ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Ann Thorac Surg 2008;86:946-951. doi:10.1016/j.athoracsur.2008.04.105
© 2008 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Morgan L. Brown
William F. Young, Jr
Hartzell V. Schaff
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brown, M. L.
Right arrow Articles by Schaff, H. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brown, M. L.
Right arrow Articles by Schaff, H. V.
Related Collections
Right arrow Mediastinum

Original Articles: General Thoracic

Mediastinal Paragangliomas: The Mayo Clinic Experience

Morgan L. Brown, MDa, Gilberto E. Zayas, BSd, Martin D. Abel, MDb, William F. Young, Jr, MDc, Hartzell V. Schaff, MDa,*

a Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
b Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Rochester, Minnesota
c Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
d School of Medicine, University of Puerto Rico, San Juan, Puerto Rico

Accepted for publication April 29, 2008.

* Address correspondence to Dr Schaff, Mayo Clinic, 200 1st St SW, Rochester MN 55905 (Email: schaff{at}mayo.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Extra-adrenal catecholamine-secreting tumors are referred to as paragangliomas. We reviewed our experience with mediastinal paragangliomas treated at Mayo Clinic over the last 30 years.

Methods: Fourteen patients were identified who had resection of a mediastinal paraganglioma between 1973 and 2007. Perioperative data obtained from the medical record and follow-up information were reviewed.

Results: The median age of patients at operation was 39 years (range, 27 to 68 years), 71% were female, and all had a history of hypertension. Preoperative diagnosis of a catecholamine-secreting tumor was confirmed through elevated 24-hour urinary norepinephrine in 12 patients and tumor location was determined with metaiodobenzylguanidine scintigraphy, computed tomography or magnetic resonance imaging scans in the majority. The tumor was adjacent to the heart or great vessels in all patients and was resected through a median sternotomy (n = 10), or with posterolateral thoracotomy (n = 4). In 6 patients, cardiopulmonary bypass was used to facilitate dissection of the paraganglioma from the heart or great vessels. There was one intraoperative death in this series due to blood loss. Ten of the 11 patients were alive at follow-up (median follow-up: 2.3 years; range, 0 to 19.4 years). Symptoms of catecholamine excess were eliminated or greatly improved in all patients who had a functioning tumor preoperatively, but 6 of these patients were still being treated with antihypertensive medications.

Conclusions: Functional paragangliomas can be diagnosed with measurement of fractionated catecholamines and metanephrines; mediastinal localization is determined with appropriate scanning techniques. These tumors can be treated successfully by surgical resection with modest surgical risk, often necessitating cardiopulmonary bypass, with good long-term survival. Hypertension may persist even after complete resection of the tumor.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Pheochromocytomas are catecholamine-secreting tumors that typically arise in the medulla of the adrenal gland and sympathetic ganglia. When these tumors are found outside the adrenal gland, they are termed paragangliomas. Surgical resection of these tumors is the treatment of choice with survival rates in excess of 95% for pheochromocytomas, with appropriate medical care [1]. We reviewed the perioperative management and outcomes of operation for mediastinal paragangliomas at Mayo Clinic.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
After approval from the Mayo Clinic Institutional Review Board, we identified 14 patients who underwent resection of a mediastinal paraganglioma at our Clinic from 1973 through 2007. Perioperative data were collected using all available medical records from the time of diagnosis to the present time. Follow-up included use of all medical records and a database that included late clinical outcomes obtained through prospective surveys. Survival was ascertained through Accurint (Philadelphia, PA; www.accurint.com). Median values and ranges were reported for all continuous variables.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
The median age of these patients was 39 years (range, 27 to 68 years) and 71% were female. All patients had a history of hypertension with varying degrees of control with standard medications. The median preoperative blood pressure was 126/76 mm Hg (range, 95/61 to 175/85 mm Hg). Prior to surgical exploration, patients were prepared with a combination of alpha-adrenergic blockade (n = 12), beta-adrenergic blockade (n = 9), and tyrosine hydroxylase inhibition (n = 7) (Table 1). One patient had a nonfunctioning paraganglioma and was not prescribed any additional medications and another was not taking any preoperative antihypertensives, as urgent operation was required after episodes of severe hemoptysis. Other clinical features at presentation included sweating (n = 5), presyncope or syncope (n = 3), dyspnea (n = 1), cough (n = 1), and weight loss (n = 1); 5 patients were asymptomatic.


