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Original Studies |
Division of Endocrinology, 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, 35123 Padova, Italy.
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Abstract |
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Introduction |
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Although many researchers have recommended diagnostic guidelines and therapeutic work-up of patients with adrenal incidentalomas (3, 4, 5, 6, 7, 8, 9), current practice varies widely and remains controversial. If most investigators agree that tumors of large diameter or with evidence of hormonal hypersecretion or suspicious of malignancy should be removed (3, 4, 5, 6, 7, 8, 9), the problem of the correct approach to small, apparently benign, nonhypersecreting lesions is still present. Clinical questions, such as the probability that these small adrenal masses evolve toward hormonal hypersecretion or malignancy and the most important prognostic factors in this respect, are still under investigation.
We evaluated the long term clinical, hormonal, and morphological outcomes of 75 patients with apparently benign adrenocortical incidentalomas in an attempt to identify prognostic factors of progression of the adrenal disease.
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Subjects and Methods |
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During the last 15 yr, 246 consecutive patients (142 females and 104 males; mean age, 56 ± 13 yr; range, 14–77 yr) with adrenal incidentalomas (207 unilateral and 38 bilateral; median diameter, 3.6 ± 2.5 cm; range, 1.0–18 cm) were seen at our institution. Part of the sample was described in a previous report (8). Surgery was performed in 91 patients, after the initial evaluation, for adrenal hyperfunction or suspicious malignancy at diagnosis or in some case at the patient’s choice. Thirty-one patients were excluded for the following reasons: adrenal abnormalities at diagnosis in 9 (hypercortisolism in 3, aldosteronism in 4, congenital adrenal hyperplasia in 2), malignancy in 8, myelolipomas in 6, pseudoadrenal masses in 3, adrenal cysts in 3, and angiomas in 2. Of these 46 patients not included in the study, 32 patients had a follow-up of less than 2 yr, and 14 refused follow-up at our institution. Twenty-eight were females, and 18 were males (median age, 59 yr; range, 30–77 yr); 37 had unilateral and 7 had bilateral adrenal masses (median diameter, 2.3 cm; range, 1.0–4.5 cm). Seventy-eight patients were available to be enrolled in a follow-up study of at least 2 yr, but 3 of them dropped out within 1 yr. The remaining 75 patients were followed for at least 2 yr. There were 52 females (mean age, 57.4 ± 11.3 yr; median, 59 yr; range, 24–77 yr) and 23 males (mean age, 52.7 ± 15.2 yr; median, 52 yr; range, 19–76 yr). Sixty patients had unilateral masses [36 in the right adrenal gland (mean diameter, 2.7 ± 0.9 cm; median, 3.0 cm; range, 1.0–5.6), 24 in the left (mean diameter, 2.2 ± 1.0 cm; median, 2.0 cm; range, 1.0–4.0; overall, mean diameter, 2.5 ± 1.0 cm; median, 2.5 cm; range, 1.0–5.6), and 15 bilaterally (mean diameter, 2.3 ± 1.0 cm; median, 2.0 cm; range, 1.0–4.3 cm)]. Forty-one patients were moderately hypertensive (overall mean systolic blood pressure, 152.7 ± 26.1 mm Hg; diastolic, 92.5 ± 14.2 mm Hg), 15 were obese (median BMI, 34 kg/m2), 9 presented with noninsulin-dependent diabetes mellitus, 18 with osteoporosis, 3 with hypothyroidism, 2 with hyperthyroidism, 1 with subclinical hyperthyroidism, and 1 with Paget’s disease. None had adrenal cortex autoantibodies.
