Many Faces of Adrenal Lesions in a Large Patient Cohort: What Has Changed Over the Last Two Decades?
Authors
Basak Ozgen Saydam1*, Mustafa Baris2, Suleyman Cem Adiyaman1, Tevfik Demir1, Mehmet Ali Kocdor3, Omer Demir4, Mustafa Secil2, Serkan Yener1
Affiliations
1 Division of Endocrinology and Metabolism, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
2 Department of Radiology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
3 Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
4 Department of Urology, Dokuz Eylul University, Izmir, Turkey
Key words
adrenal incidentaloma, adrenal lesions, adrenocortical carcinoma, subclinical Cushing syndrome, autonomous cortisol secretion
received 28.10.2022
revised 28.01.2023 accepted 07.02.2023
Bibliography
Exp Clin Endocrinol Diabetes 2023; 131: 242-250 DOI 10.1055/a-2035-6091 ISSN 0947-7349
@ 2023. Thieme. All rights reserved. Georg Thieme Verlag, Rüdigerstraße 14, 70469 Stuttgart, Germany
Correspondence
Basak Ozgen Saydam, MD Division of Endocrinology and Metabolism, Yildirim Beyazit University, Yenimahalle Training and Research Hospital 06370 Ankara Turkey Tel .: +90-312-5872023 basakozgen@gmail.com
ABSTRACT
Objective To review the presentation characteristics, clinical and hormonal evaluations, and histopathological results of patients with adrenal lesions over a 21-year period and evaluate the changes across the two decades.
Methods This single-center, retrospective study included 1003 patients with adrenal lesions who presented to our de- partment between 2000 and 2021. Clinical, metabolic, hor- monal, radiological, and pathological data of the patients were collected.
Results Forty-seven percent of the lesions were non-function- ing adrenal adenomas. Possible autonomous and autonomous cortisol secretion were detected in 22.2% of the patients. The percentages of the patients diagnosed with pheochromocyto- ma, primary hyperaldosteronism, adrenal Cushing syndrome, adrenocortical carcinoma, and adrenal metastasis were 7.4%, 4.8%, 4.7%, 0.9%, and 5.6%, respectively. Adrenalectomy was performed in 31.3 % of the patients. Functional adrenal lesions were the leading cause of surgery (46.5%), followed by large size and/or suspicious imaging features (38.6%). Among the patients referred to surgery due to large size (≥6 cm), the diagnosis in 19% was metastasis, and in 12.1 %, it was primary adrenocortical carcinoma. In patients with adrenal lesions with a size of 4-6 cm and suspicious imaging properties, the rates of metastasis and primary adrenocortical carcinoma were 44.4% and 4.8%, respec- tively. From the first to the second decade, major differences in presentation characteristics were increased detection of bilat- eral lesions and increased prevalence of possible autonomous and autonomous cortisol secretion.
Conclusions Adrenal lesions are common in the adult popu- lation, and while it is important to avoid overtreatment, hor- mone secretion, and malignancy should not be overlooked.
Introduction
Adrenal incidentalomas (Als) are adrenal masses detected inciden- tally during imaging studies performed for indications other than suspected adrenal disease [1]. The prevalence of Als was found to be 2.3% within the autopsy series and 0.5%-2% in imaging stud- ies, with the prevalence increasing with age, reaching up to 10% in
the elderly population [2,3]. The detection rate has increased over time, approaching nearly 5% of the general population, due to the widespread use of high-resolution cross-sectional imaging in medi- cal practice [4]. Imaging studies are generally sufficient to assess the risk of malignancy; however, indeterminate lesions are not rare [1]. Clinical examination and biochemical tests are required to
exclude hormone excess [1]. Although the definition of AIs is strict, the terms adrenal mass or adrenal lesion can be used for a broader definition that includes all adrenal lesions [1].
In this retrospective study covering the recent 21 years, we eval- uated the presentation characteristics, clinical findings, hormonal evaluations, and histopathological results of all adrenal lesions in a broad patient group and compared the data between the two decades. Rather than focusing on only AIs, we evaluated all adre- nal lesions to provide a more general perspective.
Participants and Methods
This study was conducted at Dokuz Eylul University Hospital, Fac- ulty of Medicine, Division of Endocrinology and Metabolism, Izmir, Turkey. Data from 1003 patients who applied or were referred to our clinic for the assessment of adrenal lesions between 2000 and 2021 were evaluated retrospectively. All patients with AIs or adre- nal lesions other than incidentalomas (patients with hormone-se- creting adrenal lesions, patients undergoing bilateral adrenalec- tomy due to adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, patients having adrenalectomy due to onco- logical surgery) were enrolled in the study. Clinical, metabolic, hor- monal, and radiological evaluations were performed on all patients.
