European Journal of Nuclear Medicine
Scintigraphy of incidentally discovered bilateral adrenal masses
Milton D. Gross1, Brahm Shapiro1, Isaac R. Francis2, Robert L. Bree2, Melvyn Korobkin2, Michael K. McLeod2, Norman W. Thompson3, Jeffrey A. Sanfield4
1 Department of Internal Medicine (Division of Nuclear Medicine), The University of Michigan and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
2 Department of Radiology, The University of Michigan and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
3 Department of Surgery, The University of Michigan and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
4 The Catherine McAuley Health Center, Ann Arbor, Michigan, USA
Received 9 October and in revised form 28 November 1994
Abstract. The purpose of this study was to determine the patterns of iodine-131 6ß-iodomethylnorcholesterol (NP-59) imaging and the correlation with computed to- mography (CT)-guided adrenal biopsy and follow-up in patients with bilateral adrenal masses. To this end we in- vestigated a consecutive sample of 29 euadrenal patients with bilateral adrenal masses discovered on CT for rea- sons other than suspected adrenal disease. Adrenal scin- tigraphy was performed using 1 mCi of NP-59 injected intravenously, with gamma camera imaging 5-7 days la- ter. In 13 of the 29 patients bilateral adrenal masses were the result of metastatic involvement from lung carcino- ma (5), lymphoma (3), adrenocarcinoma of the colon (3), squamous cell carcinoma of the larynx (1), and ana- plastic carcinoma of unknown primary (1). Among these cases the NP-59 scan demonstrated either bilaterally ab- sent tracer accumulation (in eight, all with bilateral me- tastases proven by CT-guided biopsy or progression on follow-up CT) or marked asymmetry of adrenocortical NP-59 uptake (in five). Biopsy of the adrenal demon- strating the least NP-59 uptake documented malignant involvement of that gland in five of five patients. In two patients an adenoma was found simultaneously in one adrenal with a contralateral malignant adrenal mass. In each of these cases, the adenoma demonstrated the greatest NP-59 uptake. In 16 patients diagnosis of ade- noma was made on the basis of (a) CT-guided adrenal biopsy of the gland with the greatest NP-59 uptake of the pair (n=4), or (b) adrenalectomy (n=2), or (c) ab- sence of change in the size of the adrenal mass on fol- low-up CT scanning performed 6 months to 3 years later (n=10). It is concluded that differential in vivo function- al information provided by NP-59 scintigraphy comple- ments that derived from anatomic imaging and can be used in patients with bilateral adrenal masses to select which gland would be the best choice for further diag-
nostic invasive evaluation (e.g., adrenal biopsy) or may suggest the presence of bilateral adrenal metastases in patients with incidentally discovered, bilateral adrenal masses.
Key words: Adrenal - Iodine-131 6ß-iodomethylnorcho- lesterol - Neoplasm
Eur J Nucl Med (1995) 22:315-321
Introduction
The unexpected finding of a unilateral adrenal mass on computed tomography (CT) in a patient studied for rea- sons other than suspected adrenal dysfunction is not an uncommon occurrence in our sophisticated high-resolu- tion, anatomical imaging environment [1-3]. The major- ity of these incidentally discovered masses or “inciden- talomas” are benign, even in patients with known nonad- renal malignancies, despite the relatively high predilec- tion for the adrenal as a site of metastasis of some tu- mors (e.g., lung and breast) [3-6]. Once their hormonal secretory status has been elucidated, further diagnostic attention must be paid to these masses to distinguish ad- renal adenoma from metastasis [6-8].
In contrast, incidentally discovered bilateral adrenal masses are much less common. The diagnostic problems posed by bilateral adrenal masses have not been evaluat- ed in large series, but have been noted anecdotally. In this report, we examine a subset of patients (29 of a total of 258) with incidentally discovered adrenal masses studied in our laboratory over a 16-year period. In previ- ous reports we have documented the useful role of adre- nocortical scintigraphy in depicting function of the uni- lateral, incidentally discovered, adrenal mass [4, 6, 9-11]. This report expands the use of iodine-131 6ß- iodomethylnorcholesterol (NP-59) to the evaluation of patients with incidentally discovered, bilateral adrenal masses.
