Adrenal Medullary Hyperplasia Research Articles

Evaluation of adrenal masses using 18F-FDOPA PET/CT in patients suspected with pheochromocytoma.

Pheochromocytomas (PHEOs) are chromaffin cell-derived adrenal tumors. 6-[18F]-L-fluoro-L-3, 4-dihydroxyphenylalanine (18F-FDOPA) is a radiotracer taken up in neuroendocrine chromaffin cells via the L-type amino-acid transporter. 18F-FDOPA is useful in patients with PHEO. However, more information about the use of 18F-FDOPA PET/CT scan is needed. Thus, the current study investigated various PET parameters on preoperative 18F-FDOPA PET/CT scan. The 18F-FDOPA PET/CT scan findings of 29 patients who underwent adrenalectomy after PET/CT scans were evaluated according to their pathologic diagnosis. Thereafter, the patients were classified under different risk groups which were compared based on the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). In terms of histopathologic results after surgery, 24 patients presented with PHEO. The remaining 5 patients were diagnosed with adrenal cortical adenomas or adrenal medullary hyperplasia. The maximum standardized uptake value, mean standardized uptake value, tumor-to-liver ratio, and tumor-to-contralateral adrenal gland ratio of PHEOs on preoperative 18F-FDOPA PET/CT scan were higher than those of other tumors. The metabolic tumor volume (MTV) and total lesion uptake of PHEOs in the intermediate-risk group (n = 19) were higher than those in the low-risk group (n = 5). The MTV and total lesion uptake were significantly correlated with the GAPP score. Preoperative 18F-FDOPA PET/CT is helpful to identifying PHEOs. In addition, imaging interpretation using the standardized uptake value of the suspected tumor or the tumor-to-liver/contralateral adrenal gland ratio can be effective. The metabolic parameters of PHEOs are positively correlated with the GAPP score.

Letter to the Editor from Yu: "Adrenal Medullary Hyperplasia: A Systematic Review And Meta-analysis".

Journal Article Accepted manuscript Letter to the Editor from Yu: “Adrenal Medullary Hyperplasia: A Systematic Review And Meta-analysis” Get access Run Yu, MD, PhD Run Yu, MD, PhD Division of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, California Correspondence: Run Yu, MD, PhD, Division of Endocrinology, UCLA David Geffen School of Medicine, 200 Medical Plaza Dr, Suite 530, Los Angeles, CA 90095 Phone: 310-825-7922 Fax: 310-267-1899 Email: runyu@mednet.ucla.edu https://orcid.org/0000-0003-2901-5102 Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, dgad226, https://doi.org/10.1210/clinem/dgad226 Published: 20 April 2023 Article history Received: 17 March 2023 Accepted: 17 April 2023 Published: 20 April 2023

Adrenal Medullary Hyperplasia: A Systematic Review and Meta-analysis.

Adrenal medullary hyperplasia (AMH) is a rare, incompletely described disorder of the adrenal medulla that is associated with catecholamine excess. To increase knowledge about AMH by reviewing the reported cases of this disorder. Systematic review and meta-analysis of the genotype/phenotype relationship in all reported cases of AMH. Literature review and analysis. All cases of AMH published to date. Characteristics of AMH cases and genotype-phenotype relationships. A total of 66 patients, median age of 48 years, were identified from 29 reports. More than one-half were male (n = 39, 59%). The majority had unilateral (73%, n = 48) disease; 71% (n = 47) were sporadic and 23% (n = 15) were associated with the MEN2. Most (91%, n = 60) displayed signs and symptoms of excess catecholamine secretion, particularly hypertension. Elevated catecholamine concentrations (86%, n = 57) and adrenal abnormalities on imaging were common (80%, n = 53). More than one-half (58%, n = 38) had concurrent tumors: pheochromocytoma (42%, n = 16/38); medullary thyroid cancer (24%, n = 9/38); and adrenocortical adenoma (29%, n = 11/38). Most (88%, n = 58) underwent adrenalectomy with 45/58 achieving symptom resolution. Adrenalectomy was less common in patients under 40 years and those with bilateral disease (both P < .05). AMH may be sporadic or associated with MEN2, most have catecholamine excess and imaging abnormalities. Unilateral involvement is more common. Most reported patients have been treated with adrenalectomy, which is usually curative with regard to catecholamine hypersecretion.

