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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1077
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 563-569
Copyright © 2005 by The Endocrine Society

CLINICAL CASE SEMINAR

Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension

Hilary Brown1, Philip A. Goldberg1, Jared G. Selter1, Henry S. Cabin, Norman J. Marieb, Robert Udelsman and John F. Setaro

Sections of Endocrine Surgery (H.B., R.U.), Endocrinology (P.A.G., N.J.M.), and Cardiovascular Medicine (J.G.S., H.S.C., J.F.S.), Yale University School of Medicine, New Haven, Connecticut 06520-8017

Address all correspondence and requests for reprints to: John F. Setaro, M.D., 333 Cedar Street, 3 FMP, P.O. Box 208017, New Haven, Connecticut 06520-8017. E-mail: john.setaro{at}yale.edu.


   Abstract
Top
 Abstract
Introduction
 Case Report
 Discussion
 Conclusions
 References
 
Pheochromocytomas classically present with paroxysms of hypertension and adrenergic symptoms including headaches, palpitations, tremor, and anxiety. However, these tumors can be clinically silent and occasionally present only when catecholamine release is up-regulated by exogenous stimuli. In addition, the clinical presentation of pheochromocytoma can mimic a number of more common medical conditions, including migraine headaches, cardiac arrhythmias, and myocardial infarction, making diagnosis difficult. In this report, we present the case of a young woman who, while receiving oral corticosteroid therapy for presumed migraine headaches, suffered a myocardial infarction and ultimately hemorrhaged into a previously undiagnosed pheochromocytoma. Our patient exhibited severe, labile hypertension after the administration of iv ß-blockade for presumed myocardial ischemia, raising our initial clinical suspicion for pheochromocytoma. In this paper we review some of the key clinical issues related to this complex case, including steroid-induced stimulation of catecholamine synthesis and release, the role of pheochromocytoma in myocardial ischemia and electrocardiographic changes, and the rare complication of tumor hemorrhage. We then briefly review the essential diagnostic and management strategies for this rare but potentially lethal tumor, with specific emphasis on pheochromocytoma-related cardiovascular emergencies and the surgical management of tumor hemorrhage.


   Introduction
Top
 Abstract
 Introduction
Case Report
 Discussion
 Conclusions
 References
 
PHEOCHROMOCYTOMAS ARE RARE neuroendocrine tumors deriving from chromaffin cells of the sympathetic nervous system. These tumors usually secrete catecholamines, leading to paroxysms of hypertension and/or clinical manifestations including headache, palpitations, tremor, and anxiety (1). When multiple adrenergic symptoms are present, the diagnosis of pheochromocytoma can be quite straightforward. However, due to the rarity of these tumors, they may evade clinical detection for several years; such a delay in diagnosis can be catastrophic. In this report, we present an unusual case of hemorrhagic pheochromocytoma, temporally associated with oral corticosteroid therapy and presenting as acute myocardial infarction (MI) with severe labile hypertension. We then review several key issues related to the case, including steroid-induced stimulation of catecholamine synthesis and release, the role of pheochromocytoma in myocardial ischemia and electrocardiographic changes, and the rare complication of tumor hemorrhage. Finally, we briefly discuss essential diagnostic and management strategies for this rare but potentially lethal tumor.


   Case Report
Top
 Abstract
 Introduction
 Case Report
Discussion
 Conclusions
 References
 
S.M., a 44-yr-old woman, presented to a community hospital complaining of substernal chest pressure, palpitations, and headaches. Her medical history was notable only for treated hypothyroidism and migraine headaches. She was a nonsmoker, and she had no prior history of hypertension. Over the last 3 yr, S.M. had reported gradually increasing frequency and severity of her migraines. These chronic headaches had not been associated with sweating, chest pressure, or palpitations. After a normal magnetic resonance imaging (MRI) scan of the brain, S.M. had been prescribed several prophylactic headache medications, without clinical success. Three days before her presentation, she began a therapeutic trial of oral dexamethasone, 2 mg three times daily. Within 24 h of her first steroid dose, severe headaches ensued, with the concurrent development of new, progressively worsening paroxysms of diaphoresis and heat intolerance. On d 3 of corticosteroid therapy, she then experienced chest heaviness, dyspnea, palpitations, and nausea, prompting her urgent evaluation.

