Prospective evaluation of tumor size and hormonal status in adrenal incidentalomas
S. Yener1, S. Ertilav1, M. Secil2, T. Demir1, B. Akinci1, L. Kebapcilar1, A. Comlekci1, F. Bayraktar1, and S. Yesil1 1Division of Endocrinology and Metabolism, Department of Internal Medicine; 2Department of Radiology, Dokuz Eylul University, Izmir, Turkey
ABSTRACT. Background: Because of the increased use of imaging interventions, more subjects have been diagnosed with adrenal incidentaloma in recent years. Aim: To evaluate the risk of mass enlargement, hormone hypersecretion and development of adrenal carcinomas during short-term follow- up. Subjects and methods: There were 317 subjects with in- cidentally discovered adrenal tumors in the registry. Forty subjects were excluded because of clinically overt hormone secretion at diagnosis and subjects with complete data were included in radiological (no .= 150) and hormonal (no .= 150) fol- low-up. Radiological evaluation was performed with comput- ed tomography (CT) and/or magnetic resonance imaging (MRI). There were 143 subjects with adrenal adenomas and 7 subjects with other tumor types (cyst or myelolipoma). Me- dian follow-up duration was 24 months. Results: Increase in tumor size was detected in 25 subjects (17.4%) with adeno- mas and 1 subject with adrenal myelolipoma (14.3%). De-
INTRODUCTION
Because of the developments in radiological procedures and due to the increased use of imaging interventions, more subjects have been diagnosed with adrenal inci- dentaloma in recent years (1). It is plausible to estimate that incidentally discovered adrenal tumors will be a growing clinical problem also in the future.
In adrenal adenomas, current data regarding tumor growth, development of overt or subclinical hormone secretion or malignancy depend on some prospective studies (2-17). Generally, it was demonstrated that development of a ma- lignant tumor in follow-up was quite rare. Increase in tumor size was found in 0-27% of the participants in different stud- ies. Development of hormone secretion in terms of cortisol axis was shown in 0-11% of the participants during follow- up. Despite the marked differences between these rates, cumulative risk rate for mass enlargement and hormone hy- persecretion was found to be associated with longer fol- low-up duration in most of these studies.
The objective of this study is to demonstrate the rates of tumor enlargement, hormone hypersecretion and malig- nant transformation in subjects with incidentally discovered adrenal masses during a median follow-up of 24 months.
crease in tumor size was found in 7 subjects (4.8%) with adrenal adenomas. One patient was diagnosed with adreno- cortical carcinoma during follow-up. In subjects with non-func- tioning adrenal adenoma (NFA, no .= 120) or subclinical Cush- ing syndrome (sCS) (no .= 30), no subject developed clinically overt hormone hypersecretion, while 8 (6%) subjects in the NFA group developed sCS. Tumor diameter and follow-up duration were significantly higher in subjects who developed sCS. Conclusion: In conclusion, we demonstrated that, despite being infrequent, adrenal tumors may increase in size, devel- op overt or subclinical hormone secretion or feature malig- nant transformation. Therefore, radiological and hormonal follow-up should be recommended to the patients. More in- vestigations are needed for the establishment of long-term follow-up protocols.
(J. Endocrinol. Invest. 33: 32-36, 2010)
@2010, Editrice Kurtis
MATERIALS AND METHODS
This prospective study was conducted in the Division of En- docrinology and Metabolism, Dokuz Eylul University. The local Ethics Committee of Dokuz Eylul University approved the study. All subjects who were referred to our institute with incidentally discovered adrenal tumors from 2002 were recorded. The only exclusion criterion was the presence of adrenal gland metasta- sis. Adrenal gland metastasis was diagnosed histologically in 13 subjects. Additionally, subjects with extra-adrenal malignancies and suspicious adrenal tumors in computed tomography (CT) or magnetic resonance imaging (MRI) were also excluded.
