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Clinical Neurocardiology Section (G.E., D.S.G.), National Institute of Neurological Disorders and Stroke, Department of Laboratory Medicine, Clinical Center (P.S., G.C.), and the Pediatric and Reproductive Endocrinology Branch (F.M.B., E.W.L., K.T.A., K.P.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1620
Address all correspondence and requests for reprints to: Graeme Eisenhofer, Building 10, Room 6N252, National Institutes of Health, 10 Center Drive, MSC-1620, Bethesda, Maryland 20892-1620. E-mail: ge{at}box-g.nih.gov.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Most hormonally active pheochromocytomas produce a combination of norepinephrine and epinephrine, many exclusively norepinephrine, and a much smaller proportion exclusively epinephrine. These differences in catecholamine production reflect differences in expression of phenylethanolamine-N-methyltransferase (3), the enzyme in the catecholamine biosynthetic cascade that converts norepinephrine to epinephrine (Fig. 1
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Patients with dopamine-secreting tumors are often normotensive, posing a significant diagnostic challenge (4). The difficulty of diagnosis may be further compounded by emphasis in biochemical testing on norepinephrine and epinephrine and the metabolites of these two catecholamines. Indeed, sole reliance on measurements of plasma concentrations of free normetanephrine and metanephrine, the O-methylated metabolites of norepinephrine and epinephrine (Fig. 1), can fail to detect tumors that produce exclusively dopamine (6). The O-methylated metabolite of dopamine, methoxytyramine, can, however, be measured along with normetanephrine and metanephrine, as originally reported for the assay of these compounds in plasma (7).
Here we report our findings on measurements of plasma concentrations of free methoxytyramine in patients with adrenal and extraadrenal pheochromocytomas, focusing on those patients with tumors that produced predominantly dopamine. The analysis included comparisons of plasma concentrations of free methoxytyramine with measurements of plasma and urinary dopamine.
Dopamine is produced from 3,4-dihydroxyphenylalanine (DOPA) by aromatic amino acid decarboxylase (Fig. 1). Because most dopamine in urine is derived from the renal extraction and decarboxylation of circulating DOPA (8, 9, 10), we hypothesized that urinary dopamine would be less effective for identifying dopamine-producing tumors than plasma dopamine or free methoxytyramine. The analysis therefore also included measurements of plasma DOPA and examination of the relative contributions of plasma dopamine and DOPA to urinary outputs of dopamine in patients with catecholamine-producing tumors.
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Subjects and Methods |
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Patients with dopamine-producing paragangliomas or pheochromocytomas were identified from a cohort of 120 patients who had been diagnosed with the tumors according to previously published criteria (11). These 120 patients were selected from a larger group of 279 patients with tumors, based on requirements of completeness of biochemical testing. Specifically, biochemical testing in all patients in the analysis had to have included measurements of plasma free methoxytyramine concentrations, in addition to standard measurements of the other O-methylated catecholamine metabolites, normetanephrine and metanephrine. Moreover, testing also required measurements of plasma concentrations and 24-h urinary outputs of dopamine, in addition to norepinephrine and epinephrine. Measurements for plasma tests additionally included concentrations of DOPA. All subjects provided written informed consent and were enrolled under clinical protocols approved by the appropriate NIH Institutional Review Boards.
Biochemical tests
Blood samples were collected from subjects using a forearm venous cannula with subjects supine for at least 20 min before sampling. Subjects were instructed to fast and abstain from caffeinated and decaffeinated beverages overnight and avoid taking acetaminophen for 5 d before blood sampling. Plasma was analyzed for concentrations of free methoxytyramine, in addition to free normetanephrine and metanephrine, using HPLC, as described previously (7). Plasma concentrations of catechols, including DOPA, dopamine, norepinephrine, and epinephrine, were measured by a different HPLC method (12). The latter method was also used to measure tissue concentrations of catecholamines in tumors obtained from 56 of the 120 patients in the study. Details and modifications of both HPLC methods are described elsewhere (http://www.catecholamine.org/labprocedures). Twenty-four-hour urinary outputs of catecholamines and deconjugated (free plus conjugated) fractionated metanephrines were measured by HPLC or liquid chromatography with tandem mass spectroscopy, under a contract between the NIH Clinical Center and an outside commercial laboratory (Mayo Medical Laboratories, Rochester, MN).
