LONG-TERM FOLLOW UP AND TREATMENT OUTCOMES OF A 2 YEAR-OLD-BOY WITH METASTATIC TESTOSTERONE-SECRETING ADRENOCORTICAL CARCINOMA
Danielle LoGiurato, MD1; Zoltan Antal, MD2; Ping Zhou, MD1
ABSTRACT
Objective: Treatment of metastatic adrenocortical carcinoma (ACC) is challenging and long-term survival rates are exceedingly low. Long-term outcome data for pediatric patients who received mitotane is very limited.
Methods: We describe the case of a 2-year-old boy with ACC with a lung metastasis. He was treated with surgery, chemotherapy, and mitotane, and remains disease- free 13 years after diagnosis.
Results: The key endocrine issues learned from this case include: adrenal-derived sex-steroid and insulin-like growth factor-2 levels are correlated with disease status; very high doses of glucocorticoid and mineralocorticoid are required while on treatment of mitotane; and central precocious puberty needs to be detected and treated in a timely manner to preserve final adult height.
Conclusion: We report a case of pediatric ACC with metastasis that was successfully treated with surgery, chemotherapy, and adjuvant therapy with mitotane. Appropriate endocrine testing and management are impor- tant for long-term survival and quality of life. (AACE Clinical Case Rep. 2020;6:e300-e304)
Submitted for publication May 31, 2020
From 1Pediatric Endocrinology, Montefiore Medical Center, Bronx, New York, and 2Pediatric Endocrinology, Weill Cornell Medicine, New York, New York.
Address correspondence to Dr. Danielle LoGiurato, Pediatric Endocrinology, Montefiore Medical Center, 3415 Bainbridge Avenue, Bronx, NY 10467.
E-mail: dduhame@montefiore.org.
DOI:10.4158/ACCR-2020-0354
To purchase reprints of this article, please visit: https://www.aace.com/ publications/journal-reprints-copyrights-permissions. Copyright @ 2020 AACE.
Abbreviations:
ACC = adrenocortical carcinoma; IGF = insulin-like growth factor; IGFBP = insulin-like growth factor binding protein
INTRODUCTION
Adrenocortical carcinoma (ACC) is very rare in the pediatric population, with an estimated annual incidence of 0.2 to 0.3 cases per million in the United States. Pediatric ACCs are associated with loss of p53 tumor suppression gene function and defects in chromosome 11p15 (1). ACC is associated with a high mortality rate and treatment is challenging. Surgical resection is the mainstay of treatment but recurrence is common.
Mitotane, an adrenolytic agent, has been used as adjuvant therapy in children at high risk of recurrence or with metastatic ACC. There is limited data on the long- term effects of mitotane in the pediatric population (2,3). Development of adrenal insufficiency is universal, and in order to avoid adrenal crisis, patients often require very high doses of glucocorticoids and mineralocorticoids (4). Dysfunction of the insulin-like growth factor (IGF) signal- ing pathway leading to overexpression of IGF-2 is common in ACC, and several studies have investigated the role of the IGF signaling pathway and its prospective utility as a biomarker in diagnosis of ACC and a target in treatment of disease (5).
We present the case of a 2-year-old boy with a p53 germline mutation who presented with virilization. He was found to have an androgen-secreting ACC. We discuss the role of biochemical markers in diagnosis of the disease and monitoring for recurrence. We also explore the potential utility of serum IGF and related binding proteins, the use of mitotane in adjuvant therapy, and the management of iatro-
This material is protected by US copyright law. To purchase commercial reprints of this article, visit www.aace.com/reprints. For permission to reuse material, please access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC).
genic adrenal insufficiency. The growth and pubertal long- term outcomes in our patient are covered over a period of 13 years.
CASE REPORT
The patient was a Russian boy who presented to pedi- atric endocrinology at age 2 for evaluation of increased phallus size and daily erections starting at 4 months of age. His medical history was significant only for poste- rior urethral valves. He was born to non-consanguineous parents with negative family history.
On initial physical examination, his length was 103 cm (>99th percentile, standard deviation score +3.9), weight was 21.3 kg (>99th percentile, standard deviation score +4.3), body mass index was 20.1 kg/m2 (>99th percentile, standard deviation score +2.2), and his head circumfer- ence was 54 cm (>99th percentile, standard deviation score +4.2). He was hypertensive with blood pressure of 116/66 mm Hg. He appeared obviously large for his age with prog- nathism and enlargement of his hands and feet. There was no acne, axillary hair, gynecomastia, or abdominal mass. Genitourinary exam was notable for early Tanner stage II pubic hair and prepubertal testicular volumes of 1 mL bilaterally. Penile length and width were 8 cm and 2.5 cm, respectively.