Clinical evaluations consisted of personal and family health his- tory as well as assessment for symptoms and signs of adrenal hor- mone excess. All patients were screened for hypertension, diabe- tes mellitus, metabolic syndrome, signs of extra-adrenal malignan- cy, and cardiovascular and cerebrovascular disease. Metabolic evaluations included the measurement of biochemical parameters, including blood glucose, HbA1c levels, and lipid profile. Patients underwent hormonal evaluation for the ACTH-cortisol axis, which included basal morning cortisol, ACTH, dehydroepiandrosterone sulfate (DHEAS), and an overnight 1 mg dexamethasone suppres- sion test (DST). Cortisol, DHEAS, and ACTH measurements were performed using chemiluminescence enzyme immunoassay kits (Immulite, Diagnostic Products Corporation, Los Angeles, CA, USA).
A morning cortisol level lower than 1.85 mcg/dL following over- night DST was defined as adequate suppression [1]. Possible au- tonomous cortisol secretion was defined as a post-DST cortisol level between 1.85 and 5 mcg/dL. A post-DST cortisol level ≥5 mcg/dL was defined as autonomous cortisol secretion in patients without stigmata of Cushing syndrome [1]. These definitions were chosen according to the European Society of Endocrinology Clinical Prac- tice Guideline in collaboration with the European Network for the Study of Adrenal Tumors [1]. The diagnosis of adrenal Cushing syn- drome was made after confirmation of increased cortisol secretion with two different tests (urine-free cortisol, late-night salivary cor- tisol, 1 mg overnight DST, 2 days 2 mg DST) accompanied by sup- pressed ACTH in patients with Cushingoid features [1].
Urinary fractionated normetanephrine and urinary fractionated metanephrine levels were measured in 24-h urine samples using high-performance liquid chromatography (Agilent Technologies, Santa Clara, CA, USA). Pheochromocytoma was diagnosed in pa- tients with elevated levels of 24-hour urinary metanephrine and normetanephrine.
Plasma renin activity (PRA) and serum aldosterone measure- ments were performed in patients with hypertension and/or hy-
pokalemia using radioimmunoassay kits. The aldosterone/PRA ratio was used to screen for primary hyperaldosteronism. In patients with an increased aldosterone-renin ratio, a saline infusion test was performed as a confirmatory test.
Non-contrast computed tomography (CT) was performed to as- sess the risk of malignancy for different lesions. Lesions that were ≤4 cm and had benign imaging properties (a regular shape with well-defined margins, homogeneous, lipid-rich, and attenu- ation ≤ 10 Hounsfield units) were considered benign. Magnetic res- onance imaging was performed in selected patients with indeter- minate lesions on CT.
We also defined a subgroup of patients (incidental silent adre- nal mass) who presented with non-adenomatous adrenal lesions with a benign appearance on imaging studies without any clinical or laboratory findings of hormone excess.
A multidisciplinary team decided whether adrenalectomy was required. Indications for adrenalectomy were hormone secretion (functional adrenal lesions), large mass ( ≥6 cm), malignant imag- ing features, autonomous cortisol secretion with metabolic distur- bances, and an increase in size during follow-up. Bilateral adrenal- ectomy was recommended for selected patients with ACTH-de- pendent Cushing syndrome. Adrenalectomy was also performed in some patients during nephrectomy or other operations. Histo- logical evaluation was performed by an experienced pathologist.
The study was approved by the Clinical Research Ethical Com- mittee of Dokuz Eylul University on October 21, 2019 (2019/26- 32).
Statistical analysis was performed with IBM Statistical Package for the Social Sciences for Mac version 20. Numeric variables are summarized as median (minimum-maximum). Cross-table analy- sis was performed for categorical variables, and the results are re- ported as a percentage. The Mann-Whitney U test was used for pairwise comparisons of the data that were not normally distrib- uted and categorical variables were compared using the chi-square test.
Results
The baseline characteristics of the patients are summarized in Table 1. The median age of the patients was 53.8 years (18-88), and the female/male ratio was 2.1:1. The median size of the adre- nal lesions was 25 mm. Most of the lesions were unilateral and sin- gle (76%), while 21.1 % of all lesions were bilateral. The prevalence of hypertension, diabetes mellitus, impaired glucose metabolism, and cardiovascular and cerebrovascular diseases are presented in Table 1. Extra-adrenal malignancy was diagnosed in 17.2% of the patients. The median body mass index (BMI) of the patients was 28.7 kg/m2. The basal hormonal evaluation of the patients is sum- marized in Table 1.
