Patient Report

Childhood pheochromocytoma in a survivor of central primitiveneuroectodermal tumor

Yoshiko Nakano,1* Rika Fujimaru,1* Keiichi Ishii,2 Hiroaki Sakamoto,3 Takeshi Inoue,4 Masahiro Sako5 and Hiroshi Yamada1

Departments of 1Pediatrics, 2Urology, 3Pediatric Neurosurgery, 4Pathology and 5Pediatric Hematology/Oncology, Osaka CityGeneral Hospital, Osaka, Japan

Abstract Pheochromocytoma and central nervous system primitive neuroectodermal tumor are both neural crest-derived tumors.The former is usually benign and develops mainly in adulthood and the latter brain tumor mainly occurs in childhoodand has a poor prognosis. We report a case of a 15-year-old boy who developed pheochromocytoma after more than 10years of complete remission of central primitive neuroectodermal tumor. Thus far, there have been no reports ofchildhood cancer survivors who developed pheochromocytoma. This quite rare occurrence of two tumors in a singlepatient may imply some unidentified linkage or common genetic background.

Key words hypertension, neural crest, pheochromocytoma, primitive neuroectodermal tumor.

Pheochromocytoma and central nervous system primitive neur-oectodermal tumor (CNS-PNET) are rare conditions and thereare no previously reported syndromes associated with both ofthese diseases. Here, we report a case of pheochromocytoma thatoccurred in a survivor of CNS-PNET.

Case Report

A 9-month-old boy presented to our hospital because of vomitingand abnormal eye movements. He showed no congenital anomalyor sings of familial tumor, including café-au-lait spots. Magneticresonance imaging (MRI) revealed a mass containing cystic areasand calcification in the suprasellar region (Fig. 1a). Brain tumorwas suspected and subtotally removed. Histopathological exami-nation revealed small round primitive tumor cells positive forneuron-specific enolase and synaptophysin, which confirmed thediagnosis of PNET (Fig. 1b). Initial MRI also revealed a small,well-circumscribed lesion (approximately 1.5 ¥ 1.5 cm) in the leftkidney, which was suspected to be metastasis. The patient receivedchemotherapy and high-dose chemotherapy with autologousstem cell rescue. Chemotherapy drugs used were intrathecal-methotrexate, carboplatin, pirarubicin, etoposide, ifosfamide, thi-otepa and melphalan. He did not receive radiation therapy becauseof his age. Ten months later, he achieved complete remission.Follow-up MRI did not show any lesions in the brain or kidney.Resultant panhypopituitarism was treated with steroid hormone,

levothyroxine, and desmopressin. Although he had mild intellec-tual disability, he otherwise remained well without relapse.

When he was 13 years old, mild viral enterocolitis causedsevere adrenal crisis with cardiopulmonary arrest. He was resus-citated successfully at our emergency department, but developedsevere anoxic brain damage and became bedridden. Afterward,mild hypertension was noticed, which was attributed to braindamage. Antihypertensive medication was prescribed and noprecise study on hypertension was performed.

Two years later, he was admitted to our hospital for diarr-hea, vomiting, and a tense abdomen with markedly elevatedC-reactive protein (19.8 mg/dL) and high white blood cell count.Physical examinations revealed mild non-focal tenderness in theabdomen. He was neither febrile nor dyspneic. On admission,his blood pressure was 136/74 mmHg, taking enalapril andamlodipine. Because of gastrointestinal symptoms, oral intake,including antihypertensive medications, was restricted. Subse-quently his blood pressure rose to 180/120 mmHg. For theabdominal symptoms, peritonitis or appendicitis was suspectedand enhanced computed tomography of the abdomen revealed anunexpected right adrenal mass of 6 cm in diameter (Fig. 2a). Themass was well defined, and pheochromocytoma was suspected.His fasting serum glucose concentration was 153 mg/dL andhemoglobin A1c was 6.6% (Japan Diabetes Society). Urinaryexcretion of fractionated metanephrines (normal range: 0.15–0.41 mg/24 h), catecholamines (normal range: 37–150 mg/24 h),and vanillylmandelic acid (normal range: 1.2–4.9 mg/mg creati-nine) were 19.08 mg/24 h, 11 900 mg/24 h, and 103.7 mg/mg cre-atinine, respectively. 123I-metaiodobenzylguanidine scintigraphyshowed increased uptake of the right adrenal tumor, and galliumscintigraphy and MRI revealed no metastasis. These findingswere consistent with pheochromocytoma. Anti-hypertensivetreatment was changed to the a-blocker, doxazosin. Blood

Correspondence: Yoshiko Nakano, MD, Department of Pediat-rics, Osaka City General Hospital, 2-13-22, Miyakojima-Hondori,Miyakojima, Osaka 534-0021, Japan. Email: nakanolp@gmail.com

*These authors contributed equally to this work.Received 30 June 2012; revised 18 November 2012; accepted 19

February 2013.

