The clinical spectrum of adrenal ganglioneuromas extends from severe hypertension to an asymptomatic incidentaloma. Two cases and mini review of literature.

The clinical spectrum of adrenal ganglioneuromas extends from severe hypertension to an asymptomatic incidentaloma. Two cases and mini review of literature. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The clinical spectrum of adrenal ganglioneuromas extends from severe hypertension to an asymptomatic incidentaloma. Two cases and mini review of literature. Efstratios Kardalas, George Kyriakopoulos, Vasiliki Antonopoulou, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5775520/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 May, 2025 Read the published version in Hormones → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose . Herein, we present two interesting cases of adrenal ganglioneuromas: a) a giant adrenal ganglioneuroma, which provoked a severe episode of hypertension during a therapeutic dilation and curettage for early pregnancy loss and b) a case of a composite clinically silent adrenal ganglioneuroma-pheochromocytoma. Furthermore, we conducted a mini literature review on adrenal ganglioneuromas. Case 1. A 31-year-old female patient presented with a history of early pregnancy loss at 9 ½ weeks. She underwent a therapeutic dilation and curettage during which she developed hypertension (~ 210/120 mm Hg). She reported no history of arterial hypertension, flushing or tachycardia, and her medical history was unremarkable. Further work-up, revealed a large heterogeneous tumor with microcalcifications in the left adrenal gland. Endocrine work-up was negative for hormonal excess. Magnetic resonance angiography (MRA) of the abdomen showed that the tumor was ‘surrounding and strangling’ the left renal vessels and the inferior vena cava. The patient underwent successfully an open left adrenalectomy and nephrectomy. Histology revealed an adrenal mature ganglioneuroma with schwannian stroma as dominant. Her postoperative course was uneventful and she remains recurrence-free six years after her surgery. Case 2. A 37-year-old male patient was admitted to the hospital because of abdominal pain and haematuria. Computer tomography identified a 4-cm right adrenal lesion. Due to elevated urinary metanephrines he underwent laparoscopic right adrenalectomy, after appropriate alpha-blockade preparation preoperatively. Histology was consistent with pheochromocytoma with a component of ganglioneuroma, thus a composite pheochromocytoma. His post-operative course was excellent and he remains asymptomatic and recurrence-free 60 months post-operatively. Conclusion. These are two challenging cases of a) a giant non-secreting adrenal ganglioneuroma presenting with severe hypertension due to renal vessels’ compression and b) a clinically silent composite pheochromocytoma-ganglioneuroma presenting with abdominal pain and hematuria. The size in the first case and the concurrence with a pheochromocytoma but a clinically silent phenotype in the second one, highlight the fact that adrenal ganglioneuromas can be diagnostic chameleons. adrenal ganglioneuroma hypertension pheochromocytoma composite Schwannian cell Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Highlights The clinical presentation has a broad spectrum from an asymptomatic incidentaloma to a composite pheocromocytoma-ganglioneuroma tumor and functioning syndromes They may part of genetic syndromes Imaging characteristics are not pathognomonic and diagnosis is based on histology Treatment is complete surgical excision The probability of recurrence is low and distant metastases have rarely been reported Lifelong surveillance is imperative for composite pheochromocytoma-ganglioneuromas Introduction Ganglioneuromas (GNs) are rare, benign tumors which arise from the neural crest tissue of sympathetic nervous system [ 1 ]. They are composed of Schwannian cells covered with maturing or fully mature ganglion cells. They may be localized in locations associated with sympathetic nervous tissue more frequently in the retroperitoneum, mediastinum and the adrenal glands and rarely in the head and neck [ 2 ]. The incidence of adrenal GNs (AGNs) is approximately 3.5% of adrenal incidentalomas [ 3 ]. The majority are asymptomatic and hormonally inactive and are discovered serendipitously while the rest may cause abdominal discomfort secondary to mass effect [ 4 ], [ 5 ]. Their imaging phenotype can vary widely and usually it is characterized by large size, unenhanced CT attenuation > 20 HU, calcifications and lobulated shape [ 6 ], [ 7 ]. Histopathology is the cornerstone for their diagnosis [ 8 ]. A subset of AGNs present as composite tumors with pheochromocytomas[ 4 ] [ 9 ]. Association with hereditary familial syndromes, such as Neurofibromatosis 1 and 2 (NF1) and (NF2) [ 9 ], [ 10 ], Multiple Endocrine Neoplasia (MEN) 2 [ 11 ], [ 12 ], [ 13 ], MAX mutation related syndrome [ 14 ],[ 15 ], Von Hippel-Lindau (VHL)[ 16 ] and Succinate Hydrogenase Deficiency (SHD)[ 17 ] has been reported. The objectives of this paper are 1) to present two interesting cases of adrenal ganglioneuromas. The first one concerned a giant AGN which provoked severe hypertension while on contrary the second case presented as an asymptomatic incidentaloma, thus showing the variability of their clinical spectrum and 2) to offer a mini review of the current literature for these rare benign tumors and highlight potential pitfalls in their management. Case Presentations Case 1 A 31-year-old female patient was referred to the Emergency Department due to resistant arterial blood pressure (~ 190/100 mm Hg). A few hours ago she had developed high blood pressure (~ 210/120 mm Hg) during dilation and curettage, following an early pregnancy loss at 9 ½ pregnancy weeks in another hospital. An urgent computer tomography (CT) of the abdomen ( Fig. 1 ) had showed a lobulated abdominal mass ~ 15–17 cm, with microcalcifications and an unenhanced attenuation > 20 HU arising from the left adrenal gland. The patient was admitted to the Endocrine Department for further diagnostic work-up. On admission, she was hypertensive and reported mild headaches, during the last 3–6 months. She reported no flushing, diaphoresis and palpitations and her past medical history was unremarkable. Her pregnancy had been spontaneously interrupted at 9 ½ weeks, thereby she subsequently underwent dilation and curettage. Her family history was positive for diabetes mellitus and arterial hypertension. She denied smoking or drinking alcohol. Thorax X-ray, as well as an electrocardiogram, were normal. Routine laboratory and urine tests provided normal results. Endocrine work up was negative for cortisol excess but her renin and aldosterone levels were elevated (Table 1 ). Table 1 Endocrine work up for patient 1. Cortisol (n.v 5–25) (µg/dl) 17 DHEAS (n.v 100–340)(µg/dl) 108 ACTH (n.v 10–50) (pg/ml) 35 Δ4-androstendione (n.v 1-2.5) (ng/ml) 1.9 Urinary Free Cortisol (UFC) (n.v 10–136 (µg/24hr) 46 17-hydroxyprogesterone (n.v 0.2-3) (ng/ml) 1.54 Overnight dexamethasone suppression test (n.v < 1.8) 0.6 Testosterone (n.v 9–55) (ng/dl) 26 Plasma renin activity (n.v 0.7–3.3) (ng/ml/hr) 29.66 Urinary fractionated metanephrines (n.v 52–341) µg/24hr 103/57 Aldosterone (n.v 7–30) (ng/dl) 45.4 Urinary fractionated normetanephrines (n.v 88–244) µg/24hr 255/526 The patient’s 24-h urine metanephrine levels were within the normal range (103/57 mcg/24 h, n.v. < 341, but slightly increased normetanephrine levels (255/526 mcg/24 h n.v 88–244) were noticed on one occasion. She had normal Chromogranin-A level (2.7 ng/ml, n.v < 4 ng/ml) and slightly elevated levels of Neuron-Specific Enolase (NSE) and Ca-125 tumor markers (22 ng/ml n.v < 6.3 ng/ml and 44 U/ml, n.v. <35 U/ml respectively). Further preoperative imaging work-up via magnetic resonance angiography (MRA) of the abdomen revealed that the tumor was ‘surrounding and strangling’ the left renal vessels and the inferior vena cava. The tumor was heterogenous and hypointense on T1-weighted images and did not demonstrate significant signal loss on T1-out of phase weighted images which was a sign of poor lipid content. ( Fig. 2 ) . Because of the discrepant normetanephrine results and the fact that the patient had resistant hypertension, we decided to treat her preoperatively with alpha and beta-blockade to a final dose of 100 mg phenoxybenzamine and 50 mg of propranolol. 