Clinical diagnoses of the patients are summarized in > Table 2. Forty-seven percent of the lesions were non-functioning adrenal adenomas. Possible autonomous cortisol secretion or autonomous cortisol secretion was detected in 22.2% of patients, while 4.7 % had adrenal Cushing syndrome ( Table 2). When functional adre- nal adenomas, malignant lesions, and incidental silent adrenal masses were excluded, the number of remaining patients was 694, and 32.1 % of these patients had possible autonomous cortisol se-
| Age (y) | 53.8 (18-88) |
| Gender F/M n (%) | 678 (67.6)/ 325 (32.4) |
| Lesion diameter (mm) | 25 (5-200) |
| Location of the lesion n (%) | Left single 392 (39.1) |
| Right single 370 (36.9) | |
| Left multiple 22 (2.2) | |
| Right multiple 7 (0.7) | |
| Bilateral 212 (21.1) | |
| Comorbidity n (%) | Hypertension 544 (54.2) |
| Type 2 diabetes mellitus 242 (24.1) | |
| IFG/IGT/IFG + IGT 124 (12.4) | |
| Cardiovascular disease/ cerebrovascular disease 100 (10%) | |
| Existence of an extra-adrenal malignancy (n, %) | 173 (17.2%) |
| Weight (kg) | 77 (45-162) |
| BMI (kg/m2) | 28.7 (17-59.5) |
| Waist circumference (cm) | 97 (58-150) |
| Systolic blood pressure (mmHg) | 130 (90-233) |
| Diastolic blood pressure (mmHg) | 80 (50-140) |
| ACTH (pg/mL) | 13.5 (0-316) |
| DHEA-SO4 (mcg/dL) | 64.5 (4-1000) |
| Post- 1 mg DST cortisol (ug/dL) | 1.43 (0.2-72) |
| Urinary metanephrines (ug/24h) | 50 (3-5609) |
| Urinary normetanephrines (ug/24h) | 170 (15-7765) |
ACTH; adrenocorticotrophic hormone, DHEAS; dehydroepiandrosterone sulfate, DST; dexamethasone suppression test, F; female, IFG; impaired fasting glucose, IGT; impaired glucose tolerance, M; male, n; number, y; years.
cretion or autonomous cortisol secretion. The percentages of pa- tients diagnosed with pheochromocytoma, primary hyperaldoster- onism, and adrenocortical carcinoma were 7.4%, 4.8 %, and 0.9%, respectively. The prevalence of co-secretion of cortisol was found to be 20.9% in patients with primary hyperaldosteronism. Among these patients, one had cortisol levels ≥5 mcg/dL, and nine had cortisol levels between 1.8 and 5 mcg/dL after overnight DST. Ad- renal metastasis was detected in 5.6% of the patients. Sixty-five (6.5%) patients had incidental silent adrenal masses, most of which were myelolipoma and adrenal cysts.
Adrenalectomy was performed in 314 (31.3%) patients. Func- tional adrenal lesions were the leading cause of operation (46.5%), followed by suspicious imaging features at the time of diagnosis (38.6%). Among the patients undergoing adrenalectomy, 7% were operated on due to autonomous cortisol secretion and accompa- nying metabolic disturbances (> Table 2). Among 223 patients with possible autonomous cortisol secretion or autonomous cortisol se- cretion 34 were referred to surgery. Of these patients, 22 were re- ferred to surgery based on metabolic disturbances, results of over- night DST, and suppressed basal ACTH levels [median post-DST cortisol:4.52 mcg/dL (2.19-17.57), median ACTH: 5.5 pg/mL
(0-25.2)]. The remaining 12 of these patients were referred to surgery due to large size, suspicious appearance, increased size during fol- low-up, or excision during other surgical procedures. Among the 189 patients with possible autonomous cortisol secretion or au- tonomous cortisol secretion who were not referred to surgery, the median overnight DST and basal ACTH levels were 2.76 mcg/dL (1.87-17.53), and 10.1 pg/mL (0-43.5), respectively.
Surgical indications and pathological outcomes are summarized in Table 3. Among functional lesions, diagnosis of pheochromo- cytoma was the leading cause of surgery, followed by adrenal Cush- ing syndrome and primary hyperaldosteronism. Surgery was re- commended for 58 patients due to the large size of adrenal lesions, and myelolipoma and other rare benign lesions were the leading pathological diagnoses in this group (55.2%). However, 19% of the patients in this group had metastasis and 12.1 % had primary adren- ocortical carcinoma. Moreover, among patients who had lesions with suspicious/indeterminate appearance and/or a size of 4-6 cm based on radiological imaging, metastasis was the leading patho- logical diagnosis (44.4%). Primary adrenocortical carcinoma (three patients), malignant vascular tumor, and leiomyosarcoma were the other malignant diagnoses among this patient group (> Table 3).
The relationships between pathological diagnosis, gender, age, and lesion size are summarized in » Table 4. Among the 314 pa- tients who underwent adrenalectomy, the pathological diagnosis was adrenal adenoma in 123, pheochromocytoma in 69, cortical hyperplasia in 18, myelolipoma in 18, and other rare diagnoses in 28. Metastases were detected in 47 patients, whereas adrenocor- tical carcinoma was diagnosed in 11 patients. There was a female predominance for all diagnoses except for the adrenal metastases, predominantly seen in male participants ( Table 4). The largest median size was observed in patients with other rare causes, pri- mary adrenocortical carcinoma, and myelolipoma (75 mm, 70 mm, and 66.5 mm, respectively). The median size of the adrenal adeno- mas was 30 mm, and that of pheochromocytomas was 40 mm.
Patients were also analyzed according to their cortisol secretion rate, ranging from normal (non-functioning adrenal adenoma) to adrenal Cushing syndrome. There was a marked female predomi- nance in all groups. In addition, there was a tendency toward a younger median age with an increasing cortisol secretion. Anthro- pometric measurements, lesion characteristics, and biochemical values according to the DST status of the patients are summarized in Table 5.
