Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group.

OBJECTIVE: Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. DESIGN: Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. METHODS: We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). RESULTS: We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. CONCLUSION: In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.

Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature.

Background and purpose: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods: We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.

Pediatric adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of TP53 mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.

Survival characteristics of localized pediatric adrenocortical carcinoma managed with adenectomy: A national cancer center database analysis.

INTRODUCTION: Pediatric adrenocortical carcinoma (ACC) is a rare malignancy, encompassing less than 0.2% of all childhood malignancies. Due to the scarcity of this diagnosis, it is often managed according to guidelines established for adults, as there is a lack of reliable evidence regarding optimal adjuvant treatment options for pediatric patients. It is our aim to identify recent treatment trends as well as clinical and tumor characteristics and their impact on overall survival. METHODS: Using the National Cancer Data Base (NCDB), this study identified 49 patients under 18 years old with localized ACC (M0) undergoing adrenalectomy from 2004 to 2017. Kaplan-Meier analysis was performed to determine overall survival (OS) from patient characteristics and treatments received. Comparison of survival was performed using the log rank test. RESULTS: The median age of our cohort was 3 years old with a slight female predominance of 61%. The median tumor size was 9.4 cm, and patients older than 4 years were significantly (p = 0.03) more likely to present with larger tumors (11.33 cm vs 8.76 cm). Adjuvant treatment in the form of systemic therapy was administered in 20 of 49 (41%) patients and radiation therapy in 2 of 49 (4%) patients. Three-year OS for patients 4 years old and younger was 92.6% vs 61.8% for those older than 4 years (p = 0.002). Patients presenting with tumor size ≥9 cm had worse three-year OS compared to those with tumors <9 cm (95.24% vs 67.1% respectively, p = 0.02, Fig. 1). In patients with tumors ≥ 9 cm, younger children age 0-4 years had significantly (p = 0.04) higher OS rates than older children age 5-17 years. CONCLUSIONS: ACC is a rare pediatric malignancy with a female predominance. Those older than 4 years and those with presenting tumor size ≥9 cm have decreased overall survival rates after adrenalectomy for localized disease. Additionally, children older than 4 have poorer prognosis, even after controlling for larger tumor size. This is the largest contemporary series of localized pediatric ACC to date. However, multi-institutional prospective cohort or randomized-controlled trials are necessary to better evaluate relevant prognostic factors and the role of adjuvant therapies following adrenalectomy.

Clinical Impact of Pathological Features Including the Ki-67 Labeling Index on Diagnosis and Prognosis of Adult and Pediatric Adrenocortical Tumors.

Adrenocortical tumors (ACT) in the adult and pediatric population are generally considered distinct entities due to differences in molecular events related to tumorigenesis, clinical presentation, and outcome. Furthermore, pathological criteria used for diagnosis and prognostication of ACT in adults are usually inadequate for predicting the biological behavior of ACT in children. Here, we analyzed 146 adult and 44 pediatric (< 15y/o) ACT with long-term clinical follow-up and furthered current evidence on the clinical and pathological differences between pediatric and adult tumors. Predilection for female over male gender was observed in both cohorts, but more so in adults (84% vs. 61%, p = 0.003). Cushing syndrome was more frequent in adults (p < 0.001), whereas virilization, either isolated (p < 0.001) or combined to Cushing (p = 0.047), was more common in children. The Ki67 labelling index (LI) of pediatric adenomas and carcinomas was much higher than their corresponding tumors in adults (p < 0.001). Despite these differences, pathological analyses including the evaluation of Ki67 greatly improved patient prognostication in both age cohorts. Indeed, increased Weiss scores and Ki67 indexes correlated with poor overall- and disease-free survival in adult patients with carcinoma. Among the proliferative indexes tested, Ki67 LI ≥ 10% showed the highest hazard ratio (HR) for recurrence and the Ki67 LI ≥ 3% showed the highest HR for survival. In pediatric tumors, the Wieneke score (p < 0.001) and the Ki67 LI (p < 0.001) showed high accuracy for predicting biological behavior, and increased scores/indexes correlated with worse overall and disease-free survival. In this age cohort, Ki67 LI < 10% was able to rule out malignant behavior, whereas Ki67 LI ≥ 15% may be used to predict the patients with higher risks of recurrence and/or poor outcome.

Label-free impedimetric immunosensor based on arginine-functionalized gold nanoparticles for detection of DHEAS, a biomarker of pediatric adrenocortical carcinoma.

Pediatric adrenocortical carcinoma (pACC) is a rare and aggressive malignancy of high occurrence in Southern Brazil. pACC is characterized by the usual overproduction of dehydroepiandrosterone sulfate (DHEAS), whose detection in serum or plasma can be effective to the early diagnosis of the disease. Therefore, the present paper reports, for the first time, the construction and application of a label-free impedimetric immunosensor to detect DHEAS, which was based on the modification of an oxidized glassy carbon electrode with arginine-functionalized gold nanoparticles (AuNPs-ARG) and anti-DHEA IgM antibodies (ox-GCE/AuNPs-ARG/IgM). AuNPs-ARG was synthesized by a green route, and characterized by UV-VIS spectroscopy, FTIR, TEM, DLS, and XRD. The construction of ox-GCE/AuNPs-ARG/IgM was optimized through factorial design and response surface methodology. Cyclic voltammetry and electrochemical impedance spectroscopy measurements were employed to characterize the optimized immunosensor. The DHEAS detection principle was based on the variation of charge transfer resistance (∆Rct) relative to the Fe(CN)64-/3- electrochemical probe after immunoassays in the presence of the biomarker. A linear relationship between ∆Rct and DHEAS concentration was verified in the range from 10.0 to 110.0 µg dL-1, with a LOD of 7.4 µg dL-1. Besides the good sensitivity, the immunosensor displayed accuracy, stability, and specificity to detect DHEAS. The promising analytical performance of ox-GCE/AuNPs-ARG/IgM was confirmed by quantifying DHEAS in real patient plasma samples, with results that were comparable to the reference chemiluminescence assay. Our results suggest that the presented immunosensor can find clinical applications in the early diagnosis of pACC and to monitor DHEAS levels in other adrenal pathologies.

Common module analysis reveals prospective targets and mechanisms of pediatric adrenocortical adenoma and carcinoma.

Pediatric adrenocortical carcinoma and adrenocortical adenoma are two rare diseases affecting children. Molecular analyses were performed to identify commonalities in gene expression between the diseases. Differentially expressed genes were identified for the pediatric adrenocortical adenoma and carcinoma tissues, as compared with normal tissues, using the expression dataset. Protein-protein interaction (PPI) networks were constructed for adenoma and carcinoma disease models, and common modules among the diseases were identified. A total of two common modules with 14 nodes and 20 nodes were revealed among the adenoma and carcinoma networks, respectively. Genes of the common modules were also identified to be the common hub genes of the disease models. Enrichment of the genes of the common modules suggested associations with steroid biosynthesis, the proteasome, cell cycle and metabolic pathways. Modularity, topological and functional analysis of the PPI networks revealed common modules among pediatric adenoma and carcinoma disease models, which provided insight into the underlying disease mechanisms and suggesting prospective targets for future study.