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Annales d’Endocrinologie xxx (2017) xxx-xxx
Annales d’Endocrinologie Annals of Endocrinology
Editorial
European recommendations for the management of adrenal incidentalomas: A debate on patients follow-up
Recommandations européennes pour la prise en charge des incidentalomes surrénaliens : un débat quant au suivi des patients
Keywords: Adrenal; Incidentalomas; Adenoma; Adrenocortical carcinoma; Hypercortisolism; Diabetes; Hypertension Mots clés : Incidentalomes ; Surrénales ; Adénome ; Corticosurrénalome ; Hypercorticisme ; Diabète ; Hypertension
New guidelines recommendations on the management of adrenal incidentalomas (AI) (nodules >1 cm) were published in 2016 by the European Society of Endocrinology (ESE) in part- nership with the European Network for the Study of Adrenal Tumors (ENSAT) [1]. Other recommendations guidelines had been published previously as reviews [2] or as consensus of medical associations notably by the French Endocrine Society (SFE) in 2008 [3] and the American Association of Clini- cal Endocrinologists and American Association of Endocrine Surgeons (AACE/AAES) in 2009 [4]. These new ESE recom- mendations have already received criticism [5], and differences with the previous recommendations need to be highlighted, which is the aim of this letter.
AI is defined as an adrenal mass detected on an imaging test ordered for a problem unrelated to adrenal disease. AI are found in 1% to 5% of abdominal CT scans and this frequency increases with age (<1% before 30 years, 7% after 70 years) [6]. When an AI is discovered, two standard questions are asked: (1) is the AI functional? and (2) is the AI malignant? However, a third crucial question concerns the follow-up of these patients, tak- ing into account the natural progression of AI. In this context, the new ESE recommendations have tried to address two other “practical” questions: (3) when does surgery need to be consid- ered? and (4) how should patients who do not undergo surgery be followed?
Firstly, the decision tree for imaging proposed by ESE is pre- sented in Fig. 1. A recent meta-analysis was done on 19 studies that evaluated different imaging modalities for initially diag- nosing potential malignant features of AI. The results showed that a non-contrast CT scan is the preferred choice as first-line
imaging to screen for malignancy of the mass. In patients with no known cancer history, a spontaneous density > 10 UH on the CT scan has a sensitivity of approximately 100% and a speci- ficity of approximately 72% for diagnosing malignancy [7]. The first difference between the ESE and previous recommendations concerns the follow-up with imaging tests. If the AI is homoge- nous, <4 cm and with a density ≤ 10 UH, no imaging follow-up is recommended by ECE, while SFE suggests a checkup after 6 months, 2 years and 5 years [3] and AACE/AAES after 6 months, 1 year and 2 years [4]. A review of the literature showed that with no history of cancer, the risk of developing a malignancy is very low (<0.2%) [8] or is at least an exceptional random event [9]. The risk of complications related to radiation exposure from repeated CT scans, the psychological impact and the economic costs are arguments against the systematic use of imaging tests for AI follow-up [1,8]. It should be kept in mind, however, that the cut-off values are not absolute. For instance, 3 different CT scans over a 2-year follow-up period showed that 20% of adrenal nodules with a density of around 10 UH would at some point be reclassified from benign to indeterminate [10]. In addition, the determination of the 4 cm cut-off was not based on studies with a high level of proof [1], and a borderline AI, which may be very slow growing, could also be reclassified [5]. If the benign nature of an AI is uncertain, ESE suggests discussion amongst a mul- tidisciplinary team the three following options: (1) immediate additional imaging with another method, (2) checkup at 6-12 months (via non-contrast CT scan or MRI) and (3) surgery [1]. As usually recommended, patients below 40 years and pregnant women should receive an urgent evaluation because of the higher likelihood of malignancy [2-4,6]. For these patients, imaging
0003-4266/ 2017 Elsevier Masson SAS. All rights reserved.
