J. Endocrinol. Invest. 30: 780-786, 2007

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Key-words: Ectopic ACTH secretion, Cushing’s syndrome, pheochromocy-toma, ethanol injection.

Correspondence: D.L.S. Danilovic, MD, Rua Alves Guimarães, 623, ap 161, Jardim América, São Paulo SP, CEP 05410-001, Brazil.

E-mail: debora.danilovic@gmail.com

Accepted December 13, 2006.

CASE REPORT

Ectopic ACTH syndrome caused by pheochromocytoma: Computed tomography-guided percutaneous ethanol injection as an alternative treatment

D.L.S. Danilovic1, R.A. Brandão Neto1, H. D’Abronzo1, M.R. Menezes2, A.M. Lucon3, and B.B. Mendonca1

1Disciplina de Endocrinologia e Metabologia; 2Disciplina de Radiologia; 3Divisão de Clínica Urólogica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

ABSTRACT. Ectopic ACTH secretion represents 8-18% of the cases of endogenous hypercortisolism. Pheochromocytomas correspond to 2-25% of the cases and surgery is the indicated treatment. We describe a case of ACTH-secreting pheochromo-cytoma treated with percutaneous ethanol injec-tion (PEI) guided by computed tomography (CT). A 71-yr-old man presented with diabetes, severe hypokalemia, weight loss, muscle weakness, and hypertension. Hormonal evaluation revealed el-evated levels of urinary cortisol, ACTH, catecho-lamines, and urinary metanephrines. There was no cortisol or ACTH response to desmopressin stimulation test. Magnetic resonance revealed bi-lateral adrenal nodules, larger on the left side. The suspected diagnosis was ectopic ACTH syndrome caused by pheochromocytoma. Ketoconazole treatment resulted in reduction of urinary cortisol levels but was followed by severe cholestasis and hepatic dysfunction, preventing surgery; it was

substituted by octreotide with reduction of ACTH and cortisol levels, but without improvement of cholestasis. The patient presented cachexia and developed multiple pulmonary abscesses that also prevented surgical treatment, thus he was treated with percutaneous ethanol injection guided by CT of the left adrenal tumor. During the procedure, the patient had an increase in blood pressure con-trolled by the infusion of sodium nitroprusside followed by hypotension that required infusion of dopamine and volume expansion. Afterwards, he presented hormonal normalization, normal catecholamines levels, and clinical improvement. Histological tissue analysis confirmed pheochro-mocytoma. We concluded that CT-guided PEI rep-resents an efficient alternative therapy to ectopic ACTH-secreting pheochromocytomas in patients without clinical conditions for surgery.(J. Endocrinol. Invest. 30: 780-786, 2007)©2007, Editrice Kurtis

INTRODUCTION

The ectopic ACTH syndrome corresponds to an endogenous hypercortisolism caused by an ACTH-secreting non-pituitary tumor (1). It frequently has an atypical presentation of Cushing’s syndrome, as it occurs especially in men and the clinical features that predominate are weight loss, proximal muscle

weakness with discrete changes in fat distribution, hyperpigmentation, hypertension, hypokalemia, glu-cose intolerance, and frank diabetes (2-4). This lack of common physical manifestations of cortisol excess could be related to its rapid clinical course (5). In different series, ectopic ACTH syndromes repre-sented 8-18% of patients with Cushing’s syndrome, constituting a small percentage of patients present-ing with Cushing’s syndrome (3, 4, 6, 7). Earlier re-ported series showed that almost half of the cases of ectopic ACTH syndrome were lung carcinomas, pre-dominantly small cell or oat cell type (5, 8). The more recent series observed a different predominance of carcinoids, especially bronchial ones, which consti-tuted 28-38% of all patients with ectopic ACTH-pro-ducing tumors (2, 3, 9, 10). Other types of neoplasms

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described as being responsible for biologically ac-tive ACTH are medullary carcinoma of thyroid, carcinoma and carcinoid of thymus and pancreas, gastrointestinal carcinoids and pheochromocyto-mas (2-5, 8-10). Pheochromocytomas and related tumors were responsible for 2-25% of the ectopic ACTH-producing tumors in several series and they frequently produced catecholamines (2-5, 8-10).We report a case of Cushing’s syndrome caused by ectopic ACTH secretion by a pheochromocytoma. Due to the several complications that prevented sur-gical treatment, the patient was treated with percu-taneous ethanol (PEI) injection guided by computed tomography (CT) of the left adrenal tumor.

