Onco-13-Adrenocortical Tumors in Children · the “adult cortex” originates and a more central...

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Adrenocortical Tumors in Children

Lead contributors:Raul C. Ribeiro, Carlos Rodriguez-Galindo, Gerald P. Zambetti, Maria Jose

Mastellaro, Eliane Caran, Antonio G. Oliveira Filho, Henrique Lederman, JesseJenkins, Guillermo Chantada, and Bonald C. Figueiredo

Summary

Childhood adrenocortical tumors (ACT) represent only about 0.2% of all

pediatric malignancies. At the time of diagnosis, most children show signs and

symptoms of virilization, Cushing syndrome, or both. Fewer than 10% of

patients with ACT show no endocrine syndrome at the time of presentation,

although some of these patients may have laboratory evidence of abnormal

concentrations of adrenal cortex hormones. ACT producing estrogen

(feminization) or aldosterone (Conn syndrome) is exceedingly rare in children.

ACT is commonly associated with constitutional genetic abnormalities,

particularly mutations of the TP53 gene. ACT is classified as adenoma or

carcinoma depending on the histologic features. Imaging modalities to evaluate

the extension of disease include computed tomography (CT) and magnetic

resonance (MR); the role of positron-emission tomography (PET) is still evolving,

but in some cases of disease recurrence, PET can detect tumors that are not

identified by other imaging modalities. The lungs, liver, bone, and brain are the

most common sites involved in patients with metastatic ACT. The contralateral

adrenal gland is rarely affected. Complete gross tumor resection is required to

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cure ACT. The role of chemotherapy has not been established, although

definitive responses to several anticancer drugs have been documented. For

patients who undergo complete tumor resection, favorable prognostic factors

include young age, small tumor size, virilizing signs, and adenoma histology.

Some children with ACT show abnormalities of growth and development at the

time of presentation, but these usually resolve after surgery. Prospective

studies are necessary to further elucidate the pathogenesis of ACT and to

improve patient outcome.

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Background

Because of the rarity of childhood ACT, the clinical and biological

characteristics and treatment recommendations for this entity have only

recently been characterized. It is not uncommon for pediatric oncology trainees

to have never treated a child with ACT during their training years. Moreover,

current pediatric oncology textbooks contain scarce information about this

disease. The first case of childhood ACT was reported in 1865.1Cushing

described the classic features of hypercortisolism (Cushing syndrome, Fig. 1) in

1912; however, the association between adrenal tumors and this syndrome was

not well understood until 1934.2

Childhood ACT has clinical and biological features unlike those

associated with other pediatric carcinomas. For example, the

incidence of most childhood carcinomas increases with age, whereas 65% of

cases of ACT occur in children younger than 5 years.3,4 Moreover, ACT has been

diagnosed during the first year of life and prenatally.5-7 Hence, the age

distribution resembles that of patients with tumors of embryonic origin rather

than of those whose tumors arise from mature tissues. In addition, the clinical

and molecular features of pediatric ACT differ from those of the adult

counterpart; these differences further suggest that childhood ACT

may have a unique cell origin.

In this report, we describe the clinical and biological characteristics of

childhood ACT and the treatment of ACT in children.

1Pitman. General melasma and short hair over the entire body of a child of three years, withconversion of the left supra-renal capsule into a large malignant tumor; the external organs ofgeneration resembling that of adult life. Lancet. 1865;1:175.

2Walters W, Wilder R, Kepler E. The suprarenal cortical syndrome with presentation of ten cases.Ann Surg. 1934;100:670.

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3Ribeiro RC, Sandrini Neto RS, Schell MJ et al. Adrenocortical carcinoma in children: A study of40 cases. J Clin Oncol. 1990;8:67-74.

4 Michalkiewicz E, Sandrini R, Figueiredo B et al. Clinical and outcome characteristics of childrenwith adrenocortical tumors: a report from the International Pediatric Adrenocortical TumorRegistry. J Clin Oncol. 2004;22:838-845.

5 Artigas JL, Niclewicz ED, Padua GS, Ribas DB, Athayde SL. Congenital adrenal corticalcarcinoma. J Pediatr Surg. 1976;11:247-252.

6Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressingadrenocortical carcinoma in a newborn: A case report with DNA ploidy analysis. Cancer.1988;62:507-511.

7Sarwar ZU, Ward VL, Mooney DP, Testa S, Taylor GA. Congenital adrenocortical adenoma: casereport and review of literature. Pediatr Radiol. 2004;34:991-994.

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Epidemiology

The frequency of ACT is 0.4 cases per million persons during their first 4

years of life, and it decreases to 0.1 cases per million persons during their

subsequent 10 years. It then rises to 0.2 cases per million persons during the

late teens and reaches another peak during the fourth decade of life.1 This

pattern is consistent with the concept that pediatric ACT consists of at least two

distinct disease groups. On the basis of data from the United States Surveillance

Epidemiology and End Results (SEER) program, it is estimated that there are 19

to 20 new cases of adrenocortical carcinoma per year in children and

adolescents in the United States. The estimates may be lower than the actual

incidence because cases of adrenocortical adenomas are not typically included

in population-based cancer registries. Data from hospital registries indicate that

about one third of all pediatric ACT are adenomas; hence, the actual number of

ACT cases is likely to be between 25 to 30 per year in persons younger than 20

years in the United States.

The incidence of ACT differs across geographic regions. The incidence

per million children younger than 14 years ranges from 0.1 in Hong Kong and

Bombay to 0.4 in Los Angeles to 3.4 in southern Brazil.1-5 A clustering of

pediatric ACT has been observed in southern Brazil but not in other Brazilian

regions.6,7 ACT has been diagnosed in more than 350 children during the past

30 years in seven pediatric oncology units in southern Brazil. In a single

hospital in Curitiba that admits approximately 80 to 100 new cases of

pediatric cancer per year, 125 cases of pediatric ACT have been diagnosed

between 1966 and 2003.6 In contrast, only 36 cases in the United States have

been reported to the SEER program in 20 years.1 Similarly, a recent report from

EUROCARE that included population-based cancer registries of 20 European

countries (1983-1994) revealed that only 65 of 25,457 cases of pediatric solid

malignancy (0.26%) were ACT.3

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1Bernstein L, Gurney JG. Carcinomas and other malignant epithelial neoplasms. In: Ries LAG

2 SM, Gurney JG, et al, eds. Cancer incidence and survival among children and adolescentes:United States SEER program 1975-1995. Bethesda, MD: National Cancer Institute, SEER Program,1999.; 1999:139-147.

