ORIGINAL INVESTIGATION Sensitivity of Diagnostic and Localization Tests for in Clinical Practice

Ronald M. Witteles, BA; Edwin L. Kaplan, MD; Michael F. Roizen, MD

Background: Although are be- total (100%). Testing for urine vanil- lieved to account for fewer than 0.3% of all cases of hy- lylmandelic acid, while less expensive and easier to per- pertension, aggressive diagnostic and surgical interven- form than many other tests, had a slightly lower sensi- tion is recommended whenever a pheochromocytoma is tivity (89%). The most sensitive imaging tests in the study suspected because uncontrolled release were magnetic resonance imaging (100%) and iodine from the tumors can lead to catastrophic consequences. I-131 metaiodobenzylguanidine scintigraphy (100%). The Many biochemical diagnostic and imaging localization more often used computed tomography had only 88% tests exist for detecting pheochromocytomas. We sought sensitivity. Localization was safely and successfully per- to evaluate the sensitivity of these tests used over a 35- formed on two pregnant patients using magnetic reso- year period at a single institution. nance imaging and ultrasound.

Methods: Thirty-five patients with complete medical Conclusions: By properly choosing from the wide ar- records who had pathologically confirmed pheochromo- ray of laboratory diagnostic and imaging tests, pheochro- cytomas between 1962 and 1997 at the University of mocytomas can be identified and localized with nearly Chicago Hospitals were identified. Sensitivity and 95% 100% sensitivity. These tests should be performed in any confidence intervals were calculated for 12 laboratory patient for whom the diagnosis of pheochromocytoma diagnostic tests and 5 imaging studies. is being considered.

Results: The most sensitive laboratory diagnostic tests in our study were plasma total (95%) and Arch Intern Med. 2000;160:2521-2524

HEOCHROMOCYTOMAS arise Because approximately 10% of pheo- from pheochromocytes, the chromocytomas are extra-adrenal and primary cells of the adrenal 10% are bilateral (with a higher percent- medulla, which are also age in familial syndromes), accurate pre- found in the paraganglia near operative localization of the tumor is the aorta and in the sympathetic nervous imperative for safe, expeditious surgical P 4 system ganglia. Most frequently, symp- management. Older imaging techniques, toms are present when large amounts of including retroperitoneal air insufflation, catecholamines enter the circulation, angiography, and venography, have largely which can be triggered by changes in po- been replaced by ultrasound, computed to- sition, increased abdominal pressure, mography (CT), magnetic resonance im- trauma, labor, anesthesia, surgery, stress, aging (MRI), and iodine I-131 metaiodo- or the ingestion of certain drugs or foods.1 benzylguanidine (MIBG) scintigraphy.4 Although pheochromocytomas are be- Computed tomography is believed to be lieved to account for fewer than 0.3% of the best available technique for detecting all cases of hypertension, aggressive di- adrenal lesions, and ultrasound and MRI agnostic and surgical intervention is are useful in pregnant patients; MIBG scin- From the Departments of recommended whenever a pheochromo- tigraphy has been especially useful in lo- Anesthesia and Critical Care cytoma is suspected because the uncon- calizing extra-adrenal and recurrent pheo- (Mr Witteles and Dr Roizen), 4 Medicine (Mr Witteles and trolled catecholamine release from the chromocytomas. Dr Roizen), and Surgery tumors can lead to malignant hyperten- Biochemical diagnosis of pheochro- (Dr Kaplan), University of sion, cerebrovascular accidents, or myo- mocytoma is traditionally performed by Chicago Hospitals, Chicago, Ill. cardial infarction.2,3 examining plasma and total urinary lev-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 biochemical and imaging studies for pheochromocyto- mas (Table 3). Because of the difference in controls METHODS between studies (normal patients, patients with other chronic diseases, patients with other causes for hyper- tension), such specificity data have substantial After institutional review board approval, all 6,7,13-18 patients who were treated for pheochromocytoma variability. at the University of Chicago Hospitals were identi- Twenty-four–hour urine tests are widely consid- fied from records found in the tumor registry and ered superior to plasma tests in the diagnosis of pheo- the surgery, pathology, and anesthesia depart- chromocytoma, mainly because pheochromocytomas ments. Of the 51 cases identified, 37 had complete often secrete catecholamines only intermittently. This records available from the medical records depart- fact, along with the short half-life of catecholamines, ment. Of these 37 patients, 2 died before referral can result in relatively normal plasma catecholamine to surgery (and before diagnosis of pheochromocy- levels even in the presence of a functional tumor.7 toma). Therefore, 35 patients met our inclusion In our study utilizing commercial laboratory as- criteria. All of these patients had pheochromocyto- mas confirmed by pathologic examinations. says, however, plasma total catecholamines proved to be We computed sensitivity and 95% confidence one of the most sensitive tests, with a sensitivity of 95% intervals for routine, commercially available labo- (95% confidence interval, 74.0%-99.9%), representing the ratory diagnostic tests (serum , norepi- highest lower confidence limit value in our study. Plasma nephrine, , and total catecholamines; epinephrine and values were relatively urine epinephrine, norepinephrine, dopamine, comparable in sensitivity (77% and 86%, respectively) total catecholamines, with urine epinephrine and norepinephrine values (81% [VMA], , , and total and 75%, respectively). metanephrines) and localization tests (MRI, CT, Several studies have found urine metanephrines MIBG scintigraphy, ultrasound, and angiography). to be the most sensitive test in pheochromocytoma di- agnosis.1,6,7,10 Measurement of VMA in urine is gener- ally believed to have lower sensitivity. However, since VMA has acceptable specificity (Table 3) and sensitiv- els of catecholamines and their metabolites over 24 ity (Table 1) and is relatively inexpensive and easy to hours.1,5-10 Recent studies have indicated that urine perform by colorimetry, some might choose it as an total metanephrines is the most sensitive laboratory initial “case finding” test.8,19 test for pheochromocytoma.1,6,7,10,11 In our study, urine total metanephrines correctly We retrospectively evaluated the available charts revealed a diagnosis of pheochromocytoma in all 10 pa- of patients who underwent surgery for pheochromocy- tients for whom the test was ordered. Urine VMA mea- toma at the University of Chicago Hospitals, Chicago, surement was the test ordered most frequently (n=28), Ill, from 1962 to 1997 and examined the sensitivity of but it was less sensitive than testing for urine normeta- diagnostic and localization tests used. nephrine, total metanephrine, or plasma total catechol- . RESULTS Several studies report a sensitivity at or near 100% for CT scans, but in our study CT scans failed to local- Of the 35 patients, 18 (51%) were women, and the me- ize the tumor in 3 of 26 patients (88% sensitivity).1,5,9 dian age of all patients was 40 years (interquartile Sensitivity for both MRI scans and MIBG scintigraphy range, 32-54 years). Two patients had multiple endo- was 100% in our study, correctly identifying tumors crine neoplasia (MEN) type IIA, one patient had MEN in 12 of 12 and 8 of 8 patients, respectively. Recent type IIB, and three patients had neurofibromatosis. studies have found sensitivity ranging from 90% Two patients were pregnant at the time of diagnosis to 100% for MRI scans and 88% to 94% for MIBG scin- and surgery. tigraphy.1,5,9 Sensitivity and 95% confidence intervals of the 12 Treatment of pregnant patients with pheochromo- laboratory diagnostic tests are listed in Table 1. Sensi- cytoma is high-risk and must be individualized.20 Mag- tivity and 95% confidence intervals of the 5 imaging tests netic resonance imaging and ultrasound are the prefer- are listed in Table 2. able methods for localization of tumor in pregnant patients to avoid exposing the fetus to ionizing radia- 4 COMMENT tion. In our study, one pregnant patient underwent MRI localization and the other underwent ultrasound Because of the rarity of pheochromocytomas (believed localization, with effective localization of the tumor in to exist in fewer than 0.3% of hypertensive patients), each case. this analysis was performed as a retrospective study in Because pheochromocytomas are life-threatening which only true pheochromocytoma cases were exam- without treatment, it is important that a diagnostic test ined.12 Thus sensitivity could be measured, but not exclude false-negative results as efficiently as possible. other variables, such as specificity, predictive value of False positives are relatively less important because ad- positive test results, and predictive value of negative ditional testing (including clonidine suppression and test results. We have included a table from representa- glucagon stimulation) can be performed to rule out the tive literature sources that compares the specificity of disease.7,21 We found that urine total metanephrines, se-

