Mediastinal paraganglioma: A surgical experience

Mediastinal Paraganglioma: A Surgical Experience Miguel F. Herrera, MD, Jon A. van Heerden, MB, Francisco J. Puga, MD, Michael J. Hogan, MD, and J. Aidan Carney, MD Departments of Surgery, Medicine, and Surgical Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Between October 1960 and January 1991, 5 male and 9 female patients (mean age, 44 k 19 years) were seen at the Mayo Clinic because of mediastinal paraganglioma. Nine patients presented with hypertension. In these and an additional patient, the tumors were biochemically active. In 13 patients, the mediastinal mass was localized preoperatively. All patients with functioning tumors received a-adrenergic and Padrenergic blockade preoperatively. Total resection was performed in 11 patients and partial resection in 2. In 1 patient, the tumor was found at postmortem examination. Five lesions were grossly invasive and nine were noninvasive. Blood pres-

sure returned to normal in 6 of the 8 hypertensive patients whose tumors were totally removed. In 4, catecholamine excretion normalized as well. Tumor multicentricity occurred in 6 patients. In 7 patients, the disease took a malignant course (metastases in 5 and progression of unresectable lesions in 2). The probability of 10-year survival after resection was 50% in the group with malignant tumors, and there were no deaths in the group with benign lesions. Analysis of the DNA cellular content showed no correlation between the ploidy pattern and the behavior of the disease. (Ann Thoruc Surg 2993;56:2096-200~

P

gist (J.A.C.). DNA analysis by flow cytometry was performed on ten primary tumors using previously published techniques [6]. Some of the patients included in the present series have been reported on elsewhere [7-121.

heochromocytomas arise from chromaffin cells. They are a rare and potentially fatal cause of hypertension, but remain eminently curable, which renders proper diagnosis and treatment of great importance [l]. The incidence of pheochromocytomas varies between 0.01% and 0.1% of the hypertensive population, and they occur in approximately 0.002% of the general population [2]. Pheochromocytomas have been called 10% tumors because approximately 10% are bilateral, 10%are malignant or multiple, 10% are familial, and 10% arise in extraadrenal locations, where they are termed paragangliomas [3]. Both functioning and nonfunctioning tumors may arise close to any part of the sympathetic neural chain. Fewer than 2% of the catecholamine-secreting tumors arise in the chest [4], and until 1986, only 149 well-documented cases of intrathoracic paragangliomas had been reported [ 5 ] . The rarity of the tumor in this location, and the fact that most of the published information comes from isolated case reports, has made an understanding of the biology, clinical characteristics, diagnostic approaches, and therapy somewhat difficult to acquire. The aim of the present study was to analyze a series of 14 consecutive patients with mediastinal paraganglioma treated at a single institution.

Material and Methods Between October 1960 and January 1991, 14 patients with mediastinal paragangliomas were seen at the Mayo Clinic. The medical records of these patients were reviewed and follow-up data obtained by personal interview or correspondence with the patients, their physicians, or both. All pathologic specimens were reviewed by a single patholoAccepted for publication Dec 22, 1992. Address reprint requests to Dr l'uga, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. 0

1993 by The Society of Thoracic Surgeons

Results There were 5 male and 9 female patients. Their mean age at the time of diagnosis was 44 & 19 years. Twelve patients had nonfamilial sporadic tumors, and 2 had the Carney triad [7]. Five patients had previous resection of abdominal paragangliomas (pheochromocytomas, 3; paraaortic, 2; and bladder, 1) 4 months to 9 years previously.

Clinical Presentation Nine patients were seen because of hypertension of several months' duration, coupled with other symptoms related to catecholamine excess. Atypical presentations in 3 patients included cardiac tamponade, superior vena caval obstruction, and a cervical mass due to extension of the mediastinal tumor. In 2 asymptomatic patients, the tumor was discovered incidentally on chest roentgenograms obtained for other reasons.

Biochemical Investigation Ten tumors were biochemically active. Excretion rates of the catecholamines and their metabolites are presented in Figure 1. Of the 7 patients in whom fractionated urinary catecholamineswere measured, norepinephrine excretion was elevated in all and the dopamine level was raised in 4. Two patients, 1 with a concurrent adrenal pheochromocytoma and 1 with a single aorticopulmonary tumor, exhibited markedly elevated epinephrine excretion rates. 0003-4975/93/$6.00

HERRERA ET AL MEDIASTINAL PARAGANGLIOMA

Ann Thorac Surg 1993;561096-100

found also had four retroperitoneal and three adrenal concurrent paragangliomas.

