Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9 years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx germline mutations, suggesting a need for genetic testing of all patients with this rare tumor.
Paragangliomas (PGLs) are rare extra-adrenal chromaffin cell tumors arising from neuroendocrine cells. These tumors have the ability to synthesize, secrete, store, and metabolize catecholamines, leading to clinical manifestations such as hypertension, headaches, palpitations, and sweating. Biochemical diagnosis is based on the measurement of catecholamines and metanephrines in the plasma and/or urine, and tumors can be classified on the basis of their predominant hormone secretion. Currently, 17 genes have been linked to the pathogenesis of PGL, responsible for approximately 35% of cases. Mutations in all 4 subunits (A, B, C, and D) of succinate dehydrogenase (SDH) are some of the most common, particularly SDHB and SDHD. SDH, or mitochondrial complex II, is involved in the Krebs cycle and electron transport chain, linking important cellular metabolic processes. SDH-related tumors are usually extra-adrenal and commonly multiple in number; SDHB mutations have a higher rate of metastases. Cardiac PGLs are extremely rare, constituting 1% to 3% of primary cardiac tumors. Numerous case reports have been published about cardiac PGLs; however, their genetic background, outcomes, and management have not been studied in a large series of patients. The present report summarizes our extensive experience with cardiac PGLs, focusing particularly on their genetic background.
Methods
This was a multi-institutional study that included 15 patients with documented cardiac PGLs who presented to the National Institutes of Health (Bethesda, Maryland), Tufts University Medical Center (Boston, Massachusetts), and Brigham and Women’s Hospital, Harvard Medical School (Boston, Massachusetts). These patients were selected from a large registry of pheochromocytoma and PGL patients available at each institution. Charts were reviewed to determine the genetic backgrounds, biochemical results, imaging studies, surgical pathology, treatments, and outcomes of each patient. The study was reviewed and approved by the institutional review board of each institution. All patients provided written and informed consent.
Blood samples for genetic testing of germline deoxyribonucleic acid were collected. Genomic deoxyribonucleic acid was extracted from whole blood, and polymerase chain reaction–based bidirectional sequencing for SDHB, SDHC, and/or SDHD was performed by Mayo Medical Laboratories (Rochester, Minnesota) or by the Division of Molecular Diagnostics at the University of Pittsburgh Medical Center, as previously described. Testing for large deletions was done with multiplex ligation–dependent probe amplification and Luminex FlexMap Technologies (Luminex Corporation, Austin, Texas).
Tumors were classified as adrenergic (secreting predominantly epinephrine and/or its metabolite metanephrine), noradrenergic (secreting predominantly norepinephrine and/or its metabolite normetanephrine), or dopaminergic (secreting predominantly dopamine and/or its metabolite methoxytyramine) on the basis of their predominant hormone secretion, as previously described. Elevations in biochemistry were defined as any levels higher than the upper reference limit.
Results
A total of 15 patients were identified with cardiac PGLs. The average age at diagnosis was 41.9 years (range 28 to 63). Eight patients were men (53.3%). In most patients, symptoms at presentation were typical for catecholamine excess, with 13 (86.7%) presenting with a combination of palpitations, hypertension, headaches, sweating, and anxiety ( Table 1 ). Six patients (40%), including the 2 patients without catecholamine-related symptoms, also displayed cardiac-related symptoms of chest pain and/or shortness of breath ( Table 1 ). Other less common symptoms seen only in 1 patient included weakness, flushing, sleep apnea, hot flashes, weight loss, and fatigue.
| Patient | Headache | Hypertension | Palpitations | Tachycardia | Anxiety/ Nervousness | Sweating | Nausea/ Vomiting | Dyspnea | Chest Pain |
|---|---|---|---|---|---|---|---|---|---|
| 1 | – | + | – | – | + | – | – | – | – |
| 2 | + | + | + | – | – | – | – | – | – |
| 3 | – | – | – | – | – | – | – | + | + |
| 4 | + | + | + | – | + | + | – | – | – |
| 5 | + | + | – | – | – | + | + | – | – |
| 6 | + | + | – | + | + | + | + | + | + |
| 7 | – | – | – | – | + | + | – | – | – |
| 8 | – | – | + | + | + | – | – | – | – |
| 9 | – | + | – | – | – | – | – | – | – |
| 10 | – | – | – | – | – | – | – | + | – |
| 11 | – | – | + | – | + | – | – | + | – |
| 12 | – | + | + | – | – | – | – | + | + |
| 13 | – | + | – | – | – | – | – | – | – |
| 14 | + | + | – | – | – | – | – | – | – |
| 15 | + | + | + | – | – | – | – | – | + |
Patients were diagnosed with a combination of biochemical testing and multiple imaging studies. All 15 patients underwent biochemical testing with plasma and/or urinary catecholamines and/or metanephrines. One patient (6.7%) had normal catecholamine and metanephrine levels. Of the patients with elevated biochemistry, 13 (92.8%) had noradrenergic phenotypes, with elevations of norepinephrine and/or normetanephrine; 7 of these (53.8%) also had elevated dopamine. The remaining patient (7.1%) had only elevated dopamine. Patients underwent imaging with anatomic and functional imaging technologies. Four patients underwent computed tomography and magnetic resonance imaging (MRI); 3 were positive on each technique. Nine patients underwent cardiac MRI, with all identifying the tumor. Transthoracic echocardiography was performed, with successful tumor localization in 9 patients. The most commonly used functional imaging approach was iodine-123 metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy. Although 11 patients were scanned with this technique, only 6 (54.5%) had positive results for the cardiac tumor. Ten patients underwent positron emission tomography (PET) with 18 F-fluorodeoxyglucose ( 18 F-FDG), and all 10 had positive uptake in the cardiac tumor. Seven patients underwent PET with fluorine-18 fluorodopamine and fluorine-18 fluorodopa ( 18 F-FDOPA); 4 were positive on fluorine-18 fluorodopamine (57.1%) scanning, but all 7 had uptake on 18 F-FDOPA scanning. Octreotide (indium-111 pentetreotide) scintigraphy was also used in 5 patients; 3 (60%) had positive results. A summary of each patient’s diagnostic workup and treatment is listed in Table 2 .
