Adrenal Incidentaloma and Subclinical Cushing’s Syndrome: A Longitudinal Follow-Up Study by Endoscopic Ultrasound

Abstract

Purpose Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing’s syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS.

Materials and Methods This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24 h urinary catecholamines and 2 mg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up. Each time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non-functioning nodular hyperplasias (NFH) and SCS.

Results 86 patients had non-functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (± 9.3) mm (NFM) and 19.6 (± 9.2) mm (SCS). The mean follow-up period was 31.6 ± 28.7 months. The estimated mean growth rates per year were low: They were 0.35 mm/yr [NFA], 0.02 mm/yr [NFH] and 0.53 mm/yr [SCS]. Furthermore, there was no malignant progression of any mass.

Conclusion The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups.

Zusammenfassung

Ziel Zufällig entdeckte hormonell-inaktive Nebenniereninzidentalome (AI) und solche mit subklinischen Cushing-Syndrom (SCS) erfordern ein diagnostisches Work-up inklusive Verlaufsbeobachtungen. Wir wählten hierfür in dieser Studie die Endosonografie (EUS). Unser Ziel war es, die Wachstumsraten der AI und SCS zu bestimmen.

Material und Methoden In diese retrospektive Analyse wurden 93 der 229 Patienten mit AI und SCS, die in unserer Klinik im Zeitraum von 1997 bis 2013 untersucht wurden, eingeschlossen. Die Verlaufsbeobachtungen erforderten mindestens zwei endosonografische Untersuchungen und die Erfassung des endokrinen Status. Es wurden Renin im Plasma, Aldosteron im Serum, Katecholamine im 24-Stunden-Sammelurin und ein Dexamethason-Hemmtest (2 mg) durchgeführt. Anhand dessen definierten wir drei Gruppen: hormonell-inaktive Adenome (NFA), hormonell-inaktive noduläre Hyperplasien (NFH) und SCS.

Ergebnisse 86 Patienten hatten hormonell-inaktive Tumore [NFM] (59 NFA, 48 NFH) und sieben Patienten hatten ein SCS (10 Tumore). Zu Beginn betrug der durchschnittliche Durchmesser 19,4 (± 9,3) mm (NFM) und 19,6 (± 9,2) mm (SCS). Der durchschnittliche Beobachtungszeitraum war 31,6 ± 28,7 Monate lang. Die geschätzten Wachstumsraten pro Jahr waren gering: 0,35 mm/a [NFA], 0,02 mm/a [NFH] und 0,53 mm/a [SCS]. Weiterhin konnte kein Fortschreiten hinzu einem malignen Wachstumsmuster beobachtet werden.

Schlussfolgerung Die Wachstumsraten aller Tumore waren in dieser Studie gering. Es konnte kein Unterschied zwischen diesen beobachtet werden.

Key words

adrenal gland - ultrasound - tumor - treatment planning - hyperplasia/hypertrophy

Introduction

In consequence of the widespread use of abdominal imaging procedures and the demographic change, AIs have become a more common clinical problem. AIs are defined as a mass discovered serendipitously by imaging procedures for unrelated reasons. It is a heterogeneous group of various tumors, which can be either functioning or non-functioning or malignant. The most frequent cause of endocrine alterations in cases of AI is SCS [1].

The prevalence of AI in radiological studies ranges from 1 % to 6 % [1] [2] [3]. The highest prevalence could be observed in the elderly population: 7 % of patients over 70 years of age had AI [3] [4]. However, analogous to thyroid nodules [5], size progression indicating potential malignancy during follow-up is a rarely observed incident [6]. In recent years, abdominal imaging procedures like CT, MRI and ultrasound (TUS) were used to obtain these data.

In our review of the literature, we did not find any longitudinal follow-up studies of AIs and SCS by EUS until the present day. The aim of our retrospective study was to evaluate the growth rate of AIs and SCS by EUS and to make an appropriate recommendation for clinical practice.

Patients and Methods

Patients

Between February 1997 and February 2013, 229 patients with AI or SCS were assessed by EUS in the University Hospital Mainz and Marburg. AI was defined as a mass discovered serendipitously by imaging procedures for unrelated reasons. The lesion was first diagnosed by CT, MRI, TUS or EUS.

The indications for EUS were verification of AI diagnosed by MRI, CT or TUS, pancreatic tumors and a familial pancreatic carcinoma screening program.

