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Epidemiology and Treatment of Childhood Adrenocortical Tumors. Bhaskar N. Rao, MD Carlos Rodriguez-Galindo, MD St Jude Children’s Research Hospital. St Jude Children’s Research Hospital Memphis, TN. Hospital de Clinicas Curitiba, Parana. Dr Raul C. Ribeiro Dr Bonald Figueiredo
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Epidemiology and Treatment of Childhood Adrenocortical Tumors Bhaskar N. Rao, MD Carlos Rodriguez-Galindo, MD St Jude Children’s Research Hospital
St Jude Children’s Research Hospital Memphis, TN Hospital de Clinicas Curitiba, Parana Dr Raul C. Ribeiro Dr Bonald Figueiredo Dr Gerry Zambetti Dr Richard Kriwacki
Incidence of childhood adrenocortical carcinoma in Southern Brazil The incidence of childhood ACT is at least 10 times greater in southern Brazil than in other geographic regions of the world • Worldwide: 0.30.4 per million • Southern Brazil: 3.4 per million
Constitutional Abnormalities • Beckwith-Wiedemann syndrome • Hemihypertrophy • Genitourinary malformations • Multiple endocrine neoplasia I • Neurofibromatosis • Germline P53 Mutations (Li-Fraumeni, Li-Fraumeni-Like Syndrome)
Li-Fraumeni Syndrome Criteria (Li-Fraumeni, 1988) • A proband < 45 years of age with sarcoma • First-degree relative age < 45 years with any cancer • First- or second-degree relative in the same lineage with any cancer at age < 45 years or with sarcoma at any age • Multiple primary cancers
Li-Fraumeni Syndrome • Increased familial predisposition to diverse types of cancer • Associated with P53 mutations In Li-Fraumeni families, childhood ACT accounts for 10% of all malignancies in children < 14 years of age
Adrenocortical CarcinomaBiology • Germline p53 mutations • U.S.50% of cases Exons 2-8 Li-Fraumeni syndrome • Brazil95% of cases Exon 10 No familial cancer Multiple cases in 15% families
Clinical Features in children and adolescents (n=462) • Median age; 3 years • Fewer than 10% >15 years • Female/male ratio: 2.3:1 • 0-9 years: 15:1 • >10 years: 1:1 • Functional: 90% Ribeiro RC in Textbook of Uncommon Cancer, 2sd Ed. 611, 1999
Clinical Features • Virilization 80% • Cushing 8% • Mixed 30-40% • Feminization 2.0% • Conn 1.6% • Non-Functional 2-3%
J.W. #22675 18 mo boy with virilization Labs: Mixed syndrome (virilization + hypercortisolism)
June 2005 August 2005
Signs and Symptoms: 58 patients Sandrini et al. J Clin End Metab 1997
Diagnosis • Determination of Hormonal Levels • Androgens and Corticosteroids • Imaging • CT • MRI • Bone scan • Pathology
Pathology Adenoma Carcinoma • Mitotic Index • Necrosis • Atypical Mitoses • Nuclear Grade Bugg MF. Am J Clin Pathol 101:625, 1994
International Adrenocortical Tumor Registry (IPACTR) • Established in 1990 as part of St Jude IOP: • St Jude + Clinics Hospital of Curitiba • Information-exchange website: • Strategy to improve knowledge and treatment • 200+ patients registered to date
Group Definition Treatment Group I • Small tumor < 200 cc or < 100 g • Completely resected Surgery alone Group II • Large tumor > 200 cc or > 100 g • Completely resected Surgery RPLN dissection Group III • Residual tumor • Unresectable • Regional spread (liver, kidneys, RPLN) Surgery MIT/CDDP/ETO/DOX x 8 Surgery with RPLND Group IV • Metastatic disease Surgery MIT/CDDP/ETO/DOX x 8 Surgery with RPLND ARAR0332
International Pediatric Adrenocortical Tumor Registry IPACTRwww.stjude.org/ipactr
Prognosis • Disease Stage • Limited Stage Disease • Completely resected • Small tumors • Large Tumors • Advanced Stage Disease • Gross residual tumors • Metastatic • Histology • Adenoma
From fp0804.11 International Pediatric Adrenocortical Tumor Registry
From fp0804.11 International Pediatric Adrenocortical Tumor Registry
From fp0804.11 International Pediatric Adrenocortical Tumor Registry
TreatmentMitotane • Insecticide derivative • Inhibits corticoid biosynthesis and destroys adrenocortical cells • Low doses (< 3 g/day): • Suppresses secretion of adrenal steroids • High doses (> 3 g/day): • Adrenolytic effect
TreatmentMitotane • Response Rates: 20-30% • Serum levels correlate with response: • Plateau 8 weeks • Optimal tumor responses • Therapeutic levels for prolonged periods • Levels > 14 mcg/mL
ARAR0332Research Questions • Pilot Study 1: • Benefit of RPLN dissection for large tumors • Pilot Study 2: • Response rate to MIT/CDDP/ETO in Group III • Response rate to + DOX in Group IV • Pilot Study 3: • PK of MIT • PK-guided administration of MIT