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Endocrine Care |
Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine (D.E., Y.C.K., W.F.Y.), Department of Neurosurgery (M.J.E.), and Department of Surgery (G.B.T., C.S.G., J.A.v.H.), Mayo Clinic, and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: William F. Young, Jr., M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: Young.William{at}mayo.edu
Abstract
Paragangliomas are rare tumors that arise from extraadrenal chromaffin cells. We examined the clinical characteristics, location, treatment, and outcome of 236 patients (141 females, 60%) with 297 benign paragangliomas evaluated at the Mayo Clinic during 1978–1998. The mean age (±SD) at diagnosis was 47 ± 16 yr. Of the 297 paragangliomas, 205 were in the head and neck region, and 92 were below the neck. Paragangliomas were discovered and diagnosed incidentally on imaging studies in 9% of patients. Biochemical screening was performed in 128 patients; 40 patients (17% of the total and 31% of those screened) had hyperfunctional tumors. Of the 40 patients with tumoral catecholamine excess, 38 had documented hypertension. In patients identified with catecholamine-secreting paragangliomas, the sensitivities achieved by measurements in the 24-h urine collection were 74% for total metanephrines, 84% for norepinephrine, 18% for dopamine, and 14% for epinephrine. Multiple imaging modalities were used for tumor localization. The false negative rates were 0% for magnetic resonance imaging, 5.8% for computed tomography, 3.4% for angiography, 10.7% for ultrasonography, and 39% for radioactive iodine-labeled metaiodobenzylguanidine scintigraphy. Of 192 patients (81.4%) with follow-up data (mean, 43.9 months; range, 0.5–240), operative cure was achieved in 133 (69%). Of the 59 patients without cure, 23 had persistent disease, 5 had recurrent disease, 16 had multiple persistent synchronous tumors, and 15 subsequently developed metachronous tumors. In conclusion, most paragangliomas are nonhypersecretory and located in the head and neck region. Magnetic resonance imaging was associated with the lowest false negative rate, and metaiodobenzylguanidine was the least sensitive imaging study. A significant proportion of patients (31%) has persistent or recurrent disease, and long-term follow-up is important.
PARAGANGLIOMAS ARE RARE tumors that arise from extraadrenal chromaffin cells. They represent 10–18% of all chromaffin tissue-related tumors (1, 2, 3), which are reported at a rate of 2–8 cases/million·yr (4). It is important to diagnose, localize, and treat paragangliomas, because of potential cure of symptoms associated with functional tumors, prevention of a lethal hypertensive paroxysm, and early diagnosis of malignant tumors (5). In a retrospective analysis we examined the clinical characteristics, location, association with familial neurocristopathic syndromes, treatment, and outcomes of these unusual tumors. The accuracy of HPLC with electrochemical detection for measurement of catecholamines in urine for the diagnosis of catecholamine-secreting paragangliomas was determined. In addition, given recent improvements in diagnostic imaging techniques that have facilitated the incidental discovery of adrenal pheochromocytomas (6, 7, 8, 9), we sought to determine the incidence and location of incidentally discovered paragangliomas.
Subjects and Methods
The medical records of 249 patients with a diagnosis of paraganglioma evaluated at Mayo Clinic during 1978–1998 were reviewed. The starting year of 1978 was chosen because it was the year when the HPLC assay for urinary catecholamines became available at the Mayo Clinic. Paragangliomas included all tumors of the extraadrenal paraganglion system, including functioning and nonfunctioning tumors. Thirteen patients (5%) with diagnosis of metastatic paraganglioma were excluded from the analysis. The definition of metastatic disease was based on the presence of tumor in anatomical sites where chromaffin tissue is not normally present. The 236 patients with benign paragangliomas had a total of 297 tumors; 39 (16.5%) patients had multicentric synchronous or metachronous tumors (multiple tumors occurring at different times). In the patients with multiple tumors, the total number of tumors was 2–6/patient.
Catecholamines and their metabolites were measured by HPLC at the Mayo
Medical Laboratories (10). Total metanephrines were
determined by a spectrophotometric assay (11, 12, 13).
Labetalol was discontinued a minimum of 7 d before the 24-h urine
collection. A 24-h urinary total metanephrine content of 6.6 µmol or
more (
1.3 mg) was considered positive. For urinary catecholamines, a
24-h urinary content of norepinephrine greater than 1005 nmol (>170
µg), epinephrine greater than 191 nmol (>35 µg), or dopamine
greater than 4571 nmol (>700 µg) was considered positive. Values
above these cut-off points are highly specific for tumoral
catecholamine excess (8).
