Endocrine-Related Cancer (2003) 10 99–107
Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea C A Koch1,2, F M Brouwers1, K Rosenblatt 3, K D Burman 4, M M Davis 4, A O Vortmeyer 5 and K Pacak1 1
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Disease, Building 10, Rm 9D42, Bethesda, Maryland 20892, USA 2 Department of Endocrinology and Nephrology, University of Leipzig, Philipp-Rosenthalstr. 27, 04103 Leipzig, Germany 3 Department of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Rm 2N204, Bethesda, Maryland 20892, USA 4 Department of Endocrinology, Washington Hospital Center, 110 Irving Str NW, Washington DC 20010, USA 5 Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland 20892, USA (Requests for offprints should be addressed to C A Koch; Email:
[email protected])
Abstract Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and 131 I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34–36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor. Endocrine-Related Cancer (2003) 10 99–107
Introduction Ganglioneuroma (GN) originates from cells of the neural crest that include the sympathetic ganglia and the adrenal medulla. Therefore it is related to pheochromocytoma and neuroblastoma. The majority of GNs are thoracic; adrenal GNs are rare. At present, there are no markers that can reliably distinguish benign and malignant neuroendocrine tumors such as pheochromocytomas and neuroblastomas, although efforts in this direction have been made on the histological, immunohistochemical, biochemical, and molecular levels (Clarke et al. 1998, Brodeur et al. 2000, Koch et al. 2002a). Such a distinction is clinically important, because
malignant neuroblastoma or pheochromocytoma may be lethal. Timely diagnosis may lead to better therapeutic outcomes. We here describe a patient with an adrenal GN that has been incidentally discovered, and we discuss aspects of pathogenesis, diagnosis, and the value of potential prognostic markers for this rare tumor type.
Case report A 63-year-old female neurologist developed sudden shortness of breath and ‘non-tearing’ chest pain without any radiation during a local scientific meeting in February 2001.
Endocrine-Related Cancer (2003) 10 99–107 1351-0088/03/010–099 2003 Society for Endocrinology Printed in Great Britain
Online version via http://www.endocrinology.org
Koch et al.: Adrenal ganglioneuroma During this episode, she reportedly was not diaphoretic or tachycardic but she did have a severe headache. Her blood pressure (BP) was 240/135 mmHg. She called her primary care physician colleague and was instructed to take 40 mg propranolol instantly. She felt panic and also ingested 0.5 mg alprazolam. She then left the meeting and went home. There, her BP was 210/110 mmHg. She took another 20 mg propranolol and subsequently fell asleep. After an hour, she woke up and went to the emergency department. At that time, her BP was 130/80 mmHg and her chest pain had gone. An electrocardiogram, and cardiac enzyme and troponin levels were normal. Aortic dissection was suspected and she underwent head and chest computed tomography imaging. A left adrenal mass, 5 cm in size, was found. Abdominal magnetic resonance imaging (MRI) confirmed the adrenal mass which showed a bright signal on the T2-weighted image (Fig. 1). There was no evidence of metastases. The patient denied a history of prior chest pain episodes, diaphoresis, night sweats, recent infections, flushing, palpitations, weight changes, and recent or old thromboses. However, she reported increased nervousness and loose stools 4–5 times/ day for the last 4 months. Until this episode, she had not taken any medications and she had no allergies. Her past medical history was negative. Her family history was positive for coronary artery disease (her father died aged 75 years and was found to have a dissecting aortic aneurysm) but was negative for endocrine disorders including multiple endocrine neoplasia type 2 and von Hippel-Lindau disease. She was widowed and had three healthy sons and a healthy sister aged 59 years. She did not smoke and reported drinking half a glass of wine every day. Given the incidentally discovered adrenal mass and a suspicion for pheochromocytoma, she was referred to the Clinical Center of the National Institutes of Health (NIH) for further evaluation. On physical examination, she had no features of Cushing’s syndrome or virilization, had a BP of 130/72 mmHg on 5 mg amlodipine/day, a regular pulse of 60 beats/min, and a weight of 68 kg at a height of 157 cm. The remainder of the physical examination was within normal limits. In particular, she did not have ganglioneuromas of lips, tongue, or conjunctivae; her thyroid gland, lung, heart, abdominal, skin, and neurological examinations were normal. Laboratory evaluation revealed normal electrolytes including a plasma potassium of 4.4 mmol/l. Her creatinine clearance was 90 ml/min. Liver function tests, lactate dehydrogenase, and complete blood count were normal. In plasma, calcitonin was 8 pg/ml (normal,
