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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

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Epidemiology and treatment of childhood adrenocortical tumors l.jpg

Epidemiology and Treatment of Childhood Adrenocortical Tumors

Bhaskar N. Rao, MD

Carlos Rodriguez-Galindo, MD

St Jude Children’s Research Hospital


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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


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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


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Constitutional Abnormalities

  • Beckwith-Wiedemann syndrome

  • Hemihypertrophy

  • Genitourinary malformations

  • Multiple endocrine neoplasia I

  • Neurofibromatosis

  • Germline P53 Mutations (Li-Fraumeni, Li-Fraumeni-Like Syndrome)


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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


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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


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Adrenocortical CarcinomaBiology

  • Germline p53 mutations

    • U.S.50% of casesExons 2-8Li-Fraumeni syndrome

    • Brazil95% of casesExon 10No familial cancerMultiple cases in 15% families


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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


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Clinical Features

  • Virilization 80%

  • Cushing8%

  • Mixed30-40%

  • Feminization2.0%

  • Conn1.6%

  • Non-Functional2-3%


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J.W. #22675

18 mo boy with virilization

Labs: Mixed syndrome (virilization + hypercortisolism)


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June 2005

August 2005


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Signs and Symptoms: 58 patients

Sandrini et al. J Clin End Metab 1997


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Diagnosis

  • Determination of Hormonal Levels

    • Androgens and Corticosteroids

  • Imaging

    • CT

    • MRI

    • Bone scan

  • Pathology


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Radiological Features


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IVC Involvement


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Pathology

Adenoma

Carcinoma

  • Mitotic Index

  • Necrosis

  • Atypical Mitoses

  • Nuclear Grade

Bugg MF. Am J Clin Pathol 101:625, 1994


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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


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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


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RPLN dissection


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


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Prognosis

  • Disease Stage

    • Limited Stage Disease

      • Completely resected

        • Small tumors

        • Large Tumors

    • Advanced Stage Disease

      • Gross residual tumors

      • Metastatic

  • Histology

    • Adenoma


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From fp0804.11

International Pediatric Adrenocortical Tumor Registry


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From fp0804.11

International Pediatric Adrenocortical Tumor Registry


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From fp0804.11

International Pediatric Adrenocortical Tumor Registry


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Tumor Spillage


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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


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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


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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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