NP-59) Imaging

Diagnostic Accuracy and Pitfalls of [Iodine-131]6-Beta-Iodomethyl- 19- Norcholesterol (NP-59) Imaging

Ella A. Kazerooni, James C. Sisson, Brahm Shapiro, Milton D. Gross, Albert Driedger, Gilbert A. Hurwitz, Add G. Mattar, and Neil A. Petry

Department oflnternal Medicine, Division ofNuclear Medicine, University ofMichigan Medical Center, Ann Arbor, Michigan, and Department ofNuclear Medicine, Victoria Hospital, London, Ontario, Canada.

of hormone synthesis in Cushing's syndrome (2,3), NP-59 concentrates in steroid hormone synthesizing tis primary aldosteronism (4-10), and hyperandrogenism sues, enabling scintigraphic localization and characteriza (11â€”14). In addition, scintigraphy has demonstrated tion of endocrine dysfunction in the adrenal cortex and that incidentally discovered adrenal tumors not associ ovary. Studying i 08 consecutive cases from i 982 to i 985 ated with excess hormone production (euadrenal tu and using clinical, biochemical, radiographic, and patho mors) can often be categorized as concentrating or not logic data, we performed a rigorous assessment of the concentrating NP-59, a characteristic that distinguishes accuracy and pitfalls of NP-59 scintigraphy. The evaluation between benign and malignant tumors (15â€”17). Occa was divided into categories of abnormal hormone secre sionally NP-59 scintigraphy has been employed to de tion: Cushing's syndrome, primary aldosteronism, and hy perandrogenism.Additionalcategoriesincludedeuadrenal termine if and where residual adrenal cortical tissue tumors (without detectable hormone dysfunction)and sites resides after disease or surgical intervention (18). of residual adrenal cortical tissue. The accuracy of NP-59 Although NP-59 images have clearly been helpful in scintigraphy ranged from 7i % in primary aldosteronism the diagnosis of selected patients, adrenal scintigraphy and 75% in euadrenal tumors, to i 00% for Cushing's has not been rigorously evaluated for its diagnostic syndrome and hyperandrogenism. However, more than in accuracy in patients routinely referred for study. By most nuclear medicine studies, NP-59 imaging requires examining 108 consecutive cases, the accuracy of NP well-defined indications to be met for it to be efficacious, 59 scintigraphyin its multiple applicationswas evalu including the fulfillment of clear clinical, biochemical, and ated, and equally important, the pitfalls were deline radiographic criteria. The high reproducibility of NP-59 ated. Together with interobserver variation in the above scintigraphic interpretation was demonstrated when 40 random cases underwent interinstitutional exchange and cases, an additional 40 random cases exchanged with a through interobserver evaluation at the University of Mich second institution were reviewed to determine the ac igan. Responses of 85/i 26 medical centers to question curacy of image interpretation. Finally, a survey of NP naires revealed the high level of NP-59 safety. 59 users was made to assessthe safety of this radio pharmaceutical. J NucI Med 1990; 31:526â€”534 MATERIALSAND METHODS At the University of Michigan we planned to evaluate the clinical, biochemical, and radiographic data with the results he radiolabeled cholesterol analog, [iodine- 13 1]6- of NP-59 scintigraphy in 100 consecutive cases. To ensure beta-iodomethyl-19-norcholesterol (NP-59), concen sufficient number, 108 consecutive studies performed from trates in steroid hormone synthesizing tissues such as 1982 to 1985 were reviewed. A number of these cases have the adrenal cortex and some ovarian tumors (1). Lo been reviewed in previous publications (5,15,16,19,20). Each calization enables scintigraphic definition ofthe sites of study was reviewed independently by three nuclear medicine steroid hormone synthesis and conclusions concerning specialists(JCS, BS, and MDG), knowledgeableof adrenal the functional nature of tumors in these sites. Previous disorders and imaging. All patients received a 1-mCi i.v. reports have described the diagnostic value of scinti injection of NP-59 and dulcolax tablets during imaging to reduce overlying colonic activity. In addition, all patients graphic images made with NP-59 in defining the sites studied for hyperaldosteronism and hyperandrogenism re ceived 5 mg of oral dexamethasone per day starting 7 days ReceivedJuly7, 1989;revisionacceptedNov.16,1989. prior to injection and ending on the last day of imaging, to For reprints contact: James C. Sisson, MD, U,iversity of Michigan Med@&Center,DepartmentofNuclearMedicine,1500EastMedicalCenter suppress corticosteroid synthesizing tissue. Images were ob Dr., Ann Arbor, Michigan 48109-0028. tamed at 5â€”7days postinjection, except in cases of hyperal

