatures and prognosis (Lalli & Figueiredo 2015). In addition, histopatological (Weiss score) and molecular (IGF2 overexpression, BUB1B/PINK1 expression) Endocrine-Related Cancer parameters linked to malignancy in adult tumors do not have the same predictive value in pediatric ACT (Wieneke et al 2003, Rosati et al 2008, Dehner & Hill 2009, Papotti et al 2011, Lalli & Figueiredo 2015.…”

“…In addition, histopatological (Weiss score) and molecular (IGF2 overexpression, BUB1B/PINK1 expression) Endocrine-Related Cancer parameters linked to malignancy in adult tumors do not have the same predictive value in pediatric ACT (Wieneke et al 2003, Rosati et al 2008, Dehner & Hill 2009, Papotti et al 2011, Lalli & Figueiredo 2015. In the comprehensive study from the International Pediatric Adrenocortical Tumor Registry based on the analysis of 254 patients, the major parameters influencing the risk of recurrence were age, stage at diagnosis and tumor weight (Michalkiewicz et al 2004).…”

Mouse models of adrenocortical tumors

“…Pediatric ACTs, particularly those diagnosed in the first years of life, have been hypothesized to originate in fetal adrenal cells (Lalli et al, 2015), where the fetal adrenal enhancer (FAdE) controls NR5A1 expression (Zubair et al, 2006). Although both adrenal and gonadal cells arise from a common NR5A1 -positive precursor, FAdE-driven NR5A1 expression is restricted to the adrenal primordium (Zubair et al, 2006, Zubair et al, 2008).…”