Clinical Characteristics and Long-Term Outcomes of Adrenal Tumors in Children and Adolescents
Authors
Ja Hye Kim1, Yunha Choi1, Soojin Hwang1, Ji-Hee Yoon1, Gu-Hwan Kim2, Han-Wook Yoo1, Jin-Ho Choi1
Affiliations
1 Department of Pediatrics, Asan Medical Center, Univer- sity of Ulsan College of Medicine, Seoul, Korea
2 Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Key words
adrenal tumor - Li Fraumeni syndrome - von Hippel-Lindau disease - pheochromocytoma
received 24.02.2023
revised 08.06.2023
accepted 06.07.2023 published online 06.09.2023
Bibliography
Exp Clin Endocrinol Diabetes 2023; 131: 515-522 DOI 10.1055/a-2127-9292 ISSN 0947-7349
@ 2023. Thieme. All rights reserved.
Georg Thieme Verlag, Rüdigerstraße 14, 70469 Stuttgart, Germany
Correspondence
Jin-Ho Choi, M.D., Ph. D. Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil Songpa-Gu Seoul 05505
Korea
Tel: + 82-2-3010-3991, Fax: + 82-2-473-3725 jhc@amc.seoul.kr
Additional material is available at http://dx.doi. org/10.1055/a-2127-9292
ABSTRACT
Objective Adrenal tumors are generally rare in children and can be a part of familial cancer syndrome. This research was conducted to examine the clinical outcomes, histopathological results, and genetic etiologies of adrenal tumors in children and adolescents.
Methods Thirty-one children and adolescents with adrenal tumors were included. Data on clinical outcomes and endo- crine and radiologic results were retrospectively analyzed. Molecular analysis was conducted in select patients according to their phenotype and family history.
Results The median age at diagnosis was 7.9 years (range: 0.8-17.8 years) with 5.1 ± 1.8 cm of maximum tumor diame- ter. Adrenal adenoma (n =7), carcinoma (n =5), borderline (n=2), isolated micronodular adrenocortical disease (n=2), pheochromocytoma (n=8), paraganglioma (n=3), and gan- glioneuroma (n =4) are all pathological diagnoses. The most common presenting symptom was excess production of adren- ocortical hormones (n = 15), including virilization and Cushing syndrome. Non-functioning adrenocortical tumors were found in a patient with congenital adrenal hyperplasia. Genetic eti- ologies were identified in TP53 (n=5), VHL (n=4), and PRKACA (n=1). Patients with mutations in TP53 were young (1.5±0.5 years) and had large masses (6.1 + 2.3 cm).
Conclusions This study describes clinical outcomes and the pathological spectrum of adrenal tumors in children and ado- lescents. Adrenocortical tumors mostly presented with an excess of the adrenocortical hormone. Patients with genetic defects presented at a young age and large size of tumors, necessitating genetic testing in patients at a young age.
Introduction
Adrenal tumors occur in about 5% of the general population, and the prevalence varies with age, ranging from less than 0.5% in chil- dren to 10% in elderly patients [1, 2]. Most adrenal tumors in adults are found incidentally on imaging studies, whereas 15% of adults with adrenal tumors present with symptoms and signs indicative of adrenal hormone excess [1]. Benign and non-functioning adren- ocortical adenomas are the most common adrenal tumors in adults, followed by adrenocortical carcinoma and pheochromocy-
toma (PHEO), each accounting for about 10% of cases [1, 3]. Adre- nal metastases, lymphomas, and ganglioneuromas were among the other lesions [2]. However, in children, over 90% of patients show overt features of adrenal hormone excess with a bimodal age distribution, with peaks during the first 5 years of life and adoles- cence [2,4]. Adrenal carcinomas are more common in children than in adults [2,4].
Adrenal tumors are categorized into tumors of the adrenal cor- tex, the adrenal medulla, and extra-adrenal paraganglia, according
to the World Health Organization (WHO) classification of endocrine tumors [5]. Based on the Weiss score in children, adrenocortical tumors (ACTs) are classified into benign adrenocortical adenomas and highly aggressive adrenocortical carcinomas [6]. As of the 2022 WHO classification, the term”nodular adrenal cortical hyperplasia” is no longer used; instead, the classification now refers to bilateral micronodular or macronodular adrenocortical disease [5]. These conditions are associated with genetic susceptibility and are clas- sified as benign adrenocortical tumors because of their clonal-ne- oplastic nature. The bilateral micronodular adrenocortical disease is most common in children and young adults and is usually asso- ciated with Cushing syndrome [5].
