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Functional Paraganglioma of the Middle Mediastinum
Functional Paraganglioma of the Middle Mediastinum Subroto Paul, MD, Shilpa H. Jain, MD, Robert P. Gallegos, MD, Sary F. Aranki, MD, and Raphael Bueno, MD Divisions of Thoracic Surgery, Endocrinology, Diabetes and Hypertension, and Cardiac Surgery, Brigham & Women’s Hospital, Boston, Massachusetts
We describe a 49-year-old woman with refractory hypertension resulting from a functional paraganglioma of the middle mediastinum. After aggressive medical antihypertensive control and reduction of catecholamine production, she underwent surgical resection requiring transection and subsequent reconstruction of the aorta on cardiopulmonary bypass and circulatory arrest. We believe that this is the first report of a functionally active paraganglioma of the mediastinum requiring resection with cardiopulmonary bypass and aortic reconstruction. (Ann Thorac Surg 2007;83:e14 – 6) © 2007 by The Society of Thoracic Surgeons
P
aragangliomas are rare neuroendocrine tumors that arise from chromaffin cells of extra-adrenal origin. Most tumors of chromaffin cells originate in the adrenal medulla and are classified as pheochromocytomas. Mediastinal paragangliomas are typically nonfunctional. Functional paragangliomas, which actively produce vasoactive amines, are rare and require surgical resection after adequate control of hypertension. A 49-year-old woman with refractory hypertension presented with palpitations, fatigue, and abdominal pain. The patient recalled having vague abdominal pains since the age 16 years. The remainder of the patient’s past medical and surgical history was significant for alopecia, an uncomplicated caesarean delivery at age 26 years and a left oophorectomy through a midline laparotomy at age 45 years. During induction of anesthesia for the oophorectomy, she had a hypertensive crisis. She was found to have a four-fold elevation in serum normetanephrine levels to 3.79 nmol/L (normal, 0 to 0.89 nmol/L) and a normal metanephrine level of 0.30 nmol/L (normal, 0 to 0.49 nmol/L). Twenty-four hour urine collection revealed a creatinine level of 1,103 mg/day, norepinephrine of 314 g/day (normal, 0 to 100 g/day), normetanephrine of 973 g/day (normal, 50 to 650 g/day), epinephrine ⬍2 g/day (normal, 0 to 25 g/day), and metanephrine 93 g/day (normal, 30 to 350 g/day). An abdominal computed tomographic scan was unremarkable. Scintigraphy with iodine-123 meta-iodobenzylguanidine (123-iodinated-MIBG) revealed increased uptake in the superior mediastinum only. A computed chest tomographic scan with coronal reconstruction demonstrated a mass in the middle mediastinum extending from the superior vena cava into the aortopulmonary window and the prevascular Accepted for publication Feb 28, 2007. Address correspondence to Dr Bueno, Brigham and Women’s Hospital, Division of Thoracic Surgery, 75 Francis St, Boston, MA 02115; e-mail: [email protected].
© 2007 by The Society of Thoracic Surgeons Published by Elsevier Inc
space (Figs 1A, 1B). The mass also extended into the right and left paratracheal as well as the subcarinal regions. No distinct tissue planes near the distal aortic arch were discerned and numerous presumed small feeding vessels from the bronchial circulation were identified on axial and coronal views. The patient elected to undergo extirpative surgery to prevent further growth and for blood pressure control. A physical examination was notable for blood pressure of 134/89 and a regular heart rate of 90. Preoperative medical management included blood pressure control with alpha and beta adrenergic blockers, inhibition of catecholamine synthesis with metyrosine and volume expansion with salt. Her anti-hypertensive regimen was titrated up to doxazosin (10 mg daily) and metoprolol (150 mg/day). Metyrosine, a tyrosine hydroxylase inhibitor, was increased up to 1.5 gm/day for 2 months prior to surgery. Subsequently, serum normetanephrines decreased to 1.01 nmol/L. Preoperative evaluation included pulmonary function tests (forced expiratory volume in 1 second ⫽ 3.09 [114%] and forced vital capacity ⫽ 3.82 [109%]), and an echocardiogram (ejection fraction ⫽ 60% with normal ventricular function without ventricular hypertrophy or evidence of ischemia). Preoperative embolization of the tumor feeding vessels was considered, but it was not attempted because of the potential risks of uncontrolled catecholamine release, vascular injury, and paralysis. The patient underwent a median sternotomy. The pericardium was opened anteriorly and then posteriorly to allow adequate exposure of the tumor. The tumor was first completely dissected off the superior vena cava and the brachiocephalic vein (Fig 1C). Upon exploring the aortic margin of the tumor, it was evident that the tumor was both highly vascular and