In the emergency room, S.M. appeared anxious, diaphoretic, and tremulous. At that time, her heart rate was just 83 beats per minute, with a mildly elevated blood pressure of 138/88 mm Hg. Her physical examination, including an abdominal exam, was otherwise unremarkable. Electrocardiography (ECG) showed biphasic T waves in the anteroseptal and high lateral leads, and her initial cardiac troponin I level was 0.76 ng/ml (normal < 0.05 ng/ml). At the community hospital, the patient was treated with aspirin, a single dose of low-molecular-weight heparin, and metoprolol for presumed acute coronary syndrome. Daily oral corticosteroid therapy was continued. Transthoracic echocardiography revealed normal chamber sizes, normal valves, and a mildly depressed ejection fraction of 45%, with septal and anterolateral hypokinesis. On the day after admission, persistent chest pains and dynamic ECG changes prompted the patient’s transfer to our tertiary care hospital for further management.

Asymptomatic and normotensive on arrival, S.M. soon developed recurrent chest pressure with diaphoresis, palpitations, and severe headache. Repeat ECG revealed lateral T-wave inversions and new lateral ST-segment depressions (Fig. 1Go). While awaiting coronary angiography, iv metoprolol was administered for presumed recurrent cardiac ischemia. This administration of ß-blockade was followed immediately by acute worsening of the patient’s chest pressure, palpitations, and headache. Additionally, her blood pressure paradoxically rose to 260/165 mm Hg, raising our clinical suspicion of pheochromocytoma. Given the patient’s recurrent angina, dynamic ECG changes, and positive serum cardiac markers, urgent coronary angiography was performed despite the suspicion for pheochromocytoma. The patient’s coronary arteries were free of atherosclerosis. In the catheterization laboratory, ß-blockers were withheld; paroxysms of hypertension were managed with iv nitroglycerine and labetalol.



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  		FIG. 1. ECG during recurrent chest pain showing lateral ST-segment depressions and T-wave inversions.

 
Following angiography, oral steroid therapy was discontinued. Oral terazosin therapy [1 mg twice a day (bid)] was instituted, and blood and urine screening tests were ordered to rule out pheochromocytoma. Serum chemistries and fasting lipid profile were unremarkable, ß-human chorionic gonadotropin was negative, TSH was 0.79 mIU/liter, and subsequent serum cardiac markers revealed elevated creatinine kinase-myocardial band (8.4 IU/liter, normal < 5 IU/liter) and troponin I levels [2.3 ng/dl (0.023 µmol/liter), normal < 0.9 ng/dl (<0.009 µmol/liter)].

The following morning, S.M. reported new right-upper-quadrant abdominal pain, associated with a blood pressure of 84/48 mm Hg and a drop in hematocrit from 47 to 29%. Urgent surgical consultation was obtained. Abdominal computed tomography (CT) revealed a heterogenous 5.3 x 4.2 cm right adrenal mass with retroperitoneal hemorrhage. Concurrently, the 24-h urine collection returned with marked elevations in epinephrine (16,100 µg, normal < 20 µg), norepinephrine (9,500 µg, normal < 80 µg), and vanillylmandelic acid (157 mg, normal < 5 mg) levels. Elevated plasma-free metanephrines (13.6 nmol/liter, normal < 0.5 nmol/liter) and free normetanephrines (11.3 nmol/liter, normal < 0.9 nmol/liter) were documented 3 d later. Because the patient maintained her hemoglobin and stable hemodynamic parameters, surgery was deferred to optimize preoperative adrenergic blockade.

Two days after the CT, MRI of the abdomen confirmed a 6.2 x 5.0 cm right adrenal mass with foci of internal and peripheral hemorrhage (Fig. 2Go, A and B). Repeat echocardiography revealed a hyperdynamic left ventricle with near cavity obliteration during systole, a left ventricular ejection fraction greater than 80%, and no regional wall motion abnormalities. In further preparation for surgery, metyrosine therapy was added, with concurrent titration of oral {alpha}- and ß-blockade. At the time of surgery, the patient was receiving terazosin 3 mg bid, metoprolol 50 mg bid, and metyrosine 500 mg every 6 h.



