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Cardiac Chromaffin Cell Pheochromocytoma
Introduction
Cardiac pheochromocytomas are very rare primary neuroendocrine catecholamine-secreting tumors that arise from the sympathetic paraganglia, which are composed of chromaffin cells. Paraganglia are nonneuronal cells that originate from the neural crest. The incidence of primary cardiac tumors ranges from 0.01% to 0.3% on autopsy.[1] Cardiac pheochromocytoma is currently the rarest form of primary cardiac tumor.
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. Notably, most reported cases of cardiac pheochromocytomas are benign.[2] Although malignant pheochromocytomas are uncommon, those arising from the heart appear to be more aggressive and more difficult to resect.
Results from clinical data from a small sample of 158 patients, including 137 patients with detailed imaging, showed that 85% (117/137) had an intrapericardiac tumor that either arose from branchiomeric paraganglia (in the roots of the great vessels, including the pulmonary artery, pulmonary vein, vena cava, and aorta) or visceral autonomic paraganglia (interatrial or interventricular groove).[2][3] Cardiac pheochromocytoma is an extremely vascular tumor that primarily derives its blood supply from the coronary circulation, in order of descending frequency: right coronary artery, left circumflex artery, left coronary artery, and left anterior descending artery.[2][4][5]
Etiology
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Etiology
Although data are limited, results from recent reports indicate that genetic mutations and familial factors account for 25% to 50% of pheochromocytomas.[4][6] Results from the literature review included 1 reported case of cardiac pheochromocytoma associated with multiple endocrine neoplasia.[7] Other genetic syndromes have been associated with pheochromocytomas in general,[4][8] including multiple endocrine neoplasia type 2 (RET gene), neurofibromatosis 1 (NF1), von Hippel-Lindau disease (VHL gene), adrenocortical adenoma and endocrine tumors, including Carney triad and paraganglioma syndromes types 1, 3, and 4 (SDH) gene. Germline mutations in the succinate dehydrogenase subunit B (SDHB) gene are found in 30% of patients with malignant adrenal pheochromocytomas and 48% of patients with malignant paragangliomas (extra-adrenal pheochromocytomas).[4] Cardiac pheochromocytomas can also be associated with the above syndromes.
Epidemiology
Cardiac pheochromocytomas represent the rarest form of primary cardiac tumor. The incidence of primary cardiac tumors ranges from 0.01% to 0.3% at autopsy.[1] Fewer than 2% of pheochromocytomas are found in the chest, and cardiac pheochromocytoma is the least common site. Furthermore, fewer than 300 patients with cardiac pheochromocytoma have been reported in PubMed.[2] The mean age at diagnosis is 40 years (range, 12 to 85 years), with an equal distribution between sexes, although data are limited. In general, catecholamine-secreting tumors occur in fewer than 0.2% of patients with hypertension.[9]
Pathophysiology
Cardiac pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells of the sympathetic paraganglia in the heart. These tumors are often characterized by excessive, episodic catecholamine production or secretion, including excess epinephrine, dopamine, or norepinephrine, which can lead to signs and symptoms including hypertension, sweating, headache, dizziness, perspiration, palpitations, and tachycardia.[2]
Histopathology
Macroscopically, cardiac pheochromocytomas are highly vascular tumors with well-defined hemorrhagic cut surfaces and rarely have an obvious pedicle.[2] Usually, these tumors are closely adherent to the surrounding tissues without direct invasion. However, extensive myocardial infiltration may also be noted. In findings from a report of 14 patients, the mean tumor weight was 76 g (range, 12.5-137 g). The maximum diameter ranged from 1.5 to 15 cm (mean, 5.3 cm).
Histologically, like most paragangliomas, these tumors are composed mainly of chief cells grouped in clusters or in an organoid, Zellballen pattern, with surrounding capillary networks. Pigmented cardiac pheochromocytomas have also been reported in a few patients.[2][10] The diagnosis of a malignant cardiac pheochromocytoma is primarily based on evidence of metastasis rather than on histologic features.
History and Physical
The most common presentation of cardiac pheochromocytomas is catecholamine-related signs and symptoms, including palpitations, sweating, diaphoresis, hypertension, tachycardia, dizziness, headache, syncope, and flushing. Unlike other primary cardiac tumors, shortness of breath is uncommon. Although chest pain is uncommon, some patients may present with this symptom. The likely explanation for chest pain is that the tumor may mimic angina when its blood supply is inadequate. In some patients, the initial presentation can be nonspecific, with fever, fatigue, and weight loss. These tumors are rarely asymptomatic.[2]
Evaluation
Once pheochromocytoma is suspected, clinicians should recognize that 98% of these tumors are intra-abdominal, with 90% located in the adrenal medulla, and fewer than 2% found in the chest. Among thoracic pheochromocytomas, cardiac pheochromocytoma is the rarest.
Biochemical Testing
Cardiac pheochromocytoma can be confirmed or excluded with biochemical testing for plasma or urine metanephrine levels.[11] Plasma metanephrines have a sensitivity and specificity of 99% and 89%, respectively, whereas urine metanephrines have a sensitivity and specificity of 97% and 93%, respectively. Although less accurate than metanephrines, urine and total serum catecholamine levels can be obtained as adjunctive tests. Once pheochromocytoma is diagnosed with biochemical testing, clinicians must localize the tumor. Because the abdomen, especially the adrenal gland, is the most common site, abdominal imaging should be performed to rule out intraabdominal pheochromocytoma.
