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Endocrine Care |
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (K.P.); Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke (D.S.G., G.E.); and Department of Radiology, Clinical Center (J.L.D.), National Institutes of Health, Bethesda, Maryland 20892; Division of Nuclear Medicine, Department of Radiology, University of Michigan (B.L.S.), Ann Arbor, Michigan 48109; and Division of Endocrine and Oncologic Surgery, The Johns Hopkins University (R.U.), Baltimore, Maryland 21218
Address all correspondence and requests for reprints to: Karel Pacak, M.D., Ph.D., D.Sc., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive, MSC-1583, Bethesda, Maryland 20892-1583. E-mail: karel{at}mail.nih.gov
Abstract
Most, but not all, pheochromocytomas can be localized by computed tomography or magnetic resonance imaging. Here we introduce two novel approaches for localization of pheochromocytoma in a patient in whom conventional imaging modalities failed to show the tumor. First, we establish that measurements of plasma free metanephrines coupled with vena caval sampling are useful for localizing occult pheochromocytoma, particularly when elevations in plasma catecholamines are slight or intermittent. Second, we show that positron emission tomographic scanning using the imaging agent 6-[18F]fluorodopamine as a substrate for the norepinephrine transporter offers a highly effective method for tumor localization. These novel approaches may be of value in difficult cases, where biochemical and clinical evidence of pheochromocytoma is compelling, yet conventional imaging modalities fail to locate the tumor.
PHEOCHROMOCYTOMAS ARE rare chromaffin cell tumors that produce catecholamines; this often leads to hypertension and symptoms of catecholamine excess such as headache, palpitations, and diaphoresis. Diagnosis of the tumor depends importantly on biochemical evidence of increased catecholamine release or metabolism. Once biochemical tests indicate a pheochromocytoma it is important to localize the tumor. This is usually accomplished by computed tomography (CT) or magnetic resonance imaging (MRI). When a mass is found, it is prudent to confirm that the mass actually is a pheochromocytoma, using more specific metaiodobenzylguanidine (MIBG) imaging studies.
CT and MRI can locate adrenal pheochromocytomas larger than 5–10 mm with greater than 95% sensitivity (1, 2). Occasionally, however, these imaging studies are negative despite the presence of pheochromocytoma. More importantly, the imperfect specificity of biochemical tests combined with the low prevalence of pheochromocytoma among the tested population mean that false positive biochemical test results typically far outnumber true positive results. Thus, in the majority of cases where biochemical tests suggest pheochromocytoma, imaging studies are negative because patients do not actually have a tumor.
The present case report provides an example of the above diagnostic dilemma and introduces two novel approaches for localization of pheochromocytoma when conventional methods fail. One approach employs vena caval blood sampling with measurements of plasma concentrations of normetanephrine and metanephrine, the O-methylated metabolites of norepinephrine and epinephrine. The other approach involves positron emission tomographic (PET) scanning after iv injection of the sympathoneural imaging agent, 6-[18F]fluorodopamine. The patient provided informed consent for all studies.
Case Report
Presentation
A 53-yr-old man, who 13 yr previously had undergone right adrenalectomy for pheochromocytoma, was evaluated at the NIH Endocrine Clinic for symptoms and signs suggesting recurrence of the tumor. About once per week for the preceding 4 months, he had had episodes of palpitations, pallor, visual disturbances, right flank pain, and anxiety, lasting several minutes and followed by exhaustion. Blood pressure during an attack was 180/95 mm Hg. At presentation he was not taking medications or dietary supplements. Past medical history included depression but was otherwise noncontributory. Family history was negative for familial pheochromocytoma syndromes. The patient’s vital signs were normal, and except for a well healed abdominal surgical scar, the physical examination was unremarkable.
Initial diagnostic evaluation
Initial biochemical tests for pheochromocytoma revealed elevations
of plasma concentrations of normetanephrine, metanephrine, and
epinephrine and increased 24-h urinary excretion of epinephrine and
metanephrine (Table 1
). The complete
blood count, liver function tests, and routine serum chemistries were
normal, except for an elevated fasting plasma glucose level (9.91
mmol/liter).
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).
Artifacts from these clips obviated detailed examination of the area.
The liver and spleen were unremarkable, but there was a small nodule
anterior to the left kidney in the area of the tail of the pancreas.
The left adrenal was diffusely thickened, the medial limb more than the
lateral, suggesting the possibility of a small left adrenal mass. There
was also an oblong density to the left of the aorta, consistent with a
left para-aortic node or left renal artery.
