Detecting Pheochromocytoma

Abstract

Objective:

To define the most sensitive biochemical test to establish the diagnosis of pheochromocytoma and also to assess the potential role of iodine 131-labeled metaiodobenzylguanidine scintigraphy (¹³¹I-MIBG) in the diagnosis of this tumor.

Summary Background Data:

Pheochromocytoma is a rare, catecholamine-producing tumor with preferential localization in the adrenal gland. Despite its importance, the most sensitive test to establish the diagnosis remains to be defined.

Methods:

Prospective data collection was done on patients with pheochromocytoma treated at the Duke University Medical Center and the Durham Veterans Affairs Medical Center, Durham, NC. All urinary, plasma, and platelet analyses were highly standardized and supervised by one investigator (J.M.F.). ¹³¹I-MIBG scans were independently reviewed by 2 nuclear medicine physicians.

Results:

A total of 152 patients (55.3% female) were enrolled in the present analysis. Patients were predominantly white (73.7%). Spells (defined as profuse sweating, tachycardia, and headache) and hypertension at diagnosis were present in 51.4% and 66.6%, respectively. Bilateral disease was found in 12.5%, malignant pheochromocytoma in 29.6%, and hereditary forms in 23.0%. The most sensitive tests were total urinary normetanephrine (96.9%), platelet norepinephrine (93.8%), and ¹³¹I-MIBG scintigraphy (83.7%). In combination with ¹³¹I-MIBG scintigraphy, platelet norepinephrine had a sensitivity of 100%, plasma norepinephrine/MIBG of 97.1%, total urine normetanephrine/MIBG of 96.6%, and urine norepinephrine/MIBG of 95.3%.

Conclusions:

The tests of choice to establish the diagnosis of pheochromocytoma are urinary normetanephrine and platelet norepinephrine. A combination of ¹³¹I-MIBG scintigraphy and diagnostic tests in urine, blood, or platelets does further improve the sensitivity. We thus advocate performing an MIBG scan if the diagnosis of pheochromocytoma is clinically suspected and catecholamine measurements are within the normal range.

The objective of the present investigation was to define the most sensitive biochemical tests to establish the diagnosis of pheochromocytoma. Based on prospectively collected data on 152 patients with pheochromocytoma, we found that the most sensitive tests were total urinary normetanephrine (96.9%), platelet norepinephrine (93.8%), and ¹³¹I-MIBG scintigraphy (83.7%).

Pheochromocytoma is a rare, catecholamine-producing tumor with preferential localization in the adrenal gland presenting with severe, often therapy-resistant hypertension, sweating, pallor, anxiety attacks, and headache.^1–3 Pheochromocytomas are usually curable if diagnosed and appropriately treated. However, if the disease remains undiagnosed, the excessive catecholamine secretion might have serious, even fatal consequences.^1,2,4 Therefore, postmortem detection of pheochromocytomas represents a frequent, yet disturbing phenomenon.^5,6

The diagnosis of pheochromocytomas largely depends on detecting elevated catecholamines or catecholamines metabolites in the blood and urine.^1,2,7 However, the issue of false-negative results continues to be of great relevance, and the most sensitive test to establish the diagnosis remains to be defined. There is an urgent need to find a test that reliably confirms the presence of a pheochromocytoma. Most previous studies trying to identify the most sensitive test in the detection of pheochromocytoma had small sample sizes or assessed only the few most common urinary and blood tests.^8–14 The objective of the present investigation was 3-fold: 1) to describe one of the largest ever published samples of pheochromocytoma patients, 2) to define the most sensitive test to establish the diagnosis, and 3) to evaluate the diagnostic potential of ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) scintigraphy alone as well as in combination with other tests.

MATERIALS AND METHODS

Patients

Since the early 1970, one investigator (J.M.F.) has been consulted for 152 consecutive pheochromocytoma patients treated at the Duke University Medical Center and the Veterans Affairs Medical Center in Durham, NC. The diagnosis of pheochromocytoma was confirmed by light microscopy, including histochemical stains, in surgically removed pheochromocytoma. Many of the specimens were also examined with transmission electron microscopy for the presence of neurosecretory granules and with biochemical analysis for their catecholamine content.

Malignant disease was defined as the presence of distant metastases or local tumor infiltration. Patient demographics and symptoms at admission were prospectively collected. The diagnosis was established based on urinary, plasma, and platelet analysis of metanephrines, epinephrine, norepinephrine, dopamine, serotonin, 5-hydroxyindoleacetic acid, vanillylmandelic acid, and homovanillic acid as well as positive MIBG scans. Medications potentially interfering with the urinary catecholamine determinations (eg, labetolol or methyldopa) were discontinued 72 hours prior to the 24-hour urine collection. Prior to taking blood samples, patients were supine for at least 30 minutes.