Initial radiological examination was CT in study participants. Ra- diological follow-up was performed with CT and/or MRI at the 6th and 12th months and annually in subsequent visits. Malignancy was excluded if the following criteria were met in CT: a) regular shape with well-defined margins and homogenous attenuation value of b) 10 or less Hounsfield units on unenhanced CT scan, and c) 30 or less Hounsfield units on enhanced CT scan. MRI was performed when CT scan failed to confirm the diagnosis. Additionally, MRI was preferred in cases of hypersensitivity his- tory to non-ionic iodinated contrast medium or history of im- paired renal function.
Hormonal evaluation was performed 6 months after the initial vis- it and annually in subsequent visits. Hormonal evaluation included 08.00 h cortisol, DHEAS, ACTH and in hypertensive subjects plas- ma renin activity and serum aldosterone. Subsequently, urinary free cortisol (UFC, normal range: < 110 mg), urinary normeta- nephrine (normal range: 88-444 mg/day) and urinary metanephrine (normal range: 52-341 mg/day) were measured and overnight 1 mg dexamethasone suppression test (DST) was performed.
The suppression in overnight DST was adequate when morn- ing cortisol fell below 1.8 mg/dl. When post-DST cortisol was over 1.8 mg/dl, 2-day 2 mg DST involving the administration
Correspondence: Serkan Yener, MD, Dokuz Eylul University, School of Medicine, De- partment of Internal Medicine, Division of Endocrinology and Metabolism, 35340 In- ciralti, Izmir, Turkey.
E-mail: serkan.yener@deu.edu.tr
Accepted April 9, 2009.
First published online June 18, 2009.
of 0.5 mg oral dexamethasone given every 6 h for 48 was per- formed. In subjects with non-suppressed cortisol levels, diur- nal rhythm of cortisol was also evaluated (normal: midnight cor- tisol <7.5 µg/dl). Subclinical Cushing syndrome (sCS) was de- fined if post-DST cortisol >1.8 ug/dl and at least one of the fol- lowing conditions was positive; ACTH<5 pg/ml, UFC>110 mg/day or midnight cortisol >7.5 µg/dl.
Pheochromocytoma was defined with elevated levels of urinary normetanephrine and/or metanephrine. Primary hyperaldos- teronism (PHA) was screened in hypertensive subjects with al- dosterone/plasma renin activity ratio (ARR). In subjects with ARR>25, saline infusion test was performed. Adrenal vein sam- pling was performed in one subject.
The number of subjects in the registry was 317 in December 2008. At admission, we diagnosed 16 subjects with Cushing syn- drome, 17 subjects with benign pheochromocytoma, 2 subjects with malign pheochromocytoma and 10 subjects with PHA. These patients (except 5 subjects with PHA who refused adrenalectomy) were excluded from prospective follow-up. Among the remaining 277 individuals, data of subjects with com- plete follow-up were evaluated in the prospective study. There were 150 subjects each in radiological and hormonal follow-up groups. Summary of the study was demonstrated in Figure 1. During follow-up adrenalectomy was recommended in case of development of overt hormone hypersecretion, significant mass enlargement or radiological suspicion of primary adrenal ma- lignancy.
Cortisol, DHEAS and ACTH were measured using chemilumi- nescence enzyme immunoassay kits (Immulite, Diagnostic Prod- ucts Corporation, Los. Angeles, USA). Plasma renin activity and aldosterone were measured using radioimmunoassay kits. UFC and metanephrines were measured by high performance liquid chromatography (Agilent Technologies, Santa Clara, USA).
Statistical analysis was performed with SPSS V 15.0. Each con- tinuous variable was assessed with Kolomogorov-Smirnov test. Variables with normal distribution were expressed as mean+SD. Median and range were given for the variables without normal distribution. Related samples were compared with Mc-Nemar test for dichotomous variables. Wilcoxon test or paired samples t-test was performed for continuous related samples. Comparisons between groups were performed with
Chi-square test for dichotomous variables. Independent sam- ples t-test or Mann-Whitney U test was used according to the distribution of the continuous variable.