CASE REPORT

A 71-yr-old man presented to the Hospital das Clíni-cas da Faculdade de Medicina da Universidade de São Paulo with a hyperglycemic state and severe hypokalemia (serum K concentration of 2.7 mEq/l). The diagnosis of diabetes had been made one year before, but there was no family history of the dis-ease. During the investigation of a secondary cause for the diabetes, a CT excluded pancreatic lesions and revealed bilateral adrenal nodules (Fig. 1). The patient had lost 15 kg in 4 months and had com-plained of progressive muscle weakness and hyper-tensive episodes.Endocrine evaluation revealed extremely elevated urinary free cortisol levels (2,200 μg/24h, normal range=27-86 μg/24h); plasma ACTH was elevated: 475 pg/ml (normal range <60 pg/ml) and serum cortisol was 54.3 μg/dl (normal range=7-31 μg/dl), indicating ACTH-dependent Cushing syndrome; se-rum aldosterone was 9.8 ng/dl (normal range=9-18 ng/dl); plasma renin activity was 3.0 ng/ml/h (normal range=0.2-2.8 ng/ml/h); serum testosterone was 216 ng/dl (normal range=271-965 ng/dl), serum an-drostenedione was 44 ng/ml (normal range=0.8-2.8 ng/ml), 17 -hydroxy-progesterone was 23 ng/ml

(normal range=0.6-3.3 ng/ml), dehydroepiandros-terone was 1.1 ng/ml (normal range=1.4-12.5 ng/ml) and dehydroepiandronterone sulfate was 1124 ng/ml (normal range =380-3142 ng/ml) (Table 1). Serum cortisol levels were not suppressed after 8 mg of dexametasone overnight (71.9 μg/dl). Desmopressin stimulation test did not significantly increment plas-ma ACTH and serum cortisol levels (1.8 and 1.9%, respectively). Magnetic resonance imaging (MRI) of the pituitary was normal.Clinical and laboratorial data suggested an ectopic ACTH hypersecretion. A CT of the chest was per-formed and showed a mass of 3 cm in diameter with irregular borders and a central cavitation of 1 cm in superior lobe of the right lung, and a hypoattenuat-ing thyroid nodule of 1.6 cm in diameter in the right lobe was identified. Serum calcitonin was normal and an ultrasound revealed an anechoic cyst of 1.9 cm in diameter in the right thyroid lobe. For a better characterization of the adrenal lesions, an MRI was performed and disclosed 2 different nodules in the right adrenal, the smaller one of 1 cm in diameter, composed mostly of extracellular fat tissue, which suggested the diagnosis of myelolipoma, and the larger one of 2.5 cm in diameter with a signal drop on chemical-shift imaging, which suggested a be-nign adenoma; there was another nodule in the left adrenal of 4.5 cm in diameter with a heterogeneous contrast enhancement, which aroused the suspicion of malignancy (Fig. 2).The patient had a bacteremic episode, and Entero-bacter cloacae was isolated from blood cultures. Chest radiography revealed bilateral alveolar infil-trates and another CT of the chest was performed. The latter showed that the initial right lung mass had become a cavitated lesion and several other abscesses and peribronchial condensations were identified. All of them indicated canalicular lung disease related to the bacteremia. A bronchoscopy and transbronchial biopsy were performed and con-firmed the diagnosis of chronic inflammatory airway

Fig. 1 - Computed tomography of abdo-men showing bilateral adrenal nodules.

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disorder. He received imipenem for 4 weeks with an improvement of the bronchial lesions.The hormonal evaluation for pheochromocytoma revealed that plasma norepinephrine level was el-evated at 2285 pg/ml (normal range =40-268 pg/ml), plasma epinephrine was 1301 pg/ml (normal range <75 pg/ml), plasma dopamine was 621 pg/ml (nor-mal range <83 pg/ml), urine norepinephrine was 115 μg/24h (normal range =14-80 μg/24h), urine epinephrine was 82 μg/24h (normal range =0.5-20 μg/24h), urine dopamine was 302 μg/24h (normal range =65-400 μg/24h) and urine metanephrines were 3.3 μg/mg of creatinine (normal range =0.05-1.2 μg/mg creatinine) (Table 1).

