ELSEVIER
Diagnosis of adrenocortical tumor in a neonate by detection of elevated blood 17-hydroxyprogesterone measured as a routine neonatal screening for congenital adrenal hyperplasia: a case report
Tomoro Hishikia,*, Itsuro Kazukawab, Takeshi Saitoª, Keita Teruia, Tetsuya Mitsunagaª, Mitsuyuki Nakataa, Gen Matsuuraª, Masanori Minagawab, Yoichi Kohnob, Hideo Yoshidaª
aDepartment of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
bDepartment of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan
Received 15 February 2008; revised 10 May 2008; accepted 12 May 2008
Key words:
Adrenocortical tumor; Prenatal ultrasonography; Neonatal tumor;
Newborn screening; 17-Hydroxyprogesterone
Abstract
We report herein a case of prenatally detected neonatal adrenocortical tumor (ACT). The patient was an otherwise healthy newborn girl. No signs of Beckwith-Wiedemann syndrome were identified, and her family medical history did not suggest predisposition to cancer. Computed tomography and ultrasonography after birth revealed a round solid tumor 40 mm in diameter in the right suprarenal area. The precise diagnosis of ACT was unexpectedly obtained based on results from the Japanese neonatal mass screening program. Blood 17-hydroxyprogesterone is routinely measured as a part of this program for early detection of congenital adrenal hyperplasia in Japan. Abnormally elevated level of 17-hydroxyprogesterone was reported in the patient and, thus, led to the diagnosis of ACT. Surgical resection was safely performed with perioperative steroid replacement. Adrenocortical tumors are extremely rare in childhood, particularly in the neonatal period. Some of these tumors secrete abnormally high levels of cortisol, suppressing function of the contralateral adrenal gland and, thus, leading to life-threatening postoperative adrenal insufficiency. Scheduled steroid replacement enables safe perioperative management in such cases. Adrenocortical tumor should always be considered among the differential diagnoses for neonatal suprarenal mass because precise diagnosis will enable the physician to develop appropriate treatment strategies.
C 2008 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Pediatric Surgery, Chiba University Hospital, Chiba 260-8677, Japan. Tel .: +81 43 226 2312; fax: +81 43 226 2366.
E-mail address: hishiki@faculty.chiba-u.jp (T. Hishiki).
Adrenocortical tumor (ACT) of childhood is an extremely rare solid tumor that accounts for only 0.2% of all neoplasms in this age [1]. The tumor frequently secretes hormones, resulting in unique symptoms such as virilization or Cushing’s syndrome, and nonfunctional tumors are rela-
tively rare. We report herein a case of ACT in a neonate that was detected under fetal ultrasonography. Precise diagnosis of ACT was obtained by the detection of elevated blood 17- hydroxyprogesterone (17-OHP) through a neonatal mass screening program.
1. Case report
A baby girl weighing 3140 g was vaginally delivered at term. Prenatal ultrasonography at gestational week 37 had revealed a hypoechoic right suprarenal mass. This mass was homogenous and solid, containing no cystic structures. No other abnormal findings were detected. Abdominal ultra- sonography after birth confirmed the presence of the suprarenal mass, and the baby was referred to our hospital at 7 days old.
The girl was well fed and doing well. No sign of virilization was identified. There were no apparent hemi- hypertrophy or macroglossia. A small amount of acne was seen on the face. Blood pressure was normal. A solid mass with rather poor mobility and smooth surface was palpable in the right upper abdominal quadrant. Ultrasonography revealed a homogenous solid adrenal mass 40 mm in diameter. The tumor displayed slight uptake on contrast- enhanced computed tomography (Fig. 1). Urine vanilman- delic acid and homovanilmandelic acid levels were within normal ranges. Serum studies including neuron-specific enolase also yielded normal-for-age results.
While investigating the tumor, the blood 17-OHP level measured at 5 days old as a part of the Newborn Screening Program was found to be abnormally elevated. Further hormonal analysis showed elevated levels of serum 17-OHP (45 ng/ml), dehydroepiandrosterone sulfate (7510 ng/mL), testosterone (8.82 ng/ml), and aldosterone (1600 ng/ml). Daily urinary cortisol excretion was 34.7 µg/d (157.7 µg/m2
body surface area a day; normal, 25-75 µg/m2 body surface area a day). From the above findings, right functioning ACT was diagnosed. Right adrenalectomy was performed at 35 days old. A round solid tumor measuring 53 × 40 × 33 mm with a white-yellowish surface was excised en bloc with the right adrenal gland. The tumor weighed 28 g. To avoid postoperative adrenal insufficiency, we administered hydro- cortisone intravenously immediately before surgery, then gradually tapered it postoperatively. The postsurgical course was uneventful, and the girl was discharged on postoperative day 7. Dehydroepiandrosterone sulfate and 17-OHP levels rapidly normalized. Histopathologic findings showed a thin layer of normal adrenocortical tissue surrounding the tumor tissue. The tumor comprised cells with eosinophilic cytoplasm and heterogenic nuclei with pleomorphism (Fig. 2). High rate of mitosis and nuclear atypia was observed. According to the Weiss criteria [2], the histopatho- logic diagnosis was adrenocortical carcinoma. However, because the tumor was well encapsulized and completely resected, the child received no additional treatment and remains disease free after 24 months of close observation.