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  		FIG. 2. MRI sagittal section (A) and cross-section (B) showing right-sided pheochromocytoma (white arrows).

 
On her 12th hospital day (i.e. after 10 d of medical therapy), S.M. underwent successful tumor resection via a subcostal incision. (Fig. 3Go). During surgery, blood pressure was well controlled. There was a single, unexplained episode of bradycardia that responded rapidly to glycopyrolate 0.2 mg iv. Complete tumor resection was accomplished en bloc along with the organizing retroperitoneal thrombosis that had resulted from the recent tumor hemorrhage. The patient had an uneventful postoperative course and was discharged home on the third postoperative day, normotensive and without further need for antihypertensive therapy. Pathologic examination confirmed a 6.8-cm pheochromocytoma with focal capsular and vascular invasion, marked tumor mitotic activity, and extensive tumor necrosis with organizing thrombus (Fig. 4Go, A and B). All surgical margins were free of tumor. Two months after surgery, the patient remained normotensive and clinically well. At an outside laboratory, her 24-h urine catecholamine and metanephrine levels returned to within reference ranges.



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  		FIG. 3. Intraoperative photograph demonstrating the pheochromocytoma (Pheo) and its relation to the right kidney and the inferior vena cava (IVC).

 


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  		FIG. 4. Histopathology showing tumor cells in blood vessel (vascular invasion) (A) and high mitotic index (black arrows) (B).

 

   Discussion
Top
 Abstract
 Introduction
 Case Report
 Discussion
Conclusions
 References
 
This case of hemorrhagic pheochromocytoma, temporally associated with oral corticosteroid therapy, presented as acute MI with severe, labile hypertension after the administration of iv ß-blockade. Several aspects of this dynamic case remain open to interpretation. For example, the precise timing of the tumor hemorrhage remains unclear. Early hemorrhage into the tumor could certainly have led to the patient’s presenting symptoms. However, it is equally plausible that the tumor hemorrhage occurred during or after coronary angiography. And whereas it is reasonable to conclude that corticosteroids precipitated this patient’s catecholamine crisis, the precise role played by the dexamethasone in her subsequent clinical course is difficult to ascertain. On the following pages, we review some of the important clinical issues directly relevant to this complex case.

Corticosteroids precipitating pheochromocytoma crisis

Although our patient appears to be the first reported case of a hemorrhagic pheochromocytoma temporally associated with corticosteroid therapy, previously published case reports have described pheochromocytoma presenting after steroid administration. In 1970 Cowley et al. (2) described a 57-yr-old man who developed anxiety, diaphoresis, epigastric pain, and severe hypertension (300/170 mm Hg) during an ACTH stimulation test. A 4-cm pheochromocytoma was later discovered. In 1977 Daggett and Franks (3) reported a 69-yr-old woman with giant cell arteritis who presented with palpitations, tremor, and severe hypertension during her third day of oral prednisone therapy (45 mg daily). In this case, when the prednisone dose was reduced to 5 mg daily, the patient’s symptoms resolved quickly and blood pressure returned to normal. A pheochromocytoma was later confirmed. Notably, 100 mg iv hydrocortisone given in preparation for the latter patient’s preoperative arteriogram led to acute, severe, and symptomatic hypertension.

Corticosteroids exert several clinically relevant effects on the synthesis and release of catecholamines. Epinephrine is synthesized from norepinephrine through the action of phenylethanolamine-N-methyl-transferase (PNMT) (4). Converging lines of evidence suggest that this adrenomedullary enzyme can be induced rapidly by adrenocortical steroid hormones (5). For example, following hypophysectomy in animal models, PNMT activity falls precipitously; PNMT activity can be rapidly restored by treating with ACTH or hydrocortisone (6). Additionally, steroid administration augments the release of catecholamines from isolated perfused dog adrenal glands (7). In the G1 cell line of rat pheochromocytoma, glucocorticoids induce tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (8). Dopamine ß-hydroxylase, another enzyme in the catecholamine synthetic pathway, is likewise stimulated by high glucocorticoid levels (9). Finally, corticosteroids have been shown to stimulate catecholamine synthesis in PC12 pheochromocytoma cell cultures (10).