The chest CT had also identified a right paraverte-bral thoracic nodule, which was characterized by a chest MRI as a solid nodule of 1.2 cm in diameter, with bright signal intensity with T2-weighted im-ages. It suggested a tumor of the thoracic sympa-thetic plexuses. A radionuclide scintigraphy using I131-labeled metaiodobenzylguanidine (MIBG) was further performed and indicated low probability of neuroendocrine tumor inside and outside the adre-nal glands.The treatment for Cushing’s syndrome was initi-ated with ketoconazole (800 mg/day) resulting in the decrease of total urine cortisol level to 518 μg/24h (normal range =30-300 μg/24h) after 10 days of

Fig. 2 - Magnetic resonance imaging of adrenals. Nodule in the left adrenal sus-picious of pheochromocytoma. A) T1 im-age. B) T2 image.

A B

Table 1 - Laboratory data of a patient with an ectopic ACTH syndrome caused by pheochromocytoma.

Serumcortisolμg/dl

Plasma ACTHpg/ml

Urine total cortisolμg/24h

Plasmanorepine-

phrinepg/ml

Plasma epinephrine

pg/ml

Plasma dopamine

pg/ml

Urine metanephrine

μg/g of creatinine

Basal 54.3 475 2285 1301 621 3.3

20 days keto 800 mg/day 518

7 daysoctreotide 26.9 114

6 h after PEI 19.2 19

4 days after PEI 349 423 ND ND 0.76

6 days after PEI 16.4 22

22 days after PEI 164

8 months after PEI 8.9 44 227 595 ND ND 0.48

21 monthsafter PEI 12 55

Normal range 7-31 <60 30-300 40-268 <75 <83 0.05-1.2

PEI: percutanous ethanol injection; ND: not detectable.

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treatment. Nevertheless, the patient presented progressive elevation of aminotransferase levels [as-partate aminotransferase (AST) 146 U/l and alanine aminotransferase (ALT) 176 U/l, normal range =10-34 U/l and 10-49 U/l, respectively], and alkaline phosphatase levels (647 U/l, normal range =45-122 U/l). Abdominal ultrasound showed intra-hepatic cholestasis without obstructions or gallstones. The drug was withdrawn and octreotide was initiated at a dose of 300 μg/day for 7 days. Although there was a reduction in cortisol and ACTH levels, there was no improvement of cholestasis and octreotide was also withdrawn (Table 1). AST levels reached 471 U/l, ALT levels 453 U/l, and alkaline phosphatase levels 2020 U/l. Total bilirubins increased up to 19 mg/dl (normal range =0.3-1.1 mg/dl), plasma proteins de-creased to 5.5 g/dl (normal range =6.2 to 8.2 g/dl) and plasma albumin decreased to 1.9 g/dl (normal range of 3.6 to 5.0 g/dl). Hematocrit values also de-creased from normal levels to 26.4% (normal range =40.7-50.3%). The clinical conditions of the patient prevented the surgical procedure. Therefore, a biopsy and a CT-guided PEI of the left adrenal nodule were performed, after previous treatment with prazosin (3 mg/day for 23 days). The left gland volume was 24 g and 40 ml of absolute ethanol was injected (Fig. 3). During the procedure, the patient’s blood pressure increased (210x145 mmHg), controlled by the infusion of sodium nitroprusside. It was followed by a period of hypoten-sion that required infusion of dopamine and volume expansion. After 6 h of the procedure, plasma ACTH had already decreased to 19 pg/ml (Table 1). After-wards, the patient’s clinical conditions improved with the decrease of all hormonal levels. After 8 months, total urinary cortisol was 227 μg/24h, plasma ACTH 44 pg/ml, plasma norepinephrine 595 pg/ml, and uri-nary metanephrines were 0.48 μg/mg of creatinine. Plasma epinephrine and plasma dopamine became undetectable (Table 1). The cholestatic syndrome gradually subsided. After 21 months, the patient was still asymptomatic and serum cortisol and ACTH were within the normal range.

