Full text of DOI:10.1007/BF03343941

J. Endocrinol. Invest. 24: 846-855, 2001
The natural history of incidentally discovered adrenocortical
adenomas: A retrospective evaluation
E. Grossrubatscher*, F. Vignati*, M. Possa**, and P. Loli*
*Endocrine Unit and **Nuclear Medicine Department of Onco-Hematology, Ospedale Niguarda
Cà Granda, Milan, Italy
ABSTRACT. Adrenal adenoma is the most fre-
quent lesion among adrenal incidentalomas. The
present retrospective study was undertaken to
investigate medium-term evolution of supposed
or ascertained adrenocortical adenomas in a
group of 53 subjects (16 males and 37 females,
aged 31-83 yr), with bilateral (no.=8) or mono-
lateral (no.=45) incidentally discovered adrenal
masses (size 10-50 mm, median 25 mm), who
were followed-up for 6-78 months (median 24
months). Diagnosis of adenoma was based on
size and morphovolumetric aspect of the lesion
at computed tomography (CT), scintigraphic pat-
tern using NP59 as a tracer, and it was histo-
logically confirmed in 7 patients. After an ex-
tensive hormonal investigation including morn-
ing (no.=53) and midnight (no.=28) serum cor-
tisol, plasma ACTH (no.=50), serum DHEAS
(no.=51), daily urinary free cortisol excretion
(no.=52), post-dexamethasone (1 mg) cortisol
(no.=42) and ACTH stimulation test for 17-hy-
droxyprogesterone (17-OHP) response (no.=48)
at the time of diagnosis, patients were periodi-
cally re-evaluated for hormonal function and ra-
diological aspect of the lesion(s) by CT. Seven
patients underwent surgery 6-42 months after
incidentaloma demonstration, with histological
diagnosis of adrenal adenoma. During follow-up
an increase in the size of the lesion was demon-
strated in 22 patients (41.5%); the increase was
greater than 10 mm in 8 cases. In 3 patients with
unilateral mass, a contralateral lesion appeared
10-52 months after first demonstration. Six pa-
tients (11.3%) showed reduction or disappear-
ance of the lesions. On the basis of the hormon-
al evaluation 3 patients were considered to have
subclinical Cushing’s syndrome and 10 patients
exhibited 17-OHP hyperresponse to ACTH test
consistent with partial 21-hydroxylase deficiency.
A significant difference in the size of the lesions
was observed between patients with or without
17-OHP hyperresponse to ACTH test (31.1 1.9 vs
24.1 1.2 mm; p<0.01). No significant changes in
the hormonal parameters were observed in the
patients, when retested. In conclusion, although
none of the patients of the present series ex-
hibited evolution to hypersecretion or to aber-
rant growth, in more than 40% of patients an in-
crease in the size of the mass was observed, even
after a long period of “quiescence”. This sug-
gests that a radiological re-evaluation of lesions
should be periodically undertaken.
(J. Endocrinol. Invest. 24: 846-855, 2001)
©2001, Editrice Kurtis
INTRODUCTION
prevalence of adrenal incidentalomas ranges be-
tween 0.3 and 4.3% (1-3), but higher figures are ex-
pected in the future; in fact, in autoptic series the
prevalence of adrenal incidentalomas is four times
higher (2, 3).
Among the different kinds of incidentally discov-
ered adrenal masses, non-hyperfunctioning adreno-
cortical adenomas are the most frequent lesions
with a prevalence of 30-52% (3).
Over the last two decades, due to extensive appli-
cation of abdominal computed tomography (CT) as
routine imaging technique, the incidental detection
of adrenal lesions has become a common finding.
According to different Authors, considering the
present limit of resolution of abdominal CT, the
Only in recent years, it has been recognized that 5 to
12% of so far considered non-functioning adenomas
show mild cortisol hypersecretion insufficient to cause
overt Cushing’s syndrome, the so-called subclinical
Cushing’s syndrome (4-6). Moreover, Jaresch et al.
(7), reported a high incidence of benign adrenocorti-
Key-words: Adrenal incidentaloma, subclinical Cushing’s syndrome,
adrenal adenoma, follow-up.
Correspondence: Dr. Paola Loli, Divisione di Endocrinologia, Ospedale
Niguarda Cà Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy.
E-mail: endocrinologia@ospedale-niguarda.it
Accepted March 29, 2001.
846

E. Grossrubatscher, F. Vignati, M. Possa, et al.
cal tumors in patients with congenital adrenal hyper-
plasia due to 21-hydroxylase deficiency; conse-
quently, patients with incidentalomas have been test-
ed for 21-hydroxylase enzymatic defect, which is re-
ported to be found in 30-71.2% (8, 9).
