Adrenal Ganglioneuroma in a Patient Presenting with Severe Hypertension and Diarrhea

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

1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Disease, Building 10, Rm 9D42, Bethesda, Maryland 20892, USA 2Department of Endocrinology and Nephrology, University of Leipzig, Philipp-Rosenthalstr. 27, 04103 Leipzig, Germany 3Department of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Rm 2N204, Bethesda, Maryland 20892, USA 4Department of Endocrinology, Washington Hospital Center, 110 Irving Str NW, Washington DC 20010, USA 5Molecular 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 withincreased stool frequency. An incidental adrenal mass 5 cm in size witha brightsignal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and 131I-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 malignant neuroblastoma or pheochromocytoma may be lethal. Timely diagnosis may lead to better therapeutic out- Ganglioneuroma (GN) originates from cells of the neural comes. We here describe a patient with an adrenal GN that crest that include the sympathetic ganglia and the adrenal has been incidentally discovered, and we discuss aspects of medulla. Therefore it is related to pheochromocytoma and pathogenesis, diagnosis, and the value of potential prognostic neuroblastoma. The majority of GNs are thoracic; adrenal markers for this rare tumor type. GNs are rare. At present, there are no markers that can reliably distinguish benign and malignant neuroendocrine tumors such as pheochromocytomas and neuroblastomas, Case report although efforts in this direction have been made on the histological, immunohistochemical, biochemical, and molecular A 63-year-old female neurologist developed sudden short- levels (Clarke et al. 1998, Brodeur et al. 2000, Koch et al. ness of breath and ‘non-tearing’ chest pain without any radi- 2002a). Such a distinction is clinically important, because ation during a local scientiﬁc meeting in February 2001.

Endocrine-Related Cancer (2003) 10 99–107 Online version via http://www.endocrinology.org 1351-0088/03/010–099  2003 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 12:22:29AM via free access Koch et al.: Adrenal ganglioneuroma

During this episode, she reportedly was not diaphoretic or was normal, as were catecholamines except for fractionated tachycardic but she did have a severe headache. Her blood normetanephrine (414 µg/day; normal, 52–310) and total pressure (BP) was 240/135 mmHg. She called her primary metanephrines (537 µg/day; normal, 95–475). Plasma met- care physician colleague and was instructed to take 40 mg anephrine was 0.31 nmol/l (normal, < 0.50), normetanephrine propranolol instantly. She felt panic and also ingested 0.5 mg was 0.35 nmol/l (normal, < 0.90), epinephrine was 36 pg/ alprazolam. She then left the meeting and went home. There, ml (normal if supine, < 110), norepinephrine was 252 pg/ml her BP was 210/110 mmHg. She took another 20 mg pro- (normal if supine, < 750), and dopamine was 35 pg/ml pranolol and subsequently fell asleep. After an hour, she (normal, < 30). Recumbent plasma aldosterone was 10 ng/dl, woke up and went to the emergency department. At that time, and supine plasma renin activity was 2 ng/ml/h. The patient her BP was 130/80 mmHg and her chest pain had gone. An underwent a persantine-thallium stress test which was nega- electrocardiogram, and cardiac enzyme and troponin levels tive. A 6 mCi octreoscan was negative as was a 131I- were normal. Aortic dissection was suspected and she under- metaiodobenzylguanidine (MIBG) scan. went head and chest computed tomography imaging. A left The diagnosis of pheochromocytoma or adrenocortical adrenal mass, 5 cm in size, was found. Abdominal magnetic carcinoma was considered and a unilateral left adrenalectomy resonance imaging (MRI) confirmed the adrenal mass which was performed without complications for the 5 cm mass. showed a bright signal on the T2-weighted image (Fig. 