View this table:
[in this window]
[in a new window]

  		Table 1 Blood Pressure Measurements and Preoperative Medications a
 
In 3 patients there was a family history of paraganglioma (1 SDHD gene mutation, 1 SDHB gene mutation, and 1 unidentified); 2 patients were diagnosed with Carney triad (gastric stromal tumor, pulmonary chondromas, and paraganglioma) [2]. In half of the patients, the mediastinal paraganglioma was an isolated finding, and in 7 patients there were a total of 12 additional catecholamine-secreting neoplasms including carotid body (n = 6), retroperitoneal (n = 3), adrenal (n = 1), pancreatic (n = 1), and urinary bladder tumors (n = 1). Three patients had also undergone prior resection for gastric stromal tumors.

Preoperative diagnosis of a catecholamine-secreting tumor was confirmed through elevated 24-hour urinary norepinephrine and plasma normetanephrine levels in all but one patient (Table 2). Eight patients underwent 131I or 123I-metaiodobenzylguanidine (MIBG) scintigraphy, which was positive for uptake in the mediastinum in all patients; 1 patient had an 111In-pentetreotide scan, which was positive, and tumors were seen in all 10 patients who had magnetic resonance imaging (MRI) scans of the thorax.


View this table:
[in this window]
[in a new window]

  		Table 2 Preoperative Biochemical Testing for Catecholamines and Metanephrines a
 
Locations of the tumors (Fig 1) determined surgical approach; 10 patients underwent surgical resection through a median sternotomy, and 4 patients had resection through a right (n = 3) or left (n = 1) posterolateral thoracotomy (Table 3). In all cases, the tumor was adjacent to the heart, great vessels, or other vascular structures. In 6 patients, cardiopulmonary bypass was used to facilitate dissection of the paraganglioma from the heart or great vessels. In these patients, median duration of cardiopulmonary bypass was 108 minutes (range, 61 to 344 minutes). Coronary artery bypass grafting was required in 2 patients due to involvement of the paraganglioma into the right coronary artery [4, 5]. Tricuspid valve repair was also required in one patient that has been reported previously [5]. In one patient, replacements of the ascending aorta and hemiarch were done under a 26 minute period of circulatory arrest.


Figure 1
View larger version (72K):
[in this window]
[in a new window]

  		Fig 1. Tumor locations within the mediastinum.

 

View this table:
[in this window]
[in a new window]

  		Table 3 Operative Details and Pathology of Patients With Mediastinal Paraganglioma
 
One patient (No. 6) died intraoperatively due to uncontrollable bleeding from the tumor and tumor bed; the patient had normal coagulation studies prior to operation. Bleeding requiring transfusion occurred in 6 patients (43%) with a median of 5 units of packed red blood cells (range, 1 to 20 units). The median postoperative hospital length of stay was 6 days (range, 5 to 10 days).

Among the 13 survivors, the mediastinal tumor was completely removed in 10. Two patients had positive gross margins, and one had microscopic evidence of tumor at the margin of resection and, in addition, had a positive lymph node; this patient elected to undergo radiation therapy. Late recurrence of a paraganglioma was noted in 2 of the 10 patients who were thought to have complete excision. One patient had subsequent resection of bilateral adrenal pheochromocytomas and also had metastatic gastric leiomyosarcoma. This patient had the Carney triad and treatment was considered palliative, but has survived nearly 20 years after the initial operation for mediastinal paraganglioma. The second recurrence developed 3 years after resection of the mediastinal tumor; wide-spread skeletal metastases were treated with chemotherapy.

In ten of the 11 patients who were alive at last follow-up and who had catecholamine-secreting tumors preoperatively, symptoms of catecholamine excess were eliminated or improved in all. However, 7 of 11 patients continued to require antihypertensive medications (median follow-up: 2.3 years; range, 0 to 19.4 years).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Mediastinal paragangliomas are rare tumors and therefore it is not surprising that most publications detailing treatment of mediastinal paragangliomas are single case reports [3–15]. However, physicians at the University of Michigan reported 12 intrapericardial paragangliomas in 1996 [6]. Herein we report the Mayo Clinic experience of 14 patients who had surgical resection of these tumors between 1973 and 2007.

