Journal of Surgical Oncology 2000;74:286–290
Paragangliomas—A Decade Of Clinical Experience P. SOMASUNDAR, MD,* R. KROUSE, MD, R. HOSTETTER, MD, R. VAUGHAN, MD, T. COVEY, MD Department of Surgery, West Virginia University School of Medicine, Morgantown, West Virginia
AND
Background and Objectives: This study is a review of 14 patients with paragangliomas between 1986 and 1996. The purpose was to determine the sites of origin, clinical manifestations and analyze the benefits of different treatment modalities. Methods: There were 20 tumors in 14 patients. Three (21.0%) of the patients had familial history. There were 7 (50%) females and 7 (50%) males. Anatomically 14 (70%) tumors were in head and neck, 5 (25%) were in the retroperitoneum, one (5%) was in the heart. Of the head and neck tumors 9 (64.25%) were in the carotid body, 3 (21.42%) were found in the vagus, and 2(14.33%) were found in the middle ear. The tumor found in the heart was in the atrial septum. The clinical behavior of paragangliomas is determined by cellular characteristics, secreting capabilities and tumor location. The symptoms and signs depend on the site of origin and the stage at which it presents. The clinically functioning tumors were 3 (17%) in our experience and they typically present with uncontrolled hypertension. The carotid body and mediastinal tumors usually manifested as asymptomatic masses. The intravagal tumors presented with paresis of the nerve. Malignancy rarely occurs and is defined by the existence of metastasis rather than by histology. In our series 2 (10%) of the patients presented with metastasis to lymph nodes, and the vertebrae. The diagnoses in our patients were established by CT and MRI scanning. Angiography was performed in 5 patients with carotid body tumor, two of whom underwent therapeutic embolization to reduce the tumor size. The mainstay of treatment was surgical removal, though radiation has been advocated for patients who cannot undergo surgery. Results: All patients underwent successful surgical resection of the tumor after appropriate preoperative preparation. Late mortality occurred in two (12.5%) patients at 3 and 5 years from unrelated etiology. Four (25%) patients were lost to follow-up. Three (18.7%) patients developed new primaries, two of them at two years and one after 8 years. One (6%) patient developed recurrent paraganglioma after remaining disease free for 20 years. Conclusion: In conclusion, paragangliomas are rare with multicentricity being more common in patients with familial history. The malignant potential of the tumor is determined by metastasis as there are no characteristic cellular change. Aggressive surgery is mandatory to obtain disease free survival with low morbidity and mortality. Recurrences can also be successfully operated with low morbidity. J. Surg. Oncol. 2000;74:286–290.
© 2000 Wiley-Liss, Inc.
KEY WORDS: paragangliomas of neck; paragangliomas of retroperitoneum; paragangliomas of chest *Correspondence to: Ponnandai S. Somasundar, MD, Department of Surgery, WVU Health Sciences Center, Morgantown, WV 26506. E-mail:
[email protected] Accepted 15 March 2000
© 2000 Wiley-Liss, Inc.