Besides EUS as the method of examination, the following inclusion criteria had to be fulfilled: at least two examinations including measurements of the mass, a minimum tumor diameter of 5 mm or a tumor size of more than 5 mm during the first follow-up examination and no endocrine alterations except SCS. Patients with endocrine functionality, multiple endocrine neoplasia (MEN) and tumor resection at baseline were excluded from this analysis.

Endocrine evaluation

At baseline, measurements of 24 h urinary free cortisol (UFC), plasma renin, serum aldosterone, aldosterone-renin-ratio (ARR), serum potassium, 24 h urinary catecholamines and 2 mg dexamethasone suppression test (DST; 2 mg orally at 10 p.m.) were determined. The endocrine assessment was performed at the University Hospital Mainz and Marburg and in the outpatient care unit.

SCS was defined by a pathological 2 mg DST (≥ 83 nmol/L ≙ 3 µg/dL) or suppressed cortisol levels in a range of 55 (≙ 2 µg/dL) to 83 nmol/L in combination with positive lateralization during adrenal vein sampling (AVS) in the absence of symptoms of Cushing’s syndrome. We preferred a dose of 2 mg dexamethasone and a cut-off value of 83 nmol/L to minimize the rate of false-positive results [7].

Based on the endocrine status, the study population (n = 93) was divided into two groups: non-functioning masses (n = 86) and subclinical Cushing’s syndrome (n = 7).

Endoscopic ultrasound

Endosonography was carried out using a Pentax FG32UA and FG36UX endosonoscope (Pentax Corporation, Tokyo, Japan) with a longitudinal 7.5 MHz sector array in combination with a Hitachi EUB 420 or Hitachi EUB 525 ultrasound computer (Hitachi Medical Corporation, Tokyo, Japan). Premedication was performed with 50 mg pethidine, 5 – 30 mg diazepam, and 0.125 – 0.5 mg atropine. The examination time was approximately 30 minutes. The right adrenal gland was depicted from the antrum or duodenal bulb, and the left gland from the proximal corpus region of the stomach [8]. All examinations were performed by a single experienced investigator.

Tab. 1 Main characteristics of the three groups (NFA, NFH and SCS).

	NFA n = 59	NFH n = 48	SCS n = 10	p-value
diameter (mm)	21.2 ± 9.35	17.2 ± 8.74	19.6 ± 9.19	0.079
length of follow-up (month)	32.7 ± 29.2	30.1 ± 29.1	31.9 ± 26.6	0.894
gender				0.738
male	24 (40.7 %)	16 (33.3 %)	3 (30.0 %)
female	35 (59.3 %)	32 (66.7 %)	7 (70.0 %)
side				0.681
left	38 (64.4 %)	31 (64.6 %)	5 (50.0 %)
right	21 (35.6 %)	17 (35.4 %)	5 (50.0 %)
age	59.7 ± 9.67	56.0 ± 13.3	59.5 ± 9.01	0.227
estimated mean growth rate [mm/yr]	0.35	0.02	0.53
prediction interval for size progression within one year [mm][1]
lower limit	– 6.5	– 6.8	– 6.3
upper limit	7.2	6.9	7.4

¹ Difference between the estimated tumor diameter after one year and the tumor diameter at the beginning.

Tab. 2 Characterization of SCS.

patient	sex	age [yrs]	BMI [km/m2]	blood pressure	blood glucose	UFC	DST [nmol/L]	AVS	bone density (DXA)
1	f	77	26	hypertension	n	n.d.	93.8		osteopenia
4	m	65	n.d.	hypertension	n	n.d.	85.5		n.d.
5	f	65	21	hypertension	n	n.d.	71.7	pos.	osteoporosis
12	f	60	25	hypertension	n	n	88.3		osteopenia
14	f	53	32	hypertension	IGT	n	82.8		n
16	m	49	26	n.d.	n	n	140.7		n
17	f	58	35	hypertension	IGT	n	165.3	pos.	n

n = norm, IGT = impaired glucose tolerance, n.d. = not documented, pos. = positive lateralization.

Tab. 3 Mean tumor diameter of AI mentioned in recent reports.

	mean tumor diameter [cm]	range
Barzon et al. 2003	3 – 3.5	0.5 – 25
Bülow et al. 2006	2.5	1 – 8
Caoili et al. 2002	2.2 – 2.4	1 – 6
Terzolo et al. 2005	2.6	0.5 – 6
Yener et al. 2010	2.4	0.7 – 9.7
Di Dalmazi et al. 2014	2.5	[1]

¹ Not specified.