Reference ranges
Reference ranges for plasma concentrations of free normetanephrine (18–112 ng/liter; 0.10–0.61 nmol/liter), metanephrine (12–61 ng/liter; 0.06–0.31 nmol/liter), norepinephrine (80–498 ng/liter; 0.47–2.95 nmol/liter), and epinephrine (4–83 ng/liter; 0.02–0.45 nmol/liter) were established from combined groups of 175 normotensive and 110 hypertensive (n = 110) volunteers, as detailed elsewhere (13). The same subjects were also used to establish reference ranges for plasma concentrations of free methoxytyramine (1–14 ng/liter; 0.006–0.084 nmol/liter), dopamine (2–58 ng/liter; 0.013–0.379 nmol/liter), and DOPA (1045–2529 ng/liter; 5.30–12.83 nmol/liter), as described here for the first time. Reference ranges for urinary tests are as established by the commercial laboratory that performed these measurements.
Data analysis
Patients with dopamine-producing tumors were initially identified from those in whom plasma concentrations of free methoxytyramine or dopamine or urinary outputs of dopamine were increased above the upper limits of the reference ranges for each compound. Magnitudes of absolute increases above the upper reference limits for each compound were then calculated and compared with the combined magnitudes of increases of the other two compounds in each set of measurements (e.g. increase of plasma methoxtyramine vs. combined increases of plasma normetanephrine and metanephrine). Further identification of patients with dopamine-producing tumors was then restricted to those patients in whom increases in plasma-free methoxytyramine predominated over increases in plasma-free normetanephrine and metanephrine or in whom increases of plasma or urinary dopamine predominated over combined increases of plasma or urinary norepinephrine and epinephrine. The final selection of patients with dopamine-producing tumors required that increases in at least two of the three compounds predominated over the combined increases of the other two compounds in each set of measurements. Further analysis of data concerning the final selection of patients involved review of clinical histories, laboratory studies, imaging studies, and postoperative anatomical pathology reports.
Analyses of data in the original group of 120 patients included examination of relationships of urinary outputs of dopamine with plasma concentrations of dopamine and DOPA. The combined contributions of plasma dopamine and DOPA concentrations to urinary outputs of dopamine (RE) were estimated according to the formula
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The renal elimination of plasma dopamine as urinary dopamine (REDA) was estimated by the formula
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The renal elimination of plasma DOPA as urinary dopamine (REDOPA) was estimated by the formula
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Statistical analyses included ANOVA and linear regression analysis with significance of relationships established using Pearson’s correlation coefficient.
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Results |
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Among the 120 patients selected for the analysis, 55 had elevated plasma concentrations of free methoxytyramine, 22 had elevated plasma concentrations of dopamine, and 37 had elevated urinary outputs of dopamine (Fig. 2). Among those with elevated plasma concentrations of free methoxytyramine, there were 10 in whom the magnitudes of these elevations above the upper reference limits were greater than the combined increases of plasma-free normetanephrine and metanephrine, suggesting the presence of predominantly dopamine-producing tumors. Among the 22 patients with elevations of plasma dopamine and 37 with elevations of urinary dopamine, there were seven in whom the elevations of plasma dopamine exceeded the combined elevations of plasma norepinephrine and epinephrine and 16 in whom the increases in urinary outputs of dopamine exceeded those for the combined outputs of norepinephrine and epinephrine.
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Among the 10 patients with greater increases in methoxytyramine than normetanephrine and metanephrine, eight had increases in urinary outputs of dopamine. These eight patients included seven in whom urinary outputs of dopamine exceeded the combined outputs of norepinephrine and epinephrine. In the other patient, the increase in urinary output of dopamine was 93% that of the combined increase in outputs of norepinephrine and epinephrine, this increase thus approaching but not exceeding that of the other catecholamines.
