Clinical Characteristics and Follow-Up Results of Adrenal Incidentaloma
Authors Nusret Yilmaz, Esin Avsar, Gokhan Tazegul, Ramazan Sari, Hasan Altunbas, Mustafa Kemal Balci
Affiliations
Akdeniz University, School of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Antalya, Turkey
Key words
Pheochromocytoma, Adrenal gland, Hormones, adrenal incidentaloma
| received | 04.09.2019 |
| revised | 02.12.2019 |
| accepted | 09.12.2019 |
Bibliography
DOI https://doi.org/10.1055/a-1079-4915 Published online: 2020 Exp Clin Endocrinol Diabetes @ J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York ISSN 0947-7349
Correspondence
Dr. Ramazan Sari Department of Internal Medicine, Endocrinology and Metabolism, Akdeniz University, Antalya TR-07070 Turkey Tel .: + 00 90 242 249 6868, Fax: + 00 90 242 227 4490 rsari@akdeniz.edu.tr
ABSTRACT
It is recommended that adrenal incidentaloma patients should be monitored for radiological changes, increase in size and new functionality that may occur in the future, even if they are be- nign and nonfunctional at the initial evaluation. Our aim is to evaluate the key clinical characteristics of adrenal incidentalo-
ma patients focusing on changes during follow-up and associ- ated clinical outcomes. A total of 755 patients (median age: 56 years), with an adrenal incidentaloma > 1 cm and underwent functionality tests, were included in the study. Clinical charac- teristics, functionality status and follow-up durations were recorded. During the course of follow-up, any changes in size and development of new functionality, and clinical conse- quences thereof were evaluated. In 71.8 % of patients, inciden- talomas were non-functional. Most frequent functionality (15.8%, n=119) was subclinical hypercortisolemia (SH) [10.9% (n =82) possible autonomous cortisol secretion (PACS) and 4.9% (n=37) autonomous cortisol secretion (ACS)] of all inci- dentalomas. Frequencies of Cushing’s syndrome (CS), pheo- chromacytoma and primary hyperaldosteronism were 4.9 % (n=37), 3.8% (n=29) and 3.7% (n=28), respectively. Adreno- cortical carcinoma frequency was 1.5% (n =11). Of 755 pa- tients, 43 % (n=325) were followed up regularly more than 6 months. Median follow-up duration was 24 months (6-120). A total of 17 (5.2%) patients, which had non-functional inci- dentalomas at baseline had developed new functionality during follow-up, of which 15 (4.6%) were SH [13 patients (4%) PACS and 2 patients (0.6%) ACS] and 2 (0.6%) were CS. During fol- low-up, 24% (n=78) of the patients had an increase in mass size between 5-9 mm, while 11.7% (n=38) of the patients had an increase of ≥ 10 mm. During follow-up, 4% (n =13) of the patients developed a new lesion with a diameter ≥ 10mm on the opposite side. In patients with a follow-up duration of more than 2 years, frequencies of size increase and new lesion emerg- ing at the opposite adrenal gland were higher. 14 patients (4.3% of the patients with regular follow-up) underwent sur- gery due to increase in size or development of new functional- ity during follow-up. Our study demonstrated that a necessity for surgery may arise due to increase in size and development of functionality during follow-up period in adrenal inciden- taloma patients, and thus continuing patient follow-up, even with wider intervals, will be appropriate.
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Introduction
Adrenal incidentalomas have a gradually increasing figure of detec- tion in recent years due to the development of novel imaging meth- ods and increased use thereof in the clinical practice [1-3]. In turn adrenal incidentalomas assumed an important place in endocrinol-
ogy practice. The majority of adrenal incidentalomas are benign and non-functional, and the evaluation of whether they are malignant and/or functional constitutes the basis of the clinical approach [4, 5]. In addition to clinical hyperfunctionality in patients with adrenal in- cidentaloma, the importance of subclinical hyperfunction has been emphasized for many years. Adrenal incidentaloma patients with au-
tonomous cortisol secretion have been reported to have higher mor- tality than patients with non-functional adrenal incidentalomas [6]. Similarly, shorter survival has been reported in patients with adrenal incidentaloma with less suppression of cortisol after dexamethasone suppression test (DST) [7, 8]. There are various guidelines on how to approach patients with adrenal incidentaloma, however, remarka- ble heterogeneity of patient population makes it challenging to es- tablish an optimal approach on radiological follow-up in particular, and thus a consensus has not yet been reached [5, 9]. In this study, our aim is to evaluate the key clinical characteristics of patients with adrenal incidentaloma as well as to assess the associated malignan- cy and functionality rates, change in mass size and development of functionality during follow-up, and clinical progression.
