Adrenal ganglioneuroma

MYCN Promotes the Expansion of Phox2B-Positive Neuronal Progenitors to Drive Neuroblastoma Development

Disclosure: G. Umarji: None. K. Desai: None. N.V. Kagita: None. M. Stezzi: None. S.A. Jabbour: None.Adrenal ganglioneuromas constitute <2% of all adrenal incidentalomas. Ganglioneuromas belong to the neuroblastic group of tumors. They originate from sympathetic ganglia, including the adrenal medulla, and are benign. A 23-year-old female was referred to endocrinology for a workup of an adrenal incidentaloma discovered during an emergency room visit for abdominal pain. CT scan of the abdomen with contrast reported a right 3.7 x 2.5 x 3 cm adrenal nodule without any further details. History was significant for intermittent palpitations, for which she reduced her caffeine intake. She denied sweating, pallor, easy bruising, weakness, and unintentional weight changes. Abdominal pain had resolved, which was thought to be from irritable bowel syndrome (IBS). Past medical history included class 3 obesity, cholelithiasis, migraine, and IBS. There was no history of hypertension and hypokalemia and no family history of adrenal disorders. Vital signs were BP 128/84 mmHg, HR 70 beats/min, and body mass index (BMI) 45.35 kg/m2. Physical examination was significant for moon facies, slight dorsocervical hump with no skin atrophy or wide violaceous striae. Hormonal workup was as follows: Plasma-free metanephrines - 10.7 pg/mL (0-88), plasma normetanephrine - 30.9 pg/mL (0-210.1), 24-hour urine-free cortisol - 36 microg/24h (6-42). Magnetic Resonance Imaging (MRI) of the abdomen with and without contrast showed 4.2 x 2.8 cm heterogenous R adrenal nodule, the posterior aspect of the mass demonstrated heterogenous increased T2-weighted signal posteriorly with mildly hypointense signal anteriorly. Opposed phase imaging was restricted due to respiratory motion artifact. The patient underwent a robotic-assisted laparoscopic radical right adrenalectomy. Pathology showed a 5.7 cm adrenal ganglioneuroma, extending beyond the adrenal into the peri-adrenal adipose tissue. Tumor cells were positive for S100, Neurofilament and focally for synaptophysin, predominantly in ganglion cells. Ganglioneuroma (GN) is a rare tumor comprised of ganglion cells and Schwannian stroma. 21% of GN can be seen in the adrenal glands. Adrenal GN are more commonly seen in females. They are hormonally silent but sometimes can produce catecholamines. The gold standard for diagnosis is histological features, including mature, large neuronal ganglion cells in a Schwannian stroma. Immunohistochemical staining is positive for S-100, vimentin, synaptophysin, and neuron-specific enolase. We present a fascinating case of adrenal incidentaloma in a young female that turned out to be an adrenal ganglioneuroma.Presentation: Monday, July 14, 2025

Introduction: Ganglioneuromas are benign, well differentiated tumors arising from the sympathetic nervous system. However, they arise rarely in the adrenal glands. Ganglioneuroma (GN) is a very rare (0-6% of incidentalomas) tumor that arises from sympathetic ganglion/ chain and is made of mature ganglion cells, schwann cells, neurites and nerve fibers. Most cases of adrenal ganglioneuromas are incidentally diagnosed since they are mostly asymptomatic and produce symptoms rarely due to compression of neighboring structures. case report: We hereby present a rare case of an adult female patient presented with pain in abdomen diagnosed with a non-secretory adrenal mass who underwent laparoscopic excision of the mass. she was finally diagnosed on pathological examination to be an adrenal ganglioneuroma, one of the very rare tumors reported in literature. conclusion: Adrenal ganglioneuromas occur rarely and difficult in diagnosing preoperatively since symptoms vary and are mostly nonspecific. Ganglioneuroma should not be missed as a differential diagnosis of an adrenal mass. Histopathologic examination plays a crucial role in diagnosis.