adherent through the pericardium to the arch of the aorta and to the right and main pulmonary arteries. At this point, the patient was placed on cardiopulmonary bypass and cooled to 20°C. The aorta was cross-clamped; cardioprotection was initiated with intermittent cold hyperkalemic blood cardioplegia given through the antegrade route. The ascending aorta was transected just above the level of the sinotubular junction to gain access to the remaining adherent tumor in the aortopulmonary window. The tumor was carefully mobilized en-bloc off the right and main pulmonary arteries, off the subcarinal space as well as the left side of the trachea and left main stem bronchus, where it was attached to the paratracheal lymph nodes and the recurrent laryngeal nerve, which was sacrificed. The tumor was finally dissected free from the lesser curve of the arch of the aorta (Fig 1D) under circulatory arrest. The tumor was adherent to the arch at that point, and the adventitia of the arch was denuded in two places and was repaired using a half size 26 Hemashield tube graft (Boston Scientific, Natick, MA) to replace the inferior portion of the arch. The patient was rewarmed and weaned off cardiopulmonary bypass without difficulty. However, due to excess bleeding from the resected tumor bed, the cavity was packed and the patient’s chest was left open in the intensive care unit for resuscitation and an anticipated delayed chest closure. Intraoperatively the patient was hemodynamically stable throughout the procedure despite manipulation of the tumor. The patient initially required a tracheostomy and left vocal cord 0003-4975/07/$32.00 doi:10.1016/j.athoracsur.2007.02.090
Ann Thorac Surg 2007;83:e14 – 6
CASE REPORT PAUL ET AL PARAGANGLIOMA OF MEDIASTINUM
e15
Fig 1. (A) Computed tomographic chest scan demonstrating middle mediastinal mass (*). (B) Three-dimensional computed tomographic chest scan reconstruction with volume imaging demonstrating extent of mass (shaded area). (C) Intraoperative picture with peanut showing location of anterior aspect of mass between the superior vena cava and aorta. (RA ⫽ right atrium.) (D) Gross picture of mass after excision.
medialization to wean off the ventilator and was eventually decannulated with no difficulties. Postoperative normetanephrine levels had normalized (0.88 nmol/L) 2 weeks after surgery. Histopathology revealed the tumor to be less than 0.1 cm from the periaortic surface (Fig 1D). The final margins were all negative. Immunohistochemical stains were positive for chromogranins, synaptophysin, and protein S-100. The meta-iodobenzylguanidine-1 proliferative index was focally up to 10%.
Comment Mediastinal paragangliomas and their abdominal counterparts, pheochromocytomas, are extremely well vascularized tumors originating from enterochromaffin cells that usually secrete catecholamines. These tumors account for roughly 0.1% to 0.5% of all cases of hypertension [1–3]. Mediastinal paragangliomas are rare tumors with only approximately 150 cases described in the literature to date. Functional paragangliomas are quite exceptional, with approximately 50 cases reported, which have been documented to secrete catecholamines [2]. The treatment of choice is surgical excision after preoperative control of hypertension, with postoperative radiotherapy described for specific cases [1– 4]. We believe that our patient is the first to undergo resection of a middle mediastinal functional paraganglioma requiring cardiopulmonary bypass as well as aortic transection and reconstruction. Preoperative antihypertensive therapy with alpha followed by beta adrenergic blockade and volume loading is
crucial in preventing intraoperative hypertensive crises. Metyrosine has been shown to decrease intraoperative requirements for anti-hypertensive medications, vasopressor agents, fluids, and blood products [5, 6]. Another way to potentially prevent intraoperative hypertension is to perform preoperative embolization of feeding vessels to the tumor. This approach could promote tumor necrosis as well as theoretically prevent blood loss during surgery [7]. In our case, the risk of procedure-induced spinal cord paralysis was believed to be high due to the location of the tumor and its bronchial feeding vessels. Furthermore, it was believed that tumor necrosis may induce an uncontrollable hypertensive crisis through catecholamine release. Therefore this approach was not used. We instead chose the protection afforded by cardiopulmonary bypass. Surprisingly we did not note any hypertensive episodes while manipulating the tumor prior to initiating bypass. Intraoperatively, this tumor was found to be posterior to the ascending aorta and adherent to the aorta at the underbelly of the distal arch. Surgical resection of the tumor required first transection of the ascending aorta for exposure and then reconstruction of a significant portion of the involved aorta to repair the consequences of complete resection. Bleeding in the tumor bed was not unexpected, as these tumors are highly vascular and hemostasis after cardiopulmonary bypass and circulatory arrest is often a problem even under the best of circumstances [1, 2, 4, 7]. We chose to leave the chest open to prevent tamponade until clotting factors were repleted and hemostasis en-