Hereditary tumor syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, or isolated hemihypertrophy, are associated with ACTs [7, 8]. The prognosis of adrenal tumors in chil- dren is highly variable; overall 5-year survival in pediatric patients with adrenocortical carcinoma has been reported to range from 40 % to 80 % [9,10].
PHEO arises from the adrenal medulla, whereas paraganglioma (PGL) develops from extra-adrenal paraganglia. The clinical features of PHEO and PGL rely on the oversecretion of catecholamines [11]. This condition has also been linked to hereditary cancer syndromes such as multiple endocrine neoplasia type 2, neurofibromatosis type 1, and von Hippel-Lindau disease type 2 [11]. Long-term prognosis is closely related to underlying genetic defects in terms of recurrence, malignant transformation, and overall survival [11, 12]. According to the recent WHO classification, neuroblastic tumors of the adrenal glands, such as neuroblastoma and ganglioneuroma, are included in the tumors of the adrenal medulla and extra-adrenal paraganglia [13]. Neuroblastoma is aggressive and often presents with metas- tases in other organs. Ganglioneuroma, on the other hand, is a be- nign tumor made up of Schwann cells, ganglion cells, and nerve fib- ers [13]. The adrenal glands are the most commonly affected site, accounting for approximately 30% of cases [14].
There have been some studies on the clinical and molecular characteristics of adrenal tumors in children and adolescents [9, 10, 12, 15-19]. However, these studies included small numbers of patients, and the follow-up was only for a limited duration. This study was conducted to investigate clinical outcomes, histopatho- logical findings, and genetic etiologies in children and adolescents in a single academic center.
Materials and Methods
Patients
This study included 31 unrelated patients with adrenal tumors di- agnosed before the age of 18 from March 1997 to December 2022 at the Department of Pediatrics, Asan Medical Center Children’s Hospital, Seoul, Korea. Patients with neuroblastoma were exclud- ed from this study. A retrospective chart review was used to collect clinical and endocrine data, including presenting features, family history, pathologic findings, and outcomes. This study excluded asymptomatic patients with small adrenal tumors that did not need surgical resection. This study was approved by the institutional re- view board at Asan Medical Center, Seoul, Korea (IRB No. 2021- 1699).
Endocrine and radiological investigations
Adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandros- terone sulfate (DHEA-S), plasma renin activity, and aldosterone lev- els were measured in patients with ACTs. A 24-h urine-free cortisol level was measured in patients who manifested Cushinoid features. Low- and high-dose dexamethasone suppression tests were also performed on six patients with Cushing syndrome. Biochemical tests for PHEOs and PGLs included estimation of the levels of epi- nephrine, norepinephrine, metanephrine, and normetanephrine in plasma and/or 24-h urine.
A radiologic examination was conducted according to the clini- cal features. The patients initially underwent ultrasound (US), com- puted tomography (CT), or magnetic resonance imaging (MRI). The 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) scan (n=5), whole-body MRI (n=2), or bone scan (n=5) were used to determine tumor characteristics and staging in patients with ACTs. Iodine-123 (123I)-MIBG-single photon emission computed to- mography (SPECT) (n=8) was performed in patients with PHEO and PGL to determine tumor characteristics and metastasis, and for stag- ing, an 18F-FDG-PET scan was carried out in two patients.
Molecular analysis
Molecular analysis was performed in selected patients according to their phenotype and family history. Genomic DNA was extract- ed from peripheral blood leukocytes using a Puregene DNA isola- tion kit (Qiagen, Hilden, Germany). In nine patients with ACTs, all coding exons and exon-intron boundaries of TP53 were amplified by polymerase chain reaction (PCR) with specific oligonucleotide primers. Sanger sequencing of VHL was performed in six patients with PHEO and PGL, followed by SDHB sequencing in two patients who did not have a VHL mutation. PCR products were directly se- quenced using an ABI3130x1 Genetic Analyzer (Applied Biosys- tems, Foster City, CA, USA).
