Case Report
Hiroko Narumi, Shunji Hasegawa*, Kazuyuki Waki, Ken Fukuda, Yuji Ohnishi,
Takuya Ichimura, Yousuke Fujimoto, Shunsaku Katsura, Hiroo Kawano, Eiji Ikeda,
Satoshi Okada and Shouichi Ohga
Non-androgen secreting adrenocortical carcinoma in preadolescence: a case report and literature review
DOI 10.1515/jpem-2016-0145
Received April 13, 2016; accepted August 29, 2016; previously published online October 24, 2016
Abstract: Adrenocortical carcinoma (ACC) is a rare malig- nancy in childhood. Affected children with ACC mostly present with virilization, but not the pure form of Cush- ing’s syndrome. A 9-year-old Japanese girl was hospital- ized, because of the unstable emotions and excessive weight gain. She was diagnosed as having Cushing’s syn- drome and a left adrenal tumor. The adrenalectomy led to the pathological diagnosis of ACC without metastasis. There was no mutation of PRKACA in the tumor-derived DNA, or p53 in peripheral blood-derived DNA. Testoster- one and dehydroepiandrosterone sulfate (DHEA-S) levels were normal throughout the clinical course. On the other hand, these levels were elevated in all five reported cases of preadolescent ACC children with isolated Cushing’s syndrome. The exceptional secretory behavior of ACC gave a diagnostic precaution of the rare pediatric cancer.
Keywords: adrenocortical carcinoma; children; Cushing’s syndrome; PRKACA gene; p53 gene.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant tumor in the adrenal gland. The estimated incidence of ACC in children is 0.3 patients per million per year [1]. ACC is a poor prognostic disease, often involving the somatic and germline mutation of cancer-susceptible genes. Approximately 90% of children with ACC show endocrine function in contrast to the adult cases. Virili- zation is the most common presentation in ACC patients, however, only 5.5% of patients show isolated Cushing’s syndrome [2]. On the other hand, the patients with adrenal adenoma exhibit Cushingoid symptoms alone. Recently, it has been reported that patients with unilat- eral cortisol-producing adrenal adenomas have somatic PRKACA [protein kinase A (PKA) catalytic subunit] gene mutations [3]. A part of patients with ACC have the muta- tion of the p53 gene [2].
We herein report a 9-year-old girl with ACC, who was initially diagnosed as having Cushing’s syndrome because of no clinical or subclinical evidence of virilization.
*Corresponding author: Shunji Hasegawa, MD, PHD, Department of Pediatrics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan,
Phone: +81-836-22-2258, Fax: +81-836-22-2257, E-mail: shunji@yamaguchi-u.ac.jp
Hiroko Narumi, Kazuyuki Waki, Ken Fukuda, Yuji Ohnishi, Takuya Ichimura, Yousuke Fujimoto and Shouichi Ohga: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
Shunsaku Katsura: Division of Pediatric Surgery, Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
Hiroo Kawano and Eiji Ikeda: Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
Satoshi Okada: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
Case presentation
A 9-year-old Japanese girl was hospitalized because of emotional instability and weight gain with excessive appetite. She had no familial history of carcinoma and endocrine diseases. She suffered from bronchial asthma, which was controlled by leukotriene receptor antagonist without inhaled corticosteroid.
On admission, her height and weight were 131.5 cm (± 0 SD) and 29.8 kg (+0.1 SD) [body mass index (BMI) 18.0 kg/m2, 75% tile], respectively. The non-obese girl showed the reduced growth rate, but the rapidly increased body weight in these 6 months. She had Cushingoid symptoms including moon face, acne, hirsutism, and emotional
instability. She was diagnosed as having Cushing’s syn- drome. Tanner stages were B2 and PH1. The bone age was 10.5 years. There was no evidence of virilism. Complete blood counts and serum chemistries were unremarkable. Throughout the day, serum cortisol levels were high [24.0 ug/dL, reference range (rr): 4.9-11.7 ug/dL], and serum ACTH levels were low (<1.0 pg/mL, rr: 7.2-63.3 pg/mL). The levels of catecholamine, thyroid hormone and adrenal androgen were normal. Dexamethasone suppression test indicated that the cortisol levels were unrestrained. An abdominal ultrasound (Figure 1A), contrast-enhanced computed tomography (CT) (Figure 1B), and magnetic resonance imaging (MRI) showed a 30 mm × 30 mm tumor in the left adrenal gland. Positron emission tomography (PET) showed abnormal uptake in the same region (SUV max 2.5) (Figure 1C).
