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Original Studies |
Divisions of Endocrinology (L.B., C.S., N.S., F.F., M.B.) and Nuclear Medicine (M.G., C.M.), University of Padova, Padova, Italy
Address all correspondence and requests for reprints to: Luisa Barzon, M.D., Division of Endocrinology, University of Padova, Via Ospedale 105, 35128 Padova, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From 1986, 202 consecutive patients (mean age, 55 ± 1 yr; range, 14–77 yr) with adrenal masses discovered incidentally by abdominal ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) were evaluated at our institution. There were 119 females (mean age, 54 ± 1 yr; range, 14–77) and 83 males (mean age, 56 ± 1.5 yr; range, 18–77; P = NS). Morphological examinations were set up for extraadrenal complaints, i.e. nonspecific abdominal pain (29%), check-up study (21%), hepato-cholecystopathy (12%), follow-up after abdominal surgery (11%), lumbar pain (7%), and nephropathy (5%). A mass was considered an incidentaloma when there was no history or physical finding that would suggest an adrenal functional disorder or mass. Patients suffering from severe hypertension or hypertensive crises or with hypokalemia, clinical signs suggestive of hypercortisolism and/or hyperandrogenism, or previous or concurrent malignancies were not included.
Surgical adrenalectomy was performed in 88 patients (44%).
Histological diagnosis of adrenocortical carcinoma was based on the
criteria reported by Weiss et al. (14). The criteria for
operation were mass diameter greater than 4 cm or increase in mass
size, imaging characteristics suggestive of malignancy, decreased
radiocholesterol uptake at scintiscan, abnormal hormonal function, and
willingness of the patient. In selected cases surgery was not performed
because it was refused by the patient or was excluded for age or
extensive metastases. Long term clinical, biochemical, and
morphological follow-up was performed in the remaining 114 (56%)
patients. The mean radiological follow-up period was 3.5 yr (range, 8
months to 10 yr). Incidentalomas were classified according to
morphological evaluation in unilateral (groups 1 and 2) and bilateral
(groups 3 and 4) lesions and according to endocrine evaluation in
normally functioning (groups 1 and 3) and abnormally functioning
(groups 2 and 4) adrenals (Table 1
).
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Endocrine evaluation consisted of baseline measurements of plasma cortisol at 0800 and 1800 h, morning ACTH, dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), supine and upright PRA and aldosterone, 24-h urinary free cortisol (UFC), 24-h urinary aldosterone (18-glucoronide), and 24-h urinary catecholamines and/or metanephrines. Dynamic tests included 1) the overnight, low dose dexamethasone (dex) suppression test (1 mg, orally, at 2300 h) and determination of plasma cortisol at 0800 h on the following day (a normal test was defined by a cortisol value <140 nmol/L) (15); 2) determination of cortisol and 17-OHP at baseline and 60 min after ACTH (Synacthen, Ciba, Basel, Switzerland; 0.25 mg as an iv bolus; an exaggerated response was assumed when the ACTH-stimulated 17-OHP levels exceeded 30 nmol/L) (16); adequate adrenal glucocorticoid release was defined with a peak cortisol concentration above 550 nmol/L; and 3) an ovine CRH stimulation test (Novabiochem, Laufelfingen, Switzerland; 100 µg as an iv bolus at 0900 h) with measurements of ACTH and cortisol at -15, 0, 15, 30, 45, 60, 90, and 120 min (performed in 42 patients). Plasma ACTH and cortisol responses to CRH were considered normal when their net increases above baseline value, which was calculated as the mean of the levels recorded at -15 and 0 min, were greater than 4.4 pmol/L and 200 nmol/L, respectively.
Nonclinical hypercortisolism was defined as the absence of overt signs and symptoms of hypercortisolism, the presence of cortisol levels not adequately suppressed by 1 mg overnight dex, and at least another impaired endocrine test (plasma cortisol rhythm, UFC, and baseline ACTH). The finding of an elevated plasma aldosterone (nanograms per dL)/PRA (nanograms per mL/h) ratio (>50) was considered diagnostic of primary aldosteronism (17). Adrenal medulla was considered hyperfunctioning when catecholamine and/or metanephrine levels were elevated in at least two different evaluations.