Targeted panel sequencing or whole-exome sequencing (WES) was conducted in two patients with isolated micronodular adren- ocortical disease (i-MAD). For targeted panel sequencing and WES, the SureSelect Target Enrichment system kit and SureSelect Human All Exon V6 (Agilent Technologies, Santa Clara, CA, USA) were used, respectively. The MGI DNBSEQ-T7 platform (Illumina Inc., San Diego, CA, USA) was used for sequencing. The sequenced reads were aligned to the human reference genome (hg19) using the Burrow-Wheeler Alignment program version 0.7.17. Single nucle- otide variants and indel variants were called by the HaplotypeCall- er of Genome Analysis ToolKit version 4.1.8. The Parliament2 [20] pipeline was used for copy number variation calling, and AnnotSV version 3.0.2 was used for annotation [21]. The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines were used to classify sequence variants [22].
Results
Clinical characteristics of patients with adrenal tumors at presentation
The median age at diagnosis in all patients with adrenal tumors was 7.9 years (range: 0.8 - 17.8 years), and the median follow-up dura-
tion was 5.5 years (0.5- 24.5 years) ( Table 1). The maximum tumor diameter was 5.1 + 1.8 cm on average. Adrenal adenoma (n=7,22.6%), adrenal carcinoma (n=5, 16.1%), borderline (n=2, 6.5%), i-MAD (n =2, 6.5%), PHEO (n=8, 25.8%), PGL (n=3,9.7%), and ganglioneuroma (n =4, 12.9%) are among the pathological di- agnoses included. Excess adrenocortical hormones were the most common presenting symptom (n = 15, 48.4%), followed by hyper- tension (n=8, 25.8%), adrenal incidentaloma without symptoms (n=4, 12.9%), non-specific symptoms (n=3, 9.7%), and mass ef- fect, such as hematuria and dysuria (n= 1, 3.2%).
Clinical outcomes and pathological findings of adrenocortical tumors
Among 16 patients (51.6%) with ACTs (Supplementary Table 1), 7 patients (22.6%) had adrenocortical adenoma at a median age of 7.1 years (range, 2.2 - 17.8 years) with a maximal tumor diam- eter of 3.5 ± 1.0 cm, whereas 5 patients (16.1%) were diagnosed with adrenocortical carcinoma at a median age of 1.8 years (range: 0.8 - 15.8 years) and had a large tumor size with a maximal tumor diameter of 6.8 ± 2.1 cm. Two patients (6.5%) had borderline ma- lignant ACTs with a maximum diameter of 5 cm and 9 cm diameter, respectively. The remaining two patients were diagnosed with i-MAD (6.5%) at 2.9 years and 7.7 years of age, respectively.
Functioning tumors were found in 15 patients (93.8%, 15/16) with a median age of 2.5 years (range, 0.8 - 15.1 years) and a max- imal diameter of 5.1 ± 2.3 cm. Virilization alone was the most com- mon (n=9), Cushing syndrome was observed in four patients, and the remaining two patients had mixed hormone excess, character- ized by overproduction of androgen and glucocorticoid. Cushing syndrome was more prevalent in older patients compared with those with virilization (7.6± 5.1 years vs. 2.9± 2.1 years, P=0.03). Eleven patients with androgen excesses had high DHEA-S levels (mean 1317.7±2031.7 µg/dL, normal range, 31.2 - 263 µg/dL). Six patients with Cushing syndrome demonstrated elevated 24-h uri- nary free cortisol levels at 533.8 + 320.2 ug/day. In patients with Cushing syndrome, unsuppressed serum cortisol and 24-h urine-
free cortisol levels were revealed at 23.7 + 8.1 ug/dl and 650.4± 385.3 ug/day after low-dose dexamethasone suppression tests and 27 ± 10.6 ug/dL and 622.4 + 301 ug/day after high-dose dexamethasone suppression test, respectively.
A patient with CAH was diagnosed with 6.5 cm-sized adreno- cortical carcinoma because of mass effects, such as abdominal pain, dysuria, and hematuria. He was diagnosed with CAH in the neonatal period and was treated with hydrocortisone and fludro- cortisone. However, the patient was lost to follow-up after one year of age. At the age of 5 years, he presented with precocious puber- ty; however, he did not take the medicine regularly due to poor ad- herence. At the age of 16 years, adrenocortical carcinoma was found on abdominal CT in the left adrenal gland. Histological ex- amination revealed capsular and lymphovascular invasion with ex- tensive internal hemorrhage.