Tumor Localization
The most difficult part of evaluating cardiac pheochromocytoma is often localization of the tumor. Several imaging studies can be used, including contrast-enhanced CT, positron emission tomography, MRI, echocardiography, iodine-labeled metaiodobenzylguanidine (MIBG), and technetium-labeled octreotide. The most important imaging modalities include:
- Iodine-labeled metaiodobenzylguanidine: MIBG is the most effective method to screen for cardiac pheochromocytomas. This imaging modality is useful for identifying the tumor and detecting metastasis.
- Echocardiography: Transthoracic echocardiography is less sensitive than transesophageal echocardiography because tumors are often retropericardial. When the tumor is firmly and extensively adherent to the pericardium, both modalities are less sensitive.
- MRI: Cardiac MRI is more sensitive than CT and echocardiography for localization. Cardiac MRI can also identify the relationship of the tumor to the surrounding structures.
- Cardiac angiography: Cardiac angiography is indispensable for preoperative imaging of cardiac pheochromocytoma. This modality can localize both the tumor and the feeding vessels.[3][12][13][14][15]
In summary, MIBG, MRI, and coronary angiography are necessary imaging modalities for tumor localization after laboratory confirmation, and clinicians should pursue these studies before the patient is prepared for surgical intervention.
Treatment / Management
The most effective treatment for cardiac pheochromocytomas is surgical resection.[16][17][18] However, blood pressure must be controlled preoperatively.[19] Blood pressure normalization can be achieved with α-blockers, including doxazosin, urapidil, and phenoxybenzamine, which should be initiated 2 to 3 weeks before the surgical procedure. Other medications that can be used include calcium channel blockers (eg, amlodipine and nifedipine) and angiotensin-converting enzyme inhibitors.[20] Clinicians should avoid β-blockers until adequate blood pressure control with α-blockers has been achieved. Isolated β-blocker use can cause a catecholamine storm and hypertensive crisis.[20] β-Blockers should be started at least a few days before the surgical procedure to control heart rate. Chemoradiation has no known role.[4](B3)
Differential Diagnosis
In general, the differential diagnosis for pheochromocytoma is broad and includes adrenal pheochromocytoma, hyperthyroidism, thyroid storm, cardiac arrhythmias, carcinoid tumor, migraine, stroke, medullary thyroid carcinoma, and mastocytosis. Clinicians should consider these conditions when evaluating catecholamine-related symptoms or episodic hypertension. In patients with a confirmed cardiac mass, the differential diagnosis may include a pericardial mass, abscess, or metastasis.
Surgical Oncology
The most effective treatment for cardiac pheochromocytoma is surgical resection.[21]
Prognosis
The 1-year and 5-year survival rates in a report of 91 patients who had benign cardiac pheochromocytomas were 98.2% and 78.8%, respectively.[2][22][23] Although data are limited, overall prognosis and recovery are quite good after complete resection.[4] For malignant cardiac pheochromocytoma, the prognosis remains unclear due to insufficient data.
Complications
Complications can be related to either the tumor itself or the surgical procedure. Because cardiac pheochromocytoma is a catecholamine-secreting tumor, without treatment, the tumor can cause ischemic heart disease, myocardial infarction, cardiac arrhythmias,[24] cardiomyopathy,[25] pulmonary edema, stroke, cardiogenic shock,[26] and hypertensive crisis.[27] Furthermore, the surgical treatment is high risk. Cardiac pheochromocytoma is a highly vascular tumor, complicating surgical intervention. In findings from a report of 100 patients, 5 died because of massive intraoperative bleeding.[2]
Results from a recent study suggested a correlation between the type of hormone oversecretion and the presentation of cardiac complications. Patients with greater normetanephrine excretion presented with more atherosclerotic disease and type 1 myocardial infarction, whereas patients with predominantly metanephrine overproduction presented with more Takotsubo-like cardiomyopathy and type 2 myocardial infarction.[28][29] Results from another study showed that risk factors for developing cardiac complications in patients with a diagnosis of pheochromocytoma included an elevated platelet count and combined hormone oversecretion with epinephrine and norepinephrine.[30]
Consultations
Collaboration between cardiology and endocrinology helps establish the initial diagnosis, while cardiothoracic surgery completes the surgical treatment. Other specialties, including electrophysiology and oncology, should be involved in overall patient care as needed.
Deterrence and Patient Education
Patients and their families need to be educated about the effects of catecholamines on various systems, from the heart to other organs, as well as the potential complications that may arise. Clinicians should prepare patients and families for the surgical approach without causing unnecessary fear, and education should help them understand the different tests and the overall treatment approach.
Pearls and Other Issues
Although pheochromocytomas are rare, the diagnosis should be made early to prevent cardiac complications (regardless of anatomical location). Evaluation for excess catecholamine and metanephrine levels should be considered in all patients with resistant or difficult-to-treat hypertension, as well as in patients with a constellation of symptoms, including unexplained excessive sweating, headaches, and tachycardia. Timely detection can help patients receive early treatment and avoid long-term exposure to the deleterious effects of excess catecholamines, including potentially fatal cardiac complications.
Enhancing Healthcare Team Outcomes
An interprofessional approach, including a cardiologist, cardiothoracic surgeon, endocrinologist, oncologist, electrophysiologist, intensivist, internist, pharmacist, and nurses, may be required for the appropriate treatment of patients with cardiac pheochromocytoma. The overall prognosis is quite good after complete resection.
References
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