An Extraadrenal Abdominal Pheochromocytoma Causin

Authors: Otsuka Fumio Miyoshi Tomoko Murakami Kazutoshi Inagaki Kenichi Takeda Masaya Ujike Kazuhiro Ogura Toshio Omori Masako Doihara Hiroyoshi Tanaka Yasushi Hashimoto Kozo Makino Hirofumi

Publish Date: 2005/10/01

Volume: 18, Issue: 10, Pages: 1364-1368

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Abstract

Fumio Otsuka Tomoko Miyoshi Kazutoshi Murakami Kenichi Inagaki Masaya Takeda Kazuhiro Ujike Toshio Ogura Masako Omori Hiroyoshi Doihara Yasushi Tanaka Kozo Hashimoto Hirofumi Makino An Extraadrenal Abdominal Pheochromocytoma Causing Ectopic ACTH Syndrome American Journal of Hypertension Volume 18 Issue 10 October 2005 Pages 1364–1368 https//doiorg/101016/jamjhyper200501019We report a 55yearold woman with ectopic adrenocorticotropin ACTH secretion caused by extraadrenal pheochromocytoma The patient presented with a 6month history of hypertension and diabetes mellitus Her serum and urinary cortisol levels were extremely high and dexamethasone failed to suppress the cortisol secretion Her plasma ACTH levels were also elevated 300 pg/mL and irresponsive to corticotropinreleasing hormone CRH or metyrapone administration Gel filtration analysis of the patients plasma detected the existence of large molecular weight ACTH being eluted with a major peak of authentic 139 ACTH Abdominal computed tomographic scan and magnetic resonance imaging revealed a 5cm paraganglioma located underneath the left kidney in which 123IMIBG tracer specifically accumulated Bilateral adrenal glands were diffusely enlarged After surgical removal of the paraganglioma the patients clinical symptoms improved and biochemistry normalized including plasma ACTH urinary free cortisol and urinary catecholamines Subsequent histologic evaluation of the transected paranglioma tissue revealed ACTH synaptin and chromograninA histologically immunostaining Culture of primary cells collected from the resected paraganglioma demonstrated of in vitro production of ACTH noradrenaline and adrenaline This is the first report of ectopic ACTH syndrome induced by an extraadrenal abdominal paraganglioma Am J Hypertens 2005181369–1374 © 2005 American Journal of Hypertension LtdEctopic adrenocorticotropin ACTH syndrome is characterized by hypercortisolism due to the hypersecretion of ACTH outside the pituitary gland which leads to Cushings syndrome The most common causes of ectopic ACTH syndrome are malignancies including small cell type lung carcinomas thymic carcinoids islet cell tumors of the pancreas medullary carcinomas of the thyroid and bronchial adenomas or carcinoids Adrenal pheochromocytomas involved in ectopic ACTH syndrome are very rare1 Only six cases of ACTHproducing paragangliomas have been reported to date in which two cases occurred in the paranasal sinus23 and the others were cervical4 and mediastinal/thoracic5–7 paragangliomas There has been no report of extraadrenal abdominal paraganglioma producing both catecholamines and ACTHHere we show a unique case of ectopic ACTH syndrome complicated by overproduction of catecholamines due to a paraganglioma located in the left paraaortic space We evaluated the characteristics of secreted ACTH molecules by gel filtration analysis and further proved the capability of hormonal synthesis by primary culture of cells collected from the resected paragangliomaA 55yearold Japanese woman who presented with 6month history of persistent headache palpitation hypertension and exacerbated hyperglycemia 500 mg/dL was referred to our hospital She was 1555 cm tall and weighed 516 kg body mass index 215 kg/m2 Her blood pressure was 135 to 165/90 to 105 mm Hg and pulse rate was 110 to 130 beats/min with the medication valsartan 80 mg/d She showed Cushingoid features including central distribution of body fat round face facial hirsutism and severe muscle weakness of the limbs Hyperpigmentation was not seen in the skin and the oral mucosa Abdominal computed tomographic scan CT revealed a 5cm paraaortic tumor at the level of the left kidney and remarkable bilateral enlargement of the adrenal glands Fig 1A The left abdominal tumor showed high intensity by T2weighed image unlike in the T1 image by magnetic resonance imaging MRI Fig 1B Her pituitary did not exhibit radiologic abnormalities by cranial MRI Laboratory examinations revealed leukocytosis white blood cell count 11100/μL with eosinolymphocytopenia hyperglycemia 252 to 390 mg/dL hypokalemia 13 to 29 mEq/L with metabolic alkalosis and deranged liver function tests with hypoalbuminemia 29 g/dL Endocrine profiles revealed increased levels of plasma ACTH 3184 pg/mL normal 9 to 52 pg/mL by ACTH