Imaging evaluation
Abdominal CT was performed in all cases, and CT-guided
fine needle aspiration biopsy (FNAB) was performed in 23 patients
(11%). Abdominal MRI was performed in 58 patients. Adrenal scintiscan
was performed in 136 patients (67%) using 11–14 megabecquerels
[75Se]selenio-6
-methyl-19-norcholesterol (Scintadren,
Amersham, The Netherlands). Images were obtained on days 4–7 after
tracer injection, using a large field of view, 0.5-in. crystal gamma
camera equipped with a high energy, parallel hole collimator interfaced
to a digital computer (Elscint SP1, Haifa, Israel). Scintiscan
evaluation was based on the criteria of Gross et al. (11, 12), defining the following uptake patterns. The uptake patterns in
unilateral incidentalomas were 1) tumor uptake with no visualization of
the contralateral gland (exclusive uptake), 2) prevalent uptake by the
tumor with visualization of the contralateral gland (prevalent uptake),
3) bilateral symmetric uptake (symmetric uptake), and 4) reduced or
absent uptake by the tumor (discordant uptake). Exclusive and prevalent
uptake patterns were considered concordant uptake (Table 2). The
uptake patterns in bilateral incidentalomas were 1) bilateral
symmetric uptake, 2) bilateral asymmetric uptake, and 3) bilateral
nonvisualization. Medullary scintigraphy with
[123I]metaiodobenzilguanidine ([123I]MIBG;
Sorin, Saluggia, Italy) was performed in 14 (7%) selected cases.
Images were obtained 24 and 48 h after the injection of 185–370
megabecquerels/kg [123I]MIBG, with the same gamma camera
as that used for [75Se]methylnorcholesterol scintigraphy.
All scintiscans were evaluated by experienced nuclear medicine
specialists (M.G. and C.M.), and scintigraphic techniques have not
changed over the duration of our study.
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Plasma ACTH was measured by a two-site immunoradiometric assay (Euro-Diagnostic, Amsterdam, The Netherlands; normal range, 4–18 pmol/L); plasma and urinary cortisol were determined by RIA (Diagnostic Products, Los Angeles, CA; normal range for plasma cortisol, 138–550 nmol/L; normal range for UFC, 82–330 nmol/24 h); PRA and plasma and urinary aldosterone were determined by RIA (Sorin; normal range for urinary aldosterone, 13.8–41.5 nmol/24 h; for supine plasma aldosterone, 80–280 pmol/L; for supine PRA, 1–3 ng/mL·h); plasma 17-OHP was determined by RIA (Diagnostic Systems Laboratories, Webster, TX; normal range, 1.2–10 nmol/L in males, 0.3–3.6 nmol/L during follicular phase and 1.2–14.5 nmol/L during luteal phase in premenopausal females, 0.3–1.8 nmol/L in postmenopausal females); DHEA-S was determined by RIA (Bio-Rad Laboratories, Milan, Italy; normal range, 0.5–9 µmol/L in males, 1.8–10.5 µmol/L in premenopausal females, 0.3–1.6 µmol/L in postmenopausal females). Urinary catecholamines were measured by high performance liquid chromatography using an electrochemical detector. The normal range for epinephrine was less than 80 nmol/24 h, that for norepinephrine was less than 600 nmol/24 h, that for metanephrine was 0.40–1.50 nmol/24 h, and that for normetanephrine was 0.6–1.9 nmol/24 h. In all of these methods, intra- and interassay coefficients of variation were less than 10%.
Statistical analysis
Results are given as the mean ± SE.
Comparisons between variables were tested with the Pearson
2 test and Student’s t test as appropriate.