Based on the above analysis, nine patients with tumors that produced and secreted predominantly dopamine were identified (Table 1). All had greater increases of plasma-free methoxytyramine than free normetanephrine and metanephrine (Table 2). Among these nine patients, five (patients 3, 5, 7–9) had increases of plasma concentrations and urinary outputs of dopamine that exceeded respective increases in both plasma concentrations and urinary outputs of the other catecholamines, indicating dopamine-predominant secretion. Among the other four patients, two (patients 1 and 2) had elevations of plasma concentrations of dopamine that exceeded those of norepinephrine and epinephrine, and the other two (patients 4 and 6) had increases in urinary outputs of dopamine that exceeded those of norepinephrine and epinephrine.
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Tumor tissue catecholamine concentrations were determined in 56 of the 120 patients, including two of the nine patients (patients 1 and 5) identified with dopamine-predominant tumors. The nature of the disease (e.g. widespread metastases) precluded procurement of viable tissue samples in the other seven patients with dopamine-predominant tumors. In the two patients with dopamine-predominant tumors in which tumor specimens were obtained (patients 1 and 5), tumor contents of dopamine represented 74 and 86% of the total catecholamine contents, confirming the dopamine-predominant nature of these tumors. Two other patients had tumors in which dopamine contents were 16 and 60% of the total. Both of these patients had increases in plasma-free methoxytyramine that were 16 and 18% of the combined increases of all O-methylated metabolites and increases in plasma dopamine that were 12 and 18% of the total increases of all catecholamines. Dopamine contents in the remaining 52 tumors were low relative to the other catecholamines, ranging from 0.05 to 4.7% (mean 0.6%) of total catecholamine contents. None of the 52 patients with these tumors had significant increases in plasma concentrations of dopamine or free methoxytyramine relative to the respective combined totals for plasma catecholamines or their O-methylated metabolites.
Clinical presentation
Among the nine patients with dopamine-predominant tumors, all but one (patient 6) had evidence of multifocal or metastatic disease on examination at the NIH (Table 1). In three of the nine patients (patients 4–6), this represented the first presentation of a catecholamine-producing tumor. The other six patients had their primary tumors resected 8 months to 30 yr earlier. All primary tumors had an extraadrenal location.
Initial diagnosis of the primary tumor was based on hypertension and symptoms of catecholamine excess in only two of the nine patients (patients 6 and 9). In the other seven patients, primary tumors were identified as either an incidental finding for an unrelated condition or secondary to the space-occupying complications of the lesion. This included the finding of a large pelvic mass on routine obstetric ultrasound 18 wk into the pregnancy of a woman (patient 1) who was normotensive and reported fatigue and occasional headaches as her only symptoms. Abdominal pain led to the finding of a large 10-cm retroperitoneal mass in one patient (patient 2), who otherwise suffered only nausea and dizziness. Another patient (patient 4) was evaluated for a deep vein thrombosis of the left leg, which on abdominal computed tomography was determined to be secondary to an 8-cm mass at the aortic bifurcation compressing on the inferior vena cava. This patient was normotensive and did not exhibit symptoms of catecholamine excess. Similarly another patient (patient 5) was evaluated for a right ureteral obstruction, subsequently determined to be due to a paraganglioma. This patient reported episodes of nausea, vomiting, and flushing and was found to be hypertensive.
Three other patients presented with neck pain (patient 7) or hoarseness and cough (patients 3 and 8) secondary to neck and carotid body masses. The first (patient 7) had hypertension but was otherwise asymptomatic. On resection, the 3-cm neck mass was determined to be a paraganglioma, immediately leading to further scanning, location, and resection of a second larger retroperitoneal paraganglioma. The second patient (patient 3), with a family history of paragangliomas, had two carotid body tumors removed at ages 16 and 21 yr, followed by a retroperitoneal tumor at age 30 yr, with a small recurrent retroperitoneal tumor apparent 16 yr later on presentation at the NIH. At that time he was normotensive and asymptomatic. The third patient (patient 8) presented with fatigue, nausea, and episodes of hypotension 11 yr after resection of the primary carotid body tumor, at which stage extensive metastatic disease was evident.