Unilateral adrenalectomy was performed in 14 patients with ACTs. Pathologic findings revealed adrenocortical adenoma in seven patients and adrenocortical carcinoma in five patients. The Weiss score was 0 in four and 1 in two patients with adrenocortical adenoma, respectively, and 2 in one patient with TP53 mutation [6]. Four patients with adrenocortical carcinoma had a Weiss score of 4, whereas one patient with adrenocortical carcinoma with CAH scored 2. The remaining two patients with virilization were classi- fied as borderline tumors with a Weiss score of 1: capsular invasion in Patient 8 and ischemic necrosis in Patient 9. Patient 8 revealed 10% of the Ki-67 index, and Patient 9 had a large mass with a max- imal diameter of 9 cm.
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Pathologic findings were diffuse micronodular hyperplasias in two patients with i-MAD who underwent bilateral adrenalectomy. Growth velocity was markedly improved, and weight decreased to the normal range within 6 months ( Fig. 1).
According to the European Network for the Study of Adrenal Tu- mors (ENSAT), five patients with adrenocortical carcinoma and two with borderline malignancy were stage II [23]. The Ki-67 index was determined in 6 patients with ACTs. Among them, two patients with adrenocortical carcinoma (Patients 10 and 12) with a high
| Total | ACA | Borderline | ACC | i-MAD | PHEO and PGL | GN | |
|---|---|---|---|---|---|---|---|
| No. | 31 | 7 | 2 | 5 | 2 | 11 | 4 |
| Sex: female, No. (%) | 18 (58.1) | 4 (57.1) | 2 (100) | 4 (80) | 0 | 5 (45.5) | 3 (75) |
| Age at diagnosis (yr), median (range) | 7.9 (0.8-17.8) | 6.5 (2.2-15.1) | 1.2 and 2.3 | 1.8 (0.8-15.8) | 2.9 and 7.7 | 12 (1-17.8) | 11.3 (7.7-17) |
| Presenting symptoms, No. (%) | |||||||
| Hormone excess | 26 (83.9) | 7 (100) | 2 (100) | 4 (80) | 2 (100) | 11 (100) | 0 |
| Mass effect | 1 (3.2) | 0 | 0 | 1 (20) | 0 | 0 | 0 |
| Incidental | 4 (12.9) | 0 | 0 | 0 | 0 | 0 | 4 (100) |
| Location of adrenal tumor: left, No. (%) | 14/261 (53.8) | 5 (71.4) | 0 | 4 (80) | Bilateral | 2/8 * (25) | 3 (75) |
| Adrenal mass diameter (cm), mean ± SD | 5.1±1.8 | 3.5±1.0 | 5 and 9 | 6.8±2.1 | NA | 4.9±0.9 | 6±2 |
| Recur or metastasis, No. (%) | 2 (6.5) | 0 | 0 | 0 | 0 | 2 (18.2) | 0 |
| Genetic defects, No. (%) | 10/17 (58.8) | 1/3 (33.3) | 1/2 (50) | 3/4 (75) | 1/2 (50%) | 4/6 (66.7) | - |
ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma; GN, ganglioneuroma; i-MAD, isolated micronodular adrenocortical disease; NA, not available; No., number; PGL, paraganglioma; PHEO, pheochromocytoma; SD, standard deviation; yr, years; * PGL cases were excluded; } PGL and i-MAD cases were excluded.