Diagnostic Methods

The methods of analysis were highly standardized and have been described in detail elsewhere.^15–18 Briefly, the homovanillic acid levels were measured by a thin-layer chromatographic,¹⁷ the vanillylmandelic acid with either a spectrophotometric method or a high-pressure liquid chromatography method.¹⁸ Dopamine, epinephrine, and norepinephrine were assessed using a specific radioenzymatic method (CAT-A-KIT assay system, Amersham Corp, Arlington Heights, IL) or high-pressure liquid chromatography method.^15,16 Total metanephrine and total normetanephrine measurements were done by high-pressure liquid chromatography. The normal range of values of specific metabolites was identical with the different methods of analysis (Appendix).

Patients subsequently underwent ¹³¹I-MIBG scintigraphy of chest, abdomen, and pelvis if their urinary catecholamines were elevated or borderline, or if clinically pheochromocytoma was suspected despite normal catecholamine levels. The methods of performing and analyzing ¹³¹I-MIBG scintigraphy have been described elsewhere.¹⁹ Briefly, to block the uptake of free ¹³¹I by the thyroid gland, one drop (30 mg) of a saturated solution of potassium iodide was given 3 times a day 1 day prior to the administration of ¹³¹I-MIBG and was continued for 1 week. All patients received 18.5 MBq of ¹³¹I-MIBG intravenously. Planar gammagraphic camera images were then obtained of the anterior and posterior chest, abdomen, and pelvis. Medications potentially interfering with the ¹³¹I-MIBG scan (eg, monoamine oxidase inhibitors, phenylpropanolamine, tricyclic antidepressants, or reserpine) were withdrawn 72 hours prior to the administration of ¹³¹I-MIBG.

All scans were independently reviewed by 2 nuclear medicine physicians and were graded on a scale from 0 to 4+ based on a comparison with the uptake intensity of the normal liver (0: background activity = negative scan, 1+: accumulation slightly greater than background, 2+: abnormal accumulation less than liver activity, 3+: abnormal accumulation equal to the liver, 4+: accumulation greater than liver).

Statistical Methods

Descriptive analyses were performed using median and range for continuous variables and frequencies and percentages for categorical variables.

Sensitivity is the proportion of true positive tests divided by the sum of true positive and false-negative tests; 95% confidence intervals were computed for all sensitivities.

RESULTS

Patient Characteristics

Patients had a median age of 47 years (range, 12–84 years) and were predominantly white (73.7%). Eight patients (5.3%) were younger than 20 years of age. The patient population consisted of 55.3% females and 44.7% males.

A total of 107 patients (70.4%) had benign and 45 patients (29.6%) malignant pheochromocytoma. Spells (defined as profuse sweating, tachycardia, and headache) and hypertension were present in 51.4% and 66.6% of patients, respectively.

A total of 117 patients (77.0%) had sporadic and 35 patients (23.0%) familial pheochromocytoma. In 21 patients, the pheochromocytoma was associated with MENIIA, in 3 patients with MEN IIB, in 3 patients with von Recklinghausen's neurofibromatosis, and in 2 patients with von Hippel-Lindau disease. Moreover, 6 patients had familial pheochromocytoma unrelated to any of the above diseases. Eighteen patients were diagnosed with concomitant medullary carcinoma of the thyroid gland.

Nineteen patients had bilateral (12.5%) and 133 (87.5%) unilateral disease. Adrenal disease was present in 74.5%, extra-adrenal disease in 25.5%.

The median weight of measured tumors (n = 51) was 37.0 g (range, 5–896 g); the median diameter of measured tumors (n = 120) was 6.0 cm (range, 0.6–21 cm).

Sensitivities of Catecholamines Tests

The sensitivities of the different catecholamine measurements are displayed in Table 1. Total urinary normetanephrine was the most sensitive test (96.9%, 95% confidence interval [CI]), 90.8%–100%; rate of false-negativity = 3.1%), followed by platelet norepinephrine (93.8%, 95% CI, 85.4%–100%; rate of false-negativity = 6.2%), and urine norepinephrine (77.7%, 95% CI, 70.5%–84.8%; rate of false-negativity = 22.3%). The measurement of platelet serotonin (sensitivity, 0%; 95% CI, 0%–5.4%; rate of false-negativity = 100%) and 5-hydroxyindoleacetic acid (2.2%, 95% CI, 0%–5.1%; rate of false-negativity = 97.8%) yielded the lowest sensitivity.