To investigate the differences in presentation patterns between the two decades under study, we have compared our data from the 258 patients who presented between 2000 and 2010 and the 745 patients who presented between 2011 and 2021 (> Table 6). The median age (54 years vs. 54 years); lesion diameter (24.5 mm vs. 25 mm); and the prevalence of type 2 diabetes (20.5% vs. 25.4%), hypertension (54.3 % vs. 54.3 %), and extra-adrenal tumors (16.3% vs. 17.6%) were similar between the two groups ( Table 6). Fe- male predominance was observed in both decades. There was an increased prevalence of bilateral lesions in the second ten-year pe- riod (15.1% vs. 23.2%, p=0.006). In addition, while the prevalence of non-functioning adrenal adenoma and adrenal Cushing syn- drome decreased (57 % vs. 43.5%, p <0.01 and 7 % vs. 3.9 %, p =0.043), the prevalence of incidental silent adrenal mass and
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| Clinical diagnosis | Non-functioning adrenal adenoma 471 (47 %) |
| Possible autonomous cortisol secretion and autonomous cortisol secretion 223 (22.2%) · DST 1.8-5 mcg/dl 195 (19.4%) · DST>5 mcg/dl 28 (2,8 %) | |
| Pheochromocytoma 74 (7.4%) | |
| Metastasis 56 (5.6) | |
| Incidental silent adrenal mass 65* (6.5%) | |
| Adrenal Cushing syndrome 47 (4.7%) | |
| Primary hyperaldosteronism 48 (4.8%) | |
| Adrenocortical carcinoma 9 (0.9%) | |
| ACTH-dependent Cushing syndrome 7 (0.7%) · Cushing disease 5 (0.5%) · Ectopic Cushing syndrome 2 (0.2%) | |
| Lymphoma 1 (0.1) | |
| Isolated androgen-secreting tumor 1 (0.1%) | |
| Congenital adrenal hyperplasia and adrenal rest tumor 1 (0.1 %) | |
| Surgical indications (n: 314, 31.3%) | Functional 146 (46.5%) · Pheochromocytoma 70 (47.9%) · Adrenal Cushing syndrome 46 (31.5%) · Primary hyperaldosteronism 29 (19.9%) · Isolated androgen-secreting tumor 1 (0.7%) |
| Large mass (≥6cm) 58 (18.5%) Size 4-6 cm and/or low-fat content and/or suspicious appearance 63 (20.1 %) | |
| Autonomous cortisol secretion and metabolic disturbances 22 (7%) | |
| Bilateral adrenalectomy due to ACTH-dependent Cushing syndrome 5 (1.6%) | |
| Increase in size or change in radiological appearance 5 (1.6%) | |
| Any surgical procedure ** 15 (4.8%) |
ACTH; adrenocorticotrophic hormone DST; dexamethasone suppression test, n: number. * Incidental non-functional adrenal mass (n=65).
· 19 patients with clinical diagnosis did not have an operation (myelolipoma 14, cyst 4, angiomyolipoma 1).
· 46 patients who were operated on (endothelial cyst 6, pseudocyst 3, cyst hydatid 1, dermoid cyst 1, hematoma 1, schwannoma 1, ganglioneuroma 2, malignant vascular tumor 1, leiomyosarcoma 1, abscess 1, foreign body reaction/ osseous metaplasia 1, peripheral nerve pouch tumor 1, lymphangi- oma 1, necrotizing granulomatous reaction 1, solitary fibrous tumor 1, papillary endothelial hyperplasia 1, myelolipoma 16, adenoma 5, unilateral macronodular hyperplasia 1) ** Any surgical procedure (n= 15): During radical nephrectomy 11, during Whipple operation 1, during cyst excision from liver 1, during surgery for gastrointestinal stromal tumor 1, due to adrenal hemorrhage 1.
possible autonomous cortisol secretion or autonomous cortisol se- cretion increased in the second ten-year period (3.9% vs. 7.4%, p=0.049 and 14.7% vs. 24.8%, p<0.01). Among patients under- going adrenalectomy, the three leading pathological diagnoses (adrenocortical adenoma, pheochromocytoma, and metastasis) were the same between the two decades.
Discussion
There have been many studies on the approach to and manage- ment of adrenal lesions; however, there are still issues to be clari- fied [1]. In our retrospective study, we aimed to investigate the presentation characteristics, clinical findings, hormonal evalua- tions, and adrenal histopathology of all adrenal lesions, not just AIs, in 1003 patients who were admitted to our tertiary referral center throughout a period of 21 years.
The age distribution, female predominance, and median size of adrenal lesions were in accordance with the literature [5,6]. Al- though most of the lesions were unilateral and single (76%), bilat- eral lesions were found in 21.1 % of our cohort, which was higher
than in previous studies [5,6]. However, in more recent studies, the prevalence of bilateral adrenal lesions was found to be 17%-23 %, which is more consistent with our results [7,8]. In addition, when we categorized our patients into two decades based on the year of first presentation, the prevalence of bilateral lesions was higher in the second ten-year period (15.1 % vs. 23.2%, p = 0.006). The in- creased prevalence of bilateral lesions may be caused by increased awareness of adrenal lesions and increased quality of imaging pro- cedures.
