Continuing Education Activity

Cardiac pheochromocytoma is a rare type of primary cardiac tumor. It is a catecholamine-secreting tumor that can cause serious morbidity and mortality if not promptly diagnosed and treated. This activity outlines the clinical presentations, pathophysiology, histopathology, evaluation, treatment, and prognosis of cardiac pheochromocytomas. It highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of cardiac pheochromocytomas.
• Describe the most common presentations of cardiac pheochromocytomas.
• Outline the management options available for cardiac pheochromocytomas.
• Summarize interprofessional team strategies for improving care coordination and communication to advance and improve the outcomes of cardiac pheochromocytomas.

Introduction

Cardiac pheochromocytomas (CPs) are very rare primary neuroendocrine catecholamine-secreting tumors that arise from the sympathetic paraganglia, which is made up of (chromaffin) cells. Paraganglia are non-neuronal cells that originated from the neural crest. The incidence of primary cardiac tumors ranges from 0.01 to 0.3% by autopsy.[1]. Thus far, CP is the rarest form of primary cardiac tumors. Nearly 98% of pheochromocytomas are found in the abdomen, with the adrenal gland being the most common site).[2] Less than 2% of pheochromocytomas are found in the chest, with the heart being the least common site. Most of the reported cases of CP were benign.[2] Although malignant pheochromocytomas are uncommon, the ones arising from the heart appear more aggressive and difficult to resect. In a small clinical data of 158 patients, where 137 of these patients had detailed imagings, 85% (117/137) of the patients were found to have an intra-pericardiac tumor, either arose from branchiomeric paraganglia (in the roots of the great vessels including pulmonary artery, pulmonary vein, vena cava, and aorta) or visceral autonomic paraganglia( interatrial or interventricular groove).[2] CP is an extremely vascular tumor that mostly obtains its blood supply from the coronary circulation (right coronary artery > left circumflex artery > left coronary artery > left anterior descending artery).[2][3]

Etiology

Although there is no clear data available, recent data reports that genetic mutations and familial etiology contribute up to 25% to 50% of pheochromocytomas.[3] In the literature review, one case of cardiac pheochromocytoma was associated with multiple endocrine neoplasia (MEN) was reported [4]. The following syndromes have been found to be associated with pheochromocytomas in general.[3][5] Multiple endocrine neoplasia type 2 (RET gene), neurofibromatosis 1 (NF1), Von Hippel-Lindau disease (VHL gene), adrenocortical adenoma and/or endocrines tumors as in Carney’s triad and paraganglioma syndromes type 1, 3, and 4 (SDH gene). Thirty percent (30%) of patients with malignant adrenal pheochromocytomas and forty-eight percent (48%) of patients with malignant paragangliomas (extra-adrenal pheochromocytomas) are found to have germline mutations of succinate dehydrogenase subunit B (SDH).[3] It is possible that CPs are also associated with the above syndromes.

Epidemiology

Cardiac pheochromocytomas (CPs) represent the rarest form of primary cardiac tumors. The incidence of primary cardiac tumors ranges from 0.01 to 0.3% by autopsy.[1] Only less than 2% of pheochromocytomas are found in the chest, and of these, CP accounts the least of all. Less than 300 patients with CP are described in the PubMed database.[2] The mean age at diagnosis is 40 years (ranges from 12 to 85 years) with equal distribution in both genders, although data is limited. In general, catecholamine-secreting tumors occur less than 0.2% of patients with hypertension.[6]

Pathophysiology

Cardiac pheochromocytomas are catecholamine secreting tumors that arise from chromaffin cells of the sympathetic paraganglia in the heart. They are often characterized by excessive, often episodic catecholamine production and/or secretion (Like epinephrine, dopamine, and norepinephrine) that can lead to signs and symptoms like hypertension, sweating, headache, dizziness, perspiration, palpitations, and tachycardia.[2]

Histopathology

• Macroscopically, CP are highly vascular tumors with well-defined hemorrhagic cut surfaces and rarely have an obvious pedicle.[2] Usually, these tumors are highly adjacent to the surrounding tissues without direct invasions. However, extensive myocardial infiltration may also be noted. In 14 patients, the mean weight of the tumor was 76 gram (ranges, 12.5 to 137 gram). Their maximal diameter ranged from 1.5 to 15 cm (mean diameter 5.3).
• Histologically, like most of the paragangliomas, this tumor is mainly composed of chief cells grouped in clusters or organoid (“Zellbellen”) fashion with surrounding capillary networks. Pigmented CPs were also reported in a few patients.[2][7]
• Malignancy diagnosis is mainly based on metastasis rather than histologic features.