3Drut R, Hernandez A, Pollono D. Incidence of childhood cancer in La Plata, Argentina, 1977-1987. Int J Cancer. 1990;45:1045-1047.

4Gatta G, Capocaccia R, Stiller C et al. Childhood cancer survival trends in Europe: A EUROCAREWorking Group study. J Clin Oncol. 2005;23:3742-3751.

5 Young JL, Jr., Ries LG, Silverberg E, Horm JW, Miller RW. Cancer incidence, survival, andmortality for children younger than age 15 years. Cancer. 1986;58:598-602.

6 Stiller CA. International variations in the incidence of childhood carcinomas. Cancer EpidemiolBiomarkers Prev. 1994;3:305-310.

7 Pereira RM, Michalkiewicz E, Sandrini F et al. [Childhood adrenocortical tumors]. Arq BrasEndocrinol Metabol. 2004;48:651-658.

8Latronico AC, Mendonca BB. [Adrenocortical tumors--new perspectives]. Arq Bras EndocrinolMetabol. 2004;48:642-646.

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Pathobiology

The adrenal cortex arises from the coelomic mesoderm during

approximately the sixth week of development. These mesothelial

cells proliferate between the dorsal mesentery and the developing gonad,

delineating two histologically distinct components: an outer zone from which

the “adult cortex” originates and a more central zone called the “fetal cortex.”

The latter comprises the largest portion of the adrenal cortex at birth. The fetal

cortex starts to undergo apoptosis by the last intrauterine month and

disappears toward the end of the first year of life.1The fetal cortex is

responsible for 90% of the mother’s production of dehydroepiandrosterone

(DHEA) and its sulfated derivative (DHEA-S).2

Predisposing constitutional genetic factors have been found in the

majority of children with ACT (Table 1). Li and Fraumeni observed a remarkably

high frequency of ACT (4 cases [10%]) among 44 malignancies in children from

families in which diverse cancers segregated in an autosomal dominant

pattern.3,4 Not only did members of these families have an increased risk of

childhood sarcoma and premenopausal breast cancer, but also they were at

increased risk of other malignancies, including leukemia, brain tumors,

osteosarcomas and adrenocortical carcinomas.5

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Table 1*

Condition Tumor types Observations

Li-Fraumeni syndrome andother germline TP53mutations

Adenomas,carcinomas

10% of these tumors areACT

Beckwith-Wiedmann syndrome Adenomas,carcinomas


Hemihypertrophy Adenomas,carcinomas

ACT is the second mostcommon tumor (approx.15% of children with thissyndrome)

Congenital adrenalhyperplasia

Adenoma,carcinomas


Carney complex Primary pigmentednodularadrenocorticalcarcinoma

ACT occurs in approx.25% of patients; commonin children

Multiple endocrine neoplasia I Nodules, adenomas,carcinomas

Median age of patientswith carcinomas is 40years

*Modified from Ribeiro et al 35

Other tumors possibly associated with this syndrome include melanoma;

carcinomas of the lung, pancreas, and prostate; and gonadal germ cell tumors.4,6 In 1990, Malkin and colleagues 6 screened five of these families and found

germline mutations clustered in exon 7 of the TP53 gene in all five. It is now

well recognized that most of the constitutional genetic abnormalities in young

children with ACT are germline mutations in various exons of TP53. In fact, it

is likely that more than 80% of young children with ACT have an inherited TP53

mutation or other genetic abnormalities involving this cellular pathway. There is

good evidence that the germline TP53 R337H mutation explains the high

incidence of pediatric adrenocortical carcinoma in southern Brazil and is

involved in its tumorigenesis.7,8 Laboratory findings that strongly suggest that

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TP53 R337H plays a role in adrenal tumorigenesis include the loss of

heterozygosity with retention of the mutant allele in tumor cells, the

accumulation of P53 protein in the nucleus, and the folding and other

properties of the missense P53 R337H protein in vitro.8 The penetrance of ACT

was about 10% in a large cohort of carriers of TP53 R337H in families known to

have one or more children with ACT.9 It appears that this mutation occurs in

0.3% of the population in this region10 (Bonald Figueiredo, personal

communication); the penetrance of ACT in carriers of TP53 R337H in families

that do not have at least one child with ACT has yet to been determined. Of

interest, most families that harbor TP53 R337H do not exhibit the Li-Fraumeni

or Li-Fraumeni–like cancer profile, although some families appear to have an

excess of breast cancer in persons younger than 45 years. However, in most

families of children with ACT who carry the germline TP53 R337H mutation, the

family history of cancer is unremarkable.11 This feature has also been noted for

some other TP53 mutation types as well. For example, Varley and colleagues12

found germline TP53 mutations in 9 of 13 cases of pediatric ACT selected

without reference to the family’s history of cancer. Similarly, TP53 R337H has a

relatively low penetrance for cancer in general but contributes to pediatric ACT

and, to a lesser extent, to breast cancer. We have also now described a novel

mutation that was associated with ACC but without a pervasive family history of

cancer.13 These observations suggest that the association between TP53

mutations and tumorigenesis depends on the degree in which P53 function has

been altered and the extent that other genes interacting with the TP53 pathway

in different tissues at different phases of their maturation have been also

affected; hence, genetic changes found with variable frequency

(polymorphisms) in children with TP53 R337H may contribute to adrenal cell

transformation and may in part account for the

penetrance.14-15 One remarkable example of the importance of the type of P53

mutation has been reported by van Hest et al.16 In a cancer-prone family, two

apparent pathogenic TP53 mutations were believed to account for the cancer

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phenotype: a novel TP53 intron-5 splice site mutation and a missense mutation

in exon 7 Asn235Ser (704A?G). This latter mutation had been described

previously in association with cancer-prone families and was assumed to be

involved in tumorigenesis. However, in functional studies, the intron-5 mutation

lacked biological transcriptional activity, but the p53 Asn235Ser wasbiologically

active. Consistent with these in vitro studies, germline TP53 studies in family

members revealed that the intron-5 mutation but not the Asn235Ser mutation

segregated with the persons in whom tumors developed. Therefore, the mere

observation that a germline TP53 mutation is found in a patient with cancer

does not indicate that the mutated protein has a role in tumorigenesis. The

complexity of the interactions between p53 activity and malignant

transformation has been recently reviewed.17 The implications of these findings

for genetic counseling are critical. Detailed family history and determination of

the activity of the mutant protein are required for proper genetic counseling in

cancer susceptibility.

