Provided by
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, Jesse
Jenkins, 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
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.
Page 2 of 37
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 1865.1 Cushing
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.
Pitman. General melasma and short hair over the entire body of a child of three years, with
conversion of the left supra-renal capsule into a large malignant tumor; the external organs of
generation resembling that of adult life. Lancet. 1865;1:175.
1
Walters W, Wilder R, Kepler E. The suprarenal cortical syndrome with presentation of ten cases.
Ann Surg. 1934;100:670.
2
Page 3 of 37
Ribeiro RC, Sandrini Neto RS, Schell MJ et al. Adrenocortical carcinoma in children: A study of
40 cases. J Clin Oncol. 1990;8:67-74.
3
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.
4
Artigas JL, Niclewicz ED, Padua GS, Ribas DB, Athayde SL. Congenital adrenal cortical
carcinoma. J Pediatr Surg. 1976;11:247-252.
5
Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressing
adrenocortical carcinoma in a newborn: A case report with DNA ploidy analysis. Cancer.
1988;62:507-511.
6
Sarwar ZU, Ward VL, Mooney DP, Testa S, Taylor GA. Congenital adrenocortical adenoma: case
report and review of literature. Pediatr Radiol. 2004;34:991-994.
7
Page 4 of 37
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
Page 5 of 37
1
Bernstein L, Gurney JG. Carcinomas and other malignant epithelial neoplasms. In: Ries LAG
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.
2
Drut R, Hernandez A, Pollono D. Incidence of childhood cancer in La Plata, Argentina, 19771987. Int J Cancer. 1990;45:1045-1047.
3
Gatta G, Capocaccia R, Stiller C et al. Childhood cancer survival trends in Europe: A EUROCARE
Working Group study. J Clin Oncol. 2005;23:3742-3751.
4
Young JL, Jr., Ries LG, Silverberg E, Horm JW, Miller RW. Cancer incidence, survival, and
mortality for children younger than age 15 years. Cancer. 1986;58:598-602.
5
Stiller CA. International variations in the incidence of childhood carcinomas. Cancer Epidemiol
Biomarkers Prev. 1994;3:305-310.
6
Pereira RM, Michalkiewicz E, Sandrini F et al. [Childhood adrenocortical tumors]. Arq Bras
Endocrinol Metabol. 2004;48:651-658.
7
Latronico AC, Mendonca BB. [Adrenocortical tumors--new perspectives]. Arq Bras Endocrinol
Metabol. 2004;48:642-646.
8
Page 6 of 37
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.1 The 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
Page 7 of 37
Table 1*
Condition
Tumor types
Observations
Li-Fraumeni syndrome and
other germline TP53
mutations
Adenomas,
carcinomas
10% of these tumors are
ACT
Beckwith-Wiedmann syndrome Adenomas,
carcinomas
10% of these tumors are
ACT
Hemihypertrophy
Adenomas,
carcinomas
ACT is the second most
common tumor (approx.
15% of children with this
syndrome)
Congenital adrenal
hyperplasia
Adenoma,
carcinomas
20% of these tumors are
ACT
Carney complex
Primary pigmented
nodular
adrenocortical
carcinoma
ACT occurs in approx.
25% of patients; common
in children
Multiple endocrine neoplasia I Nodules, adenomas, Median age of patients
carcinomas
with carcinomas is 40
years
35
*Modified from Ribeiro et al
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
Page 8 of 37
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
Page 9 of 37
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.
Coulter CL. Fetal adrenal development: insight gained from adrenal tumors. Trends Endocrinol
Metab. 2005;16:235-242.
1
2
Buster JE. Fetal adrenal cortex. Clin Obstet Gynecol. 1980;23:803-824.
Li FP, Fraumeni JF Jr. Rhabdomyosarcoma in children: epidemiologic study and identification of
a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365-1373.
3
Li FP, Fraumeni JF, Jr. Prospective study of a family cancer syndrome. JAMA.1982;247:26922694.
4
Page 10 of 37
Garber JE, Goldstein AM, Kantor AF et al. Follow-up study of twenty-four families with LiFraumeni syndrome. Cancer Res. 1991;51:6094-6097.