Clinical identification of expressed proteins in adrenal medullary hyperplasia detected with hypertension.

Hypertension remains a challenging public health problem worldwide, and adrenal gland-related diseases are one class of the major causes for secondary hypertension. Among them, one relatively rare pattern is adrenal hyperplastic hypertension caused by adrenal medullary hyperplasia (AMH), leading to excessive secretion of autonomic catecholamine. Given that the pathological changes of adrenal medulla are not well correlated to the onset and even severity of secondary hypertension, the molecular basis why some AMH patients are accompanied with hypertension remains unclear and is worth exploring. For this reason, this study aims at investigating differentially expressed proteins in clinical AMH tissue, with special focus on the potential contribution of these differentially expressed proteins to AMH development, in order to have a better understanding of mechanisms how AMH leads to secondary hypertension to some extent. To this end, AMH specimens were successfully obtained and verified through computed tomography (CT) and haematoxylin-eosin (HE) staining. Proteomic analyses of AMH and control tissues revealed 782 kinds of differentially expressed proteins. Compared with the control tissue, there were 357 types of upregulated proteins and 425 types of downregulated proteins detected in AMH tissue. Of interest, these differentially expressed proteins were significantly enriched in 60 gene ontology terms (P < 0.05), including 28 biological process terms, 14 molecular function terms, and 18 cellular component terms. Pathway analysis further indicated that 306 proteins exert their functions in at least one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Western blotting showed enhanced expression of phenylethanolamine N- methyltransferase (PNMT), myelin protein zero (MPZ), and Ras-related protein Rab-3C (RAB3C), and reduced expression of cluster of differentiation 36 (CD36) observed in AMH tissue in comparison with controls. Clinical AMH specimens display a different proteomic profile compared to control tissue. Of note, PNMT, MPZ, RAB3C, and CD36 are found to differentially expressed and can be potential targets for AMH, providing a theoretical basis for mechanistic exploration of AMH along with hypertension.

ODP023 Adrenal medullary hyperplasia as a differential diagnosis of paroxysmal hypertension: case report

Abstract Background Sporadic Adrenal Medullary hyperplasia (AMH) has been little described in the literature, being most often diagnosed during a genetic syndrome screening or the evaluation of an adrenal incidentaloma. Case report A 51-year-old female patient presented with progressive attacks of tachycardia, headache, nausea and mild paroxysmal hypertension, which started in December 2020. She had a history of smoking and she also presented Takotsubo syndrome in 2018. She denied other comorbidities. In March 2021, she was submitted to laboratorial testing which demonstrated indeterminate plasma fractionated metanephrines by HPLC/MS: metanephrines 0.3 nmol/L (n&amp;lt; 0.5) and normetanephrines 1.2 nmol/L (n&amp;lt; 0.9) and normal serum chromogranin A level: 82 ng/mL (n&amp;lt;93) by Directed Proteomic. Urinary metanephrines were collected in a spot sample after an adrenergic crisis episode, confirming the biochemical diagnosis: metanephrines 255 mcg/g creatinine (n 30-165), normetanephrine 824 mcg/g creatinine (n 105-375), total 1119 mcg/g creatinine (n 150- 510) by HPLC. She was submitted to an abdominal MRI, which showed bilateral adrenal thickening with medullary predominance with hyperintense sign on T2-weighted images. It was also performed a mIBG I 131 spect and a PET-CT DOTATATO-Galium 68 without abnormal uptakes. A genetic panel by NextGeneration Sequence (NGS) was also carried out for pheochromocytoma/paraganglioma (PHEO/PGL) without pathological findings. The patient underwent laparoscopic left adrenalectomy after the use of alpha and beta blockade for one month, with pathological findings suggestive of adrenal medullary hyperplasia. However, she remained symptomatic after surgery. Once again, new urinary metanephrines in a spot sample were collected after an adrenergic crisis: metanephrines 188 mcg/g creatinine (n 30-165), normetanephrines 1229 mcg/g creatinine (n 105-375), total 1417 mcg/g creatinine (n 150-510) by HPLC, which demonstrated remaining cathecolamine excess. She underwent a contralateral laparoscopic adrenalectomy without surgical complications. An anatomopathological analysis was performed in both adrenals, which confirmed bilateral adrenal medullary hyperplasia without associated PHEO. The patient showed improvement in adrenergic symptoms and normalization of plasma fractionated metanephrines levels postoperatively, currently using hydrocortisone and fludrocortisone for the treatment of adrenal insufficiency. Conclusion Adrenal Medullary hyperplasia is a rare condition, which usually presents in a milder form and is often associated with pheochromocytoma or genetic syndromes. However it should be considered in symptomatic patients without a personal or family history of PHEO/PGL, allowing an early diagnosis and treatment. Presentation: No date and time listed