10 days after her admission to the hospital she was successfully submitted to an open left adrenalectomy and nephrectomy without complications. Histology showed that most adrenal tissue was replaced by tumor (weighing more than 1.5 Kgs), which was composed of mature ganglion and Schwann cells ( Fig. 3 ). No atypia or mitotic activity was observed, while Ki-67 was 1–2%. An immunohistochemical examination showed positive staining of the ganglion and Schwann cells for S-100 ( Fig. 4 ). Thus, the tumor was diagnosed as a left adrenal maturing ganglioneuroma with dominant Schwanian stroma. Postoperative course was uneventful, even though the patient had to be closely monitored initially in the intensive care unit and then at the surgical department for a whole period of 20 days. The patient has remained asymptomatic and normotensive and no recurrence has been detected during a follow up period of 6 years. Case 2 A 37-year-old male patient was admitted to our hospital following an episode of right-side renal colic-like pain, accompanied by hematuria. Abdominal CT revealed the presence of a 4-cm lesion in the right adrenal gland, rich in microcalcifications with an unenhanced attenuation > 20 HU. Relative percentage washout following contrast enhancement was < 40%. On admission, the patient did not mention any headaches or excessive sweating. No clinical signs or symptomatology relevant to hormonal excess could be identified. The patient had no history of tachycardia, hypertension, headache, flushing, diaphoresis. His past medical history was uneventful, besides the fact that his was heterozygote for beta thalassemia minor. He had a positive family history for dyslipidemia and arterial hypertension. Both thoracic radiography and electrocardiogram were normal. Routine laboratory and urine tests provided normal results. Hormonal evaluation showed normal values of morning cortisol, ACTH, normal urinary free cortisol (UFC) and adequate suppression after an overnight dexamethasone suppression test. A normal aldosterone-to renin ratio was calculated. Surprisingly both 24-h urine metanephrine and normetanephrine levels were elevated. NSE and Ca-125 tumor markers were normal ( Table 2 ). Table 2 Endocrine work-up of patient 2. Morning cortisol (n.v 5–25) (µg/dl) 15 DHEAS (µg/dl) (65–280) 135.1 ACTH (n.v 10–50) (pg/ml) 29 Δ4-Androstendione (ng/ml) (0.5–2.7) (ng/ml 2 24hr urinary free cortisol (n.v 10–136) (µg/24hr) 52 17-hydroxyprogesterone (0.3–0.75)(ng/ml) 3.1 Overnight dexamethasone suppression test (n.v < 1.8µg/dl) 2.11 Chromogranin-A (n.v < 4) ng/ml 3 Aldosterone (n.v 7–30) (ng/dl) 17.7 Testosterone (n.v 25–83) (ng/dl) 29.4 Renin (n.v 0.7–3.3) (ng/ml/hr) 16.6 24-h urine metanephrines (mcg/24hr) (52–341) 2533 Aldosterone-to renin ratio (ARR) 1.6 24-h urine normetanephrine (mcg/24hr) (88–244) 616 14 days after his admission to the hospital and the completion of the preoperative alpha-blockade (final dose 100 mg phenoxybenzamine) and beta blockade (final dose 40 mg propranolol) and fluid loading the patient underwent uneventfully a laparoscopic right adrenalectomy. Histology revealed adrenal tissue, weighing 30 mgs, which was composed of a pheochromocytoma and a strong component (~ 10%) of ganglioneuroma in the context of a composite pheochromocytoma. ( Fig. 5 , 6 , 7 ) . There was no atypia and a low mitotic activity was observed, while Ki-67 index was < 2–3%. Immunohistochemistry showed positive staining for S-100p, CD56, Calretinin and NF. Thus, the tumor was diagnosed as a right composite pheochromocytoma (PASS Score 6) with a component of ganglioneuroma. The postoperative course was completely uneventful, and the patient was discharged after 7 days in excellent condition. During a follow up of 60 months the patient remains normotensive and no sign of recurrence from either the pheochromocytoma or the ganglioneuroma has been detected. Discussion AGN is a benign, slow-growing tumor which is due to a relocation of neural crest cells during fetal development to adrenal and ganglion at various sites. They are composed of mature Schwann cells and ganglion cells in varying proportions. AGNs correspond to 3-3.5% of adrenal incidentalomas [ 3 ][ 18 ]. These tumors mostly affect patients in the 3rd − 5th decade of life as were both our patients [ 2 ], but remarkably approximately 25% of the cases concern children and adolescents [ 6 ],[ 19 ],[ 20 ],[ 21 ]. A multicenter study (Comete Network) analyzed data from 104 patients with AGNs and reported that 63/104 6(0.6%) were incidentalomas, 89/98 (90.8%) were hormonally ‘silent’ [ 6 ] while increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 8/30 (26.7%) and 19/45 (42.2%) of cases. AGNs may rarely secrete catecholamines [ 22 ], [ 23 ] [ 24 ], usually in the context of a composite tumor with pheochromocytoma [ 9 ], [ 25 ]. There are a few reports of dopamine secreting AGNs [ 26 ],[ 27 ],[ 28 ]one in a child [ 29 ],a small number of testosterone producing tumors due to ectopic Leydig cells [ 30 ], [ 31 ], [ 32 ] and recently an ACTH secreting AGN causing Cushing syndrome [ 33 ]. In patient 1 normal UFC and adequate cortisol suppression following an overnight dexamethasone test excluded endogenous hypercortisolemia. She presented with an episode of severe hypertension during anesthesia so a catecholamine secreting tumor should be excluded. Urine normetanephine levels were twice evaluated and a discrepancy was noticed as one value was in-between normal range and the other one twice the upper limit of the reference range. It is worth noting that urine metanephrine levels can be falsely elevated up to 3–4 times the upper normal limit in a significant number of patients with pheocromocytoma [ 34 ]. One third of the false-positive results are due to physiological variations in catecholamines [ 35 ], increased sympathetic tone due to anxiety, pain, alcohol, infection or bleeding, laboratory error and drug interference [ 36 ]. The fact that patient 1 did not report previously a history of symptoms indicative of catecholamine excess (hyperhidrosis, palpitations, pallor, tremor, or nausea) reduced the pretest risk of a catecholamine producing tumor. She had only mildly elevated normetanephrines in one measurement and normal metanephrines which was in favor of an underlying sympathetic overdrive and the background of hypertension. A clonidine test may distinguish a pheocromocytoma/paraganglioma (PPGL) from other conditions that elevate catecholamines, like essential hypertension, stress, or certain drugs, especially in patients with borderline elevated noradrenaline or normetanephrine levels. Clonidine is a central α 2 -adrenoceptor agonist which has the capacity to inhibit noradrenaline release from normal adrenal glands, a response not observed in patients with catecholamine secreting tumors [ 37 ]. Dopamine secreting tumors can be missed if only epinephrine, norepinephrine and their metabolites are measured [ 38 ], and methoxytyramine is a sufficient marker of dopamine-producing tumors [ 39 ]. Due to technical reasons dopamine or 3-methoxytyramine could not be measured in our patient, but we considered it unlikely that the tumor would secrete dopamine, as these tumors usually present with hypotension and atypical symptoms [ 38 ]. We opted not to perform a clonidine test or an MIBG scan for further investigation but to proceed to alpha and beta blockade preoperatively. Τhe patient underwent an uneventful open surgery and histology revealed an adrenal ganglioneuroma and not a chromafinic tumor. Macroscopically AGNs present usually as encapsulated masses with a firm consistency, something that was observed in the first case ( Fig. 2 ). GNs