RESULTS
There were 86 males and 231 females. Mean age at di- agnosis was 54.7+13.1. Male subjects were significantly older at diagnosis (58.0±12.4 vs 53.3+13.3, p=0.005). Median tumor size at diagnosis was 24 mm (7-97 mm). There were 45 subjects with bilateral adrenal tumors, 3 subjects with multiple left adrenal gland tumors and 2 subjects with multiple right adrenal gland tumors. Right adrenal tumors were more common (190 vs 172). Initial radiological intervention was CT in 173 subjects, ultra- sonography in 113 subjects and MRI in 30 subjects. Tu- mors detected with ultrasonography were significantly larger (30.0 mm, 7-97 mm) than CT (20 mm, 8-50 mm, p<0.001) or MRI (20 mm, 8-50 mm, p<0.001) detected tumors.
Radiological diagnosis at admission was adrenal adeno- ma in 299 subjects, radiological suspicion for malignan- cy in 2 subjects (malign pheochromocytomas) and adrenal mass in 1 subject (no specific radiological diag- nose at admission; this patient featured 60 mm tumor enlargement in 6 months and diagnosed with primary adrenocortical malignancy), adrenal cyst in 9 subjects and adrenal myelolipoma in 6 subjects.
Initial hormonal evaluation demonstrated that 212 sub- jects had non-functioning adrenal adenomas, 45 subjects had sCS, 16 subjects had Cushing syndrome, 19 subjects had pheochromocytomas and 10 subjects had PHA. Baseline characteristics of the subjects regarding tumor type and hormonal evaluation are shown in Table 1.
Prospective radiological evaluation was carried out in 150 subjects. Median follow-up duration was 24 months (6- 159 months). There were 112 subjects with non-func- tioning adenomas (NFA), 27 subjects with sCS, 4 subjects with PHA and 7 subjects with adrenal cysts or myelolipo- mas in the prospective follow-up group. Characteristics of the follow-up group adjusted to the initial clinical diag-
Subjects in the registry (no .= 317)
Excluded from follow-up at admission (no .= 40) Cushing syndrome (no .= 16) Pheochromocytoma (no .= 19) PHA (no .= 5)
Evaluated for prospective follow-up (no .= 277) Non-functioning adrenal adenoma (no .= 212) Subclinical Cusching syndrome (no .= 45) Other tumors (cyst or myelolipoma) (no .= 15) PHA refused surgery (no .= 5)
Excluded from follow-up (no .= 122) Missing data Declined follow-up Single data available Inappropriate data
Radiolocical follow-up (no .= 150)
Hormonal follow-up (no .= 150)
| Groups | NFA (no .= 212, 67%) | sCS (no .= 45, 14%) | PHEa (no .= 19, 6%) | CS (no .= 16, 5%) | PHA (no .= 10, 3%) | Otherb (no .= 15, 5%) |
|---|---|---|---|---|---|---|
| Age (yr) | 56.3±12.2 | 59.6±10.0 | 46.0±12.7 | 40.7±13.2 | 50.4±11.3 | 43.3±18.1 |
| Gender (M/F) | 60/152 | 9/36 | 9/10 | 1/15 | 2/8 | 5/10 |
| Tumor size§ (mm) | 20 (8-60) | 25 (7-55) | 50 (25-97) | 35 (20-60) | 11 (7-20) | 40 (20-70) |
| Bilateral | 32 | 10 | 2 | 1 | - | - |
NFA: non-functioning adenoma; sCS: subclinical Cushing syndrome; PHE: pheochromocytoma; CS: Cushing syndrome; PHA: primary hyperaldosteronism; M: male; F: female. Data is expressed mean +SD or median (range). aTwo subjects had malign PHE (mean age: 59.0+4.2; male; median diameter: 85 mm, solitary tumor). bNine subjects with adrenal cysts and 6 subjects with adrenal myelolipomas. $p<0.001 for overall comparison (one-way analysis of variance).
