Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2526
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4383-4387
Copyright © 2005 by The Endocrine Society
Adrenal Ganglioneuromas in Children with Multiple Endocrine Neoplasia Type 2: A Report of Two Cases
Melissa S. Lora,
Steven G. Waguespack,
Jeffrey F. Moley and
Emily C. Walvoord
Department of Pediatrics, Section of Endocrinology and Diabetology, Indiana University School of Medicine, Riley Hospital for Children (M.S.L., E.C.W.), Indianapolis, Indiana 46202; Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center (S.G.W.), Houston, Texas 77030; and Department of Surgical Endocrinology and Oncology, Washington University School of Medicine (J.F.M.), St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Dr. Emily C. Walvoord, 702 Barnhill Drive, Room 5960, Indianapolis, Indiana 46202. E-mail: ewalvoor{at}iupui.edu.
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Abstract
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Context: Pheochromocytomas of the adrenal gland are a common component of the multiple endocrine neoplasia type 2 (MEN2) syndromes. However, pure adrenal ganglioneuromas, an extremely rare pediatric tumor of neural crest origin composed of mature ganglion cells, have never been reported in association with MEN2 in humans. MEN2A is comprised of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN2B is characterized by MTC, pheochromocytoma, neural abnormalities of the gastrointestinal tract, and mucosal neuromas.
Evidence Acquisition: We report two pediatric patients, one with MEN2A and one with MEN2B, who developed isolated adrenal ganglioneuromas without evidence of pheochromocytomas.
Evidence Synthesis: MEN2A and MEN2B are caused by activating mutations in the RET proto-oncogene, which encodes a tyrosine kinase receptor essential for signal transduction in neural crest-derived tissues, including the peripheral and enteric nervous systems, C cells of the thyroid gland, and chromaffin cells of the adrenal gland. Both pheochromocytomas and ganglioneuromas originate from neural crest cells. Interestingly, two mouse models of MEN2B exhibit adrenal ganglioneuroma formation. One mouse model develops only ganglioneuromas (but not pheochromocytomas) and expresses only one of the oncogenic RET isoforms. The other mouse model, created by site-directed mutagenesis to simulate the most common human mutation, develops both ganglioneuromas and pheochromocytomas.
Conclusions: Given our two cases, our current understanding of the mouse models, and the common origins of all these tumor cell types, we recommend including ganglioneuromas as a rare, but not unexpected, component of the MEN2 syndromes.
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Introduction
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BOTH OF THE multiple endocrine neoplasia type 2 (MEN2) syndromes result from gain of function point mutations in the RET proto-oncogene. RET encodes a tyrosine receptor kinase widely expressed in developing neural crest cells. The MEN2A syndrome is composed of medullary thyroid carcinoma (MTC), hyperparathyroidism, and pheochromocytoma. MEN2B consists of MTC and pheochromocytomas, with the additional features of mucosal and intestinal ganglioneuromatosis and Marfanoid features (1). All of the tissues affected are of neural crest origin.
We report two children, one with MEN2A and one with MEN2B, who, upon removal of an adrenal mass suspected to be a pheochromocytoma, were found instead to have ganglioneuromas. Ganglioneuromas, benign tumors of the sympathetic ganglia or adrenal medulla (2), have never been reported in children with the MEN2 syndromes. What makes these reports particularly interesting is that two mouse models of MEN2B also develop adrenal ganglioneuromas (3, 4), thus lending some insight into the potential mechanisms by which these tumors develop. We suggest that ganglioneuromas should be considered as a rare, but not unexpected, finding in patients with the MEN2 syndromes.
