Adrenal lesion is one of the features of multiple endocrine neoplasia type 1 (MEN1). This study aimed to assess prevalence, natural course and clinical relevance of small adrenal lesions without clinical symptoms, endocrine activity, or mechanical problems and thus without clear indication for surgical therapy by endoscopic ultrasound (EUS).
Design and methods
Forty-nine patients with familial MEN1 were studied. Twenty-seven of these with adrenal lesions were detected by EUS and at least two performed EUS examinations were included into a subgroup where changes in adrenal morphology were studied by measuring changes in the largest diameter of the dominant adrenal tumour.
EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals, 17 (35%) nodular hyperplasia, 12 (24%) adenomas and 1 (2%) cyst. Bilateral adrenal lesions were detected in 17 patients and unilateral in 19 patients. A change in the largest tumour diameter was found to be for nodular hyperplasia −0.02±1.41% per month (range −2.56 to 4.58%) and for adenomas −0.61±1.95% per month (range −6.25 to 1.15%). One patient had an adrenal cyst with significant growth. There was no evidence of carcinoma or metastatic disease during the study.
The prevalence of adrenal lesions in MEN1 is higher than that reported earlier. Except one cystic lesion, no significant change in the tumour size was observed over a mean observation period of more than 2 years. In a typical situation, small adrenal lesions in MEN1 seem to be constant in their morphology.
Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder with neoplasia of the anterior pituitary, parathyroid, endocrine pancreas and other endocrine tissues (1). Adrenal lesions are also associated with MEN1. However, the prevalence, natural course and clinical management of adrenal lesions in MEN1 have not yet been clearly defined.
In the literature, the prevalence of adrenal involvement ranges from 9 to 55% (2, 3, 4, 5, 6, 7). Most of the lesions were described as non-functional. The first reports about adrenal lesions in MEN1 refer to autopsy studies or to incidental findings at laparotomy. Later in the diagnostics of adrenal lesions in MEN1, radiological methods and abdominal ultrasound were used (2, 3, 4, 5, 6). In this study, endoscopic ultrasound (EUS) of the pancreas, paragastric/paraduodenal lymph nodes and the adrenals was performed. This method is now considered to be an established diagnostic approach in MEN1. EUS enables us to visualise small pancreatic neuroendocrine tumours down to a diameter of 1–2 mm (8, 9). The high sensitivity of EUS in the detection of adrenal lesions has been reported recently (7).
The purpose of this study was to determine prevalence, and especially natural course and thus clinical relevance of asymptomatic, small adrenal lesions (<3 cm) in MEN1 patients by EUS imaging.
Design and methods
The study was conducted according to the Declaration of Helsinki, and the study protocol was reviewed and approved by the local ethical committee. Informed written consent was obtained from each subject.
Forty-nine patients with familial MEN1 (24 female/25 male, 46±14 years) were studied. Twenty-seven of these patients with at least two performed EUS examinations and asymptomatic adrenal lesions <3 cm according to EUS criteria without endocrine activity were included into a subgroup (15 male/12 female, 46±14 years), where changes in adrenal morphology were studied prospectively. The mean observation time of this subgroup was 27±9 months (range 3–43 months). During follow-up, EUS was performed 3.6±1.0 times (range 2–5 times).
The adrenal lesions were classified according to EUS criteria as: plump adrenal; nodular hyperplasia; adenoma; cyst.
Plump adrenals were diagnosed by subjective impression of the examiner when thickening of the adrenal was striking. Nodular hyperplasia was defined as nodular transformation of the adrenals without clear capsular borders of the nodules. Adenoma was defined as a nodular lesion with a visible capsule and/or a difference in echogeneity of the lesion to the surrounding adrenal tissue. Cyst was diagnosed if an echo-free lesion was detected.
The natural course of adrenal manifestation in the subgroup of 15 males and 12 females was assessed by following the largest diameter of the dominant lesion as determined by EUS. Plump adrenals were not included into this analysis.
Dominant lesion was defined: in the case of a single tumour, this lesion; in the case of nodular hyperplasia, the largest diameter of the largest nodule; in the case of bilateral lesions, the largest lesion by regarding cyst and adenoma before nodular hyperplasia.
The slope of the regression line (change from baseline (%)/time (months)) of each single lesion referring to all measurements available for each particular lesion was taken as the change in largest tumour diameter.
EUS, which included imaging of the adrenal, pancreas, and the surrounding structures was performed by one single experienced investigator (PHK) following a routine procedure (8, 9) using a Pentax FG 32 UA endosonoscope with a longitudinal 7.5 MHz sector array in combination with a Hitachi EUB 525 ultrasound computer. Pre-medication was performed with 30 mg pentazocine, 10–30 mg diazepam, and 0.25–0.5 mg atropine. The examination time was ∼45 min.