Tab. 4 EUS criteria for adenoma and nodular hyperplasia.

	adenoma	nodular hyperplasia
echogenicity	hypoechoic	hypoechoic
echostructure	slightly heterogeneous	more homogeneous
tumor margins	capsular	non-capsular
termination of medullary echo	yes	no
perfusion	no hyperperfusion	no hyperperfusion
number of tumors	solitary	frequently multiple

Tab. 5 Initial imaging procedures of AI.

	total number of investigations	diameter (mm)	EUS: diameter (mm)	no tumor detected	difference in side distribution
CT (n = 27)[1]	49	23.8 ± 10.19	22.4 ± 8.36	9	1
MRT (n = 7)1	11	20.7 ± 7.06	22.1 ± 8.96	3
TUS (n = 9)1	10	26.0 ± 8.7	21.8 ± 9.36	5	1
EUS (n = 18)1	18	10.4 ± 4.05	10.4 ± 4.05	0

¹ No further data documented.

Besides the largest tumor diameter [9], we distinguished between adenoma and nodular hyperplasia by EUS ([Fig. 1], [2], [3], [4], [5] [Table 4]). In all cases histological preparation of the adrenal glands has not been carried out.

Fig. 1 Adenoma (NFA) of the right adrenal gland.

Fig. 2 Typical adenoma (NFA) of the right adrenal gland with clear termination of medullary echo.

Fig. 3 Adenoma (NFA) of the left adrenal gland (max. diameter = 20 mm).

Fig. 4 Nodular hyperplasia (NFH) of the left adrenal gland.

Fig. 5 Nodular hyperplasia of the left adrenal gland in one case of SCS which developed overt Cushing's syndrome after 4.5 years.

EUS imaging of the adrenal glands was performed annually, as recommended by Barzon [10].

Hormone measurements

24 h urinary free cortisol was measured by the chemiluminescence immunoassay method (Access Cortisol-Assay^®, Beckman Coulter^®, Brea, USA). Radioimmunometric assay was used for the quantitative measurement of plasma renin (RENIN III GENERATION^®, Cisbio Bioassays, Codolet, France) and serum aldosterone (ALDOCTK-2^®, Dia Sorin, Saluggia, Italy). Quantification of the catecholamines in 24 h urine samples was made with high performance liquid chromatography (ChromSystems^®, Gräfelfing, Germany).

Statistical analysis

Statistical analysis was performed by SPSS version 22.0 statistical package (SPSS, Inc.) and R-version 3.0.2. For descriptive statistics, results are presented as mean ± SD or number (%). Continuous variables were compared between the three groups by ANOVA. χ²-test was used to compare categorical variables. To estimate the growth rates for the three subtypes, a linear mixed model was fitted. This model includes fixed effects for the subtype (intercept) and subtype × follow-up time interaction (slope) and random intercepts and slopes for each adrenal gland. A Bland-Altman plot was used to evaluate the agreement between two measurements. P-values less than 0.05 were considered statistically significant.

Results

During the period of 16 years, 93 out of 229 patients with AI or SCS were longitudinally investigated by EUS. These included 58 females (62.4 %) and 35 males. The mean age at the first examination was 57.6 ± 11.7 including 72 (77.4 %) patients older than 50 years and 13 (14.0 %) patients older than 70 years. A total of 207 examinations were performed. The number of further investigations ranged from 1 to 9 times (median: 3) and the mean follow-up time was 30.1 ± 28.2 months (range 2 – 120 months). The mean time interval between two consecutive examinations was 13.4 ± 10.1 months (range 2 to 76 months). In 69 out of 93 patients a unilateral tumor was detected (44 NFAs, 22 NFHs, 3 SCS). The same tumor entity in both adrenal glands could be observed in 22 patients (7 NFAs, 12 NFHs, 3 SCS). Furthermore, in two cases different masses between the glands were found. One patient had NFA and NFH located in the right and left adrenal gland, respectively. Another patient had nodular hyperplasia in combination with SCS in the left adrenal gland and NFH was found in the opposite gland. Hence, altogether 117 masses were followed up ([Table 1]).

The majority of AIs were first detected by CT (n = 49) and in ten cases TUS was initially done. In this connection the depicted tumors were on average 2.06 mm greater than measured by EUS. 95 % of differences between the conventional examination methods (CT, MRI and TUS) and the EUS were in a range between -17.43 mm and 21.55 mm. Furthermore, in two cases there was a difference between the affected adrenal glands ([Table 5]).