Only patients with ascertained or suspected adrenal
adenoma or nodular hyperplasia were included in
the study. The diagnosis of adrenal adenoma was
based on the combination of the following criteria:
1) lesion diameter ꢀ40 mm; 2) evidence of round
or oval hypodense lesions with well-defined mar-
gins, homogeneous after contrast injection at CT;
3) concordant monolateral or prevalent uptake of
the tracer at iodocholesterol (NP-59) scintigraphy
(see below). The diagnosis of adrenocortical ade-
noma was ascertained histologically in 7 patients,
who underwent surgery during the follow-up. One
patient (no. 39) with a lesion greater than 40 mm,
operated on during the follow-up, was included be-
cause of the histological demonstration of adreno-
cortical adenoma.
Six of the patients studied (1 male and 5 females)
had suffered from primary extra-adrenal malignan-
cies (no. 16, 30, 32, 35, 45 and 52): breast carcino-
mas in two cases and lung, stomach, endometrium
and thyroid in the others.
Basal radiologic examination consisted of pre- and
post-contrast CT imaging with 5-mm thin sections.
The adrenal masses were unilateral in 45 cases
(85%) and bilateral in 8 (15%). Of the 45 unilateral
masses 21 were on the right and 24 on the left side.
The size of the adrenal lesions was ꢀ40 mm in all
but one subject (no. 39); the mean SD lesion di-
ameter was 25.9 7.9 mm (range 10-50 mm, medi-
an 25 mm).
In general, the major diagnostic concern about in-
cidentalomas is whether the lesion may represent a
malignancy or a functioning adrenal neoplasm. The
occurrence of a hypersecretory mass or of a sus-
pected malignancy (primary or metastatic) indicates
the need for a surgical approach. On the contrary,
for small benign non-hyperfunctioning adrenocor-
tical adenomas adrenalectomy seems unnecessary.
Since the natural history of small benign lesions is
still unknown, the adequate follow-up and treat-
ment is matter of debate; for example, it is still to
be elucidated whether only periodic clinical con-
trols should replace hormonal and imaging proce-
dures repeated at time intervals more or less pre-ar-
ranged.
The present study reports medium-term results
concerning the evolution of incidentally discovered
adrenocortical adenomas in a large group of pa-
tients. The aim of this a posteriori evaluation was
to obtain some information on the natural history
of these lesions and to outline a possible follow-up
profile for these lesions.
SUBJECTS AND METHODS
Fifty-three patients (16 males and 37 females, aged
31-83 yr), with supposed or ascertained adreno-
cortical adenomas, were retrospectively selected
from a larger group of patients with incidentally dis-
covered adrenal masses evaluated at our Depart-
ment during the period from 1991 to 1999. Apart
from the pathological demonstration of an adeno-
ma, the criteria for selection of patients included
the availability of sufficient data to support the di-
agnosis of adrenal adenoma and an adequate fol-
low-up (range: 6-78 months; median 24 months).
The adrenal lesions were incidentally discovered
during abdominal imaging performed for reasons
other than clinically suspected adrenal disease.
Patients with hypertension of possible endocrine
origin (i.e. paroxysmal hypertension or hyperten-
sion associated with hypokalemia) were excluded
from the study; the presence of silent pheocromo-
cytoma was excluded by 24-h urinary catecho-
lamine determination. No patients showed signs of
overt endocrine dysfunction on physical examina-
tion and none had hypokalemia in a salt-repleted
state. Epidemiological data of the patients studied
and adrenal lesion diameter at CT are shown in
Table 1.
Adrenal lesions had morphologic and densitomet-
ric features consistent with adenoma in all but two
patients; in one of these (no. 21) the lesion had
dyshomogeneous density, while in the other (no.
39) there was inhomogeneous contrast enhance-
ment and microcalcifications. Both patients were
included in the study because of the evidence of
monolateral concordant uptake at NP-59 scintigra-
phy and the diagnosis was subsequently confirmed
at surgery.
Adrenal scintigraphy with 131iodine-6β-iodomethyl-
19-norcholest-5 (10)-en-3-β-ol (NP-59) was per-
formed in 41 patients. Scintigrams were obtained
with gamma-camera on days 4 and 7 after the in-
jection of NP-59 (1 mCi). Saturated potassium io-
dide solution was administered to suppress thy-
roidal uptake of free 131I. A qualitative assessment
of NP-59 accumulation was made by the same nu-
clear medicine physician who was aware of the side
of the abnormal gland at CT. Imaging pattern was
said concordant if there was increased or lateraliz-
ing accumulation of NP-59 on the side of the ab-
normal adrenal on CT; in cases with bilateral lesions
the same definition was given when NP-59 accu-
mulation, although bilateral, lateralized on the side
847

Follow-up of incidentally discovered adrenal adenomas
Table 1 - Epidemiological, scintigraphic and basal radiological and hormonal data.
