Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience

Abstract

Background and Aims: Pediatric adrenocortical tumors (ACTs) are very rare endocrine neoplasms in childhood. In this study, we performed a retrospective analysis of children with ACT treated at our institution by examining clinical and genetic disease features, treatment strategies, and outcomes. Methods: We retrospectively analyzed a cohort of 13 children treated at the Bambino Gesù Children's Hospital from November 2010 to March 2020. Results: The median age at diagnosis was 17 months (range = 0-82 months). The female: male ratio was 3.3/1. Mixed symptomatology (>1 hormone abnormality) was the most common presentation (46.1%). In three cases, the tumor was detected during prenatal or perinatal echographic screening. All patients presented with localized disease at diagnosis and underwent total adrenalectomy. Six patients were identified as having malignancies according to the Wieneke scoring system, five benign, and two undetermined. Seven patients underwent mitotane adjuvant therapy for 12 months. There was metastatic disease in three patients, with no correlation with age or Wieneke score. The most common sites of metastases were the liver and lungs. Metastatic patients were treated with surgery (n = 2), mitotane (n = 1), chemotherapy (n = 2) associated with anti-EGFR (n = 1), or immunotherapy with anti-PD1 (pembrolizumab) (n = 1); two patients achieved complete disease remission. Overall 2-and 5-year survival rates were 100%, with a median follow-up of 5 years (range = 2-9.5 years). Two-and 5-year disease free survival was 76.9 and 84.6%, respectively (95% confidence interval = −66.78-114.76 months). All patients are alive, 12 without disease, and one with stable disease. Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one de novo). One patient had Beckwith-Wiedemann syndrome, with mosaic paternal uniparental disomy of chromosome 11, in both neoplastic and healthy adrenal tissue. Miele et al. Adrenocortical Tumors in Children Conclusion: We report the cases of 13 patients treated for ACT, including 12 aged <4 years at diagnosis, with a relative short time from symptoms onset. Our cohort experienced an excellent prognosis. TP53 mutation was found in 75% of tested patients (6/8) confirming the need to perform genetic tests and familial counseling in this disease.

Adrenocortical Carcinoma in Childhood: A Systematic Review

“…Information on metastasis was available in 69 reports [ 4 , 7 , 24 , 25 , 27 , 28 , 29 , 32 , 48 , 51 , 52 , 55 , 57 , 59 , 60 , 61 , 63 , 64 , 67 , 68 , 70 , 72 , 73 , 85 , 86 , 89 , 98 , 99 , 101 , 102 , 105 , 106 ]. Among the 2526 patients, at least one metastasis was reported in 632 (25%; 22%—at diagnosis, 3%—at relapse).…”

“…The classic Weiss criteria [ 113 ], which are well-established in the adult population, are controversial in the pediatric literature. Even though multiple authors have shown that a Weiss score >3 correlates with poor prognosis [ 9 , 26 , 29 , 38 , 54 , 71 , 88 , 94 , 95 , 96 , 97 , 115 , 116 , 117 ] ( Table 5 and Table S4 ), others have shown that Weiss criteria are not applicable in the pediatric population [ 9 , 54 , 64 , 69 , 76 , 77 , 82 , 85 , 88 , 94 , 102 , 116 ] and modifications are necessary, as suggested by Wieneke et al [ 9 ] (see Figure 2 ). There have been several studies validating the reliability of the Wieneke scoring system in both Brazilian and non-Brazilian cohorts of pediatric ACT [ 64 , 70 , 82 ], showing that it is highly predictive of the clinical outcome.…”

“…Pianovski et al suggested VEGFR1 and mTOR inhibitors for the treatment of pediatric ACC, demonstrating that almost all the patients overexpressed VEGFR and many patients had activation of the mTOR pathway [ 137 ]. However, there have been no convincing clinical reports on this approach [ 85 , 131 , 141 , 142 ]. In a network analysis comprising 18 pediatric ACC patients, CDK1, CCNB1, CDC20, and BUB1B were identified as potential biomarkers of pediatric ACC, though not as expressive as in adult cohorts [ 133 ], and as potential targets for a therapeutic approach [ 134 ].…”

“…Regarding the immune response in pediatric ACT, two studies were found: Parise et al reported an association between infiltrated CD8+ T cells and better prognosis [ 45 ], whereas Geoerger et al demonstrated responses to checkpoint inhibition (pembrolizumab) in children [ 85 , 132 ]. Further functional analyses are necessary to clarify immune escape mechanisms of pediatric ACC to provide future targeted therapies.…”

Case Series and Review of Literature of Malignant Adrenocortical Neoplasms: Experience of Two Tertiary Centers in Saudi Arabia

“…Malignant adrenocortical neoplasms may arise sporadically or can be associated with certain genetic alterations. Common genetic mutations include TP53 tumor suppressor gene and insulin-like growth factor 2 (IGF2) overexpression secondary to 11p15 chromosomal locus mutation [ 3 , 7 , 8 ]. In our case series, we present five cases, three of which occurred in female patients and two in male patients with ages ranging from one to eight years.…”