Non-functioning masses

In total, 107 non-functioning masses were detected. At the time of the first EUS examination, the mean age in the groups NFA and NFH was 59.7 ± 9.7 and 56.0 ± 13.3 years, respectively. 59 NFAs with a mean diameter of 21.2 ± 9.4 mm were followed over 32.7 ± 29.2 months. The majority of these lesions were located on the left side (38 masses, 64.4 %). In comparison, the NFH group consisted of 48 masses which had a mean tumor diameter of 17.2 ± 8.8 mm. The side distribution (left adrenal gland 64.6 %) and the follow-up period (30.1 ± 29.1 months) of NFHs were similar to those of NFAs.

Subclinical Cushing’s syndrome

In this analysis women (5 out of 7 patients) tended to suffer more often from SCS than men (p = 0.094). The mean age was 59.5 ± 9.0 years. The BMI was 27.4 ± 4.9 kg/m² (6 out of 7 cases considered). Moreover, arterial hypertension could be observed in six cases, IGT, osteoporosis, positive lateralization in AVS in two cases, and osteopenia in one patient ([Table 2]).

In this group, 7 patients had 3 adenomas and 7 nodular hyperplasias. At baseline, the mean diameter was 19.6 ± 9.2 mm ([Table 1]). Furthermore, there was no significant difference between the mean tumor diameter of NFAs, NFHs and SCS at baseline.

One patient with nodular hyperplasia in both adrenals (right 37 mm, left 29 mm, [Fig. 5]) developed arterial hypertension and osteopenia after a follow-up period of 4.5 years. The endocrine function was examined by low-dose (2 mg) and high-dose DST (8 mg) and AVS (cortisol-/aldosterone ratio threefold increased on the left side). These tests yielded pathological results corresponding to overt Cushing’s syndrome. Nodular hyperplasia of the left adrenal gland showed a size progression of 6 mm by EUS. In consequence, adrenalectomy of the left side was performed. During the postoperative control of the endocrine function, sufficient suppression during DST could be registered.

Growth rates

From the model, a mean growth rate of 0.35 mm/yr (NFA), 0.02 mm/yr (NFH) and 0.53 mm/yr (SCS) was estimated. The observed difference in the growth rates was not statistically significant (p = 0.11) ([Table 1, ] [Fig. 6]).

Fig. 6 Size progression of NFA (n = 59), NFH (n = 48) and SCS (n = 10) during follow-up.

Malignant progression

During the complete follow-up period, none of the 93 patients developed a malignant tumor.

Discussion

AIs are increasingly detected in the context of the higher number of abdominal examinations in the elderly population. Many tumors are benign and non-functional, and do not grow during follow-up [2] [3] [11]. Therefore, a method and work-up of investigation with the least harmful effects are necessary. In this retrospective study we analyzed data obtained by EUS in patients who chose this method for follow-up of their lesions.

In the present study, growth characteristics of AIs and SCS were first evaluated during longitudinal follow-up by EUS. We observed 93 out of 229 patients with 117 masses during a median follow-up of 20.2 months. The duration of follow-up is comparable to former studies, whereas the number of cases is slightly lower [11] [12] [13] [14]. The study population consisted of 58 females (62.4 %) and 35 males (37.6 %) with a mean age of 57.1 ± 11.7 years. Most patients (59 out of 93) were in the range of 50 to 70 years of age. The distribution of sex and age agrees again with recent reports [15] [16]. The most frequent lesion was the non-functioning adenoma (NFA) as it has been reported in the literature [17] [18]. In 24 patients (25.8 %) bilateral tumors were found. This rate of bilateral AIs is higher than the previously reported rate of 15 percent [19].

Based on our endocrine evaluation and endosonographic imaging, we divided the study population into the three groups NFA, NFH and SCS. The main criterion for SCS was a pathological DST. We used a low-dose DST with a dose of 2 mg dexamethasone to reduce the rate of false-positive results during the complete follow-up period. With regard to the cut-off value of DST, authors have lively discussions in the literature: The Endocrine Society recommended a cut-off value of ≥ 50 nmol/L resulting in a sensitivity of 75 – 100 % and a specificity of 72 – 82 % [20]. In contrast, the National Institutes of Health (NIH) and the American Association of Clinical Endocrinologists (AACE) advised a cut-off value of ≥ 138 nmol/L. In this case, the specificity is considerably higher (90 – 100 %) and the sensitivity is low (58 – 73 %) [3] [4] [21]. To find a compromise between sensitivity and specificity, we chose a cut-off value of ≥ 83 nmol/L [7] [22]. Suppression in a range of 55 to 83 nmol/L and positive lateralization in AVS were also categorized as SCS. In four cases of SCS the urinary free cortisol levels were within the normal range, whereas the DST was pathological ([Table 2]). In this context one has to consider that the specificity of UFC is quite a bit higher than that of the DST in obese patients [23]. Due to the low number of obese patients in the group SCS and the lack of data in three cases, it was not possible to gain convincing results to classify the obese patients based on the results of UFC and the DST. Therefore, we focused on the DST results for normal-weight and obese patients.

Endosonographic imaging showed the following tumor characteristics at baseline: Most of the tumors were detected on the left side (74 out of 117 tumors). This aspect ratio is also mentioned in the literature when imaging procedures like CT or MRI were used [13] [16]. If transabdominal ultrasound as the method of investigation was used, most tumors were detected on the right side [14] [17]. These findings depend on the use of the ultrasound method: Due to anatomy and difficult examination conditions (e. g. air in the intestines), the left adrenal gland is hard to see by abdominal ultrasound and the right adrenal gland by EUS. Additionally, the higher number of left-sided tumors can also be explained by a larger gland. Due to the fact that adrenal tumors often have their origin in adrenal cells, the prerequisite for tumor growth might be higher in a larger gland with a higher number of adrenal cells. Inclusion criteria for this study were among other things a minimal diameter of 5 mm or a tumor size of more than 5 mm during the first follow-up examination. In consequence, the tumors found by EUS are smaller than masses at the time of first diagnosis by CT, MRI or TUS and in previous reports in the literature ([Table 3]). A possible reason could be the resolution of EUS. It is far higher than that of CT or MRI. Lesions with a diameter of about 1 – 2 mm can be shown by EUS (analogous to small endocrine tumors in the pancreas) [24]. If NFMs grow, the tumors are detected at an earlier point in time and at an earlier point in tumor evolution according to a smaller diameter. Furthermore, we found 17 lesions by EUS which were not detected by CT, MRI or TUS. Similarly, Waldmann et al. reported that 33 % of the tumors found by EUS were not detected in CT studies in a prospective study of adrenal involvement in MEN 1 disease [25]. In these CT studies Hounsfield units are used to distinguish between benign and malignant tumors [18] [26] [27].

We offered EUS as an examination method for evaluating the growth process due to the fact that there is no radiation exposure. The radiation protection regulation in Germany (‘Röntgen-Verordnung’) declares that the use of one examination has to outweigh the harm (section 23, para. 1). Other methods implying the same health benefit have to be considered and possibly preferred. The risk of nuclear radiation cannot be underestimated: Cawood et al. reported a risk of cancer-related deaths due to several CT scans in 1 of 5000 deaths (> 30 years of age) [6].

However, EUS has several limitations: poor reproducibility of the cutting plane through the tumor, modified anatomical situations and possible complications resulting from sedation of patients like aspiration or cardiac decompensation. Furthermore, EUS is dependent on the physician’s experience. There will probably be more interindividual differences in measuring the tumor diameter in studies with more than one investigator.

The growth characteristics of NFMs are assessed as low. Barzon et al. described a tumor growth of more than 1 cm in 9 percent of cases [2]. Size progression is specified as 5 to 25 percent in the literature [2] [28] [29]. Libè et al. additionally proclaimed stagnation after two years [11]. Giordano et al. otherwise observed an increase of tumor size in a period of up to 8 years [1]. Besides this, a reduction in size could also be discovered in 1.3 to 5.2 percent of cases during a follow-up period of 4 years [3]. In one prospective study of SCS size, progression was noted in 3 of 22 cases (11.1 %) and size reduction in 2 cases (7.4 %) [14]. An increase in tumor size or a maximum diameter of ≥ 6 cm is chosen as a sign of malignancy. However, there is no recognized cut-off value to decide whether a tumor has become malignant or not, underscoring that the molecular pathogenesis of adrenal tumors is still poorly understood [30]. Tumors with a diameter larger than 6 cm are adenomas even more often than adrenal cortical carcinomas (ACCs) [31] [32].