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). This also showed a somewhat thickened left
adrenal gland, but without evidence of a discrete mass. There were no
hepatic, splenic, or pancreatic lesions. Additional MRI and CT scans of
the neck, chest, and pelvis were negative. [131I]MIBG scanning showed a focus of activity in the upper abdomen, immediately to the left and anterior to the left lobe of the liver. The anterior localization and disappearance of this focus 48 h after [131I]MIBG scanning suggested uptake and excretion of [131I]MIBG in the colon.
Materials and Methods
Vena caval sampling
A catheter inserted into a right femoral vein was advanced under radiological guidance for sampling blood at various intravascular sites. Blood samples (8 ml), collected into heparinized tubes, were obtained from the left and right internal, external, and common iliac veins; from several levels of the inferior vena cava; from proximal and distal portions of both renal veins; at several levels of the left adrenal vein; from the right hepatic vein; from the proximal and distal azygous veins; from the left and right ascending lumbar veins and internal jugular veins; and, for comparison, from the right femoral vein. Samples of blood were centrifuged, and plasma was analyzed for concentrations of normetanephrine and metanephrine according to the method of Lenders et al. (3) with all modifications described in more detail elsewhere (http://www.catecholamine.org/labprocedures). Samples of plasma were also analyzed for concentrations of norepinephrine and epinephrine according to the method of Eisenhofer et al. (4).
Interpretation of regional differences in concentrations of metanephrine at different intravascular sites was facilitated using existing knowledge about regional production of the metabolite (5). In particular, rates of production of metanephrine by certain tissues (e.g. the adrenals) or the flux of metanephrine at various vascular sites (F) was estimated based on differences in regional concentrations and blood flows as described previously (5), according to the formula: F = C x [BF (1 - Hct)] (Eq I), where C is the difference in plasma concentrations of metanephrine at different sampling points or across an organ, BF is the blood flow, and Hct is the hematocrit. Based on previous observations and calculations (5), blood flows were assumed to equal 300 ml/min for the common iliac veins, 600 ml/min at the bifurcation of the inferior vena cava, 750 ml/min in the inferior vena cava below the level of both kidneys, 750 ml/min for both kidneys, 2250 ml/min in the inferior vena cava immediately above both kidneys, 20 ml/min for the left adrenal vein, and 50 ml/min for the azygous vein.
The proportional contribution of various tissues or vascular regions to total circulating metanephrine (%C) was estimated by division of local rates of production or flux of metanephrine by the total rate of entry of metanephrine into the circulation, according to the formula: %C = (F/T) x 100 (Eq II), where F is calculated from Eq I above, and T is the total rate of entry of metanephrine into the circulation. The latter was estimated from the product of the total body clearance of metanephrine and the arterial plasma concentration of metanephrine. The total body clearance of metanephrine (1.8 liters/min) was assumed to equal that calculated from previously published data in patients without pheochromocytoma (5).
6-[18F]Fluorodopamine PET
PET scanning was performed using a General Electric Advance scanner (General Electric, Milwaukee, WI) with a 15-cm field of view. The patient was studied fasting and was asked to avoid caffeine, tobacco, and alcohol for at least 12 h before the scan. 6-[18F]Fluorodopamine (1.0 mCi) in about 10 ml normal saline was infused over 3 min via an antecubital iv catheter. The patient was scanned sequentially, at four levels, from the pelvis to the neck. Attenuation-corrected images at each position were combined into a composite image, revealing retained 6-[18F]fluorodopamine-derived radioactivity from the level of midchest to lower abdomen.
Results
Vena caval sampling
Peripheral venous plasma concentrations of epinephrine ranged from 0.9–1.5 pmol/ml for seven samples drawn over the period of the vena caval sampling procedure. In contrast, peripheral venous plasma concentrations of metanephrine varied from 2.8–3.4 pmol/ml. Despite lower upper reference limits for plasma metanephrine than epinephrine (0.31 vs. 0.45 pmol/ml), peripheral venous plasma concentrations of metanephrine were more than 2-fold higher than those of epinephrine and showed less fluctuation over the period of the vena caval sampling procedure (21% vs. 67% variation).
Concentrations of metanephrine more than double peripheral venous
concentrations were found in the right common iliac vein, the distal
right renal vein, the left adrenal vein, the distal azygous vein, and
throughout the inferior vena cava from the bifurcation to immediately
above the renal veins (Fig. 2). The
above-reported abnormal increases in plasma concentrations of
metanephrine above peripheral venous concentrations were 2.2 ±
0.2-fold larger than the increases in plasma concentrations of
epinephrine at the same sampling sites.