e16
CASE REPORT PAUL ET AL PARAGANGLIOMA OF MEDIASTINUM
sured. The loss of the left recurrent nerve was anticipated given the tumor’s location. In conclusion, treatment of functional mediastinal paragangliomas requires careful preoperative assessment and a multidisciplinary team involving endocrinologists, cardiac surgeons, and thoracic surgeons. The preoperative management of catecholamine excess is imperative to prevent hypertensive crises. In the case of mediastinal paragangliomas, the early use of cardiopulmonary bypass and plan to reconstruct critical vascular structures must be anticipated. We conclude that the resection of complex mediastinal paragangliomas is feasible. We would like to thank Dr Ritu Gill from radiology for her help in reformatting the computed tomographic chest scan images and Dr Vania Nose from pathology for her help in preparing the pathology for this article.
Ann Thorac Surg 2007;83:e14 – 6
References 1. Chao S, Mullins ME, Slanetz PJ. Posterior mediastinal pheochromocytoma. AJR Am J Roentgenol 2001;176:1408. 2. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1986;1:1061– 4. 3. Sahdev A, Sohaib A, Monson JP, et al. CT and MR imaging of unusual locations of extra-adrenal paragangliomas (pheochromocytomas). Eur Radiol 2005;15:85–92. 4. Petit T, de Lagausie P, Maintenant J, et al. Thoracic pheochromocytoma revealed by ventricular tachycardia. Clinical case and review of the literature. Eur J Pediatr Surg 2000;10:142– 4. 5. Steinsapir J, Carr AA, Prisant M, et al. Metyrosine and pheochromocytoma. Arch Intern Med 1997;157:901– 6. 6. Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromocytoma with the use of metyrosine. Ann Surg 1990;212:621– 8. 7. Rakovich G, Ferraro P, Therasse E, et al. Preoperative embolization in the management of a mediastinal paraganglioma. Ann Thorac Surg 2001;72:601–3.
We describe a 49-year-old woman with refractory hypertension resulting from a functional paraganglioma of the middle mediastinum. After aggressive medical antihypertensive control and reduction of catecholamine production, she underwent surgical resection requiring transection and subsequent reconstruction of the aorta on cardiopulmonary bypass and circulatory arrest. We believe that this is the first report of a functionally active paraganglioma of the mediastinum requiring resection with cardiopulmonary bypass and aortic reconstruction. (Ann Thorac Surg 2007;83:e14 – 6) © 2007 by The Society of Thoracic Surgeons
P
aragangliomas are rare neuroendocrine tumors that arise from chromaffin cells of extra-adrenal origin. Most tumors of chromaffin cells originate in the adrenal medulla and are classified as pheochromocytomas. Mediastinal paragangliomas are typically nonfunctional. Functional paragangliomas, which actively produce vasoactive amines, are rare and require surgical resection after adequate control of hypertension. A 49-year-old woman with refractory hypertension presented with palpitations, fatigue, and abdominal pain. The patient recalled having vague abdominal pains since the age 16 years. The remainder of the patient’s past medical and surgical history was significant for alopecia, an uncomplicated caesarean delivery at age 26 years and a left oophorectomy through a midline laparotomy at age 45 years. During induction of anesthesia for the oophorectomy, she had a hypertensive crisis. She was found to have a four-fold elevation in serum normetanephrine levels to 3.79 nmol/L (normal, 0 to 0.89 nmol/L) and a normal metanephrine level of 0.30 nmol/L (normal, 0 to 0.49 nmol/L). Twenty-four hour urine collection revealed a creatinine level of 1,103 mg/day, norepinephrine of 314 g/day (normal, 0 to 100 g/day), normetanephrine of 973 g/day (normal, 50 to 650 g/day), epinephrine ⬍2 g/day (normal, 0 to 25 g/day), and metanephrine 93 g/day (normal, 30 to 350 g/day). An abdominal computed tomographic scan was unremarkable. Scintigraphy with iodine-123 meta-iodobenzylguanidine (123-iodinated-MIBG) revealed increased uptake in the superior mediastinum only. A computed chest tomographic scan with coronal reconstruction demonstrated a mass in the middle mediastinum extending from the superior vena cava into the aortopulmonary window and the prevascular Accepted for publication Feb 28, 2007. Address correspondence to Dr Bueno, Brigham and Women’s Hospital, Division of Thoracic Surgery, 75 Francis St, Boston, MA 02115; e-mail: [email protected].