PSAT013 Elevated Plasma Free Metanephrines with No Evidence of Pheochromocytoma in a Patient with Multiple Endocrine Neoplasia Type 2A

Abstract Background Adrenal medullary hyperplasia (AMH) is arbitrarily defined by adrenal medullary proliferation measuring less than 1 cm while larger lesions are considered pheochromocytoma. Some patients with MEN2 present with adrenal medullary hyperplasia (AMH), which is a precursor of pheochromocytomas. Clinical Case A 22-year-old female with a past medical history of MEN2A. She is positive for germline mutation in RET proto-oncogene at 10q11.2 exon 11, position 634 from cysteine to arginine. She was evaluated for a 1cm left thyroid nodule, which required total thyroidectomy for Medullary Thyroid Cancer. Pathology revealed a 0.5cm deposit on the largest dimension, clear margins, and no angiovascular, or lymphovascular invasion, surgery was complicated by hypoparathyroidism. She complained of intermittent anxiety and fatigue but was otherwise asymptomatic. Physical examination is unremarkable except for thyroidectomy scar and multiple exostoses. On 8/5/2011 plasma-free metanephrines were elevated at 83 pg/ml (&amp;lt;57pg/ml) and Free normetanephrine was 45 pg/ml (&amp;lt;145pg/ml). Over the next years, her plasma-free metanephrine levels have been checked approximately every 6 months ranging between 63-106pg/ml with free plasma normetanephrine in normal ranges (30-81pg/ml). However, on 2/2021, her plasma normetanephrine level increased to 304pg/ml. More recently, on 11/30/2021 her free normetanephrine levels reached 671pg/ml and free Metanephrine 131pg/ml. She had two MRIs of the abdomen and pelvis over the years and both showed unremarkable adrenal glands. NM I-123 MIBG scintigraphy reported physiologic symmetric activity in the adrenal glands. Finally, she had GA-68 DOTATATE PET/CT with no suspicious radiotracer avid lesion in the abdominopelvic organs. Given the persistent elevation on plasma metanephrines, we decided to start the patient on Doxazosin prophylactically while we continue biochemical and imaging surveillance. Conclusion Our patient has a persistent elevation in plasma-free metanephrines with no evidence of pheochromocytoma in abdominal imaging. The earliest abnormality in the adrenal medulla in patients with MEN 2 is diffuse hyperplasia with a reduction in the cortical/medullary ratio (1). This hyperplasia is considered to be a precursor of pheochromocytoma in patients with MEN 2 and in our case the most likely explanation for the progressive elevation in plasma-free metanephrines (1). There is a strong molecular relationship between AMH and Pheochromocytoma (2), close monitoring for progression to pheochromocytoma is necessary for all patients with AMH. The presence of markedly elevated plasma metanephrines in an asymptomatic patient with no evidence of pheochromocytoma poses a therapeutic dilemma for preemptive use of alpha blockade and the potential need for a medical alert bracelet. References (1) Cho, K et al "Adrenal Medullary disease in Multiple Endocrine Neoplasia II". AJR 134: 23-29. (2) Korpershoek, E et al "Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome". Neoplasia. 2014 Oct; 16(10): 868–873 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Genetic Analysis of Pheochromocytoma and Paraganglioma Complicating Cyanotic Congenital Heart Disease.

Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis. Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors. We performed whole-exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample. We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of 3 cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 The Cancer Genome Atlas non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18 to 23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life. Our results highlight a key role of activated hypoxia-inducible factor 2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.

Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics

Cases in which bilateral adrenal 123I-Metaiodobenzylguanidine (123I-MIBG) scintigraphy accumulation is sometimes shown, with mildly elevated catecholamine (CA) or metanephrine (MN) levels (within 3 times the upper reference limit) are diagnostic dilemmas. We experienced 3 cases of adrenal incidentalomas with this dilemma in the differential diagnosis. The clinical diagnosis was subclinical Cushing's syndrome in 2 cases, and primary aldosteronism in 1. Despite suspected CA excess in clinical symptoms and imaging findings, the pathological findings of all these tumors were revealed to be cytochrome P450 family 11 subfamily B member 1 (CYP11B1) positive adrenocortical adenomas. Interestingly, adrenal medullary hyperplasia (AMH) was detected in the adrenal parenchyma of all those backgrounds. To clarify the clinical features of such cases, a cross-sectional study was conducted at the Kobe University Hospital from 2014 to 2020. One-hundred sixty-four patients who had undergone 123I-MIBG scintigraphy were recruited. Among them, 10 patients (6.1%) met the above criteria, including the presented 3 cases. Plasma adrenaline, noradrenaline, urinary metanephrine, and normetanephrine had values of 0.05 ± 0.05 ng/mL, 0.63 ± 0.32 ng/mL, 0.22 ± 0.05 mg/day, and 0.35 ± 0.16 mg/day, respectively. Nine cases were complicated with hypertension, and symptoms related to CA excess were observed. Half of them (5 cases) including presented 3 cases had unilateral adrenal tumors. These suggest that in cases of bilateral adrenal uptake on 123I-MIBG, AMH needs to be considered. Adrenocortical adenomas may be associated with AMH and further larger investigation is needed for this pathology.

Abstract 3132: Tumorigenesis of MEN2 pheochromocytoma

Abstract Backgrounds: Pheochromocytomas are catecholamine-secreting neuroendocrine tumors, which occur sporadically or as part of inherited syndromes, such as multiple endocrine neoplasia type2 (MEN2), caused by deleterious mutations within the RET protooncogene. Although the RET mutation is implicated in the development of MEN2-associated pheochromocytoma, there is a long (typically 40 years) latency period before the disease onset, suggesting the need of the acquisition of secondary hits. However, little is known about such secondary alterations involved in the pathogenesis of MEN2. In this study, we compared genetic profiles of MEN2 pheochromocytoma and its precursor lesion, adrenal medullary hyperplasia (AMH). Materials and methods: Samples were collected from surgical specimens in 6 MEN2 pheochromocytoma cases, including a MEN2B case with RET p.M918T and 5 MEN2A cases with RET p.C634F, p.C634F, p.C634Y, p.E768D and p.C620S, and 1 AMH case with MEN2A carrying RET p.C634Y. Spatially separated samples were collected from a tumor slice (“tumor parts”). Multiple microscale sampling was also performed from apparently normal adrenal medulla (“non-tumor parts”). Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. Result: Regarding “tumor parts”, a total of 20 samples from 6 MEN2 pheochromocytomas was analyzed. The number of somatic mutations per sample was ranging from 2 to 10. No somatic mutations commonly implicated in sporadic pheochromocytomas were detected. In a case with MEN2B, 1p, 3q and 21q losses were shared across all 3 samples, while 11p and 11q losses and 5p, 5q, 12p, 12q and 15q gains were private, suggesting that 1p, 3q and 21q losses occurred early in the tumorigenesis. In 5 MEN2A cases, 1p (80%), 3q (100%), 21q (60%) and 22q (60%) losses were frequently shared across all samples in each case. As for “non-tumor parts”, a total of 12 samples from 2 MEN2 pheochromocytoma cases and 1 AMH case were analyzed. The number of somatic mutations per sample ranged from 0 to 15. In 2 MEN2 pheochromocytoma cases, no somatic mutations were shared across the samples or no CNAs were detected, while 12 mutations were shared in two samples derived from an AMH case. Interestingly, these samples harbored 17p loss alone, while 1p, 3q, 21q or 22q losses were not found. Conclusion and perspective: MEN2 pheochromocytoma and AMH had different genetic characteristics, where 1p, 3q, 21q and 22q losses could have a role in early tumorigenesis. Further studies involving an increasing number of patients with MEN2 pheochromocytoma and AMH are warranted. Citation Format: Tatsuki Ogasawara, Yoichi Fujii, Nobuyuki Kakiuchi, Yusuke Shiozawa, Hiromichi Suzuki, Ryuichi Sakamoto, Yusaku Yoshida, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa. Tumorigenesis of MEN2 pheochromocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3132.

