Patient was a 28-year-old healthy female diagnosed with non-functional metastatic ACT at age 15 months. She did not have an antecedent of endocrine manifestations, and the tumor was discovered during the one-year routine visit to the pediatrician. She did not have a history of growth and developmental abnormalities. CT imaging of the abdomen and chest revealed a left supra-renal mass measuring 5 cm in the largest diameter and bilateral pulmonary nodules (Stage IV). She underwent resection of the primary tumor that measured 7.0 × 6.0 × 4.0 cm and weighed 130 g. The histopathological examination confirmed the diagnosis of ACC. She was transferred to St. Jude and treated with cisplatin, etoposide and mitotane. However, after four courses of chemotherapy, several pulmonary lesions remained. She underwent resection of the bilateral pulmonary metastatic nodules, and most of them showed viable metastatic tumor by histology. Chemotherapy was stopped and the patient was monitored for tumor progression. The pulmonary lesions regressed and remained very small for over 10 years. She continues to be free of disease and in good health to date, 26.5 years after the diagnosis.\nMolecular findings: No TP53 variants were observed in blood and tumor samples (). In addition, the primary tumor was negative for CTNNB1 and ATRX. Furthermore, microsatellite analysis of germline DNA revealed a pattern of homozygosity consistent with paternal UPD that was confirmed by MS-MLPA.
The patient was an 8.5-year-old female with presumptive diagnosis of BWS who presented to the local physician in 2003 with new onset of herculean habitus, clitoromegaly, pubic hair, acne, and apocrine odor. Abdominal computed tomography imaging revealed synchronous bilateral adrenal masses. There was no evidence of disease elsewhere. The patient underwent laparotomy with excision of the left adrenal gland and tumor enucleation of the right gland. The left tumor weighed 21.5 g and measured 5.5 × 1.5 × 0.7 cm, and right tumor measured 1.3 × 1.2 × 1.0 cm. Sections of both tumors showed similar cellular constituents. Tumors were composed of a uniform population of cells with ample acidophilic cytoplasm and moderate anisonucleosis that recapitulated the zona reticularis, consistent with the diagnosis of adrenocortical adenoma. The p53 staining was negative and Ki-67 labeling index (LI) was less than 2%. Inhibin-α was positive in a subset of cells. No chemotherapy was indicated. The patient remained asymptomatic until 2008, and then developed bilateral small breast nodules. The right breast mass measured 3.5 × 2.5 × 2.0 cm and the left inferior breast mass measured 3.0 × 2.0 × 2.0 cm and both were surgically removed. Histology of the first mass had features of tubular adenoma and that of the left mass of juvenile fibroadenoma. The patient remained clinically stable until the age of 18 years when she was taken off the protocol.\nMolecular findings: Blood and tumor DNA of this patient was examined by whole exome sequencing (WES) (). Results showed that the patient had a wild type sequence for TP53 in both germline and tumor DNA as well as wild type sequence for CTNNB1 and ATRX in the tumor (, ). Additional findings included the somatic p.E150K variant in the imprinted MKRN3 and the p.D155fs in the cytochrome P450 Family 17 Subfamily A Member 1, CYP17A1. Of note, the patient harbored a germline p.E257K variant in EGFR () and the p.M595T variant in the regulator of epigenetic gene silencing SIRT1. Both variants were present in the tumor in the heterozygous state (). The variant in EGFR was classified as likely benign in CLINVAR (variant ID 1123013) and the SIRT1 variant was not reported. Therefore, both variants have been reported in the Genome Aggregation Database (gnomAD) originated from unrelated individual sequences as part of population genetic studies supporting lack of biological significance for both variants in the context of adrenocortical tumors. WES analysis of blood-derived DNA did not detect 11p15 UPD. However, a pattern of homozygosity at chromosome 11p15 was verified by microsatellite markers analyses and confirmed by MS-MLPA consistent with paternal uniparental disomy (UPD) in the germline sample ().