Case
Sex
Age
Side of
the lesion*
Diameter of
the lesion (mm)*
NP-59 uptake
17-OHP
hyperresponse
to ACTH test
Abnormal
hormonal
parameters
1
2
3
4
5
6
7
8
F
M
M
F
F
F
F
F
M
F
F
M
F
F
M
M
M
F
M
F
F
F
M
F
M
F
F
F
F
F
F
F
F
M
F
F
F
F
F
F
F
F
76
61
56
47
66
83
31
53
70
61
52
67
59
72
61
42
73
56
41
67
61
66
66
60
70
51
67
57
62
80
62
69
64
53
75
58
66
67
69
60
65
69
60
46
63
60
50
62
56
50
46
55
61
Left
Left
Right
Left
18
30
25
39
25
20
25
33
35
25**
15
32**
21
30
24
16
40**
36
20
35
27
32**
10
20
32**
20
35
25
26
40
20
34
30
14**
25**
15
20**
20
-
No
No
Yes
-
-
-
C
A
Monolateral concordant
-
-
Left
Monolateral concordant
-
No
No
No
No
Yes
Yes
No
Yes
No
no
No
No
-
Yes
No
No
No
No
No
-
Yes
Yes
Yes
No
No
Yes
No
No
No
No
No
No
No
No
No
Yes
No
-
E Fc***
Right
Right
Left
Right
Bilateral
Left
Bilateral
Right
Right
Left
Left
Bilateral
Left
Left
Left
Right
Bilateral
Left
Left
Bilateral
Left
Right
Left
Right
Left
Right
Left
-
Monolateral concordant
Bilateral concordant
Monolateral concordant
Bilateral concordant
-
D E***
-
-
-
-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
-
A C
Fc
-
D
Monolateral concordant
Monolateral concordant
Prevalent concordant
Bilateral
Bilateral concordant
Monolateral concordant
-
-
Ax C
-
-
-
-
Monolateral concordant
Bilateral concordant
Prevalent concordant
Prevalent concordant
Bilateral concordant
-
Monolateral concordant
Monolateral concordant
Prevalent concordant
Monolateral concordant
Monolateral concordant
-
-
A C
-
C
D
A
B
A
-
-
-
D
-
-
D
-
D Fc
-
C Fc***
A
A D
-
-
C
Fc
A Fc
A
-
-
D
C
-
Right
Bilateral
Bilateral
Right
Bilateral
Left
-
Reduced bilateral
Bilateral concordant
Monolateral concordant
Bilateral concordant
Monolateral concordant
Monolateral concordant
Monolateral concordant
Monolateral concordant
Monolateral concordant
Prevalent concordant
Bilateral
Monolateral concordant
Monolateral concordant
Prevalent concordant
Monolateral concordant
Monolateral concordant
Prevalent concordant
Monolateral concordant
Monolateral concordant
Monolateral concordant
Left
50
31
25
18
28
22
33
19
17
23
20
19
25
30
23
Right
Right
Right
Right
Left
Right
Left
Left
M
M
F
F
F
F
M
F
M
F
M
-
No
No
No
No
No
No
No
No
No
No
Left
Right
Right
Left
Right
Right
-
*Side and diameter of lesions are evaluated by computed tomography; **in bilateral lesions greater lesion diameter is reported; ***patients with sub-
clinical Cushing syndrome. 17-OHP: 17-hydroxyprogesterone; A: subnormal DHEAS; Ax: supranormal DHEAS; B: sub-normal morning serum cortisol;
C: supranormal midnight serum cortisol; D: subnormal plasma ACTH; E: supranormal 24 h urinary free cortisol excretion; Fc: reduced cortisol suppres-
sion after dexamethasone 1 mg; F: female; M: male.
848

E. Grossrubatscher, F. Vignati, M. Possa, et al.
with the greatest lesion. Scintigraphic evaluations
of the patients studied are given in Table 1.
10-80 μg/day; serum DHEAS, chemiluminescent
(Medycal System, Genoa, Italy), reference ranges
for sex and age as reported by the supplier; serum
17-OHP, RIA (Medycal System, Genoa, Italy), nor-
mal values: female pre-menopausal in follicular
phase 0.1-1.2 ng/ml, female post-menopausal 0.1-
0.6 ng/ml, male 0.4-3.3 ng/ml.
All the hormone assays were performed in the same
laboratory. Intra-assay coefficients of variation were
4% for ACTH, 2% for serum cortisol, 3% for UFC,
3% for DHEAS, 3% for 17-OHP. Inter-assay coeffi-
cients of variation were 5, 4, 5, 6 and 5,5%, re-
spectively.