Method
The study was approved by Akdeniz University Faculty of Medicine Clinical Research Ethics Committee (Decision number: 2019/966). Data of patients admitted to Akdeniz University Faculty of Medi- cine Endocrinology Outpatient Department between January 2006 and January 2018 with an adrenal incidentaloma larger than 1 cm with complete hormonal functionality evaluation were retrospec- tively evaluated. Basic demographic data and comorbidities of pa- tients were recorded. Patients with a previously known malignan- cy were excluded from the study. Data from 879 patients were in- cluded in the study. A total of 124 patients were excluded from the study, including 80 patients with previously known malignancies and 44 patients whose functional evaluations were not fully per- formed. Data from 755 patients were analyzed.
The radiological method with which adrenal incidentaloma was detected and the reason for radiological imaging were evaluated. Computed tomography (CT) and/or magnetic resonance (MR) find- ings were reviewed and radiological pre-diagnoses (adenoma, non- adenomatous lesion, myelolipoma or cyst) of adrenal incidentalo- mas were recorded. Masses with homogeneous, uniformly limited, densities < 10 Hounsfield Units (HU) on non-contrast tomography; masses with a relative washout rate >240% and absolute washout rate > 1060% on contrast-enhanced tomography were classified as adenomas [10-15]. Adenomas were also defined as masses isoin- tense with liver in T1 and T2-weighted sequences, with mild con- trast enhancement and rapid wash-out, and signal loss in out-of- phase images, and bright-looking in in-phase images with mag- netic resonance imaging [10-15]. Masses whose radiological features were not compatible with adenoma, cyst or myelolipoma and those whose radiological features were compatible with ma- lignancy or pheochromacytoma were classified as non-adenoma- tous masses. Patients which were diagnosed with ultrasound im- aging underwent confirmatory CT and/or MRI scans. The size, lo- cation and functionality of adrenal incidentalomas were recorded.
Biochemical and hormonal data of patients were reviewed and the endocrine functions of the masses were evaluated. Incidentalo- mas in patients whose cortisol levels were suppressed (≤ 1.8 µg/ dL) following 1 mg DST, with normal 24-hour metanephrine-nor- metanephrine levels in urine, and plasma aldosterone (ng/dl)/renin (ng/ml/h) ratio < 20 were considered “non-functional”[9]. Patients
with symptoms and signs associated with hypercortisolemia (pur- ple striae, proximal muscle weakness, easy bruising, etc.), with at least 2 results from different tests performed to evaluate hypercor- tisolemia (cortisol level after 2 days-2 mg DST, late night salivary cortisol level, midnight serum cortisol level or 24-hour urinary free cortisol (UFC) level) compatible with hypercortisolemia, and low adrenocorticotropic hormone (ACTH) (<10 pg/ml) level were con- sidered to have “adrenal Cushing Syndrome (CS)“[16]. Patients with low ACTH level (<10 pg/ml) and high cortisol level after 1 mg DST, one more positive test result compatible with hypercorti- solemia (high cortisol level after 2 days-2 mg DST, high 24-hour UFC level, low dehydroepiandrosterone-sulphate (DHEA-S), high late night salivary cortisol or midnight serum cortisol level), but no symptoms or signs compatible with hypercortisolemia were con- sidered to have subclinical hypercortisolism (SH) [5, 17]. Biochem- ical and hormonal tests were performed in-house using commer- cial kits at our hospital laboratory. The cut-off value for cortisol level after 1 mg and 2 days-2 mg DST was set as 1.8 ug/dL [16].
Patients with subclinical hypercortisolemia were divided into two groups according to serum cortisol levels after 1mg DST ac- cording to the latest guidelines. Patients with serum cortisol levels between 1.9 and 5 µg/dL were classified as “possible autonomous cortisol secretion” (PACS), whereas, patients with a serum cortisol level higher than 5 µg/dL were classified as “autonomous cortisol secretion” (ACS) [9].