Relationships were investigated by calculating correlation
coefficients. P < 0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Unilateral incidentalomas (groups 1 and 2)
Of 171 patients with unilateral incidentalomas, 142 (83%) showed
normal hormonal function (group 1) and 29 (17%) presented some
abnormalities of adrenal function (group 2; Table 1
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Group 1. According to the criteria indicated in Materials and Methods, adrenal dysfunction was ruled out in all these patients. However, in some cases subtle and isolated endocrine abnormalities were noticed. Ninety-three (66%) patients of this group underwent [75Se]methylnorcholesterol scintiscan; 77 showed concordant/symmetric uptake, and 16 showed discordant uptake. The mean diameter of tumors with discordant uptake was significantly greater than that of tumors with concordant/symmetric uptake (P < 0.001). In incidentalomas with concordant or symmetric uptake, histological diagnosis showed a cortical adenoma or hyperplasia in all 15 operated cases, whereas the other 60 were benign at FNAB or were unchanged at long term follow-up. A revision of radiological imaging demonstrated false incidentalomas, e.g. lesions arising from adjacent structures, in 2 cases with symmetric uptake; in 1 case a cirrhotic nodule and in the other a pancreatic cyst (4.5 and 3 cm in diameter, respectively) were found. In patients with discordant uptake, 13 underwent surgery, with a diagnosis of cortical carcinoma in 10, malignant pheochromocytoma in 1, lung metastases in 1, and cyst in 1. The clinical study revealed metastatic deposits (lung cancer) in 2 other patients and a hematoma in 1. Hormone values were not significantly different between the 2 uptake groups. With regard to DHEA-S levels, elevated values were found in a case of adrenocortical carcinoma with discordant uptake and in another with benign adenoma and concordant uptake, whereas low DHEA-S levels were found in a similar percentage of both benign (63%) and malignant (58%) masses. Sex distribution showed a prevalence of malignant lesions (discordant uptake) in males, of benign tumors (concordant/symmetric uptake) in females (female/male ratio of malignant vs. benign, 0.5 vs. 1.7; P < 0.05). Mean age was similar in the 2 groups (57 ± 1 vs. 51.5 ± 4.5 yr; P = NS).
Five patients of this group, presenting symmetric uptake, also underwent [123I]MIBG scintiscan, showing no radiotracer accumulation.
To evaluate the relationship between hormonal function and uptake at
scintiscan, unilateral nonhypersecreting incidentalomas with symmetric
(n = 18), prevalent (n = 33), or exclusive uptake (n =
26) were compared (Table 2). Mean size of
the mass in the exclusive and prevalent uptake group was significantly
larger than that in the symmetric uptake group (P <
0.05). Hypertension was more frequent in exclusive (42%) and prevalent
uptake (36%) groups, who showed higher mean blood pressure values
(P < 0.05), than in the symmetric uptake group (16%).
With regard to hormonal data, there were no significant differences
among the three groups, with the exception of baseline and
CRH-stimulated ACTH values that were lower in the exclusive uptake
group (P < 0.05).
Scintigraphy was not performed in 49 patients of group 1, taking into
account the young age, clear signs of malignancy, increased mass size
at CT scan, imaging characteristics for myelolipoma or cyst, and lesion
diameter 2 cm or less (resolution limit of the procedure). Histological
diagnosis was available in 25 of 49 cases (Table 1).
Group 2. This group included 29 abnormally functioning incidentalomas. There were 3 women, aged 47–69 yr, with primary hyperaldosteronism, presenting with mild hypertension; aldosterone/PRA ratios of 75, 118, and 585; serum potassium levels in the low normal range; and prevalent radiocholesterol uptake by the mass (1, 1.5, and 3.7 cm at CT scan, respectively). One patient underwent unilateral adrenalectomy, and the diagnosis of aldosteronoma was made at histology. Old age and a good response to medical therapy did not indicate surgery in the other 2 cases.
Seventeen other cases presented with abnormal cortisol levels and no
clinical signs of hypercortisolism (nonclinical hypercortisolism).