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Case 1
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A 6-yr-old girl presented initially with multiple small nodules on her tongue. Upon excision, they were found to be mucosal neuromas. She was then noted to have enlargement of the left lobe of the thyroid gland without a palpable mass and several enlarged, mobile submandibular nodes. Ultrasound of the neck revealed heterogeneous echogenicity of the thyroid tissue with multiple calcified areas and multiple enlarged lymph nodes. A basal serum calcitonin level was 850 pg/ml (248.7 pmol/liter; normal range, 2–17 pg/ml). Urinary fractionated catecholamines, metanephrines, and vanillylmandelic acid levels were normal. The patient underwent a total thyroidectomy with central neck dissection. Pathological examination showed a multifocal MTC, with the largest focus being 1.8 cm. Metastatic tumor was found in nine of 16 lymph nodes removed. PCR amplification of peripheral blood DNA revealed a heterozygous point mutation in codon 918 of exon 16 of the RET proto-oncogene, consistent with the diagnosis of MEN2B. There was no prior family history of MEN2B, so it appeared that the patient had a de novo mutation.
One month after surgery, the serum calcitonin level decreased to 38 pg/ml (11.1 pmol/liter), and the serum carcinoembryonic antigen level was normal at 1.2 ng/ml (1.2 µg/liter; normal range, 0–2.5 ng/ml). Six months after thyroidectomy, the patient’s unstimulated calcitonin level had risen to 66 pg/ml (19.3 pmol/liter). A neck ultrasound at that time did not reveal any enlarged lymph nodes. She was referred to another center for a modified radical neck dissection. Six of 49 lymph nodes removed were positive for MTC.
Two and a half years after her thyroidectomy, the patient’s unstimulated calcitonin level had risen to 235 pg/ml (68.8 pmol/liter). A computed tomography (CT) scan of the abdomen revealed a 4.0 x 3.3 x 2.4-cm, hypodense, nonenhancing mass anterior to the superior portion of the left kidney contiguous with the left adrenal fossa (Fig. 1
). The plasma normetanephrine levels were normal at 0.53 nmol/liter (normal range, 0–0.89) as were the plasma metanephrine levels at 0.21 nmol/liter (normal range, 0–0.49). However, because of the patient’s known history of MEN2B, the size of the mass, and the likelihood that it still represented a pheochromocytoma, the patient was presumptively treated preoperatively with phenoxybenzamine for 
-adrenergic blockade, and a laparoscopic partial left adrenalectomy was performed. Pathology revealed a mature ganglioneuroma without evidence of pheochromocytoma (Fig. 2).
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FIG. 1. Case 1. CT scan of the abdomen revealing the ganglioneuroma located anterior to the superior portion of the left kidney.
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FIG. 2. Case 1. Light microscopy shows the ganglioneuroma, composed of scattered ganglion cells recognized by their abundant eosinophilic cytoplasm, eccentric vesicular nuclei, and prominent nucleoli (arrows). Schwann cells with spindled nuclei are seen in the collagenous background (hematoxylin and eosin stain).
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Case 2
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An 11-yr-old boy was evaluated for suspected MEN2A after his brother was identified to have MTC and a C634R mutation in the RET proto-oncogene. His mother had also been diagnosed with MTC at the age of 11 yr, and she was found to have bilateral pheochromocytomas at the age of 42 yr. Genetic analysis confirmed a C634R mutation in the patient, and he proceeded to have diagnostic studies in preparation for total thyroidectomy. An initial thyroid ultrasound showed a 5.5-mm thyroid nodule and an unstimulated calcitonin level of 44.7 pg/ml (13.1 pmol/liter; normal range, 0–11.5 pg/ml). A 24-h urine collection for vanillymandelic acid, homovanillic acid, and plasma metanephrines was normal. He had no symptoms of catecholamine excess. However, an abdominal CT revealed a hypodense, 7 x 6.4-cm mass with coarse foci of calcification in the right suprarenal fossa; the tumor displaced the inferior vena cava anteriorly (Fig. 3). An [131I]metaiodobenzylguanidine ([131I]MIBG) study demonstrated uptake within the adrenal mass (Fig. 4). Under the assumption that he had a pheochromocytoma, the patient was given blockade, and he underwent resection of the tumor. The resection was subtotal (estimated 90%) due to adherence of the mass to the inferior vena cava. During the surgery, a small portion of normal-appearing adrenal gland was identified within the mass. Upon pathological review, the tumor was confirmed to be a ganglioneuroma, maturing subtype, with one microscopic focus of immature neuroblastic cells; one abdominal lymph node also showed mature ganglioneuroma. A few months later, the patient had a total thyroidectomy, which revealed two microscopic foci of MTC, one in each lobe. To date, the patient has had normal follow-up calcitonin and carcinoembryonic antigen levels and no ultrasonographic evidence of residual or recurrent MTC. Eighteen months after resection of the ganglioneuroma, there has been no gross recurrence on CT imaging, although long-term monitoring is planned due to the subtotal resection.