For midnight serum cortisol, serum sample was collected while the patients were awake and the cut-off value was set as 7.5 µg/dL [16]. The test result was considered positive in the event of 24-hour UFC level above the reference value [16]. For late night salivary cor- tisol, the cut-off value was set as 0.27 ug/dL[18]. Patients with 24- hour urine metanephrine and/or normetanephrine levels more than 3-folds higher than the normal value were classified as pheo- chromacytoma [19]. Patients with plasma aldosterone (ng/dL)/ renin (ng/ml/h) ratio higher than 20, and of the patients with sup- pressed renin levels, those with aldosterone levels after saline sup- pression test higher than 10 ng/dL were diagnosed with primary hyperaldosteronism (PHA) [20].
After the first evaluation, patients with a follow-up of more than 6 months were investigated to figure out and record whether any functionality and increase in mass size has taken place during fol- low-up. In the event of surgery, relevant indication and pathology results were extracted from the files.
Statistical analysis
Data were analyzed using SPSS V.21 package software. Nominal data were presented as frequency (percentage); ordinal data and continuous variables were shown as median (minimum-maximum). To analyze the intergroup differences of categorical variables, X2 tests were applied. Continuous variables were evaluated using Mann-Whitney U test or independent sample t-test for independ- ent variables in pairwise comparison of subgroups. Sensitivity vs (1-specificity) was tested by receiver operating characteristic (ROC) analysis and expressed as the area under the curve (AUC). A p value <0.05 was considered statistically significant.
Results
The data of 755 patients, 497 (65.8 %) of which were female and 258 (34.2%) were male, were analyzed in the study. The patients’ basic characteristics, reasons for radiological imaging, radiological diagnoses and the diameter, size and functionality status of inci- dentalomas are shown in Table 1. Incidentalomas were most often detected in radiological imaging of gastrointestinal system (39.6%) and using CT (82%) (+Table 1).
Radiological diagnosis was reported as adenoma in 78.5 % (n=593), non-adenomatous lesion in 16.3 % (n= 123), myelolipo-
| Age (years) (median) | 56 (18-86) |
|---|---|
| Gender | |
| Male (n, %) | 258 (34.2) |
| Female (n, %) | 497 (65.8) |
| Comorbidity (n, %) | 453 (60) |
| Hypertension (n, %) | 326 (43.2) |
| Diabetes mellitus (n, %) | 214 (28.3) |
| Hyperlipidemia (n, %) | 159 (21.1) |
| Coronary artery disease (n, %) | 63 (8.3) |
| Osteoporosis (n, %) | 33 (4.4) |
| Reason for imaging | |
| Gastrointestinal (n, %) | 299 (39.6) |
| Respiratory (n, %) | 154 (20.4) |
| Genitourinary (n, %) | 100 (13.2) |
| Other/non-classified (n, %) | 202 (26.8) |
| The imaging method used in the first detection | |
| CT (n, %) | 619 (82.0) |
| MRI (n, %) | 81 (10.7) |
| Ultrasound (n, %) | 55 (7.3) |
| Radiological diagnosis | |
| Adenoma (n, %) | 593 (78.5) |
| Non-adenomatous (n, %) | 123 (16.3) |
| Myelolipoma (n, %) | 33 (4.4) |
| Cyst (n, %) | 6 (0.8) |
| Longest diameter (in mm) | 21 (10-190) |
| Lateralization | |
| Left (n, %) | 375 (49.7) |
| Right (n, %) | 274 (36.3) |
| Bilateral (n, %) | 106 (14) |
| Functionality | |
| Non-functional (n, %) | 542 (71.8) |
| SH (n, %) | 119 (15.8) |
| PACS (n, %) | 82 (10.9) |
| ACS (n, %) | 37 (4.9) |
| CS (n, %) | 37 (4.9) |
| Pheochromocytoma (n, %) | 29 (3.8) |
| PHA (n, %) | 28 (3.7) |
ma in 4.4% (n =33), and cyst in 0.8% (n=6) of the patients. The median diameter of the lesions was 21 mm (10-190) and 49.6% (n=375) were localized on the left side. Incidentalomas were bilat- eral in 14% (n = 106) of the patients (> Table 2). The median diam- eters in patients whose radiological diagnosis was reported as ad- enoma, non-adenomatous lesion, and myelolipoma were 20 mm (10-80), 45 mm (10-190), and 35 mm (10-120), respectively, and the difference between these median diameters was statistically significant (p=0.001).