526 The Journal of Nuclear Medicine â€¢Vol. 3i â€¢No. 4 â€¢April i 990 dosteronism, where imaging at 3â€”5days following injection diagnoses required definitions of the possible disorders to was designed to detect the earliest appearance of adrenal guide the interpretation ofscintigraphic images, and that such activity. definitions had not been previously established for this pur The review was conducted in three stages. The first stage pose. Using standard textbooks of endocrinology (21,22), analyzed images in the absence of clinical and biochemical definitions ofCushing's syndrome, primary aldosteronism and data, emphasizing symmetry of adrenal NP-59 concentration hyperandrogenism were devised to be used as scintigraphic and the earliest day after injection when concentration could guidelines (Tables 1â€”3).Euadrenal tumors were defined as be discerned, to determine if disagreements in diagnostic anatomic adrenal gland enlargement when there was sufficient decisions were related to interpretation of the pictorial data. evidence to conclude that no adrenal hormone was secreted In the second stage, the clinical, biochemical, and radiographic in excess. Five cases not referred for clinical questions were data available at the time of imaging were reviewed with the excluded from the review, leaving 103cases for analysis (Table images to render a diagnosis. In the final stage, correlations 4). were made of all data obtained before and after each study The clinicalusefulnessof NP-59scintigraphyis definedin (including responses to requests sent to referring physicians terms of accuracy at determining the site(s) of corticosteroid for follow-up data) to arrive at a final diagnosis. hormone synthesis, subsequently interpreted in light of the It became apparent that the diagnostic decisions and final clinical question asked by the referring physician. Questions

TABLE I Criteria for Cushing's Syndrome A. Diagnosisof Cushing'ssyndrome 1. Clinical a. Hypertension b. Obesity:centripetal,facial c. Stna:purple d. Virilizationinthesyndrome Shouldhaveat leastoneof theclinicalfeatures,and 2. Laboratory a. Evidenceof cortisolexcess 1. Highnormalor highplasmacortisol(>25 @g/dIin a.m.)or 2. Lackof diurnalvariationin plasmacortisolor 3. Elevatedrateof excretionof freecortisol(>125 @g/24hr)or 4. Elevated rate of excretion of 17-hydroxysteroids(>10 mg/24 hr),and b. Evidenceof alteredcontrolof cortisolsecretion 1. Failureto suppressplasmacortisolto <15 @g/dl,preferablyfailureto suppressto <5 @g/dlby a. 1 mgdexamethasonein eveningor b. 4 (or 16)mgof dexamethasoneover48 hr,or 2. Failureto suppressunne17-hydroxysteroidsto lessthanhalfof basalby 4 (or 16)mgof dexamethasoneover48 hr. B. Locationof primaryabnormalityin Cushing'ssyndrome 1. Pituitary a. PlasmaACTH>90 pg/mI(inam.), and b. Either 1. EvidenceofpituitaryadenomabyCTorbyremovalor 2. Presumptiveby absenceof evidenceof ectopicsourceof ACTH(bychestx-rayor othermeans),or c. Suppressionurine(orplasma)cortisolby 16mg/dbut not by4 mg/dof dexamethasoneover2 days. 2. EctopicACTHor CRH a. PlasmaACTH>90 pg/mI,and b. TumorsecretingACTHor CRHfrom 1. measurementof ACTHor CRHin bloodof veinfromtumor,or 2. measurementof hormonesin tumoror 3. reliefof clinicalandlaboratoryabnormalitiesof the syndromeuponremovalof thetumor,and c. Lackof suppressionof plasmacortisolby 16mg/dof dexamethasoneover2 days. 3. Adenoma a. Biochemical-image 1. Lackof ACTHdependenceby a. plasmaACTH<60 pg/mI(ina.m.),or b. Failureof plasmacortisolor urinei7-hydroxysteroidsto suppresswith 10mgof dexamethasoneover48 hr;and 2. Enlargement of one adrenal gland on CT or other image of anatomy, or b. Reliefof dinicalandlaboratoryabnormalitiesby removalof adenoma. 4. Bilateral nodular hyperplasia a. Lackof ACTHdependenceasdescribedunderB-2c, and b. Bilateralmorphologicabnormalitiesby 1. CTor otherimageof anatomy,or 2. histologically. 5. Carcinoma