Baseline laboratory evaluation revealed markedly elevated serum testosterone level and dehydroepiandros- terone sulfate with low gonadotropins. Serum IGF-1 and IGF-2 were elevated. His adrenocorticotropin hormone was normal and cortisol suppressed adequately after dexa- methasone suppression test. His bone age was advanced at 6 years and 0 months at chronological age 2 years and 2 months. Magnetic resonance imaging confirmed the pres- ence of a right adrenal mass (Fig. 1).
He underwent right total adrenalectomy at age 2. Pathology was diagnostic for adrenal carcinoma, weigh-
ing 32 g and 5.5 × 4.5 × 3.5 cm in size. Genetic evaluation revealed a germline nonsense mutation in the p53 tumor suppressor gene R213X. He had clinical improvement and remained asymptomatic until 4 months after the opera- tion, when he was found to have tumor recurrence with evidence of a lung metastasis. Adrenal-derived sex steroids and IGF-2 levels increased concurrently with disease status (Table 1). Given his progression to stage IV advanced disease, he was started on chemotherapy with cisplatin, etoposide, doxorubicin, and adjuvant therapy with mito- tane at 1.2 g/m2/day.
He was started on hydrocortisone at 40 mg/m2/day and fludrocortisone at 0.1mg daily. He developed acute adrenal insufficiency 2 weeks after initiation of therapy with mito- tane at doses of 2.5 to 3.2 g/m2/day and required escalating doses of both hydrocortisone and fludrocortisone (Fig. 2). The medications were titrated to maintain blood pressure and electrolytes in appropriate range. Due to persistent symptoms of adrenal insufficiency, he was trialed on pred- nisolone and demonstrated improvement in symptoms. During treatment with mitotane, he experienced poor growth and gastrointestinal symptoms that resolved after discontinuation of therapy.
At age 6, he developed central precocious puberty and was started on leuprolide which was continued until age 12. After discontinuation of leuprolide, he progressed through puberty normally. His skeletal maturity has normalized, with a bone age of 15 years 6 months at a chronological age of 14 years 10 months. He has reached an appropriate height for his mid-parental target (Fig. 3).
DISCUSSION
Given that childhood adrenocortical tumors are rare and the survival rate is generally low, medical knowl- edge regarding long-term outcome for surviving patients is scarce. Disease staging and tumor histology are used to help predict disease-specific survival rates. Despite our patient initially having several favorable factors includ- ing young age and complete surgical resection of ACC, he developed lung metastasis and worsening prognosis, prompting the decision to initiate systemic chemotherapy with adjuvant mitotane.
The use of mitotane in pediatric patients is gener- ally reserved for cases of aggressive or metastatic ACC, though data is sparse (3,6). Mitotane acts as an inhibi- tor of multiple enzymes, including CYP11A1, leading to decreased conversion of cholesterol to pregnenolone and down-regulation of steroidogenesis. It has cytotoxic effects on the adrenal cortex, with resultant necrosis of adreno- cortical tumor as well as healthy adrenal gland. Mitotane also causes induction of CYP3A4 activity resulting in accelerated metabolism of steroids and other medications. Adrenal insufficiency is a universal effect of mitotane ther- apy. There is a positive correlation between mitotane dose
| Table 1 Biochemical Evaluation at Baseline and Throughout Treatment of Adrenocortical Carcinoma | ||||||||
|---|---|---|---|---|---|---|---|---|
| T (0-10 ng/dL) | DHEA-S (13-83 µg/dL) | ACTH (7-50 pg/mL) | CORT (5.0-25.0 µg/dL) | IGF-1 (20-141 ng/ml) | IGF-2 (334-642 ng/mL) | IGFBP2 (69-480 ng/mL) | IGFBP3 (0.8-3.0 mg/L) | |
| Baseline, age 2 years 2 months | 232 | 581 | 8 | 9.0 | 168 | 823 | 177 | 3.0 |
| After adrenalectomy, age 2 years 4 months | <20 | <15 | 15 | 6.1 | 91 | 539 | 162 | 3.2 |
| Recurrence and metastasis, age 2 years 11 months | 126 | 227 | 43 | 11.7 | 127 | 1,049 | -- | 3.7 |
| After lung mass resection, age 3 years 0 months | <20 | <15 | <5 | 7.4 | 51 | 621 | 253 | -- |
Abbreviations: ACTH = adrenocorticotropic hormone; CORT = cortisol; DHEA-S = dehydroepiandrosterone sulfate; IGF = insulin-like growth factor; IGFBP = insulin-like growth factor binding protein; T = testosterone.