In most of the nine patients, disease has been progressive. Three patients (patients 7–9) died due to the complications of metastatic disease within 2 yr of their presentation at the NIH and as early as 3 yr after initial diagnosis of the primary tumor. Five other patients have multifocal recurrent disease; in four of these, the disease is clearly metastatic.
Biochemical presentation
All nine patients with dopamine-predominant tumors had substantial elevations of both plasma-free methoxytyramine and dopamine (Table 2). Seven of the nine patients had elevations of both plasma-free and urinary deconjugated normetanephrine, eight elevations of plasma norepinephrine, and six elevations of urinary norepinephrine. Elevations of plasma or urinary epinephrine and metanephrine were few, inconsistent, and where present, relatively minor in nature.
In four of the nine patients (patients 1, 2, 8, and 9), increases in plasma-free methoxytyramine and dopamine clearly predominated over normetanephrine and norepinephrine, indicating that these tumors produced comparatively little norepinephrine. All of these four patients were normotensive. In the other five patients (patients 3–7), increases in plasma-free normetanephrine and norepinephrine approached those of methoxytyramine and dopamine. Three of these patients (patients 5–7) were hypertensive.
Biochemical testing was carried out in six of the nine patients (patients 1–3 and 7–9) to assess for recurrent disease after resection of a primary tumor. In two of these patients (patients 1 and 3), biochemical test results were available from before removal of the original tumor. In both cases, there was evidence of significant dopamine secretion by the primary tumor. One patient (patient 1) had urinary outputs of dopamine (3196 µg per 24 h) that far exceeded those of norepinephrine (168 µg per 24 h) and epinephrine (5 µg per 24 h), whereas the other (patient 3) had plasma concentrations of dopamine (768 ng/liter) similar to those of norepinephrine (758 ng/liter).
Two patients (patients 1 and 2) had normal urinary outputs of dopamine despite significant elevations of plasma-free methoxytyramine and dopamine. Additionally, relative increases of plasma concentrations of free methoxytyramine and dopamine above the upper reference limits both far exceeded (P < 0.001) relative increases of urinary outputs of dopamine (Fig. 3). On average (geometric means), plasma concentrations of free methoxytyramine were increased 104-fold above the upper reference limits, compared with 56-fold for plasma dopamine and only 3-fold for urinary dopamine.
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For the combined data from the original group of 120 patients, urinary outputs of dopamine were positively related to plasma concentrations of dopamine (r = 0.71, P < 0.001) and DOPA (r = 0.68, P < 0.001), but the former relationship was primarily dependent on the presence of patients with increased plasma dopamine concentrations (Fig. 4). When these patients, and those with elevated plasma DOPA levels, were removed from the analysis, the relationship of urinary dopamine with plasma dopamine lost significance (r = 015, P = 0.17); in contrast, that with plasma DOPA retained significance (r = 0.36, P < 0.001).
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), using a formula to estimate the contributions of both plasma dopamine and DOPA to the renal elimination of dopamine (see Data analysis in Subjects and Methods).
Estimated contributions of the renal elimination of plasma DOPA and dopamine to urinary dopamine (385 µg per 24 h) were 21% higher (P < 0.001) than measured urinary outputs of dopamine (319 µg per 24 h). As shown in Fig. 4C, this difference mainly reflected influences of the dopamine-secreting tumors, which skewed the regression line away from the expected one-to-one relationship. Without these tumors, and those associated with elevated plasma DOPA concentrations, there was no significant difference between the estimated contribution to urinary dopamine and measured urinary output of dopamine (256 vs. 235 µg per 24 h). In the patients without elevations of either plasma DOPA or dopamine, the respective contributions of plasma DOPA and dopamine to urinary dopamine were 95 ± 1 and 5 ± 1%, whereas relative contributions in the patients with elevated plasma dopamine concentrations were 53 ± 7 and 47 ± 7%.