immunoradiometric assays IRMA “Yuka” kit Mitsubishi Chemical Tokyo Japan and cortisol 765μg/dL normal 8 to 25 μg/dL without normal circadian variation Fig 2A Dexamethasone 1 mg failed to suppress the endogenous cortisol secretion Neither CRH stimulation 100 μg intravenously Fig 2B nor metyrapone 15 g Fig 2C evoked any changes in plasma ACTH levels Urinary hormone secretion was as follows 17hydroxycorticosteroids 649 mg/d normal 26 to 78 mg/d 17ketosteroids 324 mg/d normal 1 to 8 mg/d free cortisol 1000000 μg/d normal 31 to 99 μg/d adrenaline 441 μg/d normal 15 μg/d noradrenaline 1905 μg/d normal 100 to 150 μg/d dopamine 10295 μg/d normal 100 to 700 μg/d vanillylmandelic acid VMA 33 mg/d normal 1 to 7 mg/d metanephrine 019 mg/d normal 005 to 023 mg/d and normetanephrine 015 mg/d normal 007 to 026 mg/d 123IMIBG scintigraphy showed specific uptake in the left midabdominal region Fig 1C indicating that the tumor is an extraadrenal paraganglioma Medication with regular insulin ∼80 U/d and supplement of potassium chloride 36 to 42 g/d was commenced for hyperglycemia and hypokalemia respectively Hypertension and tachycardia were treated with a highdose 14 mg/d of α1adrenergic antagonist doxazosin mesilate In addition metyrapone 500 mg/d was used to suppress the hypercortisolism The resected tumor was pathologically diagnosed as an ACTHproducing pheochromocytoma by immunohistochemical studies with synaptin chromograninA and ACTH Fig 3 Upon surgical removal of the paraganglioma the patients blood pressure heart rate and potassium levels normalized gradually without medication Moderate hyperglycemia persisted but was under control without insulin Postoperative levels of plasma ACTH urinary free cortisol and urinary catecholamines normalized Two weeks after the surgery circulating ACTH and cortisol restored normal circadian fluctuation with a suppression response to dexamethasone Fig 4A and normal response to CRH test Fig 4BAnalysis of the molecular size of circulating immunoreactive IRACTH was performed using the preoperative plasma by gel chromatography as previously reported8 Briefly the plasma sample 04 mL was applied to a Sephadex G75 column 1 by 46 cm AmershamPharmacia Biotech Piscataway NJ and eluted with 1 formic acid After 2mL fractions were collected and lyophilized the ACTH concentration of each fraction was determined To detect the presence of large molecular weight ACTH ACTH levels were determined by two different IRMA methods ACTH IRMA “Yuka” kit using antibodies against 124 ACTH and 1839 ACTH Mitsubishi Chemical and Nichols Allegro ACTH kit using antibodies against 117 ACTH and 3439 ACTH Nihon MediPhysics Tokyo Japan the latter of which can detect large molecular weight ACTH molecules as we previously reported9 As a result ACTH IRMA Mitsubishi “Yuka” kit detected a main peak of 139 ACTH with a small peak of big ACTH whereas Nichols Allegro ACTH kit detected three different peaks of larger molecular weight ACTH molecules including proopiomelanocoritin POMC in addition to a main molecule of 139 ACTH Fig 5After surgical removal the tissues of the paraganglioma were washed minced in icecold phosphatebuffered saline PBS and dissolved in Hanks’ balanced salt solution with trypsin 025 collagenase 025 and DNase 16 U for 15 min at 37°C The cell suspension was dispersed and replaced to a fresh Dulbeccos modified Eagles medium DMEM containing 10 fetal calf serum FCS penicillin streptomycin and Lglutamine Cell pellets were washed and strained through 70μm nylon mesh BD Falcon Bedford MA After counting cell numbers 1 by 106 viable cells per well were plated in sixwell plates with DMEM containing 1 FCS and antibiotics and then the conditioned medium was serially collected and ACTH and catecholamine levels were determined by Mitsubishi “Yuka” IRMA kit and HPLC respectively Human subject protocols were approved by our institutional committee and written permission from the patient regarding the experimental use of the tissues was obtained in advance of the surgery The results of the experiments revealed that the paraganglioma cells predominantly produce ACTH Fig 6A but also secrete noradrenaline and adrenaline Fig 6BCushings syndrome as a consequence of ACTHproducing pheochromocytoma has been reported previously however the number of reported cases is very limited Based on a recent review of the literature approximately 3 of cases of ectopic ACTH syndrome are likely associated with pheochromocytomas1 Although the mechanism that evokes ectopic ACTH production in neoplasm is still poorly understood most of the ACTHproducing tumors apparently represent undifferentiated neuroendocrine cells capable of POMC gene