ENDOCRINE SOCIETY
OXFORD
Clinical and Radiological Features of Atypical Adrenal Masses-A Multicenter Retrospective Study
Vania Balderrama-Brondani,10 Ruaa Al-Ward,1 Katja Kiseljak-Vassiliades,20D Lauren Fishbein,20D Danielle Dawes,2 Oksana Hamidi,30D Reza Pishdad,4 Juan Pablo Perdomo Rodriguez,5 Mohamad Anas Sukkari,5 Joseph R. Grajo,6 Hans Kumar Ghayee,5 Sara Bedrose,7 Roland L. Bassett,8 Amir H. Hamrahian,4 and Mouhammed Amir Habra1 İD
1Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado, Aurora, CO 80045, USA
3Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Endocrinology, Diabetes and Metabolism, Johns Hopkins University, Baltimore, MD 21218, USA
5 Division of Endocrinology, Diabetes and Metabolism, University of Florida and Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
6Department of Radiology, Division of Abdominal Imaging, University of Florida College of Medicine, Gainesville, FL 32610, USA 7Section of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA
8Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Correspondence: Mouhammed Amir Habra, MD, Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Email: mahabra@mdanderson.org.
Abstract
Context: The natural history and malignant potential of cases classified as atypical adrenal masses (AAMs) are unknown.
Objective: To describe the radiological characteristics and clinical outcomes of AAMs.
Design and Participants: A multicenter retrospective study. Patients ≥18 years old with AAMs [diameter of 10-39 mm on first imaging study and pre-contrast attenuation of >10 Hounsfield units (HU) on computed tomography] were studied. We excluded adrenal metastasis, pheochromocytoma, sarcoma, lymphoma, infiltrative lesions, and adrenal hemorrhage, as well as patients with genetic predisposition to adrenal neoplasms. Data are presented as percentages and median values with interquartile ranges (IQRs).
Results: We included 217 patients with 224 adrenal masses (61.3% women); the median age was 58 years (IQR 49-65 years). The median size was 20.5 mm (IQR 15-27 mm), with a median precontrast attenuation of 23.5 HU (IQR 17-30 HU). The median AAM growth rate was 0.3 mm/year (IQR 0-1.8 mm/year). Seventy-one masses (31.7%) underwent pathological evaluation. Adrenal adenoma (n =38; 17%) and adrenocortical carcinoma (ACC) (n = 25; 11.2%) were the 2 most common diagnoses. For the adenomas, the growth rate was 0.3 mm/year (IQR 0-2.3 mm/ year) and for ACCs, the growth rate was 12.9 mm/year (IQR 3.5-22 mm/year). The absolute contrast washout was >60% in 5 out of 7 (71.4%) ACC cases. The best growth rate cutoff for predicting malignancy was 2.68 mm/year (area under the curve 0.939; sensitivity 87.5%, specificity 88.8%).
Conclusion: AAMs carry significant malignant potential, and long-term follow-up is warranted when surgery is not pursued. Contrast washout is not reliable in predicting malignant potential of AAMs.
Key Words: adrenal incidentaloma, adrenal adenoma, atypical adrenal mass, lipid-poor adenoma, indeterminate adrenal mass, adrenal lesion
Adrenal incidentalomas (AIs) are increasingly found on im- aging studies performed to evaluate other medical conditions (1). The prevalence of AIs has increased from 0.6% in 1982 to 7.3% in 2020 (2, 3). Over the past 2 decades, the incidence of AIs has increased 10-fold, likely due to the increased use of cross-sectional imaging (4). AIs pose multiple medical chal- lenges including the burden and uncertainties arising from hormonal assessment and imaging surveillance. Most import- antly, concerns about the malignant potential of these masses often leads to either surgical resection or long-term surveil- lance, resulting in potential increased radiation exposure as well as significant costs (1).
Most AIs are lipid-rich adrenal adenomas (LRAAs), which have a high intracytoplasmic fat content (5). Despite the pathological origin of the term LRAAs, these masses are often defined radiologically as lesions with a pre-contrast attenu- ation of ≤10 Hounsfield units (HU) on computed tomography (CT) scan and demonstrate a loss of signal on out-of-phase im- aging on magnetic resonance imaging (MRI). LRAAs are asso- ciated with a benign clinical course and have an extremely low risk of malignancy, if any (6-10).
AIs with a precontrast attenuation >10 HU are often labeled atypical adrenal masses (AAMs) (1, 9-12). This label encom- passes multiple pathological diagnoses, including lipid-poor
adrenal adenomas, which comprise up to 30% of adrenal adenomas (13, 14), pheochromocytomas, and secondary ad- renal metastases, among others.