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The second highest concentration of metanephrine was in the inferior vena cava immediately below the renal veins, indicating that 79% of the elevated levels of metanephrine entered the circulation below this site and up to 64% between this site and the iliac bifurcation. A large distal to proximal gradient in plasma metanephrine concentrations across the right renal vein indicated that 29% of the elevated plasma concentrations of metanephrine resulted from entry into the circulation by way of the right renal vein. Other abnormal sites of metanephrine entry into the circulation were from the right common iliac vein and the proximal azygous vein. The fall in plasma concentrations of metanephrine along the inferior vena cava from below to above the level in the kidneys was consistent with dilution by lower concentrations of metanephrine in renal venous blood. Overall, about 96% of the elevated plasma levels of metanephrine were accounted for by entry of the metabolite into the circulation at and below the level of the renal veins.
The multiple sites of abnormal entry of metanephrine into the circulation suggested either a single tumor in the area of the right kidney, with venous drainage via multiple vessels, or multiple tumors in the right abdomen, with most of the venous drainage at or below the right renal vein. The neurochemical results for the left adrenal gland excluded this as the site of the pheochromocytoma.
6-[18F]Fluorodopamine PET
Because of urinary excretion of
6-[18F]fluorodopamine and its metabolites, the
renal pelvises showed high concentrations of
6-[18F]fluorodopamine-derived radioactivity
(Fig. 3). Nevertheless, the adrenal areas
could be examined. An area of
6-[18F]fluorodopamine-derived radioactivity was
noted in the region of the previous right adrenalectomy, suggesting
recurrent pheochromocytoma. Although MRI scanning did not reveal tumor
tissue, close comparison of the PET and MRI images indicated that the
heterogeneous area of
6-[18F]fluorodopamine-derived radioactivity
extended about 3–4 cm anteriorly and medially from the right adrenal
surgical bed to the region of the inferior vena cava.
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Although both caval sampling and
6-[18F]fluorodopamine PET indicated a similar
location of the pheochromocytoma, these approaches were considered too
investigational to justify surgery. Therefore, a decision was made to
repeat MIBG imaging, but this time with the patient sent to the
University of Michigan for [123I]MIBG single
photon emission computed tomographic scanning. This imaging procedure
confirmed the results from the vena caval sampling and
6-[18F]fluorodopamine PET scanning by showing
increased [123I]MIBG uptake in the right
adrenal bed (Fig. 4). Lack of abnormal
uptake in other areas excluded metastatic disease, justifying
surgery.
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Laparotomy revealed multiple nodules of pheochromocytoma tissue in the right adrenal surgical bed, extending to the wall of the inferior vena cava. The tissue was removed, including tissue adherent to the wall of the inferior vena cava, by local dissection and excision of the wall of the inferior vena cava. Postsurgical pathological examination indicated three separate nodules, one 2 cm in diameter, with extensive perineural invasion, and two others 0.8 cm in diameter. One of the smaller nodules was located in soft tissue, and the other was in Gerota’s fascia. There was no lymphatic or blood vessel invasion.
Discussion
This report illustrates several points about the diagnosis and localization of pheochromocytoma in difficult cases. The diagnostic evaluation scheme used here introduces two approaches for tumor localization: vena caval blood sampling, with measurements of plasma metanephrines, and 6-[18F]fluorodopamine PET scanning.
Although CT and MRI have high sensitivity for detecting adrenal pheochromocytoma, sensitivity decreases for detecting extraadrenal pheochromocytomas (1, 2, 6, 7, 8) or, as in this case, when postoperative changes obscure recurrent disease. Also, although [131I]MIBG scanning offers excellent specificity, this imaging agent suffers from imperfect sensitivity (9, 10, 11, 12). When conventional imaging studies yield negative results, but clinical and biochemical evidence indicates a pheochromocytoma, it can be important to consider other options for localizing a tumor.
Because of the imperfect specificity of biochemical tests and the low pretest prevalence of pheochromocytoma, false positive test results typically far outnumber true positive results. Thus, when the radiological testing is negative, even when biochemical testing is positive, most patients do not have pheochromocytoma. This produces a dilemma in diagnostic decision-making: when is it appropriate to continue with time-consuming and expensive procedures for localization of a tumor, and when should other avenues to confirm or exclude a tumor be pursued instead? The clonidine suppression test is one approach that can be particularly useful in helping to confirm or exclude pheochromocytoma before embarking on extensive imaging studies (13).
In this patient the decision to directly proceed with other approaches to locate rather than to confirm or exclude the tumor was justified by the high probability of pheochromocytoma. In particular, the increase in plasma metanephrine to more than 8-fold above the upper reference limits together with the parallel increases in urinary and plasma epinephrine and symptoms and signs consistent with an epinephrine-secreting tumor, provided unequivocal evidence that the patient had a pheochromocytoma. Thus, no other biochemical tests were required to confirm the presence of a tumor. Localization posed the main challenge.