Adrenal incidentaloma
Noncontrast CT
≤ 10UH Homogenous < 4cm
Indeterminate
Multidisciplinary team
No further imaging
immediate additional imaging?
Surgery?
Noncontrast CT at 6-12 months?
Contrast CT Relative wash-out > 40% Absolute washout > 60% IRM Lost of signal on out-of-phase images
↑>20% and 5mm Ø
↑<20% and 5mm Ø
«
Surgery ?
Control imaging at 6-12 months
No further imaging
can be repeated and MRI is a good compromise to avoid the radi- ation risk from additional imaging. For patients with a known history of cancer, FDG-PET/CT could replace other imaging and indeterminate lesions could be followed-up at the same interval and with the same method as primary malignancies. ESE sug- gests that nodules with a density below10 UH and smaller than 4 cm do not need follow-up [1]. However, in the meta-analysis cited above, if patients had an extra-adrenal malignancy, 7% of AI with a density below 10 UH corresponded to metastasis [7]. We therefore think that every patient with a history of cancer should keep having an imaging follow-up. Finally, follow-up should be individualized to the patient, especially for nodules with borderline characteristics.
Secondly, the decision tree proposed for laboratory screening is presented in Figs. 2 and 3. The first steps are basically similar to those previously proposed [2-4,6]. Tests to be done at diagno- sis include the routine measurement of metanephrines, screening
for hypokalemia and hyperglycemia, a mineralocorticoid eval- uation in case of hypertension or hypokalemia history and screening for hypercortisolism using the 1 mg overnight dexa- methasone suppression test (DST). The threshold for diagnosing subclinical hypercortisolism remains at 1.8 µg/dL (50 nmol/L), with 95% sensitivity and 80% specificity [11]. The use of this 1.8 µg/dL threshold is now supported due to the strong demon- stration of increased morbidity and mortality in patients with a post-DST cortisol greater than 1.8 µg/dL [12,13]. If there is evidence of hormonal hypersecretion, management should be discussed by a multidisciplinary team. With regard to follow- up, while it was previously recommended a regular reevaluation of the DST for 5 years [3,4], ESE does not recommend repeating the DST in patients with a cortisol at the first DST ≤ 1.8 µg/dL without comorbidities (diabetes or glucose intolerance, hyper- tension, obesity, dyslipidemia, osteoporosis) [1]. Reassessment of excess cortisol and comorbidities, i.e. follow-up by an
Adrenal incidentaloma
1mg DST Plasma or urinary metanephrines Kaliemia
Clinical assessment
+ aldosterone/renin ratio if hypertension, hypokaliemia + sex-hormones, steroid precursors if suspicion of adrenocortical carcinoma
Multidisciplinary team
Non functioning benign lesion
Infraclinical hypercortisolism
Clinical relevant hormone excess or malignant tumor
No further biological investigation
Surgery
ARTICLE IN PRESS
Editorial / Annales d’Endocrinologie xxx (2017) xxx-xxx
1mg DST
≤ 1,8µg/dL (<50mmol/L)
>1,8-5 µg/dL (50-138 mmol/L)
>5 µg/dL
138 mmol/L
Clinical follow-up Biological re-assessment only if appearence of comorbidities
«possible autonomous cortisol secretion »
« autonomous cortisol secretion »
ACTH, DST at 3-12months
ACTH, UFC +/- midnight salivary cortisol, liddle test
Comorbidities ?
Comorbidities Diabetes, HTA, Osteoporosis, Obesity, hypercholesterolemia
No
Yes
No
Yes
Surgery ?