may be large at diagnosis and asymptomatic, especially when they occur in the retroperitoneal space. There are a few only reports in the literature of giant AGNs [ 40 ], [ 41 ], [ 42 ], [ 43 ][ 44 ]. Patient 1 had a unilateral giant tumor (~ 15 cm), oval-shaped with microcalcifications that occupated most part of adrenal medulla, surrounded the inferior vena cava, the abdominal aorta and the left renal vessels causing dilatation of left kidney. Although MRA did not show obstruction of blood flow, we assume that encasement of left renal artery and triggering of renin- angiotensin -aldosterone cascade was the reason of her hypertensive episode. This is also supported by the fact that her renin and aldosterone levels were elevated. A case of perinephric ganglioneuroma causing renovascular hypertension in a child has also been reported [ 45 ]. Microscopically, these tumors can be classified in two major categories (mature and maturing subtypes) and they are classified as neuroblastoma (NB), ganglioneuroblastoma and ganglioneuroma (GN) [ 46 ]. The mature subtype which corresponds to ganglioneuroma is defined by mature Schwann cells, ganglion cells, and perineural cells while the maturing subtype (neuroblastoma) presents with a similar stroma, but with variant levels of maturating ganglion cells, extending from fully mature cells to neuroblasts. GN is an indolent slow growing benign tumor but a few cases reporting metastasis in lymph nodes, liver, spleen and soft tissues have been reported [ 47 ], [ 48 ]. It is assumed that they represent neuroblastoma or ganglioneuroblastoma which matured to ganglioneuroma. The second patient had a composite pheochromocytoma-ganglioneuroma and presented with atypical abdominal pain and hematuria but no catecholamine related symptomatology. Notably, although the patient was normotensive and asymptomatic, very elevated metanephrine levels and more than three times the upper normal limit normetanephrine levels were detected. Thus, it concerned a rare case of clinically silent composite pheocromocytoma-ganglioneuroma tumor. In a retrospective study of 45 cases of AGNs Dages et al reported that 20/45 (44%)[ 4 ] of the patients had combined ganglioneuroma and pheochromocytoma. Compared to pure AGNs, patients with composite tumors were older (median age, 62.5 vs. 35 years, p < .001), had smaller tumors (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). 68% of pure AGNs were nonfunctional in comparison with 5% of composite tumors. The biochemical phenotype of patients with functional tumors was 75% adrenergic (n = 15), and 15% noradrenergic (n = 3). Costa et al reviewed the literature of 110 composite pheochromocytomas [ 9 ]. In 22/110 (20%), a genetic predisposition syndrome was detected, most commonly neurofibromatosis type 1 in 15/110 (13.6%). The most common histologic type of the neuroblastic component was ganglioneuroma in 83/110 (75.5%). Twenty-seven cases reported SDHB immunohistochemistry results; but none was positive. Nine patients (8.2%) presented/developed metastatic disease, and 9 patients (8.2%) died from disease. Composite tumors (pheocromocytoma + ganglioneuroma) have been reported in a patient with VHL[ 16 ] and in two others with MAX mutation[ 49 ], [ 50 ]. A series of 18 cases of AGNs showed underlying HRAS and BRAF mutations[ 51 ]. Cases occurring in the context of (MEN2) [ 52 ], NF1[ 7 ] [ 53 ], [ 54 ], SHD[ 17 ] are relatively scarce. Patient 2 did not have clinical signs of NF-1, MEN2 syndrome or VHL but genetic testing was not performed. Preoperative diagnosis of AGNs is very difficult [ 7 ] because of the lack of pathognomonic findings, and only histology confirms a definite diagnosis. Radiologically, AGNs represent a challenge in terms of differentiating from other adrenal tumors. Their imaging features are nonspecific(5),[ 55 ] and can overlap with other adrenal tumors, making it difficult to rule out malignancy. They are usually large solid tumors and they appear with an unenhanced CT attenuation > 20 HU, calcifications and lobulated shape [ 56 ], [ 57 ]. A typical continuous wash-in of contrast where enhancement gradually increases to attain its peak in delayed venous phase has been described [ 58 ]. This specific wash-in pattern is different from the wash-out pattern observed in other adrenal neoplasms and may help in differential diagnosis. At MRI, they appear homogeneously or heterogeneously hyperintense on T2-weighted images and hypointense on T1-weighted images[ 59 ] because of the presence of myxoid stroma and relatively few ganglion cells. The tumor of patient 1 was hypointense on T1-weighted images without significant signal loss in T1-weighted out of phase images in an MRA angiography consistent with a lipid poor tumor. An unusual case of extensive lipomatous adrenal ganglioneuroma mimicking adrenal myelolipoma has been reported [ 60 ], and two rare cases of adrenal collision tumors (coexistence of a ganglioneuroma with a myelolipoma [ 61 ], [ 42 ]. In both cases that we present the tumors had non adenomatous appearance with microcalcifications in CT imaging. In conclusion, AGNs are rare benign tumors of the autonomic nervous system. Diagnosis can be challenging and can be achieved only by histology. The majority are clinically asymptomatic and hormonally silent tumors, therefore may be diagnosed incidentally during imaging studies. Indeed our first patient did not report any symptoms until a giant AGN was discovered due to an episode of severe hypertension during anesthesia, while the second patient carried a composite pheocromocytoma-ganglioneuroma but presented due to abdominal pain and hematuria. Their diagnosis may raise the possibility of genetic backround. Their treatment include open or laparoscopic surgery, depending on the size of the tumor and the risk of recurrence or malignant transformation is extremely low. Declarations Author contributions: EK and GN designed the article and collected and interpreted the data. EK wrote the initial manuscript. GN reviewed the manuscript critically. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work. Declarations: Written informed consent was obtained from the patient before the study. Conflict of interest: The authors declare no competing interests. Consent to publish: Written informed consent was provided from the patient for publication of this case report and accompanying image References Shawa H et al (2014) Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre, Clin Endocrinol (Oxf) , vol. 80, no. 3, pp. 342–347, Mar. 10.1111/cen.12320 Fliedner SMJ, Winkelmann PER, Wesley R, Vonthein R, Lehnert H (Jan. 2021) Ganglioneuromas across age groups: Systematic review of individual patient data. Clin Endocrinol (Oxf) 94(1):12–23. 10.1111/cen.14297 Ichijo T, Ueshiba H, Nawata H, Yanase T (2020) A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features. 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JCEM Case Rep 3(3). 10.1210/jcemcr/luaf027 Kline GA, Boyd J, Leung AA, Tang A, Sadrzadeh HM (2020) Very high rate of false positive biochemical results when screening for pheochromocytoma in a large, undifferentiated population with variable indications for testing, Clin Biochem , vol. 77, pp. 26–31, Mar. 10.1016/j.clinbiochem.2020.01.005 Yu R, Wei M (2010) False positive test results for pheochromocytoma from 2000 to 2008., Exp Clin Endocrinol Diabetes , vol. 118, no. 9, pp. 577–85, Oct. 10.1055/s-0029-1237699 Yu R, Wei M (2009) False Positive test Results for Pheochromocytoma from 2000 to 2008, Experimental and Clinical Endocrinology & Diabetes , vol. 118, no. 09, pp. 577–585, Dec. 10.1055/s-0029-1237699 Eisenhofer G et al (2003) Biochemical Diagnosis of Pheochromocytoma: How to Distinguish True- from False-Positive Test Results, J Clin Endocrinol Metab , vol. 88, no. 6, pp. 2656–2666, Jun. 10.1210/jc.2002-030005 Fagundes GFC, Almeida MQ (Apr. 2024) Pitfalls in the Diagnostic Evaluation of Pheochromocytomas. 