In 71.8% of the patients (n=542), incidentalomas were non- functional. Frequency of functional lesions was 15.8 % (n=119), 4.9% (n=37), 3.8% (n=29), and 3.7% (n=28) for SH [10.9% (n=82) PACS and 4.9% (n=37) ACS], CS, pheochromacytoma, and PHA, respectively ( Table 2). Functional adrenal incidentalomas were composed of a higher ratio of females (p =0.03). The incidences of hypertension, coronary artery disease (CAD), and total comorbid- ity were higher in those with functional adrenal incidentaloma than those with non-functional adrenal incidentaloma (p=0.001). The median baseline incidentaloma diameter in patients with function- al adrenal incidentaloma was greater than those with non-func- tional adrenal incidentaloma [30 mm (10-190) and 20 mm (10- 150), respectively (p=0.001) ( Table 2).
In patients with the radiological diagnosis of adenoma, the me- dian diameter of incidentaloma in patients with SH was greater than that in those with non-functional adenoma [25 mm (10-54) vs. 20mm (10-180), respectively] (p=0.001). Median initial mass diameter of patients with PACS was longer than patients with non- functional incidentaloma [26 mm (10-50) and 20 mm (10-80), re- spectively (p=0.001)]. The median initial mass diameter was also greater in patients with ACS than in patients with non-functional adrenal incidentaloma [25 mm (10-54) and 20 mm (10-80), re- spectively (p=0.005)]. Similarly, median diameter of incidentalo- ma in CS patients was greater than that in the patients with non- functional adenoma [30 mm (19-60) and 20 mm (10-80), respec- tively] (p=0.001). Functionality was not detected in any of the six patients whose radiological diagnoses were reported as cyst. Ad- ditionally, CS was more common among patients with a radiologi- cally diagnosed adenoma of ≥4 cm compared to patients with of <2 cm or between 2-3.9 cm [17.9% (n=7), 0% (n=0) and 6% (n=19), respectively (p=0.001)].
The median age of patients with bilateral adrenal incidentaloma was higher than that of patients with unilateral adrenal incidentalo- ma [59 years (30-82) and 56 years (18-86), respectively] (p=0.02]. The median longest diameter in patients with bilateral adrenal inci- dentaloma was greater than that in patients with unilateral adrenal incidentaloma [26 mm (10-120) and 20 mm (10-190), respectively (p=0.001)]. Patients with bilateral incidentaloma had a higher pro- portion of total functionality than the patients with unilateral inci- dentaloma [37.7% (n =40) and 26.8 % (n = 174), respectively, p=0.015]. Similarly, both SH and CS were more frequent in patients with bilateral incidentaloma than in patients with unilateral inciden- taloma (For SH, 23.6% (n =25) and 14.5% (n=94), respectively (p=0.012); For CS, 10.4% (n=11) and 4% (n=26), respectively (p=0.005)). The incidence of PACS was higher in patients with bilat- eral adrenal incidentaloma than patients with unilateral adrenal in- cidentaloma [17.9% (n =19) and 9.7% (n =63), respectively, p=0.006]. In contrast, the frequency of ACS was similar between bi-
lateral adrenal incidentaloma patients and unilateral adrenal inci- dentaloma patients. [5.7% (n=6) and 4.8% (n=31), p=0.47, respec- tively]. On the other hand, in terms of pheochromacytoma and pri- mary hyperaldosteronism, no difference was detected between bilateral incidentaloma and unilateral incidentaloma patients. Two patients had bilateral pheochromacytoma. One of them had von Hippel - Lindau disease and the other had multiple endocrine neo- plasia type 2A (RET oncogene positive). Both of these patients were the first cases in their families and their clinical diagnosis were made after the evaluation of adrenal incidentaloma.