In addition, as part of their clinical assessment, 19 patients underwent computed tomography (CT) during the study. Adrenal lesions as assessed by CT and described in the CT report were compared with EUS findings.
Hormone analysis and endocrine function testing were performed to exclude endocrine activity. A urinary cortisol excretion value >403 μg/24 h or a serum cortisol concentration >30 μg/l in the morning following the administration of 2 mg dexamethasone orally the preceding evening (low dose dexamethasone suppression test) were considered pathological (hypercortisolism). The cortisol in serum and urine was determined by chemiluminescence immunoassay (UniCel DxI 800, Access Immunoassay System, Beckmann Coulter GmbH, Krefeld, Germany). In case of aldosterone concentrations >15 ng/dl the aldosterone to renin ratio was determined. A ratio >5 was considered pathological (hyperaldosteronism). Aldosterone in serum was determined by RIA (Multi Kristall Gamma Counter LB 2111, Berthold Technologies GmbH & Co.KG, Bad Wildbad, Germany) and renin in plasma was determined by chemiluminescence immunoassay (Liaison Direct Renin, DiaSorin S.p.A., Saluggia, Italy). A pathological excretion of catecholamines or metabolites (adrenaline, noradrenaline, dopamine, vanillylmandelic acid, homovanillic acid, metanephrine, normetanephrine) in urine was diagnosed according to the reference ranges given by the manufacturer. In case of pathological excretion of catecholamines in urine, a clonidine test was performed. Elevated basal plasma catecholamines (according to the reference ranges given by the manufacturer) and a suppression <50% after administration of 300 μg clonidine orally were considered pathological (pheochromocytoma). Catecholamines in urine and plasma were determined by high-performance liquid chromatography using a reverse-phase technique (Autosampler Waters, Waters GesmbH, Wien, Austria).
These investigations were performed at the University Hospital of Marburg in the majority of patients, but some patients were seen at other institutions. Therefore, intervals and methods of hormone analysis and endocrine function testing could not be standardised.
Before inclusion in the study, one patient had undergone unilateral nephrectomy and adrenalectomy because of renal cancer (no. 41), one patient unilateral adrenalectomy because of an incidentaloma 4.5 cm in diameter (no. 39) and another patient bilateral adrenalectomy because of adrenocorticotrophin (ACTH)-independent Cushing's syndrome (no. 42). No regrowth of any suspicious tissue after adrenalectomy was noted during follow-up, and these data did not enter statistical analysis. One further patient (no. 31) showed ACTH-independent Cushing's syndrome due to bilateral nodular hyperplasia and underwent bilateral adrenalectomy after the first EUS investigation. This particular patient was not available for follow-up.
EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals; 17 (35%) adrenal nodular hyperplasia; 12 (24%) adrenal adenomas; 1 (2%) adrenal cysts.
Bilateral adrenal lesions were detected in 17 patients and unilateral lesions in 19 patients.
The change in the diameter of the largest tumour was found to be: for adrenal nodular hyperplasia, −0.02±1.41% per month (range −2.56 to 4.58%) (Fig. 1) and for adenomas, −0.61±1.95% per month (range −6.25 to 1.15%) (Fig. 2).
One patient had an adrenal cyst with significant growth during the last year of examination (month 0, 2.8 cm; month 7, 2.9 cm; month 10, 3.0 cm; month 22, 3.7 cm). Therefore, laparoscopic adrenalectomy was performed in this patient.
Thus, except one cystic lesion no significant change in the diameter of the adrenal lesions in our cohort of patients with MEN1 was observed. In all patients, there was no evidence for carcinoma or metastatic disease during the study.
CT reported no plump adrenals (3 detected by EUS), 6 adrenal nodular hyperplasia (12 detected by EUS) and 3 adrenal adenomas (4 detected by EUS).
In general, adrenal lesions in MEN1 are reported to be rarer than parathyroid or pancreatic endocrine lesions. According to previous studies, the prevalence of adrenal changes in MEN1 ranges from 9 to 55% (2, 3, 4, 5, 6, 7). However, in most of these studies, radiological methods (CT, magnetic resonance imaging) were performed to assess the adrenal involvement in MEN1. These methods do not seem to be completely precise. EUS enables the detection and localisation of adrenal lesions that cannot be detected by CT (7), as was also documented for pancreatic lesions in MEN1 (9). According to our results, the sensitivity of CT when compared with EUS in the detection of adrenal lesions in MEN1 was found to be low. However, CT was performed as part of the clinical routine by different investigators, but EUS by one single investigator with special attention to the adrenal lesions. Therefore, these data are probably biased.