Adrenal ganglioneuroma is a very rare tumour of sympathetic nervous system that originate from neural crest sympathogonia which are completely undifferentiated cells of the sympathetic nervous system, constituting 20 to 30% of all Ganglioneuromas (GNs). GNs are generally asymptomatic and usually do not secrete hormones and most often detected incidentally on routine imaging tests during work up. The tumour could cause some complications, if it becomes large enough to press against the adjacent organs. Ganglioneuroma generally present as solitary mass which are painless and grow slowly. The common sites of GN are posterior mediastinum (41%), retroperitoneum (37%), adrenal gland (21%) and neck (8%). Histopathologically, ganglioneuroma is entirely composed of ganglion cells and schwannian stroma and does not contain neuroblasts, intermediate cells or mitotic figures. Preoperative diagnosis of GNs is difficult and cannot be made on radiological findings alone, thus histopathological examination is required in order to confirm the diagnosis of GN. Adrenal ganglioneuroma is a rare sympathetic tumour which originated from adrenal medulla. Prognosis is good after removal of the tumour, adjuvent therapy is not required and there is no recurrence. This report is of a rare case of adrenal ganglioneuroma in a 66-year- old male from Bihar came with complaints of bipedal oedema for seven days, white coloured urine and burning pain during micturition for three months. The patient was evaluated for chyluria, routine investigations were normal but ultrasound and Computed Tomography (CT) scan of abdomen revealed non-specific solitary right adrenal mass measuring 44.8×38.2 mm. Biochemical investigations showed increased catecholamines and metanephrines in plasma. The excised mass was sent for histopathological examination which showed features of adrenal ganglioneuroma and same was confirmed by immunohistochemistry.

Expression of Acetylcholine and Its Receptor in Human Sympathetic Ganglia in Primary Hyperhidrosis

Nerve growth factor promotes the survival of populations of sensory and sympathetic neurons. Although ganglia have been used for classical assays of neurotrophin action, knowledge is incomplete regarding the spatial arrangements through which neurotrophins are delivered to responsive cells within the ganglia and their attached nerve trunks. Whereas populations of ganglionic neurons may be capable of responding to a particular neurotrophin in vitro, the spectrum of receptor components and neurotrophins expressed by the various neuronal and nonneuronal cells comprising the ganglia in adult rats remains to be elucidated in vivo. Brain-derived neurotrophic factor (BDNF) mRNA was expressed by a population of small to medium sized neurons in all sensory ganglia except in the mesencephalic nucleus of the trigeminal nerve. Interestingly, BDNF immunoreactivity was detected in a more widespread population of neurons of these ganglia, as well as in scattered satellite cells of both sensory and sympathetic ganglia. These nonneuronal cells also expressed mRNA encoding a truncated form of the BDNF receptor, trkBtrunc, and full-length transcripts of trkB appeared to be confined to neuronal populations. Several other components of neurotrophin receptors (low-affinity neurotrophin receptor, trk, and trkC) were prominently expressed by different populations of neuronal cells in sympathetic and sensory ganglia, but they were not detected in nonneuronal cells. Neither nerve growth factor nor neurotrophin-3 mRNAs were detected in these ganglia. Unexpectedly, BDNF and trkBtrunc expression was detected in oligodendrocytes myelinating the central processes of sensory neurons. Schwann cells did not express detectable quantities of either entity, thereby establishing a dramatic boundary delineated by neurotrophin/neurotrophin receptor expression that coincided with the interface between the oligodendroglia of the central nervous system (CNS) and Schwann cells of the peripheral nervous system (PNS). Localization of BDNF expression to an additional population of nonneuronal cells--satellite cells within sensory and sympathetic ganglia--suggest a more extensive role for neurotrophic factors than originally encompassed by the target-derived neurotrophic-factor-concept paradigm. These data support the hypothesis of a possible autocrine or paracrine trophic interaction between populations of neuronal and nonneuronal cells in the peripheral nervous system. BDNF expression in oligodendrocytes but not in Schwann cells at the CNS/PNS junction may provide an additional means of maintaining cell-appropriate connections in the nervous system.

Dorsal migration and formation of the secondary, permanent chain of sympathetic ganglia as revealed by confocal time-lapse analysis in chick

Satellite glial cells in sympathetic and parasympathetic ganglia: In search of function

Involvement of the peripheral nervous system (PNS) is relatively common in some neurodegenerative proteinopathies of the brain and may be pathogenetically and diagnostically important. In Parkinson's disease, neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin. The pathological process may target the PNS and CNS at the same time. In multiple system atrophy, numerous glial cytoplasmic inclusions composed of filamentous alpha-synuclein are widely distributed in the CNS, while alpha-synuclein accumulation is minimal in the sympathetic ganglia and is restricted to neurons. Neurofibrillary tangles can occur in the sympathetic and spinal ganglia in tauopathy, although they appear to develop independently of cerebral Alzheimer's disease pathology. In amyotrophic lateral sclerosis, neuronal loss with TDP-43-positive neuronal cytoplasmic inclusions in the spinal ganglia is more frequent than previously thought. Peripheral ganglia and visceral organs are also involved in polyglutamine diseases. Further elucidation and characterization of PNS lesions will have implications for intravital biopsy diagnosis in neurodegenerative proteinopathy, particularly in Parkinson's disease.