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Cureus Sep. 10.7759/cureus.44611 Menschik D, Lovvorn H, Hill A, Kelly P, Jones DP (2002) An unusual etiology of hypertension in a 5-year-old boy, Pediatric Nephrology , vol. 17, no. 7, pp. 524–526, Jul. 10.1007/s00467-002-0882-6 Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A (2022) Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas, Endocr Pathol , vol. 33, no. 1, pp. 90–114, Mar. 10.1007/s12022-022-09704-6 Srinivasan R, Koliyadan KSV, Krishnand G, Bhat SS (Jan. 2007) Retroperitoneal ganglioneuroma with lymphnode metastasis: a case report. Indian J Pathol Microbiol 50(1):32–35 Tsukamoto S et al (Nov. 2024) Adrenal ganglioneuroma with nodal metastases on 123I-MIBG SPECT/CT and 18F-FDG PET/CT. Radiol Case Rep 19(11):5128–5132. 10.1016/j.radcr.2024.07.128 Pozza C et al (May 2020) A Novel MAX Gene Mutation Variant in a Patient With Multiple and ‘Composite’ Neuroendocrine–Neuroblastic Tumors. Front Endocrinol (Lausanne) 11. 10.3389/fendo.2020.00234 Chang X, Li Z, Ma X, Cui Y, Chen S, Tong A (Aug. 2020) A Novel Phenotype of Germline Pathogenic Variants in MAX: Concurrence of Pheochromocytoma and Ganglioneuroma in a Chinese Family and Literature Review. Front Endocrinol (Lausanne) 11. 10.3389/fendo.2020.00558 Chen J, Wu Y, Wang P, Wu H, Tong A, Chang X (2021) Composite pheochromocytoma/paraganglioma-ganglioneuroma: analysis of SDH and ATRX status, and identification of frequent HRAS and BRAF mutations., Endocr Connect , vol. 10, no. 8, pp. 926–934, Aug. 10.1530/EC-21-0300 Efared B et al (Dec. 2017) Bilateral pheochromocytoma with ganglioneuroma component associated with multiple neuroendocrine neoplasia type 2A: a case report. J Med Case Rep 11(1):208. 10.1186/s13256-017-1364-6 Costa J, Jácome M, Souteiro P, Santos C, Cunha AL (2023) Composite pheochromocytoma of the adrenal gland—a review of published cases, Virchows Archiv , vol. 483, no. 2, pp. 267–275, Aug. 10.1007/s00428-023-03492-y Tachibana A, Iida K, Itami Y, Hashimura M, Hosokawa Y, Fujimoto K (2023) Composite pheochromocytoma associated with neurofibromatosis type 1, IJU Case Rep , vol. 6, no. 5, pp. 278–281, Sep. 10.1002/iju5.12603 Sandru F et al (Sep. 2021) Adrenal ganglioneuroma: Prognostic factors (Review). Exp Ther Med 22(5):1338. 10.3892/etm.2021.10773 Shao M et al (2020) Computed tomography characteristics of adrenal ganglioneuroma: a retrospective analysis of 30 pathologically-confirmed cases, Journal of International Medical Research , vol. 48, no. 11, Nov. 10.1177/0300060520945510 Xie J, Dai J, Zhou W, Sun F (2018) Adrenal Ganglioneuroma: Features and Outcomes of 42 Cases in a Chinese Population, World J Surg , vol. 42, no. 8, pp. 2469–2475, Aug. 10.1007/s00268-018-4499-8 Agrawal N, Awasthi A, Mahata R, Chakraborty PP (May 2021) Continuous and progressive ‘wash-in’ without ‘wash-out’ of contrast in adrenal mass: a useful feature of ganglioneuroma. BMJ Case Rep 14(5):e241661. 10.1136/bcr-2021-241661 Chung R et al (Jul. 2023) Adrenal Neoplasms: Lessons from Adrenal Multidisciplinary Tumor Boards. Radiographics 43(7). 10.1148/rg.220191 Bansal M, Karam AR, Chen SD, Kohnehshahri MN, Cotton TM, Moliner MLG (2021) Unusual appearance of an adrenal ganglioneuroma, Radiol Case Rep , vol. 16, no. 2, pp. 396–399, Feb. 10.1016/j.radcr.2020.11.046 Tang Q, Ji J, Zhou X, Tao R (2019) Adrenal collision tumor: a case report of the coexistence of myelolipoma and ganglioneuroma. Int J Clin Exp Pathol 12(6):2302–2304 Cite Share Download PDF Status: Published Journal Publication published 28 May, 2025 Read the published version in Hormones → Version 1 posted Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 01 Apr, 2025 Editor assigned by journal 31 Mar, 2025 First submitted to journal 31 Mar, 2025 Editorial decision: Accept but needs linguistic revision 24 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5775520","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436746351,"identity":"20befbff-0b6f-4589-bd06-509d861794f4","order_by":0,"name":"Efstratios Kardalas","email":"","orcid":"","institution":"Evaggelismos Hospital: Geniko Nosokomeio Athenon O Euangelismos","correspondingAuthor":false,"prefix":"","firstName":"Efstratios","middleName":"","lastName":"Kardalas","suffix":""},{"id":436746352,"identity":"31a289cf-5fa0-4a0a-801f-8809d7899263","order_by":1,"name":"George Kyriakopoulos","email":"","orcid":"","institution":"Evaggelismos General Hospital: Geniko Nosokomeio Athenon O Euangelismos","correspondingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Kyriakopoulos","suffix":""},{"id":436746353,"identity":"c40d2f01-273f-42c8-b98e-aac0b21f4a74","order_by":2,"name":"Vasiliki Antonopoulou","email":"","orcid":"","institution":"Evangelismos Athens General Hospital: Geniko Nosokomeio Athenon O Euangelismos","correspondingAuthor":false,"prefix":"","firstName":"Vasiliki","middleName":"","lastName":"Antonopoulou","suffix":""},{"id":436746354,"identity":"1465baef-964e-4f72-9637-b18d6bf82e67","order_by":3,"name":"Aggeliki Kyriakou","email":"","orcid":"","institution":"Evangelismos Athens General Hospital: Geniko Nosokomeio Athenon O 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Ntali","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYNACAxDB3HDgAwNDAvFaeBgYGw7OIF4LA0QLMw8xWuTdm499/FJgl2fPfrDxsG2bXR4/ewPjh485uLUYnjmWPFvGILmYhyex4XBuW3KxZM8BZsmZ2/BomZFjzCxhwJzYwwDWwpy44UYCGzMvPi3z34C01Cf28D9sOGzZVk9Yi7wEjzHjB4PDiT0SQFsY2w4T1mLAk5bMzGBwPLHnxsOGgz3njifO7DnYjNcv8u2HDzP++FOd2N6ffPjDj7LqxH725oMfPuKz5QAw2nlgPEY2MNmAWz3IFqA04w849w9exaNgFIyCUTBCAQASeFbUS+BDzAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-4737-6422","institution":"Evangelismos Athens General Hospital: Geniko Nosokomeio Athenon O Euangelismos","correspondingAuthor":true,"prefix":"","firstName":"Georgia","middleName":"","lastName":"Ntali","suffix":""}],"badges":[],"createdAt":"2025-01-06 16:55:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5775520/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5775520/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s42000-025-00676-w","type":"published","date":"2025-05-28T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79819733,"identity":"7f4632f3-9423-4072-aee6-05122833bc87","added_by":"auto","created_at":"2025-04-03 08:34:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":356971,"visible":true,"origin":"","legend":"\u003cp\u003eTransverse and coronal abdominal CT depicting the giant tumor occupying the left abdomen and coming in touch with the spleen and the left kidney.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/89097f36644f17ad2b299e68.png"},{"id":79819734,"identity":"f615618e-7e6e-4f1c-b799-a0ece8ee6221","added_by":"auto","created_at":"2025-04-03 08:34:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":646934,"visible":true,"origin":"","legend":"\u003cp\u003eMRA of the abdomen showing the giant tumor which occupied almost completely the left peritoneal cavity and caused liver displacement.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/a9c3abced61b05bd279ac649.png"},{"id":79820668,"identity":"5208d12a-af6f-4ed8-bd94-d6e95c86eb2e","added_by":"auto","created_at":"2025-04-03 08:42:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95877,"visible":true,"origin":"","legend":"\u003cp\u003eThe macroscopic appearance of the giant adrenal ganglioneuroma weighing more than 1,5Kg.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/73dc1003e9565711efd0bce6.jpg"},{"id":79819740,"identity":"8299c423-0aab-4e48-9879-ae0992948dda","added_by":"auto","created_at":"2025-04-03 08:34:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":534589,"visible":true,"origin":"","legend":"\u003cp\u003eHematoxylin and eosine stained sections of the adrenal tumor showing mature ganglion cells (arrow) in Schwannian cell dominant stroma.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/208c5ff372af5e9cd16be572.png"},{"id":79820672,"identity":"7fd5ca75-e470-47dc-a226-ec58c5d18ad1","added_by":"auto","created_at":"2025-04-03 08:42:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1291675,"visible":true,"origin":"","legend":"\u003cp\u003eComposite pheochromocytoma - Presence of at least 5% of histologically recognisable components of phaeochromocytoma (blue star) and neurogenic tumour such as ganglioneuroma (yellow star).