However, 3 yr later, 2 of these patients showed a further increase in
cortisol levels and developed overt Cushing’s syndrome without changes
in tumor size. [75Se]Methylnorcholesterol scintigraphy,
performed in 13 cases, showed exclusive uptake in 11 (all cortical
adenomas) and discordant uptake in 2 (cortical carcinomas). Of the
other 4 patients, 3 refused scintigraphy before surgery because they
already had a cytological diagnosis (FNAB) of malignancy. Cortical
carcinoma was confirmed at histology. One showed unchanged mass size
(0.8 cm) and endocrine data at follow-up (Table 3). Incidentalomas presenting with
exclusive uptake and nonclinical hypercortisolism showed significantly
higher UFC and baseline and suppressed plasma cortisol levels than
normally functioning incidentalomas with exclusive, prevalent, or
symmetric uptake (P < 0.01; Table 2), whereas baseline
and CRH-stimulated ACTH values were similar to those in
nonhypersecreting masses with exclusive uptake, but were significantly
lower than those in masses with prevalent or symmetric uptake
(P < 0.05).
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Bilateral incidentalomas (groups 3 and 4)
Twenty-two of 31 patients with bilateral incidentalomas had normal
adrenal function (group 3), and 9 had abnormal function (group 4; Table 1).
Group 3. Thirteen women (mean age, 59 ± 3 yr; range, 34–77 yr) and 9 men (mean age, 64 ± 4 yr; range, 43–75 yr; P = NS) with mean right lesion diameter of 2.9 ± 0.3 cm (range, 1–5) and mean left lesion diameter of 2.3 ± 0.2 cm (range, 1–5; P = NS) made up group 3. In some cases slight and isolated endocrine abnormalities were observed; low DHEA-S values (11 cases) and 17-OHP hyperresponse to exogenous ACTH (6 cases) were the most common. Eighteen patients were investigated using [75Se]methylnorcholesterol scintigraphy; 11 cases showed prevalent uptake by the largest mass (3 ± 0.3 cm; range, 1.8–4.5) and visualization of the contralateral mass (1.7 ± 0.2 cm; range, 0.8–3.5; P < 0.05), 6 showed symmetric bilateral uptake [larger nodules, 2.4 ± 0.3 cm in diameter (range, 1.5–3); smaller nodules, 2 ± 0.3 cm (range, 1–3); P = NS]. A reduced uptake by the largest mass was demonstrated in a patient with a metastasis of 5 cm in diameter from lung carcinoma into the right adrenal gland and a concomitant contralateral adrenal hyperplasia. Three of the other 4 patients who did not undergo scintiscan had bilateral adrenalectomy performed. Tumor size ranged from 2–5 cm. Histological diagnosis was nodular hyperplasia in all cases. All others were unchanged at long term follow-up.
Group 4. This group included 9 cases with adrenal dysfunction. Three patients (2 women, 41 and 54 yr, and 1 man, 34 yr) presented with primary hyperaldosteronism; 1 was normotensive, and 2 were hypertensive. The aldosterone/PRA ratios were 80, 104, and 68, respectively; adrenal scintigraphy showed prevalent uptake by the largest mass (3.5, 2.5, and 5 cm, respectively). One patient was surgically treated. After removal of the predominant mass at scintigraphy, which was diagnosed as an aldosteronoma, normalization of blood pressure and endocrine function was obtained. The contralateral mass remained unchanged during follow-up. The other 2 patients, who presented with bilateral hyperplasia and monolateral macronodule, received medical treatment.
Nonclinical hypercortisolism was documented in three women (Table 2).
Two of these presented with prevalent uptake by the largest nodule
(3.5–4 cm in diameter) and visualization of the contralateral nodule
(2 cm). Symmetric uptake (2 and 1.2 cm) was observed in the other.