Aside from their effects on catecholamine synthesis and release, corticosteroids also appear to play a permissive role in the action of catecholamines on peripheral tissues, including the cardiovascular system (11, 12). In animal models, adrenalectomy raises the threshold for catecholamine-induced vasoconstriction, whereas restoration of normal steroid levels rapidly reverses this phenomenon (13, 14). Additionally, in normal human subjects, pretreatment with ACTH or cortisone increases the pressor response to infused norepinephrine (15). Similarly augmented responses occur in human subjects with previously documented adrenal insufficiency (12).

In our patient (S.M.), oral corticosteroid therapy was clearly and temporally associated with the abrupt onset of signs and symptoms consistent with pheochromocytoma. In light of the published clinical and laboratory experience summarized above, we believe that this temporal association was unlikely to have been coincidental. Whether steroids played a role in the eventual hemorrhage of our patient’s tumor certainly remains unclear because other explanations for tumor hemorrhage are equally plausible (e.g. intraarterial contrast agents, {alpha}-blockade, and low-molecular-weight heparin). To our knowledge, we are the first to report an association between systemic corticosteroid therapy and hemorrhagic pheochromocytoma.

Hemorrhagic pheochromocytoma: literature review

Including the present case, we identified 42 cases of hemorrhagic pheochromocytoma in the English literature between 1944 and 2004 (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51). For these 42 patients, the mean (± SD) age at presentation was 43 ± 16 yr, with a slight female predominance. Presenting symptoms of abdominal pain and hypertension (and/or hypotension) were most frequently encountered. Three cases of hemorrhagic pheochromocytoma occurred in the setting of trauma (16, 17, 49), whereas three others were associated with systemic anticoagulation (18, 19, 20). In most cases, however, no single underlying cause was identified. In most of the 42 cases, pheochromocytoma was suspected preoperatively, and patients therefore received preparatory adrenergic blockade. In five reports, {alpha}-blockade itself was thought by the authors to contribute to eventual tumor hemorrhage (21, 22, 23, 43, 51).

In 13 (36%) cases, operative intervention was deemed emergent or urgent, and surgery was performed within several hours after initial presentation. In the remainder of surviving patients, operative intervention was elective, with surgery occurring between 1 and 6 wk after diagnosis. The mean size (± SD) of these tumors was 8.3 ± 4.3 cm, with an equal right- and left-sided predominance. Pulmonary edema and the adult respiratory distress syndrome were the two most frequently encountered perioperative complications. Cardiomyopathy, embolic stroke, renal failure, and hepatic dysfunction were also described, as were two cases of colonic ischemia (25, 26). In all, 13 deaths occurred in this series, representing a mortality rate of 31%. However, all 13 of the deaths were reported before 1987, and all nonsurviving patients either required urgent operative intervention or died before surgery (with the diagnosis made at autopsy). In conclusion, whereas an overall review of the literature suggests a high mortality rate for patients with hemorrhagic pheochromocytoma, lower mortality rates should be expected with modern supportive care and careful attention to preoperative adrenergic blockade.

Pheochromocytoma and cardiovascular emergencies

Though detrimental effects of high catecholamine levels on the myocardium have been recognized for nearly a century (52, 53), clinical reports describing the specific association between pheochromocytoma and MI date back to 1975 (54, 55, 56, 57, 58, 59, 60, 61, 62, 63). In all of these cases, myocardial damage was documented by ECG, echocardiography, angiography, and/or necroscopy. In cases in which angiographic or pathological data were presented, fewer than half of these patients had significant coronary atherosclerosis, in marked contrast to classic atherosclerosis-mediated MI (55, 56, 59, 62). Among the minority of patients who did have obstructive coronary artery disease, most also had classic coronary risk factors, such as smoking or dyslipidemia, which could account for the atherosclerosis. This lack of significant coronary atherosclerosis in most patients with pheochromocytoma and MI implies that in these cases, myocardial injury is likely due to either hemodynamic compromise of the myocardium (so-called demand ischemia) or directly toxic effects of catecholamines, including accelerated cell death and fibrosis (64). High catecholamine levels cause demand ischemia by increasing myocardial oxygen consumption, augmenting hemodynamic demand on the myocardium, and increasing cardiac afterload (65). In experimental models, the toxic effects of increased catecholamines include the induction of ventricular myocyte apoptosis (66, 67). In humans, direct myocardial damage from catecholamines is likely due to altered autonomic tone, increased lipid mobility, increased intracellular calcium (apoptosis), free radical production, or coronary vasospasm (68, 69).