nosis are demonstrated in Table 2. Increase in tumor size was detected in 17% of the subjects with adrenal ade- nomas (19.6, 11.6 and 0% for NFA, sCS and PHA, re- spectively). In other tumors group, one patient with adrenal myelolipoma featured mass enlargement during follow-up. Decrease in tumor size was 4.5 and 7.4% in NFA and sCS groups, respectively. No change in tumor size was detected in PHA subjects who were on spirono- lactone therapy. Follow-up duration was significantly longer in subjects who developed mass enlargement [21 (6-96) months vs 39 (6-159) months, p=0.025].
Adrenalectomy was suggested because of atypical ra- diological appearance of the tumor in one subject in other tumors group (pathological diagnosis was hydatid cyst of the adrenal), because of the effects of hormone hypersecretion in sCS and PHA groups (pathological di- agnosis was adrenal adenoma). Additionally, adrenalec- tomy was performed because of tumor enlargement (60 mm in 6 months) in one subject in sCS group (patho- logical diagnosis was adrenocortical carcinoma). In the NFA group, adrenalectomy was suggested because of large tumors (50 mm and 35 mm, no .= 2), mass en- largement (no .= 1) or accompanying prostate carcino- ma (no .= 1). Pathological examination revealed no ma- lignancy.
Among 257 subjects who were diagnosed with NFA or sCS at the initial visit, prospective hormonal evaluation was performed in 150 subjects. Median follow-up dura-
tion was 24 months (6-132 months). In subjects with non- functioning adrenal adenoma (no .= 120), no subject de- veloped pheochromocytoma, PHA or overt Cushing syn- drome, while 8 subjects developed sCS during follow- up. In patients with sCS (no .= 30), we did not observe development of overt Cushing syndrome during prospective evaluation. Among subjects with NFA, we showed that tumor diameter and follow-up duration were significantly higher in subjects who developed sCS (Table 3). After excluding the data of 20 subjects be- cause of mismatch between hormonal and radiological parameters in the NFA group, the risk of developing sCS was found to be higher without statistical significance (11.53 vs 6.75%, p>0.05) in subjects who featured mass enlargement during follow-up.
Five of the patients died during follow-up due to extra- adrenal conditions, coronary artery disease (no .= 2), ma- lignancy (no .= 2) and chronic obstructive lung disease (no .= 1).
DISCUSSION
In this prospective study we showed that size of adrenal adenomas tended to be stable during a short follow-up period. One new case of primary adrenocortical malig- nancy was diagnosed while no clinically overt hormone hypersecretion was described. The rate of sCS develop- ment was quite low. Tumor growth and development of
| NFA+sCS+PHA (no .= 143) | NFA (no .= 112) | sCS (no .= 27) | PHAª (no .= 4) | Otherb (no .= 7) | |
|---|---|---|---|---|---|
| Age (yr) | 56.6±11.3 | 55.3±11.6 | 62.4±8.4 | 50.4±11.3 | 43.3±18.1 |
| Gender (M/F) | 39/104 | 32/80 | 7/20 | 0/4 | 2/5 |
| Initial tumor size§,* (mm) | 20 (7-60) | 20 (8-60) | 28 (7-55) | 11 (10-20) | 35 (20-65) |
| Median follow-up (months) | 24 (6-159) | 24 (6-159) | 17 (6-187) | 26 (6-45) | 36 (8-62) |
| Increase in tumor size (no.) (%) | 25 (17.4%) | 22 (19.6%) | 3 (11.1%) | - | 1 (14.3%) |
| Increase ≥10 mm (no.) | 7 | 5 | 2 | - | 1 |
| Decrease in tumor size (no.) (%) | 7 (4.8%) | 5 (4.4%) | 2 (7.4%) | - | - |