Results
The patient population consisted of 141 women (60%) and 95 men
(40%). The mean age (±SD) at the time of diagnosis was
47 ± 16 yr (range, 14–93). Paragangliomas included 204 tumors in
the head and neck, and 93 below the neck (Fig. 1
). The most frequent paragangliomas
above the neck were carotid body tumors, and those most common below
the neck were abdominal periaortic-pericaval tumors. The clinical
presentations were diverse (Table 1). The
most frequent presenting symptoms for the patients with head and neck
tumors were palpable neck mass (55%), tinnitus (18%), and cranial
nerve palsies (16%). In patients with paragangliomas below the neck,
one or more of the classic catecholamine excess pentad of headaches
(26%), palpitation (21%), perspiration (25%), pallor (12%), and
orthostasis (6%) were observed; hypertension was present in 64%. In
9% of the entire cohort of patients (10% of those with tumors of the
head and neck, 6% with tumors below the neck), tumors were discovered
and diagnosed incidentally in asymptomatic patients during an imaging
study. In an additional 27% of patients with tumors below the neck,
the tumor was again discovered incidentally, but required pathological
examination of resected tissue before the diagnosis could be confirmed.
Of the 236 patients, 124 (53%) had hypertension (defined as blood
pressure blood pressure >140/90 mm Hg or treatment with
antihypertensive agents). At the time of diagnosis of paraganglioma,
the average duration of hypertension was 49 ± 80 months (range,
0.5–240). Medications used to treat hypertension included
ß-adrenergic receptor blockers, angiotensin-converting enzyme
inhibitors, angiotensin II receptor antagonists, calcium channel
blockers, diuretics, centrally acting
2-agonists, and phenoxybenzamine. Of the 124
patients with hypertension, 49 received treatment with a single
antihypertensive agent, 25 with 2 agents, and 11 with 3 agents; the 39
others did not receive antihypertensives. In addition, 12 normotensive
patients received antihypertensive treatment because of abnormal
biochemical results or clinical suspicion of functional tumors.
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Of the 128 patients who had a 24-h urine collection
preoperatively, 40 patients (17% of the 236 patients with benign
paraganglioma and 31% of those screened) had evidence of
hyperfunction, as defined by significant elevation (see Subjects
and Methods for cut-off values) of 1 or more values of the
following 24-h urine measurements: total metanephrines, norepinephrine,
epinephrine, or dopamine (8). The sensitivities of the
different catecholamine and metabolite measurements in the 40 patients
with catecholamine-secreting paragangliomas are shown in Table 2. The most sensitive tests were
24-h urinary excretion of norepinephrine (84%) and total metanephrines
(74%). The combined sensitivity for all 3 catecholamines was 89.9%.
The 40 patients with biochemical evidence of hyperfunctioning
paragangliomas harbored a total of 49 tumors. Of these, 17 were in the
periaortic-pericaval abdominal region, 11 in the perirenal region, 8 in
the organ of Zuckerkandl, 2 in the mediastinum, 2 in the
intracardiac area, and 9 in the head and neck region (Table 3). Of the 40 patients with
biochemical hyperfunctional tumors, 38 (95%) had hypertension.
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Localization studies were performed on 220 of the 297 tumors
(74%; Table 4). A study was considered
positive if a mass was detected. Computed tomography (CT) imaging was
performed in 154 patients with a total of 173 tumors; 163 tumors were
localized accurately, and CT was falsely negative for 5.8% of tumors
(Table 4). Magnetic resonance imaging (MRI) imaging was performed in 80
patients with a total of 106 tumors, with no false negative studies.
Angiography was performed in 123 patients with a total of 149 tumors;
144 tumors were localized accurately, and angiography was falsely
negative for 3.4% of tumors. Scintigraphy with
[131I]- or
[123I]metaiodobenzylguanidine (MIBG) was
performed in 25 patients with a total of 26 tumors; 16 tumors were
localized accurately, and MIBG was falsely negative for 39% of tumors.
Ultrasonography was performed in 25 patients with a total of 28 tumors;
25 tumors were localized accurately, and ultrasound was falsely
negative for 10.7% of tumors. Indium 111-pentreotide scintigraphy was
performed in 5 patients, and 2 studies (40%) were falsely negative.
Echocardiography identified tumors correctly in all 3 cases in which it
was performed.