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/506f4bab4b69bf215625ac90.png"},{"id":79819742,"identity":"a22bfc77-93ff-478b-a146-ad94c95e67f5","added_by":"auto","created_at":"2025-04-03 08:34:37","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1443521,"visible":true,"origin":"","legend":"\u003cp\u003eStrong cytoplasmic expression of chromogranin A in the chromaffin cells of pheochromocytoma and strong cytoplasmic expression of neurofilaments (NF) in the ganglioneuroma distinguish the two different components of the tumor.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/6728e2b1e46aaafc592895f8.png"},{"id":79819743,"identity":"ea66c64a-9426-403a-b8ef-ebf15d87eb35","added_by":"auto","created_at":"2025-04-03 08:34:37","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":171372,"visible":true,"origin":"","legend":"\u003cp\u003eStrong S100 immunohistochemical expression in the sustentacular cells of the pheochromocytoma (blue star) and in the stroma (Schwann cells) of the ganglioneuroma (yellow star).\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/7fb16d3bcb86225053333b8d.jpg"},{"id":83783121,"identity":"499921aa-dfa5-4698-b30e-c1ed09efcb96","added_by":"auto","created_at":"2025-06-02 16:10:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5631184,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5775520/v1/f3493d4d-c522-41ae-bb47-3498e310c428.pdf"}],"financialInterests":"","formattedTitle":"The clinical spectrum of adrenal ganglioneuromas extends from severe hypertension to an asymptomatic incidentaloma. Two cases and mini review of literature.","fulltext":[{"header":"Highlights","content":"\u003cp\u003e \u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eThe clinical presentation has a broad spectrum from an asymptomatic incidentaloma to a composite pheocromocytoma-ganglioneuroma tumor and functioning syndromes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThey may part of genetic syndromes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eImaging characteristics are not pathognomonic and diagnosis is based on histology\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTreatment is complete surgical excision\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe probability of recurrence is low and distant metastases have rarely been reported\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLifelong surveillance is imperative for composite pheochromocytoma-ganglioneuromas\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eGanglioneuromas (GNs) are rare, benign tumors which arise from the neural crest tissue of sympathetic nervous system [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. They are composed of Schwannian cells covered with maturing or fully mature ganglion cells. They may be localized in locations associated with sympathetic nervous tissue more frequently in the retroperitoneum, mediastinum and the adrenal glands and rarely in the head and neck [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The incidence of adrenal GNs (AGNs) is approximately 3.5% of adrenal incidentalomas [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The majority are asymptomatic and hormonally inactive and are discovered serendipitously while the rest may cause abdominal discomfort secondary to mass effect [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Their imaging phenotype can vary widely and usually it is characterized by large size, unenhanced CT attenuation\u0026thinsp;\u0026gt;\u0026thinsp;20 HU, calcifications and lobulated shape [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Histopathology is the cornerstone for their diagnosis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A subset of AGNs present as composite tumors with pheochromocytomas[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Association with hereditary familial syndromes, such as Neurofibromatosis 1 and 2 (NF1) and (NF2) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], Multiple Endocrine Neoplasia (MEN) 2 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], MAX mutation related syndrome [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e],[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], Von Hippel-Lindau (VHL)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and Succinate Hydrogenase Deficiency (SHD)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] has been reported. The objectives of this paper are 1) to present two interesting cases of adrenal ganglioneuromas. The first one concerned a giant AGN which provoked severe hypertension while on contrary the second case presented as an asymptomatic incidentaloma, thus showing the variability of their clinical spectrum and 2) to offer a mini review of the current literature for these rare benign tumors and highlight potential pitfalls in their management.\u003c/p\u003e"},{"header":"Case Presentations","content":"\u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003eA 31-year-old female patient was referred to the Emergency Department due to resistant arterial blood pressure (~\u0026thinsp;190/100 mm Hg). A few hours ago she had developed high blood pressure (~\u0026thinsp;210/120 mm Hg) during dilation and curettage, following an early pregnancy loss at 9 \u0026frac12; pregnancy weeks in another hospital. An urgent computer tomography (CT) of the abdomen \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e had showed a lobulated abdominal mass\u0026thinsp;~\u0026thinsp;15\u0026ndash;17 cm, with microcalcifications and an unenhanced attenuation\u0026thinsp;\u0026gt;\u0026thinsp;20 HU arising from the left adrenal gland.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient was admitted to the Endocrine Department for further diagnostic work-up. On admission, she was hypertensive and reported mild headaches, during the last 3\u0026ndash;6 months. She reported no flushing, diaphoresis and palpitations and her past medical history was unremarkable. Her pregnancy had been spontaneously interrupted at 9 \u0026frac12; weeks, thereby she subsequently underwent dilation and curettage. Her family history was positive for diabetes mellitus and arterial hypertension. She denied smoking or drinking alcohol. Thorax X-ray, as well as an electrocardiogram, were normal. Routine laboratory and urine tests provided normal results. Endocrine work up was negative for cortisol excess but her renin and aldosterone levels were elevated (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEndocrine work up for patient 1.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortisol (n.v 5\u0026ndash;25) (\u0026micro;g/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDHEAS (n.v 100\u0026ndash;340)(\u0026micro;g/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACTH (n.v 10\u0026ndash;50) (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eΔ4-androstendione (n.v 1-2.5) (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary Free Cortisol (UFC)\u003c/p\u003e \u003cp\u003e(n.v 10\u0026ndash;136 (\u0026micro;g/24hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17-hydroxyprogesterone (n.v 0.2-3) (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvernight dexamethasone suppression test (n.v\u0026thinsp;\u0026lt;\u0026thinsp;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTestosterone (n.v 9\u0026ndash;55) (ng/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlasma renin activity (n.v 0.7\u0026ndash;3.3) (ng/ml/hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUrinary fractionated metanephrines\u003c/p\u003e \u003cp\u003e(n.v 52\u0026ndash;341) \u0026micro;g/24hr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e103/57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAldosterone (n.v 7\u0026ndash;30) (ng/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUrinary fractionated normetanephrines (n.v 88\u0026ndash;244) \u0026micro;g/24hr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e255/526\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe patient\u0026rsquo;s 24-h urine metanephrine levels were within the normal range (103/57 mcg/24 h, n.v. \u0026lt; 341, but slightly increased normetanephrine levels (255/526 mcg/24 h n.v 88\u0026ndash;244) were noticed on one occasion. She had normal Chromogranin-A level (2.7 ng/ml, n.v\u0026thinsp;\u0026lt;\u0026thinsp;4 ng/ml) and slightly elevated levels of Neuron-Specific Enolase (NSE) and Ca-125 tumor markers (22 ng/ml n.v\u0026thinsp;\u0026lt;\u0026thinsp;6.3 ng/ml and 44 U/ml, n.v. \u0026lt;35 U/ml respectively).