Pheochromocytoma in Multiple Endocrine Neoplasia Type 2

This pheochromocytoma is from an adrenal gland of an individual with multiple endocrine neoplasia type 2. What statement is most accurate regarding pheochromocytoma in multiple endocrine neoplasia type 2?a.Pheochromocytomas in the setting of multiple endocrine neoplasia type 2 are almost always single and unilateralb.Pheochromocytoma associated with multiple endocrine neoplasia type 2 is often associated with diffuse medullary hyperplasia or small nodulesc.Pheochromocytoma is almost always the presenting feature in multiple endocrine neoplasia type 2, occurring decades before medullary thyroid carcinomad.In the setting of multiple endocrine neoplasia type 2, pheochromocytomas are usually very aggressive with a high mortality rate due to metastatic pheochromocytoma Answer: b. Pheochromocytoma associated with multiple endocrine neoplasia type 2 is often associated with diffuse medullary hyperplasia or small nodules Pheochromocytoma occurs in approximately 50% of cases of multiple endocrine neoplasia type 2. In this setting, it generally presents about a decade after medullary thyroid carcinoma.1Raue F. Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2.Clinics (Sao Paulo). 2012; 67: 69-75Crossref PubMed Scopus (49) Google Scholar In multiple endocrine neoplasia type 2, the underlying genetic abnormality is germline RET mutation. Overall, pheochromocytomas and paragangliomas in adults are associated with an underlying pathogenic germline abnormality in approximately 40% of cases.2Turchini J. Cheung V.K.Y. Tischler A.S. et al.Pathology and genetics of phaeochromocytoma and paraganglioma.Histopathology. 2018; 72: 97-105Crossref PubMed Scopus (54) Google Scholar Hereditary paragangliomas and pheochromocytomas are not limited to multiple endocrine neoplasia type 2, as they can occur with other syndromes and germline genetic abnormalities such as in von Hippel-Lindau, neurofibromatosis type 1, and succinate dehydrogenase subunit-related tumors, as well as in those associated with underlying abnormalities of TMEM127, FH, MAX, and other genes. Hereditary and sporadic pheochromocytomas and paragangliomas may be histologically similar, however, in multiple endocrine neoplasia type 2 the tumors can be multiple or single and may be associated with diffuse or nodular (micro-pheochromocytomas) adrenal medullary hyperplasia as well as hyaline globules (see figure).3Webb T.A. Sheps S.G. Carney J.A. Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2.Am J Surg Pathol. 1980; 4: 121-126Crossref PubMed Scopus (56) Google Scholar,4Gosset P. Lecomte-Houcke M. Duhamel A. et al.112 cases of sporadic and genetically determined pheochromocytoma: a comparative pathologic study.Ann Pathol. 1999; 19: 480-486PubMed Google Scholar

Pheochromocytoma arising from an ectopic adrenal tissue in multiple endocrine neoplasia type 2A.

SummaryA 21-year-old woman was referred to our hospital to treat bilateral pheochromocytomas (PCCs) after a diagnosis of multiple endocrine neoplasia type 2A (MEN2A). We performed bilateral laparoscopic adrenalectomy. One year after the operation, urinary fractionated metanephrines in 24-h urine increased. MRI showed a 30 mm tumor on the interaortocaval region and 123I-MIBG concentrated in this area. We excised the tumor and performed para-aortic lymphadenectomy. Histopathologic examination confirmed a PCC arising from ectopic adrenal tissue. Urinary fractionated metanephrines in 24-h urine declined to basal levels immediately after the operation. We detected no recurrence of paraganglioma or PCC for 5 years after the treatment.Learning points:Most ectopic adrenal tissue is associated with no symptoms and contains only the adrenal cortex.Adrenocortical tumors sometimes arise from ectopic adrenal tissues similarly to in the normal adrenal gland.PCC arising from ectopic adrenal tissue occurs infrequently.MEN2-related PCC is accompanied by adrenal medullary hyperplasia, which might be part of tumorigenesis.

Presentation, Treatment, Histology, and Outcomes in Adrenal Medullary Hyperplasia Compared With Pheochromocytoma.