Other constitutional disorders associated with a greater than expected

incidence of ACT include Beckwith-Wiedemann syndrome,18-20 congenital

hemihypertrophy,21-25 congenital adrenal hyperplasia,26-29 Carney complex,30-32 and

multiple endocrine neoplasia type 1.33, 34 There is no evidence that

environmental factors play a role in ACT. The origin of the TP53 R337H

mutation in southern Brazil remains unexplained.

1 Coulter CL. Fetal adrenal development: insight gained from adrenal tumors. Trends EndocrinolMetab. 2005;16:235-242.

2 Buster JE. Fetal adrenal cortex. Clin Obstet Gynecol. 1980;23:803-824.

3Li FP, Fraumeni JF Jr. Rhabdomyosarcoma in children: epidemiologic study and identification ofa familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365-1373.

4 Li FP, Fraumeni JF, Jr. Prospective study of a family cancer syndrome. JAMA.1982;247:2692-2694.

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5 Garber JE, Goldstein AM, Kantor AF et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 1991;51:6094-6097.

6 Malkin D, Li FP, Strong LC, et al. Germline p53 mutations in a familial syndrome of breastcancer, sarcomas, and other neoplasms. Science. 1990;250:1233-1238.

7Ribeiro RC, Sandrini F, Figueiredo B et al. An inherited p53 mutation that contributes in atissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA.2001;98:9330-9335.

8DiGiammarino EL, Lee AS, Cadwell C et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 2002;9:12-16.

9 Figueiredo BC, Sandrini R, Zambetti GP et al. Penetrance of Adrenocortical Tumors Associatedwith the Germline TP53 R337H Mutation. J Med Genet. 2005.

10 Palmero EI, Schuler-Faccini L, Caleffi M et al. Detection of R337H, a germline TP53 mutationpredisposing to multiple cancers, in asymptomatic women participating in a breast cancerscreening program in Southern Brazil. Cancer Lett. 2008;261:21-25.

11 Figueiredo BC, Sandrini R, Zambetti GP et al. Penetrance of adrenocortical tumours associatedwith the germline TP53 R337H mutation. J Med Genet. 2006;43:91-96.

12Varley JM, McGown G, Thorncroft M et al. Are there low-penetrance TP53 Alleles? Evidencefrom childhood adrenocortical tumors. Am J Hum Genet. 1999;65:995-1006.

13West AN, Ribeiro RC, Jenkins J et al. Identification of a novel germ line variant hotspot mutantp53-R175L in pediatric adrenal cortical carcinoma. Cancer Res. 2006;66:5056-5062.

14Figueiredo BC, Stratakis CA, Sandrini R et al. Comparative genomic hybridization analysis ofadrenocortical tumors of childhood. J Clin Endocrinol Metab. 1999;84:1116-1121.

15Longui CA, Lemos-Marini SH, Figueiredo B et al. Inhibin alpha-subunit (INHA) gene and locuschanges in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.J Med Genet. 2004;41:354-359.

16van Hest LP, Ruijs MW, Wagner A et al. Two TP53 germline mutations in a classical Li Fraumenisyndrome family. Fam Cancer. 2007;6:311-316.

17 Zambetti GP. The p53 mutation "gradient effect" and its clinical implications. J Cell Physiol.2007;213:370-373.

18Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C SeminMed Genet. 2005;137:12-23.

19 Koufos A, Grundy P, Morgan K, et al. Familial Wiedemann-Beckwith syndrome and a secondWilms tumor locus both map to 11p15.5. Am J Hum Genet. 1989;44:711.

20 Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.Am J Hum Genet. 1989;44:720.

21 Benson RF, Vulliamy DG, Taubman JO. Congenital hemihypertrophy and malignancy. Lancet.1963;1:468-469.

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22 Fraumeni Jr JF, Miller RW. Adrenocortical neoplasms with hemihypertrophy, brain tumors, andother disorders. J Pediatr. 1967;70:129-138.

23 Muller S, Gadner H, Weber B, Vogel M, Riehm H. Wilms' tumor and adrenocortical carcinomawith hemihypertrophy and hamartomas. Eur J Pediatr. 1978;127:219-226.

24 Tank ES, Kay R. Neoplasms associated with hemihypertrophy, Beckwith-Wiedemann syndromeand aniridia. J Urol. 1980;124:266.

25 van Seters AP, van Aalderen W, Moolenaar AJ et al. Adrenocortical tumour in untreatedcongenital adrenocortical hyperplasia associated with inadequate ACTH suppressibility. ClinEndocrinol (Oxf). 1981;14:325-334.

26Shinohara N, Sakashita S, Terasawa K, Nakanishi S, Koyanagi T. [Adrenocortical adenomaassociated with congenital adrenal hyperplasia]. Nippon Hinyokika Gakkai Zasshi.1986;77:1519-1523.

27 Varan A, Unal S, Ruacan S, Vidinlisan S. Adrenocortical carcinoma associated withadrenogenital syndrome in a child. Med Pediatr Oncol. 2000;35:88-90.

28 Daeschner GL. Adrenal cortical adenoma arising in a girl with congenital adrenogenitalsyndrome. Pediatrics. 1965;36:140.

29 Pang S, Becker D, Cotelingam J, et al. Adrenocortical tumor in a patient with congenitaladrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 1981;68:242.

30Carney JA, Hruska LS, Beauchamp GD, Gordon H. Dominant inheritance of the complex ofmyxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc. 1986;61:165-172.

31 Stratakis CA, Carney JA, Lin JP et al. Carney complex, a familial multiple neoplasia andlentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.J Clin Invest. 1996;97:699-705.

32 Groussin L, Jullian E, Perlemoine K et al. Mutations of the PRKAR1A gene in Cushing'ssyndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin EndocrinolMetab. 2002;87:4324-4329.

33Skogseid B, Larsson C, Lindgren PG et al. Clinical and genetic features of adrenocorticallesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992;75:76-81.

34 Langer P, Cupisti K, Bartsch DK et al. Adrenal involvement in multiple endocrine neoplasiatype 1. World J Surg. 2002;26:891-896.

35 Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer. 2004;40:1117-1126.