Confounding the diagnosis of MI in patients with pheochromocytoma are the ischemic-appearing ECG changes often associated with the tumors themselves (70). Pheochromocytomas can present with pathologically inverted T waves (71, 72, 73, 74), hyperacute T waves, precordial T-wave changes (75, 76), diffuse low voltage (77), and other nonspecific ECG changes, even in the absence of myocardial ischemia (78). It should be noted, however, that for patients with pheochromocytoma presenting between clinical paroxysms, electrocardiography may in fact be completely normal (79, 80, 81, 82). Catecholamines alter ion transport across cell membranes, thereby increasing the rate of depolarization (56), which likely produces these ischemic-appearing ECG changes. During a pheochromocytoma crisis, the supply-demand mismatch caused by increased afterload, catecholamine-driven tachycardia, and increased myocardial oxygen demand can precipitate true ischemia, leading to ECG abnormalities in the absence of coronary atherosclerosis (73).

Angiography represents a high-risk procedure in patients harboring a pheochromocytoma. Radiocontrast media can precipitate catecholamine release from the adrenal medulla (83), leading to severe hypertension or congestive heart failure (84). Therefore, a high index of suspicion for pheochromocytoma is necessary when approaching a patient before angiography who presents with angina and hypertension in the absence of classic coronary risk factors. Although no formal recommendations exist regarding the treatment of hypertensive crises caused by pheochromocytoma in the cardiac catheterization laboratory, immediate therapeutic strategies must be aimed at lowering blood pressure rapidly and safely. ß-Selective adrenergic antagonists should be avoided because they can worsen hypertension by creating unopposed {alpha}-adrenergic activity. Acceptable therapeutic agents include nonselective adrenergic antagonists (e.g. labetalol), {alpha}-antagonists (e.g. phentolamine), or vasodilatory agents such as nitroglycerine and/or sodium nitroprusside. If a high index of clinical suspicion for pheochromocytoma exists before urgent angiography, these agents should be kept immediately available for rapid administration.

Diagnosis and management of pheochromocytoma in unstable patients

Due to a high incidence of nonfunctioning adrenal incidentalomas found on imaging studies (85, 86), the appropriate selection of patients for pheochromocytoma screening is critical. In addition, the choice of biochemical screening test for pheochromocytoma remains controversial. In 2002 Lenders et al. (87) concluded that "plasma-free metanephrines provide the best test for excluding or confirming pheochromocytoma," based on this test’s superior receiver operating characteristics curves. In 2003 Sawka et al. (88) countered that whereas "fractionated plasma metanephrines are highly sensitive" (97%), they may "lack specificity (85% vs. 98%) when compared with the combination of 24-h urinary total metanephrines and catecholamines." In our view, assigning one test as the single best one for screening for pheochromocytoma is neither prudent nor necessary. The sensitivity and specificity of any biochemical test will necessarily be altered by the specific test methodology (e.g. urinary total vs. fractionated metanephrines), the reference ranges selected, and the types of tumors (i.e. sporadic vs. familial, benign vs. malignant) present in the patient population. Furthermore, certain clinical situations, including tumor hemorrhage, will also profoundly affect catecholamine levels. Local institutional factors also play an important role in biochemical test selection. Whereas a few institutions have rapid access to plasma-free metanephrines, others must send out this test, so that several days may pass before test results become available. However, at certain institutions 24-h urine results can be available several hours after a collection is completed. At other institutions, 24-h urine assays may be run on a far more intermittent basis, limiting their clinical utility.