© 2007 by The Society of Thoracic Surgeons Published by Elsevier Inc
space (Figs 1A, 1B). The mass also extended into the right and left paratracheal as well as the subcarinal regions. No distinct tissue planes near the distal aortic arch were discerned and numerous presumed small feeding vessels from the bronchial circulation were identified on axial and coronal views. The patient elected to undergo extirpative surgery to prevent further growth and for blood pressure control. A physical examination was notable for blood pressure of 134/89 and a regular heart rate of 90. Preoperative medical management included blood pressure control with alpha and beta adrenergic blockers, inhibition of catecholamine synthesis with metyrosine and volume expansion with salt. Her anti-hypertensive regimen was titrated up to doxazosin (10 mg daily) and metoprolol (150 mg/day). Metyrosine, a tyrosine hydroxylase inhibitor, was increased up to 1.5 gm/day for 2 months prior to surgery. Subsequently, serum normetanephrines decreased to 1.01 nmol/L. Preoperative evaluation included pulmonary function tests (forced expiratory volume in 1 second ⫽ 3.09 [114%] and forced vital capacity ⫽ 3.82 [109%]), and an echocardiogram (ejection fraction ⫽ 60% with normal ventricular function without ventricular hypertrophy or evidence of ischemia). Preoperative embolization of the tumor feeding vessels was considered, but it was not attempted because of the potential risks of uncontrolled catecholamine release, vascular injury, and paralysis. The patient underwent a median sternotomy. The pericardium was opened anteriorly and then posteriorly to allow adequate exposure of the tumor. The tumor was first completely dissected off the superior vena cava and the brachiocephalic vein (Fig 1C). Upon exploring the aortic margin of the tumor, it was evident that the tumor was both highly vascular and adherent through the pericardium to the arch of the aorta and to the right and main pulmonary arteries. At this point, the patient was placed on cardiopulmonary bypass and cooled to 20°C. The aorta was cross-clamped; cardioprotection was initiated with intermittent cold hyperkalemic blood cardioplegia given through the antegrade route. The ascending aorta was transected just above the level of the sinotubular junction to gain access to the remaining adherent tumor in the aortopulmonary window. The tumor was carefully mobilized en-bloc off the right and main pulmonary arteries, off the subcarinal space as well as the left side of the trachea and left main stem bronchus, where it was attached to the paratracheal lymph nodes and the recurrent laryngeal nerve, which was sacrificed. The tumor was finally dissected free from the lesser curve of the arch of the aorta (Fig 1D) under circulatory arrest. The tumor was adherent to the arch at that point, and the adventitia of the arch was denuded in two places and was repaired using a half size 26 Hemashield tube graft (Boston Scientific, Natick, MA) to replace the inferior portion of the arch. The patient was rewarmed and weaned off cardiopulmonary bypass without difficulty. However, due to excess bleeding from the resected tumor bed, the cavity was packed and the patient’s chest was left open in the intensive care unit for resuscitation and an anticipated delayed chest closure. Intraoperatively the patient was hemodynamically stable throughout the procedure despite manipulation of the tumor. The patient initially required a tracheostomy and left vocal cord 0003-4975/07/$32.00 doi:10.1016/j.athoracsur.2007.02.090
Ann Thorac Surg 2007;83:e14 – 6
CASE REPORT PAUL ET AL PARAGANGLIOMA OF MEDIASTINUM
e15
Fig 1. (A) Computed tomographic chest scan demonstrating middle mediastinal mass (*). (B) Three-dimensional computed tomographic chest scan reconstruction with volume imaging demonstrating extent of mass (shaded area). (C) Intraoperative picture with peanut showing location of anterior aspect of mass between the superior vena cava and aorta. (RA ⫽ right atrium.) (D) Gross picture of mass after excision.
medialization to wean off the ventilator and was eventually decannulated with no difficulties. Postoperative normetanephrine levels had normalized (0.88 nmol/L) 2 weeks after surgery. Histopathology revealed the tumor to be less than 0.1 cm from the periaortic surface (Fig 1D). The final margins were all negative. Immunohistochemical stains were positive for chromogranins, synaptophysin, and protein S-100. The meta-iodobenzylguanidine-1 proliferative index was focally up to 10%.