TABLE 1. Sensitivities and 95% Confidence Intervals of Different Tests

¹³¹I-MIBG Scans

Ninety-two patients underwent a ¹³¹I-MIBG scan. The scan was graded negative, 1+, 2+, 3+, and 4+ in comparison with the liver uptake as described in Materials and Methods. All ¹³¹I-MIBG scans were technically adequate for interpretation.

Fifteen patients (16.3%) had a negative scan, no patient was graded 1+, 1 patient 2+, 8 patients 3+, and 68 patients 4+. Thus, 77 patients had a true-positive and 15 patients a false-negative MIBG scan resulting in a sensitivity of the ¹³¹I-MIBG scan of 83.7% (95% CI, 76.1%–91.2%; rate of false-negativity = 16.3%).

Six patients had false-negative conventional catecholamines who subsequently had a true-positive MIBG scan.

Combined Analyses of Catecholamines and ¹³¹I-MIBG Scans

In combination with ¹³¹I-MIBG scintigraphy, platelet norepinephrine had a sensitivity of 100% (95% CI, 91.9%–100%), plasma norepinephrine/MIBG of 97.1% (95% CI, 91.4%–100.0%), total urine normetanephrine/MIBG of 96.6% (95% CI, 89.9%–100.0%), and urine norepinephrine/MIBG of 95.3% (95% CI, 90.8%–99.8%) (Table 2).

TABLE 2. Sensitivities and 95% Confidence Intervals of Different Tests Combined With ¹³¹I-MIBG Scintigraphy

DISCUSSION

In the present investigation based on one of the largest published collections of consecutive patients with pheochromocytoma, we found that total urinary normetanephrine was the most sensitive diagnostic test, followed by platelet norepinephrine and ¹³¹I-MIBG scintigraphy. The combined sensitivity of catecholamine measurements and ¹³¹I-MIBG scans approached 100% for many tests. We thus advocate performing an MIBG scan if the diagnosis of pheochromocytoma is clinically suspected and the catecholamine measurements are within the normal range.

Pheochromocytomas are often referred to as “10% tumors.” However, the rule of 10% did not universally apply to our patient sample: while the occurrence of bilateral pheochromocytoma was close to 10% in our patients, the percentage of extraadrenal (25.5%), familial (23.0%), and malignant (29.6%) disease was much higher than that noted in other reports.^6,20 This can be explained by the fact that Duke University had a long-standing interest in pheochromocytoma and thus was a referral center for other family members with this pathology. The diseases (MEN IIA, MEN IIB, von Recklinghausen's fibromatosis, Hippel-Lindau disease) with which familial forms of pheochromocytomas were associated in our patients have also been described in previous studies.^1,20

Despite the importance of accurately detecting pheochromocytomas to avoid the potential serious consequences of nontreatment, the most sensitive test to establish the diagnosis remains a matter of debate. Some researchers have concluded that plasma catecholamines are more sensitive in the detection of pheochromocytoma compared with urinary measurements.⁸ Others have reported that urinary catecholamines and their derivatives have higher sensitivities than plasma measurements.^9,21 More recent studies have advocated the use of plasma unconjugated metanephrines in the diagnosis of pheochromocytoma.²² Indeed, it has been postulated that plasma levels of normetanephrine and metanephrine have higher sensitivity than other tests for both sporadic and familial pheochromocytoma.^13,23 The reason for the greater sensitivity might be based on the continuous secretion of metanephrines, rather than the intermittent release of the catecholamines during the acute hypertensive episodes or other “spells.” In the present investigation, total urinary normetanephrine was the single most sensitive test with a very low false-negative rate of 3.1%. Platelet norepinephrine was also found to be very sensitive (93.8%). It is likely that the mechanism of this increased sensitivity is that the neurosecretory granules in the platelets concentrate the catecholamines that are intermittently secreted into the vascular compartment by the pheochromocytoma. This is analogous to the mechanism by which platelets concentrate the serotonin intermittently secreted into the vascular compartment by carcinoid tumors in patients harboring these neuroendocrine tumors. Interestingly, reports about platelet norepinephrine as a diagnostic test for pheochromocytoma are rarely reported in the literature, and this test is not a routine measurement in most hospitals. We thus advocate that the measurements of urine normetanephrine and platelet norepinephrine should be performed as routine tests because of their high sensitivities if pheochromocytoma is clinically suspected.

As preoperative localization of pheochromocytomas is cardinal for the surgeon to achieve a complete resection,^19,24 scintigraphic imaging with ¹³¹I-MIBG was performed on 92 patients. The successful use of ¹³¹I-MIBG as an imaging agent for pheochromocytoma is based on its structural similarities to norepinephrine.²⁵ Because of these similarities, ¹³¹I-MIBG is concentrated in neurosecretory granules and thus forms an image of the pheochromocytoma.²⁶

We found ¹³¹I-MIBG scan to be a very sensitive tool in the detection of pheochromocytomas. The sensitivity of ¹³¹I-MIBG in other studies ranged from 77% to 94.7%,^20,27–30 similar to the result found in our investigation (83.7%).