Clinical and biological follow-up for 2-4 years
endocrinologist, is only recommended by ESE for patients with a post-DST cortisol between 1.8 and 5 µg/dL and comorbidi- ties and for every patient with a post-DST cortisol ≥ 5 µg/dL without surgery. A 2-4 year follow-up is suggested [1]. This recommendation is based on the fact that the risk of develop- ing clinical hypercortisolism in patients with a normal cortisol evaluation at the AI diagnosis is extremely low (<0.7%) [8]. However, the risk of developing subclinical hypercortisolism varies considerably between the different studies, from 0% to 12%, depending on the biological criteria used [5,8]. Therefore, it remains unclear whether patients with subclinical hypercorti- solism should undergo surgery or if treatment of comorbidities is sufficient to avoid an increase in morbidity and mortality. Every patients with a post-DST cortisol > 1.8 µg/dL, even with- out comorbidities, should probably receive careful follow-up considering cardiovascular risk factors.
Finally, AI are bilateral in 2.7% to 10% of cases and correspond to bilateral metastasis in 2-30% of cases [14-17]. Because congenital adrenal hyperplasia can rarely be discov- ered [18], recommendations include the measurement of blood 17-OH progesterone in addition to the hormonal evaluation performed for unilateral AI. The ACTH stimulation test is no longer recommended [1] as it had been by SFE [3]. ESE sug- gests managing bilateral AI in the same manner as unilateral AI [1]. However, 35% to 40% of bilateral AI result in sub- clinical hypercortisolism (compared with 15-20% for unilateral AI) [19-21]. The development of subclinical hypercortisolism occurs in 15-20% of patients with bilateral AI compared with 6-10% of patients with unilateral AI [13,20]. Most of these cases eventually correspond to macronodular adrenal hyperperplasia. This disease is often diagnosed after 40 years and causes progres- sive and insidious Cushing’s syndrome [22]. Therefore, patients with bilateral AI should probably have follow-up for at least 5 years.
To conclude, the current ESE guidelines recommend lighter follow-up of patients with AI than previously proposed [2-4,6].
The importance of multidisciplinary discussions in manage- ment decisions for patients with AI is highlighted. However, it is unlikely that discussions by a multidisciplinary team could be done in all cases due to the need for access to an experi- enced team and the frequency of AI. Several questions remain regarding the management of nodules under 1 cm, the pro- gression of nodules larger than 4 cm and management of patients with subclinical hypercortisolism. Prospective stud- ies are greatly needed to support the guidelines for AI follow-up.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinol- ogy Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016;175:G1-34, http://dx.doi.org/10.1530/EJE-16-0467.
[2] Nieman LK. Approach to the patient with an adrenal inciden- taloma. J Clin Endocrinol Metab 2010;95:4106-13, http://dx.doi.org/ 10.1210/jc.2010-0457.
[3] Tabarin A, Bardet S, Bertherat J, Dupas B, Chabre O, Hamoir E, et al. Exploration and management of adrenal incidentalomas. French Soci- ety of Endocrinology Consensus. Ann Endocrinol 2008;69:487-500, http://dx.doi.org/10.1016/j.ando.2008.09.003.
[4] Zeiger MA, Thompson GB, Duh Q-Y, Hamrahian AH, Angelos P, Elaraj D, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Manage- ment of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract 2009;15:450-3, http://dx.doi.org/10.4158/EP.15.5.450.
[5] Morelli V, Scillitani A, Arosio M, Chiodini I. Follow-up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: could we be safe? J Endocrinol Invest 2017;40:331-3, http://dx.doi.org/10.1007/s40618-016-0558-x.
Editorial / Annales d’Endocrinologie xxx (2017) xxx-xxx
[6] Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Carney JA, Godley PA, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 2003;138:424-9.
[7] Dinnes J, Bancos I, Ferrante di Ruffano L, Chortis V, Davenport C, Bayliss S, et al. Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a sys- tematic review and meta-analysis. Eur J Endocrinol 2016;175:R51-64, http://dx.doi.org/10.1530/EJE-16-0461.
[8] Cawood TJ, Hunt PJ, O’Shea D, Cole D, Soule S. Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becom- ing malignant; time for a rethink? Eur J Endocrinol 2009;161:513-27, http://dx.doi.org/10.1530/EJE-09-0234.
