Adrenocortical tumors in Brazilian children: immunohistochemical markers and prognostic factors.

CONTEXT: The behavior of adrenocortical tumors (ACTs) is usually difficult to establish in childhood, and the role of immunomarkers in predicting outcome has not yet been elucidated. OBJECTIVE: To investigate the relationship between clinical, pathologic, and immunohistochemical findings and prognosis in a series of children with ACTs. PATIENTS AND METHODS: Clinical data were evaluated retrospectively in 33 children with ACTs, including age at diagnosis, sex, time between first symptoms and diagnosis, clinical signs and symptoms, tumor position, and follow-up. Histologic sections were reviewed, each tumor was classified, and staging was performed according to previously published criteria. Immunohistochemical analysis of p53, Ki-67, c-Erb-B2, and Bcl-2 was performed according to previously published techniques. RESULTS: Sixty-four percent (n = 21) of the patients were female, and the age at diagnosis in the cohort ranged from 2 to 96 months. Virilization alone affected 70% (n = 23) of the patients, and 18 patients had stage 1 disease, 9 had stage 2 disease, and 3 each had stage 3 and stage 4 disease. Female sex and stage 1 and stage 2 disease were associated with good outcome. None of the histopathologic criteria evaluated correctly predicted outcome. Only tumors with a volume exceeding 200 mL were associated with malignant behavior. Because only a small number of tumors expressed the antigens, results of these immunohistochemical tests were considered inconclusive. CONCLUSION: In this sample of pediatric ACTs, the clinical and surgical parameters are the most important prognostic factors, while the immunohistochemical markers evaluated were not predictive of outcome.

A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.

The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.