Of 755 patients, 26.6% (n=201) underwent surgery. Main indi- cations for surgery and pathology results were shown in > Table 3. More than one indication for surgery was present in 48.8 % (n=98) of the patients. We have identified co-existence of large mass/mass growth during follow-up and suspicion of malignancy in 13.4% (n=27) of the patients, large mass/mass growth during follow-up and functionality in 8% (n = 16) of the patients, and suspicion of malignancy and functionality in 7% (n = 14) of the patients who un- derwent surgery. Moreover, in 20.4% (n =41) of them, functional- ity, large mass/increased mass size during follow-up and suspicion of malignancy took place altogether. Of the patients who under- went surgery, adrenocortical carcinoma was detected in 5.5 % (1.5% of all patients) (n=11), and adrenal metastasis was detected in 5.5% (1.5% of all patients) of the patients (n = 11). A subgroup of 14 (6.9%) (4.3% of the patients with regular follow-up) patients underwent surgery during the course of follow-up. The median fol-
| Main indication for surgery | |
| Mass size (n, %) | 18 (9.0) |
| Functionality (n, %) | 150 (74.6) |
| SH (n, %) | 70 (34.8) |
| PACS (n, %) | 51 (25.3) |
| ACS (n, %) | 19 (9.5) |
| CS (n, %) | 31 (15.4) |
| Pheochromacytoma (n, %) | 28 (13.9) |
| PHA (n, %) | 21 (10.4) |
| Suspicious of malignancy (n, %) | 33 (16.4) |
| Pathology results | |
| Adenoma (n, %) | 103 (51.2) |
| Hyperplasia (n, %) | 25 (12.4) |
| Pheochromacytoma (n, %) | 33 (16.4) |
| Adrenocortical Carcinoma (n, %) | 11 (5.5) |
| Metastasis (n, %) | 11 (5.5) |
| Myelolipoma (n, %) | 4 (2.0) |
| Ganglioneuroma (n, %) | 2 (1.0) |
| Hyperplasia and myelolipoma (n, %) | 1 (0.5) |
| Epithelial cyst (n, %) | 2 (1.0) |
| Adenoma and myelolipoma (n, %) | 1 (0.5) |
| Hemorrhage and degenerative changes (n, %) | 1 (0.5) |
| Pseudocyst (n, %) | 3 (1.5) |
| Hyperplasia and cyst (n, %) | 1 (0.5) |
| Cavernous hemangioma (n, %) | 1 (0.5) |
| Extramedullary hematopoiesis (n, %) | 1 (0.5) |
| Schwannoma (n, %) | 1 (0.5) |
low-up duration of these patients was 25.5 months (12-120). The indication for surgery was increased mass size in 2 patients, devel- opment of functionality in 9 patients- one had CS and 8 had SH (7 patients PACS and 1 patient ACS), and both increased mass size and development of functionality in 3 (1 patient PACS, 1 patient ACS and 1 patient CS) patients. Out of the subgroup of surgery during follow-up, 5 had a follow-up duration of more than 5 years until the time of surgery. Pathology results of these patients revealed ade- noma in 10 patients, hyperplasia in 3 patients and adrenocortical carcinoma in one patient.
An analysis of histopathological diagnoses revealed that a mass diameter of 40 mm had 80 % sensitivity and 78 % specificity in dis- tinguishing adrenal adenoma and hyperplasia from malignant ad- renal mass and pheochromacytoma (AUC = 0.884, 95 % CI: 0.829- 0.938, p=0.001). In patients underwent surgery none with a mass diameter > 460 mm had a pathology report of adrenal adenoma or adrenal hyperplasia.
Of 755 patients, 43 % (n = 325) were followed up regularly more than 6 months. The median follow-up duration of these patients was 24 months (6-120). The characteristics of patients who were followed-up regularly were provided in > Table 4. In the follow-up
| Age (years) (median) | 57 (21-82) |
| Gender | |
| Male (n, %) | 104 (32) |
| Female (n, %) | 221 (68) |
| Follow-up duration (months) (median) | 24 (6-120) |
| Radiological diagnosis | |
| Adenoma (n, %) | 282 (86.8) |
| Myelolipoma (n, %) | 20 (6.2) |
| Non-adenomatous (n, %) | 21 (6.5) |
| Cyst (n, %) | 2 (0.6) |
| Lateralization | |
| Left (n, %) | 166 (51.1) |
| Right (n, %) | 112 (34.5) |
| Bilateral (n, %) | 47 (14.5) |
| Initial longest diameter (in mm) | 20 (10-120) |
| Final longest diameter (in mm) | 20 (10-158) |
| Functionality during Follow-up | |
| Non-functional (n, %) | 308 (94.8) |
| Development of functionality (n, %) | 17 (5,2) |
| SH (n, %) | 15 (4.6) |
| PACS (n, %) | 13 (4) |
| ACS (n, %) | 2 (0.6) |
| CS (n, %) | 2 (0.6) |
| Lesion at the opposite side during follow-up (n, %) | 13 (4.0) |
| Mass size during follow-up | |
| No change | 113 (34.8) |
| Decrease | 73 (22.5) |
| Increase | 139 (42.8) |
| <5 mm | 23 (7) |
| 5-9 mm | 78 (24) |
| ≥ 10mm | 38 (11.7) |
group, 14 patients underwent surgery during follow-up. Through- out the follow-up, 5.2% (n = 17) of the patients developed func- tionality, which were classified as 15 (4.6%) SH [13(4%) patients PACS and 2 (0.6%) patients ACS] and 2 (0.6%) CS ( Table 4).
