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The Journal of Clinical Endocrinology & Metabolism
Copyright 2000 by The Endocrine Society
CLINICAL CASE SEMINAR
Metastatic Congenital Adrenocortical Carcinoma: A Case
Report with Tumor Remission at 31⁄2 Years
MUSHTAQ A. GODIL, MARK P. ATLAS, ROBERT I. PARKER, CEDRIC J. PRIEBE,MICHELLE M. ZERAH, PHILIP KANE, JAMES TSUNG, AND THOMAS A. WILSON
Departments of Pediatrics (M.A.G., M.P.A., R.I.P., M.M.Z., J.T., T.A.W.), Surgery (C.J.P.), andPathology (P.K.), State University of New York, Stony Brook, New York 11794-8111
in remission at 3 1⁄2 yr. Because of the rarity of this condition, we
We describe a case of metastasizing congenital adrenocortical car-
discuss step-by-step problems encountered during management.
cinoma and a follow-up of 3 1⁄2 yr. Treatment with surgery and mi-
(J Clin Endocrinol Metab 85:
3964 –3967, 2000)
totane was associated with multiple complications. The patient was
ADRENOCORTICAL CARCINOMA is a rare malig- pleural based density in the right lung. Serum cortisol was
nancy, especially in children. The overall incidence is
916 nmol/L; AFP, 204,000 IU/mL (mean, 173,800 Ϯ 53,462
approximately 2 cases per million per year, which accounts
IU/mL for premature infants) (11); human chorionic gona-
for 0.2% of all cancers (1). In children, the incidence is 0.3
dotrophin, negative; and neuron-specific enolase, 89.5
cases per million per year except in Southern Brazil, where
ng/mL (4.8 –19.4 ng/mL in cord blood for full-term infants)
the incidence is 3.4 – 4.2 cases per million per year (2). Most
series show a female preponderance. It is described in chil-
On the second day of life, the patient experienced hypoxia,
dren of all age groups, but it usually appears before the age
with a tonic clonic seizure and epistaxis. Mechanical venti-
of 5 yr (3). It is very uncommon in early infancy, and only a
lation was required. A chest x-ray revealed diffuse haziness,
few cases have been reported in the newborn period (4 –10).
with an air bronchogram. He became anemic, and pulmo-nary hemorrhage was suspected. Coagulation studies were
normal. A head sonogram revealed grade I intraventricular
The patient was born at 34 weeks gestation, to a 20-yr-old
hemorrhage. His electroencephalogram (EEG) was normal.
woman, by cesarean section (because of low biophysical
The patient was started on hydrocortisone (100 mg/
profile and decreased fetal movements). A prenatal sono-
m2⅐day), and a laparotomy was performed on the third day
gram at 33 weeks gestation showed an abdominal mass of
of life. A large homogenous mass was completely resected
6.5 ϫ 4.9 ϫ 5.6 cm. Amniocentesis revealed a normal karyo-
from the right side, and the left adrenal gland was biopsied.
type, normal ␣-fetoprotein (AFP), and human chorionic go-
The tumor was well circumscribed (7 ϫ 7 ϫ 4.5 cm) and
nadotrophin. Birth weight was 1.7 kg; and length, 40.6 cm.
weighed 117 g. There was a central area of necrosis, with
Apgar scores were 9 at 1 and 5 min. Blood pressure was 62/41
hemorrhage. Histopathology showed marked nuclear pleo-
mm Hg; pulse, 157/min; temperature, 98.4 F; and respiratory
morphism. Mitotic figures were identified (although not nu-
rate, 44/min. Physical examination confirmed a right ab-
merous, but present in all histologic sections). The neoplastic
dominal mass of 5 ϫ 6 cm, firm in consistency, with a smooth
cells were arranged in a diffuse pattern and had abundant
surface. He had no pubic hair, and genitalia were normal for
eosinophilic cytoplasm. Foci of coagulative necrosis were
a male infant. An axial computed tomography (CT) scanrevealed a large mass in the right abdomen replacing the
identified, in relation to organizing thrombi in small veins.
right adrenal gland. The mass was low in density, with
There was no evidence of capsular, venous, or sinusoidal
multiple areas of hyperdensity suggestive of necrosis (Fig 1).
invasion. Immunohistochemical staining was positive for
A small pleural based density, approximately 4 mm at the
AFP, vimentin, ␣1-antitrypsin, and Ki-67 (nuclear associated
base of the right lung, was also identified. Magnetic reso-
proliferation marker); weakly positive for neuron-specific
nance imaging confirmed the right abdominal mass and the
enolase; and negative for chromagranin and synaptophysin.
The diagnosis of adrenocortical carcinoma was made. The
Received March 2, 2000. Revision received July 13, 2000. Accepted
biopsy of the left adrenal gland was normal.
A CT scan, 2 weeks after the surgery, revealed an addi-
Address all correspondence and requests for reprints to: Thomas A.
tional 4-mm soft-tissue density in the right lung, located
Wilson, M.D., Department of Pediatrics, State University of New York,
posteriorly and inferiorly. No local recurrence in the right
Stony Brook, New York 11794-8111. E-mail: firstname.lastname@example.org.
abdomen was noted. A follow-up CT, 1 month after the
day). Because of persistently low levels of free T4, the doseof l-T4 was increased to 50 g, and then 75 g, every day. Thehyponatremia persisted, and the dose of fludrocortisone wasincreased to 0.2 mg, and then 0.4 mg, twice a day, withcorrection of the hyponatremia. He also developed gyneco-mastia during the course of chemotherapy with mitotane.
Follow-up CT scans showed no change in the size or con-figuration of the three pulmonary nodules.
Because of persistent seizures, carbamazepine was added
to the anticonvulsant regimen in doses increasing to 400mg/day. His developmental assessment at the age of 5months showed adaptive functioning at a 4- to 8-weeks level;and gross and fine motor skills, at a 4-weeks level.
A CT scan, after almost 6 months of chemotherapy, re-
vealed only two nodules in the right lung, measuring 2 and4 mm, respectively (an improvement from the prior study).
Because of persistent seizure activity and the possibility ofpermanent toxic effects of mitotane on the central nervoussystem, the dose of mitotane was gradually decreased. Hisdevelopment progressed slowly on decreasing doses of mi-totane. The dose of fludrocortisone and hydrocortisone wasalso decreased because of suppressed PRA and ACTH levels.
A CT scan, at the age of 1 yr, showed only one nodule in the
FIG. 1. CT scan of the abdomen, demonstrating large right abdom-
After completing 1 yr of chemotherapy, mitotane was dis-
surgery showed another 6-mm nodular density in the right
continued. The patient became seizure free. Gynecomastia
resolved. Repeat EEGs were normal. Neurologic develop-
At the age of 6 weeks, he underwent a right thoracotomy.
ment improved significantly. Seizure medication and l-T4
Three lesions were identified in the right lower lobe. A lo-
were discontinued, with subsequent normal thyroid function
bectomy was performed. The histological features of the lung
tests. Developmental evaluation, at the age of 20 months, was
lesions were consistent with those of the previously resected
at about a 10- to 12-months level. CT scans, at 3, 10, and 16
primary adrenal tumor. Immunohistochemical staining was
months after the discontinuation of mitotane, showed no
positive for ␣1-antitrypsin and weakly positive for AFP.
evidence of lung nodules or recurrence of tumor in the ab-
Two weeks after thoracotomy, a CT scan showed three
domen. One and a half years after discontinuing mitotane, he
new 2- to 3-mm nodules in the right middle lobe. He was
became hypertensive and hypokalemic. Fludrocortisone was
started on chemotherapy with mitotane (o, pЈ-DDD; 250 mg,
discontinued, and both the hypertension and hypokalemia
by mouth, every day), and the dose was progressively in-
resolved. He remained on hydrocortisone (17 mg/m2⅐day).
creased, by 250 mg/week, to a total of 2000 mg/day (ap-
The most recent developmental evaluation showed delay in
proximately 8000 mg/m2⅐day). Replacement with hydrocor-
expressive speech, marginal delay in receptive language, and
tisone (15 mg/m2⅐day) and fludrocortisone (0.05 mg/day)
continuous progression in motor skills.