| Imaging pattern | Lesion diameter (±SD) | Diagnosis | |
|---|---|---|---|
| Left (range) | Right (range) | ||
| Bilateral | 2.6±1.5 cm | 2.2±1.5 cm | Adenoma (8)a |
| symmetric visualization (8) | (2-5 cm) | (2-5 cm) | |
| Bilateral | 2.4±1.4 cm | 2.9±1.4 cm | Adenoma (8)b Carcinomac Colon (2)d Lung (2)d Larynx (1) |
| asymmetric visualization (13) | (1-5 cm) | (1-5 cm) | |
| Bilateral nonvisualization (8) | 4.4±1.6 cm (2-7 cm) | 5.6±1.7 cm (3.5-10 cm) | Carcinomae Lung (3) Lymphoma (3) Colon (1) Anaplastic (1) |
a Proven by no change in CT contour≥6 months in seven cases, and by CT-guided bilateral biopsy in one
b Proven by CT-guided adrenal biopsy in five cases (mass with increased NP-59 uptake) and by no change in CT contour in>6 months in three
c Proven by CT-guided adrenal biopsy (mass with decreased NP-59 uptake) in three cases and by bilateral biopsy in two
d One patient with an adrenal adenoma and a coexistent contralateral adrenal metastasis
e Proven by CT-guided adrenal biopsy of largest mass in three cases and by bilateral biop- sy in four, and all with CT evidence of progression
Materials and methods
Between January 1976 and January 1992, 258 patients with adre- nal masses discovered incidentally during CT examinations of the abdomen or chest performed for reasons other than clinically sus- pected adrenal disease were studied with NP-59 scintigraphy. Twenty-nine of the 258 patients had bilateral adrenal masses. CT was initially performed on an EMI-5005, and later on a Picker 1200SX at the VA Medical Center, Ann Arbor, and GE-8800 or GE-9800 scanners at the University of Michigan Medical Center. Contiguous 5- to 10-mm sections on the newer scanners were ob- tained after intravenous (IV) and/or oral radiographic contrast ad- ministration. Adrenal biopsies were performed either at or within 1 week of the time of the initial CT and were done before NP-59 scintigraphy.
All patients referred for NP-59 scintigraphy gave their written informed consent for the study, which was approved by each hos- pital’s Institutional Review Board for Human Experimentation. One mCi of NP-59 was injected IV and was followed by posterior, anterior, and lateral abdominal scans (50000 counts per image) performed on days 5 and/or 7 after injection [12]. Saturated potas- sium iodide solution, 1 drop, was administered thrice daily, 24 h prior to and throughout the imaging sequence to suppress thyroi- dal uptake of free 131I. A mild laxative (bisacodyl) was also given, 10 mg, twice daily, to most patients beginning 2 days before the 1st day of planned imaging to reduce potentially interfering colon- ic 131I radioactivity [13].
In each patient various combinations of blood and urine bio- chemical measurements were obtained the exclude the presence of adrenal cortical or medullary dysfunction. These included in most cases, normal plasma levels of cortisol, renin activity, aldosterone, epinephrine, norephinephrine, urinary 17-hydroxycorticosteroids, 17-ketosteroids, and vanillymandelic acid, and normal cortisol re-
sponses to dexamethasone and in some cases adrenocorticotro- phin (ACTH) administration. All medications that might interfere with either the scintigraphic or the biochemical studies were stopped prior to study. One of these 29 cases has been included in a study of scintigraphy in adrenal masses [9], and magnetic reso- nance imaging (MRI) of 10 of the 29 has been previously report- ed [14, 15].
The relationship of relative NP-59 uptake between the adrenals was assessed qualitatively. Under these circumstances evaluation was more difficult than with unilateral lesions as there was no morphologically normal adrenal in which the level of NP-59 up- take might be considered “normal” [10, 11]. Thus, in patients with CT-demonstrated bilateral adrenal masses, the presence of identi- fiable adrenal NP-59 uptake that visually approximated or exceed- ed that of the contralateral adrenal and/or liver (a tissue that accu- mulates NP-59) was considered compatible with a benign process (e.g., an adenoma), while markedly decreased or absent NP-59 uptake as compared to the contralateral adrenal and/or liver was considered abnormal and compatible with a destructive space-oc- cupying or malignant adrenal mass. Bilaterally symmetric NP-59 uptake (within the limits of the normal and previously established degree of adrenal asymmetry) was considered normal [16]. Statis- tical analyses were performed using Student’s t test [17].