The mediastinal paragangliomas in our study were generally discovered during the investigation of unexplained hypertension, or other typical symptoms such as excessive diaphoresis or palpitations. This presentation is similar to that described with adrenal pheochromocytomas [16]. However, in one patient the discovery occurred incidentally during the course of imaging studies obtained for other reasons.

Generally, paragangliomas predominantly produce norepinephrine and normetanephrine and may result in symptoms of sustained hypertension, headaches, and diaphoresis [1, 17, 18]. In contrast, adrenal pheochromocytomas may produce a combination of norepinephrine, normetanephrine, epinephrine, and metanephrine. In patients with multiple endocrine neoplasia type 2, adrenal pheochromocytomas predominantly hypersecrete epinephrine and metanephrine [1, 18].

Malignant changes are present in 10% of catecholamine-secreting tumors and 15% to 20% are familial [1]. Mediastinal paragangliomas are rare, representing only 2% of all catecholamine-secreting tumors [1]. Mutations in the succinate dehydrogenase (SDH) subunit genes (eg, SDHB, SDHD, or SDHC) are associated with most cases of familial paraganglioma and malignant predisposition is increased with the SDHB mutation [1]. Three patients (21%) in our study had a family history of paraganglioma, but identification of the specific gene mutation was only possible in 2 patients.

In all patients, except for one patient who had a nonsecreting paraganglioma and one patient who did not have urinary testing, the diagnosis of paraganglioma was confirmed by increased levels of 24-hour urine fractionated metanephrines and catecholamines, and, in 10 patients, with testing for plasma fractionated metanephrines. Plasma fractionated metanephrines were considered the most sensitive test for diagnosis (sensitivity 99%, specificity 81%) in one study that compared biochemical markers in the detection of catecholamine-secreting tumors [19]. Anatomic localization of tumors can be made with computed tomography (CT) or MRI once biochemical studies have confirmed the presence of a catecholamine-secreting tumor.

123I-MIBG scintigraphy is used for both localization and staging of neuroendocrine tumors. Metaiodobenzylguanidine is structurally similar to noradrenaline and is actively transported into catecholamine storage vesicles of adrenergic nerve endings. The majority of our patients underwent MIBG scintigraphy (n = 8). 123I-MIBG scintigraphy must be interpreted with caution, as multiple drugs can interfere with the uptake of MIBG causing false-negative results (eg, antipsychotics, cocaine, calcium channel blockers, tricyclic antidepressants, labetalol, and sympathomimetics) [18]. Also, false positive uptake of MIBG may occur, and all suspected metastases should be confirmed with CT or MRI [5, 19, 20].

Patients are at risk of both hypertension and hypotension during the operative procedure and some of the preoperative goals are to normalize hemodynamic variables (blood pressure, heart rate), reverse intravascular volume depletion, and avoid surges in catecholamine release with tumor manipulation during surgery [18, 21, 22]. Preoperative volume expansion helps decrease the likelihood of sudden hypotension upon removal of the tumor. To avoid a perioperative hypertensive crisis, alpha-adrenergic blockade (eg, phenoxybenzamine) is generally prescribed for 7 to 10 days preoperatively, with beta-adrenergic and calcium channel blockade used as adjuncts when blood pressure or tachycardia can not be controlled. Goldstein and colleagues [23] found that 4.5% of patients had a complicated hypertensive course during surgery when placed on {alpha}-adrenoceptor blockade preoperatively compared with 69% of patients without preoperative {alpha}-adrenoceptor blockade. However, the downside to the use of phenoxybenzamine is in the immediate period after tumor removal and for up to 24 hours after when its prolonged action can contribute to hypotension. Metyrosine is used in those patients who have intolerance to the usual medications or who remain symptomatic on medical therapy or when intraoperative tumor manipulation is anticipated before venous outflow can be controlled [18, 24, 25]. Some centers also suggest preoperative embolization in posterior mediastinal tumors, in an effort to reduce intraoperative blood loss [26–28]. This was not performed in any patient in our series.

When the tumor invades surrounding vascular structures resection may be difficult. Removal of these invasive tumors resulted in major blood loss in 3 of our patients. In one patient with a large tumor (7.5 x 5.0 x 2.5 cm) (Fig 2) involving the left atrial wall, intraoperative death was due to uncontrollable blood loss. The patient was advised that surgical resection carried a high operative mortality without the promise of complete resection. Cardiopulmonary bypass should be employed in those cases where there is invasion into the heart, coronary arteries, or other great vessels.