was started, with chemotherapy. Two months after the startof chemotherapy, repeat CT scans showed three pulmonarynodules within the right lung (the largest measuring 8 mm
in the right mid-lower lung; others were 5 mm). During
The etiology of adrenal tumors is not understood. They
escalation of the dose of mitotane, he became fussy and
may be found in association with Beckwith-Wiedmann and
cranky. His feeding decreased. When the mitotane was in-
Li-Fraumeni syndromes. Reports in siblings and in families
creased to 2000 mg/day, he became lethargic, lost appetite,
with a strong history of malignancy suggest a genetic pre-
lost weight, and developed twitching of the extremities. EEG
disposition (1, 13). Cytogenetics and an analysis using re-
and CT scans of the head were normal. Thyroid function tests
striction fragment length polymorphism suggest that a locus
became progressively abnormal on mitotane (low T4, normal
on chromosome 11p15 is involved in adrenocortical carci-
thyroid stimulating hormone, and normal T4-binding glob-
noma (14). Commonly, these tumors are associated with 11p
ulin). He became hyponatremic (Na, 122 milliequivalents/L)
uniparental disomy and insulin-like growth factor II gene
and hyperkalemic (K, 6 milliequivalents/L). PRA was ele-
overexpression (15). Loss of heterozygosity at the multiple
vated (8.3 ng/L⅐sec). He was started on l-T4 (25 g every
endocrine neoplasia 1 gene locus at 11q13 is associated with
day). The dose of hydrocortisone was progressively in-
creased to 75 mg/m2⅐day; and fludrocortisone, to 0.1 mg/
Adrenocortical carcinomas are classified as functional or
day. His feeding improved significantly, but seizure-like ac-
nonfunctional (3). Most (95%) adrenocortical carcinomas in
tivity continued. An EEG showed spike and wave activity.
children are functional ,as opposed to 50% in adults. Viril-
Magnetic resonance imaging of the brain was essentially
ization, with or without hypercortisolism, is the most com-
normal. He was started on phenobarbitol (15 mg, twice a
monly associated endocrine syndrome in children with ad-
renocortical tumor. Nonfunctional tumors are rare (5%) in
extensive metastasis. Radical excision with enbloc resection
children, occur more commonly in males, and have a high
of any local invasion offers the best chance for cure (13).
likelihood of malignant behavior and poor prognosis (13).
Continued surveillance is required, even after apparent cure,
Endocrine evaluation should include serum cortisol
because recurrence even after 10 –12 yr has been reported (3).
(pre- and post dexamethasone), dehydroepiandrosterone
Adjuvant chemotherapy has been used, but the experience
(DHEA), dehydroepiandrosterone sulfate (DHEAS), testos-
with cytotoxic agents other than mitotane (o, pЈ-DDD) is
terone, androstenedione, aldosterone, PRA and 24 h urinary
limited, especially in children. Mitotane blocks 11-␤ hy-
17 ketosteroids, 17 hydroxysteroids, and free cortisol. Ele-
droxylation and decreases cortisol production. Chronic ad-
vation of 17 urinary ketosteroids is the most sensitive tumor
ministration results in adrenal atrophy and glucocorticoid
marker, and DHEAS provides the most specific assessment
and mineralocorticoid deficiency. Mitotane also affects the
of adrenal androgen production (2, 13). All patients should
peripheral metabolism of steroids. This often necessitates
also be screened for pheochromocytoma (3) and neuroblas-
greater-than-normal replacement doses of adrenal steroids
toma. Although our patient underwent surgery before we
(26, 27). Our patient required three to four times the usual
could obtain these studies, he was not virilized, cushingoid,
recommended doses of hydrocortisone and fludrocortisone
or hypertensive. The baseline cortisol concentration of 916
nmol/L could indicate hypercortisolism or may have been
Improved survival with mitotane is controversial and is
attributable to the stress of his associated pulmonary con-
reported in only a few series (28, 29). There are isolated cases
dition. Measurement of DHEAS may have been a useful
of cure with mitotane therapy, even in metastatic disease (30,
31), and some suggest its use in all patients after surgery (28).