While computed tomography represents an excellent diagnostic tool for detecting adrenal pheochromocytoma, its sensitivity decreases for extra-adrenal disease.³¹ One of the great advantages of ¹³¹I-MIBG scintigraphy is its ability to perform whole-body scanning, allowing the simultaneous imaging of adrenal and extra-adrenal sites.³² Indeed, ¹³¹I-MIBG scanning seems to be particularly useful in the detection of extra-adrenal, metastatic, and recurrent disease.1,27,30,31,33–36 Moreover, both CT scanning and MRI are known to be associated with false-positive results,³¹ while the “specificity” of MIBG has been reported close to 100% in sporadic, familial, benign, and malignant pheochromocytoma.^27,31 Nonetheless, as the costs of MIBG scanning are considerable,^37,38 we do not recommend performing routine MIBG scans in all patients with suspected pheochromocytoma but only if patients present with the clinical symptoms of pheochromocytoma despite negative catecholamines.

MIBG is also concentrated in other neuroendocrine tumors such as neuroblastomas and carcinoid tumors.³⁹ Although neuroblastomas are relatively rare tumors that occur in children, carcinoid tumors, which in our experience are 5 times as common as pheochromocytomas, occur in adults. The majority of carcinoid tumors that concentrate MIBG would synthesize and secrete serotonin. Thus, patients harboring carcinoid tumors have significantly elevated urinary 5-HIAA excretion and significantly elevated serum and platelet serotonin concentrations. We ruled out the possibility that the patients with suspected pheochromocytoma had carcinoid tumors by measuring 5-HIAA excretion and platelet and serum serotonin concentration.

If catecholamine tests and ¹³¹I-MIBG were combined in the present investigation, the sensitivities considerably increased and many were close to 100%. While MIBG scanning represents primarily a tool to localize pheochromocytoma, it proved to be very sensitive in establishing the diagnosis in our study. As previously suggested by others,^27,30,36 we thus propose that ¹³¹I-MIBG scanning should be performed in patients with clinically suspected pheochromocytoma if the catecholamine measurements are normal. Indeed, in the present investigation, 6 patients had false-negative conventional catecholamines who subsequently had a true-positive MIBG scan. This represents a relevant finding, considering the potentially fatal consequences of undiagnosed pheochromocytoma. Not only does MIBG scanning enable the confirmation of the diagnosis, but it also helps the surgeon in the preoperative localization of the tumors. It is particularly helpful in the preoperative identification of multiple pheochromocytomas or metastases from malignant pheochromocytomas.

Limitation and Strengths

We would like to acknowledge the limitation of the present analysis: All patients in our dataset did have pheochromocytoma; therefore, we were unable to compute the specificity (no false-positive results) of the different tests. However, as advocated by others,¹ we think that the most relevant characteristic of a test to establish the diagnosis of pheochromocytoma is its sensitivity as it is imperative to avoid false-negative results.¹ A missed diagnosis due to a false-negative result can have deleterious, even fatal, consequences for patients with pheochromocytoma, whereas a false-positive result can be clarified by further testing.¹

Furthermore, we have purposefully refrained from providing information on the various combinations of different catecholamine tests. This would lead to the problem of “multiple comparisons,” which is well known to be associated with spurious (false-positive) associations.^40–43

The strengths of the present investigation are the large sample size as well as the quality and consistency with which laboratory tests were performed. Furthermore, the number of different urine, plasma, and platelet tests that were assessed in our study are, to the best of our knowledge, unprecedented.

CONCLUSION

We found that total urinary normetanephrine is the single most sensitive test in the detection of pheochromocytoma followed by platelet norepinephrine. These 2 tests are not yet performed in many institutions and should, however, belong to the standard diagnostic if pheochromocytoma is clinically suspected. In combination with MIBG scintigraphy, platelet norepinephrine had a sensitivity of 100% (no false-negative findings). Clearly, ¹³¹I-MIBG scintigraphy improves the level of confidence to the preoperative diagnosis of a pheochromocytoma. Therefore, if pheochromocytoma is clinically suspected and the patient has normal catecholamine levels, MIBG scan should be performed. MIBG scanning is not only a complementary approach to improve the sensitivity of the urine, plasma, and platelets tests, but also critically important to the surgeon in the preoperative localization of the pheochromocytoma.

APPENDIX. Normal Ranges