Sympathetic neurons and endocrine chromaffin cells of the adrenal medulla are catecholaminergic cells that derive from the neural crest. According to the classic model, they develop from a common sympathoadrenal (SA) progenitor that has the ability to differentiate into both sympathetic neurons and chromaffin cells depending on signals provided by their final environment. Our previous data revealed that a single premigratory neural crest cell can give rise to both sympathetic neurons and chromaffin cells, indicating that the fate decision between these cell types occurs after delamination. A more recent study demonstrated that at least half of chromaffin cells arise from a later contribution by Schwann cell precursors. Since Notch signalling is known to be implicated in the regulation of cell fate decisions, we investigated the early role of Notch signalling in regulating the development of neuronal and non-neuronal SA cells within sympathetic ganglia and the adrenal gland. To this end, we implemented both gain and loss of function approaches. Electroporation of premigratory neural crest cells with plasmids encoding Notch inhibitors revealed an elevation in the number of SA cells expressing the catecholaminergic enzyme tyrosine-hydroxylase, with a concomitant reduction in the number of cells expressing the glial marker P0 in both sympathetic ganglia and adrenal gland. As expected, gain of Notch function had the opposite effect. Numbers of neuronal and non-neuronal SA cells were affected differently by Notch inhibition depending on the time of its onset. Together our data show that Notch signalling can regulate the ratio of glial cells, neuronal SA cells and nonneuronal SA cells in both sympathetic ganglia and the adrenal gland.

Invited Commentary

Morphological, physiological and pharmacological evidence indicates that opioid peptides, which in the brain are located intraneurally, may function as neurotransmitters. Similar evidence is not yet available for the opioid peptides that are stored in chromaffin cells of adrenal medulla and in axon terminals located in adrenal medulla and sympathetic ganglia. The present report contributes evidence suggesting that the opioid peptides which are stored in the axon terminals of the splanchnic nerves located in adrenal medulla may function as neuromodulators of the acetylcholine receptors located on chromaffin cells that are involved in catecholamine release. We support this functional role of the opioid peptides by showing that primary cultures of chromaffin cells of bovine medulla contain opiate receptors. When these receptors are occupied by specific agonists, the number of nicotinic receptors and the amount of catecholamine released by maximal doses of nicotine are reduced. Thus, like in other neuronal systems also in adrenal medulla, the action of opioid peptides is inhibitory. The specificity of this action is in part supported by the inability of opiate receptor agonists to reduce the Ca2+-dependent release of catecholamines elicited by K+ ions.

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. We report two pediatric patients, one with MEN2A and one with MEN2B, who developed isolated adrenal ganglioneuromas without evidence of pheochromocytomas. 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. 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.

Adrenal ganglioneuroma (AGN) is an extremely rare, benign tumor that originates from the neural crest tissue of the sympathetic nervous system. The majority of cases are detected incidentally, since the disease often lacks clear clinical manifestations or is asymptomatic. In addition, AGN is often misdiagnosed as being an adrenal adenoma or adrenal pheochromocytoma. The present study describes a 58-year-old female who visited the outpatient clinic of the Affiliated Hospital of Guangdong Medical College (Zhanjiang, Guangdong, China) with symptoms of face and lower extremity dropsy. Color Doppler ultrasonography revealed a solid tumor in the right kidney, and abdominal computed tomography identified an irregular, solid tumor measuring ~6×4.5×7 cm3 and arising from the right adrenal gland, with a clear boundary. Magnetic resonance imaging was not performed. An initial diagnosis of adrenal adenoma was established. The patient was treated by laparoscopy in order to remove the tumor. However, following surgery, a pathological examination suggested that the tumor was a GN originating from the adrenal medulla. The formation of a correct diagnosis can be extremely challenging, as AGNs do not exhibit any specific clinical manifestations. Therefore, detection often depends entirely upon imaging studies, and the final diagnosis can be only by confirmed following a histopathological evaluation.

Tissue samples of adrenal ganglioneuromas were obtained from two patients: 35- and 47-year-old males. Light microscopic studies showed that these tumors contained Schwann cells and ganglion cells. Electron microscopic examinations revealed numerous unmyelinated and myelinated axons surrounded by Schwann cells. The ganglion cells in the tumors had abundant organelles, such as well-developed cisternae of the rough endoplasmic reticulum, many profiles of the Golgi apparatus, mitochondria, lysosomes, microtubules and neurofilaments. Electron dense cored granules resembling catecholamine granules were present in the ganglion cell bodies and neural processes. These features resmebled those of normal sympathetic ganglion cells. It is concluded that adrenal ganglioneuroma originates from sympathetic ganglion tissue.