Incidentalomas included in the study were apparently benign adrenocortical tumors on the basis of radiological, endocrine, and scintigraphic evaluation at diagnosis, as previously described (8). Briefly, all patients underwent abdominal computed tomography (CT) and/or magnetic resonance imaging (MRI). On the CT scan most adrenal masses appeared hypodense and round, with well defined margins and without enhancement after iv contrast medium; in 2 patients the masses were partially cystic (diameters, 3 and 5.6 cm); in 3 cases they were heterogeneous, with calcifications in 2. Mass diameter was less than 4 cm in all but 2 cases (4.3 and 5.6 cm). [75Se]Methylnorcholesterol adrenal scintigraphy was performed in 67 cases. The 8 patients who did not undergo adrenocortical scintigraphy presented with small adrenal lesions (diameter, 2 cm or less, which is the resolution limit of this procedure). Scintiscan evaluation was based on the criteria of Gross et al. (6, 10), defining the following uptake patterns: in unilateral incidentalomas: 1) exclusive uptake by the tumor with no visualization of the contralateral gland, 2) prevalent uptake by the tumor with visualization of the contralateral gland, 3) symmetrical uptake, and 4) reduced or absent uptake by the tumor (discordant uptake); in bilateral incidentalomas: 1) bilateral symmetric uptake, 2) bilateral asymmetric uptake, and 3) bilateral nonvisualization. In the group of unilateral incidentalomas, [75Se]methylnorcholesterol scintigraphy showed exclusive uptake at the side of the adrenal mass in 21 cases, prevalent uptake in 22, and bilateral symmetric uptake in 11. In the group with bilateral masses, bilateral symmetric uptake was observed in 8 cases, and bilateral asymmetric uptake was prevalent at the side of the larger mass in 5. 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 catecholamines and/or metanephrines, and dynamic tests (1 mg overnight dexamethasone suppression test, ACTH test, and, in some cases, CRH test). According to the criteria previously reported (8), hypercortisolism, primary aldosteronism, and pheochromocytoma were ruled out in all these patients. However, in some cases subtle and isolated endocrine abnormalities were noticed, the most frequent being low ACTH and DHEA-S levels.
Follow-up protocol
Informed consent was obtained from all subjects, and the investigation was performed in accordance with the principles of the Declaration of Helsinki. The criteria of inclusion in the study were mass with benign radiological and scintigraphic appearance and absence of overt adrenal dysfunction. After the initial diagnosis, patients were reinvestigated at 6 and 12 months and then at 1-yr intervals by clinical examination (blood pressure, BMI, etc.), routine chemistry, hormonal determinations (UFC, 24-h urinary catecholamines/metanephrines, plasma cortisol rhythm, morning ACTH and DHEA-S, and upright aldosterone/PRA ratio), and morphological evaluation (CT scan or MRI). Abnormal tests at diagnosis were repeated during follow-up. The mean follow-up period was 4.6 yr (median, 4 yr; range, 2–10 yr).
The criteria for surgery were indirect signs of malignancy at radiological investigation, development of hormonal hyperfunction, and willingness of the patient. Seven patients refused operation despite an increase in mass size and are still under follow-up observation.
Statistical analysis
Results are given as the mean ± SD.
Correlations were examined by linear regression analysis. Comparisons
between variables were tested with Pearson’s 
2 test and
Student’s t test, as appropriate. Survival analysis was
used to estimate the likelihood of developing adrenal hyperfunction or
radiological signs of malignancy, which were considered the events of
interest. Radiological signs of malignancy were defined as a 1-cm or
greater increase in maximum diameter of the tumor within 1 yr, a change
in the radiological aspect (irregular shape and margins, heterogeneous
density at CT scan, hyperintense MRI images in T2). Kaplan-Meier curves
(11) were generated for estimating outcomes. All patients entered the
life-table when their adrenal mass was first characterized by CT scan
or MRI. To evaluate factors predictive of progressive disease, we
arbitrarily selected nine parameters (age, sex, obesity, arterial
hypertension, diabetes, endocrine abnormalities, mass size, mass
location, and scintigraphic uptake) as possible risk factors. The
log-rank statistic (12) was used to compare survival distributions of
two subcategories for each of the risk factors considered. Risk factors
were dichotomized; cut-off points were chosen according to the results
of long standing clinical observation and/or median values. Nine risk
factors were considered and dichotomized: 1) age (cut-off, 56 yr), 2)
sex (females vs. males), 3) mass diameter (cut-off, 3.0 cm),
4) side (unilateral vs. bilateral incidentalomas), 5)
presence of arterial hypertension (blood pressure value cut-off, 160/95
mm Hg); 6) presence of diabetes; 7) presence of obesity (BMI cut-off,
30 kg/m2); 8) presence of isolated endocrine abnormalities
(below or over normal range); and 9) scintigraphic pattern
(exclusive/bilateral asymmetric uptake vs.
prevalent/symmetric uptake). P < 0.05 was considered
statistically significant.
