PEDIATRICS ® OFFICIAL JOURNAL OF THE AMERICAN ACADEMY OF PEDIATRICS
Delayed Diagnosis and False Relapse Due to Paternal Testosterone Use in Adrenocortical Carcinoma Adam L. Green, Abhinash Srivatsa and Carlos Rodriguez-Galindo Pediatrics 2014;133;e1772; originally published online May 5, 2014; DOI: 10.1542/peds.2013-1454
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/133/6/e1772.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright @ 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
American Academy of Pediatrics DEDICATED TO THE HEALTH OF ALL CHILDREN™
CE. PEDIATRICS ®
Delayed Diagnosis and False Relapse Due to Paternal Testosterone Use in Adrenocortical Carcinoma
abstract
The prognosis of pediatric adrenocortical carcinoma often depends on prompt diagnosis to begin treatment before metastatic progression. We discuss a girl who presented at 8 months of age with virilization, which was thought to be due to exposure to a topical testosterone preparation being used by her father. Her testosterone level did not decrease promptly after her father discontinued the medication, how- ever, and when she followed up with signs of Cushing syndrome 5 months later, metastatic adrenocortical carcinoma was diagnosed. The patient was successfully treated with surgery and multiagent che- motherapy. Nine months after the end of treatment, her testosterone level was again found to be elevated. Testosterone precursors were now absent, however, and there were no imaging signs of recurrence. Further history showed that her father had restarted topical testos- terone, and this time, exogenous exposure was correctly diagnosed. As use of topical testosterone becomes more prevalent, exogenous ex- posure must be considered in the differential diagnosis of childhood virilization. Any persistent testosterone elevation after exposure ceases or signs of hypercortisolism, however, are inconsistent with this diag- nosis. We believe that the risk-benefit ratio favors abdominal ultra- sound to rule out malignancy in all children presenting with virilization. Pediatrics 2014;133:e1772-e1776
AUTHORS: Adam L. Green, MD,a,b Abhinash Srivatsa, MD,c and Carlos Rodriguez-Galindo, MDa,b
“Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and bDivision of Hematology/Oncology, and ªDivision of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts
KEY WORDS
adrenocortical carcinoma, children, delay, diagnosis, exogenous, paternal, recurrence, testosterone, topical, virilization
ABBREVIATIONS
ACC-adrenocortical carcinoma CT-computed tomography DHA-dehydroepiandrosterone DHEAS-dehydroepiandrosterone sulfate
Dr Green is the patient’s oncology attending, formerly her oncology fellow, who compiled the case and references, wrote most of the first draft of the manuscript, and created the figures; Dr Srivatsa is the patient’s endocrinologist and diagnosed her tumor, and reviewed the related endocrinology literature, provided appropriate references, and edited the manuscript; Dr Rodriguez-Galindo is the patient’s former oncology attending, raised the idea of the case report and its teaching points, and edited the manuscript; and all authors approved the final draft as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2013-1454
doi:10.1542/peds.2013-1454
Accepted for publication Nov 26, 2013
Address correspondence to Adam L. Green, MD, Dana-Farber Cancer Institute, Dana 3, 450 Brookline Ave, Boston, MA 02215. E-mail: adam.green@childrens.harvard.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright @ 2014 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
Adrenocortical carcinoma (ACC) is a rare solid tumor in children that most often presents with virilization. The differential diagnosis for virilization in children is broad, however, and has recently come to include exogenous testosterone exposure due to parental use. The treatment and prognosis of ACC change dramatically with pro- gression to metastatic disease, so prompt diagnosis is crucial. Therefore, in virilized children, pediatricians and endocrinologists must be able to effi- ciently negotiate the differential di- agnosis. History, physical examination, measurement of levels of testosterone and its precursors, and targeted im- aging are all useful tools in this process. Here we present an instructive case addressing these issues.