5
Malkin D, Li FP, Strong LC, et al. Germline p53 mutations in a familial syndrome of breast
cancer, sarcomas, and other neoplasms. Science. 1990;250:1233-1238.
6
Ribeiro RC, Sandrini F, Figueiredo B et al. An inherited p53 mutation that contributes in a
tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA.
2001;98:9330-9335.
7
DiGiammarino EL, Lee AS, Cadwell C et al. A novel mechanism of tumorigenesis involving pHdependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 2002;9:12-16.
8
Figueiredo BC, Sandrini R, Zambetti GP et al. Penetrance of Adrenocortical Tumors Associated
with the Germline TP53 R337H Mutation. J Med Genet. 2005.
9
Palmero EI, Schuler-Faccini L, Caleffi M et al. Detection of R337H, a germline TP53 mutation
predisposing to multiple cancers, in asymptomatic women participating in a breast cancer
screening program in Southern Brazil. Cancer Lett. 2008;261:21-25.
10
Figueiredo BC, Sandrini R, Zambetti GP et al. Penetrance of adrenocortical tumours associated
with the germline TP53 R337H mutation. J Med Genet. 2006;43:91-96.
11
Varley JM, McGown G, Thorncroft M et al. Are there low-penetrance TP53 Alleles? Evidence
from childhood adrenocortical tumors. Am J Hum Genet. 1999;65:995-1006.
12
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.
13
Figueiredo BC, Stratakis CA, Sandrini R et al. Comparative genomic hybridization analysis of
adrenocortical tumors of childhood. J Clin Endocrinol Metab. 1999;84:1116-1121.
14
Longui CA, Lemos-Marini SH, Figueiredo B et al. Inhibin alpha-subunit (INHA) gene and locus
changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.
J Med Genet. 2004;41:354-359.
15
van Hest LP, Ruijs MW, Wagner A et al. Two TP53 germline mutations in a classical Li Fraumeni
syndrome family. Fam Cancer. 2007;6:311-316.
16
Zambetti GP. The p53 mutation "gradient effect" and its clinical implications. J Cell Physiol.
2007;213:370-373.
17
Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin
Med Genet. 2005;137:12-23.
18
Koufos A, Grundy P, Morgan K, et al. Familial Wiedemann-Beckwith syndrome and a second
Wilms tumor locus both map to 11p15.5. Am J Hum Genet. 1989;44:711.
19
Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.
Am J Hum Genet. 1989;44:720.
20
Benson RF, Vulliamy DG, Taubman JO. Congenital hemihypertrophy and malignancy. Lancet.
1963;1:468-469.
21
Page 11 of 37
Fraumeni Jr JF, Miller RW. Adrenocortical neoplasms with hemihypertrophy, brain tumors, and
other disorders. J Pediatr. 1967;70:129-138.
22
Muller S, Gadner H, Weber B, Vogel M, Riehm H. Wilms' tumor and adrenocortical carcinoma
with hemihypertrophy and hamartomas. Eur J Pediatr. 1978;127:219-226.
23
Tank ES, Kay R. Neoplasms associated with hemihypertrophy, Beckwith-Wiedemann syndrome
and aniridia. J Urol. 1980;124:266.
24
van Seters AP, van Aalderen W, Moolenaar AJ et al. Adrenocortical tumour in untreated
congenital adrenocortical hyperplasia associated with inadequate ACTH suppressibility. Clin
Endocrinol (Oxf). 1981;14:325-334.
25
Shinohara N, Sakashita S, Terasawa K, Nakanishi S, Koyanagi T. [Adrenocortical adenoma
associated with congenital adrenal hyperplasia]. Nippon Hinyokika Gakkai Zasshi.
1986;77:1519-1523.
26
Varan A, Unal S, Ruacan S, Vidinlisan S. Adrenocortical carcinoma associated with
adrenogenital syndrome in a child. Med Pediatr Oncol. 2000;35:88-90.
27
Daeschner GL. Adrenal cortical adenoma arising in a girl with congenital adrenogenital
syndrome. Pediatrics. 1965;36:140.
28
Pang S, Becker D, Cotelingam J, et al. Adrenocortical tumor in a patient with congenital
adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 1981;68:242.