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Results |
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None of our patients showed malignant transformation during
follow-up. Fifty-eight patients had unchanged CT and/or MRI
characteristics of their adrenal mass and did not develop endocrine
hypo- or hyperfunction (group 1), 11 had only adrenal mass size
variations (group 2), 3 developed endocrine hyperfunction with no
changes in mass size (group 3), and 3 showed adrenal mass enlargement
associated with adrenal hyperfunction (group 4). Clinical data of
patients who developed adrenal hyperfunction and/or mass size variation
are summarized in Table 1
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Group 2. Three males and 8 females (median age, 60 yr; range,
31–71 yr) with adrenal incidentalomas (median diameter, 2.5 cm; range,
1.1–4.0 cm) showed mass enlargement (patients 1–11 in Table 1
). Two
patients underwent surgery because of an increase of mass size from 2
to 3 cm in patient 1 and from 1.1 to 4 cm, with MRI images of
calcifications, heterogeneous signal on T1-weighted images and
hyperintense on T2, in patient 2. Adrenocortical adenomas were
diagnosed at histology. Five patients (patients 3–7) showed an
increase of about 1 cm in tumor size, within the first year of
observation in four cases and after 6 yr in patient 3. No further
variations were subsequently observed. In two cases (patients 8 and 9),
a slight increase in the adrenal lesion and the appearance of a
contralateral adrenal mass (1.2 and 1.8 cm, respectively) were observed
1 and 3 yr after the initial diagnosis; in both cases adrenal masses
remained unchanged during the subsequent follow-up. In 2 cases
(patients 10 and 11) a partial reduction of the adrenal mass (from 3.2
to 2.5 cm and from 3 to 1 cm, respectively) after 1 and 4 yr of
observation was documented; the adrenal mass was partially cystic at
the initial CT scan in patient 11.
Group 3. Three patients (patients 12–14) developed nonclinical hypercortisolism (inadequate cortisol suppression after 1 mg dexamethasone overnight, increased UFC, absent cortisol rhythm, low ACTH, but no clinical signs of hypercortisolism) that progressed to overt Cushing’s syndrome in two with no increase in the adrenal mass size (patients 12 and 13). Adrenal adenomas were histologically demonstrated and glucocorticoid replacement therapy in the postsurgical period was required. Patient 14, with bilateral incidentaloma, received medical treatment with aminoglutethimide.
Group 4. Of these three patients, subjects 15 and 16 developed nonclinical hypercortisolism and a concomitant increase of about 1 cm in the adrenal mass diameter (from 3.5 to 4.4 cm and from 3.4 to 4.5 cm, respectively); histology demonstrated nodular hyperplasia and adrenocortical adenoma, respectively. In patient 17, we documented an increase in mass size (from 1.5 to 2.8 cm) and concomitant catecholamine hypersecretion associated with hypertensive crises 3 yr after the initial observation. A pheochromocytoma was diagnosed at histology. Normalization of blood pressure and catecholamine levels was obtained after surgery. This patient had completely normal hormone results at diagnosis, including urinary catecholamines. Her adrenal mass, hypodense at diagnosis, showed unchanged density at CT scan during follow-up, whereas it was hypointense in T1 and slightly hyperintense on T2 at MRI before surgery.
Survival analysis and risk factors
The estimated cumulative risk to develop mass enlargement
and adrenal hyperfunction is shown in
Figs. 1–3. The cumulative risk for adrenal
hyperfunction was 4% after 1 yr, 9.5% after 5 yr, and 9.5% after 10
yr. All hyperfunction patients developed this problem within 3 yr from
diagnosis. The cumulative risk of mass enlargement was 8% after 1 yr,
18% after 5 yr, and 22.8% after 10 yr. Most cases were observed
within the first 3 yr from diagnosis. No patients developed adrenal
malignancy or radiological images suspicious of malignancy, with the
exception of the case of adrenocortical adenoma with calcifications and
hyperintense signal in T2 reported above (patient 2). Table 2 summarizes positive predictive values
and cumulative risks for adrenal hyperfunction and mass enlargement
according to risk factors (sex, age, presence of obesity, hypertension,
diabetes, presence of abnormal endocrine tests, mass size, mass
location, and scintigraphic uptake pattern). The occurrence of adrenal
hyperfunction was significantly associated with adrenal mass diameter
of 3.0 cm or more at initial CT scan (2 = 5.18; df
= 1; P < 0.025; Fig. 1) and with a scintigraphic
pattern of exclusive (unilateral incidentalomas) or bilateral
asymmetric (bilateral incidentalomas) uptake (2 = 5.61;
df = 1; P < 0.025; Fig. 2). Development of endocrine
hyperfunction was more frequent in female, older, hypertensive subjects
with endocrine abnormalities at diagnosis (Table 2). Adrenal mass
enlargement was significantly associated with the presence of abnormal
endocrine tests at diagnosis (2 = 4.0; df = 1;
P < 0.05; Fig. 3) and
was relatively more frequent in older subjects (Table 2). The existence
of any relationship between tumor size at diagnosis and endocrine data