Diagnostic Accuracy and Pitfalls in NP-59 Imaging â€¢Kazerooni et al 527 TABLE2 Criteriafor PrimaryAldosteronism A. Diagnosis of primary Aldosteronism 1. Clinical Hypertension(usuallywithoutedema) 2. Laboratory a. Usualentryevidence Hypokalemla â€”spontaneous,i.e.,in absenceof diuretics,or â€”difficuftto repairbyoralpotassiumwithdiuretics. b. Moredefinitivecriteria 1. Plasma renin value is low and cannot be elevated by upright posture (walking)for 3 hr plus and/or injection of furosernide. 2. Urinaryaldosteroneleveliselevatedandisnotsuppressedby â€”oralsodium, 200 mEoJdfor 3 days, or â€”desoxycorticosteroneinjections. 3. Interpretation â€”b1)plusb 2)makethediagnosisdefinite. â€”Hypertension,hypokalemla,anda low reninvaluein uptightpositionmakethediagnosisprobable. â€”Hypertensionand hypokalemiamake the diagnosis possible. B. Forconfirmationof thetypeof primaryakiosteronism,thefollowingarerequired: 1. Adenoma a. Definitiveevidence 1. Resectionof anadenoma(byhistology),and a. noevidenceofabnormalityinthecontralateraladrenalglandonCT,and b. disappearance of hypertension or least disappearance of hypokalemia. 2. Levelsof aldosteroneIn bloodfromone adrenalveinthat are twentyor moretimeshigherthanthosein bloodfromthe contralateralvein. b. As presumptiveevidenceis:tumorInoneadrenalgland<2.5 cm in diameterwhennooperationhasbeenperformed. 2. Bilateralhyperplasia a. Definite I . Either no abnormality or bilateral enlargement of adrenal glands on CT and decline in blood pressure and repair of hypokalemiaby spironolactonetreatment,or 2. Equal(lessthan two-folddifference)and substantialconcentrationsof aidosteronein bloodfromthe adrenalveinsand decline in blood pressure and repair of hypokalemiaby spironolactonetreatment. b. Possibleor probable:nonoduleor tumoror morethanborderlineandequalenlargementof adrenalglandsby CT. 3. Carcinoma(rarebutwehavecases) Invasionof tissueby tumoras seen a.bysurgeonor b. by pathologistor c. byangiographyor d. by CT(whichmayshowmetastases). of Cushing's syndrome, primary aldosteronism,and hyper Questionnaires asking for information on adverse reactions androgenismask ifthe diseaseis in one or more sites;a single weresent to 126institutions using NP-59 to determine how site usually signifyinga potentially resectable tumor. For many and what types of adversereactionswere experienced euadrenal tumors, the clinical question asks ifthere is evidence between April 1984 and September 1987. Adverse reactions of function in the tumors, the implicationbeingthat a func weredividedinto three groupsaccordingto severity. tioning tumor is more likely to be benign (15). The clinical question ofresidual adrenal tissue asks where the tissue resides. RESULTS If the clinicalquestions were not properly formulated,then the accuracy of the scintigraphicprocedure could not be Accuracy assessed. Therefore, when in retrospect the clinical question Cushing's Syndrome. Twenty-three cases were re was improper because the patient did not clearly have the ferred for the evaluation of Cushing's syndrome, how indicated disease, the case was relegated to a group labeled ever, in five instances clinical and biochemical data Improper Question (Table 4). were insufficient to support the diagnosis. NP-59 scm Twenty randomly selected cases from the University of tigraphy rendered the correct diagnosis in the remaining Michiganand 20 randomlyselectedcasesfrom VictoriaHos 18 cases (100% accuracy) (Tables 4 and 5). pital in London, Ontario were exchanged to determine inter There were 12 cases of bilateral NP-59 adrenal con observer variation in the interpretation ofNP-59 scintigraphic images as unilateral, bilateral, or absent concentration. Three centration consistent with adrenal hyperplasia. Given additional nuclear medicine physicians(AD, GAH, AGM) that seven patients had elevated or nonsuppressible from Victoria Hospital carried out the review.In addition, ACFH levels, the diagnosis ofpituitary ACTH-depend agreementbetween the three Universityof Michiganinter ent Cushing's syndrome was made (2,21,22). These preters was evaluated. patients had pituitary enlargement on CT and became