100

8

1097

80

a-

Pa thology

I 6 0

Of the 11 totally resected specimens, the mean size was 5.3 ? 3 cm. All tumors had the characteristic microscopic pattern of a paraganglioma. Metastatically involved adjacent lymph nodes were found in a patient with a noninvasive lesion. Based on flow cytometric analysis, seven tumors exhibited a DNA diploid pattern, two had an aneuploid pattern, and one a tetraploid pattern.

a,

2 240 c

m

5

20 0

Metanephrines

VMA

Fractionated catecholamines

( ) = positive testsnotaltests

Fig 1. Urinary catecholamine metabolites in patients with mediastinal paragangliomas. (VMA = vanillylmandelic acid.)

Localization Procedures Two patients treated before the era of computed tomography were evaluated by chest roentgenogram and tomography. In 10, 4, and 5 patients, respectively, computed tomography, magnetic resonance imaging, and iodine 131-metaiodobenzylguanidine (MIBG) scanning were performed. The positivity rate of these tests is shown in Figure 2.

Preoperative Preparation All 10 patients with functioning tumors received a-adrenergic and padrenergic blockade for more than 1 week preoperatively. None of these patients nor the asymptomatic patients who did not receive blockade experienced intraoperative complications related to hemodynamic fluctuations.

Complications Two patients had unilateral vocal cord paralysis due to intentional resection of a segment of the vagus nerve involved by the tumor. Diaphragmatic paralysis occurred in 1 patient after extensive manipulation of the phrenic nerve during dissection. There was no operative mortality.

Adjuvant Treatment Four patients, 1 with lymph node metastases and 3 with macroscopic invasion, received postoperative radiotherapy. Chemotherapy (doxorubin hydrochloride) was administered to 1 patient.

Mu1ticen tricity Six patients each had a single paraganglioma at multiple sites. In all patients with multicentric lesions, one or more tumors had been resected before chest exploration. One of these patients underwent resection of synchronous multicentric abdominal paragangliomas at the time of mediastinal exploration, and a metachronous lesion also developed in 1 patient 2 years later.

Surgical Treatment

Therapeutic Response

Ten patients presented with well-demarcated lesions and 4 with invasive paragangliomas. Eleven patients underwent complete resection of the tumor; only partial resection was performed in 2 because of local invasion. Left thoracotomy, median sternotomy, right thoracotomy, and cervical exploration were carried out in 6, 5, 1, and 1 patient, respectively. In 1 patient whose lesion was approached through a median sternotomy, cardiopulmonary bypass was used, as resection of the tumor mass required partial resection and repair of the left atrium. Two of the patients in whom the tumor was totally resected had had a previous thoracic operation. Open chest biopsy had been performed in both, and a pericardial window created in 1. In 1 patient, the tumor was encountered at the time of postmortem study. In 9 patients, single tumors arose from ganglia located along and under the aortic arch. These tumors were adherent to the aortic and pulmonary artery wall. In 2 patients, paragangliomas were encountered in the posterior mediastinum along the sympathetic chain. One tumor arose from the left atrium and one from the interatrial septum. A coronary paraganglioma was found in 1 patient. A patient with multiple paragangliomatosis in whom ten intrathoracic aortosympathetic tumors were

Within 6 months of resection, 4 of the 8 hypertensive patients who had the tumor totally removed had become normotensive and exhibited normal catecholamine excretion. In 2 other patients, blood pressure returned to

..

CT

MRI

13'

I-MIBG

( ) = positivetesEs/tdaltests

Fig 2. Accuracy of imaging modalities in the localization of mediastinal paragangliomas. (CT = computed tomography; MRI = magnetic resonance imaging; 1311-MIBG = iodine 131-labeled metaiodobenzylguanidine.)

