Cardiac Arrest in a Patient With Asthma: Role of Hemorrhagic Pheochromocytoma Discovered at Autopsy

It is extremely rare that an unprovoked, occult, and benign pheochromocytoma causes death in modern times.1 Here we describe such a case and address the role of intratumoral hemorrhage in the patient’s death. A previously healthy, 57-year-old woman suddenly felt nauseated and vomited in the early evening, with simultaneous development of shortness of breath. She went to the emergency department 4 hours later. Her medical history was remarkable only for asthma (for which she took inhaled fluticasone and salmeterol as needed) and mild glucose intolerance. She did not have a history of hypertension or paroxysmal palpitation, headache, or sweating. Her family history included melanoma and breast cancer. At the emergency department she was found to be afebrile, with a pulse rate of 86 beats per minute, respiratory rate of 24 breaths per minute, blood pressure of 104/81 mm Hg, and oxygen saturation of 97% on oxygen supplementation (2 L/min). Capillary blood glucose was 187 mg/dL. Physical examination revealed wheezing on bilateral lung fields without other abnormal findings. The patient was given inhaled asthma treatment without improvement and her breathing became more labored and her hands turned cold. Two hours after arriving at the emergency department, her pulse rate was 96 beats per minute, respiratory rate was 29 breaths per minute, blood pressure was 65/47 mm Hg, and oxygen saturation was 79% on 2 L/min oxygen supplementation. Her oxygen saturation continued to deteriorate and hypotension persisted. Two and half hours after arriving at the emergency department she was intubated. She developed supraventricular tachycardia and was given adenosine 3 consecutive times, 6, 12, and 18 mg each, without slowing heart rate. She became profoundly hypotensive and went into asystole at 4 hours after arriving at the emergency department. Cardiopulmonary resuscitation was unsuccessful and the patient died. Laboratory tests drawn at half an hour before death showed a white blood cell count of 18.2/nL, glucose 319 mg/dL, sodium 139 meq/L, potassium 5.0 meq/L, bicarbonate 8 meq/L, creatinine 2.5 mg/dL, troponin 36.04 ng/mL (<0.3), brain natriuretic peptide 804 pg/mL (<100), pH 6.94, and carbon dioxide partial pressure 37.6 mm Hg. Electrocardiography and echocardiography were not performed. An autopsy was performed 2 days after the patient’s death. There were bilateral moderate serosanguineous pleural effusions present. The heart was of normal size, weighed 320 g, and had normal ventricular wall thickness (2.0 cm for the left and 1.0 cm for the right). The coronary arteries harbored moderate atherosclerosis without thrombi. The right adrenal gland contained a 5.2×4.7×2-cm mass, weighing 45 g. The cut surface of the mass was diffusely hemorrhagic with focal cystic degeneration (Figure 1A). The left adrenal gland, other visceral organs, and the brain were grossly unremarkable. Microscopically, the right adrenal tumor showed typical features of pheochromocytoma (Figure 1B). The tumor cells were diffusely and strongly positive for neuroendocrine markers chromogranin A and synaptophysin (Figure 1C). There was extensive accumulation of extravasated red blood cells but no hemosiderin-laden macrophages. Microscopic examination of the heart revealed many wavy, hypereosinophilic myocardial fibers, accompanied by diffuse interstitial edema with infiltration by neutrophils (Figure 1D). Patchy areas of interstitial fibrosis and scarring were evident especially at the apex (Figure 1E). The lungs displayed features of pulmonary edema and asthma. It is highly likely that the pheochromocytoma caused the cardiogenic shock and death based on the following lines of evidence. The patient’s pheochromocytoma was likely highly functional, as sizeable adrenal pheochromocytomas are usually biochemically very active.1 The patient’s myocardial scarring, suggesting chronic myocardial damage, also supports that her pheochromocytoma had been biochemically active for some time. The patient’s chronic and acute myocarditis and increased cardiac enzymes and brain natriuretic peptide levels before death are consistent with catecholamine-induced cardiomyopathy.2 More importantly, there is no clinical or pathological evidence of atherosclerosis, alcoholism, valvular disease, or drug toxicity, more common causes of cardiomyopathy. (A) Coronal section through dissected left adrenal mass. The lesion is of a dark brown color with fine granular texture. It is surrounded by a thin capsule and contains blood-tinged cystic degeneration. (B) Microscopic section of the left adrenal mass reveals pleomorphic tumor cells with open chromatic, large nucleoli and deep magenta-colored granular cytoplasm. Note the extravasated erythrocytes. (C) The tumor cells are positive for chromogranin A, stained with immunoperoxidase technique. (D) Sections of the heart show wavy cardiomyocytes associated with influx of interstitial leukocytes. (E) Masson trichrome stain of the left ventricular apex shows extensive old fibrosis (papillary muscle and endocardium is on the right and epicardial surface is on the left). Original magnifications: ×200 (B and D), ×100 (C), and ×50 (E). The classical paroxysmal symptoms and hypertension are only present in a fraction of patients with pheochromocytoma in modern practice and approximately a third of patients present with an incidentally identified adrenal mass.3 The most severe complications of pheochromocytoma: congestive heart failure or cardiogenic shock, can unfortunately be the presenting syndrome.2 The triggering event of acute cardiac complications may be stress-related.4 Although hemorrhage into a pheochromocytoma can be associated with sudden release of catecholamines,5 the role of the diffuse hemorrhage in this patient’s pheochromocytoma in causing acute myocarditis is not immediately clear. We therefore examined the significance of intratumoral hemorrhage in 63 patients at our institution for whom gross pheochromocytoma morphology was available (Table). The 63 patients were divided into 4 groups: (1) those without hemorrhage, necrosis, or cystic changes; (2) those without hemorrhage but with necrosis or cystic changes; (3) those with focal hemorrhage; and (4) those with patchy or diffuse hemorrhage. Intratumoral hemorrhage was common and 37 of the 63 patients (59%) had pheochromocytoma with various degrees of hemorrhage. The demographics of the 4 groups were similar. Tumor size in the first group was significantly smaller than that in the remaining three groups. Biochemical marker levels were significantly higher in patients who had pheochromocytomas with hemorrhage (the third and fourth group combined). More patients with hemorrhagic pheochromocytoma presented with cardiac complications (7 of 30=23%) than those without (3 of 23=13%), but the difference was not statistically significant. Furthermore, patients with diffuse intratumoral hemorrhage had even higher rates of cardiac complications (27%). Therefore, the diffuse hemorrhage in this patient’s pheochromocytoma may have contributed to her acute myocarditis. The patient had an atypical presentation of a rare disease. She had no classical symptoms suggesting pheochromocytoma before the acute presentation. In the emergency department, had electrocardiography or chest radiography been done, the likely abnormal ST-T changes and pulmonary edema could have been noted and cardiac disease suspected. It is not clear whether cardiac supportive measures including intraaortic balloon pump could have helped stabilize her condition.6 Adenosine given for reverting supraventricular tachycardia in this patient also antagonizes catecholamine action at the myocardium and prevents hypertensive crisis of pheochromocytoma.7 In patients with pheochromocytoma-induced cardiomyopathy, adenosine’s side effect of torsades de pointes associated with preexisting long QT syndrome8 makes its use somewhat concerning as such patients often already have prolonged QT.9 In this patient, however, torsades de pointes did not occur after adenosine use, so adenosine unlikely contributed to the patient’s rapid decline. This case illustrates that pheochromocytoma can cause sudden cardiac complications and death without history of classical signs and symptoms. The diffuse intratumoral hemorrhage may play a role in releasing large amounts of catecholamines and contribute to the sudden onset of cardiac complications.