There are limited data about the natural history of AAMs and their malignant potential. In 2 previous retrospective re- ports, AAMs were associated with a low risk of malignancy; however, these reports had limitations regarding the variabil- ity of follow-up and imaging data (15-17). Thus, to fill this im- portant clinical knowledge gap and potentially improve the management of these masses, we explored the growth patterns and the malignant potential of AAMs.
Methods
This was a multicenter retrospective cohort study among member centers of the American-Australian-Asian Adrenal Alliance, which is an international adrenal research consor- tium. The Institutional Review Board of The University of Texas MD Anderson Cancer Center approved this overall study (PA12-0933), and informed consent was waived. Each center had their own institutional review board approval.
Patients ≥18 years old with AAMs, diagnosed from January 2000 through January 2021, were included in this study to al- low for sufficient follow-up time. Adrenal masses 10 to 39 mm in diameter on the first available imaging scan and with pre- contrast attenuation >10 HU were included. Other inclusion criteria were a minimum follow-up duration of 6 months be- tween the first and last available imaging studies or having a pathological evaluation (surgical resection or biopsy) at any time. We excluded cases of suspected or proven adrenal me- tastasis, pheochromocytoma, sarcoma, lymphoma, myeloli- poma, infiltrative lesions, and adrenal hemorrhage. We also excluded patients with a personal/familial history of genetic predisposition to adrenal neoplasms such as Li-Fraumeni syn- drome, Lynch syndrome, and multiple endocrine neoplasia type 2 or familial syndromes associated with hereditary pheo- chromocytoma/paraganglioma.
Clinical characteristics (patient sex, age, and race/ethnicity, mode of lesion discovery, and clinical presentation), labora- tory results (levels of serum potassium, serum glucose, serum cortisol, basal and plasma adrenocorticotropic hormone, sal- ivary cortisol, 1-mg overnight dexamethasone suppression test, 24-hour urinary cortisol, serum dehydroepiandrosterone sulfate, 11-deoxicortisol, testosterone, estradiol, aldosterone, plasma renin activity, plasma metanephrine and normeta- nephrine, and urinary metanephrine and normetanephrine), and imaging data were collected from the medical records.
We reviewed the imaging characteristics of these adrenal masses, including size, location, attenuation, heterogeneity, calcification, and necrosis on CT, as well as signal drop-out on T1 in and out of phase imaging and T2 hyperintensity on MRI. The absolute contrast enhancement washout and the relative contrast enhancement washout were calculated when available (18-20). The absolute growth of the adrenal mass was defined as the change in size (in mm) between the ini- tial evaluation and the last available imaging study (7). The tu- mor growth rate was calculated by dividing the absolute growth by the total time (in years) between the first and the last available imaging study. The duration of follow-up was the period between the first imaging study and the last avail- able imaging study or between the first imaging study and the date of pathological evaluation (surgical resection or biopsy).
The definitive histopathological diagnosis was considered when patients underwent pathological evaluation achieved by biopsy or adrenal mass resection.
The patients’ follow-up information was collected by re- viewing medical records per the assessment of the treating team.
Each institution collected data using Research Electronic Data Capture software hosted locally and shared the d-identi- fied data with the MD Anderson Cancer Center team (Fig. 1).
Statistical Analysis
Wilcoxon rank-sum tests were used to compare the distribu- tion of continuous parameters between groups. Fisher’s exact tests were used to compare the distribution of categorical var- iables between groups. Receiver operating curve analysis was used to assess the performance of the tumor growth rate to predict malignancy. Performance was assessed by the area under the curve. The optimal cutoff was chosen by maximiz- ing the sum of sensitivity and specificity. The sensitivity, spe- cificity, positive predictive value, negative predictive value, and accuracy were reported for the analysis. Logistic regres- sion was used to assess the association between malignancy and characteristics of interest. All statistical analyses were performed using R version 4.3.1. All statistical tests used a sig- nificant level of 5%. No adjustments for multiple tests were made.
Results
Clinical and demographic characteristics were collected from 217 patients who met the inclusion and exclusion criteria and are summarized in Table 1. Women comprised 61.3% (133 cases) of the cohort, and the median age was 58 years (IQR 49-65 years). The 217 patients had 224 AAMs that met the in- clusion and exclusion criteria and were analyzed in this study (Fig. 1). The AAMs were incidentally discovered in 154 (71%) patients and were found during cancer surveillance for a his- tory of extra-adrenal malignancy in 46 (21.2%) patients. These 46 masses did not undergo pathological evaluation; however, according to the local treating team’s assessment, based on clinical and radiological evaluation, these masses were not suspected metastasis. Thirty-two (14.7%) patients were initially evaluated due to discovery of hormonal over- production and 17 (7.8%) due to pain or presumed mass ef- fect. The median follow-up period was 44.4 months (IQR 17.3-76.6 months) for the whole cohort and 52.7 months (IQR 26.2-82.6 months) for those who did not have an ad- renal mass resection or biopsy.