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Ann Thorac Surg 1993;56109&100

HERRERAETAL MEDIASTINAL PARAGANGLIOMA

Table 1. Clinical Features, Pathologic Findings, and Treatment in 7 Patients With Malignant Mediastinal Paragangliomas

Site of

Age (y)

Sex

Lesion

44

M

36

Gross

AP

Noninvasive

Pattern Diploid

F

AP

Partial

Invasive

15

M

AS

55

F

AP

77

M

AP

Total resection and RT Total resection and RT Total resection

17 66

F M

AS

Total resection Partial resection and RT

Noninvasive Invasive

AP

Appearance

Ploidy

Treatment Total resection

resection and RT + QT

Time to

Function

Recurrence

Yes

28 mo

Aneuploid

Yes

...

Invasive

Diploid

Yes

14 mo

Invasive

Diploid

Yes

Invasive

...

No

43 mo

Aneuploid Aneuploid

No No

11 Y

...

...

Metastases Liver,

paraaortic

Outcome (Y) A-NED (5)

ganglia

...

D-ED (2)

LN, lung, bone

D-ED (13)

LN

A-ED (1)

LN, lung, bone Lung

D-ED (6)

...

A-ED (13) D-ED (5)

~~~~~

A-NED = alive, no evidence of disease; AP = aorticopulmonary; A-ED = alive with evidence of disease; = dead of disease; LN = lymph nodes; QT = chemotherapy; RT = radiotherapy.

normal despite persistently elevated catecholamine excretion rates. Two patients remained hypertensive, 1 with elevated catecholamine excretion and 1 with normal catecholamine levels.

Survival The patients were followed up for a mean of 7 years (range, 6 months to 30 years) from the date of operation. In 7 patients, the tumor had a malignant course, with 4 patients dying of their disease (Table 1). The most common locations for metastases were the liver, lung, bone, and regional lymph nodes. In 2 patients, metastatic disease occurred after an asymptomatic period in which the catecholamine levels were normal following surgical excision. Most of the metastases occurred within 5 years after resection. There was no mortality in the group of patients with benign lesions. The 2 patients with unresectable lesions died of the disease. The probability of survival for patients with malignant tumors was 50% at 7 years with no survivors after 13 years (Fig 3). There was no correlation between the ploidy pattern and the gross appearance of invasion, but the four grossly invasive tumors and the three nondiploid tumors followed a malignant course (Table 2).

Comment Although paragangliomas are extremely rare, surgeons should be familiar with their presentation and treatment, because patients will be encountered with a clinical picture of catecholamine hypersecretion in whom a pheochromocytoma (the usual cause of the finding) cannot be found, and an extraadrenal lesion (sometimes a mediastinal paraganglioma) is responsible. The extraadrenal paraganglion system has been divided into four families: (1) branchiomeric (associated with

AS = aorticosympathetic;

D-ED

arterial vessels and cranial nerves of the ontogenic branchial arches), (2) intravagal, (3) aorticosympathetic (associated with the sympathetic chain and retroperitoneal ganglia), and (4) visceral autonomic [13]. Thoracic paragangliomas are located mainly in the posterior and middle mediastinum. The former arise from the region of the aortosympathetic or intravagal paraganglia, and the latter arise around either the branchial arch structures (ie, coronary and aorticopulmonary paraganglia) or the visceral-autonomic paraganglia of the cardiac atria and interatrial septum [14]. The number of catecholamine-secreting paragangliomas is less than the number of secreting adrenal pheochromocytomas, and this seems to be related to the family to which the tumor belongs. The proportion of aorticosympathetic functioning tumors is approximately 35%, whereas, in the case of branchiomeric and visceralautonomic tumors, the proportion is 10%or less [5]. In the present series, the rate of functioning paragangliomas

80

-

-

60

Benign resected (n = 6) Malignant resected (n= 5) Malignant unresected (n = 2)

0

&

0

111111 12345

I 10

,

I

15

20

Years Fig 3 . Probability of survival for 23 patients with mediastinal paragangliomas according to the presence of malignancy and the magnitude of resection (Kaplan-Meier).

, 30

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Ann Thorac Surg 1993:56:1096-100

Table 2. lnvasion and DNA Ploidy Pattern of Malignant and Benign Mediastinal Paragangliomas Gross Appearance

DNA Pattern

Behavior

Invasive

Noninvasive