160
4.5
140
4.0
Hydrocortisone Dose (mg/m2)
120
3.5
Mitotane Dose (g/m2) and
Fludrocortisone Dose (mg)
100
3.0
80
2.5
Hydrocortisone (mg/m2)
2.0
60
Mitotane (g/m2)
1.5
40
1.0
Fludrocortisone Dose (mg)
20
0.5
0
0.0
1
2
3
4
5
7
9
11
13
16
18
19
21
Month
and its impact on steroid metabolism (3,6-8). Although there are no accepted guidelines for glucocorticoid replace- ment in patients being treated with mitotane, it is known that patients require supraphysiologic doses of steroids for maintenance therapy.
Our patient developed adrenal insufficiency with salt wasting after initiation of mitotane therapy, and required extremely high doses of both glucocorticoids and miner- alocorticoids for stabilization (up to 150 mg/m2/day of hydrocortisone and up to 0.5 mg/day of fludrocortisone). In our experience, synthetic steroids were more effective than hydrocortisone in controlling symptoms of adrenal insuf- ficiency, even at equivalent doses. He requires ongoing supplementation of hydrocortisone at physiologic dosing since discontinuation of mitotane.
Mitotane has a narrow therapeutic window, with the goal of maintaining serum mitotane >14 mg/L for efficacy, but <20 mg/L to prevent toxicity. Additional toxic effects of mitotane include neurological effects such as confu- sion and ataxia, gastrointestinal effects, hepatotoxicity,
and endocrinopathies including hypothyroidism, growth arrest, and hypogonadism (7,8). Our patient experienced gastrointestinal and neurologic side effects that were more pronounced when serum mitotane levels were >20 mg/L and resolved after discontinuation of treatment. Over the long term, he has had mild cognitive impairment, but continues to improve with therapy.
Children with ACC may be at higher risk of central precocious puberty after treatment due to premature activa- tion of the gonadotropin-releasing hormone pulse genera- tor. Mitotane is also known to have estrogenic action, which may have an impact on bone age advancement (8). Our patient developed central precocious puberty and was successfully treated with gonadotropin-releasing hormone agonist which normalized his bone age. He has now completed puberty and has reached an appropriate mid- parental target height.
Although our patient currently remains disease-free 13 years after treatment, overall survival in ACC remains quite poor and further research into novel therapies is necessary
| Mothor's Future Fathora Punture | ||||
|---|---|---|---|---|
| Done | Agt | Vocht | Portare | UU |
2 to 20 years: Boys Stature-for-age and Weight-for-age percentiles
NAME
RECORD #
12 13 14 15 16 17 18 19 20
AGE (YEARS)
cm
In
76
190
74
PL
185
---- > ==
70
180
72
-40-
70
175
“To Calculate Bilifl: Waight fugl . Rature com) + Stature jemt # 10.000
24
ce Wa-ght Joj . Stitur fing - Stature (r) x, 700
170
68
10
66
in
cm
3
5
6
4
10
165
150
160
64
62
—← > ==
155
155
62
60
150
150
60
58
145
Chronological
-55-
140
Age
Bone Age
105
230
54
135
100
220
52
130
b
95
210
50
125
90
200
48
00’
120
85
190
46
115
80
180
44
75
110
75
170
42
150
105
70
40
150
W
100
M
66
140
E
38
95
60
36
10
130
0
90
55
120
H
34
1
85
50
110
32
80
45
100
30
40
90
80
35
35
80
$ == 6x1
70
70
60
30
30
25
25
60
50
40
20
20
50
40
30
15
15
30
Ib
10
AGE (YEARS)
10
kg
kg
1b
2
3
4
5
6
7
8
9
10
12
13
14
15
16
17
18
19
20
Postotos Vay 36, 2000 pholflod Tias ocg.
