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Epidemiology and Treatment of Childhood Adrenocortical Tumors

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

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  1. Epidemiology and Treatment of Childhood Adrenocortical Tumors Bhaskar N. Rao, MD Carlos Rodriguez-Galindo, MD St Jude Children’s Research Hospital

  2. 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

  3. 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: 0.30.4 per million • Southern Brazil: 3.4 per million

  4. Constitutional Abnormalities • Beckwith-Wiedemann syndrome • Hemihypertrophy • Genitourinary malformations • Multiple endocrine neoplasia I • Neurofibromatosis • Germline P53 Mutations (Li-Fraumeni, Li-Fraumeni-Like Syndrome)

  5. 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

  6. 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

  7. 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

  8. 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

  9. Clinical Features • Virilization 80% • Cushing 8% • Mixed 30-40% • Feminization 2.0% • Conn 1.6% • Non-Functional 2-3%

  10. J.W. #22675 18 mo boy with virilization Labs: Mixed syndrome (virilization + hypercortisolism)

  11. June 2005 August 2005

  12. Signs and Symptoms: 58 patients Sandrini et al. J Clin End Metab 1997

  13. Diagnosis • Determination of Hormonal Levels • Androgens and Corticosteroids • Imaging • CT • MRI • Bone scan • Pathology

  14. Radiological Features

  15. IVC Involvement

  16. Pathology Adenoma Carcinoma • Mitotic Index • Necrosis • Atypical Mitoses • Nuclear Grade Bugg MF. Am J Clin Pathol 101:625, 1994

  17. 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

  18. 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

  19. RPLN dissection

  20. International Pediatric Adrenocortical Tumor Registry IPACTRwww.stjude.org/ipactr

  21. Prognosis • Disease Stage • Limited Stage Disease • Completely resected • Small tumors • Large Tumors • Advanced Stage Disease • Gross residual tumors • Metastatic • Histology • Adenoma

  22. From fp0804.11 International Pediatric Adrenocortical Tumor Registry

  23. From fp0804.11 International Pediatric Adrenocortical Tumor Registry

  24. From fp0804.11 International Pediatric Adrenocortical Tumor Registry

  25. Tumor Spillage

  26. 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

  27. 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

  28. 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

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