At the initial evaluation of patients who developed CS during follow-up, SH was not detected, and they developed CS during fol- low-up. Eight of the 15 patients who developed SH during follow- up, and one of the 2 patients who developed CS during follow-up were operated during follow-up. Surgery was also recommended to the other patient who developed CS during follow-up, but the patient did not consent and was lost to follow-up later on. None of the patients under follow-up developed hyperaldosteronism or pheochromacytoma. In our study, the increase in mass size during follow-up and follow-up duration was not correlated to develop- ment of SH during follow-up. Similarly, no relationship was detect- ed between the development of SH during follow-up and baseline mass size.
During follow-up, 24% (n=78) of the patients had an increase in mass size between 5-9 mm, while 11.7% (n= 38) of the patients had an increase of 10 mm or higher (> Table 4). Of these patients, 2 were operated during follow-up due to increased mass and 3 were operated during follow-up due to both increased mass size and de- velopment of functionality. A statistically significant enlarged mass was detected during follow-up in 5 CS patients [Initial size 30 mm (28-47), final size 41 mm (32-70), (p=0.04)]. A higher proportion of CS patients had an increase in size > 10 mm compared to the pa- tients with non-functional incidentaloma [60% (n =3) and 11.8% (n=31), respectively, p=0.009]. CS patients had a larger final mass than that in patients with non-functional incidentaloma [42 mm (30-110) and 20 mm (10-95), respectively, p =0.001]. During fol- low-up, 4% (n= 13) of the patients developed a new lesion with a diameter > 10 mm on the opposite side. Radiological diagnoses of these patients were adenoma in 12 patients and myelolipoma in one patient. One of the patients with the radiological diagnosis of adenoma was previously hormonally active and was diagnosed with PHA. None of the patients who had a new lesion on the opposite side during follow-up developed a new functionality. None of the patients who had a new lesion on the opposite side during follow- up required surgery.
In patients with the radiological diagnosis of adenoma, the amounts of increase by < 5 mm, 5-9 mm and ≥ 10 mm in the size of adenoma was higher in patients followed up for more than 2 years compared with the patients followed up for < 2 years [48.9% (n=64) and 33.1 % (n=50) (p=0.025), 28.2% (n=37) and 16.6% (n=25) (p=0.013), 13.7% (n=18) and 6.6% (n=10) (p=0.036), respectively]. In the same patient group, the incidence of adeno- ma on the opposite side was likewise higher in patients followed up for > 2 years than in patients followed up for < 2 years [6.9% (n=9) and 2% (n=3), respectively, (p=0.041)].
In patients diagnosed with myelolipoma, significantly higher number of patients experienced a size increase of ≥ 10 mm during follow-up compared to the patients with patients with adenoma or non-adenomatous lesion [30% (n=6), 9.9% (n=28) and 9.5% (n=2), respectively, (p=0.016)].
Discussion
Adrenal incidentalomas are predominantly non-functional, with non-functional incidentalomas reported at various rates from 43.9-89% [17,21-25]. In a recent large study, 72.6% of adrenal incidentalomas were reported as non-functional, which is very sim- ilar to our study [25]. Reports on incidence of functionality in ad- renal incidentaloma vary greatly. In adrenal incidentalomas, the proportion of functionality ranges between 5.7-30, 0-4, 1.6-8.6, and 1.1-11.6% for SH, CS, PHA, and pheochromacytoma, respec- tively [2, 17, 21, 25-32]. Consistent to with previous studies, in our study, most common functionality was SH, with a proportion of 15.8%. The main reason behind the wide range of SH incidence is the variability of criteria used for SH diagnosis. In the light of recent guidelines, we also classified and evaluated as patients subclinical hypercortisolemia as PACS and ACS based on cortisol levels after 1 mg DST [9]. Accordingly, the incidence of PACS and ACS in adre- nal incidentaloma patients was 10.9% and 4.9%, respectively. None of our patients with a radiological diagnosis of cyst had any func- tionality suggesting that performing functionality evaluations may not be necessary for cystic adrenal masses.