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Tumors were surgically extirpated in 264 operations (including
patients who had operations for primary synchronous or metachronous
tumors at our or an outside institution). One carotid body
paraganglioma was embolized during angiography. One tumor was found on
autopsy. One patient with a glomus vagale tumor received external
radiation as primary therapy. Twenty-five tumors were observed without
treatment intervention. The location of these included 12 carotid body,
7 glomus jugulare, 4 glomus vagale, and 1 each of glomus tympanicum and
mediastinum. According to pathology reports available for 246 tumors
with primary disease, the average volumes of head and neck tumors were
17.1 and 94.1 cm3 for tumors below the neck
(Table 5). DNA ploidy analysis was
performed in 20 tumors, 9 of which were aneuploid. Abnormal ploidy did
not appear to correlate with recurrence; however, the sample size was
limited. One patient with a tetraploid paraganglioma had recurrent
disease. The locations of aneuploid tumors were as follows: 2
perirenal, 2 organ Zuckerkandl, 2 periaortic, 2 carotid body, and 1
urinary bladder. Five tetraploid tumors were found in the carotid body,
and 1 each in perirenal, prostatic, periaortic, and organ Zuckerkandl
locations. One diploid tumor was located in perirenal region, and 1 in
the pericaval region.
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Multicentric tumors
Multicentric tumors (99 total, with 2–6 paragangliomas per patient) were present in 39 patients; 26 (67%) had disease in the head and neck, 7 (18%) had disease below the neck, and 6 (15%) had disease both within the head and neck and below the neck. Twenty-four patients with multiple paragangliomas presented with 66 synchronous tumors, and 15 patients presented with 33 metachronous tumors. The mean time (±SD) from diagnosis of the first tumor to diagnosis of a metachronous tumor was 80.8 ± 62.8 months (range, 6–180). Treatment of additional multifocal disease consisted of surgical removal of all but 2 metachronous tumors. In patients with synchronous tumors, 15 tumors were removed surgically, 21 were observed, 5 were irradiated, and 1 was embolized during angiography. Patients with multifocal disease did not have an increased incidence of functioning tumors (P = 1.0) compared with patients without multifocal disease.
Incidentalomas
Two tumor groups were assigned as incidentalomas. The first group consisted of those patients who harbored tumors that required pathological examination of an indeterminate mass to confirm the diagnosis. Of the paragangliomas in the head and neck, 1.2% were diagnosed after surgical resection of an indeterminate mass, as were 27.2% of the tumors below the neck. The majority (86%) of the incidental paragangliomas below the neck were pulmonary parenchymal incidentalomas that were described as indeterminate nodules on imaging studies of the chest. The mean size of pulmonary parenchymal tumors was less than 0.1 cm3. The sites of the other tumors in the indeterminate mass group after imaging studies included one each in the following locations: carotid body, glomus jugulare, duodenum, prostate, and periaortic. On the basis of clinical presentation, none of these tumors was suspected of being hyperfunctional.
The second group of tumors described as being incidentalomas was tumors incidentally discovered on imaging and suspected (based on imaging characteristics) of being paragangliomas preoperatively (n = 22). These included 16 tumors in the head and neck (8 carotid body, 3 glomus vagale, 3 glomus jugulare, 1 glomus tympanicum, and 1 foramen magnum). Six tumors were below the neck (3 mediastinal, 1 cardiac, and 2 periaortic).
Family history
Twenty-nine patients (12.3%) had a family history of paragangliomas, five (2.1%) of these had von Hippel-Lindau disease (retinal hemangiomatosis, cerebellar hemangioblastoma, renal cell carcinoma, and pheochromocytoma), and one (0.4%) had multiple endocrine neoplasia type IIB. In four other patients (1.5%) who presented with the Carney triad (paraganglioma, gastric leiomyosarcoma, and pulmonary chondroma), familial transmission was not documented (14). The family history of paragangliomas did not predict the presence of hyperfunctioning tumors, but did predict a high probability of multiple tumors by Fisher’s exact two-tailed test (P < 0.001).
Follow-up
Of the 236 patients, 44 (18.6%) were lost to follow-up. For the
other 192 patients, the mean follow-up was 43.9 months (range,
0.5–240). Operative cure was defined as no evidence of tumor in
follow-up imaging studies and normal biochemical studies in patients
with functional tumors. Cure was achieved in 133 patients (69% of
those with follow-up; Fig. 2). Cure was
not achieved in 59 (31%), as evidenced by persistent or recurrent
disease or subsequent development of metachronous tumors. Patients with
synchronous tumors treated with observation or irradiation were
assigned to the group that was considered to be cured (Fig. 2).