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No. of No. With Positive Sensitivity Test Normal Range Patients Results (95% CI) Plasma epinephrine 0-270 pmol/L 22 17 77 (54.6-92.2) Plasma norepinephrine 0.66-3.89 nmol/L 22 19 86 (65.1-97.1) Plasma dopamine 0-10 pg/mL 12 5 42 (15.2-72.3) Plasma total catecholamines 123-671 pg/mL 19 18 95 (74.0-99.9) Urine epinephrine 11-131 nmol/d 21 17 81 (58.1-94.6) Urine norepinephrine 90-590 nmol/d 20 15 75 (50.9-91.3) Urine dopamine 52-480 µg/24 h 9 1 11 (0.3-48.3) Urine total catecholamines 26-121 µg/24 h 15 13 87 (59.5-98.3) Urine vanillylmandelic acid 0-30 µmol/d 28 25 90 (71.8-97.7) Urine metanephrine 0.2-1.6 µmol/d 26 19 73 (52.2-88.4) Urine normetanephrine 0.5-2.7 µmol/d 12 11 92 (61.5-99.8) Urine total metanephrines 0.7-3.8 µmol/d 10 10 100 (69.2-100.0)

*CI indicates confidence interval.

Table 2. Sensitivity of Imaging Tests*

Test No. of Patients No. With Positive Results Sensitivity (95% CI) Magnetic resonance imaging 12 12 100 (73.5-100.0) Computed tomography 26 23 89 (69.9-97.5) Iodine I-131 metaiodobenzylguanidine scintigraphy 8 8 100 (63.1-100.0) Ultrasound 6 5 83 (35.9-99.6) Angiography 3 2 67 (9.4-99.2)

*CI indicates confidence interval.

Table 3. Specificity of Biochemical and Imaging Tests From the Literature*

Specificity, %

Urine Plasma Imaging

Source Epi Nor DA TCat VMA Met NMet TMet Epi Nor DA TCat MRI CT MIBG Eisenhofer et al13 96 100 95 86 Peaston et al14 89 82 70 96 97 Plewe et al15 82 93 100 Hanson et al16 88 62 82 91 88 Young et al17 95 90 94 Peplinski and Norton18 67 83 83 83 80 80 17 17 50 20 100 29 Lenders et al6 98 Heron et al7 82

*Because of the difference in controls between studies (normal patients, patients with other chronic diseases, patients with other causes for hypertension), specificity data have substantial variability. Epi indicates epinephrine; Nor, norepinephrine; DA, dopamine; TCat, total catecholamines; VMA, vanillylmandelic acid; Met, metanephrine; NMet, normetanephrine; TMet, total metanephrines; MRI, magnetic resonance imaging; CT, computed tomography; and MIBG, iodine I-131 metaiodobenzylguanidine scintigraphy.

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