History and Physical

The most common presentations of cardiac pheochromocytomas are catecholamine-related symptoms:[2] palpitations, sweating, diaphoresis, hypertension, tachycardia, dizziness, headache, syncope, perspiration, and flushing. Unlike other primary cardiac tumors, shortness of breath is uncommon. Although uncommon, some patients may present with chest pain. The likely explanation of the chest pain is that the tumor itself may mimic angina if it does not get enough blood supply. Sometimes initial presentation can be nonspecific: fever, fatigue, and weight loss. These tumors are rarely asymptomatic.

Evaluation

Once there is a suspicion of a pheochromocytoma, one should keep in mind that 98% of these tumors are intra-abdominal (90% in the adrenal medulla), and less than 2% are found in the chest. Of these in the chest, CP is one of the rarest ones.

Biochemical Testing

• Cardiac pheochromocytoma can be confirmed or excluded with biochemical testing by using serum and urine metanephrines.[8] Plasma metanephrines have sensitivity and specificity of 99% and 89%, respectively, while urine metanephrines have sensitivity and specificity of 97% and 93%, respectively. Although less accurate compared to metanephrines, urine, and total serum catecholamines can be obtained as well.
• Once pheochromocytoma is diagnosed with chemical testing, then the tumor has to be localized. Since the abdomen, especially the adrenal gland, is the most common site, intra-abdominal imagings should be done to rule out intra-abdominal pheochromocytomas.

Tumor Localization

The most difficult part of this tumor is not by diagnosing it but to localize it. There is a number of imagings (including but not limited to CT or enhanced CT, PET scan, MRI, echocardiogram, labeled metaiodobenzylguanidine (MIBG), or Tc labeled octreotide) that can be used. The most important imagings for CP localization will be reviewed below.

• Iodine labeled metaiodobenzylguanidine (MIBG) is the most effective method to screen cardiac pheochromocytomas. It is very useful to identify the tumor and also detect the presence of metastasis.
• Echocardiogram: transthoracic echocardiogram (TTE) is less sensitive than transesophageal echocardiogram (TEE) as tumors are often retro-pericardiac. When the tumor is firmly and extensively adherent to the pericardium, both of them are less sensitive.
• Magnetic Resonance Imaging (MRI): cardiac MRI is very sensitive compared to CT scan and echocardiogram for localization. It can also identify the relation of the tumor to the surrounding structures.
• Cardiac angiogram (cardiac catheterization): This is indispensable pre-operative imaging of CP. It can localize both the tumor and the feeding vessels.

In summary: MIBG, MRI, and coronary angiogram are indispensable pre-operative imaging modalities for tumor localization after laboratory confirmation.

Treatment / Management

The most effective treatment of cardiac pheochromocytomas is surgical resection.[9][10] However, blood pressure has to be controlled pre-operatively. Blood pressure normalization can be achieved with alpha-blockers (doxazosin, urapidil, phenoxybenzamine) initiating 2 to 3 weeks prior to the surgery. Other medications that can be used are calcium channel blockers (amlodipine, nifedipine) and angiotensin-converting enzyme inhibitors (ramipril).[11] It is very important to avoid using beta blockers until good blood pressure control with alpha-blockers. Isolated beta-blocker use can cause a catecholamine storm and hypertensive crisis.[11] It is recommended to start beta-blockers 2 days prior to surgery to control heart rate. There is no known role for chemoradiation.[3]

Differential Diagnosis

In general, differential diagnosis of pheochromocytomas is broad, and these include but not limited to adrenal pheochromocytomas, hyperthyroidism, thyroid storm, cardiac arrhythmias, carcinoid tumor, migraine, stroke, medullary thyroid carcinoma, mastocytosis, etc.

In patients with a confirmed cardiac mass, the differential diagnosis may include pericardial mass, abscess, or metastasis.

Surgical Oncology

The most effective treatment of cardiac pheochromocytomas is surgical resection. 

Prognosis

The one- year and 5- year survival rate date of 91 patients who had benign CP were 98.2% and 78.8%, respectively.[2] Although data is limited, overall prognosis and recovery are quite good after complete resection. For malignant CP, the prognosis is not clear yet, as not enough data is available.

Complications

Complications can be related to either the disease itself or the procedure. Since it is a catecholamine-secreting tumor, if not treated, it can cause ischemic heart disease, myocardial infarction, cardiac arrhythmias, cardiomyopathy, pulmonary edema, stroke, and hypertensive crisis. The procedure is high risk. CP is a highly vascular tumor. In data of 100 patients, 5 died due to massive intraoperative bleeding.

Enhancing Healthcare Team Outcomes

An interprofessional approach including a cardiologist, a cardiothoracic surgeon, an oncologist, an electrophysiologist, an intensivist, an internist, and the nurse is required for proper care and management of patients with CP. The overall prognosis is quite good after total resection.