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Persistent tumors affected 23 patients (11.9%): 3 carotid body, 8
glomus jugulare, 2 vagal, 2 intraspinal, 3 mediastinal, 2 periaortic
and pericaval, 1 sacral, 1 atrium of heart, and 1 perirenal. Persistent
disease was treated surgically in 2 patients, with conventional
irradiation in 3 patients, with 
-knife irradiation in 3 patients,
with laser in 1, and with observation in 14 patients. Five (2.6%)
patients had recurrent disease (i.e. tumor at the same site
as the primary tumor). Recurrent tumor location included 2 in the
tympanic membrane, 2 in the glomus jugulare, and 1 in the carotid body.
Recurrent disease was treated surgically in 4 patients and with
-knife irradiation in 1.
Discussion
The optimal nomenclature for paragangliomas is controversial (2, 15, 16, 17), and few reports in the literature provide details about the specific locations of extraadrenal catecholamine-secreting paragangliomas (4, 18, 19, 20). The majority of paragangliomas in the current study (69%) were located in the head and neck area and included tumors of the carotid body, glomus jugulare, glomus vagale, glomus tympanicum, and foramen magnum. The clinical presentation of these tumors was dominated by local mass effect symptoms (neck masses, tinnitus, and cranial nerve dysfunction). A significant proportion of patients (10%) had head and neck paragangliomas diagnosed (because of the typical imaging characteristics of the tumor) incidentally during an imaging study performed for multiple reasons. A small proportion (4%) of head and neck paragangliomas were hyperfunctional; however, this is greater than the 1% prevalence reported previously (16).
Only 93 paragangliomas were below the neck; their locations were periaortic and pericaval, perirenal, mediastinal, intracardiac, pulmonary parenchymal, intraspinal, sacral, duodenal, jejunal, pancreatic, or in the organ of Zuckerkandl, bladder, or prostate. A significant proportion of these tumors were hyperfunctional (43%), and the typical clinical presentation included headache, perspiration, palpitations, pallor, and hypertension. In 21% of patients pain was noted at the anatomical site of the tumor. Of the paragangliomas below the neck, 27% were discovered only on pathological examination of an indeterminate mass discovered incidentally with imaging studies. The sites of these incidentalomas included pulmonary parenchyma (19 tumors), periaortic area (1 tumor), prostate (1 tumor), and duodenum (1 tumor). Note that all of the pulmonary tumors were small, and none of the incidentalomas had signs or symptoms suggestive of hyperfunction.
The biochemical diagnosis of hyperfunctional paraganglioma or adrenal pheochromocytoma is based on excessive excretion of catecholamines and their metabolites. Determination of 24-h urinary excretion of total metanephrines and catecholamines (norepinephrine, epinephrine, and dopamine) has been used widely as a screening test panel (21, 22). We previously reported that when both urinary catecholamines and total metanephrines were measured in a 24-h collection, the sensitivity was 99% for adrenal pheochromocytoma (8). In the current study 40 patients with extraadrenal paragangliomas had biochemical evidence of catecholamine hypersecretion. The sensitivities of the 24-h urine studies were 74% for total metanephrines, 84% for norepinephrine, 14% for epinephrine, and 18% for dopamine. The combined sensitivity for all 3 catecholamines was 89.9%. This is lower than that of previous reports, which used different diagnostic precision cut-offs (12, 23). Temporal sampling errors are caused by sampling when patients are asymptomatic or when paragangliomas are not hypersecreting (24). We found false negative results in 6 (14.2%) of 42 patients who had multiple urinary collections.
Localization studies are used to confirm the biochemical diagnosis of paraganglioma, to further evaluate an unknown mass, to screen for multicentric disease, and to direct the surgical approach. In our study MRI and CT were the optimal localizing studies. Although MIBG scintigraphy has a high specificity (97–100%), the data on sensitivity vary dependent upon the proportion of patients with extraadrenal pheochromocytomas (21, 22, 23, 24, 25). Scintigraphic localization with MIBG was positive in only 25 of 35 (71%) patients: 21 with functional tumors and 4 with nonfunctional tumors. This sensitivity is lower than previous reports (25, 26, 27, 28, 29). Ten (29%) patients had negative MIBG scintigraphic findings despite 8 of them having catecholamine-secreting paragangliomas. The low sensitivity of MIBG scintigraphy may be related to small tumor size (30). However, it is important to note that in 4 patients with biochemically hyperfunctional tumors and negative results on other imaging techniques, the paragangliomas were localized only with MIBG. Thus, although MIBG is not highly sensitive for paragangliomas, it still is a very important localizing study (31, 32).