ContextInformation about adrenal medullary hyperplasia (AMH) is scarce.ObjectiveTo study a large cohort of AMHs.Design, Setting, and ParticipantsNineteen AMH cases were compared with 95 pheochromocytomas (PCCs) without AMH. AMH without (n = 7) and with PCC (n = 12) were analyzed separately.ResultsOf 936 adrenalectomies, 2.1% had AMH. Mean age was 47.2 ± 15.1 years. Only two (11%) AMHs had no concurrent PCC or adrenocortical adenoma. In AMHs, a genetic syndrome was present in 58% vs 4% in PCCs (P < 0.001). The noradrenaline/metanephrine levels were lower in AMHs, whereas suppression of dexamethasone was less than in PCCs. Cushing syndrome was found in 11% of AMHs. More AMHs were found during screening and less as incidentalomas. PCC symptoms were less prevalent in AMHs. Surgical management was similar; however, fewer of the AMHs were pretreated with alpha-blockers. Adrenalectomy improved blood pressure slightly less in AMHs. The disappearance of glycemic disturbances was similar to the PPCs. During a period of 11.2 ± 9.4 years, a new PCC developed in 32% of patients with AMH, 11% died, but no PCC metastasis occurred (PCCs: 4%, P < 0.001; 14% and 5%). AMHs without PCC had milder symptoms but more often Cushing disease than patients with PCC, whereas AMH with PCC more often displayed a familiar syndrome with more PCC recurrences.ConclusionA total of 2.1% of all adrenalectomies displayed AMH. AMH seemed to be a PCC precursor. The symptoms and signs were milder than PCCs. AMHs were mainly found due to screening. Outcomes seemed favorable, but new PCCs developed in many during follow-up.

MON-375 Chronic Hypertension Causing by Adrenal Medulla Hyperplasia Mimicking the Presentation of Pheochromocytoma

Background: Well-known causes of endocrine hypertension include primary hyperaldosteronism, pheochromocytoma, Cushing’s syndrome, etc. (1). In the international literature, adrenal medullar hyperplasia (AMH) has not been familiar for the clinicians as a cause of hypertension, and it possibly leads to misjudgment in the clinical treatment/outcomes. We reported an unusual case of resistant and prolonged hypertension caused by AMH. Clinical case: A 49-year-old female was referred to the Endocrinology clinic for possible having pheochromocytoma with prolonged hypertension. The patient had hypertension for 10-15 years which she is currently on metoprolol, losartan, clonidine, hydrochlorothiazide, and amlodipine for her home regimen. She also complained of having episodic hypertension which was associated with headaches, diaphoresis, palpitations, and chest pain for several years. Her blood pressure has been ranging from 100-160 over 60 -115 mmHg even though she is compliant to the medications. Also, she once was admitted to the hospital because of hypotension and needed to be taking care of in the intensive care unit. Her past medical history was significant for diabetes mellitus type 2 and anxiety. On physical examination, she had elevated blood pressure of 170/115 mmHg. The patient had no enlarged thyroid, no cushingoid appearance and denied using steroid supplements. Initial workup revealed elevated normetanephrines level in 24-hr urine and serum (1070 mcg/g; n 85-514 mcg/g and 477 pg/mL; n <148 pg/mL). In contrast with metanephrines in 24-hr urine and serum which were in normal range (154 mcg/g; n 33-192 mcg/g and <25 pg/mL; n <57 pg/mL). Serum aldosterone and cortisol level were within normal limit. An abdominal CT scan with contrast showed a 15 mm. mass was noted in the left adrenal gland with a density of -22 HU in the non-contrast image, 27 HU in portal venous phase, and 15 HU in the delay images. Pheochromocytoma was suggested at that time. The patient underwent a left adrenalectomy and pathology report revealed adrenal medullary hyperplasia. Postoperatively, her blood pressure is in the normal range, and she is able to discontinue taking all the anti-hypertensive medication. Discussion: AMH is a rare and frequently unrecognized disorder that causes hypertension. The etiology of AMH remains unknown and still unclear in etiology along with pathogenesis. Currently, there is no standard evaluation and treatment guideline for this condition. Researchers still debate that it may be a precursor lesion of pheochromocytoma since their presentation can be similar. Histopathology is still a definite diagnosis to determine the difference between both these conditions.

Abstract #124 Adrenal Medullary Hyperplasia as a Cause of Secondary Hypertension and Metanephrines Excess.

Abstract #124 Adrenal Medullary Hyperplasia as a Cause of Secondary Hypertension and Metanephrines Excess.

Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study

During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study.In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation.In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90).These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues.