2. Discussion
Adrenocortical tumor in childhood is an extremely rare neoplasm with an incidence of around 0.3 per million, representing 0.2% of all childhood tumors [1]. High occurrence of ACT has been reported in southern Brazil [3]. Adrenocortical tumor is strongly associated with germ- line TP53 mutations. Adrenocortical tumor is the tumor most increased in frequency in families with Li-Fraumeni syndrome [4,5]. The Brazilian patients typically carry a unique TP53 mutation (R337H) in the oligomerization domain of the protein [6]. The mutation dramatically increases predisposition to childhood ACT but not to other cancers and explains the increased frequency of ACT
observed in this geographic region [7]. Familial medical history of the present case did not suggest a familial tumor syndrome, and we have so far not carried out a thorough screening for TP53. Children with Beckwith-Wiedemann and hemihypertrophy syndromes also are known to have a predisposition to cancer, and as many as 20% of their neoplasms is ACT [8].
In children, most ACTs are functional, with 80% to 90% having endocrine manifestations at diagnosis and up to 94% secreting excess hormones on further evaluation [7]. The most frequent symptom is virilization caused by excess androgen secretion. Less frequently, children present with Cushing’s syndrome caused by excess glucocorticoids, feminization or gynecomastia caused by excess estrogens, hypertension and hypokalemia caused by hyperaldosteron- ism, or a mixture of these symptoms [7]. The peak of first presentation is younger than 4 years old, and extremely few cases are detected during the neonatal period [9-13]. The present case lacked signs of virilization despite the remarkable increase of blood testosterone level. This suggests that the tumor in this case rapidly enlarged in the last weeks of gestation.
Precise diagnosis of an incidentally detected suprarenal tumor in a neonate based on radiographic and laboratory examinations may be difficult [14,15]. Differential diagnoses for suprarenal mass in the neonatal period include neuro- blastoma, adrenal hemorrhage, renal cystic disorders, focal renal dysplasia, pulmonary sequestrations, enteric duplica- tion cysts, and congenital mesoblastic nephroma [15]. When the patient is nearly asymptomatic, as in the present case, preoperative diagnosis of ACT depends largely on hormonal examinations. A suprarenal solid tumor accompanied by elevated levels of adrenal cortex hormones represents a clear diagnosis. However, given the rarity of the entity, these examinations are unlikely to be routinely ordered for neonatal suprarenal tumors. In the present case, elevation of these hormones was recognized through the Japanese newborn screening program. This program was initiated in 1977 for early detection of inborn metabolic or endocrino- logic disorders that are severe, frequent, and treatable [16]. Currently, screening for phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, congenital hypothyr- oidism, and congenital adrenal hyperplasia is included in the program. Health organizations in 13 countries perform newborn screening for congenital adrenal hyperplasia by measuring blood 17-OHP [17]. The rate of positive screening ranges from 15,000 to 20,000 to 1, with high sensitivity and specificity. The present case unexpectedly benefited from this screening program. For countries and areas in which 17- OHP screening is not available for neonates, we suggest adrenocortical hormone examinations if the physician sees a neonatal suprarenal tumor with uncertain diagnosis, with or without signs of virilization.
Whether a preoperative diagnosis of ACT is made may have impact on the safe management of surgical resection. Because some of these tumors secrete abnormally high levels
of endogenous cortisol constitutively, function of the contralateral adrenal gland may have become suppressed. Such suppression leads to acute corticoid deficiency post- operatively, resulting in cardiovascular collapse in the most severe cases. Patients displaying ACT with cushingoid features are, thus, routinely treated with perioperative steroid replacement [18,19]. The necessity of steroid replacement for ACT with marginal hypercortisolism without apparent clinical cushingoid symptoms remains a matter of discussion [20,21]. However, considering the life-threatening conse- quences of adrenal insufficiency in early infancy, we suggest perioperative steroid replacement to secure safe periopera- tive management for newborns with ACT.
Distinguishing an adrenal cortical adenoma from adrenal cortical carcinoma on the basis of histologic findings is often difficult, especially in children. Histologic criteria for predicting the malignant behavior of the tumor in adults have been established in the literature [2,22,23]. However, it is often the case that a child with an adrenal cortical neoplasm with apparently poor prognostic features based on adult criteria will have a good clinical outcome [24], and there is a need for histologic criteria for the pediatric population. At present, a tumor can be clearly labeled as malignant only if there is distant metastasis or apparent local invasion present at the time of presentation [12]. Histo- pathologically, the present case would be classified as an adrenocortical carcinoma based on the criteria by Weiss [2], but according to the proposed criteria of Wieneke et al [24] for children, the tumor contained only one factor that suggests malignant potential. The benefit and risk of chemotherapy for ACT in children, including mitotane (O, P’-DDD) or other chemotherapeutic agents, are still controversial [7]. Taking these into consideration, we decided not to treat the patient with adjuvant chemotherapy.
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