Nodular hyperplasia was diagnosed in the patient (female, 47 yr) who
underwent surgical removal of the predominant mass at scintiscan. After
operation, she showed normalization of blood pressure and endocrine
function, and at follow-up, the size of the contralateral mass, which
was considered a nonhypersecreting incidentaloma, was unchanged.
Adrenal insufficiency was diagnosed in two patients (female, 75 and 77 yr) presenting with bilateral masses (range, 5–6.5 cm in diameter) with inhomogeneous density and irregular margins at CT. Autoptic diagnosis of stage IV bilateral adrenocortical carcinoma was performed in one case; in the other case, who showed bilateral nonvisualization at [75Se]methylnorcholesterol scan, primary bilateral adrenal non-Hodgkin’s lymphoma was diagnosed.
Basal plasma 17-OHP was markedly elevated (172 and 190 nmol/L before and after ACTH stimulation, respectively) in a male patient bearing bilateral adrenal hyperplasia with a monolateral macronodule. He also presented with elevated ACTH and DHEA-S levels (28 pmol/L and 12 µmol/L, respectively). Congenital adrenal hyperplasia due to 21-hydroxylase deficiency was diagnosed with genetic testing.
Overall findings were summarized in a pie chart (Fig. 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Differentiation between benign and malignant lesions on the basis of imaging studies was initially focused on adrenal mass size (1, 21). The risk of malignancy should always be considered in the presence of masses larger than 4–5 cm in diameter, except for those presenting with typical characteristics of myelolipomas, cysts, or hematomas at CT or MRI. Although the risk of malignancy seems to be directly proportional to size and increases with lesions 5 cm or more in diameter, small malignant tumors must also be considered (1, 2, 3, 4, 5), as in our patient with a nodule 2 cm in diameter.
Adrenocortical scintigraphy is an effective tool in distinguishing benign from malignant lesions, as all unilateral, malignant, space-occupying lesions showed discordant [75Se]methylnorcholesterol uptake; conversely, all benign adrenocortical masses presented concordant or symmetric uptake, apart from their hormonal secretory activity. The risk of malignancy has been reported to increase with bilateral lesions, especially in oncological patients (3). In our series, the prevalence of bilateral masses was 15%, similar to that reported in the literature (12, 22). At variance with previous findings (12), however, that reported about 50% malignant tumors in bilateral incidentalomas, only 10% of our patients presented with malignancy, a prevalence similar to that found in unilateral lesions. In the presence of bilateral incidentalomas, decreased or absent radiocholesterol accumulation at scintigraphy may indicate malignancy, as in our case of bilateral adrenocortical carcinoma or the patient with lung carcinoma metastases of the right adrenal gland and concomitant contralateral nodular hyperplasia in whom radiotracer uptake was absent on the side of the metastase.
According with previous reports (2, 7, 19, 22, 23, 24, 25, 26, 27, 28, 29), clearly abnormal adrenal function (without typical clinical features) was found in 20% of our patients. In others, more subtle isolated endocrine abnormalities, such as low DHEA-S, low ACTH, abnormal cortisol circadian rhythm, and 17-OHP hyperresponse to ACTH, were observed.
The risk that nonclinical hypercortisolism (10% of our cases) evolves toward Cushing’s syndrome is not known. The development of a continuous spectrum of abnormalities, ranging from nonhyperfunction to the so-called pre-Cushing’s syndrome and finally to clinical Cushing’s syndrome, has been hypothesized (13, 23, 24). This seems to be the case in our two patients who developed overt Cushing’s syndrome during 3-yr follow-up.
Primary hyperaldosteronism was found in three unilateral and three bilateral incidentalomas with normal potassium levels and mild hypertension. Measurement of the plasma aldosterone/PRA ratio provides a simple and sensitive screening test for diagnosis.
An enhanced 17-OHP response to exogenous ACTH stimulation was a frequent finding in our study, in agreement with others (25, 28, 29, 30, 31). This may reflect partial enzymatic defects (21-hydroxylase and/or 11ß-hydroxylase) intrinsic to the tumor or may result from a general defect in the adrenal cortex. Molecular genetic studies are needed to clarify the role of steroidogenic gene deficiency in the pathogenesis of adrenal incidentalomas.