Distinguishing an adrenal cortical adenoma from adrenal
Mitotane is lipid-soluble, has a very long half-life, and re-
cortical carcinoma on the basis of histologic findings is most
mains in the tissue for an extended time (probably months)
problematic, especially in children. The distinction between
after discontinuing the therapy (27), perhaps explaining the
benign and malignant tumors is usually made after careful
disappearance of pulmonary densities after the cessation of
consideration of clinical, gross and microscopic features (17).
chemotherapy in our patient. Therefore, replacement of ex-
In general, most adenomas are less then 100 g and are usually
ogenous glucocorticoid and mineralocorticoid should be dis-
encapsulated, whereas carcinomas are usually greater then
continued slowly and cautiously while observing the pa-
500 g and may or may not be encapsulated (13). Three sys-
tient’s weight, blood pressure, potassium level, and adrenal
tems for assessing the malignant potential of an adrenal
cortical tumor, based (in part) on histologic findings, have
The side effects of mitotane have reduced its tolerance. The
been suggested (17–19). Based on these classification sys-
side effects are largely dose-related and include anorexia,
tems, our patient’s tumor would be classified as clearly ma-
diarrhea, vomiting, rashes, gynecomastia, arthalgia, and leu-
lignant in the Van Slooten and the Weiss systems and prob-
copenia. Neurotoxicity, manifested by lethargy, somnolence,
ably malignant in the Hough system. The significance of
weakness, confusion, seizures, headache, ataxia, or dysar-
histological features in children has been questioned by
thria, can occur (3, 29). The toxic effects of mitotane are
many authors, who conclude that the morphologic criteria
reversible after its discontinuation (31), as noted by the im-
for biologic behavior are different in pediatric and adult
provement in the seizures, progression of development, and
tumors (20, 21). At present, a tumor can be clearly labeled as
normalization of EEG after the discontinuation of mitotane
malignant only if there is distant metastasis or apparent local
in our patient. In Van Slooten’s series (28), a low T4 level was
invasion present at the time of presentation.
seen in all patients who received mitotane. This was asso-
On immunohistochemical staining, normal adrenal cortex
ciated with an increase in T3 resin uptake, suggesting a de-
expresses intermediate filaments, cytokeratin predomi-
crease in T4-binding globulin. However, we did not observe
nantly, and vimentin minimally. In contrast, most adrenal
low T4-binding globulin in our patient. The low free T4 level
cortical carcinomas show no-to-minimal reactivity for cyto-
with normal TSH in our patient reflects either central hypo-
keratin but express vimentin intensely (22). Similarly, Hoak
thyroidism or euthyroid sick syndrome.
noted that neuroendocrine protein synaptophysin and neu-ron-specific enolase was focally present in the normal cortex,whereas extensively positive in adrenal tumors, suggesting
neuroendocrine differentiation of the adrenal cortical cell
Considering the rarity of congenital adrenal carcinoma, it
after neoplastic transformation (23). Our patient’s tumor was
is understandable that few long-term follow-up reports are
positive for vimentin, weakly positive for neuron-specific
available in the literature. Most of these patients died by a
enolase, and negative for keratin (suggesting malignant
few months of age. We are aware of one patient who had
surgery at the age of 24 days, followed by local recurrence
Four stages, I-IV, have been proposed for adrenocortical
and a second surgery at the age of 4 yr, and was well at the
carcinoma, depending on the tumor size, extent of involve-
age of 5 yr (4). To the best of our knowledge, no neonate has
ment, presence or absence of nodal involvement, and distant
been described in the literature who received mitotane after
metastasis (24, 25). Patients with stage I or II disease have the
surgery. Our patient had metastasis twice after surgery but
best chance of cure, whereas patients with stage III-IV have
responded well to mitotane and was alive and disease-free
poor prognoses (1, 2, 24). Our patient’s tumor would be
at the age of 31⁄2 yr. The toxic effects of mitotane, although
serious, were largely reversible after the discontinuation of
Surgery is the treatment of choice, even in patients with
the drug. This observation supports the suggestion that mi-
totane should not be discontinued prematurely, even if se-
16. Kjellman M, Roshani L, The BT, et al.
1999 Genotyping of adrenocortical
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have a beneficial effect on survival.
17. Weiss LM.
1984 Comparative histologic study of 43 metastasizing and non-
functioning adrenocortical tumors. Am J Surg Pathol. 8:163–169.
18. Hough AJ, Hollifield JW, Page DL, et al.
1979 Prognostic factor in adrenal
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1985 Morphologic character-
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1987 Comparison of adrenocortical
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