Figure 2
View larger version (60K):
[in this window]
[in a new window]

  		Fig 2. Computed tomographic scan demonstrating a large tumor that was not completely resectable. This patient died secondary to hemorrhage in the operating room.

 
Transplantation has been suggested as a potential therapeutic strategy in those patients who have paragangliomas that invade the atrioventricular groove with or without distortion of the mitral valve, have direct coronary artery involvement, or extend into the left ventricle [29]. However, there are few reports of transplantation in the literature and late results are unknown [30, 31].

Surgical resection of mediastinal paragangliomas is an effective treatment with most cases being curative. However, even with complete resection of the mediastinal tumor, the majority of our patients (64%) remained hypertensive. At follow-up, the majority of patients were taking antihypertensive medication despite the absence of any known residual or recurrent catecholamine-secreting neoplasm. Two patients with recurrence had reoperation early in the series because of incomplete initial resection. One patient developed late wide-spread skeletal metastases and underwent chemotherapy. In all patients, life-long surveillance for recurrence should be performed with regular checkups employing biochemical testing for fractionated metanephrines and catecholamines and imaging techniques such as 123I-MIBG, CT, and MRI when appropriate.

Successful resection of mediastinal paragangliomas was achieved in the majority of patients with no evidence of recurrence. Hypertension may remain a problem even after complete resection of the tumor.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Young Jr WF. Adrenal Medulla, Catecholamines, and PheochromocytomaIn: Goldman L, Ausiello D, editors. Cecil Medicine. 23rd edition. Philadelphia, PA: Saunders Elsevier; 2008. pp. 1721-1727.
  2. Carney JA, Sheps SG, Go VCW, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma N Engl J Med 1977;296:1517-1518.[Medline]
  3. Orringer MB, Sisson JC, Glazer G, et al. Surgical treatment of cardiac pheochromocytomas J Thorac Cardiovasc Surg 1985;89:753-757.[Abstract]
  4. McGann C, Tazelaar H, Cho SR, et al. In vivo detection of encapsulated intracardiac paraganglioma by delayed gadolinium enhancement magnetic resonance imaging J Cardiovasc Magn Reson 2005;7:371-375.[Medline]
  5. Sawka AM, Young WF, Schaff HV. Cardiac phaeochromocytoma presenting with severe hypertension and chest pain Clin Endocrinol (Oxf) 2001;54:689-692.[Medline]
  6. Hamilton BH, Francis IR, Gross BH, et al. Intrapericardial paragangliomas (pheochromocytomas) J Thorac Cardiovasc Surg 1985;89:753-757.[Abstract]
  7. Yuan WQ, Wang WQ, Su TW, et al. A primary right atrium paraganglioma in a 15-year-old patient Endocrine 2007;32:245-248.[Medline]
  8. Leshnower BG, Morris RJ, Pechet TT. Management of an anterior mediastinal pheochromocytoma causing tracheomalacia Ann Thorac Surg 2007;84:2088-2090.[Abstract/Free Full Text]
  9. Bouhouch A, Hendriks JM, Lauwers PR, De Raeve HR, Van Schil PE. Asymptomatic pheochromocytoma in the posterior mediastinum Acta Chir Belg 2007;107:465-466.[Medline]
  10. Beiras-Fernandez A, Uberfuhr P, Kaczmarek I, et al. Mediastinal pheochromocytoma with single coronary blood supply: a case report Heart Surg Forum 2007;10:E196-E198.[Medline]
  11. Spector JA, Willis DN, Ginsburg HB. Paraganglioma (pheochromocytoma) of the posterior mediastinum: a case report and review of the literature J Pediatr Surg 2003;38:1114-1116.[Medline]
  12. Kojima Y, Kitahara H, Kimura H, Nakamura T, Ina H, Yokota S. Anesthetic management of simultaneous coronary artery bypass grafting and cardiac pheochromocytoma resection under cardiopulmonary bypass J Anesth 2007;21:504-506.[Medline]
  13. Taylor MJ, McIndoe A. Unresponsive asystolic cardiac arrest responding to external cardiac pacing in a patient with phaeochromocytoma Anaesthesia 2007;62:838-841.[Medline]