Among the original group of 120 patients with pheochromocytomas or paragangliomas, there were 37 with elevations in urinary outputs of dopamine, including 16 in whom the increases exceeded those of norepinephrine and epinephrine. However, nine of these 16 patients had relatively insignificant or no increases in plasma concentrations of dopamine or free methoxytyramine to support the presence of predominantly dopamine-producing tumors. Seven of the nine patients, however, had increased plasma concentrations of DOPA, ranging from 2650 to 7849 ng/liter, and another had a plasma DOPA concentration (2492 ng/liter, 12.6 nmol/liter) close to the upper reference limit (2529 ng/liter, 12.8 nmol/liter).
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Discussion |
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Other descriptions of pheochromocytomas or paragangliomas that produce predominantly dopamine are largely limited to single case reports (16, 17, 18, 19, 20, 21, 22, 23). An exception is the report by Proye et al. (4), in which measurements of urinary catecholamines were used to identify three patients with tumors that secreted exclusively dopamine and several others with tumors secreting mixtures of dopamine and other catecholamines. Such tumors were noted to usually have an extraadrenal location and often be malignant. The tumors also had an atypical clinical presentation, most patients being normotensive, with the tumors detected because of cough, a large palpable mass, or imaging studies carried out to seek the cause of abdominal pain or scan for a neoplasm.
The above experience closely mirrors our own, in which all nine cases involved extraadrenal tumors, of which two thirds were clearly malignant and without signs and symptoms of catecholamine hypersecretion. All three patients with hypertension had markedly elevated plasma concentrations of norepinephrine in addition to dopamine, whereas the six who were normotensive or hypotensive tended to have relatively larger increases in plasma dopamine than norepinephrine. This observation is consistent with those of two previous studies (4, 23), in which it was suggested that the vasodilatory actions of dopamine might counteract the vasoconstrictor actions of norepinephrine.
The presence of a catecholamine-secreting tumor was initially suspected in only two of our nine patients with dopamine-secreting paragangliomas. Tumors in the other seven patients were discovered either as an incidental finding on imaging studies for an unrelated condition or because of space-occupying complications of the lesions. Primary tumors were generally large, consistent with the presentation of dopamine-secreting tumors in other reports (4, 17, 23). Presumably, the attainment of large size in such tumors, compared with those more usually encountered, reflects the relatively mild signs and symptoms associated with predominantly dopamine-secreting tumors.
Nausea, sometimes accompanied by vomiting, which may be related to emetic effects of dopamine (24), was present in three of our nine patients and has been described in another case of a dopamine-secreting tumor (23). Apart from flushing in one patient and orthostatic hypotension in another, there were no other signs or symptoms that could be ascribed to dopamine hypersecretion.
The clinical presentation of dopamine-secreting tumors is clearly atypical of more usually encountered tumors that secrete mainly norepinephrine or epinephrine, in which measurements of plasma concentrations of free normetanephrine and metanephrine provide a sensitive diagnostic test (11). Thus, additional measurements of plasma-free methoxytyramine are unlikely to improve detection of pheochromocytomas in the majority of patients tested for these tumors because of signs and symptoms of catecholamine excess. We also found that elevations of plasma-free methoxytyramine or dopamine are not significant findings in patients with von Hippel-Lindau syndrome or multiple endocrine neoplasia type 2, in which increases in plasma-free normetanephrine in the former and plasma-free metanephrine in the latter are characteristic of pheochromocytomas in these syndromes (25). Thus, additional measurements of plasma-free methoxytyramine are unlikely to improve diagnosis of pheochromocytoma in patients screened for the tumor because of these two hereditary syndromes.
Measurements of plasma concentrations of free methoxytyramine may, however, be useful in selected patients with an atypical clinical presentation for identification of tumors that produce predominantly dopamine. This may be particularly important for the follow-up of patients with a previous history of unusually large extraadrenal catecholamine-producing tumors, particularly those previously identified to secrete dopamine. As indicated in this study, such tumors are likely to recur at the site of previous resection and present or develop into multifocal or malignant disease. More generally, measurements of methoxytyramine might be useful for identification of dopamine-predominant tumors in patients with paragangliomas. Carotid body tumors, in particular, are being increasingly described as capable of producing dopamine (18, 19, 20, 26).
