Cardiac Chromaffin Cell Pheochromocytoma

Etiology

Although there is no clear data available, recent reports showed that genetic mutations and familial etiology contribute up to 25% to 50% of pheochromocytomas.[4] In the literature review, one case of cardiac pheochromocytoma associated with multiple endocrine neoplasia (MEN) was reported [6]. Other genetic syndromes have been found to be associated with pheochromocytomas in general, [4][7] including Multiple Endocrine Neoplasia type 2 (RET gene), neurofibromatosis 1 (NF1), Von Hippel-Lindau disease (VHL gene), adrenocortical adenoma and/or endocrine 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).[4] The CPs can also be 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 the CP is the least common of all. Less than 300 patients with CP are described in the PubMed database.[2] The mean age at diagnosis is 40 years old (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.[8]

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, episodic catecholamine production and/or secretion (like epinephrine, dopamine, and norepinephrine) that can lead to different signs and symptoms including 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 invasion. However, extensive myocardial infiltration may also be noted. In a report of 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][9]

Malignancy diagnosis is mainly based on metastasis rather than histologic features.

History and Physical

The most common presentation of cardiac pheochromocytomas is with catecholamine-related signs and symptoms[2] including palpitations, sweating, diaphoresis, hypertension, tachycardia, dizziness, headache, syncope, perspiration, and flushing. Unlike other primary cardiac tumors, shortness of breath is uncommon. Also 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 with 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 the rarest one.

Biochemical Testing

• Cardiac pheochromocytoma can be confirmed or excluded with biochemical testing by using serum and urine metanephrines.[10] 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 imaging should be done to rule out intra-abdominal pheochromocytoma.

Tumor Localization

The most difficult part of this tumor is not diagnosing it, but localizing it. There is a number of imaging studies (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 of those studies will be reviewed below.[11][12][13][14][3]

• Iodine labeled metaiodobenzylguanidine (MIBG) is the most effective method to screen for 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 necessary imaging modalities for tumor localization after laboratory confirmation and they should be pursued before patient is scheduled for surgical intervention.

Treatment / Management

The most effective treatment for cardiac pheochromocytomas is surgical resection.[15][16][17] However, blood pressure has to be controlled pre-operatively. Blood pressure normalization can be achieved with alpha-blockers (doxazosin, urapidil, phenoxybenzamine) initiated 2 to 3 weeks prior to the surgery. Other medications that can be used are calcium channel blockers (like amlodipine, nifedipine) and angiotensin-converting enzyme inhibitors.[18] It is very important to avoid using beta-blockers until good blood pressure control with alpha-blockers has been achieved. Isolated beta-blocker use can cause a catecholamine storm and hypertensive crisis.[18] It is recommended to start beta-blockers at least a few days prior to surgery to control heart rate. There is no known role for chemoradiation.[4](B3)

Differential Diagnosis

In general, differential diagnosis of pheochromocytomas is broad, and may include but not be 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[19]. 

Prognosis

The one- year and 5- year survival rate in a report of 91 patients who had benign CP were 98.2% and 78.8%, respectively.[2][20][21] Although data is limited, overall prognosis and recovery are quite good after complete resection.[4] 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 a report of 100 patients, 5 died due to massive intraoperative bleeding.[2]