After the demonstration of the adrenal adenoma,
the patients underwent the following hormone de-
terminations: 1) serum DHEAS (no.=51); 2) morning
serum cortisol (mean of 3 blood samples taken ev-
ery 20 min; no.=53); 3) midnight serum cortisol
(no.=28); 4) morning plasma ACTH (mean of 3 blood
samples taken every 20 min; no.=50); 5) 24-h ex-
cretion of urinary free cortisol (UFC; no.=52).
In addition, morning (08:00 h) cortisol after over-
night low-dose dexamethasone administration
(no.=42), dexamethasone 1 mg orally at 23:00 h,
was determined. Adequate dexamethasone sup-
pression was demostrated when morning cortisol
fell below 5 μg/dl. Lastly, basal (no.=52) and post-
stimulation (no.=48) serum 17-hydroxyproges-
terone (17-OHP) concentrations were evaluated to
detect possible 21-hydroxylase deficiency [0.25 mg
ACTH (1-24), Synacthen, Ciba Geigy, administered
iv as a bolus dose with determination of 17-OHP
concentration at 60 min]. Partial 21-hydroxylase de-
ficiency was demostrated when 17-OHP peak was
higher than 10 ng/ml. Pre-menopausal women
(no.=3) were studied in the early follicular phase of
the mestrual cycle. The ACTH stimulation test was
repeated in 26 patients (6 hyperresponders and 20
with normal response) in the course of the follow-
up. Probable subclinical Cushing’s syndrome was
arbitrarily assumed in the presence of at least 3 of
the following criteria: supranormal UFC excretion;
suppressed plasma ACTH levels (<5 pg/ml); ab-
sence of cortisol rhythm with midnight cortisol lev-
els above 5 μg/dl; inadequate morning cortisol sup-
pression after low-dose dexamethasone (>5 μg/dl);
unilateral NP-59 uptake on the side of the adrenal
mass.
All hormonal and radiological data obtained in each
patient during follow-up were included in the study;
but since this was a retrospective evaluation, the
timing of hormonal and/or radiological evaluations
was not uniform (Fig. 1). All patients had at least one
morphological re-evaluation of the adrenal mass by
thin sections abdominal CT. All the imaging studies
were performed at our Institution and a single radi-
ologist, unaware of the clinical course of the patient,
compared basal and follow-up images.
Hormonal variables were measured by RIA or IRMA
or chemiluminescent methods, using commercially
available kits: plasma ACTH, IRMA (Byk Gulden
ITALIA, Cormano, Italy), normal values: 5-52 pg/ml;
serum cortisol, chemiluminescent (Bayer Spa,
Milano, Italy), normal morning values: 8-25 μg/dl;
urinary cortisol, RIA after dichloromethane extrac-
tion (Medycal System, Genoa, Italy), normal values:
Statistical analysis
Results of continuous variables are expressed as
mean SD. Level of statistical significance was set
at p<0.05.
We used χ2 test for comparisons of proportions,
and Mann-Whitney U-test for comparisons of quan-
titative variables.
RESULTS
Adrenalectomy was performed in 7 of the 53 pa-
tients, 6-42 months after incidentaloma demon-
stration. Histological diagnosis was adrenocortical
adenoma in 6 patients and adrenal adenoma with
necrotic-hemorrhagic degeneration in one. Surgical
excision of the mass was performed to meet the
wish of the patient in 3 cases (no. 4, 15 and 24), be-
cause of growth of lesion above 1 cm in 2 patients
(no. 21 and 39), one of whom (no. 39) suffered from
subclinical Cushing’s syndrome, and because of
subclinical Cushing’s syndrome in two cases (no. 5
and 7).
The radiological and hormonal follow-up of the pa-
tients studied is reported in Table 2.
Radiological data
In each patient adrenal CT was repeated during the
follow-up. In patients with evidence of an increase
in the size of the adrenal lesion and in whom
surgery was not performed, a re-evaluation by CT
or ultrasonography was undertaken at short time
interval. The last radiological control was performed
6-74 months (median 24 months) after incidentalo-
ma demonstration (Fig. 1).
In 24 patients (45%) neither size nor morphological
changes of the lesions were observed.
Instead, 22 patients (41.5%) showed an increase in
the size of the lesions that was <10 mm (range 2-8
mm) in 14 cases (26.4%) and ꢁ10 mm (range 10-140
mm) in 8 (15.1%). Necrotic-hemorrhagic degenera-
tion caused a marked increase (+140 mm) of the
849

Follow-up of incidentally discovered adrenal adenomas
Radiological and hormonal re-evaluation
Radiological re-evaluation
Hormonal re-evaluation
Patient operated on
Fig. 1 - Timing of hormonal
and radiological evaluations in
the follow-up of the 53 pa-
tients studied. (patient’s order
as in Tables).