SOURCE: Destinoned by Bu Personal Carter To Beals Dretstus za codsoorten we Fu fisienel Orme for Chronic Gramme Prevention and Heith Pramotion (2000). Mty:// www.sứcqua.growl/xp/at
CDC
BAFER.HEALTHIER.PROFLE”
to improve survival rate. Molecular testing may provide useful information regarding tumor pathophysiology, as well as a possible target for novel therapies. Recent studies have investigated the role of the IGF signaling pathway in ACC.
The IGF system is an important regulator of growth and cell programming in many tissues, and overexpression in ACC tumors is thought to play a role in promotion of malignant transformation and tumor growth. Malignant tumors in adults are more likely to be associated with elevated IGF-2 protein than benign tumors (9). One study reported increased mRNA expression of IGF-binding protein-3 (IGFBP3) in adrenal tumors compared to healthy controls (10). Pediatric ACC is associated with increased IGF-1 receptor expression and has been associated with increased risk of metastasis (5). Clinical trials are being conducted to investigate the efficacy of anti-IGF-1 receptor antibodies in the treatment of ACC.
There is limited data on the usefulness of serum IGF-2 and IGFBPs as diagnostic and prognostic biomarkers in
pediatric ACC. One study found that patients with meta- static ACC had significantly higher levels of IGFBP2 than those with local disease, but serum IGF-2 and IGFBP3 were not evaluated (11). In our patient, serum IGF-2 levels were elevated at the time of diagnosis, increased further corresponding with his recurrence, and decreased into normal range after resection of metastases and initiation of adjuvant therapy. His other biochemical parameters includ- ing testosterone and dehydroepiandrosterone sulfate also changed concordantly. Our case demonstrates the potential utility of monitoring serum IGF-2 levels in children with ACC as an additional parameter for evaluation of disease stage and progression, although further investigation is needed.
CONCLUSION
During mitotane treatment, adrenal insufficiency is difficult to manage and often requires extremely high doses of both glucocorticoid and mineralocorticoids. Synthetic
steroids may be effective in the management of adrenal insufficiency in patients who have suboptimal response with hydrocortisone. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, as prompt recognition and treatment of adrenal insufficiency is crucial for survival. Serum growth factors, such as IGF-2, may serve as a supplemental surveillance tool in monitor- ing disease progression or recurrence. Timely recognition and treatment of central precocious puberty after treatment of ACC can restore normal puberty and growth.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
REFERENCES
1. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocorti- cal tumors. J Clin Endocrinol Metab. 1997;82:2027-2031.
2. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98:4551-4564.
3. Kasperlik-Zaluska AA. Clinical results of the use of mitotane for adrenocortical carcinoma. Braz J Med Biol Res. 2000;33: 1191-1196.
4. Robinson BG, Hales IB, Henniker AJ, et al. The effect of o,p’- DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol (Oxf). 1987;27:437-444.
5. Almeida MQ, Fragoso MC, Lotfi CF, et al. Expression of insu- lin-like growth factor-II and its receptor in pediatric and adult adre- nocortical tumors. J Clin Endocrinol Metab. 2008;93:3524-3531.
6. Zancanella P, Pianovski M, Oliveira B, et al. Mitotane associ- ated with cisplatin, etoposide, and doxorubicin in advanced child- hood adrenocortical carcinoma: mitotane monitoring and tumor regression. J Pediatr Hematol Oncol. 2006;28:513-524.
7. Chortis V, Taylor AE, Schneider P, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5a-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab. 2013;98:161-171.
8. Oddie PD, Albert BB, Hofman PL, Jefferies C, Laughton S, Carter PJ. Mitotane in the treatment of childhood adrenocorti- cal carcinoma: a potent endocrine disruptor. Endocrinol Diabetes Metab Case Rep. 2018;2018:18-0059.
9. Fottner C, Hoeflich A, Wolf E, Weber MM. Role of the insulin- like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res. 2004;36:397-405.
10. Ilvesmaki V, Liu J, Heikkila P, Kahri AI, Voutilainen R. Expression of insulin-like growth factor binding protein 1-6 genes in adrenocortical tumors and pheochromocytomas. Horm Metab Res. 1998;30:619-623.
11. Boulle N, Baudin E, Gicquel C, et al. Evaluation of plasma insu- lin-like growth factor binding protein-2 as a marker for adrenocor- tical tumors. Eur J Endocrinol. 2001;144:29-36.