Diploid/ Tetraploid

Benign Malignant

0 4

7 3

4 3

Aneuploid 0 3

was higher than that previously reported. Nine patients presented with hypertension, and increased catecholamine secretion was demonstrated in 10 (71%). The frequency of functioning tumors according to the location of the tumor was 60%, loo%, and 100% for the branchiomeric, aorticosympathetic, and visceral-autonomic families, respectively. As the enzyme that catalyzes the N-methylation of norepinephrine to form epinephrine (phenylethanolamine-N-methyl transferase) is localized in the adrenal medulla and its activity is partially controlled by cortisol [14], epinephrine is produced by tumors arising from this location and not extraadrenal locations. It was surprising, therefore, to find elevated urinary levels of epinephrine in 2 patients. In 1, the concurrence of an adrenal pheochromocytoma fully explains the finding, but in the absence of adrenal disease in the second patient, we think the aorticopulmonary tumor was an epinephrine-producing paraganglioma. Paragangliomas tend to be multicentric [15]. We found multiple tumors in 6 of the 14 cases (43%). Multicentric lesions did not show a specific pattern of distribution. Instead, there was a wide variety in terms of the number and location of the tumors involved. Two patients exhibited the Carney triad, a nonfamilial syndrome that affects predominantly young women and comprises gastric epithelioid leiomyosarcomas and pulmonary chondromas, in addition to functioning extraadrenal paragangliomas [7]. The latter has occurred in about 30% of the patients with the syndrome and greatly outnumber the cases of adrenal paragangliomas (pheochromocytomas) seen in the disorder. Many imaging modalities have been used successfully to localize paragangliomas in intrathoracic locations. Chest tomography, computed tomography, magnetic resonance imaging, angiography, selective venous sampling, and two-dimensional echocardiography are the most frequently used [5, 12, 16, 171. Shapiro and colleagues [18] were able to localize middle mediastinal paragangliomas

Table 3 . Comparison of Features of Mediastinal Paragangliornas and Adrenal Pheochromocytomas" Feature Function Multicentricity Malignancy Diploid tumors with malignant course a

Mediastinal

Adrenal [2, 21, 221

71% (42-92%) 43% (18-71%) 43% (18-71%) 43% (1042%)

92% (8697%) 13% (7-21%) 20% (13-29%) 0 (0-18%)

Numbers in parentheses represent the 95% limits of confidence.

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by MIBG scanning in 8 patients in whom the lesion had not been detected before the performance of scintigraphy. Because of the retrospective nature of the present series and the fact that radiologic studies were done using different generations of machines, a comparative analysis of the sensitivity of the various imaging modalities cannot be done. Adequate localization of the tumor was established preoperatively in 13 patients (93%). The patient with a cardiac paraganglioma that was not localized was studied in 1977. We think that with the currently available highly sensitive scanners and the use of MIBG scanning, the probability of localizing chest paragangliomas should be 100%. The reported incidence of malignancy for cases of paraganglioma varies from 20% to 50% [3, 19, 201. Approximately 98% of the malignant tumors are located in the abdomen, and the diagnosis of malignancy is based on either the presence of local invasion or the development of metastases. In the current series, the incidence of malignancy was 43%. The 10-year survival of the 6 patients with resected malignant tumors was 50%, and there were no 13-year survivors. To investigate differences in behavior between mediastinal paragangliomas and pheochromocytomas, we did a comparative analysis of the current population versus previous reported series of patients with adrenal pheochromocytomas seen at our institution (Table 3). Although the limits of confidence of most evaluated aspects overlap, probably due to the small number of patients in the mediastinal group, it is apparent that mediastinal paragangliomas are less often functioning, more often multicentric and malignant. The correlation between the ploidy pattern and the behavior of the tumor displayed different characteristics in the settings of paragangliomas and pheochromocytomas. Invasive and aneuploid mediastinal paragangliomas followed a malignant course.