0
10
20
30
40
50
60
70
80
Months of follow-up
adrenal mass in one patient (no. 39). In 3 patients
(no. 9, 44 and 53), 10-52 months after detection of
the incidentaloma, a controlateral, oval shaped, ipo-
dense adrenal mass, was demonstrated.
Six patients (11.3%) showed a reduction or disap-
pearance of the adrenal lesion during follow-up: in
5 cases (no. 2, 10, 14, 17 and 35) the size reduction
ranged from 2 to 5 mm, while in one patient (no.
34), with bilateral lesions at the start of the study
consistent with adrenal hyperplasia, normalization
of both adrenal glands was demonstrated after 33
months.
Hormonal data
DHEAS levels were normal, according to sex and
age, in 41 patients (80.4%), reduced in 9 (17.6%)
and elevated in one case (no. 17).
During the follow-up no significant changes of
mean DHEAS level were seen in 29 of the 53 pa-
tients in whom the hormone concentration was
850

E. Grossrubatscher, F. Vignati, M. Possa, et al.
Table 2 - Radiological and hormonal follow-up of the patients studied.
Case
Basal
Last
Size
modifications
(mm)*
Hormonal Case
changes
Basal
Last
Size
modifications
(mm)*
Hormonal
changes
diameter
follow-up
diameter
follow-up
(mm)a diameter (mm)*
(mm)a diameter (mm)*
1
18
30
20
27
25
39
25
20
25
33
35
20
15
42
33
26
24
16
37
36
32
38
40
36
21
20
32
20
39
+2
-3
-
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
25
26
25
26
40
28
34
30
0
Unchanged
Unchanged
Unchanged
+8
-
-
2
-
3
25
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged
Bilateralization
-5
-
40
-
4
39
-
20
-
5
25
G H
34
Unchanged
Unchanged
F
-
6
20
-
30
7
25
L
14**
25**
15
Bilateral disappearance
-
-
8
33
-
20
15
26
26
190
31
25
18
40
28
35
25
20
27
24
19
25
32
33
-5
9
35
I
Unchanged
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
25**
15
-
20**
20
+6
-
Unchanged
+10
-
+6
-
32**
21
-
50
+140
B
G
-
+12
-
31
Unchanged
30
-4
-
25
Unchanged
24
Unchanged
Unchanged
-3
-
18
Unchanged
-
16
-
28
+12
I
40**
36
-
22
+6 and bilateralization
-
Unchanged
+12
-
33
+2
-
20
-
19
+6
A
-
35
+3
-
17
+3
27
+13
-
23
+4
-
32**
10
+4
A E G
20
+4
Unchanged
Unchanged
+3
-
+11
-
-
19
D
-
20
Unchanged
Unchanged
Unchanged
+4
25
32**
20
-
30
-
-
23
+10 and bilateralization
B
35
C
*Side and diameter of lesions are evaluated by CT, **in bilateral lesions greater lesion diameter is reported, A: DHEAS: from subnormal to normal; B:
DHEAS: from normal to subnormal; C: morning serum cortisol: from subnormal to normal; D: morning serum cortisol: from normal to subnormal; E: mid-
night serum cortisol: from supranormal to normal; F: midnight serum cortisol: from normal to subnormal; G: plasma ACTH: from normal to subnormal;
H: 24 h UFC excretion: from supranormal to normal; I: 24-h UFC excretion: from normal to supranormal; L: lost of normal cortisol suppressibility after
dexamethasone 1 mg.
monitored (0.70 0.7 μg/ml basal vs 0.6 0.6 at last
follow-up); in particular, normalization of DHEAS
levels was observed in two patients (no. 22 and 46)
with low DHEAS concentration at the beginning of
the study, whereas reduction of DHEAS to subnor-
mal values was observed in two other cases (no. 39
and 53). At the beginning of the study, morning
serum cortisol was normal in all but one patient (no.
27) in whom it was reduced. During the follow-up
mean morning serum cortisol did not change sig-
nificantly in 33 out of 53 patients in whom it was
repeatedly assessed (12.8 4.1 μg/dl basal vs
12.7 3.9 μg/dl at last follow-up). When taken sin-
gularly one patient (no. 50) showed a reduction of
morning serum cortisol to subnormal values; where-
as the one (no. 27), with subnormal values at the
beginning of the study, normalized the hormone
concentration during follow-up.
851

Follow-up of incidentally discovered adrenal adenomas
Table 3 - Hormonal findings at first evaluation in patients with
Midnight serum cortisol was determined at the start
of the study in 28 patients; in 8 of whom (29%) it
was higher than 5 μg/dl: one of these 8 patients
had subclinical Cushing’s syndrome.