29
Carney JA, Hruska LS, Beauchamp GD, Gordon H. Dominant inheritance of the complex of
myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc. 1986;61:165-172.
30
Stratakis CA, Carney JA, Lin JP et al. Carney complex, a familial multiple neoplasia and
lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.
J Clin Invest. 1996;97:699-705.
31
Groussin L, Jullian E, Perlemoine K et al. Mutations of the PRKAR1A gene in Cushing's
syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol
Metab. 2002;87:4324-4329.
32
Skogseid B, Larsson C, Lindgren PG et al. Clinical and genetic features of adrenocortical
lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992;75:76-81.
33
Langer P, Cupisti K, Bartsch DK et al. Adrenal involvement in multiple endocrine neoplasia
type 1. World J Surg. 2002;26:891-896.
34
Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer. 2004;40:11171126.
35
Page 12 of 37
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.
Page 13 of 37
Table 2
Feature
Virilization
Pubic and facial hair (hirsutism)
Hypertrophy of clitoris or penis
Deep voice
Acne
Accelerated growth velocity
Cushing Syndrome
Moon face
Centripetal fat distribution
Buffalo hump of the neck
Hypertension
Nonfunctional
Abdominal mass
%
45-50
Hormones
Dehydroepiandrosterone
Androstenedione
Dehydroehiandrosteronesulphate
Testosterone
5-8
Cortisol
Deoxycortisol
5-8
Feminization
Gynecomastia (males)
Pseudopuberty (girls)
Conn
Hypertension
Hypokalemia
Mixed
Include signs and symptoms
found in cases of virilization and
Cushing syndrome
<1
May have elevated
secretion of adrenocortical
hormones
Estraidol
Estrone
Estriol
Aldosterone
Desoxycorticosterone
<1
45-50
Two or more hormones
from different categories,
most commonly increased
secretion of cortisol and
androgens
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
Page 14 of 37
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
Page 15 of 37
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
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.
1
Ribeiro RC, Sandrini Neto RS, Schell MJ et al. Adrenocortical carcinoma in children: A study of
40 cases. J Clin Oncol. 1990;8:67-74.
2
Lee PDK, Winter RJ, Green OC. Virilizing adenocortical tumors in childhood. Eight cases and a
review of the literature. Pediatrics. 1985;76:437-444.
3
Lack EE, Mulvihill JJ, Travis WD, Kozakewich HP. Adrenal cortical neoplasms in the pediatric and
adolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemiological
and prognostic factors. Pathol Annu. 1992;27 Pt 1:1-53.
4
Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.
1997;82:2027-2031.
5
Artigas JL, Niclewicz ED, Padua GS, Ribas DB, Athayde SL. Congenital adrenal cortical
carcinoma. J Pediatr Surg. 1976;11:247-252.
6
Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressing
adrenocortical carcinoma in a newborn: A case report with DNA ploidy analysis.Cancer.
1988;62:507-511.
7
Kafrouni G, Oakes MD, Lurvey AN, De Quattro V. Aldosteronoma in a child with localisation by
adrenal vein aldosterone: collective review of the literature. J Pediatr Surg. 1975;10:917-924.
8
Halmi KA, Lascari AD. Conversion of virilization to feminization in a young girl with adrenal
cortical carcinoma. Cancer. 1971;27:931-935.
9
Itami RM, Admundson GM, Kaplan SA, et al. Prepubertal gynecomastia caused by an adrenal
tumor. Am J Dis Child. 1982;136:584-586.
10
Leditschke JF, Arden F. Feminizing adrenal adenoma in a five-year-old boy. Aust Paediatr J.
1974;10:217-221.
11
Page 16 of 37
Ranew RB, Meadows AT, D'Angio GJ. Adrenocortical Carcinoma in Children: Experience at the
Children's Hospital of Philadelphia, 1961-1980. In: Humphrey GB, Grindey GB, Dehner LP, Acton
RT, Pysher TJ, eds. Adrenal and Endocrine Tumors in Children.1. Boston: Martinus Nijhoff
Publishers; 1983:303-305.
12
13
Loridan L, Senior B. Cushing's syndrome in infancy. J Pediatr. 1969;75:349-359.