CASE
The patient is a 3-year-old girl who began to develop pubic hair at the age of 8 months, along with rapid weight gain. Her father was using Androgel 1% (37.5 mg testosterone topically once daily) prescribed by his physician for symp- toms including fatigue and moodiness. The family brought her symptoms to her pediatrician’s attention at her 9-month physical, and the patient was referred to endocrinology. At her initial endocrinol- ogy visit at 9 months, her parents de- scribed her as a happy baby with a big appetite. She was noted to have Tanner II pubic hair on the labia majora, without other signs of puberty or virilization. Her blood pressure was 90/50. Her weight was 9.4 kg (72nd percentile), with length 70.2 cm (38th percentile); on growth chart review, her weight had most re- cently been in the 25th to 50th percentile range, with height between the 75th and 95th percentile, as shown in Fig 1. The patient was felt to have virilization alone, without signs of hypercortisolism. She had a testosterone level of 19 ng/dl (normal range 2-10; all normal values given are Boston Children’s Hospital
clinical laboratory age-specific refer- ence ranges), 17-hydroxyprogesterone of 27 ng/dl (normal <100), dehy- droepiandrosterone sulfate (DHEAS) of 20.3 µg/dL (normal 5-30), and dehy- droepiandrosterone (DHA) of 38 ng/dl (normal 20-100). At the endocrinolo- gist’s recommendation, the patient’s fa- ther began using gloves to apply the gel, and only to an area of the body normally covered by clothing. Two weeks later, the testosterone level was 18 ng/dL. Figure 2 shows the patient’s key hormone levels over the course of her care.
When seen by a different endocrinologist at 13 months of age, 1 month after her father had completely stopped Androgel, she was noted to have a round face and Tanner III pubic hair on examination. Her weight at this visit was 11.2 kg (86th percentile), with length 72.1 cm (13th percentile). Her testosterone level was 23 ng/dl, with 17-hydroxyprogesterone 29 ng/dl, DHEAS 32.8 µg/dl (normal 5-40), and androstenedione 34 ng/dl (normal 10-47). Because of the pa- tient’s accelerated weight gain and de- celerated linear growth, along with her facial appearance, a dexamethasone suppression test was performed. The early morning cortisol level before dexamethasone was 22.6 µg/dL (normal 5-25), with an undetectable (<5 pg/mL) adrenocorticotropic hormone level; after the dose of dexamethasone, the cortisol level the next morning was 21.8 µg/dl, with adrenocorticotropic hormone still undetectable. With the unsuppressed serum cortisol and a persistently ele- vated testosterone despite elimination of the potential exogenous source, an ab- dominal ultrasound was performed and showed a 5 × 6 × 5-cm calcified right suprarenal mass.
The patient subsequently underwent computed tomography (CT) ofthe chest, abdomen, and pelvis to further char- acterize the mass; the scan was notable for multiple, bilateral pulmonary nod- ules. She underwent resection of her
right adrenal mass and wedge resec- tions of pulmonary nodules in the right upper and right lower lobes, all of which showed ACC. After recovery from sur- gery, the patient was treated on the Children’s Oncology Group protocol ARAR0332 with 8 cycles of chemo- therapy that included cisplatin (total dose 750 mg/m2), etoposide (2400 mg/m2), doxorubicin (400 mg/m2), and mitotane (given by gastrostomy tube in a lipophilic suspension, with serum lev- els followed to maintain a level of 14-20 µg/mL throughout therapy). One month postoperatively and 5 days after com- pleting her first cycle of chemotherapy, her DHEAS, DHA, and androstenedione had all become undetectable; the first testosterone level on treatment, checked after 2 cycles, was also undetectable. These markers remained undetectable on checks after every 2 cycles for the remainder of treatment. The patient’s remaining pulmonary nodules stabilized by CT after 2 cycles, improved after 4 cycles, and disappeared after 6 cycles. She completed therapy at 23 months of age.
Subsequent laboratory tests and CT done on therapy completion and every 3 months through 6 months off therapy showed undetectable androgen levels and no evidence of recurrent disease. Nine months off treatment, the testos- terone level had increased to 42 ng/dL. CT of the chest, abdomen, and pelvis again showed no evidence of disease, but the endocrinology and oncology teams were concerned for recurrence. It was noted that DHEAS, DHA, and androstenedione were again undetectable. The patient continued to show no signs of virilization on physical examination. On further questioning, the family stated that the patient’s father had resumed his use of topical testosterone; he again dis- continued use of the medication, and on repeat testing 1 month later, the patient’s testosterone level was again undetect- able. She continues in remission, now 28 months off therapy.