In our study, the masses of patients with functional adrenal in- cidentaloma were larger than those in patients with non-function- al adrenal incidentaloma. The sizes of masses of patients with CS, SH, PACS and ACS with radiological diagnoses of adenoma were larger than those in patients with non-functional counterpart. In the same patient group, CS was more frequent among patients with a mass size larger than 4 cm. These findings indicate that clin- ical and subclinical hypercortisolemia is more likely in patients with a larger initial mass size. In a previous study, a higher frequency functionality was attributed to masses larger than 3 cm [33]. Sev- eral other studies have similarly reported a greater initial diameter of mass in patients with SH and CS than that in patients with non- functional adenoma [26, 32-35]. Our study has shown that the fre- quency of detecting functional incidentaloma among females is higher. Likewise, in their study, Cho et al. reported that female sex is a risk factor for functional adrenal incidentalomas [23].
The majority of incidentalomas in our cohort originated from the left adrenal gland. The proportion of bilateral incidentaloma was 14%. Some of the former studies have reported that the inci- dentalomas of the left adrenal gland were more common while other studies reported just the opposite, and highly variable rates were reported regarding the location of adrenal incidentalomas. One report mentions 30-62 % of the incidentalomas originate from the left adrenal gland and 32-59 % from the right adrenal gland, whereas 7.6-24.8 % are bilateral [17, 19, 28, 34, 36-38].
In the study by Vassilatou et al., there was no difference between unilateral and bilateral adrenal incidentaloma patients in terms of mass size (the longest diameter of the largest mass) [34]. In anoth- er study, unilateral adrenal incidentaloma patients had larger mass- es than the bilateral incidentaloma patients [25]. On the other hand, Patova et al. argued that bilateral adrenal incidentaloma pa- tients have a greater largest mass diameter than the unilateral in- cidentaloma patients [39]. In our study, mass size (the longest di- ameter of the largest mass) in patients with bilateral adrenal inci- dentaloma was larger than that in unilateral adrenal incidentaloma patients.
Previous studies have reported a higher incidence of SH in bilat- eral incidentaloma patients in comparison to unilateral inciden- taloma patients [25, 34]. In corroboration for previous results, our cohort had higher incidences of CS, SH and PACS in bilateral inci- dentaloma patients. In contrast, there was no difference in the fre- quency of ACS between patients with bilateral and unilateral adre- nal incidentalomas. In a study where saline suppression test was conducted following dexamethasone suppression, higher aldos- terone levels were detected in patients with bilateral adrenal inci- dentaloma than in patients with unilateral adrenal incidentaloma, although no difference was identified between bilateral and unilat- eral adrenal incidentaloma patients in terms of autonomous aldos- terone secretion [40]. Similarly, there was no difference in our study between bilateral and unilateral adrenal incidentaloma patients in terms of primary hyperaldosteronism and pheochromacytoma prevalence.
Various rates have been reported in relation to sensitivity and specificity of mass size represented as diameter in differentiation of malignant and benign lesions. For instance, a study reported a cut-off value of 5.4 cm has 93 % sensitivity and 71 % specificity [41]. In another study, a cut-off value of 46 mm was reported to have 88.2% sensitivity and 95.5% specificity [25]. Kastelan et al. specu- lated that a mass diameter of 4 cm has a high specificity albeit a low sensitivity in distinguishing benign adrenal masses from malignant adrenal masses and pheochromacytoma [26]. In our study, a mass diameter of 40 mm has an acceptable sensitivity (80%) and speci- ficity (78%) to differentiate adrenal adenoma and hyperplasia from malignant adrenal mass and pheochromacytoma.
Only 43 % of the patients in our study had a follow-up period longer than 6 months. Our center is a tertiary referral university hospital. Due to the fact that a significant portion of the patients in our study were referred to us from centers from surrounding cit- ies, some patients may not have applied to our center again, de- spite the fact that they were offered follow-up by us, because they reside in remote cities.