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FIG. 3. Case 2. CT of the abdomen showing the hypodense right adrenal mass with coarse foci of calcifications.
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Discussion
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The MEN2 syndromes are autosomal dominant diseases comprised of MTC and pheochromocytoma. Parathyroid hyperplasia also occurs in MEN2A, whereas a Marfanoid body habitus, neural abnormalities of the gastrointestinal tract, and mucosal neuromas occur in MEN2B. MEN2A and MEN2B are caused by activating mutations in the RET proto-oncogene. Located on chromosome 10, the RET gene codes for a tyrosine kinase receptor that is essential for intracellular signal transduction in neural crest-derived tissues, including the peripheral nervous system, enteric nervous system, C cells of the thyroid gland, and chromaffin cells of the adrenal gland (4).
Approximately 50% of patients with MEN2A and MEN2B develop pheochromocytomas (5). Pheochromocytomas are tumors that produce catecholamines and are located in the sympathoadrenal system. Most arise from the chromaffin cells in the adrenal medulla (in a background of diffuse adrenal medullary hyperplasia in MEN2 syndromes), but pheochromocytomas may also be found in the ganglia of the sympathetic nervous system or in the paraganglia adjacent to the aorta (6), in which case they are termed paragangliomas. Clinical findings are due to the release of catecholamines from the tumor and classically include paroxysmal or persistent hypertension resistant to treatment, headache, diaphoresis, and palpitations (7). Interestingly, pheochromocytomas in MEN2 are distinct from other heritable pheochromocytomas (such as seen in von Hippel-Lindau syndrome), in that subjects have more of an adrenergic phenotype secondary to predominant epinephrine production from the tumor (8). Nearly all pheochromocytomas present after the onset of puberty, although they have occurred in patients with codon 634 mutations as early as 5 and 10 yr of age (1). Biochemical abnormalities include elevated plasma and urinary catecholamines and metanephrines and an increase in the ratio of urinary epinephrine to norepinephrine (5, 9). Tumors may be identified or confirmed by CT scan, magnetic resonance imaging, or uptake of [123I]- or [131I]MIBG (5). Typical features of pheochromocytoma on CT scan may include focal areas of necrosis and calcification (6).
The patients in the current report developed ganglioneuromas, with no evidence of pheochromocytomas. Ganglioneuromas are rare tumors, with an approximate incidence of 1 case/million·yr in the United States for children under the age of 15 yr, with the median age at diagnosis being 7 yr (10). These tumors originate from neural crest cells in the sympathetic ganglia or adrenal medulla and represent the most differentiated form of neuroblastic tumor in the spectrum of neuroblastoma-ganglioneuroblastoma-ganglioneuroma (2). They occur in the posterior mediastinum, retroperitoneum, adrenal glands, and neck. Only about 20% of ganglioneuromas occur in the adrenal gland (10). Ganglioneuromas may arise primarily or may differentiate from neuroblastomas or ganglioneuroblastomas, tumors that have both ganglioneuroma and neuroblastoma elements. Histological examination of a ganglioneuroma reveals ganglion cells, Schwann cells, neurites, and fibrous tissue (11).
On imaging studies, ganglioneuromas are relatively homogeneous, encapsulated tumors with well-defined borders that do not invade adjacent structures (2, 10). They contain calcium in 40–60% of the cases (10). Although many ganglioneuromas have no metabolic activity, increased catecholamine secretion and MIBG uptake may occur, with 57% of tumors accumulating MIBG in one study (11). Most ganglioneuromas are asymptomatic and are discovered incidentally through imaging studies, although some may present due to compressive symptoms. The prognosis is very good with surgical removal of the tumor.