Masses were unilateral in 195 (89.9%) cases and on the left side in 111 (56.9%). The median size was 20.5 mm (IQR 15-27 mm), and the median pre-contrast attenuation on CT scan was 23.5 HU (IQR 17-30 HU). Of the 197 masses that were first evaluated with a CT scan, 45 (22.8%) were hetero- geneous, 5 (2.5%) contained calcifications, and 2 (1%) had necrosis. Absolute contrast enhancement washout was re- ported in 104 adrenal masses and was >60% in 74 (71.1%) cases. Fifty-seven masses were evaluated with MRI scan at any time of follow-up; 34 (59.6%) had a loss of T1 signal dropout, and 15 (26.3%) had a hyperintensity on T2. The me- dian growth of AAMs was 2 mm (IQR, 0-6 mm), and the me- dian tumor growth rate was 0.3 mm/year (IQR 0-1.8 mm/ year) (Table 2).
295 patients assessed for eligibility from six centers
Excluded (n=78)
· Adrenal masses diagnosed out of study period (n=16)
· Masses <10 or >39 mm (n=15)
· Pheochromocytoma (n=16)
· UH≤10 or absent (n=12)
· Period of follow-up less than six months (n=5)
· History of genetic predisposition to adrenal neoplasms (n=3)
· Metastasis (n=1)
· Missing data (n=10)
217 evaluable patients
239 adrenal masses
Excluded (n=15) from bilateral adrenal cases
· UH≤10 or absent (n=3)
· Masses <10 or >39 mm (n=2)
· Missing data (n=10)
224 atypical adrenal masses
153 atypical adrenal masses on imaging surveillance
71 atypical adrenal masses that required pathological evaluation.
Pathological data were available for 71 (32.7%) masses; pa- tients underwent adrenalectomy for 64 (90.1%) of the masses and biopsy for 7 (9.9%) (Table 2). The pathological evaluation was done in 36 cases (50.7%) due to tumor growth during follow-up, in 19 cases (26.8%) due to concerns about the radiological features on imaging, in 13 cases (18.3%) due to tumor growth and development of hormonal overproduction, and in only 3 cases (4.2%) due to hormonal overproduction. The median tumor growth rate in this group was 2.5 mm/ year (IQR 0-12.4 mm/year). Adrenal adenoma was the defini- tive diagnosis in 38 (17%) cases, adrenocortical carcinoma (ACC) in 25 (11.2%) cases, adrenal hyperplasia in 4 (1.8%), adrenal neoplasm of uncertain behavior in 3 (1.3%), and be- nign anastomosing hemangioma in 1 (0.4%) case. The median tumor growth rate of adrenal adenomas was 0.3 mm/year (IQR 0-2.3 mm/year), whereas the median tumor growth rate of ACCs was 12.9 mm/year (IQR 3.5-22 mm/year) (Fig. 2). The median time between the initial evaluation of AAMs and the surgical resection of ACC cases was 34.3 months (IQR 16.5-59.7 months). Table 3 shows the clinical and radiological characteristics of 25 confirmed ACC cases.
A total of 153 (68.3%) adrenal masses remained under surveil- lance at the end of the study period. These masses had a median follow-up time of 52.7 months (IQR 26.2-82.6) and a median tu- mor growth rate of 0.2 mm/year (IQR 0-0.9 mm/year).
The receiver operating curve analysis of the tumor growth rate for predicting malignancy growth rate had an area under the curve of 0.939, which indicates that the growth rate is an excellent predictor of malignancy. The maximum sum of sen- sitivity and specificity is achieved at a growth cutoff of 2.68 mm/year (sensitivity 87.5%, specificity 88.8%, positive predictive value 50%, negative predictive value 98.2%, and accuracy 88.6%) (Fig. 3).
Laboratory results at baseline evaluation are available in Supplementary Table S1 (21). None of the patients had meta- nephrine or normetanephrine secretion at baseline. Hormonal overproduction developed during the follow-up period in 23 (10.6%) patients as follows: cortisol in 12 (5.5%) after a me- dian time of 62.2 months of follow-up (IQR 36.5-97.0), al- dosterone in 4 (1.8%) after a median time of 76.2 months of follow-up (IQR 57.7-94.8), sex hormones in 3 (1.3%) after a median time of 26.7 months of follow-up (IQR 18.2-43.8), and mixed hormonal secretion in 4 (1.8%) patients after a me- dian time of 65.9 months of follow-up (IQR 53.9-84.5). Of these 23 AAMs that developed hormonal overproduction, 16 were resected or biopsied for pathologic diagnosis (9 were definitive ACCs, 7 were adrenal adenomas), and 7 are still under imaging surveillance.