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Clinical Manifestations

The analysis of the first 254 children and adolescents enrolled in the

International Pediatric Adrenocortical Tumor Registry (IPACTR) contributed

important information about the clinical and outcome features of ACT.1 The

median age at the time of ACT diagnosis was 3.2 years. Fewer than 15% of

patients were 13 years or older at the time of diagnosis. The incidence was

higher among girls, with the overall ratio of females to males being 1.6:1. The

reason(s) for this predilection for females is not understood. Signs and

symptoms of virilization were the most common presenting clinical

manifestation (>80% of patients), as reported previously. 2-5 Clinical

manifestations of ACT can be present at birth or during the first few months of

life.6,7

In a detailed review, the presenting features of 58 cases of childhood

ACT (Table 2) was described.5 Features of virilization (Fig. 2) included pubic

hair (pseudoprecocious puberty), facial acne, clitorimegaly, voice change, facial

hair, hirsutism, muscle hypertrophy, growth acceleration, and increased penis

size. Virilization was either observed alone (40% of patients) or accompanied

by clinical manifestations of the overproduction of other adrenal cortical

hormones, including glucocorticoids, androgens, aldosterone, or estrogens

(mixed type, 45%) (Fig. 3). About 10% of patients showed no clinical evidence of

an endocrine syndrome at the time of presentation (nonfunctional tumors).

Finally, overproduction of glucocorticoids alone (Cushing syndrome) was

evident in only 3% of patients. None of these patients manifested either primary

hyperaldosteronism (Conn syndrome) or pure feminization; both of which have

been observed very rarely.8-11 The most frequent sign of feminization was

gynecomastia. Presenting manifestations of hyperaldosteronism include

headache, weakness of proximal muscle groups, polyuria, tachycardia with or

without palpitation, hypocalcemia, and hypertension.

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Table 2

Feature % HormonesVirilization

Pubic and facial hair (hirsutism)Hypertrophy of clitoris or penisDeep voiceAcneAccelerated growth velocity

45-50 DehydroepiandrosteroneAndrostenedioneDehydroehiandrosterone-sulphateTestosterone

Cushing SyndromeMoon faceCentripetal fat distributionBuffalo hump of the neckHypertension

5-8 CortisolDeoxycortisol

NonfunctionalAbdominal mass

5-8 May have elevatedsecretion of adrenocorticalhormones

FeminizationGynecomastia (males)Pseudopuberty (girls)

<1 EstraidolEstroneEstriol

ConnHypertensionHypokalemia

<1 AldosteroneDesoxycorticosterone

MixedInclude signs and symptoms

found in cases of virilization andCushing syndrome

45-50 Two or more hormonesfrom different categories,most commonly increasedsecretion of cortisol andandrogens

Tumor weight is typically large in patients with newly diagnosed disease.

It was greater than 200 g in 83 of 182 cases in the IPACTR report.1 There was

no predominant tumor laterality. Bilateral tumors were not observed in patients

enrolled in the IPACTR, but they have been occasionally reported.8,12,13

Hypertension, which is more common in patients with glucocorticoid-secreting

tumors (Cushing syndrome or mixed type), can be also noted in patients with

signs of virilization only or in those with nonfunctioning tumors. Elevated blood

pressure was noted in 55% of the 58 cases of childhood ACT mentioned, and

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12% of those with elevated blood pressure had hypertensive crises (associated

with seizures in one patient). Treatment of hypertension in patients with ACT

can be challenging. Deaths due to hypertensive crisis have been reported.5

Severe hypertension should be considered a medical or surgical emergency.

Management of hypertension due to increased production of adrenocortical

hormones may require one or more pharmacologic agents targeted to the

adrenocortical hormone believed to be involved in the origin of the

hypertension until definitive treatment (tumor resection) occurs.14

Because ectopic adrenal cortical tissue can be found in the celiac plexus,

kidney, genitalia, broad ligaments, epididymis, and spermatic cord,15 these

extra-adrenal sites can be areas in which ACT develops. In fact, ectopic ACT has

been observed in the spinal canal,16 paratesticular region,17 and intrathoracic

cavity.18

Children and adolescents with functional ACT are subject to growth

disturbances.19 Pure androgen and estrogen excess most often results in

increased growth velocity and premature epiphyseal closure. In the Curitiba

series,1 the heights and weights of children with ACT often exceeded the 50th

percentile at the time of diagnosis. Patients with a greater than expected height

for age included not only those with the virilizing form of ACT but also those

with the mixed form. Bone age was advanced more than 1 year in

68% of the patients. Markers of growth and development have consistently

remained within the normal range in long-term survivors.20

It is relatively common that the diagnosis of childhood ACT is delayed

because of the healthy appearance of the affected child. A carefully obtained

history complemented by the inspection of photographs of the child taken over

an extended period of time can reveal clinical changes associated with an

increased production of adrenal cortical hormones several months and even

years before the diagnosis. In these instances, the increased somatic growth of

these children may divert the clinician from the possibility of a malignant

tumor. Small tumors can lead to exuberant clinical endocrine signs; hence, a

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palpable abdominal mass is not a common first complaint in about half of the

patients. To avoid delaying the diagnosis of ACT, the clinician should consider

any child younger than 4 years with pubarche (pubic hair) to have ACT until

proved otherwise. In addition, the presence of acne on an infant can be

considered pathognomonic of an adrenocortical lesion. Finally, because

Cushing syndrome is very rare in children, it should be considered highly

indicative of ACT in children younger than 10 years.21

1 Michalkiewicz E, Sandrini R, Figueiredo B et al. Clinical and outcome characteristics of childrenwith adrenocortical tumors: a report from the International Pediatric Adrenocortical TumorRegistry. J Clin Oncol. 2004;22:838-845.

2 Ribeiro RC, Sandrini Neto RS, Schell MJ et al. Adrenocortical carcinoma in children: A study of40 cases. J Clin Oncol. 1990;8:67-74.

3Lee PDK, Winter RJ, Green OC. Virilizing adenocortical tumors in childhood. Eight cases and areview of the literature. Pediatrics. 1985;76:437-444.

4Lack EE, Mulvihill JJ, Travis WD, Kozakewich HP. Adrenal cortical neoplasms in the pediatric andadolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemiologicaland prognostic factors. Pathol Annu. 1992;27 Pt 1:1-53.

5Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.1997;82:2027-2031.

6Artigas JL, Niclewicz ED, Padua GS, Ribas DB, Athayde SL. Congenital adrenal corticalcarcinoma. J Pediatr Surg. 1976;11:247-252.