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Pediatrics International (2013) 55, e100–e102 doi: 10.1111/ped.12074

© 2013 The AuthorsPediatrics International © 2013 Japan Pediatric Society

pressure was stabilized at 100–120/70–90 mmHg. Hyperglyc-emia, as a complication of pheochromocytoma, was treated withinsulin. The tumor was successfully excised by laparotomy.Laparoscopic surgery was not possible because of tight adhesionof the tumor with adjacent tissues, including liver and inferiorvena cava. The excised tumor measured 7.5 ¥ 4.2 ¥ 3.5 cm andwas well capsulated. Histological examination confirmed prolif-eration of neoplastic cells arranged in a nested, zellballen growthpattern (Fig. 2b). No necrosis, mitosis, or vascular invasion wasfound. The immunostaining for synaptophysin was positive,while MIB-1 was negative. S100 was positive only in sustentacu-lar cells. These findings confirmed the benignancy of the tumor.The postoperative course was uneventful. His blood pressure andglucose returned to normal range with no medication. Urinemetanephrine concentration fell to normal within 1 month. Hehas been in complete remission for 15 months.

Discussion

To the best of our knowledge, this is the first case report ofpheochromocytoma and PNET occurring in a single patient.

Pheochromocytoma is a neural crest-derived tumor, whichmostly originates from chromaffin cells of the adrenal medulla.They usually occur as benign tumors in adults but about 10% aremalignant and 10–20% of them occur in children.1,2 Secretedcatecholamines are responsible for the clinical signs and symp-toms of pheochromocytomas and hypertension is the most impor-tant presenting sign. CNS-PNET, which also develops fromneural crest lineage, usually arises during the first decade of lifeand its prognosis is poor.3 The prevalence of pheochromocytomais 2/1 000 000 in pediatric patients, and the prevalence of PNETis much less.1–3 Therefore, the occurrence of these tumors in thesame patient is an exceedingly rare condition.

(a) (b)(a) (b)

Fig. 1 (a) Enhanced magnetic resonance imaging shows a cystic mass with calcification in the suprasellar region. (b) Histopathologicalexamination confirmed pheochromocytoma (hematoxylin–eosin stain, ¥400).

(a)(a) (b)(b)

Fig. 2 (a) Computed tomography shows a right-sided pheochromocytoma (arrow). (b) Histopathological examination confirmed pheochro-mocytoma (hematoxylin–eosin stain, ¥400).

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© 2013 The AuthorsPediatrics International © 2013 Japan Pediatric Society

About 10–20% of pheochromocytomas are familial andusually occur as a component of von Hipple–Lindau diseasesmultiple endocrine neoplasia type 2 or neurofibromatosis type 1,caused by mutations of the VHL gene, RET gene, or NF1 gene,respectively.2,4 In addition, the SDHB and SDHD genes encodingthe B and D subunits of succinate dehydrogenase, also known asmitochondrial complex II, have been reported to be associatedwith pheochromocytoma.5 Furthermore, 10% of patients withsporadic pheochromocytoma have been reported to have muta-tion in the four susceptible genes described above.6 In addition,neurofibromatosis 1, which is related to neurofibromin, is alsorelated to pheochromocytoma. Although there is one publicationdescribing a 7-year-old boy in a family with VHL disease whopresented with PNET, common genetic abnormality of pheochro-mocytoma and PNET has not been reported.7 The present casehas no particular family history associated with inherited neo-plastic syndromes and has not been tested for genetic alterationyet. Future elucidation of tumor-associated genes may help tounderstand the etiology of this case.

Histological study of the tumor excised found no malignancy,but a diameter exceeding 6 cm itself is known to be a risk factorfor malignancy. The long-term prognosis of the patient is notcertain in this case and he should be followed up closely forrecurrence and even other malignancy.8,9

As a clinical lesson, the present case reminded us of theimportance of pheochromocytoma as a differential diagnosis ofchildhood hypertension, even in a complicated case. Pheochro-mocytoma accounts for about 1% of pediatric hypertension.10

Although his verbal inability hampered our understanding ofsymptoms associated with pheochromocytoma, in the future weshould monitor his blood pressure with caution. Considering thesize of the tumor and its adhesion to adjacent tissues, it mayalready have been there for several years without our realizing.

In conclusion, we report a rare case of pheochromocytomaoccurring in a survivor of PNET. Although both are neural

crest-derived tumors, whether these tumors have any commongenetic background related to tumorigenesis remains unknown.

References

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2 Young WF. Pheochromocytoma in Children. 2012. [Cited 10August 2011.] Available from URL: http://www.uptodate.com

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4 Bausch B, Borozdin W, Mautner VF et al. Germline NF1 muta-tional spectra and loss-of-heterozygosity analysis in patients withpheochromocytoma and neurofibromatosis type 1. J. Clin. Endo-crinol. Metab. 2007; 92: 2784–92.

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6 Neumann HP, Bausch B, McWhinney SR et al. Germ-line muta-tions in nonsyndromic pheochromocytoma. N. Engl. J. Med. 2002;346: 1459–66.

7 Becker R, Bauer BL, Mennel HD, Plate KH. Cerebellar primitiveneuroectodermal tumor with multipotent differentiation in a familywith von Hippel-Lindau disease: Case report. Clin. Neuropathol.1993; 12: 107–11.

8 Goldstein RE, O’Neill JA, Jr, Holcomb GW, 3rd et al. Clinicalexperience over 48 years with pheochromocytoma. Ann. Surg.1999; 229: 755–64.

9 Pham TH, Moir C, Thompson GB et al. Pheochromocytoma andparaganglioma in children: a review of medical and surgical man-agement at a tertiary care center. Pediatrics 2006; 118: 1109–17.

10 Wyszynska T, Cichocka E, Wieteska-Klimczak A, Jobs K,Januszewicz P. A single pediatric center experience with 1025children with hypertension. Acta Paediatr. 1992; 81: 244–6.

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