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TABLE I. Demographics, Histories, and Presentations of Patients With Paragangliomas Age
Gender
Site
35
F
70
F
61 70 83
M M M
69
F
52
F
55 52 39 46 25 43 13
F F M M M F M
Right & left carotid & glomus vagale Glomus tympanicum Right & left carotid Right carotid Left carotid with recurrences Left carotid glomus tympanicum Left glomus vagale Right carotid Right gomus vagale Right carotid Left peri-renal Left extra adrenal Left extra adrenal Celiac ganglia Left atrium
Symptoms
Family history
Metastasis
Functional status
Neck mass
No
No
No
Intermittent hearing loss
No
No
No
Neck mass Neck mass Neck mass Paraparesis Left aural fullness
Yes No No
Yes No Yes
No No No
Yes
No
No
Neck mass
Yes
No
No
Neck mass Neck mass Hypertension Hypertension Hypertension polycythemia Incidental Chest pain, hypertension
No No Yes No No No No
No No No No No No No
No No Yes Yes Yes No Yes
INTRODUCTION Paragangliomas arise from neuroendocrine cells of the autonomic nervous system. They are rarely encountered in every day surgical practice. Because of their rarity, little is known about the natural history of these tumors and the results of the treatment. The tumors originate in the adrenal medulla, carotid and aortic bodies, organs of Zuckerkandl, and other unnamed paraganglia occurring in the distribution of the sympathetic and parasympathetic nerves. They can be unicentric or multicentric, tend to be locally invasive and, therefore have a high incidence of local recurrence. The adrenal medulla bilaterally represents the largest collection of this paraganglionic tissue, and tumors derived from it occur much more frequently than in extra-adrenal locations. It has been estimated, that as many as 10% of paragangliomas arise outside the adrenal glands. Head and neck paragangliomas have an indolent course, often spanning >10 years. Paragangliomas of the retroperitoneum arise from dispersed paraganglia that tend to be symmetrically distributed in close relation to the aorta and sympathetic nervous system. About 2% of all paragangliomas are located in the chest, and a few are within the pericardium. Because of the rarity of these tumors natural history is not always clear and treatment protocols have not been established. We reviewed the experience in our tertiary referral center of this uncommon tumor. MATERIALS AND METHODS Fourteen patients with paragangliomas were identified at West Virginia University from 1986 to 1996 (Table I). There were 20 tumors in these 14 patients. They were classified according to the anatomic sites as described by Glenner and Grimley [15]. Fourteen (70%) tumors were
in the head and neck, 5 (25%) were in retroperitoneum, and one (5%) was intra atrial. There were 14 tumors in 9 patients with head and neck paraganglioma. Nine patients had paragangliomas in the head and neck region that were operated upon over a period of 10 years. Nine (64.25%) tumors originated from the carotid body, 3 (21.42%) from glomus vagale and 2 (14.33%) from glomus tympanicum. Seven of these patients presented with an asymptomatic mass in the neck. Two of the patients with glomus tympanicum arising from the middle ear presented with intermittent hearing loss. All of the 9 patients had lesions identified by computed tomography (CT) scan or magnetic resonance imaging (MRI) (Fig. 1). Five of the 9 patients underwent angiography (Fig. 2) for identification of the feeding vessel, presence of multicentricity, and therapeutic embolization to reduce the size of the tumor where indicated. Two patients underwent therapeutic embolization before surgery with significant reduction in vascularity. Three patients who had angiogram revealed evidence of multicentricity. Two patients had metastasis, 1 had metastasis to the adjacent regional lymph node, and the other patient had tumor metastasis to the third thoracic vertebra. The patient with fractured third thoracic vertebra had a compression fracture and hence required stabilization with surgery using a rod. All the patients underwent successful surgical resection. On follow up, 2 patients died of other diseases, and 1 was lost to followup. The other 6 patients are being followed without evidence of recurrence of the disease. The longest follow-up on a patient was 9 years. The retroperitoneal paragangliomas were identified between ages of 25 and 43 years. Three of these tumors were perirenal, 1 was proximal to the bifurcation of aorta,
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Fig. 1.
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MRI scan showing evidence of tumor in right side of neck.
and 1 was in the celiac ganglia. Four of the 5 were functional tumors secreting norepinephrine. All patients with functional tumors presented with uncontrolled hypertension. One patient presented with polycythemia, that was corrected on removal of the tumor. The patient with celiac ganglia tumor was associated with neurofibromatosis and cerebellar astrocytoma. All patients underwent resection of the tumor successfully with no mortality. One patient with a perirenal tumor presented 8 years after surgery with recurrence of hypertension and polycythemia. A work-up revealed an isolated tumor present below the aortic bifurcation, that was removed. One patient has been followed up for 9 years and other 3 patients were followed for an average of 2 years without further disease. A 13-year-old patient presenting with chest pain, shortness of breath, and hypertension was found to have a paraganglioma in the interatrial septum. The tumor was confirmed with trans-esophageal echocardiogram and MRI scan. The patient underwent successful resection of the tumor and is well at 1-year follow up. DISCUSSION Paragangliomas are rare tumors causing considerable difficulty in both diagnosis and treatment. Glenner and Grimley [15] considered the extraadrenal portion of the paraganglion system as interrelated “families” grouped on the basis of anatomic distribution, innervation, and microscopic structure. The branchiomeric and intravagal paraganglionic system (parasympathetic paraganglia) is
Fig. 2.