a
Patient 15
100
Patient 15
+3 SD
190
Height (cm)
+3 SD
+2 SD
Weight (kg)
180
+1 SD
90
+2 SD
0
170
-1 SD
80
160
-2 SD
+1 SD
-3 SD
70
0
150
60
140
-1 SD
130
50
-2 SD
-3 SD
120
40
110
30
100
20
90
80
10
75
3
6
9
12
15
18
3
6
9
12
15
18
Age (years)
Age (years)
b
Patient 16
Patient 16
+3 SD
Height (cm)
+2 SD
190
Height (cm)
+3 SD
+2 SD
100
+1 SD
180
+1 SD
95
0
0
1 SD
170
-1 SD
90
160
-2 SD
-2 SD
-3 SD
85
-3 SD
150
80
140
75
130
70
65
120
60
110
55
100
50
90
45
80
0
6
12
18
24
30
35
75
3
6
9
12
15
18
Age (months)
Age (years)
20
Patient 16
Patient 16
19
Weight (kg)
100
+3 SD
Weight (kg)
18
97th
17
95th
90th
90
+2 SD
16
15
75th
80
50th
+1 SD
14
13
25th
70
0
12
10th
5th
11
3rd
60
-1 SD
10
-2 SD
9
50
-3 SD
8
7
40
6
30
5
4
20
3
2
10
0
6
12
18
24
30
35
3
6
9
12
15
18
Age (months)
Age (years)
Ki-67 index (15 and 20%, respectively) were treated with mitotane for 12 months. One patient (Patient 12) with Li-Fraumeni syndrome required hydrocortisone replacement therapy. Five patients with
ACTs were transitioned to central precocious puberty after a me- dian of 28.5 months (range, 4- 70 months) postoperatively and were treated with gonadotropin-releasing hormone agonists. They
included two patients with adrenocortical adenoma, two with bor- derline tumors, and one with adrenocortical carcinoma. There was no tumor recurrence in 10 patients with non-malignant and five patients with adrenocortical carcinomas during the median 6.5 years (range, 1.6- 16.5 years) and 10.5 years (range, 3 - 17.3 years) of follow-up, respectively.
Clinical outcomes and pathological findings of adrenal medullary tumors
Eleven patients with PHEO (n= 8) and PGL (n=3) were diagnosed at a median age of 12 years (range, 12 months - 14.7 years), and a maximum tumor diameter was 4.9 ± 0.9 cm. Four patients (12.9%) with ganglioneuroma were diagnosed at median age of 11.3 years (range, 7.7- 17 years) with a maximum diameter of 6 ± 2 cm.
Eight patients with PHEO or PGL had hypertension, and four had additional symptoms such as palpitation (n=1), sweating (n=2), vomiting (n=2), or blurred vision (n=2). Plasma norepinephrine and 24-h urine normetanephrine levels were prominently elevated in patients with PHEO and PGL (Supplementary Table 2). Three patients with PHEO or PGL manifested non-specific symptoms, such as failure to thrive, abdominal pain, or diarrhea; however, these pa- tients revealed excessive sweating without hypertension. All PHEO was unilaterally located without metastasis, and all PGL occurred in the retroperitoneum.
All patients with PHEO and PGL underwent surgical resection of the tumors. One patient with PHEO revealed locoregional and con- tralateral recurrences 5 months and 3.5 years after surgical resec- tion, respectively, during the median 5.8 years of follow-up in pa- tients with PHEO and PGL. Another patient with PHEO recurred in the contralateral side 9 years after surgery and developed retro- caval PGL 22 years after the initial surgery. Recurred tumors were found due to signs of catecholamine oversecretion, such as exces- sive sweating and headache. These two patients harbored muta- tions in VHL.
Ganglioneuroma was discovered on CT or US in 3 and one pa- tient, respectively, during the evaluation of precocious puberty (n=1), abdominal pain (n=2), or scoliosis (n=1). These patients with ganglioneuroma were treated with surgical resection. During the 4.3 years of median follow-up, there was no recurrence.
Molecular characteristics of patients with adrenal tumors
A genetic test for TP53 was performed in seven patients with ACTs, and one of them had a family history (> Table 2 and Supplemen- tary Table 1). Five of them harbored mutations in TP53, of which two of the previously reported pathogenic variants were found in one patient with adenoma (p.R213P) and one patient with border- line tumor (p.T125T) [24]. Three patients with adrenocortical carci- noma were found to have three different TP53 mutations (p.R175H, p.A347T, and p.P219S) [24]. The p.R175H was documented as path- ogenic, and p.A347T and p.P219S were reported as likely pathogen- ic. Patients with TP53 mutation were young (1.5 + 0.5 years), and tumor size tended to be large (6.1 + 2.3 cm). Parental testing was performed on one patient (Patient 3) because of the grandfather’s history of lung cancer, and her father also carried the same muta- tion (p.R213P). However, he had no history of cancer yet.
Targeted exome sequencing or WES was performed in two pa- tients with i-MAD. One patient harbored a PRKACA duplication, a known pathogenic mutation associated with i-MAD [25]. Com- pound heterozygote CYP21A2 mutations were identified in a pa- tient with CAH: c.293-13 A> G and p.E163Dfs * 24.