Six patients repeated determination of midnight
cortisol during follow-up: in one patient (no. 22)
there was normalization of this parameter, whereas
another (no. 32) showed an increase of hormone
concentration to supranormal values.
subclinical Cushing’s syndrome.
Case
UFC
(μg/24 h)
ACTH
(pg/ml)
Midnight
cortisol
(μg/dl)
Post DEXA
cortisol
(μg/dl)
5
134
180
39
9
2
-
5
15.2
4.3
8
7
39
11
12.9
DEXA: dexamethasone; UFC: urinary free cortisol.
Mean ACTH concentration was low-normal (13.1 9.7
pg/ml); taken singularly 8 cases (15%) had subnormal
values.
without hyperresponse (31.1 6.1 mm vs 24.1 7.4
mm; p<0.01). There was no significant difference
in the proportion of patients showing an increase
in the size of the incidentaloma between hyper- and
normoresponders (20% vs 50%; p>0.05). In partic-
ular, of the 20 patients with normal response at in-
cidentaloma demonstration in whom ACTH stimu-
lation test was repeated, 11 showed an increase in
the size of the lesion (range 3-140), one showed a
reduction of the adrenal lesion and 8 did not show
size changes of the adrenal mass.
On the basis of the established criteria, 3 patients
(5.7%) had subclinical Cushing’s syndrome (Table
3). During follow-up cortisol suppressibility after
dexamethasone worsened in two patients (no. 5
and 39) and became pathologic in one (no. 7); one
patient, who showed a reduction of ACTH concen-
trations to suppressed levels, exhibited a normal-
ization in 24-h UFC excretion (no. 5). In no cases
clinical evolution to overt disease was observed.
These patients underwent adrenalectomy and post-
operative hypoadrenalism occurred in each, lasting
2-16 months after surgery; one patient (no. 5) with
Type 2 diabetes recovered a normal glycemic con-
trol post-operatively, whereas hypertension per-
sisted in two patients (no. 5 and 7).
Mean ACTH level remained unchanged during the
follow-up in 16 of the 19 patients in whom it was
assessed (12.8 4.1 pg/ml basal vs 11.1 7.9 pg/ml
at last follow-up), whereas in 3 patients (no. 5, 22
and 40) ACTH level became <5 pg/ml.
At the beginning of the study, mean UFC excretion
was normal (49.6 27.6 μg/24 h, range 14-180) in
all but two patients (no. 5 and 7) who had values
higher than normal; both these patients had sub-
clinical Cushing’s syndrome.
During follow-up mean UFC excretion did not
change significantly in the 24 patients in whom it
was assessed (55 35.2 μg/24 h basal vs 53.8 22.8
μg/24 h at follow-up). During the follow-up one pa-
tient (no. 5) normalized the hormone excretion
whereas in two cases (no. 9 and 43) hormone levels
became higher than normal.
Adequate post-dexamethasone cortisol suppres-
sion was observed in 36 of 42 patients (86%) eval-
uated; 2 of the 6 patients (no. 5 and 39) who did
not suppress, had subclinical Cushing’s syndrome.
Instead one other patient with subclinical Cushing’s
syndrome (no. 7) lost cortisol suppressibility during
follow-up. No significant difference in cortisol sup-
pressibility was observed in the 32 patients in whom
the test was repeated (basal 3.3 3.7 vs 3.7 4.4
μg/dl, last follow-up).
Baseline 17-OHP concentration was normal in 50
of 52 patients in whom the hormone was evaluated;
in the two patients (no. 16 and 35) who had slight-
ly supranormal levels, normalization of hormone
concentration was observed during follow-up.
Of the 48 patients, in whom ACTH stimulation test
was made, 38 (79%) showed 17-OHP normal re-
sponse and 10 (21%) supranormal response (mean
15.2 3.2 ng/ml; range: 11.5-19.6 ng/ml). No dif-
ference was observed in the mean age of patients
with or without hyperresponse to ACTH stimulation
(63.8 8.6 vs 59.8 10.1 yr). No change in 17-OHP
response to ACTH was observed in each of the pa-
tients re-tested during follow-up.
In the follow-up none of the patients with normal
adrenal function at the diagnosis showed evolution
to hypercortisolism, when re-tested; particularly,
none of the patients with single hormonal alter-
ations (such as inadequate cortisol suppression test
or suppressed ACTH levels) showed evolution to
autonomous adrenal secretion.