Glucose metabolism disturbances, hypertension, and cardio- vascular diseases accompanied the adrenal lesions in patients. In a cross-sectional population-based survey from Turkey, the preva- lence of type 2 diabetes was reported to be 13.7% in 2010 [9], while it was 14% in a study from the United States in 2016 [10]. Howev- er, the prevalence of type 2 diabetes was higher in our population of patients with adrenal lesions (24.1%) and increased from the first to the second decade (20.5 % vs. 25.4%). Reimondo et al. [11] showed in their study that the patients with adrenal lesions had higher BMI, waist circumference, and higher prevalence of diabe- tes than patients without adrenal lesions; therefore, they concluded
Table 3 Further description of surgical indications and pathological outcomes.
| Reason for surgery | Pathological diagnosis |
|---|---|
| Functional (n=146) · Pheochromocytoma 70* (47.9%) · Adrenal Cushing syndrome 46 (31.5%) · Primary hyperaldosteronism 29 (19.9%) · isolated androgen-secreting tumor 1 (0.7%) | Adenoma 71 (48.6%) |
| Hyperplasia 6 (4.1 %) | |
| Pheochromocytoma 67 (45.9%) | |
| Primary adrenocortical carcinoma 1 (0.7%) | |
| Schwannoma 1 (0.7%) | |
| Large mass (≥6cm) (n=58) | Adenoma 8 (13.8%) |
| Metastasis 11 (19%) | |
| Primary ACC 7 (12.1 %) | |
| Myelolipoma 12 (20.7%) | |
| Other rare ** 20 (34.5%) | |
| Size 4-6 cm and/or low-fat content and/or suspicious appearance (n= 63) | Adenoma 18 (28.6%) |
| Hyperplasia 3 (4.8%) | |
| Pheochromocytoma 2 (3.2%) | |
| Metastasis 28 (44.4%) | |
| Primary ACC 3 (4.8%) | |
| Myelolipoma 4 (6.3%) | |
| Other rare *** 5 (7.9%) | |
| Autonomous cortisol secretion and metabolic disturbances (n=22) | Adenoma 19 (86.4%) |
| Hyperplasia 3 (13.6%) | |
| Bilateral adrenalectomy due to ACTH-dependent Cushing syndrome (n=5) | Hyperplasia 5 (100%) |
| Increase in size or change in radiological appearance (n= 5) | Adenoma 1 (20%) |
| Metastasis 2 (40%) | |
| Myelolipoma 1 (20%) | |
| Other rare **** 1 (20%) | |
| During any surgical procedure (n= 15) | Adenoma 6 (40%) |
| Hyperplasia 1 (6.7%) | |
| Metastasis 6 (40%) | |
| Myelolipoma 1 (6.7%) | |
| Other rare **** 1 (6.7%) |
* Among 70 patients undergoing surgery due to suspicion of pheochromocytoma, 67 had a pathological diagnosis of pheochromocytoma, while 1 had adenoma, 1 had adrenocortical carcinoma, and 1 had a schwannoma. ** endothelial cyst 4, pseudocyst 3, cyst hydatid 1, dermoid cyst 1, hematoma 1, schwannoma 1, ganglioneuroma 1, abscess 1, foreign body reaction/ osseous metaplasia 1, peripheral nerve pouch tumor 1, lymphangioma 1, necrotizing granulomatous reaction 1, solitary fibrous tumor 1, hematoma 1, coagulation necrosis 1. *** endothelial cyst 1, ganglioneuroma 1, malignant vascular tumor 1, leiomyosarcoma 1, papillary endothelial hyperplasia 1. **** endothelial cyst 1. ***** hematoma
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that AIs were associated with an increased risk of type 2 diabetes. According to the same study, the prevalence of diabetes in patients with AIs was 31.8%, while it was 14.2% in patients without AIs [11]. However, in their study, only 50% of the patients were able to suppress cortisol after 1 mg DST [11]. According to our findings, the prevalence of type 2 diabetes in patients with non-functioning adrenal adenoma (post-DST cortisol < 1.85 mcg/dL) was 21 %, which was still above the prevalence in the general population. Fur- ther studies are needed to understand whether insulin resistance and metabolic syndrome are the cause or the consequence of ad- renal lesions. In addition, the prevalence of hypertension (54.2%) was higher in our study than in the general population (31 %) [9]. Moreover, when only non-functioning adrenal adenomas were con- sidered, the prevalence of hypertension was found to be 48.8 %, which is still higher than the prevalence of the general population. In our previous study, we observed that patients with non-func- tioning adrenal adenomas had more metabolic disturbances asso-
ciated with increased cardiovascular risk when compared to BMI- matched counterparts [12]. This increased risk may be due to sub- tle cortisol autonomy in patients with adrenal adenomas, even though they have suppressed cortisol levels.