The univariate logistic regression analysis for malignancy showed that higher attenuation on CT [odds ratio (OR)
| Variables | n = 217 |
|---|---|
| Sex (%) | |
| Female | 133 (61.3) |
| Male | 84 (38.7) |
| Median age, years (IQR) | 58 (49-65) |
| Race (%) | |
| American Indian/Alaska Native | 2 (0.9) |
| Asian | 8 (3.7) |
| Black | 36 (16.6) |
| Hispanic | 16 (7.4) |
| White | 151 (69.6) |
| NA | 4 (1.8) |
| Mode of discovery (%) | |
| Incidentally | 154 (71) |
| Hormonal overproduction | 32 (14.7) |
| Pain or mass effect | 17 (7.8) |
| NA | 14 (6.5) |
| Type of first imaging study (%) | |
| CT | 192 (88.5) |
| MRI | 22 (10.1) |
| PET CT | 3 (1.4) |
| Unilateral or bilateral (%) | |
| Unilateral | 195 (89.9) |
| Left | 111 (56.9) |
| Right | 84 (43.1) |
| Bilateral | 22 (10.1) |
| Median follow-up, months (IQR) | 44.4 (17.3-76.6) |
Abbreviations: CT, computed tomography; IQR, interquartile range; MRI, magnetic resonance imaging; NA, not available; PET, positron emission tomography.
1.03, 95% confidence interval (CI): 1.01,1.06; P =. 0053), higher tumor growth rate (OR 3.17, 95% CI: 1.62, 6.21; P =. 0008), right side laterality (OR 2.51, 95% CI: 1.06, 5.97; P =. 0324), and hormonal overproduction (OR 8.51, 95% CI: 3.1, 23.3; P <. 0001) were significantly associated with higher probability of malignancy.
Discussion
The challenge in managing AIs in clinical practice is to identify which have a high enough malignant potential to warrant closer follow-up or surgical resection. The optimal imaging study for AIs and the frequency of imaging have not been es- tablished, and recommendations for hormonal and imaging evaluations vary between different guidelines (1, 22-24). The major limitation of all these guidelines stems from the lack of strong data to establish the natural history of AIs, es- pecially AAMs. The cost-effectiveness of surveillance imaging is questionable, especially when patients’ clinical and bio- chemical phenotypes are reassuring and the adrenal mass has precontrast HU < 10.
This study shows that AAMs were associated with signifi- cant malignant potential, and long-term follow-up is war- ranted when resection of the adrenal mass is not pursued. The tumor growth rate is valuable for assessing and following up on these lesions and might help to define their manage- ment. Moreover, CT washout is not reliable to predict malig- nancy in AAMs.
Epidemiological studies of AIs have shown that their eti- ology includes benign and malignant pathologies. The fre- quency of etiologies varies across studies due to different inclusion and exclusion criteria, hormonal and imaging as- sessments, and follow-up periods (1, 4, 9, 10, 16, 25-31). Certain features such as the appearance (homogenous vs heterogenous), attenuation on unenhanced CT, contrast washout characteristics (absolute and relative contrast en- hancement washouts), lesion size, and hormonal functionality
| Variables | Total cohort | Imaging surveillance | Pathologically evaluatedª | |
|---|---|---|---|---|
| 224 AAMs | 153 AAMs currently under surveillance | 38 adenomas | 25 ACC | |
| Median size, mm (IQR) | 20.5 (15-27) | 20 (15-25) | 21.5 (15-28) | 24 (17-30) |
| Median attenuation, HU (IQR) | 23.5 (17-30) | 22 (16-29) | 24 (18-31.5) | 32 (26-37) |
| Left (%) | 125 (55.8) | 87 (57.1) | 22 (57.9) | 9 (36) |
| Right (%) | 99 (44.2) | 66 (42.9) | 16 (42.1) | 16 (64) |
| Absolute washoutb (%) | 104 (100) | 74 (100) | 19 (100) | 7 (100) |
| =< 60% | 30 (28.8) | 20 (27) | 5 (26.3) | 2 (28.6) |
| >60% | 74 (71.2) | 54 (73) | 14 (73.7) | 5 (71.4) |
| Relative washoutb (%) | 95 (100) | 68 (100) | 17 (100) | 6 (100) |
| =< 40 | 23 (24.2) | 12 (17.6) | 5 (29.4) | 4 (66.7) |
| >40 | 72 (75.8) | 56 (82.4) | 12 (70.6) | 2 (33.3) |
| Absolute growth, mm (IQR) | 2 (0-6) | 1 (0-4) | 1 (0-5.8) | 32 (14-65) |
| Median variation in size from baseline, (IQR, %) | 8.7 (0-30.8) | 5 (-3-20) | 3.1 (0-32.3) | 170.6 (57.7-291.3) |
| Growth rate, mm/year (IQR) | 0.3 (0.0-1.8) | 0.2 (0.0-0.9) | 0.3 (0.0-2.3) | 12.9 (3.5-22.0) |
| Median follow-up, months (IQR) | 44.4 (17.3-76.6) | 52.7 (26.2-82.6) | 14.4 (5.2-44.8) | 34.3 (16.5-59.7) |
Abbreviations: AAM, atypical adrenal masses; ACC, adrenocortical carcinoma; HU, Hounsfield unit.