Klibanski A, Stephen AE, Greene MF, Blake MA, Wu CL. Case records of the Massachusetts
General Hospital. Case 36-2006. A 35-year-old pregnant woman with new hypertension. N Engl J
Med. 2006;355:2237-2245.
14
Page DL, DeLellis RA, Hough AJ. Embryology and Postnatal Development. In: Page DL, DeLellis
RA, Hough AJ, eds. Tumors of the Adrenal.23. Washington, D.C.: Armed Forces Institute of
Pathology; 1986:25-35.
15
Kepes JJ, O'Boynick P, Jones S et al. Adrenal cortical adenoma in the spinal canal of an 8-yearold girl. Am J Surg Pathol. 1990;14:481-484.
16
McWhirter WR, Stiller CA, Lennox EL. Carcinomas in childhood. A Registry-based study of
incidence and survival. Cancer. 1989;63:2242.
17
Medeiros LJ, Anasti J, Gardner KL, Pass HI, Nieman LK. Virilizing adrenal cortical neoplasm
arising ectopically in the thorax. J Clin Endocrinol Metab. 1992;75:1522-1525.
18
Hauffa BP, Roll C, Muhlenberg R, Havers W. Growth in children with adrenocortical tumors. Klin
Padiatr. 1991;203:83-87.
19
Schmit-Lobe MC, DeLacerda L, Ribeiro RC, Kohara SK, and Sandrini R. Patterns of growth and
development in 26 children operated for adrenocortical carcinoma (ACC) and disease-free for
more than one year. [abstract]. Pediatr Res. 1990;38:622.
20
21
Gilbert MG, Cleveland WW. Cushing's syndrome in infancy. Pediatrics. 1970;46:217-229.
Page 17 of 37
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, yellow
tumor (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.
Page 18 of 37
Figure 2
Histopathology of Adrenal Cortical Carcinoma
A: Diffuse proliferation of neoplastic cells with occasional enlarged
hyperchomatic nuclei (arrows).
B, C and D: Large, polygonal and eosiniophilic tumor cells are arranged in nest
or cords where groups of cells are occasionally separated by dilated sinusoids
(arrows).
E: Bizarre cells with extremely pleomorphic and/or multiple nuclei and variable
proinent nucleoli (H & E).
Page 19 of 37
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.
Page 20 of 37
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 shows
entrapped normal adrenal medullary cells which are strongly positive for
chromogranin 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 EMA
positive.
Page 21 of 37
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
Page 22 of 37
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.
Page 23 of 37
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 17ketosteroids (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
Page 24 of 37
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 T2weighted 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
Page 25 of 37
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.
7
Sandrini 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.
Page 26 of 37
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.
Page 27 of 37
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.
Page 28 of 37
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.
2
Godine 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.
5
Schulick 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.
Page 29 of 37
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
Page 30 of 37
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
Page 31 of 37
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.
2
Hah JO. Intensive chemotherapy with autologous PBSCT for advanced adrenocortical carcinoma
in a child. J Pediatr Hematol Oncol. 2008;30:332-334.
3
Arico 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.
4
Crock 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.
Page 32 of 37
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.
De Leon DD, Lange BJ, Walterhouse D, Moshang T. Long-term (15 years) outcome in an infant
10
with metastatic adrenocortical carcinoma. J Clin Endocrinol Metab. 2002;87:4452-4456.
Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide,
11
doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group
for the Study of Adrenal Cancer. Cancer. 1998;83:2194-2200.
12
Khan 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.
Page 33 of 37
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.
2
Chudler RM, Kay R. Adrenocortical carcinoma in children. Urol Clin North Am. 1989;16:469-
479.
Page 34 of 37
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.
Page 35 of 37
Table 3
Stage
Description
I
Tumor totally excised, tumor size <100 g or 200 cm 3,
absence of metastasis, and normal hormone levels after
surgery
II
Tumor totally excised, tumor side >100 g or >200 cm3,
absence of metastasis, and normal hormone levels after
surgery
III
Unresectable tumor, gross or microscopic residual tumor,
tumor spillage during surgery, persistence of abnormal
hormone levels after surgery, or retroperitoneal lymph
node 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.
1
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.
Page 36 of 37
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.
4
Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab.
1997;82:2027-2031.
Page 37 of 37