Clinical and Biological Correlates and Outcomes in Children with Adrenocortical Tumors without Germline TP53 Mutations: A Report from the International Pediatric Adrenocortical Tumor Registry and the Children’s Oncology Group

Presentation Number: LB MON 50
Date of Presentation: April 3rd, 2017

Emilia Modolo Pinto*1, Carlos Rodrigues Galindo2, Stanley Pounds2, Lei Wang2, Michael R Clay2, Catherine G Lam2, Alberto Pappo2, Gerard P Zambetti2 and Raul C Ribeiro2
1St. Jude Children's Research Hospital, Memphis, TN, 2St. Jude Children's Research Hospital


Background: Pediatric adrenocortical tumor (ACT), an uncommon malignancy, is often associated with Li–Fraumeni syndrome, a familial cancer predisposition disorder caused by germline mutations in the tumor suppressor gene TP53. However, germline TP53 mutations are absent in 35%–40% of children with ACT. Mechanisms of tumorigenesis and tumor progression as well as prognostic markers of ACT have not been systematically evaluated in these patients.

Objective: We describe clinical correlates, biological and molecular features, and outcomes of children with ACT without germline TP53 mutations.

Design and Methods: Medical records were screened for clinical, biological, and outcome variables of 60 children with ACT. Genomic DNA was analyzed for TP53, CTNNB1, ATRX, and chromosome 11p15 alterations. Expression of β-catenin and Ki-67 was evaluated by immunostaining. Primary endpoints were overall survival and progression-free survival (PFS) stratified by biological markers.

Results: Median age of 42 girls and 18 boys was 3.3 years (range 0.25–21.7 years). Virilization alone (n=23) or with hypercortisolism (n=10) was observed in 55% of patients. Complete resection was achieved in 32 patients (stage I, n=18 and stage II, n=14). Persistent or metastatic disease was observed in 28 patients (stage III, n=13 and stage IV, n=15). Histologically, tumors were classified as carcinoma (n=43), adenoma (n=10) and undetermined (n=7). At a median follow-up of 2.7 years, 47 patients were alive and 13 died of disease. The 3-year PFS and overall survival were 69.9% and 78%, respectively. Loss of heterozygosity at chromosome 11p15 occurred in 85% of patients. Acquired CTNNB1, TP53, and ATRX mutations occurred in 43.4%, 16.7%, and 5.7% of patients, respectively. Ki-67 labeling index (LI) was ≥15% in 27 (48.2%) patients. Acquired TP53 mutations, age, disease stage, and Ki-67 LI were each significantly associated with PFS in single predictor Cox regression models. Greater Ki-67 LI and age were significantly associated with worse outcome.

Conclusions: Our study reveals considerable overlap among clinicopathologic features, molecular attributes, and outcomes of children with ACT irrespective of germline TP53 status. However, patients with wild-type TP53 tend to be older, have higher frequency of CTNNB1 activation mutations, and lower frequency of virilization than those with germline TP53 mutations. The strong association of Ki-67 LI with prognosis suggests that evaluation of Ki-67 LI might improve the histopathological classification of ACTs.

Funding:This work was supported by a grant from Centocor, Inc., National Institutes of Health Cancer Center Support Grant CA21765, and ALSAC.


Nothing to Disclose: EMP, CRG, SP, LW, MRC, CGL, AP, GPZ, RCR