Angiogram showing evidence of tumor.
represented principally by the carotid, vagal, and jugulotympanic bodies, although similar collections of cells have been demonstrated in other sites such as the paranasal or laryngeal regions [2]. Neoplasms arising from the aorticosympathetic paraganglia have been referred to as extra-adrenal pheochromocytomas because of their histologic, biochemical, and clinical similarities to adrenal pheochromocytomas. The preferred terminology, however, is simply paraganglioma, with an indication of the anatomic site of origin. Histologically, most are composed of well-differentiated neuroendocrine cells disposed in small clusters (zellballen) or cords separated by prominent fibrovascular stroma. Distinctive within the cells in most tumors are dark neurosecretory granules that contain catecholamines. Sometimes the cells are spindle shaped. Mitoses are usually infrequent, but occasional tumors are overtly anaplastic and pleomorphic and contain numerous mitoses. Although most are benign, about 10% of those in the carotid body and as many as 50–60% of those arising elsewhere recur. The malignant potential is determined by local invasion and also distant metastases. Paragangliomas of the head and neck region are usually symptomatic tumors. Carotid bodies and related paraganglia have been ascribed a homeostatic role by sensing fluctuations in blood pH and oxygen tension [1]. The most common site of origin of head and neck paragangliomas is at the carotid bifurcation followed by the region of the ganglion nodosum [2]. Head and neck paragangliomas are recognized to occur in two forms: a sporadic form, and with a familial autosomal dominant pat-
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tern [3]. It is estimated that the familial incidence of head and neck paragangliomas is approximately, 10% [4]. Four (33%) of the patients in our series had family history of paraganglioma. Other etiological factors has been due to chronic hypoxia, that has been linked to development of carotid body tumors, especially in individuals living at altitudes over 2000 m above sea level [16]. Head and neck paragangliomas have shown to exhibit genomic imprinting i.e., expression of the imprinted gene/s depends on the gender of the transmitting parent— individuals that inherit the familial paraganglioma (FP) gene/s from their father will develop the disease [17]. The FP gene/s for tumors involving the head and neck have been postulated to be located on the long arm of chromosome 11 [18]. None of the patients with paragangliomas of the head and neck region manifested endocrine symptoms associated with catecholamine production and there were no distinguishing clinical features among familial as compared with non-familial cases. The incidence of multicentricity was 33% as reported in other series [5]. They are asymptomatic initially, however with progression they could invade the skull base and affect cranial nerves. The most frequent presenting symptom is that of palpable neck mass in carotid paraganglioma, located below the angle of the jaw and deep to the sternomastoid muscle, that either the patient or the family physician noticed on routine physical examination. Classically, these masses are vertically fixed and laterally mobile. The mass is frequently pulsatile and a bruit can be auscultated. In jugulotympanic paraganglioma the clinical course consist of slow continuous growth with few symptoms until the tumor has become far advance. The patient usually presents with a complaint of pulsatile tinnitus. Other complaints may include aural fullness or hearing loss. Cranial nerve deficits may be seen with larger tumors. Deficits of cranial nerves IX and X are most commonly seen but cranial nerves VII, VIII, XI, and XII can also be affected. None of our patients presented with cranial nerve palsies. The blood supply for the carotid bodies is by multiple tiny feeding vessels from the proximal internal and external carotid arteries and from the crotch between these arteries. Glomus tympanicum tumors may be supplied by either external carotid branches or tympanic branches of the internal carotid. Glomus jugulare tumors when small are usually supplied by the ascending pharyngeal artery but when large may be supplied by a variety of vessels. Glomus vagale tumors are supplied by ascending pharyngeal artery and may parasitize the internal carotid when large [19]. MRI and CT scans show the typical carotid body tumor located at bifurcation of the cervical common carotid artery. MRI reveals a lesion that is mildly hypointense or isointense to adjoining muscle on a T1 weighted image sequence and is moderately hyperintense on a T2