Vena caval sampling for measurements of catecholamines is an accepted means to localize pheochromocytoma in difficult cases (14, 15, 16). As illustrated in this case, measurement of plasma metanephrines has several advantages for localizing tumors over measurement of catecholamines. In particular, catecholamine release by pheochromocytomas occurs episodically, so that transient changes in catecholamine release during sampling can confound interpretation of results. In contrast, metanephrines are produced within tumors continuously and independently of catecholamine secretion and, as a consequence, show less fluctuation (17, 18). Similar to catecholamines, plasma free metanephrines have a rapid circulatory clearance, but in pheochromocytoma invariably show proportionately much larger increases above normal than plasma catecholamines (5, 19, 20). This difference was particularly important in this patient, who had much larger increases in plasma metanephrine than in epinephrine, making abnormal gradients in plasma metanephrine more useful than those in epinephrine for locating the tumor.
As pheochromocytomas that secrete predominantly epinephrine typically have an adrenal location, the most likely location of the tumor in this patient was thought at first to be in the remaining left adrenal gland. Indeed, the thickening of the left adrenal gland indicated by CT and MRI supported this possibility. Abnormally high ratios of norepinephrine to epinephrine concentrations in adrenal venous plasma have been used to locate adrenal pheochromocytomas (15). In this patient such an approach was not possible, because the pattern of catecholamine secretion was similar to that of a normal adrenal. Instead, exclusion of the remaining adrenal as the site of the tumor was facilitated by estimation of the contribution of the adrenal gland to the total body production of metanephrine. The finding that the left adrenal gland made only an 8% contribution to the high levels of circulating metanephrine was essential for excluding a pheochromocytoma at this site. The simple calculation of metanephrine flux rates, however, not only allowed exclusion of the remaining adrenal as the site of the tumor, but also allowed estimation of the proportionate contributions of the tumor, at various vascular sites, to the total body production of metanephrine. Thus, the bulk of the abnormally high levels of metanephrine entered the vena cava below or via the right renal vein, a result that indicated the general location of the tumor in the right abdomen at or below the level of the right kidney.
6-[18F]Fluorodopamine PET scanning confirmed the vena caval sampling results and provided more accurate information about the location of the tumor. As dopamine is a better substrate for the norepinephrine transporter than most other amines, including norepinephrine (21), there are theoretical reasons why an analog of dopamine might be useful in this setting. Compared with MIBG scanning, the radiation risk is lower, there is no need for preoperative thyroid block with iodine solution, and PET scanning has important advantages in terms of temporal and spatial resolution compared with single PET and planar scanning. PET scanning can also be carried out immediately after the administration of 6-[18F]fluorodopamine, as opposed to the 24–48 h necessary for background radioactivity to clear after MIBG. 6-[18F]Fluorodopamine PET scanning is, however, expensive, is available in the U.S. currently only at the NIH Clinical Center, and has not been compared formally with MIBG scanning in terms of sensitivity and specificity.
In our patient the results of 6-[18F]fluorodopamine PET scanning and vena caval sampling did not agree with those of CT, MRI, and [131I]MIBG imaging, the latter showing, if anything, abnormalities in the left abdomen. Because of this and because 6-[18F]fluorodopamine is currently an investigational drug that is not approved for diagnostic use, it was important to confirm the right abdominal location of the pheochromocytoma with another imaging modality before recommending surgery. Somatostatin receptor scintigraphy using 111-indium-labeled pentetreotide provides an imaging modality that could have been used to locate this patient’s pheochromocytoma (9, 22, 23). However, we chose to use [123I]MIBG scintigraphy, which revealed the tumor after [131I]MIBG planar imaging failed to do so, further supporting the superiority of [123I]MIBG over [131I]MIBG for tumor localization (24, 25). Unfortunately, [123I]MIBG is not currently commercially available in the U.S., and scanning with this agent is available at only a few U.S. academic medical centers, such as University of Michigan (26, 27).
In summary, most cases of pheochromocytoma can be localized by conventional imaging modalities, but in some cases successful localization requires additional strategies. The novel approaches outlined here may be of value in difficult cases, where biochemical and clinical evidence of pheochromocytoma is compelling, yet conventional imaging modalities fail to locate the tumor.
Footnotes
Abbreviations: CT, Computed tomography; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography.
Received October 23, 2000.
Accepted April 16, 2001.
References
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