Left adrenalectomy was performed under the diag- nosis of left cortisol-secreting adrenocortical tumor. The removed tumor was a marginal and smooth mass, in total measuring 30×24x30 mm and weighing around
11 g (Figure 2A). A microscopic examination revealed atypical cells with pleomorphic atypic nuclei, promi- nent nuclei, and eosinophic cytoplasm. There was no evidence of necrosis, vascular invasion or sinusoidal invasion, but the capsular invasion of small amounts of tumor cells (Figure 2B, C). The pathological diagnosis was ACC with 6/9 of the Weiss criteria, 3/9 of the Weineke criteria, and 14% of MIB labeling index. Mitotane was started as adjuvant chemotherapy, but stopped for the adverse events including neutropenia, elevated y-GTP level, irritation and auditory hallucination. She is alive and well with growth recovery on the steroid replace- ment. There was neither recurrence nor metastasis of ACC 2 years after operation.
The immunohistochemical analysis showed that tumor cells were strongly positive for steroidogenic factor-1 (SF-1), and negative for dehydroepiandrosterone sulfotransferase (DHEA-ST). No mutation was identified in the PRKACA gene (exon 6-8) in the tumor-derived DNA, or the p53 gene in peripheral blood-derived DNA.
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Discussion
The present patient showed pure Cushingoid symptoms, but not virilization or subclinical increase of circulating androgen levels. Cushing’s syndrome caused by cortisol- producing adrenal tumor rarely occurs in children [4, 5]. ACC has been found in pediatric patients presenting with cortisol-producing adrenal tumor and virilization, but not Cushingoid manifestations [2, 6]. In contrast, patients with the pure form of Cushing’s syndrome exclusively have adrenocortical or pituitary adenomas. The early dis- crimination between ACC and adrenal adenoma is critical for the distinct outcome.
There have been several reports of pediatric ACC with isolated Cushing’s syndrome. Table 1 summarizes all five preadolescent cases [1, 6, 10-12]. Four patients suc- cessfully received adrenalectomy prior to the metastasis, and one patient with advanced stage (patient 4) died 1 month after surgery. All patients showed elevated levels of testosterone (5 of 5 patients) or dehydroepiandroster- one sulfate (DHEA-S) (4 of 4 examined patients) at diag- nosis. However, our patient showed normal testosterone and DHEA-S levels. The immunohistochemistry of the tumor cells were strongly positive for SF-1 and negative for DHEA-ST. SF-1 is a major regulator of cholesterol metabo- lism in steroidogenic cells, as it stimulates the expression of nearly all the factors involving cholesterol mobilization and steroid hormone biosynthesis [13]. It is expressed in
both normal and abnormal human adrenal cortex [14]. No SF-1 expressions were reported in the carcinomas from other origins, such as kidney, liver, and adrenal medulla [14]. SF-1 is a valuable marker for the differential diagnosis of adrenocortical tumors versus other endocrine tumors [13]. These results suggest that the tumor of our patient was derived from the adrenal gland. DHEA-ST catalyzes the conversion of dehydroepiandrosterone (DHEA) to DHEA-S in the adrenals [15]. DHEA-ST is often expressed in ACC, and induces the elevation of DHEA-S levels [15]. These findings were consistent with her absent virilization and normal androgen levels.