The majority of paragangliomas in our patients (89%) were excised
surgically. A functional paraganglioma should be recognized
preoperatively to allow pharmacological preparation to prevent or block
the effects of acute release of catecholamines during anesthesia
induction and surgery that may potentially produce lethal
complications (33). -Adrenergic blockade is the
antihypertensive therapy of choice to prevent intraoperative
hypertensive crises (4). Thirty-four (12.6%) patients
required iv antihypertensive therapy intra- or perioperatively or
needed resuscitation with iv fluids for hypotension; only 41% had
documented hyperfunction preoperatively. Clinically and biochemically
silent paragangliomas may cause hemodynamic instability when they are
manipulated during surgery.
Hypertension was diagnosed in 124 patients, of whom 38 had biochemical evidence of paraganglioma hyperfunction; thus, their hypertension may have been related to catecholamine excess. In 66% of these patients, hypertension was cured with removal of the tumor. In the remainder, hypertension was not cured due to either persistent disease or concurrent essential hypertension. This hypertension persistence rate in catecholamine-secreting paraganglioma patients is consistent with previous reports of persistent hypertension in 25% of patients with pheochromocytomas (34, 35).
On follow-up, paraganglioma was cured in approximately 69% of patients. Persistent disease was most commonly found in those with glomus jugulare, carotid body, and mediastinal paragangliomas. Metachronous multicentric tumors developed in 7.8% of patients and occurred within a mean of 6.7 yr postoperatively; all but 2 were cured by a second operation. Annual testing for at least 10 yr with 24-h urine excretion of total metanephrines and catecholamines is indicated for those patients that had surgically treated functioning paragangliomas. Periodic computerized imaging is indicated for those patients with surgically treated biochemically silent paragangliomas. Because metachronous multicentric disease was frequently associated with a family history of extraadrenal tumors, we recommend that such patients have lifelong surveillance.
In conclusion, most paragangliomas are nonhypersecretory and located in
the head and neck region. Although its occurrence is unusual, all
patients with suspected head and neck paragangliomas should be screened
for catecholamine excess because approximately 4% prove to be
hyperfunctional, and appropriate preoperative adrenergic blockade is
essential. Almost half of the below the neck paragangliomas prove to be
associated with catecholamine hypersecretion, and more than one 24-h
urine collection may be needed in the asymptomatic patient. MRI is
associated with the lowest false negative localization rate, and MIBG
scintigraphy is the least sensitive imaging study. Although lacking in
sensitivity, MIBG scintigraphy is highly specific and may be the only
positive imaging test in some patients. Clinically and biochemically
silent paragangliomas may cause hemodynamic instability when they are
manipulated during surgery, and empiric low dose -adrenergic
blockade should be considered in most patients. Surgical resection is
the treatment of choice for most paragangliomas. In those hypertensive
patients with catecholamine excess, the majority demonstrate resolution
of hypertension with surgery. Approximately one third of patients have
persistent or recurrent paragangliomas, and long-term follow-up is
important.
Footnotes
Copyright 2000 Mayo Foundation.
Abbreviations: CT, Computed tomography; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging.
Received December 18, 2000.
Accepted July 19, 2001.
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W. F YOUNG JR Paragangliomas: clinical overview. Ann. N.Y. Acad. Sci., August 1, 2006; 1073: 21 - 29. [Abstract] [Full Text] [PDF]
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 W. F. Young Jr and A. L. Abboud Paraganglioma--all in the family. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 790 - 792. [Full Text] [PDF]
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 V. D. Garovic, M. C. Hogan, S. K. R. Kanakiriya, C. S. Grant, and W. F. Young Jr Labile hypertension, increased metanephrines and imaging misadventures Nephrol. Dial. Transplant., April 1, 2004; 19(4): 1004 - 1006. [Full Text] [PDF]
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A. L. Young, B. E. Baysal, A. Deb, and W. F. Young Jr. Familial Malignant Catecholamine-Secreting Paraganglioma with Prolonged Survival Associated with Mutation in the Succinate Dehydrogenase B Gene J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4101 - 4105. [Abstract] [Full Text] [PDF]
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