1). Intraoperatively, the blood pressure slightly increased from There was no evidence of metastases. The patient denied a 128/60 mmgHg to 150/80 mmHg. Histopathological evalu- history of prior chest pain episodes, diaphoresis, night ation of the 5×5×4 cm grossly homogenous mass revealed a sweats, recent infections, flushing, palpitations, weight mature GN (Fig. 2). Immunohistochemistry with an antibody changes, and recent or old thromboses. However, she directed to vasoactive intestinal peptide (VIP) was positive reported increased nervousness and loose stools 4–5 times/ in ganglion cells (Fig. 3). In serial sections, there was no day for the last 4 months. evidence for a composite tumor with pheochromocytoma or Until this episode, she had not taken any medications neuroblastoma components. Plasma catecholamine levels and she had no allergies. Her past medical history was including metanephrines on postoperative day 4 were normal. negative. Her family history was positive for coronary artery The patient is no longer suffering from frequent loose stools disease (her father died aged 75 years and was found to have and is doing fine on 6-month follow-up. Her serum potassium a dissecting aortic aneurysm) but was negative for endocrine level is around 3.7 mmol/l. In retrospect, the patient reported disorders including multiple endocrine neoplasia type 2 and having undergone some emotional stress related to family von Hippel-Lindau disease. She was widowed and had three issues. healthy sons and a healthy sister aged 59 years. She did not smoke and reported drinking half a glass of wine every Loss of heterozygosity analyses day. Given the incidentally discovered adrenal mass and a Tissue was obtained under an Internal Review Board suspicion for pheochromocytoma, she was referred to the (IRB)-approved protocol at the National Institutes of Health. Clinical Center of the National Institutes of Health (NIH) After evaluating the paraffin-embedded tumor stained with for further evaluation. On physical examination, she had no hematoxylin and eosin, representative sections were prepared features of Cushing’s syndrome or virilization, had a BP of for microdissection. Under direct light microscopic visualiz- 130/72 mmHg on 5 mg amlodipine/day, a regular pulse of 60 ation using a 30-gauge needle, a modified microdissection beats/min, and a weight of 68 kg at a height of 157 cm. The procedure was performed, as previously described remainder of the physical examination was within normal (Zhuang & Vortmeyer 1998). Samples of non-tumor control limits. In particular, she did not have ganglioneuromas of tissue were also obtained from the same slides. lips, tongue, or conjunctivae; her thyroid gland, lung, heart, We performed loss of heterozygosity (LOH) analyses, abdominal, skin, and neurological examinations were normal. using the following polymorphic markers: D1S1646 Laboratory evaluation revealed normal electrolytes (mapping to 1p36.3), D1S468 (1p36.3), FGR (1p34–36), including a plasma potassium of 4.4 mmol/l. Her creatinine TP53 (mapping to 17p13.1, the p53 gene locus), in the clearance was 90 ml/min. Liver function tests, lactate dehy- presence of [32P]dCTP (0.1 µCi/µl) (Dupont, Merck Phar- drogenase, and complete blood count were normal. In maceutical Co., Wilmington, DE, USA). For all the above plasma, calcitonin was 8 pg/ml (normal, <14), corticotropin named primers, PCR conditions using AmpliTaq Gold was 10 pg/ml (normal, 9–52), dehydroepiandrosterone DNA polymerase (Perkin Elmer Roche, Indianapolis, IN, (DHEA) was 190 ng/dl (normal, 50–540), DHEA-sulfate was USA) in a Hybaid Omnigene thermal cycler were as fol- 0.46 µg/ml (normal, 0.35–4.3), thyrotropin was 0.11 µU/ml lows: initial denaturation at 95 °C for 10 min, then 35 (normal, 0.4–4.0), and free thyroxine was 1.3 ng/dl (normal, cycles, each with 1 min denaturation at 95 °C, 1 min 0.7–1.8). Twenty-four-hour urinary free cortisol excretion annealing at 57 °C, and 1 min extension at 72 °C; PCR