Histological analysis of the left adrenal tissue showed an adrenal tumor. Immunohistochemical studies revealed staining for chromogranin and synapto-physin, which suggested the diagnosis of pheochro-mocytoma.

DISCUSSION

This case described an ectopic ACTH syndrome caused by a pheochromocytoma. Elevated levels of serum cortisol, urinary free cortisol and plasma ACTH confirmed the ACTH-dependent Cushing’s syndrome. As Wajchenberg et al. (4) previously de-scribed in men with ectopic ACTH syndrome, tes-tosterone levels were decreased, probably due to a direct effect of hypercortisolism on testicular an-drogenesis; androstenedione and 17 -hydroxy-pro-gesterone level were elevated as a consequence of increased adrenal androgen production in parallel to cortisol. DHEAS was normal and presented no cor-relation to serum cortisol levels or other androgens. Cortisol levels were not suppressed after a high overnight dose of dexamethasone, but increased, which could be attributed to an anomalous effect of glucocorticoids on ACTH-precursors (11). Ectopic ACTH secretion was also suggested by the lack of response to the desmopressin test (12).The first lesion suspected of being the cause for the ectopic ACTH syndrome was the lung cavitated mass. However, cavitation in lung lesions is extremely rare in small cell carcinomas; and it is more frequent-ly present in squamous cell carcinoma, which has no report of ACTH secretion (13-15). The dissemination of the lung infection in our especially susceptible patient due to the severe hypercortisolism, contrib-uted to the exclusion of this cause. Another possible ACTH-secreting tumor in our patient was a medul-lary carcinoma of the thyroid, but the thyroid nodule at the ultrasound was characterized as a cyst, rather than a hypoechoic nodule, and the calcitonin level was normal. The CT and MRI of abdomen revealed multiple adrenal nodules. In a series of 27 patients with ectopic ACTH secretion studied by Doppman

Fig. 3 - Computed tomography (CT)-guid-ed percutaneous ethanol injection. With the patient lying in the prone position, the needle was inserted into the left adrenal nodule under CT guidance. Contrast ma-terial mixed into absolute ethanol (10%) provided visualization of the complete diffusion of the ethanol into the tumor.

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(10), 7% of the patients had normal CT scans, and 37% demonstrated marked adrenal hyperplasia; multiple unilateral or bilateral nodules were not seen in any of the patients. In spite of the higher ACTH levels and the older age of patients with the diagno-sis of ectopic ACTH syndrome, macronodular hyper-plasia in ectopic ACTH syndrome has not been more commonly described than in Cushing’s disease (4, 16). Nodules in hyperplastic glands could hide the presence of a pheochromocytoma. At MRI, pheo-chromocytomas usually present with bright signal intensity on T2 weighted images and hyperplastic adrenocortical tissue remains of low signal intensity (17). The left adrenal tumor of our patient had bright signal intensity in T2 images; however, he also pre-sented a lesion with similar features in the paraver-tebral thoracic area, which made the diagnosis even more intriguing. The clinical presentation of pheochromocytoma in our patient was sustained hypertension without typi-cal paroxysms. Hypertension is present in 90-100% of the patients with pheochromocytomas, sustained hypertension in approximately half and paroxysmal hypertension in only a third of them (18). The eleva-tion of catecholamines could have been attributed to the infectious state of the patient; however, the higher specificity of urinary metanephrines con-firmed the biochemical diagnosis of pheochromo-cytoma (19). The MIBG scanning did not contribute to the diagnosis; nevertheless, it has a reported sen-sitivity of only 78% (20). Surgical management is considered the only defini-tive treatment to ectopic ACTH producing tumors, particularly benign ones such as pheochromocyto-mas, which have a good curative prospective (4, 10). The use of ketoconazole and octreotide was meant to relieve symptoms and complications of the hy-percortisolism during the investigation in order to improve our patient’s clinical conditions for surgery. Ketoconazole is an antimycotic agent that interferes with several cytochrome P-450-dependent enzymes and acts by inhibiting several enzymes involved in adrenal and gonadal steroid production (4). Steen et al. also suggested a direct effect of the drug on ec-topic ACTH secretion from a thymic carcinoid tumor (21). However, the major side effect of ketoconazole is hepatotoxicity (22). Hepatic transaminases revers-ibly elevate in approximately 5-10% of patients, but serious hepatic injury is rare, described at around 1 in 15,000 patients (23). Ketoconazole hepatotox-icity is idiosyncratic, and was reported in a patient with Cushing’s syndrome within 7 days of the start of treatment (24). Because of the cholestatic syndrome present in our patient, ketoconazole was withdrawn and octreotide initiated. It has been reported that

