Adrenocortical tumors and hyperplasias in childhood--etiology, genetics, clinical presentation and therapy (original) (raw)
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Frontiers in Oncology, 2020
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.
Journal of Clinical Oncology, 2004
Purpose We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. Patients and Methods Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. Results The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, a...
Journal of Clinical Medicine
Pediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight ≥ 200 g (p < 0.001), tumor size ≥ 5 cm (p < 0.05), Weiss score ≥ 5 (p < 0.05), Wieneke index ≥ 3 (p < 0.001) and Ki67 ≥ 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). ...
Childhood adrenocortical tumours
European Journal of Cancer, 2004
Childhood adrenocortical tumours (ACT) constitute only about 0.2% of all paediatric malignancies. However, the incidence of ACT varies across geographic regions and is remarkably high in southern Brazil. At presentation, most children show signs and symptoms of virilisation, which may be accompanied by manifestations of the hypersecretion of other adrenal cortical hormones. Fewer than 10% of patients with ACT show no endocrine syndrome at presentation; these are often older children and adolescents. ACT is commonly associated with constitutional genetic abnormalities, particularly mutations of the P53 gene. Histological features are used to classify the tumours as adenomas or carcinomas; however, the distinction between these two subtypes is often difficult. The extent of disease is best evaluated by computed tomography or magnetic resonance imaging; the role of positronemission tomographic scans has not been defined. Cure of ACT requires complete tumour resection. The role of chemotherapy or radiotherapy has not been established, although definitive responses to several anticancer drugs have been documented. Among patients who undergo complete tumour resection, favourable prognostic factors include age < 4 years, smaller tumour size, signs of virilisation alone at presentation, and adenomatous tumour histology. Some children with ACT show abnormalities of growth and development at the time of presentation, but these usually resolve after surgery.
Childhood Adrenocortical Tumours: a Review
Hereditary Cancer in …, 2006
Childhood adrenocortical tumour (ACT) is not a common disease, but in southern Brazil the prevalence is 15 times higher than in other parts of the world. One hundred and thirty-seven patients have been identified and followed by our group over the past four decades. Affected children are predominantly girls, with a female-to-male ratio of 3.5:1 in patients below 4 years of age. Virilization alone (51.6%) or mixed with Cushing's syndrome (42.0%) was the predominant clinical picture observed in these patients. Tumours are unilateral, affecting both glands equally. TP53 R337H germline mutations underlie most childhood ACTs in southern Brazil. Epidemiological data from our casuistic studies revealed that this mutation has ~10% penetrance for ACT. Surgery is the definitive treatment, and a complete resection should always be attempted. Although adjuvant chemotherapy has shown some encouraging results, its influence on overall outcome is small. The survival rate is directly correlated to tumour size; patients with small, completely excised tumours have survival rates close to 90%, whereas in those patients with inoperable tumours and/or metastatic disease it is less than 10%. In the group of patients with large, excisable tumours, half of them have an intermediate outcome. Recent molecular biology techniques and genomic approaches may help us to better understand the pathogenesis of ACT, the risk of developing a tumour when TP53 R337H is present, and to predict its outcome. An ongoing pilot study consisting of close monitoring of healthy carriers of the TP53 R337H mutation - siblings and first-degree relatives of known affected cases - aims at the early detection of ACTs and an improvement of the cure rate.
Genetics and genomics of childhood adrenocortical tumors
Molecular and Cellular Endocrinology, 2011
Adrenocortical tumors in children are usually diagnosed because of signs of virilization and their prognosis is poor. They possess several distinct pathological features compared to adrenocortical tumors in adults and have an exceptional prevalence in southern Brazil, where they are nearly invariably linked to the presence of a germline specific TP53 (R337H) mutation. Other important factors in childhood adrenocortical tumor
The Journal of Clinical Endocrinology & Metabolism, 2000
It has been previously shown that adrenocortical tumors (ACT) in adults exhibit structural abnormalities in tumor DNA in approximately 30% of cases. These abnormalities involve chromosome 11p15 and include loss of heterozygosity, paternal isodisomy, and overexpression of the gene for insulin-like growth factor II (IGF2), correlating with DNA demethylation at this locus. It has been hypothesized that these events occur late in the tumorigenic process in adults and seem to correlate with a worse prognosis. We present 4 pediatric cases of ACT diagnosed at 2.5 yr, 10 months, 12 yr, and 2.2 yr. All 4 patients presented with virilization, and 1 patient also showed signs and symptoms of glucocorticoid excess. The youngest patient's maternal aunt had surgical excision of a more than 15-cm ACT 18 yr previously, but the aunt is doing well at age 23 yr. They all had surgical removal of their tumors. The 2.5-yr-old child also received chemotherapy and radiotherapy because of capsular rupture and, after 3 local recurrences, died 3.3 yr after initial presentation. We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis. All 4 tumors
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017
Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression...
[Childhood adrenocortical tumors]
Arquivos brasileiros de endocrinologia e metabologia, 2004
Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Paraná, Brazil, is 15 times higher than that worldwide. We describe the clinical, laboratory and treatment characteristics and outcome of 125 patients treated in a single institution in the State of Paraná. The median age at diagnosis was 4.3 years, with a female:male ratio of 2.6:1. The most common forms of presentation were isolated virilization (51.2%) and virilization and Cushing's syndrome (42%). Nonfunctioning tumors comprised 4.8% of the cases. Two patients (1.6%) had isolated Cushing's syndrome and 1 (0.8%) had Conn's syndrome. Fifty-six percent presented hypertension. Surgery is the only curative treatment. Our data show that disease stage 1, absence of spillage during surgery and absence of intravenous thrombus were associated with better survival rates.