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC associated factor X) gene has been reported in a few cases. Here, we investigated a 25-year-old patient with multiple PHEOs associated with a non-sense germline MAX mutation. Preoperative 18F-FDOPA PET/CT revealed bilateral adrenal involvement with multiple tumors. In addition, both adrenal glands were found to have diffuse or nodular adrenal medullary hyperplasia (AMH), a histopathological feature previously described as a precursor of MEN2- and SDHB-related PHEOs but not MAX. After bilateral adrenalectomy, different paraffin-embedded and frozen samples were analyzed for allelic imbalances of the MAX gene using allelic quantification by pyrosequencing. The expression of the protein MAX was studied by immunohistochemistry. All PHEOs but also nodular AMH exhibited a loss of the normal allele. By contrast, the diffuse AMH did not show loss-of-heterozygosity. Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH. The present case shows that both nodular and diffuse AMH belongs to the spectrum of MAX-related disease. These data support the possible continuum between nodular AMH and PHEO, expanding the qualification of micro-PHEO to nodular AMH.

Frequency of Cushing\u2019s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center

Cushing’s syndrome due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions has occasionally been described. We retrospectively reviewed all 164 cases of Cushing’s syndrome and 77 cases of pheochromocytomas during 10 years. Of all cases with Cushing’s syndrome, only two cases (1.2 %) were due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions (one case of pheochromocytoma and one case of adrenal medullary hyperplasia). Of all pheochromocytomas only the above-mentioned case (1.3 %) also gave rise to an ectopic adrenocorticotropic hormone syndrome. The clinical presentation of adrenocorticotropic hormone-secreting pheochromocytoma and adrenal medullary hyperplasia can be anything from mild to dramatic. These are rare conditions important to bear in mind in the workup of a patient with Cushing’s syndrome or with pheochromocytoma. The identification of ectopic adrenocorticotropic hormone secretion from adrenal medullary lesions can be life-saving.

Changes of adrenomedullin and natriuretic peptides in patients with adrenal medullary hyperplasia prior to and following pharmacological therapy and adrenalectomy.

The aim of the present study was to investigate the pathophysiological functions of adrenomedullin (ADM), atrial and brain natriuretic peptides (ANP and BNP) in patients with adrenal medullary hyperplasia (AMH). Plasma ADM, ANP and BNP concentrations were measured in 20 patients with AMH, 35 patients with essential hypertension (EH), and 40 healthy control subjects. Following effective antihypertensive therapy, the values in AMH and EH patients were measured again and laparoscopic adrenalectomy was performed for AMH patients. At 2 weeks after surgery, the three peptides were measured again. The AMH patients had higher plasma concentrations of ADM, ANP and BNP compared with the EH and control subjects. There were significant differences in the values of ADM, ANP and BNP between adrenal vein and inferior vena cava and between AMH and contralateral adrenal vein. Plasma ADM concentration was correlated with serum epinephrine and norepinephrine and urine vanillylmandelic acid, in addition to systolic and diastolic blood pressure, left ventricular ejection fraction, left ventricular mass index and ANP and BNP values in the AMH group. Following antihypertensive treatment, ADM, ANP and BNP were significantly decreased in EH patients, but remained unchanged in AMH subjects. However, these concentrations significantly decreased following surgery. Therefore, the present results suggest that ADM, ANP and BNP may be involved in regulating adrenal medulla functions.

Adrenal medullary hyperplasia recognized initially as incydentaloma

Adrenal medullary hyperplasia recognized initially as incydentaloma

Adrenomedullary Hyperplasia in a Patient with Poorly Controlled Hypertension and Neurofibromatosis Type 1: A Case Report

A 73-year-old male with a known diagnosis of neurofibromatosis type 1 (or Von Recklinghausen’s disease) was referred to the authors’ unit because of suspected pheochromocytoma. He had poorly controlled hypertension with elevated metanephrine levels and incomplete cortisol suppression at 1 mg overnight dexamethasone test. Adrenal CT showed bilateral adrenal hyperplasia and a nodule suspected of being a pheochromocytoma, while 123I-MIBG SPECTCT showed intense hyperfixation in the left adrenal gland. Left transperitoneal Laparoscopic adrenalectomy was performed and the histologic diagnosis was diffuse and nodular adrenal medullary hyperplasia. We believe that medullary adrenal Hyperplasia is, among the causes of secondary hypertension, a separate entity and should be considered as a possible diagnosis in all patients with poorly controlled hypertension and radiological findings not typical of adenoma.