528 TheJoumal ofNuclearMedicine â€¢Vol. 31 â€¢No. 4 â€¢April1990 TABLE 3 Criteria for Hyperandrogenism A. Diagnosisof vinlization(adultwomen) 1. Clinical a. Notspecificbut almost 1. Hirsutism,morespecificif floridandof few monthsduration 2. Acne b. Morespecificof vinlization(atleastonefeatureshouldbe present) 1. Cliteromegaly 2. Frontalbalding 3. Deepeningvoice c. Onsetoverweeksor few months. 2. Laboratory a. Ovary 1. Plasmatotaltestosterone:>1 ng/mlusually>2 ng/ml;or 2. Freetestosteroneelevationif totaltestosteroneis notelevatedand b. Adrenal (the tumors are usually large) 1. 17-ketosteroids(urine)elevation,and/or 2. DHEA-S(plasma)elevation,and c. LHandFSH.(Plasma)lowlevels. d. Caution 1. Manypatientswith hirsutismdo nothaveanendocrinecausefor hairgrowth,andfew haveandrogen-secretingtumors. Forexamplethe polycysticovariansyndromeusuallyis associatedwith hirsutism,amenorrhea,andmodestelevationin plasmatestosterone(<2ng/ml);ahighLHandlowFSHarealsocommonlyseeninwomenafflictedwiththisdisorder. 2. Adrenalgenitalhyperplasiainadultcasestypicallywillbeassociatedwithclinicalvinlizationandincreased17-ketosteroids excretion. The diagnosis is supported by an elevation in the serum 17-hydroxyprogesteronelevels. 3. Cushing'ssyndromemaybeassociatedwithclinicalvinlization;usuallythereareotherdinicalmanifestationsof Cushing's syndromeandthecriteriaof Cushing'ssyndrome(Table6)wouldbefulfilled. B. Criteriafor determiningsite(s)androgenproduction(tumorin theovarymaybesmall). 1. Probable: a. CTor MRIor ultrasoundevidenceof tumorinovaryor adrenal,or b. Excisedtumorappearingmorphologicallytypicalof anandrogensecretingtumor. 2. Definition a. Levelsof the offendingandrogen in venous effluentof the adrenal gland or the ovary are much higher (>5-fold)than those fromthe contralateralgland, or b. Disappearanceof clinicalandbiochemicalabnormalitiesuponremovalof thetumor. well following pituitary adenoma resection. In the re- Three cases of early unilateral NP-59 concentration maining five cases with bilateral NP-59 concentration were interpreted as Cushing's syndrome secondary to and normal ACTH levels, the diagnosis of primary adrenal adenoma. Following unilateral adrenalectomy, adrenal cortical hyperplasia was made (19,21,22). Four remission of clinical features confirmed the diagnosis ofthese five patients underwent bilateral adrenalectomy (2,21,22). confirming bilateral nodular hyperplasia and a single The final three patients with Cushing's syndrome patient received chemotherapeutic ablation of adrenal demonstrated no concentration of NP-59 in the region hypersecretion with mitotane. All five patients were of either adrenal gland, representing adrenal cortical well on follow-up. carcinoma. Malignant adrenal cortical carcinomas usu

TABLE4 Summary of Cases with Correct Diagnosis of NP-59 correctCushing'ssyndrome23501818100PrimaryDiagnosisNo. casesImproper questionNo proofEvaluatedcasesNo. correct%

071Hyperandrogenism1aldosteronism2767141 08022100Euadrenal tumorst393362775Residual tissue44Hyperestrogenism11.Researchadrenal

cases44Total1082315705786.5%.

applicable.tNot See text.