the SS analogue, octreotide, did not inhibit ACTH release in vivo in ACTH-secreting pituitary tumors (25), despite the in vitro evidence of the presence of SS receptors in human adenomatous corticotrophs (26, 27). On the contrary, chronic administration of octreotide in ectopic ACTH syndrome directly inhib-its ACTH release, contributing to the management of hypercortisolism. This effect is attributed to the pres-ence of SS and octreotide receptors in the majority of tumors of neuroendocrine origin (28-31). An adverse effect of octreotide, especially with long-term use, is the increased incidence of cholesterol gallstones, occurring in 20-30% of patients (32). Several factors probably contribute to the formation of gallstones, such as inhibition of gallbladder emptying and intes-tinal motility, inhibition of the secretion of prokinetic peptides such as cholecystokinin and increased in-testinal and biliary production of deoxycholic acid, all of which promote the nucleation and aggrega-tion of cholesterol crystals (33). Since there was no improvement in our patient’s cholestatic alterations after ketoconazole withdrawal, all drugs were sus-pended and the CT-guided PEI was performed in the most suspicious adrenal nodule. Percutaneous biopsy of pheochromocytomas is usu-ally not attempted because of potential complica-tions, such as hemodynamic instability, hypertensive crises followed by hypotension or cardiac arrhyth-mias, during manipulation of tumors by stimulating cathecolamine secretion, and uncontrolled adrenal hemorrhage because of the increased vasculariza-tion of this kind of adrenal tumor (34-36).Wang et al. presented a series of 41 patients submit-ted to CT-guided PEI for the treatment of pheochro-mocytoma (37). It has been reported that ethanol may cause vascular embolism, dehydration and co-agulative cell necrosis, and, in pheochromocytomas, it has a tumor-necrotizing effect, eradicating the source of abnormal catecholamine secretion (38). We presented the first case of an ectopic ACTH-se-creting pheochromocytoma treated with CT-guided PEI. The choice of this procedure was due to the lack of clinical conditions of the patient in order to be submitted to surgery. A surgical procedure was prevented by liver dysfunction and severe cholesta-sis. The pharmacokinetic parameters of anesthetics, muscle relaxants, analgesics, and sedatives could change due to decreased binding to plasma pro-teins, detoxification or excretion. Susceptibility to infections could be further increased because of the altered function of hepatic reticuloendothelial cells and other changes in the immune system. Important post-operative hepatic dysfunction is more likely to occur in patients with pre-existing liver disease. Stud-ies of patients with obstructive jaundice identified

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some predictors of post-operative mortality, which included hematocrit values less than 30%, bilirubin levels greater than 11 mg/dl and hypoalbuminemia (39). Such patients, as ours, are at a particular risk of hypotension and acute renal failure (40). Neverthe-less, if continuous monitoring of vital signs is pro-vided, especially arterial pressure, CT-guided PEI seems to be a relatively safe management of ectopic ACTH syndrome caused by pheochromocytoma, es-pecially in patients with contraindication to surgical procedure (37).As described above, our patient was prepared for the PEI by receiving prazosin, an -receptor antago-nist, to control hypertension and prevent the risk of severe hypotension after it. The volume of 40 ml of ethanol was sufficient to contrast the whole tumor during the procedure. Despite the use of prazosin, he actually presented transient hypertension fol-lowed by hypotension, which was corrected with dopamine infusion and fluid replacement. The diagnosis of pheochromocytoma was confirmed by histological analysis and the clinical and biochem-ical evolution of the patient after PEI confirmed the diagnosis of ectopic ACTH-secreting pheochromo-cytoma. There was no recurrence of Cushing’s syn-drome 21 months after the procedure, but long-term follow-up will be necessary to prove the success of CT-guided PEI. In summary, we reported the first case of ectopic ACTH syndrome due to a pheochromocytoma treat-ed successfully by CT-guided PEI with resolution of Cushing’s syndrome and normalization of catecho-lamine levels.

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