Five patients with PHEO and one with PGL underwent a genetic test. Among them, 3 PHEO patients and one PGL patient harbored VHL mutations (p.R161Q, p.E70K, and p.R167Q), which were pre- viously reported to be pathogenic [26]. These patients presented with retinal hemangioma or hemangioblastoma and had family members of von Hippel-Lindau disease.
Discussion
In this study, the majority of pediatric patients with ACTs exhibited oversecretion of adrenal androgen or cortisol. Cushing syndrome was more prevalent in older age. Adrenocortical carcinoma mani- fested a larger mass at a young age. In addition, patients diagnosed at a young age were more likely to have genetic defects. Clinical and endocrine characteristics in patients with PHEO and PGL were similar between mutation-positive and -negative patients; howev- er, tumor recurrence and metastasis were more common in pa- tients with genetic defects.
Functional ACTs in adults consist of cortisol- or aldosterone-se- creting tumors. Meanwhile, in children, androgen-secreting tumors are predominant, followed by cortisol-secreting tumors [27-29]. In the present study, all ACTs except a patient with CAH were function- al tumors, and virilization was the most common manifestation in both adrenocortical adenomas and carcinomas. The clinical features of ACTs within the first two years of life are closely associated with the development of the adrenal gland [24]. The fetal adrenal gland consists of a large portion of the fetal zone and a narrow definitive zone [30]. The fundamental product of the fetal zone is dehydroepi- androsterone (DHEA) and its sulfate [31]. After birth, the adrenal gland undergoes dramatic remodeling, with robust fetal zone re- gression and development of the definite zone. Massive apoptosis induces postnatal regression of the fetal adrenal cortex, whereby perturbation in the apoptotic machinery, p53, leads to disrupted re- gression of fetal adrenal cells and tumorigenesis [31]. Thus, ACTs caused by TP53 defects in early childhood usually manifest viriliza- tion. Adrenal tumors can occur in untreated patients with CAH [32]. Persistent stimulation of the adrenal glands by ACTH can cause ne- oplastic proliferation of the hyperplastic adrenal tissue. Among pa- tients with CAH, the prevalence of adrenal tumors was 29.3%, with myelolipoma (8.6%) being the most common [33].
The age of onset of adrenocortical carcinoma was younger than that of adrenocortical adenoma, and the tumor sizes were likely to be larger, which were consistent with the previous studies [9, 10]. Surgical resection is the treatment of choice for localized adreno- cortical carcinoma, and the overall 5-year survival varies by 60 - 80% in adults. However, prospective data suggest that overall 5-year survival in cases with complete resection of localized tumors can be as high as 90% [34]. Pediatric patients with completely re- sected small tumors, less than 200 g, showed an excellent progno- sis [9]. Since our patients had resectable Stage II tumors of less than 200 g, there was no recurrence or fatal cases during the follow-up period.
| No. | Diagnosis | Genetic analysis | Nucleotide change | Amino acid change | ACMG guideline | Family history |
|---|---|---|---|---|---|---|
| 3 | ACA | TP53 | c.638 G>C | p.R213P | P | Father |
| 8 | ACA | TP53 | c.375 G>A | p.Thr125 = | P | – |
| 10 | ACC | TP53 | c.524 G>A | p.R175H | P | – |
| 12 | ACC | TP53 | c. 1039 G>A | p.A347T | LP | – |
| 13 | ACC | TP53 | c.655 C>T | p.P219S | LP | – |
| 14 | ACC | CYP21A2 | c.293-13 A>G/c.489del | Splicing/p.E163Dfs * 24 | P/P | – |
| 16 | i-MAD | Targeted exome sequencing | PRKACA duplication | P | – | |
| 18 | PHEO | VHL | c.482 G> A | p.R161Q | P | Mother |
| 19 | PHEO | VHL | c.208 G>A | p.E70K | P | Father |
| 22 | PHEO | VHL | c.500 G> A | p.R167Q | P | Father |
| 26 | PGL | VHL | c.208 G>A | p.E70K | P | Mother |
ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma; LP, likely pathogenic; ND, not detected; P, pathogenic; PHEO, pheochromocytoma.