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(A)

Figure 1 T2-weighted MRI of the abdomen. The axial image in (A) shows an approximately 5 cm large hyperintense adrenal mass (arrow) on the left side. The coronal spiral (B) image in (B) demonstrates the vertical diameter of this mass.

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(A)

(B)

Figure 2 Hematoxylin and eosin stained sections of the adrenal mass showing mature ganglion cells (arrow) in Schwannian cell dominant stroma. (A) ×200 magniﬁcation; (B) ×400 magniﬁcation.

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(A)

(B)

Figure 3 Immunohistochemical analysis of the adrenal mass with antibodies directed to VIP. (A) magniﬁcation ×200 and (B) magniﬁcation ×400, reveal cytoplasmic staining (brown color) of the ganglion cells.

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are found in this (mostly sporadic) tumor type (reviewed in Brodeur et al. 2000). All these neural crest-derived adrenal tumors are develop- mentally related, arising from a primitive stem cell (Brodeur et al. 2000, Tischler 2000). This concept might explain why some neuroblastomas spontaneously regress or become ganglioneuromas, the more differentiated, mature form of a neuroblastoma (Carlsen 1990, Ambros et al. 1995). Approximately Figure 4 LOH analysis of the adrenal GN using polymorphic 90% of neuroblastomas produce and secrete catecholamines, markers for the chromosomal loci 1p34–36 and 17p13.1. See mainly homovanillic acid and dopamine (LaBrosse et al. text for details. T, tumor tissue; N, normal tissue. 1980, reviewed in Brodeur et al. 2000), and are positive on MIBG scanning (Geatti et al. 1985, Brodeur et al. 2000). In 35% of cases, neuroblastoma is located in the adrenal gland was completed with a final extension at 72 °C for 10 min. (n=330, National Neuroblastoma Study, Brodew et al. 2000). The amplicons were resolved on a 6% polyacrylamide gel. Symptoms are mostly related to local compression effects Gels were dried and exposed to Kodak XAR film. All caused by the tumor mass. In contrast, GNs are often disco- PCR reactions were performed in triplicate. vered incidentally and are usually located in the thorax All aforementioned markers were informative (Fig. 4): (Enzinger & Weiss 1995, Geoerger et al. 2001). In less than microdissected tumor tissue displayed heterozygosity as did 21% of cases, GNs occur in the adrenal gland (Celik et al. normal non-neoplastic tissue. 1996, Chen et al. 2000). GNs with high signal intensity on T2-weighted MRI histologically consist of a large amount of Discussion myxoid stroma and relatively few cellular and fibrous components (Zhang et al. 2001). Their size can be up to 18 cm This case of a sporadic adrenal GN illustrates several impor- (Chen et al. 2000, Leavitt et al. 2000, Geoerger et al. 2001). tant aspects of neural crest-derived adrenal tumors. These The adrenal tumor in our patient was 5 cm. Confusing in this tumors are rare and comprise pheochromocytomas, neuro- setting may be the so-called composite tumors which make blastomas, ganglioneuroblastomas, and GNs. Paragangliomas up 4% of intra-adrenal tumors and consist of pheochromocy- are extra-adrenal pheochromocytomas. Adrenal medulla, toma associated with neuroblastoma, ganglioneuroblastoma, chemoreceptors (aortic and carotid bodies), vagal body and or GN (Linnoila et al. 1990, Tischler 2000). As in our small groups of cells associated with the cervical, thoracic patient, an adrenal lesion with a bright T2-image on MRI and abdominal sympathetic ganglia belong to the paragang- might indicate a GN, pheochromocytoma, composite tumor, lion system (reviewed in Whalen et al. 1992). There are or adrenal carcinoma. Most adrenal carcinomas lead to gluc- ‘functional’, i.e. catecholamine-producing and -secreting ocorticoid and/or androgen excess, neither of which were pheochromocytomas/paragangliomas, and ‘nonfunctional’ present in our patient, in whom histopathological evaluation pheochromocytomas. Histologically, pheochromocytomas/ of the adrenal lesion clearly indicated a mature GN. paragangliomas are composed predominantly of chief cells Clinical symptoms of GNs are nonspecific and related to and sustentacular cells, whereas GNs contain ganglion cells, the location site. Despite their generally benign nature, GNs neurites, and Schwann cells. Most of these tumors are spor- may come to attention by compressing neighboring structures adic but a few are familial (Brodeur et al. 2000, Koch et al. (Hayes et al. 1989, Geoerger et al. 2001). Our patient had 2002b, Neumann et al. 2002). The molecular pathogenesis normal catecholamine levels and presented with nonspecific of sporadic adrenal tumors remains largely unknown chest pain, hypertension, and a history of diarrhea. Less than (Brodeur et al. 2000, Reincke et al. 2000, Koch et al. 2002c). 30% of patients have elevated plasma and urinary cat- By contrast, in hereditary adrenal tumors, one defect is echolamine levels but rarely symptoms of catecholamine known from birth on the inherited gene mutation or deletion. excess (Schuman et al. 1984, Lucas et al. 1994, Geoerger et Subsequent genetic changes may then more easily be put into al. 2001). MIBG uptake is less common (57% of cases) than the context of tumor formation, as recently demonstrated in in patients with neuroblastomas (92%) (Geoerger et al. multiple endocrine neoplasia type 2 (MEN 2)-related tumors 2001). In general, MIBG positivity is mainly determined by and von Hippel-Lindau-associated pheochromocytoma an active sodium-and chloride-dependentprocess via the cell (Bender et al. 2000, Huang et al. 2000, 2003, Koch et al. membrane norepinephrine transporter, called Uptake 1. 2001). Although there are reports on familial neuroblas- False-negative MIBG scans can result from concomitant tomas, linkage analyses did not reveal a defined gene locus administration of certain medications including antihyperten- (Maris et al. 1996), leaving the pathogenesis of neuroblas- sive drugs such as labetalol and calcium channel blockers, toma widely unknown despite the fact that many genetic all of which should be discontinued at least 2 weeks before alterations including LOH on numerous chromosomal loci performing MIBG scanning (Khafagi et al. 1989, Solanki et