7 Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressingadrenocortical carcinoma in a newborn: A case report with DNA ploidy analysis.Cancer.1988;62:507-511.

8 Kafrouni G, Oakes MD, Lurvey AN, De Quattro V. Aldosteronoma in a child with localisation byadrenal vein aldosterone: collective review of the literature. J Pediatr Surg. 1975;10:917-924.

9Halmi KA, Lascari AD. Conversion of virilization to feminization in a young girl with adrenalcortical carcinoma. Cancer. 1971;27:931-935.

10 Itami RM, Admundson GM, Kaplan SA, et al. Prepubertal gynecomastia caused by an adrenaltumor. Am J Dis Child. 1982;136:584-586.

11 Leditschke JF, Arden F. Feminizing adrenal adenoma in a five-year-old boy. Aust Paediatr J.1974;10:217-221.

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12 Ranew RB, Meadows AT, D'Angio GJ. Adrenocortical Carcinoma in Children: Experience at theChildren's Hospital of Philadelphia, 1961-1980. In: Humphrey GB, Grindey GB, Dehner LP, ActonRT, Pysher TJ, eds. Adrenal and Endocrine Tumors in Children.1. Boston: Martinus NijhoffPublishers; 1983:303-305.

13 Loridan L, Senior B. Cushing's syndrome in infancy. J Pediatr. 1969;75:349-359.

14 Klibanski A, Stephen AE, Greene MF, Blake MA, Wu CL. Case records of the MassachusettsGeneral Hospital. Case 36-2006. A 35-year-old pregnant woman with new hypertension. N Engl JMed. 2006;355:2237-2245.

15 Page DL, DeLellis RA, Hough AJ. Embryology and Postnatal Development. In: Page DL, DeLellisRA, Hough AJ, eds. Tumors of the Adrenal.23. Washington, D.C.: Armed Forces Institute ofPathology; 1986:25-35.

16 Kepes JJ, O'Boynick P, Jones S et al. Adrenal cortical adenoma in the spinal canal of an 8-year-old girl. Am J Surg Pathol. 1990;14:481-484.

17 McWhirter WR, Stiller CA, Lennox EL. Carcinomas in childhood. A Registry-based study ofincidence and survival. Cancer. 1989;63:2242.

18Medeiros LJ, Anasti J, Gardner KL, Pass HI, Nieman LK. Virilizing adrenal cortical neoplasmarising ectopically in the thorax. J Clin Endocrinol Metab. 1992;75:1522-1525.

19Hauffa BP, Roll C, Muhlenberg R, Havers W. Growth in children with adrenocortical tumors. KlinPadiatr. 1991;203:83-87.

20 Schmit-Lobe MC, DeLacerda L, Ribeiro RC, Kohara SK, and Sandrini R. Patterns of growth anddevelopment in 26 children operated for adrenocortical carcinoma (ACC) and disease-free formore than one year. [abstract]. Pediatr Res. 1990;38:622.

21 Gilbert MG, Cleveland WW. Cushing's syndrome in infancy. Pediatrics. 1970;46:217-229.

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Diagnosis and Classification

The diagnosis of ACT is highly suggested by specific clinical features and

particular results of laboratory tests and imaging studies. However, the

definitive diagnosis is made on the basis of the gross (Figure 1) and histologic

appearance of tissue obtained surgically (Figure 2).

Figure 1

Macroscopy of Left Adrenal Mass: cut surface of a large, multinodular, yellowtumor (weight, 192 grams; size 9 x 8 x 6.5 cm) with areas of necrosis (arrows),replacing the adrenal gland. External surface of the tumor is inked in black.

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Figure 2

Histopathology of Adrenal Cortical Carcinoma

A: Diffuse proliferation of neoplastic cells with occasional enlargedhyperchomatic nuclei (arrows).B, C and D: Large, polygonal and eosiniophilic tumor cells are arranged in nestor cords where groups of cells are occasionally separated by dilated sinusoids(arrows).E: Bizarre cells with extremely pleomorphic and/or multiple nuclei and variableproinent nucleoli (H & E).

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In general, ACT is histopathologically classified as adenoma, carcinoma,

or tumor of undetermined histology. However, the pathologic classification of

pediatric ACT is troublesome. Even an experienced pathologist can find it

difficult to differentiate adenoma from carcinoma. Diagnostically useful

immunohistochemical markers include inhibin, melan A (MART-1),

synaptophysin, and chromogranin A (Figure 3, inset in chromogranin A

photomicrograph shows entrapped normal adrenal medullary cells which are

strongly positive). Most will be positive for the first three but negative for

chromogranin A. In some tumors, a small number of cells might be positive for

chromogranin A suggesting neuroendocrine differentiation in an otherwise

typical ACT. However, if chromogranin A is extensively positive,

pheochromocytoma would be a more appropriate diagnosis. Tumors combining

the features of both adrenocortical tumor and pleochromocytoma have been

reported in the literature. ACTs are nearly always positive for vimentin,

cytokeratins of various molecular weight, and epithelial membrane antigen but

these markers are not sufficiently specific to be diagnostically useful. Inset in

EMA photomicrograph (Figure 3) shows entrapped normal adrenal medullary

cells which are strongly positive.

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Figure 3

Immunohistochemical analysis of Adrenal Cortical Carcinoma

A and B: Cytoplasmatic expression of Inhibin and Melan A.C: Strong Synaptophysin immunoreactivity.D: There is no expression of Chromogranin A by tumor cells. Insert showsentrapped normal adrenal medullary cells which are strongly positive forchromogranin A.E: Strong and diffuse Vimentin immunoreactivity.F: Focal cytoplasmic expression of pancytokeratin.G: Epithelial membrane antigen (EMA) is diffusely expressed by tumor cells.Insert shows entrapped normal adrenal medullary cells which are EMApositive.

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In adults, Weiss and colleagues 1, 2 and Hough et al.3 formulated

classification systems based on macroscopic, microscopic, and clinical features.