Birth
3
6
9
12
15
18
21
24
27
30
33
36
in
cm
AGE (MONTHS)
cm
in
41
Chemotherapy start
Chemotherapy end
41
L
40
95
☒
40
E
39
100
100
90
☒
39
N G
38
75
☒
37
95
95
38
Initial presentation
50 ☒
37
T
H
36
90
25 ☒
10 ☒
90
36
35
35
34
5 ☒
85
33
☒
32
80
☒
☒
17
38
31
☒
☒
95
L E
30
75
90
☒
36
16
N
29
28
34
T
70
75
☒
15
27
H
32
26
65
14
25
50
☒
☒
30
W E
24
60
13
23
25
☒
28
I
☒
22
G
55
10
12 ☒
H
21
26
5 ☒
T
20
50
11
24
19
☒
18
45
17
☒
☒
☒
10
22
16
40
☒
☒
9
20
15
8
18
16
7
AGE (MONTHS)
16
14
12
15
18
21
24
27
30
33
36
kg
1b
W
6
E I
Mother’s Stature Father’s Stature
Gestational Age:
12
Weeks
Comment
5
Date
Age
Weight
Length
Head Circ.
10
Birth
H
T
4
8
6
3
2
lb
kg
Birth
3
6
9
50
Testosterone (ng/dL)
40
Dehydroepiandrosterone sulfate (ug/dL)
Tumor resection
30
Paternal testosterone use
Level
Chemotherapy start (includes mitotane)
Chemotherapy end
20
10
0
0
3
6
9
12
15
18
21
24
Months from Presentation
DISCUSSION
In prepubertal children, testosterone is made largely by the adrenal glands. Synthesis of testosterone from cho- lesterol is a multistep process that includes 17-hydroxyprogesterone, DHA, and androstenedione as intermediate products (Fig 3).1 More than 99% of DHA is sulfated to form DHEAS before ex- cretion from the adrenal gland; DHEAS is the most abundant steroid in the body and appears to be a circulating precursor that can be desulfated by a variety of peripheral tissues and subsequently converted to various es- trogenic and androgenic compounds.2 DHA and DHEAS tend to be most ele- vated in ACC with virilization but not hypercortisolism. Because the pro- duction of cortisol shunts precursors away from DHA and DHEAS, these are
usually less elevated or normal in ACC with virilization and hypercortisolism, which was the situation in our patient. Because androstenedione is the im- mediate precursor to testosterone, its levels tend to closely mirror tes- tosterone.1 Because it equilibrates with testosterone via 173-reductase, however, it is less useful than other precursors in differentiating exoge- nous from endogenous testosterone production.
ACC in children is a rare occurrence, with approximately 25 new cases oc- curring annually in the United States, equating to an incidence of 0.2 to 0.3 cases per million. The median age of presentation is 3 to 4 years. Almost all children present with hormonally functioning tumors, most commonly leading to virilization, with a mixed
virilization-hypercortisolism pattern somewhat less common.3-5 Most chil- dren have resectable disease at pre- sentation, with distant metastases present in fewer than one-third. Stage of disease, based on tumor in- vasiveness and size, is a major pre- dictor of outcome. Long-term survival is expected in >90% of patients with small, completely resectable tumors, whereas in patients with distant me- tastases, survival plummets to ~10%,6 emphasizing the need for prompt di- agnosis. Historically, surgery has been the mainstay of treatment. Now, clinical trials are investigating the role of in- tensive, multiagent chemotherapy, in- cluding mitotane, in addition to surgery. Mitotane is an insecticide derivative that both inhibits corticoid biosynthesis and causes necrosis of adrenocortical cells;7 it has been used extensively in adult ACC.
In our case, the paternal use of topical steroids clearly made the diagnosis of ACC more difficult, but a close exami- nation reveals lessons that can be ap- plied to future patients. Virilization in children due to exposure to topical testosterone being used by caregivers has been documented in several case reports and series.8,9 In all of the cases in which testosterone levels were re- ported, however, levels returned to normal on the next measurement after exposure to the exogenous source was
Cholesterol
x Mitotane effect
20,22-Desmolase
Sulfotransferase
Pregnenolone
17-OH Pregnenolone
DHA
DHEAS
Sulfokinase
2 steps
17a-Hydroxylase
17a-Lyase
2 steps
3ß-Hydroxysteroid dehydrogenase
Deoxycorticosterone
11-Deoxycortisol
Androstenedione
11ß-Hydroxylase
11ß-Hydroxylase
17ß-Reductase
Aldosterone
Cortisol
Testosterone
removed. With increasing use of topical testosterone,10 the diagnosis of exoge- nous virilization in children is likely to become more common. Providers must consider other possibilities carefully, however. Any delay in nor- malization of testosterone levels after removal of the source is inconsistent with the diagnosis of topical testos- terone exposure. Any symptoms of hypercortisolism also rule out exoge- nous testosterone exposure. In retro- spect, hypercortisolism was first suggested in our patient by her de- crease in height percentile that ac- companied her increase in weight percentile. These inconsistencies must prompt an immediate search for other causes. Measurement of other andro- gen precursors may be of use in some cases. Although our patient’s initial normal precursor levels could have fit with either exogenous testosterone
exposure or ACC,11 in the more com- mon scenario of purely virilizing ACC, it is likely that DHA and DHEAS would have been elevated in addition to tes- tosterone, ruling out exogenous expo- sure. Imaging, ultimately, is likely to be necessary to clarify the diagnosis. Even though ACC is rare, we feel that the enormous outcome differences from delayed diagnosis necessitate abdom- inal ultrasound in any child presenting with virilization.