Differentiating ganglioneuromas from pheochromocytomas in children can be difficult. On unenhanced CT, ganglioneuromas appear as well-circumscribed homogenous masses that have a lower attenuation than that of muscle. As seen in case 2, calcification may be identified in many cases (12). Similar to pheochromocytoma, these neoplasms can have a bright signal on T2-weighted magnetic resonance images (12, 13). Consequently, imaging characteristics may not reliably distinguish ganglioneuroma from pheochromocytoma or other tumors of ganglion cell origin (14). Although ganglioneuromas do not concentrate the radionucleotide metaiodobenzylguanidine ([123I]- or [131I]MIBG) as well as neuroblastomas or pheochromocytomas, as previously noted, nearly 60% of ganglioneuroma cases can show some uptake with MIBG. Additionally, excessive catecholamine secretion may or may not be present in ganglioneuroma. The degree of tumor catecholamine secretion and MIBG uptake may be related to the extent of immature elements within the tumor (11). Therefore, although some clinical characteristics (or the lack thereof) may suggest the diagnosis of ganglioneuroma, there does not appear to be a single reliable imaging modality or biochemical test that will accurately differentiate a ganglioneuroma from a neuroblastoma or pheochromocytoma (13).
It is frequently difficult to differentiate benign from malignant adrenal tumors. In adult patients, National Institutes of Health consensus guidelines suggest that adrenal lesions less than 4 cm can safely be observed (15). However, in children, a much higher proportion of adrenal tumors are malignant; thus, it is recommended that all adrenal masses discovered in children more than 3 months of age be removed, because neither size nor imaging characteristics are useful discriminators (16).
Pure ganglioneuromas have never been reported in a patient with MEN2A or MEN2B. Although tumor cells were found in a lymph node in case 2, we do not believe that this represents malignant spread, suggesting that the tumor was actually a ganglioneuroblastoma, because regional lymph nodes may contain islands of tumor cells attributed to matured neuroblasts in association with ganglioneuromas (17). Additionally, at the time of resection, pathology was most consistent with a ganglioneuroma, maturing subtype, according to the currently used classification scheme (18). The benign nature of the ganglioneuroma in case 2 is also supported by the lack of recurrence or identification of metastasis after 18 months of follow-up.
There have been two reports of adult patients with MEN2A who developed composite tumors of the adrenal gland, containing elements of pheochromocytoma and ganglioneuroma, ganglioneuroblastoma, or neuroblastoma. One 49-yr-old man died with symptoms due to catecholamine excess after an orthopedic operation (19). Autopsy examination revealed metastatic MTC and an adrenal tumor that was found to have elements of both pheochromocytoma and ganglioneuroblastoma. Analysis of DNA from peripheral blood showed a cysteine to arginine mutation in codon 634 of exon 11 of the RET proto-oncogene, consistent with a diagnosis of MEN2A. Another patient, a 34-yr-old man with a known diagnosis of MEN2A, presented for evaluation of symptoms of catecholamine excess (20). Magnetic resonance imaging revealed two masses within the left adrenal gland that also exhibited increased uptake of radionucleotide on MIBG scintigraphy. The patient also had elevated levels of urinary catecholamines. Gross examination of the left adrenal gland showed a 1.6-cm medullary nodule and two smaller medullary nodules. Pathologic examination and immunohistochemical staining of the large nodule demonstrated both pheochromocytoma and ganglioneuroma.
Interestingly, two mouse models of MEN2B exhibit ganglioneuroma formation (3, 4). The first was a transgenic mouse model developed using the human dopamine ß-hydroxylase (DßH) promoter to induce the expression of RETMEN2B in the sympathetic and enteric nervous systems and adrenal chromaffin cells in mice. All of the transgenic mice were found to have neuroglial hyperplasia of the sympathetic ganglia and neuroglial proliferation in the adrenal gland histologically identical with human ganglioneuroma. The animals had no evidence of pheochromocytoma. The unexpected occurrence of ganglioneuromas in the adrenal glands of the DßH-RETMEN2B mice was postulated to be due to either differences in the timing of expression of the gene based on the DßH promoter activity in mice vs. humans or differential expression levels of the known RET isoforms.