Diagnostic Accuracy and Pitfalls in NP-59 Imaging â€¢Kazerooni et al 529 5 location of a 0.5-cm left adrenal adenoma, while the Site(s)of HormonTABLEe ExcessSyndromeAdrenalin Cushingâ€˜s remaining two investigators believed that the timing of NP-59Type the images was improper and the study was indetermi concentrationNo.Pituitary7of Cushing'sNo. nate. A right adrenal mass measuring 11x 10x7 cm on Bilateral7Nodular CT demonstrated distorted NP-59 concentration and Bilateral5Adrenalhyperplasia5 was held to be carcinoma, a diagnosis confirmed at Unilateral3Adrenaladenoma3 operation. None3Scintigraphycarcinoma3 Hyperandrogenism. Ten cases of hyperandrogenism correct:1 8/18 or 100% were referred for evaluation. In the two cases meeting the defined criteria (Table 3), the accuracy was 100%. ally do not concentrate NP-59, either because function There was no radiotracer concentration on the side of is low per unit mass or because cholesterol is synthesized a 12-cm right adrenal mass on CT consistent with the de novo in the tumor (15). The excess production of adrenal cortical carcinoma subsequently confirmed at cortisol suppresses ACTH secretion and consequently adrenalectomy (21,22,24). In the second case, there was the function of the contralateral adrenal gland (15,23, NP-59 concentration in the pelvis corresponding to the 24). The tumors were delineated on CT and carcinoma 3-cm left ovarian mass on ultrasound and CT and confirmed at operation. normal adrenal concentration. The interpretation that Primary Aldosteronism. Twenty-seven cases of pri excess androgens arose from an ovarian tumor proved mary aldosteronism were referred for evaluation to be correct when a benign lipoid cell ovarian tumor, (Tables 4 and 6). Six cases with insufficient data to previously described as a cause ofvirilization (26), was support the diagnosis and seven additional cases with resected. out independent proof of the site of excess aldosterone Euadrenal Tumors. Thirty-nine patients were re production were omitted from the review. Accuracy in ferred for the evaluation ofeuadrenal tumors discovered the remaining cases was 10/14 or 71%. incidentally on CT. In two cases euadrenalism was not Only one ofthree cases ofnodular hyperplasia exhib clearly established (21,22), and in a third case with ited bilateral NP-59 concentration (two of three inter normal symmetric NP-59 activity, MRI determined preters) in enlarged adrenal glands containing 1-cm that the 4-cm mass did not involve the adrenal gland, nodules (adrenalectomy). In another case, adrenal size leaving 36 for further study (Tables 4 and 7). The was at the upper limits of normal on CT suggesting a accuracy was 27/36 or 75%. bilateral disorder, but there was no appreciable concen There were 18 cases of asymmetric increased NP-59 tration of NP-59 in the adrenal glands, characteristic of concentration in adrenal tumors measuring 1.7â€”5cm normal dexamethasone suppressed adrenal glands (25). in diameter on CT. Dissent among interpreters occurred In the third case, all three interpreters believed image when a single interpreter believed NP-59 concentration quality was too poor to render a diagnosis. was symmetric in one case. Tissue diagnosis obtained Ten patients had adrenal adenomas (6 left, 4 right), in four cases revealed corresponding unilateral nodular 0.5â€”2.5cm in diameter at resection, except for a single hyperplasia at autopsy and three adenomas at adrenal 0.8-cm adenoma on CT that has not been removed. In ectomy. The remaining patients had no tissue diagnosis, eight cases NP-59 images correctly located the unilateral but were alive and well 2â€”6yr later. site of the excess aldosterone production. However, in NP-59 concentration was decreased or distorted in one patient all three interpreters identified bilateral NP nine euadrenal tumors, six measuring >5 cm in diam 59 concentration, yet a 1x2-cm adenoma was resected eter by CT and/or resection. The other three cases and subsequently all clinical features (21,22) remitted. included a 2-cm adrenal tumor without tissue diagnosis, In another case, one interpreter correctly identified the a 1-cm tumor in a patient with MEN-l syndrome corresponding to nodular hyperplasia at adrenalectomy, and a small adrenal mass without tissue diagnosis in a 6 Site(s) of HormoneTABLEExcessAldosteronismAdrenalin Primary NP-59Type concentrationNo.Nodularof aldosteronismNo. TABLE 7 NP-59 Concentration in Euadrenal Tumors hyperplasia3 Bilateral Scintigraphicpatternintumor 2Adenoma1 Indeterminate1 gland)No.Increased18Decreased(compared to contralateral 0 Unilateral Bilateral 1 1Carcinoma1 Indeterminate8 distorted9Equalor Distortionof glands8Indeterminate1Helpfulin both gland1Scintigraphy one correct:1 0/14 or 71% in defining tumor function:27/36 or 75%.