| Decrease ≥10 mm (no.) | 1 | 1 | - | - | - |
| Surgery in follow-upc (no.) (%) | 7 (4.8%) | 4 (3.6%) | 2 (7.4%) | 1 (25%) | 1 (14.3%) |
NFA: non-functioning adenoma; sCS: subclinical Cushing syndrome; PHA: primary hyperaldosteronism; M: male; F: female. Data are expressed as mean +SD or median (range). ªSubjects who refused adrenalectomy and followed with spironolactone. bSubjects with adrenal cysts (no .= 3) or adrenal myelolipo- mas (no .= 4). cAdrenalectomy was suggested because of atypical radiological appearance in one subject in other tumors group (pathological diagnosis: adrenal hydatid cyst), because of the effects of hormone hypersecretion in sCS and PHA groups. In the NFA group, adrenalectomy was suggested be- cause of large tumors (50 mm and 35 mm, no .= 2), mass enlargement (no .= 1) or accompanying prostate carcinoma (no .= 1). Additionally, in one subject from sCS group, tumor size increased by 60 mm in 6 months and the subject was diagnosed with adrenocortical carcinoma after surgery. §p<0.001 for overall comparisons (one-way analysis of variance). sp<0.05 for Other vs NFA, sCS or PHA; * p<0.05 for sCS vs PHA (one-way analysis of variance).
| NFA follow-up Silent (no .= 112) | NFA follow-up Developed sCS (no .= 8) | p | ||
|---|---|---|---|---|
| Age (yr) | 55.5±11.6 | 57.3±9.3 | 0.685 | |
| Gender (M/F) | 32/80 | 2/6 | 0.982 | |
| Tumor size (mm) 20 (8-60) | 25 (20-40) | 0.017 | ||
| Initial 8.00 cortisol (µg/dl) | 14.2±5.8 | 12.4±3.7 | 0.546 | |
| Initial post-DST cortisol (ug/dl) | 1.33±0.37 | 1.36±0.25 | 0.615 | |
| Initial ACTH (pg/ml) | 18.01±8.9 | 27.3±18.7 | 0.320 | |
| Initial DHEAS (ug/dl) 96.1±95.6 | 94.3±45.9 | 0.470 | ||
| Follow-up duration (months) 24 (6-132) | 62 (16-80) | 0.009 | ||
DST: dexamethasone suppression test; NFA: non-functioning adenoma; sCS: subclinical Cushing syndrome; M: male; F: female. Comparisons were performed with Mann-Whitney U test. Data are expressed as mean ±SD or median (range).
subclinical hormone secretion was significantly associat- ed with follow-up duration.
Mean age of the subjects with adrenal adenomas who did not have clinically overt hormone secretion (NFA + sCS, no .= 255) was 56.9 years and age distribution peaked at the sixth decade. This condition could be ex- plained with the increased number of diagnostic inter- ventions in elderly subjects. However, it should be not- ed that previous autopsy studies demonstrated in- creased number of cortical nodules in elderly subjects that could be partially explained by compensatory hy- perplasia of cortical cells to aging-associated ischemia and atrophy (18-20). Subjects with clinically hormone active tumors were significantly younger as they were diagnosed without delay by the recognition of specific symptoms. Participants with other tumor types of the adrenal gland were also younger and only 3 patients were older than 60. In spite of the lack of specific symp- toms, these tumors might have been discovered more rapidly with their larger sizes.
In the whole sample adrenal tumors were more frequent at the right side. Right adrenal gland can be visualized better by ultrasonography (20). In the present study, ul- trasonography detected right adrenal gland tumors were more common (81 vs 51), while CT (93 vs 104) and MRI (17 vs 16) did not have significant differences in tumor localization.