(i.e. UFC excretion, basal plasma cortisol levels and after
1 mg overnight dexamethasone suppression, ACTH, and DHEA-S
levels) was investigated with regression analysis. A negative
correlation between mass diameter and basal ACTH levels was
demonstrated (r = -0.27; P < 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although the increase in size has been considered suggestive of malignancy (3, 5, 24), in none of our patients who showed adrenal mass enlargement greater than 1 cm in diameter was a malignant transformation proven at either subsequent follow-up or histology. Also, the appearance of a mass in the contralateral adrenal, as observed in two cases, was not a sign of malignancy. No patients showed in concomitance with tumor enlargement radiological images suggestive of malignancy (i.e. irregular margins, heterogeneous tissue, or hyperintensity on T2-weighted images). Therefore, we cannot exclude that the presence of these morphological aspects may be more reliable markers of malignancy than tumor size increase. Reduction or disappearance of the adrenal mass has been reported in several cases (16, 19). In our series a reduction of mass volume was documented in only one case, whereas in another the reduction in size was probably due to a cystic mass shrinkage. Overall, incidentalomas, after a period of increasing mass size, tended to remain unchanged. If this behavior is confirmed by further observation, it may indicate the existence of a programmed end point of growth of adrenal masses. The mechanism by which tumoral masses stop their growth is unknown; however, local factors involved in steroidogenesis regulation, cell proliferation, and/or apoptosis (25, 26, 27) may be involved.
The second adverse outcome for patients with adrenal incidentalomas may be endocrine morbidity. At variance with other series (21) in which a spontaneous endocrine normalization occurred in a high percentage of cases, in our patients hormonal abnormalities tended to persist unchanged throughout the period of observation. Moreover, about 10% of cases developed endocrine hyperfunction, such as hypercortisolism or pheochromocytoma. This incidence is consistent with the available literature (13, 14, 15, 16, 17, 18, 19, 20, 21), although the appearance of overt clinical syndromes in our series was more common than previously appreciated.
By analysis of risk factors, the presence of isolated endocrine abnormalities at diagnosis had predictive value for tumor enlargement. It is noteworthy that in these patients slight adrenal hyperfunction was usually associated with low circulating ACTH levels, suggesting an autonomous adrenal function or, alternatively, the presence of factors other than ACTH, able to influence adrenal steroidogenesis and adrenal growth (28, 29). In the latter case, mass enlargement and/or development of bilateral masses may be explained. In agreement with recent reports (30, 31), a relationship between tumor size and adrenocortical function or ACTH levels was also observed in our series. Our findings point out that the size of the tumor should be considered a risk factor of adrenal hyperfunction. The scintigraphic uptake pattern had relevance for the occurrence of hyperfunction. In our previous study (8), we found a relationship between endocrine data and radiocholesterol uptake pattern at scintigraphy, indicating that tracer uptake by the mass with contralateral adrenal suppression is highly suggestive for mild hyperfunction (6, 17). Patients showing exclusive radiocholesterol uptake by the mass were at major risk of adrenal hyperfunction. It shows that the exclusive uptake pattern may represent an early stage of functional autonomy of adrenal adenomas, also in the presence of normal hormonal data. In the case of bilateral masses with asymmetric uptake pattern, the presence of incidentalomas with different biological characteristics should be considered (8, 32).
In conclusion, our data indicate that a conservative management is appropriate in the majority of incidentalomas. Indeed, the risk of malignancy seems to be very low also in the case of a slight increase in mass size. On the other hand, the incidence of adrenal hyperfunction over time seems to be relatively high, and therefore, a prolonged morpho-functional follow-up is recommended, especially in those patients with subtle endocrine abnormalities, exclusive radiocholesterol uptake, or mass size of 3 cm or more at diagnosis, indicating a higher risk of disease progression. The cost/benefit ratio in the management of this "new disease," including the advantages of early diagnosis and treatment in asymptomatic patients, and the risk of overtesting and overtreating due to anxiety from both the patient and the physician are still open issues.
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Footnotes |
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Received September 10, 1998.
Accepted October 27, 1998.
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References |
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. Horm Metab Res. 30:432–435.[Medline]
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