Subsequent exposure to exogenous testosterone in a child with ACC is likely to be an extremely rare occurrence. The contrast in our patient’s androgen markers at diagnosis and false alarm recurrence, though, is illustrative. Our patient’s androgen markers became undetectable immediately on starting mitotane, likely due to effects of the drug on steroidogenesis. With recurrent disease, we would have expected at
least detectable levels of testosterone precursors in addition to testosterone, even with the lasting effects of mitotane present. Therefore, an elevation of tes- tosterone alone, to a level higher than was ever produced by her ACC, was clear evidence of exogenous exposure. This was confirmed by normalization after removal of the source. In cases of childhood virilization, providers must differentiate exogenous from endoge- nous testosterone exposure and promptly evaluate for ACC to minimize morbidity and maximize survival in this rare but deadly childhood cancer.
ACKNOWLEDGMENTS
The authors thank Mark Kellogg, PhD, Associate Director of Chemistry in the Department of Laboratory Medicine at Boston Children’s Hospital, for his as- sistance with determining appropriate reference values for the androgen levels.
REFERENCES
1. Donohoue PA. Adrenal disorders. In: Kappy MS, Allen DB, Geffner ME, eds. Pediatric Practice Endocrinology. New York, NY: McGraw-Hill; 2010:131-141
2. Hornsby PJ. Biosynthesis of DHEAS by the human adrenal cortex and its age-related decline. Ann N Y Acad Sci. 1995;774:29-46
3. Ciftci AO, Senocak ME, Tanyel FC, Büyükpamukçu N. Adrenocortical tumors in children. J Pediatr Surg. 2001;36(4):549-554
4. Driver CP, Birch J, Gough DCS, Bruce J. Adrenal cortical tumors in childhood. Pediatr Hematol Oncol. 1998;15(6):527-532
5. Ribeiro RC, Sandrini Neto RS, Schell MJ, Lacerda L, Sambaio GA, Cat I. Adrenocortical
carcinoma in children: a study of 40 cases. J Clin Oncol. 1990;8(1):67-74
6. 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(5):838-845
7. Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009;27 (27):4619-4629
8. Brachet C, Vermeulen J, Heinrichs C. Chil- dren’s virilization and the use of a testosterone
gel by their fathers. Eur J Pediatr. 2005;164 (10):646-647
9. Kunz GJ, Klein KO, Clemons RD, Gottschalk ME, Jones KL. Virilization of young children after topical androgen use by their parents. Pediatrics. 2004;114(1):282-284
10. Basaria S, Dobs AS. New modalities of transdermal testosterone replacement. Treat Endocrinol. 2003;2(1):1-9
11. Kulasingam V, Jung BP, Blasutig IM, et al. Pediatric reference intervals for 28 chem- istries and immunoassays on the Roche cobas 6000 analyzer-a CALIPER pilot study. Clin Biochem. 2010;43(13-14):1045- 1050
Delayed Diagnosis and False Relapse Due to Paternal Testosterone Use in Adrenocortical Carcinoma Adam L. Green, Abhinash Srivatsa and Carlos Rodriguez-Galindo Pediatrics 2014;133;e1772; originally published online May 5, 2014; DOI: 10.1542/peds 2013-1454
| Updated Information & Services | including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/133/6/e1772.full. html |
| References | This article cites 10 articles, 4 of which can be accessed free at: http://pediatrics.aappublications.org/content/133/6/e1772.full. html#ref-list-1 |
| Permissions & Licensing | Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml |
| Reprints | Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml |
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright C 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
American Academy of Pediatrics DEDICATED TO THE HEALTH OF ALL CHILDREN™
AMERICAN ACADEMY. … . OF -PEDIATRICS ®