In this study, EUS detected adrenal lesions in 36 (73%) patients. Hence, we find adrenal involvement in MEN1 to be more common than that reported previously (Table 1). However, plump adrenals are subjective impressions when performing EUS and have to be considered carefully. Nevertheless, according to our data, ‘objective’ adrenal involvement (adrenal adenoma, nodular hyperplasia, cyst) occurred in 30 (61%) MEN1 patients. This study showed that there was no significant change in the diameter of small asymptomatic adrenal lesions in patients with MEN1, which confirms the results of previous studies over a time period of 15 years using different, however, less precise, imaging methods (7, 14).
Frequency of adrenal tumours in multiple endocrine neoplasia type 1 (MEN1) patients (literature data).
|Study||Total||With adrenal tumours|
|Skogseid (1995)||43||17 (40%)|
|Burgess (1996)||33||12 (36%)|
|Carty (1998)||34||3 (9%)|
|Giraud (1998)||62||15 (24%)|
|Langer (2002)||67||18 (26%)|
|Barzon (2001)||20||7 (35%)|
|Waldmann (2007)||38||21 (55%)|
|O Vierimaa (2007)||82||29 (35%)|
|Present study||49||36 (73%)|
In our study, in almost all patients, mutations in the MEN1 gene have been detected (Table 2). In three (6%) patients, no mutation could be demonstrated, corresponding well to previously reported data (10, 11, 12, 13, 14). These individuals may have mutations in promoter or UTRs, which remains to be investigated. In a recently published study, a genotype–phenotype correlation between different mutations and the incidence of non-functioning pancreatic tumours and gastrinomas could be established (15). However, this correlation was lacking for adrenal lesions.
Patient number, age at date of last endoscopic ultrasound (EUS) (years), sex (M, male; F, female), clinical characteristics (pHPT, primary hyperparathyroidism; PIT, pituitary adenoma; NEP, neuroendocrine pancreatic tumour), morphology of the adrenals (n/v, not visible), genetic diagnosis (n/d, no mutation detected; n/a, data not available).
|Age||Sex||MEN1 characteristics||Left adrenal||Right adrenal||Genetics|
|1||22||M||pHPT, NEP (inactive)||Adenoma||Nodular hyperplasia||67 Ins AGCCC|
|2||47||M||pHPT, NEP (inactive)||Adenoma||Nodular hyperplasia||67 Ins AGCCC|
|3||28||M||pHPT, NEP (inactive)||Nodular hyperplasia||Normal||E116X Ex 2|
|4||21||F||pHPT, NEP (insulinoma)||Adenoma||Plump||L168P Ex 3|
|5||42||F||pHPT, PIT (prolactinoma), NEP (gastrinoma, glucagonoma)||Adenoma||Normal||F448X Ex 9|
|6||51||F||pHPT, NEP (gastrinoma)||Plump||Plump||427 del 6bp 1390 (GTCCCA)|
|8||60||M||pHPT, NEP (inactive), bronchial carcinoid||Nodular hyperplasia||Nodular hyperplasia||E116X Ex 2|
|9||60||F||pHPT, NEP (inactive)||Nodular hyperplasia||n/v||1652–1653 ins G, E530X Ex 10|
|10||55||M||pHPT, PIT (prolactinoma), NEP (inactive)||Adenoma||Normal||E116X Ex 2|
|11||70||M||pHPT, NEP (PPoma)||Nodular hyperplasia||Nodular hyperplasia||n/a|
|12||53||M||pHPT, NEP (gastrinoma)||Nodular hyperplasia||n/v||E530X Ex 10|
|13||60||F||pHPT, PIT (prolactinoma)||Nodular hyperplasia||Nodular hyperplasia||n/a|
|14||41||F||NEP (inactive)||Cyst||Normal||L168P Ex 3|
|15||25||F||pHPT, PIT (inactive), NEP (inactive)||Normal||Plump||K119X Ex 2|
|16||37||F||pHPT, PIT (prolactinoma), NEP (insulinoma), bronchial carcinoid||Adenoma||Normal||K120X Ex 2|
|17||65||F||PHPT, gastral carcinoid||Normal||n/v||Y90X|
|18||50||M||pHPT, NEP (gastrinoma)||Nodular hyperplasia||Normal||466 14bp del|
|19||54||F||pHPT, PIT (prolactinoma), NEP (gastrinoma)||Adenoma||Plump||E116X Ex 2|
|20||49||M||pHPT, NEP (gastrinoma)||Adenoma||Normal||514 ins C|
|21||68||M||pHPT, PIT (prolactinoma), NEP (inactive)||Adenoma||Normal||n/d|
|22||42||F||pHPT, NEP (inactive)||Plump||Normal||S155F Ex 3|
|23||69||M||PIT (inactive), NEP (inactive)||Normal||Normal||n/a|
|25||38||M||NEP (inactive)||Normal||Normal||L168P Ex 3|
|26||53||F||pHPT, PIT (prolactinoma), NEP (inactive)||Normal||n/v||Intron 4 G→A|
|27||45||M||pHPT, PIT (prolactinoma), NEP (gastrinoma)||Nodular hyperplasia||Normal||545|
|28||28||F||pHPT, NEP (probably insulinoma)||Normal||Normal||E26K|
|29||48||M||pHPT, PIT (inactive), NEP (inactive), thymus carcinoid||Adenoma||Adenoma||n/d|
