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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

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: 0.30.4 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 casesExons 2-8Li-Fraumeni syndrome

    • Brazil95% of casesExon 10No familial cancerMultiple 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%

  • Cushing8%

  • Mixed30-40%

  • Feminization2.0%

  • Conn1.6%

  • Non-Functional2-3%


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


Radiological Features


IVC Involvement


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


RPLN dissection


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


Tumor Spillage


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


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