Previous studies of patients with adrenal lesions showed that the median prevalence of non-functioning adenomas, autonomous cortisol secretion, primary hyperaldosteronism, and pheochromo- cytoma was 75% (71-84%), 12% (1-29%), 2.5% (1.6-3.3%), and 7% (1.5-14%), respectively. The median prevalence of adrenocor- tical carcinoma and metastasis was 8 % (1.2-11) and 5% (0-18), respectively [1-3,6]. These studies were all carried out before 2003. Our study shows similar findings for the prevalence of pheochro- mocytoma, adrenocortical carcinoma, and metastasis and a slight- ly increased prevalence of primary hyperaldosteronism compared to previous studies. However, our data indicate a lower prevalence of non-functioning adrenal adenomas (47%) and an increased prev- alence of possible autonomous cortisol secretion or autonomous
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| Histology | Number of patients (n) (%) | F/M (%) | Age (y) (median, min-max) | Diameter (mm) (median, min-max) |
|---|---|---|---|---|
| Adenoma | 123 (39.2) | 98/25 (80/20) | 48 (23-77) | 30 (10-76) |
| Pheochromocytoma/ Adrenal medullary hyperplasia | 69 (22) Pheochromocytoma-66 Adrenal medullary hyperplasia-3 | 39/30 (56.5/43.5) | 46 (18-88) | 40 (9-90) |
| Metastasis | 47 (15) | 7/40 (15/85) | 60 (31-81) | 40 (10-120) |
| Cortical Hyperplasia | 18 (5.7) | 11/7 (61/39) | 52 (34-77) | 21 (5-53) |
| Primary adrenocortical carcinoma | 11 (3.5) | 7/4 (64/36) | 50 (23-73) | 70 (35-200) |
| Myelolipoma | 18 (5.7) | 15/3 (83/17) | 60 (41-72) | 66.5 (5-120) |
| Others | 28 (8.9) Endothelial cyst-6 Pseudocyst-3 Cyst hydatid-1 Dermoid cyst-1 Hematoma-2 Schwannoma-2 Ganglioneuroma-2 Malignant vascular tumor-1 Leiomyosarcoma-1 Abcess-1 Foreign body reaction/osseous metaplasia-1 Peripheral nerve pouch tumor-1 Solitary fibrous tumor-1 Lymphangioma-1 Necrotizing granulomatous inflammation-1 Coagulation necrosis-1 Lymphoma-1 Papillary endothelial hyperplasia-1 | 19/9 (68/32) | 44 (21-82) | 75 (21-160) |
| F; female, M; male, max; maximum, min; minimum, n; number, y; years. | ||||
cortisol secretion (22.2%). The lower prevalence of non-function- ing adrenal adenomas may be partly due to the inclusion of all ad- renal lesions rather than only AIs. Notably, when the patients with overt hormone excess, incidental silent adrenal mass, and malig- nant lesions were excluded, the prevalence of possible autonomous cortisol secretion and autonomous cortisol secretion was 32.1 %, which is even higher than in the previous studies.
At present, cortisol secretion without Cushingoid features has garnered major focus among those treating and studying patients with adrenal lesions [13]. To improve the definition of this clinical entity, the term “subclinical Cushing syndrome” has been replaced with “autonomous cortisol secretion” in recent years [1]. Autono- mous cortisol secretion gained importance in recent years because of its close association with hypertension, dyslipidemia, obesity, type 2 diabetes mellitus, impaired glucose metabolism, cardiovas- cular diseases, osteoporosis, and mortality [14,15]. According to the literature, the prevalence of increased autonomous cortisol se- cretion at diagnosis was 5-30%, while up to 8 % of patients with adrenal lesions developed autonomous cortisol secretion during follow-up [2,16,17]. The definition and the diagnostic criteria used for this clinical entity affect the prevalence. In our previous study, in which the prevalence of subclinical Cushing syndrome was 10.9%
[5], the term subclinical Cushing syndrome was used to define pa- tients with adrenal adenomas showing no signs or symptoms of Cushing syndrome with post-DST cortisol > 1.8 mcg/dL, and at least one of the following criteria: ACTH <5 pg/mL, urinary free corti- sol> 110 mcg/day, or midnight cortisol >7.5 mcg/dL. However, in our current study, we separated the patients into groups accord- ing to the level of cortisol suppression after DST and used the terms, “possible autonomous cortisol secretion” and “autonomous cortisol secretion,” which are currently recommended by recent guidelines [1]. Therefore, the increased prevalence we observed could be attributed to the use of different criteria [2]. On the other hand, when we divided our data into two decades, the prevalence data from