Several genetic abnormalities associated with adrenal tumor have been reported [3, 11, 13, 16-20]. The mutation of the p53 gene is estimated to occur in 80-90% of all pediatric adrenocortical tumors [11]. This muta- tion leads to an abnormal folding of the TP53 protein and accumulation in the nucleus; loss of heterozygosity at this locus is though to be involved in tumorigenesis [19, 20]. In a study evaluating the penetrance, 10% of 240 carriers of this constitutional mutation developed adrenocortical tumors [19]. Beushlein et al. revealed that somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas [3]. The PRKACA gene encodes the PKA catalytic subunit. Sato et al. [17] reported the mechanism that PRKACA mutation induces corticotropin-independent Cushing’s syndrome. The PRKACA mutation (p.L206R) abolished its binding to
| Age/Sex | Endocrinological dataª | Tumor | Familial cancer/ Genetic test | Treatment | Outcome | Ref. | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cortisol, µg/dL | DHEA-S, µg/dL | Testosterone, ng/dl | Site | Size, mm | Volume, g Metastasis | |||||
| 1 2.5 month/M | 230 (2.8-23ª) | 596 (20-95ª) | 504 (60-400a) | Rt | 75×55×20 | nd No | No/nd | Adrenalectomy chemotherapy (mitotane) | Alive, 15 years | 1 |
| 2 3 month/M | 1.240 (4.5-22.7ª) | 251 (16-96ª) | 185 (6-77ª) | Rt | 32 ×24×25 | 20 No | No/p53(-) | Adrenalectomy | Alive, 6 month | 10 |
| 3 6 month/F | 240 (4.5-22.7ª) | 401 (16-96ª) | 185 (6-77ª) | Rt | 52×40×35 | 43 No | No/p53 (-) | Adrenalectomy | Alive, 30 month | 11 |
| 4 ≥ 5 years/F | Normal | Increased | Increased | nd | nd | nd No | nd/nd | Adrenalectomy | Death, 1 month | 12 |
| 5 7 years/M | nd | 1.080 (35-430a) | nd | Rt | nd | nd Liver | nd/nd | Adrenalectomy rt. lobectomy | Alive, 116 month | 6 |
| 9 years/F | 24.0 (4.9-11.7a,b) | 22 (75.6-159.0ª,b) | ≤ 0.03 (<20a,b) | Lt | 30×24×30 | 11 No | No/PRKACA (-), p53 (-) | chemotherapy Adrenalectomy | Alive, 2 years | Ours |
aNormal range; breferences [7-9]; nd, not described.
PRKARIA, the regulatory subunit of PKA. The inhibited catalytic activity of PRKACA leads to constitutive, cAMP- independent PKA activation [17]. The cAMP-independent activation of cAMP/PKA signaling by somatic mutations resulted in corticotropin-independent cortisol production [17]. According to the previous reports, PRKACA mutation was detected in 35-52% of adrenocortical adenomas [3, 16, 17]. In 82 patients with the other types of adrenal tumors (including 42 patients with ACC), this mutation was not detectable [3]. Specimens of ACC from our patient had no mutations of the PRKACA gene (exon 6-8). It remains unclear for the relationship between adrenal tumors and PRKACA gene mutation. Further genetic studies are needed to clarify the tumorigenesis and clinical behavior of the non-androgen secreting ACC.
In addition to PRKACA and p53 genes, adenomatous polyposis coli (APC), regulatory R1A subunit of protein kinase A (PRKARIA) and protein kinase A (PKA) genes were reportedly involved in the pathophysiology of adren- ocortical tumor [21-23]. We have a limitation in this report, because the genetic predispositions other than PRKACA and p53 were not searched for this patient.
We first report a preadolescent case of ACC lacking the androgen secretion. There were no mutations in PRKACA in the tumor cells and p53 genes in the peripheral blood, respectively. Considering the review of all pediatric cases, normal androgen levels may hamper early diagnosis of the rare pediatric malignancy.
Acknowledgments: We thank to Drs. Maiko Shimomura (Department of Pediatrics, Yamaguchi University Gradu- ate School of Medicine), Takashi Iwai, and Yuichi Ishi- kawa (Division of Pediatrics, Yamaguchi-ken Saiseikai Shimonoseki General Hospital) for management. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Hiroko Narumi, Shunji Hasegawa, and Shouichi Ohga were the princi- pal investigators taking primary responsibility for the paper. Kazuyuki Waki and Ken Fukuda confirmed the clinical and laboratory data. Kazuyuki Waki, Ken Fukuda, Takuya Ichimura, Yousuke Fujimoto, and Yuji Ohnishi supported the clinical study with helpful discussions. Shunsaku Katsura performed surgical intervention. Hiroo Kawano and Eiji Ikeda performed pathological examina- tion. Satoshi Okada performed the genetic tests. Hiroko Narumi and Shunji Hasegawa wrote the first draft of the manuscript.
Research funding: None declared. Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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