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weighted sequence. The characteristic and almost pathognomonic finding of flow vids within the lesion on spin echo MRI or flow augmentation on gradient echo sequences represents the large blood vessels within the carotid body tumor, a finding usually not present in other histologic tumor types present in this location [19]. The mainstay of treatment is surgical excision. The surgical resection of the carotid body is begun inferiorly and extended superiorly. Because the carotid body lies on the posterior medial aspect of the internal carotid artery in the area of the bulb, this may be the most difficult area to resect and is approached last. If necessary, the external carotid artery is ligated to permit rotation or rolling of the internal and common carotid arteries. A plane is more likely to be obtained in the posterior lateral aspect of the carotid artery. There is an argument in the literature whether the resection is in the subadventitial plane or periadventitial plane, but most authors refer to this plane as a subadventitial tissue plane. Surgery is offered to all people who do not have a specific medical reason to contraindicate the operative procedure [19]. Historically, carotid paragangliomas have been considered radioresistant. There have been a few studies that have shown good local control rates but others that have persistent disease in those paragangliomas treated with primary radiotherapy. Most often primary radiation therapy is used in cases where the patient is a poor surgical candidate, the tumor is unresectable with carotid sacrifice and the patient fails balloon occlusion testing, or the patient refuses surgery [21,22]. Paragangliomas of the retroperitoneum are a group of tumors that cause considerable difficulty in both diagnosis and treatment. They occur most commonly in the paraaortic area from the origin of the inferior mesenteric artery to the aortic bifurcation. This conforms to the distribution of paraganglia first characterized in the human fetus by Zuckerkandl in 1901 [6]. Biedl and Wiesel in 1902 demonstrated the pressor effects of extracts of the organs of Zuckerkandl (referred to as “aortic bodies” [7]) the physiologic role of extra-adrenal paraganglia in the retroperitoneum is assumed to be the homeostatic maintenance of blood pressure in early human life [8]. In our experience there was a predilection for males to have the tumor. The average age was about 30 years. An accurate preoperative clinical diagnosis of paraganglioma is seldom made unless there are overt symptoms related to excess catecholamine secretion. In our series three of the four patients with retroperitoneal paragangliomas were secreting norepinephrine. One patient manifested with polycythemia in addition to catecholamine secretion. This has been reported to be due to erythropoietin synthesized by the tumor [9].
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The polycythemia was cured once the tumor was removed in our patient. Most patients with nonfunctional tumors have painful mass and occasionally have symptoms of metastases [10]. Angiography has been replaced by CT scanning for initial evaluation of retroperitoneal and abdominal masses but may still be helpful in revealing vascular invasion or in demonstrating small metastases [11]. Although CT scan is also the first modality used to localize functional tumors, metaiodobenzylguanidine (MIBG) scans may be used to delineate multiple tumors and small tumors not seen on CT scan [12]. The role of MIBG in nonfunctional tumors is unclear [10]. The combined use of spin-echo images and threedimensional time-of-flight MR angiography can result in an increased detection rate of paragangliomas. Compared with digital subtraction angiography, MR angiography only allows visualization of feeding vessels in cases of large paragangliomas. The ability, however, to display vascular structures in the axial plane without superimposition and the ability to show vessel encasement yield additional information for the surgical approach [20]. All our patients underwent complete surgical resection. One patient had an occurrence of a new primary after eight years, and underwent surgical resection, with no further recurrence at 2 years follow up. Reports in the literature reveal a malignancy rate of 22–44%. In our series of retroperitoneal paragangliomas none of our patients presented with metastases, the longest follow up being at 8 years. One patient had an intra atrial paraganglioma resected. Primary cardiac tumors are uncommon, occurring in 0.001–0.03% of the general population [13]. Paragangliomas of the middle mediastinum arise from either the branchiomeric (i.e., coronary or aortopulmonary) or visceral-autonomic (i.e., atrium or interatrial septum) family. Paragangliomas are rare tumors of the heart with a predilection for the left atrium. Complete surgical excision is the treatment of choice as local recurrence has been documented. Our patient underwent complete surgical excision with no recurrence at 2 years. Surgery remains the mainstay of treatment of all paragangliomas. Once the diagnosis of paraganglioma is made, every attempt should be made to perform a complete surgical resection [10]. Resection is often challenging as these highly vascular tumors are located near multiple vital blood vessels. If a tumor is felt to be unresectable at surgery, attempts to reduce its size by chemotherapy or radiation or embolization may be indicated because resection offers the only chance of cure. In conclusion, paragangliomas are rare. The malignant potential of the tumor is determined by metastasis as there are no characteristic cellular change. Aggressive
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