Results
All 29 patients had bilateral adrenal masses on CT. The clinical indications for CT were a search for metastases in 17, abdominal pain in nine, and ascites, renal failure, and pneumonia in one case each. The mean lesion diam- eter was 3.3±1.4 cm (range: 1-7 cm) on the right, and
3.4±1.5 cm (range: 1-10 cm) on the left (P=ns) (Table 1). CT-guided adrenal biopsies were performed in 19 of the 29 patients. Unilateral adrenal biopsy was performed in 12 of 19 patients while bilateral adrenal biopsies were done in the remaining seven. Adrenal biopsy was per- formed as part of a research protocol during the interval from 1985 to 1988 [14, 15] while biopsies performed be- fore 1985 and after 1988 were done as deemed neces- sary for clinical diagnostic purposes. All biopsies were done at the time of initial CT or shortly thereafter. Bilat- eral adrenal biopsies were performed when considered feasible, based upon the clinical status of the patient, ac- cessibility of both masses for biopsy, and the degree of
clinical suspicion of metastasis to the adrenals. When unilateral biopsies were performed, the larger of the two masses was usually selected for biopsy. Metastases were eventually determined to be present in 13 patients: lung carcinoma in five, lymphoma in three, adenocarcinoma of the colon in three, laryngeal carcinoma in one, and anaplastic carcinoma of unknown origin in one. In 16 cases an eventual diagnosis of adenoma was made by adrenal biopsy in four, by unilateral adrenalectomy in two, and by unchanged findings on repeat CT scans per- formed at 6 months to 3 years after the initial CT exami- nation in the remaining 12 (including the two cases in which unilateral adrenalectomy was performed).
Variable patterns of NP-59 uptake were observed in the 29 patients with bilateral adrenal masses (Table 1). Bilateral nonvisualization was observed in eight patients in whom CT-guided adrenal biopsy confirmed metastatic involvement in one or both glands, and with progression on follow-up CT (Fig. 1). CT-guided adrenal biopsy per- formed in five of eight patients with asymmetric NP-59 uptake demonstrated that those adrenals with the great- est NP-59 accumulation of the pair (adrenal cortical up- take exceeding the contralateral adrenal or equal to liver) had benign cytology compatible with adenoma. The re- maining three cases showed no change in adrenal con- tour over at least a 6-month follow-up period. Alterna- tively, CT-guided adrenal biopsy of masses exhibiting marked asymmetry of NP-59 uptake were the biopsy was directed to the gland exhibiting the least NP-59 up- take of the pair (less than the contralateral adrenal and/or liver) revealed metastatic disease on cytology in five of five patients (Table 1).
In two patients with markedly asymmetric NP-59 up- take, an adenoma in one adrenal was found to coexist with a contralateral metastatic deposit (lung and colon carcinoma, respectively) (Fig. 2), while of the remaining eight patients, all with bilaterally symmetric NP-59 up- take, seven had no change in adrenal contour over at least a 6-month follow-up period (Table 1). The remain- ing patient with bilateral 2-cm-diameter adrenal masses, had CT-guided biopsy evidence of adenoma (Fig. 3).
Discussion
Although a far less common problem, the clinical dilem- ma posed by incidentally discovered bilateral adrenal masses is not unlike that of the unilateral adrenal mass. Diagnosis is first dependent upon a hormonal evaluation sufficient to exclude either a hypersecretory state from bilateral adrenal sources or adrenal insufficiency due to complete destruction of the adrenal cortex [1, 2, 18]. Ad- renal gland dysfunction with bilateral masses has been observed in primary aldosteronism [19], hypercortiso- lism due to either bilateral adenoma [20] or bilateral cor- tical nodular hyperplasia [21], congenital adrenal hyper- plasia [22], pheochromocytoma particularly in the multi- ple endocrine neoplasia syndromes 2A and 2B [23, 24], and neuroblastoma [25]. Adrenocortical hypofunction with bilateral masses has been reported in tuberculosis [26], fungal diseases [27], bilateral adrenal hemorrhage [28], and rarely adrenal destruction from bilateral, pri- mary adrenal neoplasms [29, 30] or as a result of bilater- al metastases to the adrenals [31, 32]. The commonest sources of metastases to the adrenal are from lung carci- noma (bronchogenic) followed by breast, thyroid, and renal carcinoma, melanoma, and non-Hodgkin’s lym- phoma [31, 32]. In patients with underlying malignancy, adrenal metastases are usually noted in the presence of extensive metastatic disease to other sites (e.g., liver, bone, and lymph nodes). In this setting adrenal masses do not constitute a major diagnostic or therapeutic prob-
lem. However, when a patient has a known primary ma- lignancy and adrenal masses and no other evidence of metastases, the presence of adrenal masses raises critical issues of tumor staging and further management.