\u003c/p\u003e \u003cp\u003eFurther preoperative imaging work-up via magnetic resonance angiography (MRA) of the abdomen revealed that the tumor was \u0026lsquo;surrounding and strangling\u0026rsquo; the left renal vessels and the inferior vena cava. The tumor was heterogenous and hypointense on T1-weighted images and did not demonstrate significant signal loss on T1-out of phase weighted images which was a sign of poor lipid content. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBecause of the discrepant normetanephrine results and the fact that the patient had resistant hypertension, we decided to treat her preoperatively with alpha and beta-blockade to a final dose of 100 mg phenoxybenzamine and 50 mg of propranolol. 10 days after her admission to the hospital she was successfully submitted to an open left adrenalectomy and nephrectomy without complications. Histology showed that most adrenal tissue was replaced by tumor (weighing more than 1.5 Kgs), which was composed of mature ganglion and Schwann cells \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNo atypia or mitotic activity was observed, while Ki-67 was 1\u0026ndash;2%. An immunohistochemical examination showed positive staining of the ganglion and Schwann cells for S-100 \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Thus, the tumor was diagnosed as a left adrenal maturing ganglioneuroma with dominant Schwanian stroma. Postoperative course was uneventful, even though the patient had to be closely monitored initially in the intensive care unit and then at the surgical department for a whole period of 20 days. The patient has remained asymptomatic and normotensive and no recurrence has been detected during a follow up period of 6 years.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003eA 37-year-old male patient was admitted to our hospital following an episode of right-side renal colic-like pain, accompanied by hematuria. Abdominal CT revealed the presence of a 4-cm lesion in the right adrenal gland, rich in microcalcifications with an unenhanced attenuation\u0026thinsp;\u0026gt;\u0026thinsp;20 HU. Relative percentage washout following contrast enhancement was \u0026lt;\u0026thinsp;40%.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eOn admission, the patient did not mention any headaches or excessive sweating. No clinical signs or symptomatology relevant to hormonal excess could be identified. The patient had no history of tachycardia, hypertension, headache, flushing, diaphoresis. His past medical history was uneventful, besides the fact that his was heterozygote for beta thalassemia minor. He had a positive family history for dyslipidemia and arterial hypertension. Both thoracic radiography and electrocardiogram were normal. Routine laboratory and urine tests provided normal results. Hormonal evaluation showed normal values of morning cortisol, ACTH, normal urinary free cortisol (UFC) and adequate suppression after an overnight dexamethasone suppression test. A normal aldosterone-to renin ratio was calculated. Surprisingly both 24-h urine metanephrine and normetanephrine levels were elevated. NSE and Ca-125 tumor markers were normal \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEndocrine work-up of patient 2.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorning cortisol (n.v 5\u0026ndash;25) (\u0026micro;g/dl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDHEAS (\u0026micro;g/dl) (65\u0026ndash;280)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e135.1\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACTH (n.v 10\u0026ndash;50) (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eΔ4-Androstendione (ng/ml) (0.5\u0026ndash;2.7) (ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24hr urinary free cortisol (n.v 10\u0026ndash;136) (\u0026micro;g/24hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17-hydroxyprogesterone (0.3\u0026ndash;0.75)(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvernight dexamethasone suppression test\u003c/p\u003e \u003cp\u003e(n.v\u0026thinsp;\u0026lt;\u0026thinsp;1.8\u0026micro;g/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChromogranin-A (n.v\u0026thinsp;\u0026lt;\u0026thinsp;4) ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAldosterone (n.v 7\u0026ndash;30) (ng/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTestosterone (n.v 25\u0026ndash;83) (ng/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenin (n.v 0.7\u0026ndash;3.3) (ng/ml/hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24-h urine metanephrines (mcg/24hr) (52\u0026ndash;341)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2533\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAldosterone-to renin ratio (ARR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24-h urine normetanephrine\u003c/p\u003e \u003cp\u003e(mcg/24hr) (88\u0026ndash;244)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e616\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e14 days after his admission to the hospital and the completion of the preoperative alpha-blockade (final dose 100 mg phenoxybenzamine) and beta blockade (final dose 40 mg propranolol) and fluid loading the patient underwent uneventfully a laparoscopic right adrenalectomy. Histology revealed adrenal tissue, weighing 30 mgs, which was composed of a pheochromocytoma and a strong component (~\u0026thinsp;10%) of ganglioneuroma in the context of a composite pheochromocytoma. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e,\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e,\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was no atypia and a low mitotic activity was observed, while Ki-67 index was \u0026lt;\u0026thinsp;2\u0026ndash;3%. Immunohistochemistry showed positive staining for S-100p, CD56, Calretinin and NF. Thus, the tumor was diagnosed as a right composite pheochromocytoma (PASS Score 6) with a component of ganglioneuroma. The postoperative course was completely uneventful, and the patient was discharged after 7 days in excellent condition. During a follow up of 60 months the patient remains normotensive and no sign of recurrence from either the pheochromocytoma or the ganglioneuroma has been detected.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAGN is a benign, slow-growing tumor which is due to a relocation of neural crest cells during fetal development to adrenal and ganglion at various sites. They are composed of mature Schwann cells and ganglion cells in varying proportions. AGNs correspond to 3-3.5% of adrenal incidentalomas [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These tumors mostly affect patients in the 3rd − 5th decade of life as were both our patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], but remarkably approximately 25% of the cases concern children and adolescents [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e],[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e],[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e],[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA multicenter study (Comete Network) analyzed data from 104 patients with AGNs and reported that 63/104 6(0.6%) were incidentalomas, 89/98 (90.8%) were hormonally ‘silent’ [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] while increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 8/30 (26.7%) and 19/45 (42.2%) of cases. AGNs may rarely secrete catecholamines [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], usually