DISCUSSION
The decision to surgically treat an incidentally dis-
covered adrenal mass implies the evaluation of ra-
diological appearance, size, secretory activity and
the possible concomitant presence of an extra-
adrenal malignancy. Whereas for malignant and/or
hyperfunctioning lesions surgical excision is manda-
tory, in small benign non-hypersecretory lesions a
Patients hyperresponsive to ACTH stimulation test
had adrenal masses significantly larger than patients
852

E. Grossrubatscher, F. Vignati, M. Possa, et al.
surgical approach seems unnecessary. However, to
decide not to remove an adrenal lesion one should
be confident that no malignant evolution or hor-
monal hyperfunction will take place.
of at least two abnormalities in HPA function as-
sessed by routine endocrine test (11). However, it
clearly appears that is difficult to establish diag-
nostic parameters for an entity that cannot be well-
defined on a clinical ground.
The radiological appearance and the scintigraphic
pattern may reasonably help in excluding the pres-
ence of a malignant lesion in an adrenal inciden-
taloma; however the potential for malignant trans-
formation or growth or hormonal hyperfunction is
unpredictable when the adrenal mass is firstly seen.
As far as the hormonal activity is concerned, at vari-
ance with a report by Barzon et al. (10), the present
data show that during two years of median obser-
vation (range 6-78 months), no patients with nor-
mal adrenal function at diagnosis, developed signs
or symptoms of hyperfunction. Particularly, the pa-
tients who had shown a single hormonal alteration
did not show, when re-tested, evolution towards
autonomous secretion of the adrenal cortex.
In the present selected series the prevalence of
subclinical Cushing’s syndrome (5.7% of cases) is
comparable with that reported in the literature (4, 5,
9). The real prevalence among adrenal inciden-
talomas of lesions with subtle adrenal autonomy
has not been definitely established; in fact it is
strongly influenced by the precision with which hy-
pothalamo-pituitary-adrenal (HPA) axis abnormali-
ties are searched for, when incidentaloma is dis-
covered. The relative low prevalence of Cushing’s
syndrome in the general population in comparison
with that of adrenal incidentalomas suggests that
the vast majority of patients with adrenal inciden-
talomas and biochemical signs of subtle cortisol ex-
cess will never progress to clinically overt disease.
In line with this observation is the finding that one
of the patients of the present series with subclinical
hypercortisolism at the diagnosis, followed up for
a particularly long period before operation (42
months), did never progress to full blown Cushing’s
syndrome. On the other hand the occurrence of hy-
poadrenalism after adrenalectomy proves that the
biochemical signs of autonomous adrenal secre-
tion, although mild, do express a condition of per-
sistent hypercortisolism in spite of the absence of
biochemical or clinical evolution.
Our results indicate that the finding of low for sex
and age DHEAS levels is not a valuable marker of
adrenal adenoma at variance with previous reports
(12, 13). Subnormal DHEAS levels were found only
in 17.6% of cases of this series and changes in the
hormone levels during follow-up occurred rarely
and did not reflect evolution towards autonomy.
Actually, 2 patients normalized previously subnor-
mal hormone concentration and the reduction of
DHEAS levels observed during the follow-up in 2
other cases was not accompanied by additional bio-
chemical derangements consistent with autonomy.
Therefore, other explanations in addition to the
negative feedback exerted by supranormal cortisol
levels on ACTH, might justify low DHEAS levels in
patients with an adrenal adenoma (14).
Overall, even if it has been supposed that cortisol
secreting masses represent a continuous spectrum
of abnormalities, evolving from mild alterations to
overt adrenal Cushing’s syndrome, the data of the
present series do not support this hypothesis, at
least over a medium-term observation.
In this study, in accordance with data of the litera-
ture, the differentiation between benign and malig-
nant lesions was made on the basis of mass diame-
ter, morphological and densitometric features seen
on CT and functional information provided by NP-59
scintigraphy (15-19). According to these criteria we
were reasonably confident that the patients studied
did not harbor a malignant tumor at the beginning
of the study, when they were selected. In the course
of the follow-up with one exception, none of the pa-
tients studied showed size or densitometric changes
of the lesion consistent with malignancy.
Accordingly, although more than 40% of patients
showed an increase in the size of the lesion, this
was overall of a small entity and, more importantly,
not rapidly evolutive as documented by a morpho-
logic evaluation repeated at short time interval,
without changes in the morphodensitometric ap-
pearance of the masses. The only case that might
have suggested the presence of a malignant tumor
for the impressive increase in the size of the mass,
was actually an adenoma with necrotic hemorrhag-
ic changes at surgery. Similarly an adrenal adenoma
turned out to be another mass that had increased
moderately in size during the follow-up. Therefore,
an increase in size may be expected in the natural
history of an adenoma at any time during the fol-
low-up even after a long period of “quiescence”
At variance with data reported by Terzolo et al. (6),
none of the patients with subclinical hypercorti-
solism included in this series, showed regression of
the biochemical abnormalities. This might depend
on a difference in the criteria selected for defining
the condition of sub-clinical hypercortisolism in the
present study. According to the National Italian
Study Group on Adrenal Tumors, subclinical
Cushing’s syndrome can be defined by the absence
of clinical signs of hormone excess in the presence
853

Follow-up of incidentally discovered adrenal adenomas
(up to 43 months in the present series). Similarly
necrotic hemorrhagic degeneration of an adenoma
may also occur, suggesting, for its radiologic ap-
pearance, the presence of a carcinoma.