Comment Mediastinal paragangliomas and their abdominal counterparts, pheochromocytomas, are extremely well vascularized tumors originating from enterochromaffin cells that usually secrete catecholamines. These tumors account for roughly 0.1% to 0.5% of all cases of hypertension [1–3]. Mediastinal paragangliomas are rare tumors with only approximately 150 cases described in the literature to date. Functional paragangliomas are quite exceptional, with approximately 50 cases reported, which have been documented to secrete catecholamines [2]. The treatment of choice is surgical excision after preoperative control of hypertension, with postoperative radiotherapy described for specific cases [1– 4]. We believe that our patient is the first to undergo resection of a middle mediastinal functional paraganglioma requiring cardiopulmonary bypass as well as aortic transection and reconstruction. Preoperative antihypertensive therapy with alpha followed by beta adrenergic blockade and volume loading is
crucial in preventing intraoperative hypertensive crises. Metyrosine has been shown to decrease intraoperative requirements for anti-hypertensive medications, vasopressor agents, fluids, and blood products [5, 6]. Another way to potentially prevent intraoperative hypertension is to perform preoperative embolization of feeding vessels to the tumor. This approach could promote tumor necrosis as well as theoretically prevent blood loss during surgery [7]. In our case, the risk of procedure-induced spinal cord paralysis was believed to be high due to the location of the tumor and its bronchial feeding vessels. Furthermore, it was believed that tumor necrosis may induce an uncontrollable hypertensive crisis through catecholamine release. Therefore this approach was not used. We instead chose the protection afforded by cardiopulmonary bypass. Surprisingly we did not note any hypertensive episodes while manipulating the tumor prior to initiating bypass. Intraoperatively, this tumor was found to be posterior to the ascending aorta and adherent to the aorta at the underbelly of the distal arch. Surgical resection of the tumor required first transection of the ascending aorta for exposure and then reconstruction of a significant portion of the involved aorta to repair the consequences of complete resection. Bleeding in the tumor bed was not unexpected, as these tumors are highly vascular and hemostasis after cardiopulmonary bypass and circulatory arrest is often a problem even under the best of circumstances [1, 2, 4, 7]. We chose to leave the chest open to prevent tamponade until clotting factors were repleted and hemostasis en-
e16
CASE REPORT PAUL ET AL PARAGANGLIOMA OF MEDIASTINUM
sured. The loss of the left recurrent nerve was anticipated given the tumor’s location. In conclusion, treatment of functional mediastinal paragangliomas requires careful preoperative assessment and a multidisciplinary team involving endocrinologists, cardiac surgeons, and thoracic surgeons. The preoperative management of catecholamine excess is imperative to prevent hypertensive crises. In the case of mediastinal paragangliomas, the early use of cardiopulmonary bypass and plan to reconstruct critical vascular structures must be anticipated. We conclude that the resection of complex mediastinal paragangliomas is feasible. We would like to thank Dr Ritu Gill from radiology for her help in reformatting the computed tomographic chest scan images and Dr Vania Nose from pathology for her help in preparing the pathology for this article.
Ann Thorac Surg 2007;83:e14 – 6
References 1. Chao S, Mullins ME, Slanetz PJ. Posterior mediastinal pheochromocytoma. AJR Am J Roentgenol 2001;176:1408. 2. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1986;1:1061– 4. 3. Sahdev A, Sohaib A, Monson JP, et al. CT and MR imaging of unusual locations of extra-adrenal paragangliomas (pheochromocytomas). Eur Radiol 2005;15:85–92. 4. Petit T, de Lagausie P, Maintenant J, et al. Thoracic pheochromocytoma revealed by ventricular tachycardia. Clinical case and review of the literature. Eur J Pediatr Surg 2000;10:142– 4. 5. Steinsapir J, Carr AA, Prisant M, et al. Metyrosine and pheochromocytoma. Arch Intern Med 1997;157:901– 6. 6. Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromocytoma with the use of metyrosine. Ann Surg 1990;212:621– 8. 7. Rakovich G, Ferraro P, Therasse E, et al. Preoperative embolization in the management of a mediastinal paraganglioma. Ann Thorac Surg 2001;72:601–3.