[9] Belmihoub I, Silvera S, Sibony M, Dousset B, Legmann P, Bertagna X, et al. From benign adrenal incidentaloma to adrenocortical carci- noma: an exceptional random event. Eur J Endocrinol 2017;176:K15-9, http://dx.doi.org/10.1530/EJE-17-0037.
[10] Hammarstedt L, Thilander-Klang A, Muth A, Wängberg B, Odén A, Hellström M. Adrenal lesions: variability in attenuation over time, between scanners and between observers. Acta Radiol Stockh Swed 1987 2013;54:817-26, http://dx.doi.org/10.1177/0284185113482688.
[11] Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-40, http://dx.doi.org/10.1210/jc.2008-0125.
[12] Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. Cortisol as a marker for increased mortality in patients with inciden- tal adrenocortical adenomas. J Clin Endocrinol Metab 2014;99:4462-70, http://dx.doi.org/10.1210/jc.2014-3007.
[13] Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15- year retrospective study. Lancet Diabetes Endocrinol 2014;2:396-405, http://dx.doi.org/10.1016/S2213-8587(13)70211-0.
[14] Al-Thani H, El-Menyar A, Al-Sulaiti M, ElGohary H, Al-Malki A, Asim M, et al. Adrenal mass in patients who underwent abdominal com- puted tomography examination. North Am J Med Sci 2015;7:212-9, http://dx.doi.org/10.4103/1947-2714.157482.
[15] Davenport C, Liew A, Doherty B, Win HHN, Misran H, Hanna S, et al. The prevalence of adrenal incidentaloma in routine clinical practice. Endocrine 2011;40:80-3, http://dx.doi.org/10.1007/s12020-011-9445-6.
[16] Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1049 consecutive adrenal
masses in patients with no known malignancy. AJR Am J Roentgenol 2008;190:1163-8, http://dx.doi.org/10.2214/AJR.07.2799.
[17] Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85:637-44, http://dx.doi.org/10.1210/jcem.85.2.6372.
[18] Jaresch S, Kornely E, Kley HK, Schlaghecke R. Adrenal inci- dentaloma and patients with homozygous or heterozygous congen- ital adrenal hyperplasia. J Clin Endocrinol Metab 1992;74:685-9, http://dx.doi.org/10.1210/jcem.74.3.1311000.
[19] Olsen H, Nordenström E, Bergenfelz A, Nyman U, Valdemarsson S, Palmqvist E. Subclinical hypercortisolism and CT appearance in adrenal incidentalomas: a multicenter study from Southern Sweden. Endocrine 2012;42:164-73, http://dx.doi.org/10.1007/s12020-012-9622-2.
[20] Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab 2014;99:827-34, http://dx.doi.org/10.1210/jc.2013-3527.
[21] Vassilatou E, Vryonidou A, Ioannidis D, Paschou SA, Panagou M, Tzavara I. Bilateral adrenal incidentalomas differ from unilateral adrenal inciden- talomas in subclinical cortisol hypersecretion but not in potential clinical implications. Eur J Endocrinol Eur Fed Endocr Soc 2014;171:37-45, http://dx.doi.org/10.1530/EJE-13-0848.
[22] Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009;23:245-59, http://dx.doi. org/10.1016/j.beem.2008.10.011.
Stéphanie Espiard (CCA, MD, PhD) * Kanza Benomar (CCA, MD) Camille Loyer (CCA, MD) Claire Vahé (CCA, MD) Marie-Christine Vantyghem (PU-PH, MD, PhD) Service d’endocrinologie-métabolisme, hôpital C .- Huriez, CHRU de Lille, 59037 Lille, France
* Corresponding author. Service d’endocrinologie-métabolisme, hôpital C .- Huriez, rue Polonovski, Lille University Hospital, 59037 Lille cedex, France.
E-mail address: stephanie.espiard@live.fr (S. Espiard)