In an attempt to apply these classification systems to pediatric ACT, Bugg et al.4

used modified criteria of Weiss and colleagues1,2 to analyze a large series of

patients. In their study, the adrenal tumors were divided into three groups:

adrenocortical adenomas, high-grade carcinomas, and low-grade carcinomas. A

study from the Pathology Armed Forces Institute of Pathology showed that

features associated with an increased probability of malignant activity included

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tumor weight, tumor size, vena cava invasion, capsular and/or vascular

invasion, extension into periadrenal soft tissue, severe nuclear atypia, >15

mitotic figures per 20 high-power fields, and the presence of atypical mitotic

figures (Figure 4) and confluent necrosis (Figure 5). In a multivariate analysis,

vena cava invasion, necrosis, and increased mitotic activity were each

independently associated with malignant clinical behavior.5 More recently, gene

expression studies have identified specific signatures associated with

adenomas and carcinomas.6 It is possible that these studies will generate

meaningful insights into the biologic and prognostic variables of pediatric ACT.

Figure 4

Mitotic activity evaluation of Adrenal Cortical Carcinoma

A: Atypical mitotic figure (arrow) (H & E, 400X).B: Strong nuclear immunoreactivity of MIB-1 (Ki-67) by neoplastic cells.

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Figure 5

Histopathology of Adrenal Cortical Carcinoma

A and B: Extensive areas of tumor necrosis (H & E, 200X).

Most children with ACT have increased urinary concentrations of 17-

ketosteroids (17-KS). In one review,7 48 of 49 patients tested positive for

increased 17-KS concentrations, whether their tumors caused Cushing

syndrome or virilization. Urinary 17-hydroxycorticosteroid (17-OH)

concentrations are increased when there are clinical signs of excessive

glucocorticoid production. Routine laboratory evaluation for suspected ACT

includes measurement of urinary 17-KS, 17-OH, and free cortisol as well as of

plasma cortisol, DHEA-S, testosterone, androstenedione,

17-hydroxyprogesterone, aldosterone, renin activity, deoxycorticosterone

(DOC) and other 17-deoxysteroid precursors. This comprehensive panel of tests

not only contributes to the diagnosis but also provides useful markers for the

detection of tumor recurrence. Plasma DHEA-S concentrations are abnormally

high in approximately 90% of cases; thus, DHEA-S is a very sensitive tumor

marker. Accurate urinary detection of these adrenal cortex hormone

metabolites requires 24-hour urine collection, which is troublesome,

particularly in small children. These urinary tests, although reliable, have been

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essentially replaced by the determination of the plasma concentrations of

adrenal cortex hormones. The simultaneous presence of abnormally high

concentrations of glucocorticoids and androgen is a strong indication of ACT.

Imaging studies provide critical information for diagnosis and about

disease extension in children and adolescents with ACT. CT, sonography, MR

imaging, and PET are most commonly used. Although ultrasonography has its

limitations, it is important for evaluating tumor extension into the inferior vena

cava and right atrium.8 MR imaging, which has steadily increased over the past

few years, has several advantages over CT, including the absence of ionizing

radiation, the capability of imaging multiple planes, and improved tissue

contrast differentiation. CT shows many characteristics that are suggestive of

ACT.

ACT is usually well demarcated with an enhancing peripheral capsule.

Large tumors usually have a central area of stellate appearance caused by

hemorrhage, necrosis, and fibrosis. This stellate zone is hyperintense on T2-

weighted and (short tau inversion recovery) STIR MR images. Calcifications are

common. Because ACT is metabolically active, fluorodeoxyglucose (FDG)-PET

imaging is increasingly used in patients with ACT9 (Fig. 4). C-Metomidate (MTO),

a marker of sustained 11-β-hydroxylase activity, has been investigated as an

alternative PET tracer for adrenocortical imaging. The clinical indications for PET

with this new tracer are still evolving.10 Although FDG/MTO-PET is unlikely to

add information to that obtained with CT or MR imaging of the primary tumor

and its regional extension, it can disclose distant metastases that are not

readily detected by CT or MR imaging. Because very small tumors can secrete

hormone to a level that results in somatic changes but no definitive

abnormalities in CT or MR imaging, PET may have greater sensitivity in

detecting tumor recurrence in a few cases. However, this technique has not

been systematically evaluated in pediatric ACT. Presently, our recommendation

is that, in addition to ultrasonography, all patients who have a suspected

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adrenal tumor should be examined by CT or MR imaging. To determine the

extent of the newly diagnosed disease, CT or MR imaging of the chest and

abdomen are recommended for all patients. The liver and lungs are the most

common sites of metastasis at the time of diagnosis. The skeleton and central

nervous system are involved in a few cases. Technetium bone scans are

typically obtained in the initial evaluation of children with ACT. Imaging of the

central nervous system is not routinely performed at the time of presentation.

1 Weiss LM, Medeiros LJ, Vickery AL, Jr. Pathologic features of prognostic significance in

adrenocortical carcinoma. Am J Surg Pathol. 1989;13:202-206.

2 Weiss LM. Comparative study of 43 metastasizing and nonmetastasizing adrenocortical

tumors. Am J Surg Pathol. 1984;8:163-169.

3 Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortical tumors:

A mathematical analysis of clinical and morphologic data. Am J Clin Pathol. 1979;72:390-399.

4 Bugg MF, Ribeiro RC, Roberson PK et al. Correlation of pathologic features with clinical

outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group

for Treatment of Childhood Adrenocortical Tumors. Am J Clin Pathol. 1994;101:625-629.

5 Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population:

a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol.

2003;27:867-881.

6 West AN, Ribeiro RC, Jenkins J et al. Identification of a novel germ line variant hotspot mutant

p53-R175L in pediatric adrenal cortical carcinoma. Cancer Res. 2006;66:5056-5062.

7Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.

1997;82:2027-2031.

8 Kikumori T, Imai T, Kaneko T et al. Intracaval endovascular ultrasonography for large adrenal

and retroperitoneal tumors. Surgery. 2003;134:989-993.

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9 Ahmed M, Al Sugair A, Alarifi A, Almahfouz A, Al Sobhi S. Whole-body positron emission

tomographic scanning in patients with adrenal cortical carcinoma: comparison with

conventional imaging procedures. Clin Nucl Med. 2003;28:494-497.

10 Minn H, Salonen A, Friberg J et al. Imaging of adrenal incidentalomas with PET using (11)C-

metomidate and (18)F-FDG. J Nucl Med. 2004;45:972-979.