One of the main objectives of the present study was the prospective evaluation of tumor size in subjects with adrenal adenomas. We also prospectively evaluated 4 subjects with PHA who refused adrenalectomy and 7 sub- jects with adrenal cysts or myelolipomas. In subjects with adrenal adenomas (NFA + sCS + PHA; no .= 143), 78% of the tumors were stable in size during 24 months. Increase in tumor size was detected in 17% while decrease was detected in 5% of the subjects. Mass enlargement ≥10 mm was detected in 4.8% and decrease in size ≥10 mm was detected in 0.7% of the adenoma group. The rate of mass enlargement during follow-up was more com- mon in NFA when compared with sCS. Mass enlarge- ment was frequently small in adrenal tumors reflecting the benign nature of the tumor. Barzon et al., in their re-
view (1), evaluated published series of adrenal adeno- mas between 1989 and 2002 (2-6, 8-17). They demon- strated that during a mean follow-up duration of 3 years, 9% of the cases showed mass enlargement greater than 10 mm while mass reduction or disappearance was re- ported in 3.6% of the cases. In our study the follow-up period is shorter than those reported previously and this may explain the difference between mass enlargement rates. In a recent prospective, multicenter study, Bülow et al. demonstrated that 12.6% of the cases showed mass enlargement and 5.2% had mass size reduction during 24-month follow-up (7). The follow-up duration and ac- cordingly mass enlargement rate of this study were par- allel with our results. In our series, follow-up duration seemed to be the most important factor associated with increased risk of mass enlargement. Despite the small numbers in each group, we also showed that subjects with PHA who were on medical therapy and subjects with other tumor types featured stable tumor size during fol- low-up.
Eight subjects (NFA no .= 4, sCS no .= 2, PHA no .= 1 and myelolipoma no .= 1) were suggested adrenalectomy dur- ing follow-up. Adrenalectomy was suggested because of mass enlargement in one subject in the sCS group. She was a 68-year-old female patient with a 24 mm right adrenal mass. In 6 months adrenal tumor became 84 mm and she was operated. Pathological diagnosis was adrenocortical carcinoma. In the remaining subjects in the sCS group and in subjects in the PHA group surgery was suggested because of the effects of hormone hy- persecretion. We suggested surgery because of atypical radiological appearance of the tumor in one subject in other tumors group and diagnosed adrenal hydatid cyst. In subjects with NFA, adrenalectomy was suggested be- cause of the history of prostate carcinoma in one patient, because of mass enlargement in one patient and because of large tumors (50 and 35 mm) in two subjects. Mass en- largement was slow and small reflecting the presence of a benign tumor, and it was confirmed with pathological examination.
In this study, none of the patients in the NFA group de- veloped overt Cushing syndrome, pheochromocytoma or PHA during follow-up. Besides, none of the subjects with sCS developed overt Cushing syndrome. Among subjects in the NFA group, after a median follow-up du- ration of 24 months, the rate of sCS development was found to be 6.6%. The previous literature on this issue has demonstrated a wide range of cortisol hyperfunction rates from % to 11.1% (2-6, 8-17). Barzon et al. demon- strated that estimated cumulative risk of subclinical glu- cocorticoid production was 3.8% after 1 year and 6.6% af- ter 5 years (3). The variety between our findings and re- ported rates may be associated with different diagnos- tic criteria of sCS among studies.
We showed that larger tumor size at diagnosis and longer follow-up duration were associated with sCS develop- ment. In addition, sCS developed more frequently in growing tumors. These findings may suggest that devel- opment of glucocorticoid hypersecretion might be asso- ciated with an increase in mass size.
The leading limitation of our study was its single center design. Additionally, the number of excluded patients
because of missing data, single data or unwillingness was higher than expected.
In conclusion, this prospective, short-term follow-up study demonstrated that, despite being infrequent, adrenal tu- mors may increase in size, develop overt or subclinical hor- mone secretion or feature malignant transformation. There- fore, radiological and hormonal follow-up should be rec- ommended to the patients. More investigations are need- ed for the establishment of long-term follow-up protocols.
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