  14. Delgado V, Vidal B, Sitges M, Azqueta M, Pare C. A rare association of pheochromocytoma and thoracic paraganglioma: utility of 2D contrast enhanced echocardiography Int J Cardiol 2007;117:e66-e67.[Medline]
  15. Paul S, Jain SH, Gallegos RP, Aranki SF, Bueno R. Functional paraganglioma of the middle mediastinum Ann Thorac Surg 2007;83:e14-e16.[Abstract/Free Full Text]
  16. Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma: advances in genetics, diagnosis, localization, and treatment Hematol Oncol Clin North Am 2007;21:509-525.[Medline]
  17. Eisenhofer G, Walther MM, Huynh TT, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes J Clin Endocrinol Metab 2001;86:1999-2008.[Abstract/Free Full Text]
  18. Pacak K. Preoperative management of the pheochromocytoma patient J Clin Endocrinol Metab 2007;92:4069-4079.[Abstract/Free Full Text]
  19. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427-1434.[Abstract/Free Full Text]
  20. Takasu N, Hayashi M, Takara M, et al. False-positive 123I-metaiodobenzylguanidine (MIBG) scan in a patient with angiomyolipoma; positive MIBG scan does not necessarily indicate the presence of pheochromocytoma Intern Med 2007;46:1717-1721.[Medline]
  21. Roizen MF, Hunt TK, Beaupre PN, et al. The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma Surgery 1983;94:941-945.[Medline]
  22. Witteles RM, Kaplan EL, Roizen MF. Safe and cost-effective preoperative preparation of patients with pheochromocytoma Anesth Analg 2000;91:302-304.[Abstract/Free Full Text]
  23. Goldstein RE, O'Neill Jr JA, Holcomb 3rd GW, et al. Clinical experience over 48 years with pheochromocytoma Ann Surg 1999;229:755-764.[Medline]
  24. Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromocytoma with the use of metyroxine Ann Surg 1990;212:621-628.[Medline]
  25. Young WF, Kaplan NM. Treatment of pheochromocytoma in adults. In: Rose BD, ed, UpToDate, UpToDate, Waltham, MA, 2007. Available at www.uptodate.com/online/content/topic.do?topicKey=adrenal/19996&selectedTitle=2~150&source=search.result. Accessed April 30, 2008.
  26. Matsumoto J, Nakajima J, Takeuchi E, Fukami T, Nawata K, Takamoto S. Successful perioperative management of a middle mediastinal paraganglioma J Thorac Cardiovasc Surg 2006;132:705-706.[Free Full Text]
  27. Drucker EA, McLoud TC, Dedrick CG, Hilgenberg AD, Geller SC, Shepard JA. Mediastinal paraganglioma: radiologic evaluation of an unusual vascular tumor AJR Am J Roentgenol 1987;148:521-522.[Free Full Text]
  28. Rakovich G, Ferraro P, Therasse E, Duranceau A. Preoperative embolization in the management of a mediastinal paraganglioma Ann Thorac Surg 2001;72:601-603.[Abstract/Free Full Text]
  29. Jeevanandam V, Oz MC, Shapiro B, Barr ML, Marboe C, Rose EA. Surgical management of cardiac pheochromocytoma. Resection versus transplantation. Ann Surg 1995;221:415-419.[Medline]
  30. Gowdamarajan A, Michler RE. Therapy for primary cardiac tumors: is there a role for heart transplantation? Curr Opin Cardiol 2000;15:121-125.[Medline]
  31. Goldstein DJ, Oz MC, Rose EA, Fisher P, Michler RE. Experience with heart transplantation for cardiac tumors J Heart Lung Transplant 1995;14:382-386.[Medline]



This article has been cited by other articles:


Home page
 ICVTSHome page
M.-W. Lin, Y.-L. Chang, Y.-C. Lee, and P.-M. Huang
Non-functional paraganglioma of the posterior mediastinum
Interactive CardioVascular and Thoracic Surgery, September 1, 2009; 9(3): 540 - 542.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
H. K Ghayee, B. Havekes, E. P M Corssmit, G. Eisenhofer, S. R Hammes, Z. Ahmad, A. Tessnow, I. Lazurova, K. T Adams, A. T Fojo, et al.
Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior
Endocr. Relat. Cancer, March 1, 2009; 16(1): 291 - 299.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Morgan L. Brown
William F. Young, Jr
Hartzell V. Schaff
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brown, M. L.
Right arrow Articles by Schaff, H. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brown, M. L.
Right arrow Articles by Schaff, H. V.
Related Collections
Right arrow Mediastinum

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS