Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features
Takamasa IchijoHajime UeshibaHajime NawataToshihiko Yanase
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2020 年 67 巻 2 号 p. 141-152


The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing’s syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

THE INCIDENCE of clinically inapparent and incidentally discovered adrenal masses, called adrenal incidentalomas (AIs), has increased dramatically over the last two decades as a result of the widespread use and technical improvement of abdominal imaging devices, including ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) [1]. The current prevalence of AI, which is defined as an adrenal mass occasionally and unexpectedly discovered by abdominal imaging procedures performed for non-adrenal-related reasons, is approximately 1% to 5% in abdominal CT scan series [2-4], and most cases are discovered before they become severe or critical. However, this rate might be underestimate. In fact, the incidence of adrenal nodules at autopsy is as high as 32% among patients who had no evidence of adrenal disease prior to their deaths [3-5].

Many AIs, even if they are diagnosed as non-functioning adenomas (NFAs), are associated with metabolic syndrome [6]. In addition, adrenocortical carcinoma (ACC) is rare, with an estimated yearly incidence of 0.5 to 2 per 1 × 106 patients [7], although its prevalence becomes as high as 25% among patients with AI [8]. The prognosis of ACC is generally poor, and the overall 5-year survival rate after diagnosis is 7% to 65% [9].

Therefore, once an AI is detected, it raises challenging questions for physicians and their patients, and a series of diagnostic evaluations should be performed to determine whether the lesion is hormonally hyperactive or non-functioning, whether it is malignant or benign [10] and whether the nodule is growing in size or not, although these evaluations are usually very demanding. As a consequence, AIs have become a common clinical problem [11]. Under these circumstances, some consensual diagnostic and therapeutic guidelines have been established. A consensus meeting for AIs was held at the National Institutes of Health in 2002 [10], and the guidelines of the European Society of Endocrinology (ESE) collaborated with the European Network for the Study of Adrenal Tumors (ENSAT) [3], the American Association of Clinical Endocrinologists (AACE) collaborated with the American Association of Endocrine Surgeons (AAES) [12], Korean Endocrine Society [13], and some reviews discussing this issue have been reported [14], and it has been becoming clear how to manage AIs. We therefore performed a nationwide multicenter study as a project of the Research Committee on Disorders of Adrenal Hormones, proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. We present here the overview of a 5-year nationwide survey including more than 3,600 patients with AIs in Japan. This is the first report from our entire study and all data shown in this report are from the first study. A long-term follow up study was conducted as the second study from 2013 to 2016, and we will report those other data, for example, suspicious mass’s diameter for ACC by ROC analysis, the ratios of complications such as hypertension, hyperglycemia, dyslipidemia, or metabolic syndrome, and so on, soon after this report. To the best of our knowledge, this is the first report of a nationwide survey of AIs in Asia.

Subjects and Methods

Study designs

Our study contains 2 nationwide multicenter studies. The first study conducted from 1999 to 2004 as a cross-sectional and 5-year followed up study and the second from 2013 to 2016 as a long-term follow-up study. A nationwide multicenter study of AIs by the Research Committee on Disorders of Adrenal Hormones was firstly proposed and performed on behalf of Japanese Ministry of Health, Labour and Welfare (MHLW) from 1999 to 2004 (with chief investigator the late Yukitaka Miyachi, then of Toho University and Hajime Nawata, Kyushu University) as the first study. Since more than 10 years had passed since the above first nation-wide study of AIs, a long-term follow up study of AIs was proposed and conducted by the Research Committee on Disorders of Adrenal Hormones on behalf of the Japanese MHLW from 2013 through 2016 (with chief investigator Toshihiko Yanase, Fukuoka University) as the second study, and we will report later on. This report of a nationwide multi center survey on AIs was a five-year project starting in 1999, and 1,014 hospitals with more than 200 beds, identified based on the official medical facilities list, were annually requested to review all of their cases of AIs since 1995. All questionnaires were individually checked for inconsistencies, such as clinical signs of hormonal hypersecretion or multiplicate inclusion of the same patients, before statistical analysis, and 3,672 cases were finally included in this study (Fig. 1). The questionnaire is shown in the supplemental figure. The all data shown in this report are from the first study conducted from 1999 through 2004.

Fig. 1

Study design and history.

The original project as the first study, a national survey of AIs as a cross-sectional study, was started in 1999 and ended in 2004. After 9 years, a long-term follow-up study started as the second study and ended in 2016 (A). The total number of each mass type, the number of adrenalectomy (Adx), histological evaluated (Histol.), and how many patients were followed more than 1 year in the first study are shown (B). Those abbreviations NFA, CPA, APA, Pheo, ACC, Adx, and N.D. represent non-functioning adenoma, cortisol-producing adenoma, aldosterone-producing adenoma, pheochromocytoma, adrenocortical carcinoma, adrenalectomy and “no data reported”, respectively.

The definition of AIs

We defined “adrenal incidentaloma” as a clinically inapparent mass, which is discovered accidentally through imaging procedures performed for non-adrenal reasons, regardless of complications such as hypertension or diabetes, which could be caused by the adrenal mass.

The image interpretation and endocrinological evaluation

Imaging characteristics of CT and MRI were reported on the basis of descriptions by radiologists or specialists in each center based on consensus findings of each mass type [15, 16] (Table 1). Endocrinological data were collected through questionnaires, including levels of serum cortisol, plasma adrenocorticotropic hormone (ACTH), serum aldosterone concentration (PAC), plasma renin activity (PRA) and/or plasma renin concentration (PRC), serum dehydroepiandrosterone sulfate (DHEA-S), plasma adrenaline (Adr), plasma nor-adrenaline (N-Adr), urinary Adr excretion, urinary N-Adr excretion, fasting plasma glucose (FPG), and fasting serum immunoreactive insulin (F-IRI). Hormonal and biochemical data were reported as raw data and described qualitatively as high, normal, or low, according to the normal range or interpretation used in individual centers. The PAC and PRA were considered as elevated and suppressed when the PAC over the referential value at each center and less than 1.0 ng/mL/hr, respectively. The PAC to PRA ratio (ARR) was considered as elevated when the ratio was over 20 with ng/dL as PAC units. The circadian rhythm of serum cortisol was considered as preserved when serum cortisol levels were normal in the early morning and fell to 5 μg/dL or lower after 9:00 pm. The glucocorticoid-induced feedback mechanism, which regulates cortisol secretion from the adrenal glands, was considered normal when serum cortisol levels fell to 3 μg/dL or lower at 8:00 am after an overnight low dose (1 mg) dexamethasone suppression test (DST) [17], and/or when serum cortisol levels and urinary 17-hydroxycorticosteroid (17-OHCS) levels were suppressed under one fourth of the starting value in a classic 6-day, 2-mg and 8-mg DST [18]. The response in a corticotropin releasing hormone (CRH) test using 100 μg of CRH was considered normal when the plasma ACTH levels reached more than twice the starting value at either the 30- or 60-minute time points. Patients with values over 2.7 in a homeostasis model assessment ratio (HOMA-R) were considered as insulin resistant [19].

Table 1 The general characteristics of major adrenal masses.
Adenoma Pheochromocytoma ACC Metastatic tumors
Unenhanced CT attenuation value <10 HU >10 HU >10 HU >10 HU
Enhanced effects Weakly enhanced Rapid washout ≧50% in 10 min Well enhanced Slow washout <50% in 10 min Weakly enhanced Slow washout <50% in 10 min Weakly enhanced Slow washout <50% in 10 min
MRI T2WI: iso-intensity with liver T2WI: high intensity T2WI: iso or high intensity T2WI: iso or high intensity
Findings/Shape Round, homogenous Cystic change, bleeding, calcification Irregular shape, heterogenous Irregular shape, heterogenous
Size, Laterality <4 cm, unilateral Various size, possibly bilateral >4 cm Often bilateral

Those abbreviations ACC and T2WI represent adrenocortical carcinoma and T2 weighted image.

Classification of each mass’ type

The classification of each mass’ type was based on the report in questionnaire. The clinically diagnosed cases were reported only clinical data without pathological diagnosis and the histologically diagnosed cases were reported both with clinical and pathological findings. Histological diagnoses were reported according to the pathologists’ descriptions at each center based on the agreement General Rule for Clinical and Pathological Studies on Adrenal Tumor (The 1st Edition) published by Japanese Urological Association and The Japanese Society of Pathology in 1992. The classification into NFAs or hormonally hypersecreting adenomas, such as cortisol-, aldosterone-, and androgen-producing adenomas (CPAs, APAs, and AnPAs, respectively), was based on the combination of clinical hormonal evaluation with or without pathological diagnosis as adenomas by each physician. Although the guidelines or diagnostic criteria for functional adrenal nodules authorized by any Endocrine Societies had not been established at the time when this study started, those diagnoses were reached through expert consensus as presented in text books, except for subclinical (preclinical) Cushing’s syndrome, for which diagnostic criteria had been reported [20]. The classification into ACCs was also based on the reported diagnosis in the questionnaire and the histological reports in some cases were based on Weiss’ criteria; the presence of degenerative changes (necrosis, hemorrhage, fibrosis, or calcification); invasion of the adrenal capsule, blood vessel wall, or both; and typical mitotic figures [21].

The AIs’ characteristics were shown based on the reported diagnosis in 2 categories in Table 2 as mentioned above, either the cases including both clinically with or without histological reports based on the questionnaires as clinically diagnosed cases or only cases reported both clinical and histological diagnosis as histologically diagnosed cases. The reason of decision for undergoing surgery or observational follow up in each patient was made by each physician. The questionnaire did not collect this issue, thus decision-making process is unclear. In purpose to show closer real prevalence of mass types avoiding surgical selection bias in AIs, the number of both all reported classification as “clinically diagnosed” in the left column and only histologically proven classification “histologically diagnosed” in the right column were shown in Table 2.

Table 2 Patient backgrounds for each clinically or histologically diagnosed nodule type
Clinically Diagnosed Histologically Diagnosed
Number M/F (%) Age (yr) Diameter (cm) Number M/F (%) Age (yr) Diameter (cm)
NFA 1,866 56/44 60.1 ± 12.1 2.4 ± 1.4 445 55/45 57.9 ± 11.4 2.6 (0.5–14.0)
CPA 386 29/81* 55.5 ± 12.4*** 2.8 ± 1.4*** 227 26/74* 53.5 ± 11.3* 2.9 (1.0–20.0)
APA 187 39/61* 52.6 ± 12.9*** 1.9 ± 1.0*** 104 32/68* 49.2 ± 12.7* 2.0 (0.5–7.0)**
AnPA 7 29/71 46.4 ± 21.1** 4.9 ± 4.6 6 50/50 41.3 ± 14.4* 3.5 (1.2–11.8)
Other adenomas 26 35/65 58.2 ± 11.7 2.8 ± 1.0* 11 30/70 52.8 ± 7.8 2.5 (1.5–4.5)
Hyperplasia 147 57/43 60.0 ± 10.5 3.0 ± 1.7** 85 59/41 59.9 ± 10.0 3.0 (1.5–10.5)
ACC 51 55/45 58.3 ± 13.5 8.4 ± 4.5*** 42 52/48 55.7 ± 13.0 7.0 (0.9–20.0)***
Pheochromocytoma 312 54/46 53.8 ± 14.8*** 4.5 ± 2.9*** 239 52/48 53.1 ± 14.9* 4.0 (0.7–30.0)***
Myelolipoma 132 52/48 56.3 ± 13.5** 5.0 ± 2.8*** 74 56/44 56.1 ± 12.9 5.3 (0.6–17.0)***
Metastatic tumor 140 69/31* 65.2 ± 10.1 4.2 ± 2.8*** 51 67/33 65.0 ± 10.2* 4.0 (1.0–10.0)***
Cyst 84 49/51 53.3 ± 12.7*** 3.9 ± 2.8*** 36 59/41 43.3 ± 18.1 3.5 (1.0–11.0)*
Ganglioneuroma 59 64/36* 43.1 ± 18.3 5.2 ± 2.1*** 50 64/36 48.3 ± 13.8* 5.0 (1.0–12.0)***
Pseudo-adrenal mass 22 37/63 51.0 ± 14.1*** 4.2 ± 2.9** 8 25/75 52.9 ± 15.1** 5.0 (0.5–10.0)
Others 253 58/42 59.8 ± 14.7 3.2 ± 2.2 62 45/55 52.9 ± 15.1 4.0 (0.5–18.0)***
Total or mean 3,672 52/48 58.1 ± 13.0 3.0 ± 2.2 1,440 52/48 54.9 ± 13.2 3.7 ± 2.5

The numbers of patients according to nodule classification are presented with gender prevalence, mean age, and mean nodules’ sizes. The prevalence of gender was presented in % and the mean ages and diameter with SDs are presented. All asterisks represent statistically significant difference comparing to NFA (*: p < 0.01, **: p < 0.001, ***: p < 0.0001 vs. NFAs). Each number in “Total or mean” column presented total number of patients, gender prevalence, mean age, and mean nodules’ sizes of each category in same manner. The symbol † are represented statistically significance comparing to the clinical diagnosed cases (: p < 0.0001). The statistical analysis was performed by Student’s t-test, and Mann-Whitney U test with Bonferroni correction for the age, gender and masses’ sizes, respectively.

A follow-up study was conducted to assess size changes, and mass’ size reported 894 cases out of 933 cases, excluding cases without their sizes at 1-year follow-up or unilateral nodules with adrenalectomy, were annually followed for size changes. We considered increased or decreased when the nodules’ size changed 0.5 cm or more.

Approvement of ethical committee

These studies were approved by the ethical committees of the two research centers, Fukuoka University and Toho University. In this study, we report the overview of the first 5-year nationwide survey of over 3,600 patients with AI in Japan.

Statistical analysis

Numerical results were expressed as median with range or mean ± SD. Those cases with missing data were omitted from the analyses. Student’s t-test and analysis of variance (ANOVA) with Fisher’s protected least significant difference (PLSD) as a post-hoc test were used for continuous parametric variables, and the Mann-Whitney U test with Bonferroni correction was used for non-parametric variables. The multivariate analysis of variance (MANOVA) was used to evaluate variables between mass types. Fisher’s exact probability test for 2 × 2 tables was used for categorical variables. Statistical significance was set to p < 0.05. All data were analyzed with a software program (JMP ver. 13.0, SAS institute Inc., NC).

Role of the funding source

The Japanese Ministry of Health, Labour and Welfare funded the study through the Health and Labor Sciences Research Grants and monitored this study.


General background of patients

The overall number of received questionnaires was 3,728; 56 cases were excluded because of blank or duplicated reports, and 3,672 cases were finally included in this study. The patients’ backgrounds are shown in Table 3. There was no significant difference in gender in the included patients, with 1,874 males (51.0%), 1,738 females (47.3%) and 60 not reported cases (1.6%), aged between 6 months and 92 years (mean ± SD, 58.0 ± 13.0 years), taking part in the study. The numbers of each diagnostic technique represent the final main diagnostic imaging technique. Median nodule size was 2.5 cm (range, 0.5–30, mean ± SD, 3.0 ± 2.2 cm), the mean ± SD of body mass index (BMI) was 23.5 ± 3.8 kg/m2 (range, 12.1–39.9), and the mean ± SD of HOMA-R was 2.1 ± 1.4 (range, 0.4–7.2). Hypertension, diabetes, and obesity were observed in 24.1%, 12.2%, and 12.0% of patients, respectively (data not shown). A total of 933 cases of patients including adrenalectomy performed were followed up, and their median follow-up period was 2 years (range, 1–19).

Table 3 The patients’ backgrounds are presented for the 3,672 cases reported in this study.
Total number of cases 3,672
Gender (cases)
 Male 1,874 (51.0%)
 Female 1,738 (47.3%)
 Not Reported 60 (1.6%)
Age at diagnosis (yr)
 Total cases (n = 3,612) 58.1 ± 13.0 (0–92)
 Male (n = 1,874) 58.2 ± 12.5 (0–92)
 Female (n = 1,738) 57.8 ± 13.5 (4–89)
 Not Reported (n = 60)
Side of masses (cases)
 Right 1,320 (35.9%)
 Left 1,466 (39.9%)
 Bilateral 214 (5.8%)
 Not Reported 672 (18.3%)
Diagnostic technique (cases)
 US 843 (23.0%)
 CT 2,207 (60.1%)
 MRI 117 (3.2%)
 Not Reported 505 (13.8%)
Mass size (cm) (n = 3,266)
 Median 2.5 (0.5–30)
 Mean 3.0 ± 2.2
BMI (kg/m2) (n = 1,559)
 Mean 23.5 ± 3.8 (12.1–39.9)
HOMA-R (n = 153)
 Mean 2.1 ± 1.4 (0.4–7.2)
Cases followed-up for more than 1 year (mean follow-up term, range) 933 (2 yr, 1–19 yr)

The median follow-up term for 933 patients is presented in parentheses with the range in the column of cases followed-up for more than one year. Percentages are given in parentheses in the columns of gender, laterality of the masses, and diagnostic techniques. The numbers of each diagnostic technique represent the final main diagnostic imaging technique. The ages, BMIs, and HOMA-Rs are presented as mean ± SD with the range in parentheses. The median and mean ± SD of mass size is presented with the range in parentheses.

The prevalence of each nodule type and patients’ background

The clinically diagnosed classification and prevalence of each nodule among the 3,672 cases, including both with and without histologically diagnosed (Fig. 2A) or only histologically diagnosed 1,440 cases (Fig. 2B), were as follows: 1,866 or 445 NFAs (prevalence, 50.8%, 30.9%, respectively), 386 or 227 CPAs, including patients with subclinical Cushing’s syndrome (SCS; 10.5%, 15.8%), 312 or 239 pheochromocytomas (8.5%, 16.6%), 187 or 104 APAs (5.1%, 7.2%), 147 or 85 hyperplasias (4.0%, 5.9%), 140 or 51 metastatic tumors (3.8%, 3.5%), 132 or 74 myelolipomas (3.6%, 5.1%), 84 or 36 cysts (2.3%, 2.5%), 59 or 50 ganglioneuromas (1.6%, 3.5%), 51 or 42 ACCs (1.4%, 2.9%), 7 or 6 AnPAs (0.2%, 0.4%), and 22 or 8 pseudo-adrenal masses (0.6%, 0.6%), respectively.

Fig. 2

The classification and prevalence of each AI nodule type.

The prevalence of AIs diagnosed both clinically and histologically for all 3,672 cases (A). Prevalence for the 1,440 cases diagnosed histologically (B). The frequencies of each nodule type in percentages are shown. Those abbreviations NFA, CPA, APA, AnPA, and ACC represent non-functioning adenoma, cortisol-producing adenoma, aldosterone-producing adenoma, androgen-producing adenoma and adrenocortical carcinoma, respectively.

For the cases both clinically and histologically diagnosed, information regarding classification, prevalence, gender, and nodule diameters (mean ± SD) are shown in Table 2. CPAs and APAs were significantly more common in females (p < 0.0001) compared to NFAs. Patients with CPAs, APAs, AnPAs, pheochromocytomas, ganglioneuromas, and pseudo-adrenal masses were significantly younger (p < 0.0001), and patients with metastatic tumors were significantly older (p < 0.0001), than those with NFAs (Table 2).

Endocrinological evaluation

Endocrinological data were collected through questionnaires, including levels of serum cortisol (n = 2,454), plasma ACTH (n = 1,947), serum aldosterone (n = 2,238), PRA and/or PRC (n = 1,938), serum DHEA-S (n = 645), plasma Adr (n = 2,052), plasma N-Adr (n = 2,050), urinary Adr excretion (n = 1,265), urinary N-Adr excretion (n = 1,270), FPG (n = 1,034), and F-IRI (n = 130). Endocrinological analyses in this report were performed only in histological diagnosed cases, thus those results could be affected by selection bias. There were several measurement kits for aldosterone, cortisol, catecholamines and the others, and standardized had not done yet at the time of this study conducted. Thus, we determined those hormone values by high, low, and normal according to the reference value of each center.

Pheochromocytomas were the second or most common among hormonally hyper-secreting tumors, in clinically or histologically diagnosed series, respectively (Fig. 2 A and B). The catecholamine data were reported as raw data and described qualitatively as high, normal, or low, according to the normal range or interpretation used in individual centers. The hypersecretion of catecholamine was evaluated qualitatively in those patients, and urinary catecholamine excretion was elevated in 86.5% (147 of 170), and plasma catecholamine levels were elevated in 76.5% (153 of 200) among those data reported cases. They were both significantly higher in patients with pheochromocytomas than in those with other types (p < 0.0001, for both, Fig. 3A).

Fig. 3

Hormonal overview of the patients with AI. Clinical and hormonal characteristics of 239 patients with pheochromocytomas (A). The red bars represent pheochromocytomas, and the white bars represent the other masses. *: p < 0.0001. Abnormalities of the HPA axis in 227 patients with CPAs and the other types (B). The yellow bars represent CPAs, and the white bars represent the other masses. *: p < 0.0001. Clinical and hormonal characteristics of 104 patients with APAs (C). The orange bars represent APAs, and the white bars represent the other masses. *: p < 0.0001. Adrenal steroid hormones and their metabolites in 31 patients with ACCs (purple bars) or the other types (white bars) (D). Hormonal values are presented as mean ± SD. *: p < 0.0001. The all statistical analysis was performed by Student’s t-test.

CPAs, including 39.4% of SCSs, were the most common in clinically diagnosed cases (Fig. 2A), and this type of tumor, including 31.7% of SCSs, was the second most common in hormonally hyper-secreting AIs, among histologically diagnosed cases (Fig. 2B). Over-weight with BMI >25 was seen in 24.8% and 31.1% of patients showed elevated fasting plasma glucose (FPG) among histologically diagnosed cases.

The prevalence of hypertension was significantly higher in patients with CPAs than in those with other types (60.0% vs. 38.7%, p < 0.0001). Endocrinological abnormalities among histologically diagnosed cases were: low plasma ACTH levels in 49.2%, elevated serum cortisol levels in the morning in 25.0%, non-suppressed by overnight 1-mg DST in 67.8%, hypo- and non-response of plasma ACTH to CRH administration in 47.7%, and abnormality of cortisol circadian rhythm in 77.4% of cases. These frequencies were significantly higher in patients with CPAs than in those with other types (p < 0.0001, Fig. 3B).

APAs were the third common hormonally hyper-secreting tumor type among AIs in both the clinically and the histologically diagnosed patients (Fig. 2A and B). Among histologically diagnosed patients, PRA levels were suppressed in 77.0%, PAC and ARR were elevated in 81.5% and 98.8%, respectively, and low serum potassium levels were observed in 61.6% of cases. Hypertension was observed in 78.4% of patients with APAs (Fig. 3C). The prevalence of low PRA, high PAC, high ARR, hypokalemia, and hypertension was significantly higher in patients with APAs than in those with other types (p < 0.0001).

The endocrinological evaluation of ACCs revealed elevated serum DHEA-S and urinary 17-ketosteroids (KS) levels in 58.3% and 35.3% of patients, respectively. These frequencies were both significantly higher in patients with ACCs than in those with other types (p < 0.0001), while the frequencies of patients with high serum cortisol levels, high PAC, and high 17-OHCS levels showed no significant differences between the types (Fig. 3D).

We also evaluate glucose intolerance by HOMA-R in each nodule type. However, only 153 cases had reported both fasting plasma glucose and immunoreactive insulin levels needed to calculate HOMA-R; thus, we performed the analysis only for nodule types present in 10 cases or more. As a result, we performed the analysis only for NFAs, CPAs, and pheochromocytomas, and HOMA-Rs were 2.0 ± 0.2, 2.4 ± 1.7, 2.5 ± 0.4 (mean ± SD), respectively, with no statistically significant differences.

Nodule sizes and growth speeds of AI types

The mean diameters for each clinically and histologically diagnosed nodule type are presented in Table 2. Compared to NFAs, tumor diameters were significantly larger in ACCs, pheochromocytomas, CPAs, myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01), while they were significantly smaller in APAs (p < 0.001).

A total of 894 cases out of 933, excluding those cases without nodule sizes in follow-up, were followed-up annually for changes in nodule sizes, with 37.0% and 20.1% of patients showing enlargement or shrinkage of >0.5 cm during follow-up, respectively. The ratio of nodules increasing in size by >0.5 cm (Fig. 4A) and the % annual increase (Fig. 4B) for each nodule type were 36.5% (230 of 631), 2.8 ± 12.2% for NFAs; 29.5% (13 of 44), 2.7 ± 14.4% for CPAs; 14.3% (2 of 14), 2.5 ± 12.6% for APAs; 31.8% (7 of 22), 3.8 ± 14.3% for hyperplasias; 50.0% (3 of 6), 12.6 ± 15.0% for ACCs; 50.0% (11 of 22), 4.9 ± 11.1% for pheochromocytomas; 45.2% (14 of 31), 1.2 ± 8.4% for myelolipomas; 70.8% (17 of 24), 42.2 ± 76.2% for metastatic tumors; 40.9% (9 of 22), 13.4 ± 36.0% for cysts; and 50.0% (1 of 2), 12.5 ± 17.7% for ganglioneuromas, respectively. The ratio of nodules with increased sizes was significantly higher in patients with metastatic tumors than in those with NFAs (p < 0.005) (Fig. 4A), and only metastatic tumors and cysts showed significantly faster growth in their sizes than NFAs (p < 0.0001, p < 0.01; respectively) (Fig. 4B). Although those nodule-size change in hyperplasias are shown above, it is not clear if de novo nodules were newly found or nodular hyperplasias were enlarged in follow-up period.

Fig. 4

The ratios of patients whose tumor diameters, measured by CT, had increased (red), decreased (blue), or not changed (white) (A), and the ratio of increase per year in % increase ± SD (B) according to the tumor types are shown. The numbers of patients are presented for each tumor type. *: p < 0.01, **: p < 0.005, ***: p < 0.0001. The both statistical analysis was performed by ANOVA with Fisher’s PLSD.


To the best of our knowledge, this is the largest clinical survey in the literature of adrenal incidentalomas in Asia. Most patients were recruited in the last three years as a result of increasing rates of discovery and greater awareness of adrenal incidentaloma.

There was no significant difference in prevalence between the genders in this series of AIs, as previously reported [10]. In the overall series, HOMA-R was 2.1 ± 1.4 and the AIs in our series showed little tendency towards insulin resistance, since HOMA-R <1.5 is usually considered as indicating no resistance [19], although the majority were hormonally non-hypersecreting nodules. Some reports have demonstrated that even NFAs display varying steroidogenesis [22], and such subtle autonomous cortisol secretion might be one of the factors underlying metabolic syndrome in patients with insulin resistance.

In most previous reports, the vast majority of cases, approximately 70%, of AIs were NFAs [23]. In our series, NFAs accounted for 50.8% and 30.9% of clinically or histologically diagnosed cases, respectively, and this is a comparatively lower frequency than that in most previous reports [24, 25]; however, our data are quite similar to those of another Japanese report (53%) [26]. A part of this reason for these discrepancies could be explained by the difference of the criteria for NFAs, because the diagnosis of nodules’ types was made by center reviews or single-center criteria in most of those reports rather than questionnaire in this study.

Patients with CPAs and APAs were significantly frequently female, whereas those with metastatic tumors were frequent in male. This corresponds to the higher prevalence of subclinical Cushing’s syndrome and primary aldosteronism (PA) in females [27, 28], and carcinomas in males [29]. CPAs, including subclinical Cushing’s syndrome, were the second most common type in our series; subclinical hypercortisolism is the most common hormone abnormality detected in patients with AI in many reports [30]. One of the reasons hypercortisolism is not the most common but rather the second most common in our series might be due to differences between reports in the criteria used for the classification of each nodule type, including the clinical or histological diagnosis of AIs. The prevalence of patients who presented with low plasma ACTH, high serum cortisol, non-suppression in a 1-mg dexamethasone suppression test, abnormalities in a 100-μg CRH test, and/or disruption of cortisol circadian rhythm was significantly higher among CPAs than in the other nodule types, and this confirmed the effectiveness of these endocrine tests in the evaluation of the hypothalamo-pituitary-adrenal (HPA) axis. The reason the ratio of patients with non-suppressed cortisol level by 1-mg DST is comparative low in ourseries is unclear. One possibility is the criterion of 1-mg DST for overt Cushing’s syndrome (cortisol >5.0 μg/dL) could be employed instead of subclinical Cushing’s syndrome (Cortisol >3.0 μg/dL), because there was only one category to select for CPA in our questionnaire. Another possibility is the diagnosis of CPA could be clinically made based on the other test, for example low ACTH, low DHEA-S, luck of circadian rhythm and/or abnormal scintigraphy accumulation.

Most patients with pheochromocytomas showed elevation of urinary or plasma catecholamines, as previously reported [11]. Pheochromocytomas may eventually present with a hypertensive crisis which can even lead to death [8]. To avoid future crisis, an early diagnosis, by examining urine metanephrines and circulating catecholamines, and immediate adequate therapy is necessary. Recently, many reports suggested the effectiveness of measuring plasma metanephrines with high sensitivity and specificity [31-33]. Therefore, when AIs are diagnosed, the plasma and urine catecholamines or metanephrines levels should be measured in all patients for screening.

Many reports have highlighted the effectiveness of ARR with confirmatory tests in screening for primary aldosteronisms (PAs) [34, 35]. In our study, high ARR was observed in 98.8% of patients with histologically confirmed APAs. Some reports have pointed out that very low levels of PRA could amplify the prevalence of PAs, even in cases with normal serum aldosterone, resulting in inaccurate detection of APAs [28], although this ratio is the gold standard for screening in many guidelines [35]. Hypokalemia was observed in 50.0% of clinically diagnosed APAs and this prevalence is double of that in most reports. One of the reasons might be the diagnostic criteria of APAs: no clinical guidelines for PAs authorized by Endocrine Societies had been established yet anywhere in the world when this this survey started, as previously mentioned, and only typical or severe cases might be screened and diagnosed as APAs in our series.

The most common endocrinological abnormalities in patients with ACCs were concomitant hypersecretion of glucocorticoids and androgens [36]. In our study, high serum DHEA-S and high urinary 17-KS were significantly more frequent in patients with ACCs than in those with other types, while no significant difference was observed in serum cortisol and aldosterone or urine 17-OHCS levels. No reliable biomarker has been established yet to diagnose ACCs, and those parameters are only available for us now. Then, the usefulness were confirmed as the previous reports [7].

Our study demonstrated that 37.0% or 20.1% of patients presented with nodule size enlargement or shrinkage of >0.5 cm during follow-up, respectively. According to previous reports, 8–20% of cases presented with nodule size enlargement of >1 cm during follow-up, and 1.3–3.6% with shrinkage [37]. Compared to these data, our prevalence appears higher, although we employed as a cut-off value of 0.5 cm and not 1 cm, as the referenced studies. Metastatic tumors presented with the highest rate of growth among AIs, as expected, and their average annual % increase was 40%; this means that the metastatic tumors could increase their volume 2.7 times in a year.

Although the incidence of ACCs in the general population is only 1–2/1,000,000/year [38], compared to our series in which ACCs constituted 1.4% of the AIs, the overall 5-year survival rate is 16–18% and 0% for stage 4, and this indicates quite poor prognosis [38]. Given these facts, it is important to promptly determine whether or not a tumor discovered as an AI is an ACC, to immediately treat it if it is malignant.

However, this study has many limitations because this is mostly retrospective and based on questionnaires. First of all, this study has a selection bias, because we sent the questionnaires to hospitals with more than 200 beds, and each reported case was considered an AI by each physician, thus our cases might include some nodules detected by images performed for screening of adrenal disease. Second, the diagnosis of an adrenal lesion on an image was based on the reports of the radiologists in each center, which may cause between-center variation. Third, the clinical guidelines for endocrinologically hyperfunctioning nodules except subclinical Cushing’s syndrome [39], which had been established by the former study group of the Research Committee on Disorders of Adrenal Hormones proposed on behalf of the Japanese Ministry of Health and Welfare, had not been established yet when this survey started, and clinical diagnosis was made by each center according to expert consensus as presented in text books. Actually, the guideline for Cushing’s syndrome with clear cut off value of cortisol and Primary Aldosteronism by Endocrine Society were established both in 2008. The guideline of Pheochromocyoma was even established in 2014 by Endocrine Society, although the clear cut off value of blood test was still unclear. Moreover, those for the other types of adrenal masses have not determined yet. Thus, the clinical classification was made only based on the questionnaire. Fourth, there were so many non-reported data including endocrinological data, thus the numbers of cases analyzed in endocrinological evaluations are different from those in classification of nodules’ types.

In conclusion, our data indicate that a conservative management is appropriate in the majority of AIs. However, the prevalence of ACCs among AIs, and the frequency of nodules with hormonal hypersecretion seem to be comparatively high; therefore, careful and cost-effective follow-up, and a decision for surgery at the appropriate time are recommended, especially in patients with a potentially higher risk of malignancy and/or progressive hypersecretion. Our further studies are focused on ACCs and metabolic syndrome among patients with AIs, and 10-year outcomes and more data will be reported soon.


We acknowledge the Ministry of Health, Labour and Welfare for Adrenal Disease Research Grants and all members of this study group. We also express special thanks to all medical, co-medical, and office members who participated in reporting cases from all over Japan and for supporting this project. We acknowledge Prof. Yukitaka Miyachi who organized and conducted this project with us, but sadly passed away through illness in 2003. We also thank Dr. Hideaki Nakagawa and Dr. Katsuyuki Miura, from the Department of Epidemiology and Public Health of Kanazawa Medical University, for insightful suggestions. We would also like to thank Editage (www.editage.jp) for English language editing.


This study was partly supported by Health and Labour Sciences Research Grants, Research on Intractable Diseases, Research Committee on Disorders of Adrenal Hormones from the Ministry of Health, Labour, and Welfare, Japan (No. 16769897, No. H29-Nanji-Ippan-046).

Role of the funding source

Observation of this study.

© The Japan Endocrine Society