| Pt | Age (yrs) | Genetics | Biochemistry ∗ | Surgical Resection | Tumor Size (cm) | Tumor Location | Mlt | Mets | Treatment | Died | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SDHB | SDHC | SDHD | CgA | DA | MTX | NE | NMN | VMA | |||||||||
| 1 | 36 | + | 0 | 0 | — | 0 | — | + (p, u) | + (p, u) | + (u) | + | 2.9 x 2.2 x 2.4 | L atrium | + | 0 | 0 | 0 |
| 2 | 38 | + | 0 | 0 | — | — | + (p, u) | + (p, u) | — | + | 3 x 2 x 2 | R ventricle | + | 0 | 0 | 0 | |
| 3 | 50 | + | 0 | 0 | — | 0 | — | 0 | 0 | — | + | 8 x 7 | L ventricle | 0 | 0 | 0 | 0 |
| 4 | 33 | 0 | + | 0 | — | + (u) | — | + (u) | + (u) | — | + | 5.3 x 5.6 | R AV groove | + | 0 | 0 | 0 |
| 5 | 37 | 0 | + | 0 | — | 0 | — | + (u) | + (p) | — | + | 3.6 | R atrium/AV groove | + | 0 | cisplatin/ etoposide | 0 |
| 6 | 46 | 0 | + | 0 | + (p) | + (p) | 0 | 0 | 0 | — | + † | 3.2 x 2.3 | L atrium | 0 | 0 | CVD (pre-operative) | + |
| 7 | 28 | 0 | 0 | + | — | + (u) | + (u) | + (u) | + (u) | — | + | 7 x 3 x 2 | L AV groove | + | 0 | 0 | 0 |
| 8 | 31 | 0 | 0 | + | + (p) | + (u) | — | + (p, u) | + (p) | — | + | 2.5 x 1.9 x 2.1 | R AV groove | + | 0 | 0 | 0 |
| 9 | 39 | 0 | 0 | + | + (p) | + (p) | — | + (p) | + (u) | + (u) | ND | L atrium | + | 0 | 0 | 0 | |
| 10 | 63 | 0 | 0 | + | — | + (p, u) | — | + (p, u) | + (p, u) | + (u) | + | 3.5 x 3.4 x 4.2 | R atrium | + | 0 | 0 | 0 |
| 11 | 59 | 0 | — | 0 | — | + (u) | — | + (u) | + (p, u) | — | + | 6.7 | AV groove | 0 | + | CVD | 0 |
| 12 | 33 | 0 | 0 | 0 | + (p) | + (p, u) | + (p) | + (p, u) | + (p, u) | — | + | 3.4 cm | L atrium | 0 | 0 | 0 | 0 |
| 13 | 63 | 0 | 0 | 0 | + (p) | 0 | — | 0 | + (p) | — | + | 4.3 x 4.0 x 3.5 | R atrium/R ventricle | + | 0 | 0 | 0 |
| 14 | 32 | — | — | — | — | 0 | — | + (p) | 0 | — | + | — | 0 | + | 0 | + | |
| 15 | 40 | — | — | — | — | 0 | — | + (p) | 0 | — | + | L atrium | + | + | radiation | + | |
∗ Epinephrine and metanephrine values are not listed because they were negative in all tested patients.
† Tumor was successfully resected, but patient suffered intraoperative complications after resection and did not survive.
In 13 patients (86.7%), surgery was the initial treatment for the cardiac tumor. None of the patients experienced intra- or postoperative complications. One additional patient (6.7%) was first treated with 7 cycles of chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) in an attempt to shrink the tumor before surgery; however, the tumor did not respond to this regimen. The patient was then taken to the operating room, with successful resection of the tumor; however, postoperatively, he bled from the left main coronary artery, leading to ventricular fibrillation arrest and death. The remaining patient did not undergo a surgical procedure or any treatment but is undergoing careful surveillance. After surgery, 1 patient (6.7%) had residual tumor on follow-up imaging. Another patient (6.7%) had a recurrent tumor in the heart, which mandated a second resection. This patient had positive surgical margins in the first operation, for which she underwent 6 cycles of chemotherapy with cisplatin and etoposide. Ten patients (66.7%) had multiple primary tumors, commonly located in the carotid body (4 of 9 [44.4%]) and jugular foramen (4 of 9 [44.4%]), although other locations were also found. One of the 10 patients had a history of adrenal pheochromocytoma. Three patients (20%) later developed metastases; one of these patients underwent CVD chemotherapy, and a second received external-beam radiation for lesions in the spine. Two of the patients who developed metastases died; the third has stable disease and is receiving CVD chemotherapy ( Table 2 ).
Thirteen patients underwent genetic testing; 10 (76.9%) had mutations identified in subunits of the SDH complex. Three had SDHB mutations, 3 SDHC, and 4 SDHD. Of the remaining patients, 2 underwent testing for all 3 of these genes and had no mutations identified; 1 had negative test results for SDHB and SDHD ( Table 2 ).
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