the 2000-2010 period were similar to those in the liter- ature, while the data from the second decade showed a significant decrease in the percentage of non-functioning adrenal adenomas and an increase in incidental silent adrenal masses compared to the literature [1-3,6]. In addition, the increased percentage of auton- omous cortisol secretion (formerly defined as subclinical Cushing syndrome) compared to the literature may be due to the changes in the definition criteria, as we previously described [1]. However, when we compared our patients across the two decades, we also found a statistically significantly increased prevalence in the second
| Non-functioning adrenal adenoma (post- 1 mg DST cortisol <1.85ug/dL) (n=471) | Possible autonomous cortisol secretion (post- 1 mg DST cortisol 1.85-5ug/dL) (n=195) | Autonomous cortisol secretion (post-1 mg DST cortisol ≥5ug/dL) (n=28) | Adrenal Cushing syndrome (n=47) | |
|---|---|---|---|---|
| Age (y) | 55 (27-81) | 57 (23-78) | 50 (35-74) | 46 (23-68) |
| Gender F/M n (%) | 328/143 (69.6/30.4) | 148/47 (76/24) | 25/3 (89/11) | 41/6 (87.2/12.8) |
| Weight (kg) | 78 (45-143) | 77 (45-144) | 79 (50-105) | 80 (49-162) |
| BMI (kg/m2) | 29 (17.7-58.8) | 29 (18.5-52.4) | 29.9 (22.2-43.7) | 28.9 (20.4-59.5) |
| Waist circumference (cm) | 97 (68-130) | 97 (58-150) | 92 (78-116) | 98.5 (80-112) |
| Tumor diameter (mm) | 20 (5-75) | 30 (9-68) | 30 (14-70) | 30 (5-65) |
| Side of the lesion n (%) | Unilateral single 350 (74.3) Unilateral multiple 15 (3.2) Bilateral 106 (22.5) | Unilateral single 133 (68.2) Unilateral multiple 10 (5.1) Bilateral 52 (26.7) | Unilateral single 19 (67.9) Unilateral multiple 1 (3.6) Bilateral 8 (28.6) | Unilateral single 41 (87.2) Unilateral multiple 1 (2.1) Bilateral 5 (10.6) |
| Cortisol after overnight DST (ug/dL) | 1.14 (0.2-1.84) | 2.7 (1.87-4.96) | 7.2 (5.3-17.6) | 18.4 (3.3-40.7) |
| DHEAS (mcg/dL) | 75 (6-294) | 44 (6-324) | 39 (4-685) | 32 (13-83) |
| FPG (mg/dL) | 97 (68-286) | 95 (75-254) | 95 (81-224) | 97 (68-254) |
| Hba1c (mmol/mol) | 41 (27-132) | 44 (27-140) | 45 (36-61) | 48 (36-95) |
| TC (mg/dL) | 216 (95-337) | 217 (139-411) | 161 (129-282) | 232 (158-306) |
| LDL (mg/dL) | 133 (48-234) | 138 (65-266) | 96 (68-181) | 141 (49-207) |
| TG (mg/dL) | 133 (32-935) | 148 (48-516) | 135 (58-446) | 146 (64-440) |
| HDL (mg/dL) | 50 (28-112) | 52 (24-88) | 47 (17-81) | 56 (34-88) |
BMI; body-mass index, DHEAS; dehydroepiandrosterone sulfate DST; dexamethasone suppression test F; female, FPG; fasting plasma glucose, HDL; high-density lipoprotein cholesterol, LDL; low-density lipoprotein cholesterol, M; male, max; maximum, min; minimum, n; number, TC; total cholesterol, TG; triglycerides, y; years.
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decade despite using the same criteria for both decades (14.7% vs. 24.8%). The increased prevalence of possible autonomous cortisol secretion or autonomous cortisol secretion in more recent years may be due to increased awareness of the concept, increased re- ferral to clinics due to adverse metabolic effects, and the more ac- curate and sensitive tests for cortisol measurement and proper ap- plication of overnight DSTs. Diagnostic problems caused by the cy- clic secretion pattern of cortisol may also contribute to differences in prevalence. Therefore, some of the lesions previously considered to be non-functioning may have had possible autonomous cortisol secretion. However, the clinical importance and relevance of this concept and the adverse clinical effects still need to be clarified.
Primary hyperaldosteronism, the most common cause of sec- ondary hypertension, affecting 6.1 % of the hypertensive popula- tion, was reported in 3.4% of patients with AIs [18,19]. According to a prospective study investigating the prevalence of primary hy- peraldosteronism in patients with AIs, all patients with primary hy- peraldosteronism had hypertension with or without accompany- ing hypokalemia [19]. These results are also compatible with our data, according to which the prevalence of primary hyperaldoster- onism was 4.8%, and 100% of the patients had hypertension. Therefore, the suggestions of the guidelines are applicable for screening patients with AIs only if there is concurrent hypertension and/or hypokalemia.