expression as well as posttranslational processing10 The POMC gene expression was previously demonstrated in pheochromocytomas unrelated to Cushings syndrome by de Keyzer et al11 in which all the tumors contained a short splicing form of POMC mRNA in comparison with the pituitary that expresses the long form of the POMC transcripts However the mechanism underlying posttranslational processing of ACTH peptides remains unclear in ACTHsecreting pheochromocytomasIn the present case aberrantly processed ACTH molecules together with authentic 139 ACTH molecules were clearly detected by gel chromatography of the preoperative plasma sample Considering the remarkable increase in urinary cortisol excretion and a major peak of bioactive 139 authentic ACTH detected in the plasma the capability of bioactive ACTH production by the present paraganglioma was unexpectedly high Based on the in vitro experiments using primary paraganglioma cells the cells secreted 139 ACTH which can be selectively detected by Mitsubishi IRMA method as well as noradrenaline and adrenaline The levels of ACTH in the conditioned media were the highest on the first day of primary culture then gradually reduced to 100 pg/mL which remained steady for the 10day culture Given that the primary cell viability was preserved for 10 days in culture leading to gradual increase in catecholamine levels in the media this decrease of ACTH levels could be due to effects of proteolytic degradation of 139 ACTH during the cultureIn the therapeutic aspect metyrapone was effective to suppress the preoperative cortisol secretion from the hypertrophic adrenals It was notable that replacement therapy with hydrocortisone was unnecessary in our case throughout the perioperative period suggesting that the hypothalamopituitaryadrenal HPA axis was not functionally suppressed This condition could be associated with the following issues 1 duration of hypercortisolism was relatively short considering the clinical onset and 2 preoperative metyrapone treatment was helpful in stimulating the secretion of endogenous CRH and ACTHMetyrapone is also reported to reduce ACTH and ACTH precursors in an ACTHproducing adrenal pheochromocytoma12 This suggests that either metyrapone had direct effects at the level of the tumor to inhibit the production of ACTHrelated peptides or that endogenous glucocorticoids could be a key regulator for inducing ACTHrelated peptides On the contrary the paradoxic increase in ACTH precursors is also observed after hydrocortisone treatment in a subset of patients with postadrenalectomy Cushings disease13 Thus the regulation of ACTH precursors seems to not exactly follow the regulatory pattern for the mature ACTH moleculeSpontaneous remission of hypercortisolism due to ectopic ACTH syndrome by adrenal pheochromocytoma was reported in three cases14–16 The cause of the disappearance of hypercortisolism is unclear The decrease in ACTH secretion might be explained by a change in tumor differentiation or endocrine activity accompanied by a decrease in POMC gene transcription17 The synthesis of adrenaline depends on the activity of the enzyme phenylethanolamineNmethyltransferase PNMT The enzymatic activity of PNMT is enhanced by increased ambient cortisol concentrations18 Furthermore some studies show that the activity of tyrosine hydroxylase which contributes to the synthesis of the noradrenaline and dopamine is in turn stimulated by ACTH19 Hence the ACTH–cortisol axis is mutually related to catecholamine production in pheochromocytomasIn our patient a significant increase in the secretion of adrenaline and noradrenaline was observed whereas the levels of the urinary metabolites including metanephrine normetanephrine and VMA were within normal ranges This discrepancy was also described in two other patients with adrenal ACTHsecreting pheochromocytoma1516 Considering the generally high sensitivity of metanephrine and VMA measurement for the diagnosis of pheochromocytomas20 it is speculated that hypercortisolism or ectopic ACTH production may negatively affect the detection of urinary metanephrine excretion or the metabolic process of catecholamine including monoamine oxidase MAO or catecholOmethyltransferse COMT activationIn summary we presented a case of ectopic ACTH syndrome that was developed by extraadrenal pheochromocytoma The existence of hormonal production of catecholamine ACTH and its precursors was further clarified by plasma analysis and in vitro study using resected paraganglioma This case provides a new clinical etiology of ectopic ACTH syndrome caused by extraadrenal abdominal paraganglioma

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