Mutations in TP53 are the most common genetic defects in pa- tients with ACTs [35]. In a retrospective single-center study includ- ing 23 pediatric patients, 50% of patients harbored mutations in TP53[29]. The mutation-carrying rate ranged from 58 % in those diagnosed before the age of 12 years to 25 % in those diagnosed between the ages of 12 and 20 years [24]. In the present study, TP53 mutations were found in 5 of 7 patients, with three of them having adrenocortical carcinoma. As in the previous study, the clin- ical features and prognosis for ACTs were similar in patients with or without TP53 mutations [36]; however, patients harboring TP53 mutations were more likely to be diagnosed at a young age.
I-MAD is composed of multiple small adrenocortical nodules (<1 cm), which produce cortisol [5]. Genetic defects in PRKACA are one of the main causes [37]. In the human adrenal glands, PRKACA encodes the catalytic protein kinase A isoform, and activating mu- tations of PRKACA increase the activities of protein kinase A and its downstream target, cAMP response element-binding protein (CREB) [37]. Recently, germline mutations in PDE11A[38] and PDE8B[39] have been described in a few patients with i-MAD. This condition is a very rare cause of Cushing syndrome but should be suspected in cortisol excess without focal lesions in the adrenal glands at an earlier age.
Hypertension was the most common clinical feature of PHEO in our study. Although PHEO accounts for only 0.5%-2% of second- ary hypertension in children [11], children with hypertension should be evaluated for concomitant symptoms such as palpita- tion, paroxysmal headache, sweating, and diaphoresis. Diagnosis of PGL can be difficult due to variable clinical features caused by oversecretion of catecholamines [40]. If left untreated, this condi- tion has a devastating outcome due to prolonged exposure to cat- echolamines [40]. In our study, one patient with PHEO and two with PGL experienced non-specific symptoms such as failure to thrive, diarrhea, mild fever, and weight loss.
The frequency of genetic defects is much higher in pediatric pa- tients with PHEO than in adults, ranging from 30 % to 80 % [12, 15, 41]. Germline mutations in RET, VHL, NF1, and SDHx are most frequently identified in patients with PHEO and PGL. Howev- er, recent advances in molecular genetics have revealed germline
mutations in more than 18 tumor-causing genes [42]. In our study, six patients were subjected to Sanger sequencing for VHL or SDHB, and pathogenic variants were discovered in four of them (4/6, 66.7%). These mutation-carrying patients had a familial history, of which three patients already presented with retinal hemangioma or hemangioblastoma. Recurrence can occur even 20 years after surgery; therefore, a lifelong follow-up is needed for patients with genetic defects [43]. Therefore, genetic testing is important be- cause the frequency of relapse increases in patients with genetic defects.
Recent advances in molecular biology have facilitated the iden- tification of underlying genetic etiologies of adrenal tumors. Pa- tients with TP53 mutations are at high risk for developing various tumors, including adrenocortical carcinoma, especially at a young- er age. Considering the significant implications of a germline TP53 mutation for both the patients and family members, genetic test- ing should be recommended for patients with adrenocortical car- cinomas [42]. In the present study, Sanger sequencing of TP53, VHL, or SDHB was performed in select patients according to their clini- cal phenotypes. Although targeted gene panel sequencing or WES was introduced recently, its widespread adoption is still limited due to its high cost.
This study is limited by its retrospective study design in a single academic center. In addition, genetic testing and immunohisto- chemical staining were not performed in all patients. Genetic test- ing was mainly performed on recently diagnosed patients, and ge- netic screening tests were not performed on the family members of some patients in our cohort.
In conclusion, children and adolescents with ACTs were diag- nosed at a relatively young age and showed a good prognosis re- gardless of the presence of a TP53 mutation. In the case of PHEO and PGLs, clinical suspicion was important when the patients man- ifested non-specific symptoms. Genetic testing in patients with ad- renal tumors is necessary to predict their clinical outcomes.
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Author Contributions
J.H.K. and J.H.C. designed the study. J.H.K., Y.C., S.H., and J.H.Y. col- lected the data, and J.H.K. analyzed and interpreted the data. J.H.C. and H.W.Y. mainly diagnosed and followed patients. G.H.K. per- formed and interpreted genetic testing. The manuscript was writ- ten by J.H.K., and J.H.C. led the study and supervised manuscript preparation. All authors reviewed and approved the final manu- script.
Fundings
This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. NRF2021R1F1A104593011).
National Research Foundation of Korea (NRF) - NR- F2021R1F1A104593011
Conflict of Interest
All authors have nothing to disclose.
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