“Data from the most frequent diagnoses are shown.
Total number of available cases.
120
0
0
100
0
Tumor growth rate (mm/year)
80
0
60
0
40
0
*
20
00 00
0
·
8
8
0
8
8
8
-20
.
-40
☐ Adrenocortical carcinoma
Adenoma
Adrenal masses in surveillance
| Case | Sex | Age | Side | Size (mm) | Hormonal hypersecretion | Precontrast attenuation (HU) | Absolute Washout (%)ª | Absolute growth (mm) | Tumor growth (mm/year)“ | Follow-up time (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 44 | Left | 17 | Yes | 35 | NA | 29 | 3.5 | 101.2 |
| 2 | M | 75 | Right | 27 | No | 15 | 61.4 | 13 | 1.8 | 87.7 |
| 3 | F | 49 | Right | 24 | No | 19 | NA | 29 | 2.7 | 128.8 |
| 4 | F | 33 | Right | 38 | No | 35 | NA | 14 | 7.8 | 22.0 |
| 5 | M | 56 | Right | 17 | Yes | 34 | NA | 133 | 14.3 | 112.4 |
| 6 | F | 44 | Right | 10 | No | 55 | NA | 10 | 8.5 | 25.5 |
| 7 | M | 69 | Left | 11 | No | 29 | 78.1 | 43 | 16.9 | 34.2 |
| 8 | F | 57 | Right | 19 | Yes | 17 | NA | 81 | 9.0 | 108.6 |
| 9 | F | 58 | Right | 34 | Yes | 18 | NA | 90 | 22.0 | 54.6 |
| 10 | F | 47 | Left | 25 | No | 30 | NA | 65 | 21.9 | 35.6 |
| 11 | M | 50 | Left | 23 | Yes | 32 | NA | 67 | 28.3 | 2.4 |
| 12 | M | 38 | Right | 28 | No | 37 | NA | 32 | 48.0 | 8.6 |
| 13 | F | 56 | Right | 38 | No | 59 | NA | 52 | 79.0 | 7.9 |
| 14 | F | 55 | Left | 26 | No | 29 | 63.8 | 15 | 3.1 | 59.5 |
| 15 | F | 72 | Left | 14 | Yes | 95 | 68 | 44 | 18.9 | 29.7 |
| 16 | F | 56 | Right | 22 | Yes | 19 | NA | 58 | 12.7 | 59.7 |
| 17 | F | 68 | Right | 27 | No | 49 | NA | 12 | 17.9 | 16.5 |
| 18 | F | 58 | Right | 34 | Yes | 28 | NA | 1 | 0.3 | 54.6 |
| 19 | M | 56 | Right | 35 | No | 58 | NA | 75 | 100.0 | 9.0 |
| 20 | M | 28 | Right | 30 | Yes | 44 | NA | 8 | 12.7 | 8.5 |
| 21 | F | 44 | Left | 17 | Yes | 37 | NA | 29 | 3.5 | 101.5 |
| 22 | F | 45 | Left | 16 | No | 26 | 15 | 96 | 55.4 | 21.3 |
| 23 | F | 50 | Left | 19 | Yes | 29 | 69.4 | 3 | 1.2 | 49.8 |
| 24 | F | 59 | Right | 36 | No | 35 | 53.4 | 28 | 115.9 | 6.7 |
| 25 | M | 79 | Right | 12 | NA | 20 | NA | 35 | 13.1 | 34.3 |
Abbreviations: HU, Hounsfield unit; NA, not available.
“The absolute washout was calculated when available, at any time during the follow-up.
‘The absolute growth of the adrenal mass was defined as the change in size (in mm) between the initial evaluation and the last available imaging study.