Both CT and MRI have been used to identify bilateral adrenal masses and distinguish benign from malignant neoplastic involvement [2, 3, 15, 33-35]. Characteristic patterns of imaging seen on CT have demonstrated high sensitivity and specificity [33, 36, 37]. Recently devel- oped MRI pulse sequences have been used to distinguish benign from malignant masses in some patients [38, 39]. However, up to one-third of adrenal masses may not be correctly characterized by CT or MRI [2, 14, 15, 40]. Many series of incidentally discovered adrenal lesions report a small number of patients who present on CT (or MRI) with incidentally discovered bilateral adrenal masses. These series have generally considered each of the neoplasms as separate lesions and interpretative at- tention has been placed upon an analysis of “individual” masses according to diagnostic criteria versus normal. There has not been a detailed comparison of one side versus the other with respect to anatomic and functional characteristics. Scintigraphic evaluations use the accu- mulation of radiocholesterol as an in vivo marker of dif- ferential adrenal cortical function. Thus, a reduction in or absence of adrenal 131I-NP-59 uptake in non-dexa- methasone-suppressed patients suggests adrenal gland replacement or destruction due to involvement with neo- plasm or other space-occupying lesions [2, 4, 10, 11].
A nonexhaustive, but representative review of the lit- erature published between 1981 and 1994 notes 632 cases of adrenal masses of which 108 (17%) were bilat- eral [5-8, 14, 33, 35, 37, 39-49] (Table 2). Of those pa- tients with bilateral adrenal masses in whom data were available that distinguished benign from malignant masses, 52% had malignant involvement of the adrenals. In the present series, 29 of 258 (11%) had incidentally discovered bilateral adrenal masses, and 13 of the 29 (45%) had metastatic disease to one (2 of 13) or both (11 of 13) adrenals. Bilateral benign masses were noted in 16 of the 29 patients (55%) despite the fact that 17 (59%) had a preexisting malignancy. Thus, in our series it is slightly more likely that a patient presenting with bi- lateral adrenal masses would have bilateral benign rather than malignant adrenal involvement, even in the pres- ence of a preexisting malignancy elsewhere. Our data may differ from the published literature as a result of re- ferral bias, as we considered only those cases of truly in- cidental and nonhypersecretory adrenal masses.
More intriguing is the simultaneous presence of a be- nign non-hypersecreting adenoma and a contralateral ad- renal metastasis, a phenomenon that has been previously reported [41, 45] and was documented in two cases in our series. Furthermore, multiple metastases to one gland [45] and an unusual case of a metastasis to an ad- renal adenoma have also been noted [50]. There are also reports of bilateral adrenal masses in which one adrenal lesion was hypersecreting (e.g., aldosteronoma) while the
| Authors | Year | Total cases | Bilateral | Benign | Malignant |
|---|---|---|---|---|---|
| Cedarmark and Ohlsen | 1981 | 5a | 2 | 0 | 2d |
| Zornoza et al. | 1981 | 21ª | 2b | - | - |
| Heaston et al. | 1982 | 14c | 2 | 1 | 1 |
| Berkman et al. | 1984 | 16 | 2b | - | |
| Oliver et al. | 1984 | 32 | 6 | 4 | 2 |
| Hussain et al. | 1985 | 43ª | 5 | 2 | 3 |
| Abecasis et al. | 1985 | 21 | 2 | 2 | 0 |
| Katz and Shirkhoda | 1985 | 16c | 7 | 3 | 4 |
| Belldegrun et al. | 1986 | 38ª | 6 | 3 | 3d |
| Hussain et al. | 1986 | 57 | 6 | 0 | 6 |
| Glazer et al. | 1986 | 28a | 5 | 2 | 3 |
| Doppman et al. | 1987 | 81ª | 13b | - | |
| Berland et al. | 1988 | 44e | 7b,f | - | - |
| Reincke et al. | 1989 | 32ª | 8b | - | - |
| Krestin et al. | 1989 | 25ª | 4 | 2 | 2 |
| Virkkala et al. | 1989 | 20 | 2 | 2g | 0 |
| Khafagi et al. | 1991 | 45h | 6 | 0 | 6 |
| Jockenhovel et al. | 1992 | 36ª | 4b | - | |
| Reinig et al. | 1994 | 53a | 7b | - | - |
| Haab et al. | 1994 | 12a | 12 | 10 | 2 |
| Total | 632 | 108 (17%) | 31 (48%) | 34 (52%) |
a Series with hypersecreting and nonhypersecreting adrenal masses
b Did not distinguish bilateral benign from bilateral malignant masses
c Patients with known preexisting malignancy
d Patient with coexisting ipsilateral benign and contralateral adrenal metastasis
e Masses all <5 cm in diameter
f Either bilateral benign or bilateral malignant masses
& Patient with nonsuppressible urinary cortisol metabolites
h Masses all ≥5 cm in diameter
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.
