Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation.

BACKGROUND: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. OBJECTIVE: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. METHODS: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. RESULTS: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). CONCLUSIONS: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry.

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, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION: Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.

Flow cytometric nuclear DNA content analysis of renal tumors in children: prognostic significance of nuclear DNA ploidy.

We studied, by flow cytometry, the DNA contents of paraffin-embedded tumor specimens from 90 infants and children with kidney tumors, and analyzed the relationship of DNA ploidy with histological types and prognosis. Data of adequate quality were obtained from 90 cases: 65 tumors with favorable histology, 5 congenital mesoblastic nephromas and 20 tumors with unfavorable histology. The 90 cases had nuclear DNA histogram patterns that were classified as DNA diploid in 64 tumors, aneuploid in 19 and tetraploid in 7. There were no significant correlations between DNA ploidy and histological types or clinical stages. Survival rates for patients with diploidy were 80 and 70% at 2 and 5 years, respectively, and those of patients with aneuploidy were 72 and 61% at 2 and 5 years, respectively. On the other hand, patients with a DNA tetraploid pattern had significantly worse survival rates of 43 and 29% at 2 and 5 years, respectively. Among patients with aneuploidy or tetraploidy, the S-phase fractions in those who died (mean +/- SD: 10.3 +/- 4.1 and 22.1 +/- 11.6%, respectively) appear to be greater than those in their surviving counterparts (8.8 +/- 4.0 and 12.1 +/- 2.8%). Hence, although the differences between diploid and aneuploid DNA patterns were not correlated with differential prognosis in children with kidney tumors, a tetraploid pattern clearly indicates a poor prognosis, especially in combination with histological types and clinical stages.