‘The tumor growth rate was calculated by dividing the absolute growth by the total time (in years) between the first and the last available imaging study.
“The duration of follow-up was the period between the first imaging study and the date of pathological evaluation.
1.0
0.8
Sensitivity
0.6
0.4
0.2
AUC: 0.939
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Specificity
of these tumors are used to guide the decision between obser- vation and surgical intervention for the treatment of AIs (1, 22, 32-34).
In our cohort, we followed 217 patients with 224 AAMs for a median time of about 45 months. The proportion of lesions with benign behavior was 87.1% (68.3% were adrenal lesions with benign behavior based on the slow tumor growth and stability of the lesion but without pathology, 17% were con- firmed adrenal adenomas, and 1.8% were confirmed adrenal hyperplasia).
Change in nodule size has been predicted to be a potential worrisome feature for AIs. In a cohort of 3043 patients with AIs, a change in adenoma size compared to baseline occurred in 6.3% of cases, and an increase ≥10 mm was reported in only 2.5% of those AIs (9). Interestingly, in a review of the follow-up of 4121 patients with AIs, none developed adrenal cancer (9). In our cohort, 140 (62.5%) AAMs had an increase in size, and an increase ≥10 mm occurred in 40 (17.8%) AAMs. The median tumor growth rate of the confirmed ad- renal adenomas was similar to that of the 153 adrenal lesions under imaging surveillance.
Malignancy incidence in AIs cohorts varies from 0% to 7.14% (15, 16, 25-27, 29). The evaluation of a cohort with 106 patients with a documented history of cancer (nonadrenal cancer) and an adrenal mass showed a risk of malignancy of 47.2% (35). None of the reported metastatic tumors or ad- renal malignancies had an attenuation lower than 10 HU on CT, corroborating the defined threshold attenuation of ≤10 HU used to rule out nonadenomas (6-8, 35). In our study, 71 (31.7%) adrenal masses were pathologically evaluated, and ACC was the definitive diagnosis in 11.2% of all cases. This contrasts with a previous study of 321 atypical AIs in which only 6 (1.8%) cases had histologic evaluation, and none of those masses were malignant (15). In that study, the average adrenal mass size was 21 mm, which was similar to ours; however, no lesion increased during follow-up imaging (15). In our cohort, only 40 (17.8%) lesions did not change in the size compared to the baseline evaluation. One reason for the differences is that the study selected atypical AIs but benign-appearing lesions and no clinical suspicion of hormo- nal hyperfunctioning, and a minimum of 1 year of stability on
imaging or 2 years of stability on clinical follow-up was required, which contrasts with our inclusion criteria.
A retrospective review of a surgical database reported 136 adrenal cases; 111 (91.6%) were benign lesions, 25 were ma- lignant lesions [19 (14%) were metastatic lesions, and 4 (2.9%) were adrenocortical carcinomas], and there was no difference between the benign and malignant masses regard- ing the initial size at presentation (7). The malignant lesions presented a median tumor growth of 8 mm at 3 to 12 months of follow-up, while benign lesions presented a median growth of 1 mm in the same period, and the tumor growth rate of 16 mm/year had a sensitivity of 50% and specificity of 83.1% for predicting malignancy in this subset group (7). We reported a lower tumor growth rate cutoff for predicting malignancy than previously mentioned, which might result from our homogeneous malignant sample based on confirmed ACC cases (n =25) and a more extended median follow-up period. In a previous retrospective study, 25 ACC cases with previous imaging studies were evaluated (36). Five (20%) pa- tients had normal adrenal glands, while 20 (80%) had a pre- existing adrenal lesion (median size of 28 mm and median precontrast attenuation of 36 HU) (36). The median time from initial imaging of the adrenal lesion to ACC diagnosis was 20 months (36). Another retrospective review of 20 pa- tients with ACC who had preexisting lesions diagnosed as AIs (mean size of 32 mm) showed a mean time from the first CT scan to ACC diagnosis of 44.1 months (37). The mean in- crease of those lesions was 19 mm/year, and 35% had an aver- age growth rate of <10 mm/year (37). In our cohort, we reported a median time of 34.3 months from the first imaging study evaluation until the pathological diagnosis of ACC. We had access to the absolute contrast enhancement washout of 7 ACC cases, and interestingly, it was >60% in 5 (71.4%) cases. This highlights that contrast washout does not predict the ma- lignant potential of AAM.
The tumor growth rate of the confirmed ACC cases was 12.9 mm/year, which was significantly higher than the tu- mor growth rate of the benign lesions in our cohort (P <. 001) (Fig. 2). It is known that the velocity of tumor growth is a characteristic of malignancy and is related to de- creased survival in ACC patients (38). Here, we reported that lesions characterized as AAMs carried a reasonable risk of malignancy.