530 The Journal of Nuclear Medicine â€¢Vol. 3i â€¢No. 4 â€¢April i 990 patient alive and well four years later. The tumors larger from Victoria Hospital agreed that concentration was than 5 cm included a myelolipoma, lymphoma, renal bilateral, and the three interpreters from the University cell carcinoma, ganglioneuroma, adrenal cortical car of Michigan believed it was unilateral; the reason for cinoma and metastatic bronchogenic carcinoma. this remarkable discrepancy is unknown. Unilateral alteration of adrenal gland function could A high level ofconcurrence was found in 95% of the not be detected in the remaining nine cases; in seven of cases studied with unanimous agreement of all six these cases the adrenal masses measured 1â€”4cm on interpreters in 36/40 cases (90%) and high agreement CT. NP-59 concentration was symmetric. There was (5/6) in anothertwo (95%).Of the casesmeetingthe subcutaneous extravasation of NP-59 in one case, and diagnostic criteria for further evaluation at the Univer in another case two interpreters believed NP-59 concen sity of Michigan, there was unanimous agreement by tration was symmetric, while the third believed concen all three interpreters in 66/70 or 94% of the cases tration was decreased on the side opposite a 1.2-cm studied. In the remaining four cases, two of three inter adrenal tumor. In only one of these nine cases was preters agreed. histologic correlation available (solitary cortical ade Safety noma). Eighty-five of 126 medical centers using NP-59 re ResidualAdrenal Glands. In this group of four cases, sponded to the questionnaire. At the University of two patients had known malignancies. In the first case, Michigan, 138 doses were given and a total of729 doses a CT before right adrenalectomy for adrenal carcinoma were evaluated. Adverse reactions were reported for demonstrated a small left adrenal nodule. Postopera eight doses. tively, there was only left adrenal NP-59 concentration, Seven minor reactions (self-limited reactions not re consistent with surgery. In the second case, a left ne quiring treatment) arose in six 2-mCi doses and in a 1- phrectomy was performed 10 yr previously for renal mCi dose. A 21-yr-old female with a history of adverse cell carcinoma and more recently a lobectomy for ad reactions to multiple procedures experienced the single enocarcinoma of the lung. Subsequently, right adrenal intermediate reaction that required treatment. Nausea enlargement was detected on CT and ultrasound. NP and dizziness developed at the end of a slow, 5-mm, 2- 59 concentration was only present on the right suggest mCi NP-59 injection. This was accompanied by flush ing either previous left adrenalectomy during nephrec ing, headache, difficulty breathing, chest and back pain, tomy, a hyperfunctioning right adenoma suppressing a 10â€”20-secloss of consciousness, tachycardia, and the left adrenal, or less likely left adrenal destruction by hypertension (150/1 10). After receiving 25 mg of di disease as no mass in the adrenal bed was seen on CT. phenhydramine hydrochloride orally, her symptoms The patient was alive and well at follow-up 3 yr later. cleared within 1 hr and her vital signs stabilized. Other Another patient without biochemical abnormality ex patients receiving injections from the same batch num hibited bilateral asymmetrically enlarged adrenal glands ber experienced no adverse reactions. No patient had a on CT, with corresponding asymmetric but apparently severe, life-threatening reaction. normal NP-59 concentration (27). In the fourth case, NP-59 concentration was absent despite ACTH stimu DISCUSSION lation in a patient with Addison's disease studied to The accuracy for determining the site of excess hor determine ifthere was any residual functioning adrenal mone secretion by scintigraphy is high, ranging from cortical tissue. 7 1% in the evaluation of primary aldosteronism to Institutional Exchange 100% in Cushing's syndrome, when the correct diag Of the 20 cases from the University of Michigan nostic criteria are met. This high level of accuracy in reviewed at Victoria Hospital, the six' interpreters were locating the site of hormone excess in Cushing's syn in unanimous agreement in 19 cases (95%) regarding drome is of diagnostic value since the site of hormone the sites of NP-59 uptake. In the single case of disagree production in this disorder may be unilateral or bilat ment, five interpreters believed NP-59 concentration eral, and not always detected on CT (19,28). The most was bilateral and one unilateral. In one case with bilat difficulty locating the site of hormone production was eral concentration, all six interpreters questioned the encountered in patients with primary aldosteronism. quality of the images and in another case the images Given the small size of aldosterone producing adeno were of such poor quality that the ability of all inter mas and the availability of sensitive biochemical tests preters to confidently interpret them was impaired. ofthe renin-angiotension-aldosterone axis, this was not Of the 20 cases from Victoria Hospital, there was unexpected. The percentage of correct diagnoses, 71%, complete agreement in 17 cases. In one case, five of six is less than previously reported (4,5,10,29â€”31), perhaps, interpreters believed the concentration was bilateral. In because the cases reviewed represented all stages of another case, four interpreters believed concentration aldosteronism. Additionally, this may reflect changing was bilateral, one unilateral and one indeterminate due referral patterns in which the most difficult and confus to image quality. In the third case, all three interpreters ing cases are sent for scintigraphy.