If one regards the estimated growth rates of NFAs, NFHs and SCS in this study, one sees that the thesis of low growth during follow-up can be confirmed. When comparing the subtypes NFA, NFH and SCS, one can notice that the rate of SCS tends to be the highest. However, there was no significant difference between the various growth rates. As far as it is currently known, there is no comparable data of growth rates due to the fact that no one used a method with equally high resolution.

In one case of NFA, tumor size was 43 mm at baseline. After 10 months a diameter of 31 mm was measured. Unfortunately, the same cutting plane was not reproducible. Consequently, the decline might not be real tumor shrinkage. In the further course the size increased to 51.5 mm after surgical resection of the contralateral adrenal gland. During the postoperative course, the lesion decreased again to 42.1 mm six years after surgery.

In the groups NFA and NFH, no alteration of the endocrine function occurred during follow-up in our study. If one considers the frequency of developing endocrine function in cases of AI, it could also be seen at a low rate (about 1 %) [6]. A cumulative risk to develop SCS would be 3.8 % after one year and 6.6 % after five years in another study [10]. Worsening of the endocrine status was observed in 12 % of cases during a follow-up period of 15 years [33].

Our clinical findings concerning arterial hypertension, impaired glucose metabolism, obesity and osteoporosis in the SCS group correspond to former statements in the literature. Although SCS is defined as a diagnosis without any specific clinical manifestation caused by subtle hypercortisolism, these comorbidities frequently occurred [15] [34] [35] [36]. During follow-up, all cases remained in the SCS group. These findings correspond to former publications [15] [36].

In our study no malignant progression of any tumor was detected. Possible reasons are the low incidence of ACCs and a low risk for developing malignancy (less than 1 of 1000 tumors) [37].

In light of all factors, we searched for an appropriate algorithm for follow-up of AIs and SCS by EUS. The recommendations of former statements were an annual evaluation of the endocrine function (1 mg DST, metanephrines in plasma or 24 h urinary excretion; serum potassium and ARR in case of hypertension) for four years and another imaging procedure 3 to 6 months after the first detection of AI. Further investigations by CT or MRI were recommended over a whole period of 12 to 24 months [3] [20] [21] [29] [37].

On the basis of recommendations in the literature and our results regarding endocrine function and the estimated growth rates of NFAs, NFHs and SCS, we recommend the following algorithm for long-term follow-up of AIs: First re-evaluation of size should be done after 6 months and 2 years. A mass with a relative growth of more than 20 percent and absolutely of more than 10 mm should undergo another investigation by EUS after 6 months or be treated directly by surgery. Indications for surgery are rapid tumor growth, development of hormonal functionality or newly occurred signs of malignancy shown by EUS. Endocrine assessment should be repeated after 24 months. In cases of subclinical Cushing’s syndrome an additional re-evaluation (including blood pressure monitoring, bone densitometry and oral glucose tolerance test) after three years is recommended.

We chose these intervals to detect a growing adrenocortical carcinoma at an early point in time. Due to the fact that the growth rate is low, we looked for a compromise between early monitoring and sufficient time for developing potential size progression during follow-up.

Limitations of our analysis are the retrospective character, the definition of SCS by a single test (DST) and different test procedures during the follow-up period due to different centers of investigation and outpatient examinations of endocrine function. We made every diagnosis on the basis of the endosonographic results without any histological review. Moreover, it should be mentioned that EUS only displays two-dimensional representations of tumors. In consequence, the real tumor volume may not be calculated correctly.

To the best of our knowledge, this study is the first one regarding the longitudinal follow-up of NFMs and SCS by EUS. In contrast to CT, MRI and abdominal ultrasound, tumors with a smaller diameter were assessed in this study. We could confirm the low growth of NFMs and SCS reported in recent statements. The estimated growth rate of SCS tended to be higher than the rate of NFAs and NFHs. All in all, EUS can be a good alternative to conventional tomography techniques. It provides high resolution imaging and avoids radiation exposure. Furthermore, contrast media are not required.

Abbreviations

AI: adrenal incidentaloma

AVS: adrenal vein sampling

DST: dexamethasone suppression test

EUS: endoscopic ultrasound

IGT: impaired glucose tolerance

MEN: multiple endocrine neoplasia

NFA: non-functioning adenoma

NFH: non-functioning nodular hyperplasia

NFM: non-functioning mass

SCS: subclinical Cushing’s syndrome

TUS: transabdominal ultrasound

No conflict of interest has been declared by the author(s).

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