The leading indication for surgery was a functional adrenal le- sion, followed by a large mass and/or suspicious appearance. Pa- tients with adrenal lesions ≥6 cm were referred to adrenalectomy independent of other imaging features, and among the 58 patients referred to surgery due to large size of adrenal lesions, 19% had
metastasis and 12.1 % had primary adrenocortical carcinoma, while the remaining pathological diagnoses were benign entities. In con- trast, among patients with 4-6 cm adrenal lesions and/or low-fat content and/or other suspicious appearance, the prevalence of me- tastasis was found to be 44.4%, and that of primary adrenocortical carcinoma was 4.8 %. Moreover, in this group, one patient had a di- agnosis of a malignant vascular tumor, and one patient had leio- myosarcoma. Meanwhile, 47.6% of the patients who underwent surgery due to indeterminate appearance during imaging, such as poor lipid content, had benign pathological diagnoses. Among these patients, two patients who did not have a presurgical diag- nosis of pheochromocytoma had a pathological diagnosis of phe- ochromocytoma. Considering that 91.5 % of the patients with me- tastases were diagnosed with concomitant malignancy, it is impor- tant to take a detailed medical history and consider the possibility of metastasis in patients with extra-adrenal tumors. When patients with extra-adrenal malignancies were excluded, the prevalence of malignant lesions in patients with indeterminate lesions was 20.7%. All in all, there is still a gray zone for patients with indeterminate lesions, and the interpretation of these lesions should take various factors into account rather than deciding the malignancy risk based only on size.
When patients who have undergone surgery are considered, al- though the three leading pathological diagnoses were the same across two decades in our cohort (adrenocortical adenoma, pheo- chromocytoma, and metastasis), the three leading pathological diagnoses in the literature were adrenocortical adenoma, adreno- cortical carcinoma, and pheochromocytoma [1]. The reason me- tastasis was determined to a greater extent in our cohort may be
| All adrenal lesions | 2000-2010 (n=258) | 2011-2021 (n=745) | p |
|---|---|---|---|
| Age (y) | 54 (18-81) | 54 (21-88) | NS |
| Gender (F/M) | 2.49 | 1.97 | NS |
| Lesion diameter (mm) | 24.5 (10-160) | 25 (5-200) | NS |
| Type 2 diabetes mellitus n (%) | 53 (20.5) | 189 (25.4) | NS |
| Hypertension n (%) | 140 (54.3) | 405 (54.3) | NS |
| Bilateral adrenal tumors n (%) | 39 (15.1) | 173 (23.2) | p=0.006 |
| Extra-adrenal malignancy n (%) | 42 (16.3) | 131 (17.6) | NS |
| Hormonal work-up and clinical diagnosis n (%) | Non-functional adrenal adenoma: 147 (57%) | Non-functional adrenal adenoma 324 (43.5%) | p<0.01 |
| Possible autonomous cortisol secretion and autonomous cortisol secretion 38 (14.7%) | Possible autonomous cortisol secretion and autonomous cortisol secretion 185 (24.8%) | p<0.01 | |
| Pheochromocytoma: 19 (7.4%) | Pheochromocytoma 55 (7.4%) | NS | |
| Adrenal Cushing syndrome: 18 (7%) | Adrenal Cushing syndrome 29 (3.9%) | p=0.043 | |
| PHA 12 (4.7%) | PHA 36 (4.8%) | NS | |
| Incidental silent adrenal mass 10 (3.9%) | Incidental silent adrenal mass 55 (7.4%) | p=0.049 | |
| Metastasis 10 (3.9%) | Metastasis 46 (6.2%) | NS | |
| Adrenocortical carcinoma 3 (1.2%) | Adrenocortical carcinoma 6 (0,8 %) | NS | |
| ACTH-dependent Cushing syndrome 1 (0.4%) | ACTH-dependent Cushing syndrome 6 (0.8%) | NS | |
| N/A | Isolated androgen-secreting tumor 1 (0.1 %) Lymphoma 1 (0.1 %) Congenital adrenal hyperplasia 1 (0.1%) | N/A | |
| Patients who had undergone adrenalectomy | 2000-2010 (n=79) | 2011-2021 (n=235) | |
| Pathological diagnosis n (%) | Cortical adenoma 36 (45.6%) | Cortical adenoma 87 (37%) | NS |
| Pheochromocytoma 19 (24%) | Pheochromocytoma 50 (21.3%) | NS | |
| Metastasis 9 (11.4%) | Metastasis 38 (16.2%) | NS | |
| Other rare 5 (6.3%) | Other rare 23 (9.8%) | NS | |
| Myelolipoma 4 (5.1%) | Myelolipoma 14 (6%) | NS | |
| Adrenocortical carcinoma 3 (3.8%) | Adrenocortical carcinoma 8 (3.4%) | NS | |
| Hyperplasia 3 (3.8%) | Hyperplasia 15 (6.4%) | NS | |
| n; number, y; years, F; female, M; male, N/A; non-applicable, NS; non-significant. | |||
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the collaboration of general surgery and urology with endocrinol- ogy for the evaluation of all adrenal lesions, even though there was an obvious extra-adrenal malignancy.
The major limitation of our study is its retrospective pattern. In addition, there was a significant increase in the number of patients in the second decade, and ample evidence has been collected in the last years under study. These discrepancies might have a con- founding effect on the conclusions regarding the cases.
Conclusions
Adrenal lesions are common in the adult population, and in most cases, they are non-functioning adrenal adenomas. However, while it is important to avoid overtreatment, hormone secretion, and ma- lignancy should not be overlooked. Further studies are needed to generate further evidence-based recommendations for the initial assessment, follow-up, and referral of adrenal lesions to surgery.
Conflict of Interest
The authors declare that there is no conflict of interest.
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