|30||58||F||pHPT, PIT (acromegaly)||Nodular hyperplasia||Plump||n/a|
|31||47||F||Nodular hyperplasia||Nodular hyperplasia||n/a|
|32||36||M||pHPT, PIT (carcinoma), NEP (inactive)||Normal||Normal||n/a|
|33||54||M||pHPT, NEP (gastrinoma, insulinoma)||Nodular hyperplasia||n/v||Q554X|
|34||31||M||pHPT, PIT (prolactinoma), NEP (inactive)||Nodular hyperplasia||Nodular hyperplasia||nt 894 G→A|
|35||46||F||pHPT, PIT (n/a), NEP (inactive)||Nodular hyperplasia||Nodular hyperplasia||R436Y|
|36||39||M||pHPT, PIT (prolactinoma), NEP (gastrinoma)||Normal||Normal||C488G→stop|
|37||47||M||pHPT, NEP (inactive)||Normal||Normal||T193I|
|38||35||F||pHPT, NEP (gastrinoma)||Adenoma||Normal||n/d|
|39||33||F||pHPT, NEP (inactive)||Adrenalectomy||Plump||T193I|
|40||38||M||pHPT, PIT (inactive), NEP (inactive)||Adenoma||Plump||K285X|
|41||65||F||pHPT, PIT (inactive), NEP (inactive)||Adenoma||Nephrectomy and adrenalectomy||n/a|
|42||60||F||pHPT, NEP (gastrinoma)||Adrenalectomy||Adrenalectomy||splice Intron 4 C894 G→A|
|43||41||F||pHPT, NEP (inactive)||Adenoma||Adenoma||P529X Ex 10|
|45||73||M||pHPT, NEP (inactive)||Plump||Plump||n/a|
|46||48||M||PIT (prolactinoma), NEP (VIPoma)||Normal||n/v||L168P Ex 3|
|47||21||F||Normal||Normal||S155F Ex 3|
|48||20||F||Normal||Normal||S155F Ex 3|
|49||55||M||pHPT, PIT (prolactinoma), NEP (gastrinoma)||Nodular hyperplasia||Nodular hyperplasia||L168P Ex 3|
No carcinoma or metastatic disease was detected in our cohort during the study period. However, Skogseid et al. reported a series of 17 MEN1 patients with adrenal involvement, three of whom (18%) had adrenocortical carcinomas (ACC) that exhibited adrenocortical hormone excess (2). According to Langer et al. (6), 22% of patients with adrenal involvement in MEN1 developed ACC. Consequently, the malignant potential of adrenal changes in MEN1 can be striking. For this reason, a thorough control of adrenal changes in patients with MEN1 should be routinely performed.
In our study, by definition and inclusion criteria all patients available for follow-up had hormone-inactive adrenal lesions. Only two patients had an endocrine active adrenal lesion (ACTH-independent Cushing's syndrome due to bilateral adrenocortical hyperplasia). Bilateral adrenalectomy was performed in these patients and they were not taken for analysis. None of the patients of the present study were observed to have a pheochromocytoma or an aldosterone-secreting lesion of the adrenals. There was also no clinical evidence for the secretion of sexual steroids. However, in previous studies, pheochromocytoma as part of the MEN1 syndrome has been reported (ranging from 0 to 3%) (4, 6). Three cases of aldosterone-secreting adrenal tumours as a possible part of the MEN1 syndrome have also been documented in the literature (16, 17, 18, 19). Therefore, the MEN1 syndrome may include the whole spectrum of adrenocortical and medullary pathology, but most of the adrenal lesions are non-functional.
According to our data, EUS can be considered a very sensitive and precise method in the detection of adrenal lesions in MEN1. Our results indicate that, in general, asymptomatic, endocrine-inactive, small adrenal lesions in MEN1 patients are frequent and demonstrate no change in their size over years. In all patients, there was no evidence for carcinomas and metastatic disease. Thus, the risk of malignant/metastatic disease from morphologically stable, asymptomatic, endocrine-inactive adrenal lesions can be considered low.
It may be suggested to assess adrenal lesions in MEN1 by EUS surveillance due to the high sensitivity of this method. The authors would recommend a control investigation after 6 months following first diagnosis. In the case of a stable lesion, control intervals of 2 years seem to be sufficient. Growing lesions have to be judged as atypical; taking notice of the higher incidence of ACC in other studies, instead of assessment and control by EUS imaging surgical intervention needs to be considered.
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S Schaefer and M Shipotko contributed equally to this work