As shown by Erickson et al. (2), most patients with paragangliomas do not exhibit biochemical evidence of catecholamine hypersecretion, at least as assessed using measurements of urinary catecholamines and total metanephrines. Possibly, measurements of plasma-free methoxtyramine might be useful for identifying additional dopamine-producing tumors among such patients, but confirmation of this ideally requires a prospective study. Similarly, patients identified with familial paraganglioma or pheochromocytoma syndromes due to mutations of genes for members of the succinate dehydrogenase family (27, 28) might represent another group in which measurements of plasma-free methoxytyramine might prove useful; again this requires further investigation.
Elevated plasma concentrations or urinary outputs of dopamine are more often associated with malignant than benign pheochromocytomas (29, 30, 31). Thus, measurements of plasma-free methoxytyramine might also be useful for identifying malignant tumors or those with increased propensity for malignancy. This possibility is supported here by the presence of metastatic disease in most of the nine patients with dopamine-predominant tumors.
Do measurements of plasma concentrations of free methoxytyramine offer advantages over more commonly available measurements of plasma or urinary dopamine? The present data indicate clear advantages over urinary outputs of dopamine, which were normal in two patients with dopamine-producing tumors and in the others showed much smaller percentage increases above the upper limit of normal than those for plasma-free methoxytyramine or dopamine. These differences are explained by the renal extraction and decarboxylation of circulating DOPA to form dopamine, the latter functioning in the kidney as a natriuretic hormone and subsequently excreted in large amounts in urine (8, 9, 10).
In the present analysis, plasma concentrations of DOPA were estimated to make a 95% contribution to urinary outputs of dopamine in patients with tumors that did not secrete dopamine. This large contribution of plasma DOPA to urinary dopamine would be expected to decrease by 20-fold the contribution of any increases in plasma dopamine to increases in urinary dopamine. Consistent with this, the patients with dopamine-secreting tumors had 19-fold smaller increases in urinary outputs than plasma concentrations of dopamine. The large contribution of plasma DOPA to urinary dopamine also explained findings in several other patients of large increases in urinary outputs of dopamine in which there was no other evidence for a dopamine-secreting tumor. Thus, urinary dopamine is not only a relatively insensitive marker for dopamine-secreting tumors but is also relatively nonspecific.
In contrast to urinary dopamine, all patients with large increases in plasma-free methoxytyramine also had large increases in plasma dopamine, indicating that the latter measurement also provides a useful marker of dopamine-producing tumors. Plasma concentrations of dopamine and free methoxytyramine are, however, normally both low, compared with the other catecholamines and O-methylated metabolites, making their accurate measurement in usually encountered patient samples difficult. This represents a disadvantage, compared with measurements of urinary dopamine. Urinary outputs of sulfate-conjugated methoxytyramine, measured after a deconjugation step, offer another potential marker of dopamine-producing tumors. Currently, however, these measurements, along with those of plasma-free methoxytyramine described in the present study, are not widely available.
Further carefully designed studies are required to assess the diagnostic sensitivity and specificity of measurements of dopamine and methoxytyramine in plasma and urine. Such studies will need to address the relative merits of including such measurements in the diagnosis of all catecholamine-producing tumors, compared with, as we suggest here, select groups of patients in whom predominantly dopamine-producing tumors might be present. In the meantime, the present data indicate that diagnosis of dopamine-producing tumors could benefit from alternatives to the currently widely used measurements of urinary dopamine. The combination of measurements of plasma-free methoxytyramine and dopamine offers such an alternative, which appears to provide an effective means to identify dopamine-producing paragangliomas. With increased use of these plasma markers, such tumors may prove to be not quite as rare as previously thought.
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Footnotes |
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Abbreviations: DOPA, 3,4-Dihydroxyphenylalanine; RE, renal elimination.
Received October 15, 2004.
Accepted January 4, 2005.
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), increases in only plasma dopamine (
), increases in only plasma DOPA (•), and patients with no increases of either dopamine or DOPA (
).