Two major isoforms of the RET protein have been identified (21). Formed through alternative mRNA splicing, these isoforms differ in the length of the C-terminal domains, resulting in short (nine amino acids) and long (51 amino acids) RET isoforms, called RET9 and RET51, respectively. Both are oncogenic in fibroblasts and cause neuronal differentiation in rat pheochromocytoma PC12 cells to varying degrees. However, the two isoforms, particularly when associated with the MEN2B mutation, have distinct biological activities. RET51 is a powerful inducer of neuronal differentiation, whereas RET9 causes only weak neurite extension in PC12 cells (22). In fact, RET51 is six to seven times more powerful at promoting neurite differentiation compared with RET9. Interestingly, only RET9 is expressed in these DßH-RETMEN2B mice (3).
The second mouse model of MEN2B was generated using the Cre/loxP technique to introduce a site-directed Met919Thr mutation (equivalent to the human Met918Thr mutation) into the mouse ret gene (4). Mice homozygous for the Met919Thr mutation developed C cell hyperplasia, pheochromocytomas, and ganglioneuromas. These ganglioneuromas appeared to develop in adjacent sympathetic ganglia and then invade the adrenal glands. Heterozygous mice had milder phenotypes with less frequent C cell hyperplasia, rare pheochromocytomas, and no ganglioneuroma formation. The mechanism of ganglioneuroma formation in this model is also unclear, but may be due to altered differentiation or survival of sympathoadrenal precursor cells. Interestingly, the ganglioneuromas in this model seemed to develop first in the retroperitoneum, a common location for ganglioneuroma formation in humans as well (10), with subsequent extension into the adrenal gland.
Our patients represent the first reported cases of noncomposite ganglioneuromas occurring in association with the MEN2 syndromes in humans. Although the composite tumors previously reported in the two adults with MEN2A contained both chromaffin and ganglion cell types, raising the possibility that these tumors had a different origin than the tumors reported here, all of these tumors (pheochromocytomas and neuroblastic tumors) arise from neural crest derivatives (23). Therefore, a causative role of activating RET mutations in the pathogenesis of ganglioneuromas in our patients is not proven, it is possible that under specific circumstances in patients with MEN2, other adrenal cells of neural crest origin, in addition to chromaffin cells, may be affected by activating RET mutations.
This discovery is especially fascinating when considering the occurrence of ganglioneuromas in the mouse models of MEN2B. The fact that the DBH-RETMEN2B transgenic mice expressed only RET9 and developed ganglioneuromas may indicate that greater expression of RET9 in MEN2 is necessary for the phenotypic expression of ganglioneuroma in humans. Because RET51 is a powerful inducer of neuronal differentiation in the pheochromocytoma PC12 cells, relative underexpression of RET51 may explain the absence of development of pheochromocytoma in the transgenic mouse model of MEN2B. Additional investigation of the biochemical roles of the RET isoforms in the development of ganglioneuroma and pheochromocytoma is necessary to fully understand the role of RET in the phenotypic expression of MEN2A and MEN2B in humans. Given our two cases, our current understanding of the mouse models, the common origins of all of these tumor cell types, and the two composite tumors reported previously in MEN2A patients, we would recommend including ganglioneuromas as a very rare, but not unexpected, component of the MEN2 syndromes.
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Acknowledgments
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We acknowledge the pathological expertise of Dr. Kimberley Crone in reviewing the pathology slides of case 1 and the excellent clinical care provided to the patient in case 2 by Drs. David Bliss, Benjamin Carcamo, Carla Scott, and Michael Willcutts.
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Footnotes
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First Published Online April 12, 2005
Abbreviations: CT, Computed tomography; DßH, dopamine ß-hydroxylase; MEN2, multiple endocrine neoplasia type 2; MIBG, metaiodobenzylguanidine; MTC, medullary thyroid carcinoma.
Received December 23, 2004.
Accepted April 5, 2005.
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Abstract
Introduction