in the context of a composite tumor with pheochromocytoma [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. There are a few reports of dopamine secreting AGNs [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e],[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e],[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]one in a child [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e],a small number of testosterone producing tumors due to ectopic Leydig cells [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and recently an ACTH secreting AGN causing Cushing syndrome [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn patient 1 normal UFC and adequate cortisol suppression following an overnight dexamethasone test excluded endogenous hypercortisolemia. She presented with an episode of severe hypertension during anesthesia so a catecholamine secreting tumor should be excluded. Urine normetanephine levels were twice evaluated and a discrepancy was noticed as one value was in-between normal range and the other one twice the upper limit of the reference range. It is worth noting that urine metanephrine levels can be falsely elevated up to 3–4 times the upper normal limit in a significant number of patients with pheocromocytoma [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. One third of the false-positive results are due to physiological variations in catecholamines [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], increased sympathetic tone due to anxiety, pain, alcohol, infection or bleeding, laboratory error and drug interference [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The fact that patient 1 did not report previously a history of symptoms indicative of catecholamine excess (hyperhidrosis, palpitations, pallor, tremor, or nausea) reduced the pretest risk of a catecholamine producing tumor. She had only mildly elevated normetanephrines in one measurement and normal metanephrines which was in favor of an underlying sympathetic overdrive and the background of hypertension. A clonidine test may distinguish a pheocromocytoma/paraganglioma (PPGL) from other conditions that elevate catecholamines, like essential hypertension, stress, or certain drugs, especially in patients with borderline elevated noradrenaline or normetanephrine levels. Clonidine is a central α\u003csub\u003e2\u003c/sub\u003e-adrenoceptor agonist which has the capacity to inhibit noradrenaline release from normal adrenal glands, a response not observed in patients with catecholamine secreting tumors [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDopamine secreting tumors can be missed if only epinephrine, norepinephrine and their metabolites are measured [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and methoxytyramine is a sufficient marker of dopamine-producing tumors [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Due to technical reasons dopamine or 3-methoxytyramine could not be measured in our patient, but we considered it unlikely that the tumor would secrete dopamine, as these tumors usually present with hypotension and atypical symptoms [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe opted not to perform a clonidine test or an MIBG scan for further investigation but to proceed to alpha and beta blockade preoperatively. Τhe patient underwent an uneventful open surgery and histology revealed an adrenal ganglioneuroma and not a chromafinic tumor.\u003c/p\u003e \u003cp\u003eMacroscopically AGNs present usually as encapsulated masses with a firm consistency, something that was observed in the first case \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e GNs may be large at diagnosis and asymptomatic, especially when they occur in the retroperitoneal space. There are a few only reports in the literature of giant AGNs [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e][\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Patient 1 had a unilateral giant tumor (~ 15 cm), oval-shaped with microcalcifications that occupated most part of adrenal medulla, surrounded the inferior vena cava, the abdominal aorta and the left renal vessels causing dilatation of left kidney. Although MRA did not show obstruction of blood flow, we assume that encasement of left renal artery and triggering of renin- angiotensin -aldosterone cascade was the reason of her hypertensive episode. This is also supported by the fact that her renin and aldosterone levels were elevated. A case of perinephric ganglioneuroma causing renovascular hypertension in a child has also been reported [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMicroscopically, these tumors can be classified in two major categories (mature and maturing subtypes) and they are classified as neuroblastoma (NB), ganglioneuroblastoma and ganglioneuroma (GN) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The mature subtype which corresponds to ganglioneuroma is defined by mature Schwann cells, ganglion cells, and perineural cells while the maturing subtype (neuroblastoma) presents with a similar stroma, but with variant levels of maturating ganglion cells, extending from fully mature cells to neuroblasts. GN is an indolent slow growing benign tumor but a few cases reporting metastasis in lymph nodes, liver, spleen and soft tissues have been reported [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. It is assumed that they represent neuroblastoma or ganglioneuroblastoma which matured to ganglioneuroma.\u003c/p\u003e \u003cp\u003eThe second patient had a composite pheochromocytoma-ganglioneuroma and presented with atypical abdominal pain and hematuria but no catecholamine related symptomatology. Notably, although the patient was normotensive and asymptomatic, very elevated metanephrine levels and more than three times the upper normal limit normetanephrine levels were detected. Thus, it concerned a rare case of clinically silent composite pheocromocytoma-ganglioneuroma tumor.\u003c/p\u003e \u003cp\u003eIn a retrospective study of 45 cases of AGNs Dages et al reported that 20/45 (44%)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] of the patients had combined ganglioneuroma and pheochromocytoma. Compared to pure AGNs, patients with composite tumors were older (median age, 62.5 vs. 35 years, p \u0026lt; .001), had smaller tumors (median size, 3.9 vs. 5.7 cm, p = .016) and were discovered incidentally less frequently (65% vs. 84%, p = .009). 68% of pure AGNs were nonfunctional in comparison with 5% of composite tumors. The biochemical phenotype of patients with functional tumors was 75% adrenergic (n = 15), and 15% noradrenergic (n = 3).\u003c/p\u003e \u003cp\u003eCosta et al reviewed the literature of 110 composite pheochromocytomas [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In 22/110 (20%), a genetic predisposition syndrome was detected, most commonly neurofibromatosis type 1 in 15/110 (13.6%). The most common histologic type of the neuroblastic component was ganglioneuroma in 83/110 (75.5%). Twenty-seven cases reported SDHB immunohistochemistry results; but none was positive. Nine patients (8.2%) presented/developed metastatic disease, and 9 patients (8.2%) died from disease.\u003c/p\u003e \u003cp\u003eComposite tumors (pheocromocytoma + ganglioneuroma) have been reported in a patient with VHL[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and in two others with MAX mutation[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. A series of 18 cases of AGNs showed underlying HRAS and BRAF mutations[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Cases occurring in the context of (MEN2) [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], NF1[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e], SHD[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] are relatively scarce. Patient 2 did not have clinical signs of NF-1, MEN2 syndrome or VHL but genetic testing was not performed.