In emergent clinical situations in which pheochromocytoma is suspected, selecting an appropriately sensitive screening protocol is critical because a missed diagnosis due to a false-negative result could have serious clinical consequences (89). Thus, in the critical care setting, clinicians should consider using 24-h urine collections and plasma-free metanephrines in combination (allowing for institutional variability), to optimize both the sensitivity and timing of the diagnosis.

Whereas it is usually best to establish the diagnosis of pheochromocytoma biochemically before radiologic confirmation is pursued, adrenal imaging may be required early in the course of unstable patients with pheochromocytoma. In these situations, CT remains the imaging modality of choice because it is readily available and can be performed rapidly, even in unstable patients. Even in stable patients, CT usually remains the diagnostic modality of choice, although MRI may allow superior detection of extraadrenal tumors (86). Metaiodobenzylguanidine scanning may be valuable in selected cases due to its high diagnostic specificity (>95%), particularly for extraadrenal tumors. At the present time, octreotide and positron emission tomography scans play very limited roles in the initial diagnosis of pheochromocytoma (86).

The medical management of pheochromocytoma is primarily designed to prepare the patient for definitive surgical resection. {alpha}-Receptor blockade with iv phentolamine or oral phenoxybenzamine is commonly recommended. However, more nonselective {alpha}-blockers (e.g. prazosin, doxazosin, terazosin) have also been employed with clinical success (90, 91). As a therapeutic adjunct, metyrosine, which inhibits the rate-limiting step in catecholamine synthesis (tyrosine hydroxylase), can be used to lower perioperative catecholamine levels, thereby reducing postoperative vasopressor dependence and colloid requirements (92). Medical therapy can usually be rapidly discontinued after successful surgical resection of the tumor.

The timing of surgery for hemorrhagic pheochromocytoma should be determined by each patient’s presentation and clinical course. In malignant cases with life-threatening blood loss and/or hemodynamic instability, emergent intervention is obviously warranted. However, preoperative adrenergic blockade (for at least 7–14 d) is generally preferred where clinically feasible. Once a patient’s hemodynamic stability and intravascular fluid status have been optimized, surgical intervention can then be safely performed on an elective or semielective basis.


   Conclusions
Top
 Abstract
 Introduction
 Case Report
 Discussion
 Conclusions
References
 
We have reported an unusual case of hemorrhagic pheochromocytoma, apparently unmasked by systemic corticosteroid therapy and presenting as MI with severe labile hypertension. Because the key to diagnosing pheochromocytoma is clinical suspicion, this potentially catastrophic tumor should be considered in three distinct clinical situations: 1) adrenergic symptoms or hypertension associated with corticosteroid therapy; 2) ECG changes or acute coronary syndrome in the absence of known coronary risk factors; and 3) severe, labile hypertension after the administration of ß-blockade. Remarkably, all three of these clinical scenarios were present in our patient in addition to the rare and serious complication of tumor hemorrhage.

A review of the literature suggests that hemorrhagic pheochromocytoma carries a high mortality rate. However, more contemporary reports suggest that these patients do quite well, especially in the setting of careful preoperative medical therapy. For stable patients with hemorrhagic pheochromocytoma, adrenergic blockade should be administered with or without metyrosine. Ideally, definitive surgical intervention can then occur once hemodynamic stability has been established. In unstable patients, emergent operative intervention may be required.


   Acknowledgments
 
The authors thank Bethany Austin, M.D.; Jeptha Curtis, M.D.; Richard Donabedian, M.D.; and Silvio Inzucchi, M.D., for their valuable intellectual contributions to this report.


   Footnotes
 
This work was supported by Juvenile Diabetes Research Foundation Fellowship Grant 3-2003-95 (to P.A.G.).

First Published Online October 27, 2004

1 H.B., P.A.G., and J.G.S., listed in alphabetical order, contributed equally to this work and should all be considered first authors of this multidisciplinary paper. Back

Abbreviations: bid, Twice a day; CT, computed tomography; ECG, electrocardiography; MI, myocardial infarction; MRI, magnetic resonance imaging; PNMT, phenylethanolamine-N-methyl-transferase.

Received June 7, 2004.

Accepted October 13, 2004.


   References
Top
 Abstract
 Introduction
 Case Report
 Discussion
 Conclusions
 References
 

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