104 Downloaded from Bioscientifica.comwww.endocrinology.org at 09/29/2021 12:22:29AM via free access Endocrine-Related Cancer (2003) 10 99–107 al. 1992). The lower rate of MIBG uptake in GNs might be In addition to these molecular findings, our patient’s GN due to their histological composition. GNs are composed of was positive for VIP which is the product of ganglion cells ganglion cells, neurites, Schwann cells, and fibrous tissue, as (Hansen et al. 1980, Salmi et al. 1988). (Increased) VIP shown in our patient (Fig. 2). Immature elements such as expression in GNs and neuroblastomas correlates with a neuroblasts, which can easily take up MIBG (Kimmig et al. more favorable prognosis (Lacey et al. 1989, Qualman et al. 1984, Leung et al. 1997), are not part of a mature GN. If 1992). Large amounts of VIP secretion from neuroendocrine neuroblasts are present, the tumor is called ganglioneuroblas- tumors may cause severe watery diarrhea (Said & Faloona toma, an intermediate lesion between the rather mature GN 1975, Kaplan et al. 1980, El Shafie et al. 1983). In our and rather immature/less differentiated neuroblastoma patient, it remains unclear whether the adrenal GN secreted (Shimada et al. 1999a,b). GNs are Schwannian stroma- sufficient amounts of VIP to explain the patient’s rather dominant tumors (Katsetos et al. 1994, Shimada et al. recent history of increased frequency of loose stools, 1999a,b). Some investigators believe that Schwann cells although the cessation/discontinuation of these symptoms arrive in neuroblastomas by migrating into the tumor and are after removal of the adrenal GN is suggestive of VIP involve- able to inhibit proliferation by inducing the differentiation of ment. On the other hand, patients with VIP-positive tumors neuronal/ganglion cells (Ambros et al. 1996). such as GNs and neuroblastomas may not have any symp- In neuroblastoma, LOH is found on many chromosomal toms or signs of VIP secretion (Kogner 1995). GNs can also loci including deletions in the short arm of chromosome 1 produce and secrete other hormones such as testosterone, (1p36) which for a long time has been believed to contain a indicating the pluripotency of its precursor cell (Mack et al. tumor suppressor gene important in malignant transformation 1978, Aguirre & Scully 1983). (Huang et al. 2001, reviewed in Brodeur et al. 2000). Exten- Taken together, in our case of a 63-year-old woman with sive but unsuccessful attempts to identify a ‘neuroblastoma an incidentally discovered adrenal GN showing a bright gene’ on 1p36 may indicate that involvement of 1p36 is asso- signal on T2-weighted MRI, we interpret our combined find- ciated with tumor progression rather than initiation. This ings of no LOH on chromosomal loci 1p34-36 and 17p13, view is also supported by 1p36 LOH being associated with negative biochemical and scintigraphic evaluation, positive poor prognosis (Ambros et al. 1995, Caron et al. 1996). VIP immunohistochemistry, and histopathological evaluation There are apparently two groups of neuroblastomas: one with indicating a mature GN, as favorable prognostic markers. LOH of 1p36 which is combined with less favorable prognosis and another without LOH of this locus and with good prognosis. In our patient with an adrenal GN, we did not References detect LOH at 1p34–36 with the informative polymorphic Aguirre P & Scully RE 1983 Testosterone-secreting adrenal markers used. This might indicate that the GN was patho- ganglioneuroma containing Leydig cells. American Journal of genetically related to and possibly preceded by a neuroblas- Surgical Pathology 7 699–705. toma without 1p36 LOH. This further suggests that this locus Ambros PF, Ambros IM, Strehl S, Bauer S, Luegmayr A, Kovar may not be involved in tumorigenesis of this tumor type, if H, Ladenstein R, Fink FM, Horcher E & Printz G 1995 a tumor suppressor gene is held to be causative. If LOH at Regression and progression in neuroblastoma. Does genetics 1p36 were associated with tumor progression as stated above, predict tumour behaviour? European Journal of Cancer 31A investigation for LOH at this locus becomes important when 510–515. Ambros IM, Zellner A, Roald B, Amann G, Ladenstein R, Printz one considers that there are less mature tumor forms such as D, Gadner H, & Ambros PF 1996 Role of ploidy, chromosome ganglioneuroblastomas, the diagnosis of which may often be 1p, and Schwann cells in the maturation of neuroblastoma. New missed by histopathological evaluation of only selected sec- England Journal of Medicine 334 1505–1511. tions of the specimen. Bender BU, Gutsche M, Glasker S, Muller B, Kirste G, Eng C & Inactivation of TP53 is known to occur in more than Neumann HP 2000 Differential genetic alterations in von 50% of all human cancers (Hollstein et al. 1991). Because Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. Journal of Clinical Endocrinology and genetic alterations of p53 are frequently found in adrenal Metabolism 85 4568–4574. tumors and have not been studied in ganglioneuroma (Vogan Brodeur GM, Sawada T, Tsuchida Y & Voute PA 2000 et al. 1993, Reincke et al. 1994, Koch et al. 2002c), we Neuroblastoma, 1st edn. Amsterdam, The Netherlands: Elsevier screened our patient’s adrenal GN for allelic loss on 17p13.1, Science. the locus for p53. We did not detect LOH, suggesting that Carlsen NL 1990 How frequent is spontaneous remission of this locus also might not be involved in tumor formation or neuroblastomas? Implications for screening. British Journal of progression. 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