Incidentally discovered pheochromocytomas were not infrequent in our series, accounting for 5% of the cases. The finding of abnormal urinary catecholamine levels in normotensive patients is an indication for [123I]MIBG scintiscan. This diagnostic procedure should also be performed in the presence of suggestive CT/MRI characteristics and discordant radiocholesterol scintiscan. Nevertheless, the possibility of false negative results at [123I]MIBG scan (32) must be considered (two in our series). Our four cases of nonhypersecreting pheochromocytomas and ganglioneuromas, diagnosed only at surgery, demonstrate that the finding of normal catecholamine and metanephrine values cannot exclude the presence of a chromaffin tumor, in agreement with a recent report (33). The diagnosis may sometimes be unexpected, as in the case of a 5-cm right adrenal mass associated with isolated elevation of urinary noradrenaline levels and negative [123I]MIBG that was demonstrated at histology and immunohistochemistry to be a cortical adenoma with islets of medulla.
In addition to differentiation between benign and malignant masses, adrenal scintigraphy provides a functional characterization of adrenal lesions due to specific accumulation of radiocholesterol by functioning adrenocortical tissues (3). A relationship between the degree of uptake and the level of hormonal dysfunction has been previously reported (13, 34) and was present in our study. All unilateral cortisol-hypersecreting adenomas showed exclusive radiocholesterol uptake, with suppression of the contralateral adrenal gland. This information in the case of a surgical approach to the adrenal mass becomes crucial in deciding the need for glucocorticoid replacement therapy.
Although the spatial resolution is a general limitation of scintiscan sensitivity, in 66% of our cases with masses 2 cm or less, this technique yielded correct information by concordant or discordant uptake. This supports the ability of scintigraphy to investigate small incidentalomas also (35).
In our series of 31 bilateral incidentalomas, endocrine abnormalities were more common than in unilateral incidentalomas, accounting for 29% of the cases. The concomitant presence of a cortical adenoma or hyperplasia with a contralateral malignant or space-occupying lesion shows asymmetric uptake at scintigraphy (12, 36), as in our case of a metastase associated with contralateral cortical hyperplasia. Very interesting are the cases of a patient with a cortisol-producing adenoma and one bearing an aldosteronoma, both associated with contralateral nonhypersecreting adrenal masses, because they demonstrate that incidentalomas with different biological characteristics may be present at the same time (37, 38). They both showed bilateral asymmetric uptake and normalization of endocrine function after removal of the predominant mass at scintigraphy, indicating that this technique may help identify hypersecreting tumors. Bilateral incidentalomas can also be the result of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (39, 40), as in one of our cases. Bilateral nonvisualization at scintigraphy is usually the result of bilateral cancers, as in 2 of our cases. Although we did not observe bilateral pheochromocytomas, this disease should be considered in the differential diagnosis, especially in patients with slightly elevated catecholamine values or with a positive history for multiple endocrine neoplasia. In these cases, [123I]MIBG scintiscan is a useful tool to localize the tumor.
The main steps of the suggested diagnostic approach to patients
with incidentally discovered adrenal masses, based on our experience,
are indicated in Fig. 2. In conclusion,
although hormonal evaluation is mandatory to determine adrenal
activity, in both unilateral and bilateral lesions endocrine testing
failed to differentiate benign from malignant tumors. With the
limitation that the percentage of our patients who underwent
scintigraphy was greater than the percentage of those who had
histological diagnosis (72% and 44%, respectively), a
morphofunctional examination by scintiscan seems to provide valuable
data in assessing malignancy, more so than conventional radiological
studies.
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Footnotes |
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Received July 9, 1997.
Revised September 24, 1997.
Accepted October 6, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxyprogesterone response to ACTH in silent
adrenal adenoma: cause or effect? Clin Endocrinol (Oxf). 42:273–277.[Medline]
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