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0
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Adenoma/ Adenoma
Adenoma/ Metastasis
Metastasis/ Metastasis
other was a nonhypersecreting adenoma [51, 52]. Per- haps, a slowly expanding intra-adrenal metastasis, a less aggressive primary malignancy, or a nonglucocorticoid hypersecreting neoplasm would allow the development of compensatory hyperplasia leading to a functioning, but not hypersecretory, contralateral adrenal mass [53].
Recommendations for further diagnostic evaluations based upon the size of an adrenal mass alone may be misleading. Thus, in a patient with bilateral masses and a preexisting cancer, biopsy of the larger of the two masses may not invariably disclose the presence of ma- lignancy. In the current series, 2 of 29 patients (2 of 13 with asymmetric NP-59 uptake) had an adenoma and a contralateral metastasis where the malignant mass was smaller (2 and 3 cm versus 3 and 4 cm, respectively) than the benign adenoma. As a group the sizes of the malignant masses were not significantly greater than the sizes of those that were benign (Fig. 4). Further, in two reports of patients with primay aldosteronism and bilat- eral adrenal masses the smaller of the two masses was later proven to be an aldosterone-secreting adenoma while the larger mass was a nonhypersecretory adenoma [51, 52].
The scintigraphic evaluation of bilateral incidentally
discovered adrenal masses represents a far more difficult problem than for unilateral lesions as the present inter- pretative algorithm depends upon the presence of an an- atomically normal contralateral adrenal gland (by CT criteria) for comparison [10]. Accumulation of NP-59 that approaches or exceeds that of liver, a tissue that ac- cumulates NP-59, and bilateral but asymmetric NP-59 uptake (that exceeds normal adrenal asymmetry) may be useful in guiding further invasive evaluation. In six cases (including the adenomas in the two patients with coexis- tent contralateral malignant masses) biopsy and in two cases adrenalectomy of the most prominent adrenal (that gland with the most NP-59 uptake as assessed visually) were benign, while biopsy of the adrenal mass with the least NP-59 uptake of the pair disclosed adrenal metas- tases in five cases. While these numbers are small, the results of NP-59 imaging in bilateral adrenal masses suggests that further studies (e.g., adrenal biopsy) would be best directed toward the adrenal mass with the least iodocholesterol uptake, since in a patient with a known malignancy it usually matters little to further diagnostic evaluation and therapy whether one or both glands are affected. Bilateral masses on CT with bilateral nonvisu- alization of the adrenals on NP-59 scintigraphy was pre- dictive of bilateral metastases in eight of eight patients. It was perhaps not surprising that this group had the largest adrenal masses (Table 1). The scintiscan depicts adrenal cortical effacement by neoplasm, a pattern of imaging that has been previously described [2, 6, 10, 11, 54]. In some cases, exogenous hormone therapy to pro- tect against the development of adrenocortical insuffi- ciency may be contemplated if both adrenals are re- placed by a metastatic or other infiltrative processes [28-31]. It is, however, unusual for patients to present with adrenal cortical insufficiency from bilateral adrenal metastases since more than 90% of the adrenal must be replaced before cortical hypofunction becomes clinically apparent [30, 31].
Scintigraphy of bilateral adrenal masses may provide unique, non-invasive information regarding relative dif- ferential adrenal function that can be used to identify le- sions requiring further diagnostic evaluation [5]. The da- ta available to date document that adrenal masses, and especially bilateral adrenal masses, are of heterogeneous etiology. With respect to our series of incidentally dis- covered bilateral adrenal masses, the following conclu- sions seem most appropriate:
1. Bilateral masses in patients with malignancies appear to be slightly more likely to be adenomas than metastases. 2. Although the larger the mass the greater the likelihood of malignancy, size remains a poor discriminator of ma- lignancy in patients with bilateral adrenal masses in the 2-5 cm range.
3. Although the situation is uncommon, an adrenal ade- noma and a contralateral adrenal malignancy can coexist. 4. NP-59 may be used to functionally characterize bilat- eral (and unilateral) adrenal neoplasms and as a means to select masses for further diagnostic evaluation(s).
Acknowledgements. The authors thank Thomas Mangner, PhD, and Clarke Hagen for the synthesis of NP-59; the Phoenix Memo- rial Laboratories for the use of their radiochemistry facilities; Shirley Zempel, RN, for assistance with patient care and data management, and Mary Beth Linn and Elizabeth Hazel for secre- tarial assistance.
This work was partially supported by grants RO1-CA-43300-01, NCI CA09015, NIAMDD RO1-AM2147702 RAD, and GCRC- HEW 3 M01RR-0042-21SI CLR from the National Institutes of Health; and the Department of Veterans Affairs Research Service and the Nuclear Medicine Research Fund of The Division of Nu- clear Medicine, The University of Michigan.
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