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Management

Surgery

Surgery is the cornerstone of the management of pediatric ACT. There

has been no documented instance in which chemotherapy alone has led to a

complete local response of a primary unresected tumor. Surgery is performed

by a transabdominal approach, usually using an ipsilateral subcostal incision,

which may be modified to a chevron or bilateral subcostal incision. En bloc

resection, which may include the kidney, portions of the pancreas and/or liver,

or other adjacent structures, may be necessary in rare cases of large, locally

invasive tumor. A thoracoabdominal incision is indicated in rare cases. The role

of regional lymph node dissection in pediatric ACT has not been evaluated, but

it has been advocated because patients with large tumors commonly

experience local relapse. An ipsilateral modified node dissection is performed,

extending from the renal vein to the level of bifurcation of the common iliac

vessel. If there are contralateral, clinically enlarged lymph nodes, they should

be removed as well. The Children’s Oncology Group (COG) has recently

launched a study to obtain data on lymph node dissection in newly diagnosed

ACT, but the effect of this procedure to improve local or distant control will not

be known for several years. Because of tumor friability, rupture of the

capsule and spillage of the tumor are frequent (they occur in approximately

20% of cases during the initial procedure and in 43% after local recurrence).1

Infiltration of the vena cava may make radical surgery difficult in some cases,

although successful complete resection of the tumor thrombus with

cardiopulmonary bypass has been reported.2,3 Surgery requires careful and

precise perioperative planning. All patients with a functioning tumor are

assumed to have suppression of the contralateral adrenal gland; therefore,

steroid replacement therapy is given. Special attention to electrolyte balance,

hypertension, surgical wound care, and infectious complications is critical.

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Surgical resection of recurrent local and distant disease, generally in

conjunction with radiotherapy, has been found to prolong survival.4,5 Multiple

surgical resections may be necessary to render patients free of disease.

This approach has not been systematically studied in pediatric ACT.6

1 Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.

1997;82:2027-2031.

2Godine LB, Berdon WE, Brasch RC, Leonidas JC. Adrenocortical carcinoma with extension into

inferior vena cava and right atrium: report of 3 cases in children. Pediatr Radiol. 1990;20:166-8;

discussion 169.3 Chesson JP, Theodorescu D. Adrenal tumor with caval extension--case report and review of the

literature. Scand J Urol Nephrol. 2002;36:71-73.

4 Bellantone R, Ferrante A, Boscherini M et al. Role of reoperation in recurrence of adrenal

cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal

Cortical Carcinoma. Surgery. 1997;122:1212-1218.

5Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in

patients with adrenocortical carcinoma. Ann Surg Oncol. 1999;6:719-726.

6 Hacker FM, von Schweinitz D, Gambazzi F. The relevance of surgical therapy for bilateral

and/or multiple pulmonary metastases in children. Eur J Pediatr Surg. 2007;17:84-89.

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Chemotherapy

The role of chemotherapy in the management of childhood ACT has not

been established, although it is consistently recommended for children with

locally advanced or recurrent disease. This recommendation is based on several

case reports or small series of patients whose disease has been successfully

managed with this approach.1-3 However, because of the rarity of

ACT, the role of chemotherapy remains undetermined.

Mitotane [1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane or

o,p/-DDD], an insecticide derivative that causes adrenocortical necrosis, has

been used extensively in adults with ACT. Recent studies3,4 suggested a benefit

of this agent when used in an adjuvant setting. However, its efficacy in pediatric

ACT has not been studied systematically. Mitotane has been used to

treat advanced metastatic ACT, has been given before surgery to reduce to

tumor size in cases of inoperable tumors or after surgery in patients at high

risk of relapse (adjuvant chemotherapy), has been combined with other agents,

and has been used to control symptoms associated with increased production

of adrenal cortex hormones. Objective responses to mitotane have been noted

in 15% to 60% of treated adult patients.5 The wide variation in response rates

may be in part due to the pharmacokinetics of mitotane. There has been

evidence of greater tumor response when the plasma concentration of mitotane

is >14 mg/L.8 The most important common toxicities of mitotane are nausea,

vomiting, diarrhea, and abdominal pain. Less frequent reactions include

somnolence, lethargy, ataxic gait, depression, and vertigo. Of interest, males

and prepubertal girls can develop gynecomastia and thelarche, respectively.

Another shortcoming of mitotane treatment is that it significantly alters steroid

hormone metabolism; therefore, blood and urine steroid measurements cannot

be used as markers of tumor relapse. Given the spectrum of toxicities, unique

metabolic properties, interaction with the metabolism of other drugs, and the

need to maintain a certain therapeutic level, mitotane is a difficult

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drug to administer and monitor. Most information regarding the schedule of

administration and guidelines to monitor plasma concentrations has been

obtained from studies of adults. Recently, Zancanella et al.1 reported mitotane

plasma concentrations and toxicity when the drug was administered in

combination with cisplatin, etoposide, and doxorubicin. Eleven patients

received mitotane at an initial dose of 1 mg/m2 per day, divided in three doses.

If the initial dose was tolerated, it was increased weekly to a goal of 4 mg/m2

per day and a plasma concentration between 14 mg/L and 20 mg/L. In general,

doses of mitotane that exceed 3 g daily are considered to be adrenolytic; to

avoid manifestations of adrenal insufficiency, patients receive replacement

therapy that consists of prednisone and fluorohydrocortisone. The dosages of

these compounds are adjusted on the basis of each patient’s clinical condition.

The degree of the adrenocorticotropic hormone (ACTH) suppression can also

provide a measure of exogenous steroid replacement effect. During infectious

complications the dosages of steroids have to be increased substantially.

In the study by Zancanella et al.,1 mitotane was mixed in an emulsion of

medium-chain triglycerides to increase tolerance and absorption. Mitotane

plasma concentrations were monitored every 2 to 4 weeks depending on the

concentrations. It was monitored every 2 weeks, if the previous concentration

was >10 mg/L. These investigators noted remarkable intrapatient variability

regarding the dosage of mitotane required to achieve the range of therapeutic

concentrations (1.0 to 5.2 mg/m2). The toxicity profile of mitotane

used in combination with the three drugs apparently did not differ substantially

from that seen when mitotane was used as a single agent, but the number of

children in the study was too small to draw definitive conclusions.

Long-term complications of mitotane have not been studied. Because this

drug crosses the blood-brain barrier and causes significant encephalopathy,9 it

is possible that mitotane may cause long-term sequelae, particularly in young

children.10

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Other chemotherapeutic agents, including 5-fluorouracil, etoposide,

cisplatin, carboplatin, cyclophosphamide, doxorubicin, and streptozocin, have

been used alone or in combination to treat ACT, with varied results.11,12 The

combination used most often in pediatrics consists of cisplatin and etoposide

with or without doxorubicin given with mitotane. Novel therapeutic strategies

aimed to affect tumor-specific aberrant pathways have not been studied in

pediatric ACT.