References 1. Sheps SG. Pheochromocytoma. In: Spittell JA Jr, ed. Clinical medicine, vol 7. Philadelphia: Harper & Row, 1986:l-26. 2. Van Heerden JA, Sheps SG, Hamburger 8, et al. Pheochromocytoma: current status and changing trends. Surgery 1982;911367-73. 3. Edis AJ, Grant CS, Egdahl RH. Manual of endocrine surgery, 2nd ed. New York Springer Verlag, 1984. 4. Manger WM, Gifford RW. Hypertension secondary to pheochromocytoma. Bull NY Acad Med 1982;58:139-58. 5. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1986;l: 10614. 6. Herrera MF, van Heerden JA, Katzmann JA, Weiland LH, Nagorney DM, Ilstrup DM. Evaluation of DNA nuclear pattern as a prognostic determinant in resected pancreatic ductal adenocarcinoma. Ann Surg 1992;215:120-4. 7. Carney JA. The triad of gastric epitheloid leiomyosarcoma, pulmonary chondroma and functioning extra-adrenal paraganglioma: a five-year review. Medicine 1983;62:159-69. 8. Hodgkinson DJ, Telander RL, Sheps SG, Gilchrist GS, Crowe JK. Extra-adrenal intrathoracic functioning paraganglioma (pheochromocytoma)in childhood. Mayo Clin Proc 1980;55: 271-6.

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9. Karasov RS, Sheps SG, Carney JA, van Heerden JA, DeQuattro V. Paragangliomatosis with numerous catecholamineproducing tumors. Mayo Clin Proc 1982;57590-5. 10. Hodgson SF, Sheps SG, Subramanian R, Lie JT, Carney JA. Catecholamine-secreting paraganglioma of the interatrial septum. Am J Med 1984;77157-61. 11. Margulies KB, Sheps SG. Carney’s triad: guidelines for management. Mayo Clin Proc 1988;63:49&502. 12. Cueto-Garcia L, Shub C, Sheps SG, Puga FJ. Twodimensional echocardiographic detection of mediastinal pheochromocytoma. Chest 1985;87834-6. 13. Glenner GG, Grimley PM. Tumors of the extra-adrenal paraganglion system (including chemoreceptors). In: Atlas of tumor pathology; 2nd series; fasc 9. Washington, DC: Armed Forces Institute of Pathology, 1974. 14. Cohen PS, Israel MA. Biology and treatment of thoracic tumors of neural crest origin. In: Roth JA, Ruckdeschel JC, Weisenburger TH, eds. Thoracic oncology. Philadelphia: Sanders, 1989:520-40. 15. Zak FG, Lawson W. The paraganglionic chemoreceptor system. Physiology, pathology, and clinical medicine. New York: Springer-Verlag, 1982.

Ann Thorac Surg 1993;561096-100

16. Spizarny DL, Rebner M, Gross BH. CT evaluation of enhancing mediastinal masses. J Comput Assist Tomogr 1987;ll: 99c-3. 17. Barakos JA, Brown JJ, Brescia RJ, Higgins CB. High signal intensity lesions of the chest in MR imaging. J Comput Assist Tomogr 1989;13:797-802. 18. Shapiro B, Sisson J, Kalff V, et al. The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 1984;87814-20. 19. Levine SN,McDonald JC. The evaluation and management of pheochromocytomas. Adv Surg 1984;17281313. 20. Scott HW Jr, Reynolds V, Green N, et al. Clinical experience with malignant pheochromocytoma. Surg Gynecol Obstet 1982;154801-18. 21. Van Heerden JA, Roland CF, Carney JA, Sheps SG, Grant CS. Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 1990;1432.5-9. 22. Hosaka Y, Rainwater LM, Grant CS, Farrow GM, van Heerden JA, Lieber MM. Pheochromocytoma: nuclear deoxyribonucleic acid patterns studied by flow cytometry. Surgery 1986;100:1003-10.

The Society of Thoracic Surgeons: Thirtieth Annual Meeting Mark your calendars for the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, which will be held at the New Orleans Convention Center in New Orleans, Louisiana, January 31-February 2, 1994. Members may register for the Scientific Sessions at no charge. There will be a $250 registration fee for nonmember physicians except for Scientific and Poster Session presenters and residents. Registration for the Postgraduate Course is separate from the Annual Meeting. There will be a $65 registration fee for attendees of the Postgraduate Program, which will be held Sunday, January 30. The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons.

Advance registration forms, hotel reservation forms, and details regarding transportation arrangements, as well as the complete meeting program, will be mailed to Society members this fall (1993). Nonmembers wishing to receive information on attending the meeting should write to the Society’s Secretary, Richard P. Anderson.

Richard P. Anderson, M D Secretary The Society of Thoracic Surgeons 401 N Michigan Ave Chicago, IL 60611-4267 (312) 644-6610