During follow-up, novel functionality development was at a rate of 5.2%. Similar to other studies, the most common novel function- ality that developed during follow-up was SH (4.6%). The incidence of PACS and ACS during follow-up was 4% and 0.6%, respectively. SH development during the follow-up period has been reported at varying rates between 0-8.2% [33,35, 42]. In the study by Bulow et al. where the follow-up results of 229 patients were evaluated, development of CS in two patients and pheochromacytoma in one patient was reported [29]. In the study by Barzon et al., the esti- mated cumulative risk for the development of clinical and subclin- ical hypercortisolemia after 1 and 5 years was reported as 3.8 % and 6.6%, respectively [22]. From the point of the development of func- tionality with clinical importance, two patients in our study devel- oped CS while none of the patients in our study developed pheo- chromacytoma or PHA. Our findings suggest that the re-evaluation of patients throughout the follow-up in terms of pheochromacy- toma and PHA development is not necessary, but their follow-up for the development of clinical and subclinical hypercortisolemia would be appropriate. On contrary to the studies that report the baseline mass size and follow-up duration are correlated to the de- velopment of functionality and SH along follow-up, there were no corroborating findings in our study [26, 34, 35, 43]. In our study,
follow-up duration, initial mass diameter and increase in size dur- ing the follow-up were not found to be correlated to SH develop- ment during follow up. Our findings suggest that SH development occurs independent of size increase during follow-up, and there is no relationship between follow-up duration and SH development.
Available literature implies a wide spectrum of size increase in adrenal incidentaloma throughout the follow-up period. In the study by Bulow et al., the increase in size was 5 mm or higher in 7.4% of the patients and 10 mm or higher in 5.2% of the patients at the end of a median follow-up duration of 25 months [29]. In an- other study, the increase in size was 10 mm or higher in 20.3 % of the patients at the end of a median follow-up duration of 25.5 months [43]. Results of Giordano et al. were prolonged by the end of 3 years and increment was approximately 25 % [42]. In the study by Yener et al., increased size measurement during follow-up oc- curred in 17.4% of adrenal adenomas, and an increase higher than 10 mm in size was observed in 4.9% of the patients [35]. Morelli et al. reported that there is at least 1 cm increase in size in 8.3%, and development of adenoma on the opposite adrenal gland in 2.4 % of the patients who were followed up for more than 5 years [33]. In a study where 18 studies were reviewed, an increased size was detected in 9% of patients [2]. We have measured size increase be- tween 5-9 mm in 24% and equal to or < 10 mm in 11.7% of our, and a new lesion developed at the opposite adrenal gland in 4% of the patients. In our study, both size increase and emergence of a new lesion at the opposite adrenal gland were at higher ratios in patients with a follow-up duration longer than 2 years. These findings indi- cate that in patients with radiological diagnosis of adenoma, the longer the follow-up duration is the higher the risk of both increase in size and development of adenoma at the opposite adrenal gland. In our study, 4.3 % of the patients with regular follow-up were op- erated due to a novel functionality and/or size increase during this period. The median follow-up duration of these patients was 25.5 months (12-120) (mean 45.4± 38.4). Out of the subgroup of sur- gery during follow-up, 5 had a follow-up duration of more than 5 years until the time of surgery. One of the patients was operated due to increase in size and development of CS at the end of a 96- month period, and the pathology report of the patient stated adrenocortical carcinoma. Overall, our findings suggest that adre- nal incidentaloma patients should be regularly checked by radio- logical means and to assess any novel hypercortisolemia, albeit at a decreasing frequency, and the patients should not be removed from the follow-up list.
Our study is limited by its nature as a retrospective, single-cent- er study. The fact that evaluation of radiological images of patients was carried out by different people during the follow-up period is the another limitation of our study. Another major limitation to our study is that the incidence of nonclassic congenital adrenal hyper- plasia, which is an uncommon cause of adrenal incidentalomas [44], could not be determined due to the fact that the patients were not evaluated for nonclassic congenital adrenal hyperplasia. On the other hand, the fact that the duration of our study is as long as 10 years and being one of the larger studies in the literature makes our study valuable.
In conclusion, our study suggests that some portion of adrenal incidentaloma patients may need to undergo surgery during the course of follow-up due to increase in size and development of a
novel functionality, and thus, continuing the patient follow-up, even with wider intervals, will be appropriate.
Conflict of Interest
The authors declare that they have no conflict of interest.
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