1 Zancanella P, Pianovski MA, Oliveira BH et al. Mitotane associated with cisplatin, etoposide,

and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and

tumor regression. J Pediatr Hematol Oncol. 2006;28:513-524.

2Hah JO. Intensive chemotherapy with autologous PBSCT for advanced adrenocortical carcinoma

in a child. J Pediatr Hematol Oncol. 2008;30:332-334.

3Arico M, Bossi G, Livieri C, Raiteri E, Severi F. Partial response after intensive chemotherapy for

adrenal cortical carcinoma in a child. Med Pediatr Oncol. 1992;20:246-248.

4Crock PA, Clark ACL. Combination chemotherapy for adrenal carcinoma - response in a 5- 1/2-

year-old male. Med Pediatr Oncol. 1989;17:62-65.

5 Terzolo M, Angeli A, Fassnacht M et al. Adjuvant mitotane treatment for adrenocortical

carcinoma. N Engl J Med. 2007;356:2372-2380.

6 Fareau GG, Lopez A, Stava C, Vassilopoulou-Sellin R. Systemic chemotherapy for adrenocortical

carcinoma: comparative responses to conventional first-line therapies. Anticancer Drugs.

2008;19:637-644.

7 Icard P, Goudet P, Charpenay C et al. Adrenocortical carcinomas: surgical trends and results of

a 253-patient series from the French Association of Endocrine Surgeons study group. World J

Surg. 2001;25:891-897.

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8 Baudin E, Pellegriti G, Bonnay M et al. Impact of monitoring plasma 1,1-

dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with

adrenocortical carcinoma. Cancer. 2001;92:1385-1392.

9 Bollen E, Lanser JB. Reversible mental deterioration and neurological disturbances with o,p'-

DDD therapy. Clin Neurol Neurosurg. 1992;94:S49-51.

10De Leon DD, Lange BJ, Walterhouse D, Moshang T. Long-term (15 years) outcome in an infant

with metastatic adrenocortical carcinoma. J Clin Endocrinol Metab. 2002;87:4452-4456.

11Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide,

doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group

for the Study of Adrenal Cancer. Cancer. 1998;83:2194-2200.

12Khan TS, Imam H, Juhlin C et al. Streptozocin and o,p'DDD in the treatment of adrenocortical

cancer patients: long-term survival in its adjuvant use. Ann Oncol. 2000;11:1281-1287.

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Survival

In the IPACTR series, 157 (61.8%) of the 254 patients with known

outcomes were alive at a median follow-up of 2.4 years (range, 5 days to 22

years).1 Ninety-seven (38.2%) died. Only about 5% of those 97 died of causes

unrelated to tumor progression (two died of infection, one of hypertensive

complication, one of massive hemorrhage during surgery, and one of an

unspecified complication). The 5-year event-free survival (EFS) and overall

survival estimates were 54.2% (95% CI, 48.2% to 60.2%) and 54.7%

(95% CI, 48.7% to 60.7%), respectively. The outcome in the IPACTR series is

similar to that reported by others.2

1 Michalkiewicz E, Sandrini R, Figueiredo B et al. Clinical and outcome characteristics of children

with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor

Registry. J Clin Oncol. 2004;22:838-845.

2Chudler RM, Kay R. Adrenocortical carcinoma in children. Urol Clin North Am. 1989;16:469-

479.

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Prognosis

Complete tumor resection is the most important prognostic indicator.

Patients who have residual disease after surgery have a dismal prognosis. Of 57

patients in the IPACTR series who had distant or local, gross or microscopic

residual disease after surgery, only 8 have remained free of disease.

Conversely, the long-term survival rate is approximately 75% for children with

completely resected tumors. Among the latter, tumor size has prognostic value.

IPACTR data showed that among 192 such patients, those with tumors

weighing more than 200 g had an EFS estimate of 39%, compared with 87% for

those with smaller tumors. Tumor size has been consistently associated with

prognosis in several studies of pediatric and adult ACT.1,2 For example, in a

study of 501 adults with ACT, Sturgeon and colleagues3 noted that the

likelihood of a tumor being malignant was increased by a factor of two when

the largest diameter of the tumor was ?4 cm and by a factor of nine when the

largest diameter of the tumor was ?8 cm. Children whose tumors produce

excess glucocorticoids appear to have a worse prognosis than children who

have pure virilizing manifestations.

Classification schemes or disease staging systems to guide therapy for

pediatric ACT are still evolving (Table 3). A modification of the staging system,

which includes tumor volume and resectability,4 has been adapted by COG

investigators.

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Table 3

Stage Description

I Tumor totally excised, tumor size <100 g or 200 cm3,absence of metastasis, and normal hormone levels aftersurgery

II Tumor totally excised, tumor side >100 g or >200 cm3,absence of metastasis, and normal hormone levels aftersurgery

III Unresectable tumor, gross or microscopic residual tumor,tumor spillage during surgery, persistence of abnormalhormone levels after surgery, or retroperitoneal lymphnode involvement

IV Distant tumor metastasis

It is likely that prognostic factor analysis can be further refined by adding

other predictive factors. For example, rupture of the tumor pseudocapsule

during surgery and invasion of the vena cava were found to be associated with

poor prognosis, even among patients whose tumors were completely resected,

but these variables have yet to be prospectively analyzed. Finally, some

histologic tumor features, such as vascular or capsular invasion, extensive

necrosis, and marked mitotic activity, have been independently associated with

prognosis in a recent study.1 However, because of the difficulties in determining

a set of histologic criteria independently linked to prognosis, alternative and

reproducible methods are being developed. Gene expression profiling can

distinguish between adenoma and carcinoma. It remains to be determined

whether this method will be able to identify a specific signature for those

patients with carcinoma who are destined to have relapsed disease.

1Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population:

a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol.

2003;27:867-881.

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2 Michalkiewicz EL, Sandrini R, Bugg MF et al. Clinical characteristics of small functional

adrenocortical tumors in children. Med Pediatr Oncol. 1997;28:175-178.

3 Sturgeon C, Shen WT, Clark OH, Duh QY, Kebebew E. Risk assessment in 457 adrenal cortical

carcinomas: how much does tumor size predict the likelihood of malignancy? J Am Coll Surg.

2006;202:423-430.4Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.

1997;82:2027-2031.

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