Diagnostic Accuracy and Pitfalls in NP-59 Imaging â€¢Kazerooni et al 531 Experience interpreting NP-59 scintigraphy in hyper to exclude hormone excess. Similarly, if the clinical androgenism is limited (11â€”14)and cases were too few usefulness of NP-59 scintigraphy has not been estab to draw a firm conclusion. Given good cross-sectional lished, as in the case of hyperandrogenism, particularly radiographic imaging and biochemical studies, other polycystic ovarian disease (32), then NP-59 scintigra investigators have suggested NP-59 scintigraphy has phy could not be diagnostically efficacious. Concern for potential in evaluating hyperandrogenism, and possibly focused clinical questions led to the development of in ovarian disorders, particularly when the site of excess diagnostic criteria from standard texts (21,22) to guide hormone production is small, such as hyperthecosis the clinical question regarding the site(s) of excess cor and in functional, nontumorous abnormalities (32). tisol, aldosterone or androgen production. The criteria Scintigraphy successfully characterized 27 of 36 eu for scintigraphy to evaluate euadrenal tumors are more adrenal tumors into functioning or nonfunctioning tu easily defined as clear evidence of an adrenal tumor mors. Unlike categories with hormonal disturbance, the using radiographic images (CT, ultrasound, MRI) and indications for biopsy or excision in these cases was the absence of excessive hormone secretion from both uncommon and histologic proofwas frequently absent. the adrenal cortex and medulla by clinical and biochem NP-59 appears useful in distinguishing benign from ical data. Still, unless the hormonal status is clear, even malignant euadrenal tumors using the concept that the diagnosis of euadrenal tumor cannot be made with functioning, NP-59 concentrating adrenal cortical tu confidence. mors are benign, while nonfunctioning tumors are more In 23 patients undergoing NP-59 scintigraphy in this worrisome and possibly malignant (15). Malignancy study, the clinical question was improper and no diag was common among the nine nonfunctioning tumors, nostic interpretation of images was possible. For ex particularly those >5 cm in diameter (100%). The ample, in cases referred for the evaluation of euadrenal nonfunctioning euadrenal tumors classified as benign tumors, ifthere was insufficient clinical data to support were all <5 cm in diameter, supporting previous pro or exclude the diagnosis of Cushing's syndrome (21, posals that euadrenal tumors <5 cm in diameter on CT 22), the scintigraphic pattern of unilateral left adrenal images can be treated as benign (33,34). While it is activity could be interpreted as either a Cushing's ade possible that functioning tumors larger than 5 cm will noma (Fig. 1) or euadrenal tumor (Fig. 2). Therefore, be found to be benign, and nonfunctioning tumors <5 clinical and biochemical information are essential to cm will be malignant, this number will probably be few. proper interpretation. In the majority of cases referred Not infrequently, euadrenal tumors are associated with for the evaluation of hyperandrogenism, 8 of 10 had relative suppression of the contralateral adrenal gland testosterone levels <1 .8 ng/dl. Each was thought to function (1 7). NP-59 can provide useful information in such cases, because if the functioning tumor is re moved, peri-operative corticosteroid replacement may be needed until function of the contralateral gland resumes. In the final group of four assorted cases, help was requested for varying questions, but the small number makes it difficult to draw conclusions. Occasionally, surgeons must know if the adrenal glands remain when additional surgery near the adrenal bed is planned. NP 59 should be helpful in such cases, especially if previous surgical intervention or disease obscures anatomy on CT and MRI (18). There appears to be little difficulty in reproducibly interpreting NP-59 scintigraphic images, when image quality is sufficient. Independent interpretations of NP 59 images at two different institutions showed remark able levels of agreement. Nevertheless, two particular pitfalls of NP-59 scintig raphy were recognized. These differ from the pitfalls that apply to nuclear medicine imaging in general such as subcutaneous injection of radiotracer. The greatest pitfall occurred when the clinical question was not FIGURE1 UnilateralintenseNP-59concentrationin the left adrenalgland clearly and fully stated. That is, when there was insuf with suppressionof contralateraladrenal gland uptake in a ficient clinical and biochemical data to support a state left adrenalCushing'sadenoma;imageon day 5 after injection of hormone excess, or in the case of euadrenal tumors, of NP-59.

532 TheJournalof NuclearMedicineâ€¢Vol.31 â€¢No.4 â€¢April1990 the detection of aldosteronomas (usually <1 cm) and nodular hyperplasia, and less for Cushing's adenomas (usually >2 cm) (28). Beyond this, NP-59 scintigraphy can detect functional abnormalities below the spatial resolution of CT and MRI, especially tiny aldosteron omas or functional hyperplasia in normal-sized adrenal glands, and therefore has an important role in the evaluation of adrenal cortical abnormality.