In a review of 16 158 cases of AIs, the prevalence of hormo- nal overproduction was 27.5% (31). The most frequent condi- tions were autonomous cortisol secretion/mild autonomous cortisol secretion detected in 11.7%, primary aldosteronism in 4.4%, pheochromocytoma in 3.8%, and Cushing syndrome in 3.1% of cases (31). The lipid-rich AIs have a low tumor growth rate during follow-up, and the conversion rate to mild autonomous cortisol secretion or clinical hypercortiso- lism varies from 0% to 22%, depending on the duration of follow-up (9, 10, 29, 30). In our AAMs cohort, we showed that hormonal overproduction developed during follow-up in 10.6% of our cohort (n = 23), and the median time for the development was 4.6 years (IQR 3.1-7.7) after the first im- aging study. This highlights the necessity of a long-term follow-up when surgery is not pursued.
The limitations of our study may include but are not lim- ited to its retrospective nature; the description of the images was obtained from medical records and the images were not reviewed, the resected adrenal masses were not independent- ly evaluated, the inability to do secondary pathological
review though most cases were seen in major referral centers with known pathological expertise for this report, the poten- tial for differences in CT techniques due to multicenter design, the imaging intervals that were defined based on physicians’ discretion, and a possible selection bias since our institutions are tertiary referral centers. These limita- tions add to the importance of having future prospective study that can be conducted consistently, allowing for a more accurate calculation of the growth rate of atypical ad- renal masses.
Conclusion
Although our cohort might have referral bias, atypical ad- renal masses carry significant malignant potential, and long- term follow-up is warranted when surgical resection is not pursued. The tumor growth rate is valuable for assessing and monitoring AAMs and may help define their manage- ment. Moreover, contrast washout does not predict malig- nant potential in AAMs.
This study is the foundation for a multicenter, long-term prospective study and provides insights into the natural his- tory, management, and follow-up of atypical adrenal masses.
Acknowledgments
Editorial assistance was provided by Dawn Chalaire, MD Anderson Editing Services, Research Medical Library.
Funding
National Institutes of Health/National Cancer Institute Cancer Center Support grant (award number P30 CA016672) and Biostatistics Resource Group.
Disclosures
K.K .- V .: Advisory board, HRA Pharma; H.K.G .: Consultant, Corcept Therapeutics. All other authors declare no competing interests.
Data Availability
Datasets analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
References
1. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023;189(1):G1-G42.
2. Glazer HS, Weyman PJ, Sagel SS, Levitt RG, McClennan BL. Nonfunctioning adrenal masses: incidental discovery on computed tomography. AJR Am J Roentgenol. 1982;139(1):81-85.
3. Reimondo G, Castellano E, Grosso M, et al. Adrenal incidentalo- mas are tied to increased risk of diabetes: findings from a prospect- ive study. J Clin Endocrinol Metab. 2020;105(4):e973-e981.
4. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(11):894-902.
5. Low G, Dhliwayo H, Lomas DJ. Adrenal neoplasms. Clin Radiol. 2012;67(10):988-1000.
6. Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of noncontrast computed tomography attenuation value (houns- field units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: cleveland clinic experience. J Clin Endocrinol Metab. 2005;90(2):871-877.
7. Pantalone KM, Gopan T, Remer EM, et al. Change in adrenal mass size as a predictor of a malignant tumor. Endocr Pract. 2010;16(4): 577-587.
8. Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol. 1998;171(1):201-204.
9. Elhassan YS, Alahdab F, Prete A, et al. Natural history of adrenal incidentalomas with and without mild autonomous cortisol ex- cess: a systematic review and meta-analysis. Ann Intern Med. 2019;171(2):107-116.
10. Podbregar A, Kocjan T, Rakusa M, et al. Natural history of non- functioning adrenal incidentalomas: a 10-year longitudinal follow- up study. Endocr Connect. 2021;10(6):637-645.
11. Korobkin M, Giordano TJ, Brodeur FJ, et al. Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology. 1996;200(3):743-747.
12. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive ad- renal masses in patients with no known malignancy. AJR Am J Roentgenol. 2008;190(5):1163-1168.
13. Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental ad- renal lesions: principles, techniques, and algorithms for imaging characterization. Radiology. 2008;249(3):756-775.
14. Boland GW. Adrenal imaging: why, when, what, and how? Part 2. What technique? AJR Am J Roentgenol. 2011;196(1):W1-W5.
15. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental indeter- minate adrenal mass on CT (> 10 H) in patients without cancer: is further imaging necessary? Follow-up of 321 consecutive indeter- minate adrenal masses. AJR Am J Roentgenol. 2007;189(5): 1119-1123.
16. Hong AR, Kim JH, Park KS, et al. Optimal follow-up strategies for adrenal incidentalomas: reappraisal of the 2016 ESE-ENSAT guidelines in real clinical practice. Eur J Endocrinol. 2017;177(6): 475-483.
17. Angelousi A, Jouinot A, Bourgioti C, Tokmakidis P, Bertherat J, Kaltsas G. Transformation of a benign adrenocortical adenoma to a metastatic adrenocortical carcinoma is rare but it happens. JCEM Case Rep. 2024;2(8):luae131.
18. Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F. CT time-attenuation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol. 1998;170(3):747-752.
19. Dunnick NR, Korobkin M. Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol. 2002;179(3):559-568.
20. Korivi BR, Elsayes KM. Cross-sectional imaging work-up of ad- renal masses. World J Radiol. 2013;5(3):88-97.
21. Balderrama-Brondani V, Ward RA, Kiseljak-Vassiliades K, et al. 2024. Data from: Clinical and radiological features of atypical adrenal masses-a multicenter retrospective study. OpenWorks@MD Anderson. Deposited October 10, 2024. http://openworks. mdanderson.org/endocrineneoplasia/1
22. Zeiger MA, Thompson GB, Duh QY, et al. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the man- agement of adrenal incidentalomas. Endocr Pract. 2009;15(Suppl 1):1-20.
23. Maas M, Nassiri N, Bhanvadia S, Carmichael JD, Duddalwar V, Daneshmand S. Discrepancies in the recommended management of adrenal incidentalomas by various guidelines. J Urol. 2021;205(1):52-59.
24. Kapoor A, Morris T, Rebello R. Guidelines for the management of the incidentally discovered adrenal mass. Can Urol Assoc J. 2011;5(4):241-247.
25. Herrera MF, Grant CS, van Heerden JA, Sheedy PF, Ilstrup DM. Incidentally discovered adrenal tumors: an institutional perspec- tive. Surgery. 1991;110(6):1014-1021.
26. Terzolo M, Ali A, Osella G, Mazza E. Prevalence of adrenal carcin- oma among incidentally discovered adrenal masses. A retrospective study from 1989 to 1994. Gruppo piemontese incidentalomi surre- nalici. Arch Surg. 1997;132(8):914-919.
27. Lee JE, Evans DB, Hickey RC, et al. Unknown primary cancer pre- senting as an adrenal mass: frequency and implications for diagnos- tic evaluation of adrenal incidentalomas. Surgery. 1998;124(6): 1115-1122.
28. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal inci- dentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637-644.
29. Cawood TJ, Hunt PJ, O’Shea D, Cole D, Soule S. Recommended evaluation of adrenal incidentalomas is costly, has high false- positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a re- think? Eur J Endocrinol. 2009;161(4):513-527.
30. Schalin-Jantti C, Raade M, Hamalainen E, Sane T. A 5-year pro- spective follow-up study of lipid-rich adrenal incidentalomas: no tumor growth or development of hormonal hypersecretion. Endocrinol Metab (Seoul). 2015;30(4):481-487.
31. Sconfienza E, Tetti M, Forestiero V, Veglio F, Mulatero P, Monticone S. Prevalence of functioning adrenal incidentalomas: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2023;108(7):1813-1823.
32. Sherlock M, Scarsbrook A, Abbas A, et al. Adrenal incidentaloma. Endocr Rev. 2020;41(6):775-820.
33. Vaidya A, Hamrahian A, Bancos I, Fleseriu M, Ghayee HK. The evaluation of incidentally discovered adrenal masses. Endocr Pract. 2019;25(2):178-192.
34. Lee JM, Kim MK, Ko SH, et al. Clinical guidelines for the manage- ment of adrenal incidentaloma. Endocrinol Metab (Seoul). 2017;32(2):200-218.
35. Samsel R, Nowak K, Papierska L, et al. Risk of malignancy in ad- renal tumors in patients with a history of cancer. Front Oncol. 2023;13:1018475.
36. Ozsari L, Kutahyalioglu M, Elsayes KM, et al. Preexisting adrenal masses in patients with adrenocortical carcinoma: clinical and radiological factors contributing to delayed diagnosis. Endocrine. 2016;51(2):351-359.
37. Nogueira TM, Lirov R, Caoili EM, et al. Radiographic characteris- tics of adrenal masses preceding the diagnosis of adrenocortical cancer. Horm Cancer. 2015;6(4):176-181.
38. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326.
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