\u003c/p\u003e \u003cp\u003ePreoperative diagnosis of AGNs is very difficult [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] because of the lack of pathognomonic findings, and only histology confirms a definite diagnosis. Radiologically, AGNs represent a challenge in terms of differentiating from other adrenal tumors. Their imaging features are nonspecific(5),[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] and can overlap with other adrenal tumors, making it difficult to rule out malignancy. They are usually large solid tumors and they appear with an unenhanced CT attenuation \u0026gt; 20 HU, calcifications and lobulated shape [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. A typical continuous wash-in of contrast where enhancement gradually increases to attain its peak in delayed venous phase has been described [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. This specific wash-in pattern is different from the wash-out pattern observed in other adrenal neoplasms and may help in differential diagnosis. At MRI, they appear homogeneously or heterogeneously hyperintense on T2-weighted images and hypointense on T1-weighted images[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] because of the presence of myxoid stroma and relatively few ganglion cells. The tumor of patient 1 was hypointense on T1-weighted images without significant signal loss in T1-weighted out of phase images in an MRA angiography consistent with a lipid poor tumor. An unusual case of extensive lipomatous adrenal ganglioneuroma mimicking adrenal myelolipoma has been reported [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e], and two rare cases of adrenal collision tumors (coexistence of a ganglioneuroma with a myelolipoma [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e], [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In both cases that we present the tumors had non adenomatous appearance with microcalcifications in CT imaging.\u003c/p\u003e \u003cp\u003eIn conclusion, AGNs are rare benign tumors of the autonomic nervous system. Diagnosis can be challenging and can be achieved only by histology. The majority are clinically asymptomatic and hormonally silent tumors, therefore may be diagnosed incidentally during imaging studies. Indeed our first patient did not report any symptoms until a giant AGN was discovered due to an episode of severe hypertension during anesthesia, while the second patient carried a composite pheocromocytoma-ganglioneuroma but presented due to abdominal pain and hematuria. Their diagnosis may raise the possibility of genetic backround. Their treatment include open or laparoscopic surgery, depending on the size of the tumor and the risk of recurrence or malignant transformation is extremely low.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eEK and GN designed the article and collected and interpreted the data. EK wrote the initial manuscript. GN reviewed the manuscript critically. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from the patient before the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u0026nbsp;to\u0026nbsp;publish:\u0026nbsp;\u003c/strong\u003eWritten informed consent was provided from the patient for publication of this case report and accompanying image\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShawa H et al (2014) Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre, \u003cem\u003eClin Endocrinol (Oxf)\u003c/em\u003e, vol. 80, no. 3, pp. 342\u0026ndash;347, Mar. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/cen.12320\u003c/span\u003e\u003cspan address=\"10.1111/cen.12320\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFliedner SMJ, Winkelmann PER, Wesley R, Vonthein R, Lehnert H (Jan. 2021) Ganglioneuromas across age groups: Systematic review of individual patient data. 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Int J Clin Exp Pathol 12(6):2302\u0026ndash;2304\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"adrenal ganglioneuroma, hypertension, pheochromocytoma, composite, Schwannian cell","lastPublishedDoi":"10.21203/rs.3.rs-5775520/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5775520/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e. Herein, we present two interesting cases of adrenal ganglioneuromas: a) a giant adrenal ganglioneuroma, which provoked a severe episode of hypertension during a therapeutic dilation and curettage for early pregnancy loss and b) a case of a composite clinically silent adrenal ganglioneuroma-pheochromocytoma. Furthermore, we conducted a mini literature review on adrenal ganglioneuromas.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 1.\u003c/strong\u003e A 31-year-old female patient presented with a history of early pregnancy loss at 9 ½ weeks. She underwent a therapeutic dilation and curettage during which she developed hypertension (~ 210/120 mm Hg). She reported no history of arterial hypertension, flushing or tachycardia, and her medical history was unremarkable. Further work-up, revealed a large heterogeneous tumor with microcalcifications in the left adrenal gland. Endocrine work-up was negative for hormonal excess. Magnetic resonance angiography (MRA) of the abdomen showed that the tumor was ‘surrounding and strangling’ the left renal vessels and the inferior vena cava. The patient underwent successfully an open left adrenalectomy and nephrectomy. Histology revealed an adrenal mature ganglioneuroma with schwannian stroma as dominant. Her postoperative course was uneventful and she remains recurrence-free six years after her surgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2.\u003c/strong\u003e A 37-year-old male patient was admitted to the hospital because of abdominal pain and haematuria. Computer tomography identified a 4-cm right adrenal lesion. Due to elevated urinary metanephrines he underwent laparoscopic right adrenalectomy, after appropriate alpha-blockade preparation preoperatively. Histology was consistent with pheochromocytoma with a component of ganglioneuroma, thus a composite pheochromocytoma. His post-operative course was excellent and he remains asymptomatic and recurrence-free 60 months post-operatively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion.\u003c/strong\u003e These are two challenging cases of a) a giant non-secreting adrenal ganglioneuroma presenting with severe hypertension due to renal vessels’ compression and b) a clinically silent composite pheochromocytoma-ganglioneuroma presenting with abdominal pain and hematuria. The size in the first case and the concurrence with a pheochromocytoma but a clinically silent phenotype in the second one, highlight the fact that adrenal ganglioneuromas can be diagnostic chameleons.\u003c/p\u003e","manuscriptTitle":"The clinical spectrum of adrenal ganglioneuromas extends from severe hypertension to an asymptomatic incidentaloma. Two cases and mini review of literature.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 08:34:32","doi":"10.21203/rs.3.rs-5775520/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-01T08:24:20+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-01T08:22:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T03:29:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hormones","date":"2025-03-31T22:57:44+00:00","index":"","fulltext":""},{"type":"decision","content":"Accept but needs linguistic revision","date":"2025-02-24T06:14:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3f0ef368-7751-45dd-8e88-91b0c03449f6","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T16:07:28+00:00","versionOfRecord":{"articleIdentity":"rs-5775520","link":"https://doi.org/10.1007/s42000-025-00676-w","journal":{"identity":"hormones","isVorOnly":false,"title":"Hormones"},"publishedOn":"2025-05-28 15:56:59","publishedOnDateReadable":"May 28th, 2025"},"versionCreatedAt":"2025-04-03 08:34:32","video":"","vorDoi":"10.1007/s42000-025-00676-w","vorDoiUrl":"https://doi.org/10.1007/s42000-025-00676-w","workflowStages":[]},"version":"v1","identity":"rs-5775520","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5775520","identity":"rs-5775520","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}