In the course of the follow-up adrenalectomy was
performed in 7 patients and in each case the re-
moved lesion was benign. Overall these data sug-
gest that the criteria selected to exclude malig-
nancy prove reliable; although based on a single
observation, it seems reasonable to consider a con-
servative approach also for lesions >4 cm in partic-
ular cases, when the patient is not a candidate for
surgery as long as other criteria to exclude malig-
nancy are respected.
Our data also show that the increase in the size of
the adrenal masses is not related to the presence of
a steroidogenic defect such as 21-hydroxylase de-
ficiency. Indeed although patients hyperresponsive
to the ACTH stimulation test had adrenal masses
significantly larger than patients without hyperre-
sponse, no significant difference was observed in
the proportion of patients showing an increase in
the size of the incidentaloma between hyper and
normoresponders.
There is no simple explanation for this finding; a cor-
relation between the size of an incidentaloma and
the peak 17-OHP response to ACTH in patients with
enzymatic defect has been observed by Seppel et
al. (8). Moreover reversibility of enzyme dysfunction
after surgical removal of tumoral tissue has been re-
peatedly reported (5, 8), suggesting an intra-tumoral
21-hydroxylase defect. It could be hypothesized that
the occurrence of the enzyme dysfunction represents
a gain for the growth of the tumor; the intratumoral
nature of the enzymatic defect could explain the ab-
sence of differences in plasma ACTH concentrations
between normo- and hyperresponders (8). However,
that would not explain the evidence of a similar po-
tential for growth of the mass in patients with nor-
mal or supranormal 17-OHP response during follow-
up. In addition in no cases the increase in the size of
the mass was accompanied by a change in the re-
sponsiveness to the ACTH stimulation test in 11 out
of 20 normoresponder patients in whom the test was
repeated, in line with this observation.
we could also observe size reduction or even disap-
pearance of mono and bilateral adrenal lesions in six
patients. This finding support the view that further CT
scans are probably not required in patients showing
evidence of size reduction of their adrenal lesions.
Overall the present data indicate that a conservative
management of non secreting, benign, adrenal inci-
dentalomas is appropriate for small lesions (<4 cm)
and can be considered for lesions greater than 4 cm
in particular cases, provided that adequate radiolog-
ical, hormonal and scintigraphic evaluation is made
at the diagnosis. Considering that small adrenal mass-
es, although unchanged in size or appearance over a
number of years, have a potential for growth, we do
not agree with Barry et al. (20), that only a comparison
CT should be made three months after diagnosis, but
we suggest that CT should be repeated periodically
(every 2 yr) until a greater knowledge of long-term
evolution of adrenal incidentalomas is available.
No patients of the present series, with normal
adrenal function at diagnosis, developed signs or
symptoms of hyperfunction nor patients with a sin-
gle hormonal alteration showed, when re-tested,
evolution towards autonomous secretion of the
adrenal cortex. This finding is in accordance with a
recent report by Rossi et al. showing unchanged
clinical and hormonal features in 38 patients with
non-functioning incidentally discovered adrenal ade-
noma (21). The present data suggest that each pa-
tient with an adrenal incidentaloma should have an
accurate initial hormonal evaluation to detect func-
tional autonomy of the lesion. The presence of hor-
monal derangements, balanced with the presence
and relevance of possible clinical signs (such as hy-
pertension, glucose intolerance), should help to se-
lect the appropriate therapeutical solution. So far,
due to the lack of clearcut criteria to define pre-clin-
ical Cushing’s syndrome and to the limited data on
the follow-up of these patients, there is no convinc-
ing evidence of an evolution from a subclinical to
an overt expression of Cushing’s syndrome.
Although limited to a medium-term period, our da-
ta indicate that there is no need to repeat testing
during follow-up in patients who bear non-func-
tioning adenomas.
Similarly, not related to the presence of an enzy-
matic defect, is another interesting finding of the
present report, i.e. the occurrence of a bilateral in-
volvement of the adrenals in the course of the fol-
low-up in subjects with evidence of a monolateral
lesion at the beginning of the study. This occur-
rence is not related to the presence of hormonal
derangements.
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