CONCLUSIONS In any procedure, care must be taken, but especially with NP-59 scintigraphy, interpretation is dependent on the formulation ofthe proper clinical question based on thorough clinical and biochemical evaluation. Given adequate clinical, biochemical, and radiographic infor mation; reproducible image interpretation; and the safety of [iodine-13 l]6-beta-iodomethyl-l9-norcholes terol, NP-59 scintigraphy is an excellent modality for determining the site(s) and nature of adrenal cortical and perhaps ovarian abnormalities. FIGURE2 Functioning left euadrenal tumor in a patient without detecta ble clinicalor biochemicalevidenceof hormonehypersecre ACKNOWLEDGMENTS tion; there is little differencein the appearanceof this image from Figure1. This research was directly supported by FDA grant #FD R-000130 and by a previousCRC grant. The authors thank Karen Grahl for her expert assistance in have a functional disorder such as polycystic ovarian the preparation of this manuscriptand the many physicians disease, a diagnosis made with clinical and biochemical who referred their patients for evaluation. Additional thanks data. to T. Mangner, PhD and the Phoenix Memorial Laboratory The second pitfall of NP-59 scintigraphy was the for the synthesis of NP-59 and the use of their radiochemical facilities. patient preparation prior to the study. In the evaluation of all patients, the major steps in preparation include a laxative to reduce NP-59 activity in the colon (35), the REFERENCES injection ofthe correct radiotracer dose, and the sched 1. Sarkar SD, Beierwaltes WH, Ice RD. et al. A new and superior uling of images over a sufficient number of days to adrenal scanning agent, NP-59. J Nuci Med 1975; 16:1038â€” obtain adequate images of the adrenal glands. When 1042. imaging for primary aldosteronism, images must be 2. MosesDC, SchteingartDE, SturmanMF, BeierwaltesWH. scheduled to observe the earliest appearance of adrenal Efficacyof radiocholesterolimaging of the adrenal glands in Cushing's Syndrome. Surg Gynecol Obsiet 1974; 139:1â€”4. radioactivity (5), as early unilateral concentration sug 3. Barbarino A, DE-Maninis L, Liberale I, Menini E. Evaluation gests the presence of a functioning adrenal adenoma. of steroid laboratory tests and adrenal gland imaging with In addition, it is essential that dexamethasone be given radiocholesterolin the etiologicaldiagnosisofCushing's Syn for a week prior to injection and during imaging to drome. C/in Endocrino/ 1979; 10:107â€”121. reduce the function of the normal cortisol-producing 4. FreitasJE,GrekinRJ,ThrallJH,GrossMD. Adrenalimaging with iodomethylnorcholesterol (1-131) in primary aldoster adrenal cortical tissue. onism. JNuc/Med 1979;20:7â€”10. NP-59 scintigraphy is a useful modality to function 5. GrossMD, ShapiroB, GrekinRi, et al.Scintigraphiclocal ally characterize adrenal abnormalities detected with ization of adrenal lesions in primary aldosteronism. Am J cross-sectional radiographic imaging and is useful to Med 1984;77:839â€”844. determine the functional (benign) or nonfunctional (po 6. GrossMD, Valk TW, SwansonDP, Thrall JH, Grekin Ri, Beierwaltes WH. The role of pharmacologic manipulation in tentially malignant) nature of adrenal masses detected adrenal cortical scintigraphy. Semin Nuc/Med 1981; 11:128â€” incidentally. While CT and MRI have comparable sen 148. sitivities in detecting lesions >1â€”1.5 cm, CT may be 7. Conn JW, BeierwaltesWH, Lieberman LM, et al. Primary superior to MRI in detecting lesions <1 cm. While this aldosteronism: pre-operative tumor visualization by scintil may improve with the application of newer technology, lationscanning.Endocrinology1971;89:713â€”716. 8. Rifai A, Beierwaltes WH, Freitas JE, Grekin Ri. Adrenal given this and the inability of MRI to characterize scintigraphy in low renin hypertension. C/in Nuc/Med 1978; adrenal function, CT is perhaps a better study for 7:282â€”286. delineation ofmorphologic abnormalities, especially for 9. Conn JW, Monte R, Cohen EL, Beierwaltes WH, McDonald

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534 The Journal of Nuclear Medicine â€¢Vol. 31 â€¢No. 4 â€¢April 1990