The Clinical Course Of Patients With Adrenal Incidentaloma .
Clinical StudyD Kastelan and othersClinical management of adrenalincidentaloma173:2275–282The clinical course of patients with adrenalincidentaloma: is it time to reconsider thecurrent recommendations?Darko Kastelan1,2, Ivana Kraljevic1, Tina Dusek1,2, Nikola Knezevic3, Mirsala Solak1,Bojana Gardijan4, Marko Kralik5, Tamara Poljicanin6, Tanja Skoric-Polovina1 andZeljko Kastelan2,31Department of Endocrinology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia,School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia, 3Department of Urology,University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia, 4Department of Internal Medicine,University Hospital Merkur, Zajceva 19, 10000 Zagreb, Croatia, 5Department of Radiology, University HospitalCentre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia and 6Croatian Institute of Public Health,Rockefellerova 7, 10000 Zagreb, CroatiaEuropean Journal of Endocrinology2Correspondenceshould be addressedto D bjective: The current guidelines for the management of adrenal incidentaloma advise hormonal and radiological follow-upof patients for 2–5 years after the initial diagnosis. However, the vast majority of adrenal incidentaloma are non-functionalbenign cortical adenomas that require no treatment, so the routine application of the current strategies often results ina number of unnecessary biochemical and radiological investigations. The aim of this study was to analyse the clinicalcourse of patients with adrenal incidentaloma and to provide a critical review of the current management strategy ofthe disease.Design and methods: This was a retrospective study performed in the Croatian Referral Center for adrenal gland disorders.The study included 319 consecutive patients with adrenal incidentaloma, 174 of which were followed for at least 24 months.Results: The vast majority of patients were diagnosed with benign adrenal masses, whereas in about 5% of them adrenaltumor corresponded to adrenal carcinoma or metastasis. Tumor density was found to be superior to tumor size indistinguishing benign adrenal masses from malignant tumors and pheochromocytomas. During the follow-up, no patientdemonstrated a clinically significant increase in tumor size. In addition, no changes, either in metanephrines andnormetanephrines or in the activity of renin–aldosterone axis, were observed during the follow-up. Six patients developedsubclinical Cushing’s syndrome (SCS) whereas eight patients with SCS showed biochemical remission during follow-up.Conclusion: The study suggests that the risk of an adrenal mass initially diagnosed as benign and non-functionalbecoming malignant or hormonally active is extremely low. Therefore, the clinical management of those patients shouldbe tailored on an individual basis in order to avoid unnecessary procedures.European Journal ofEndocrinology(2015) 173, 275–282IntroductionThe term ‘adrenal incidentaloma’ covers a wide range ofadrenal pathologies unexpectedly found during work-upperformed for an indication unrelated to suspected adrenaldisease. The prevalence of such incidentally discoveredadrenal masses increases with age and is reported in morethan 7% of patients aged over 70 (1). The major clinicalwww.eje-online.orgDOI: 10.1530/EJE-15-0199Ñ 2015 European Society of EndocrinologyPrinted in Great Britainconcern in adrenal incidentaloma is the risk of malignancy and hormone overproduction, but the vast majorityof adrenal masses are non-functional benign corticaladenomas that require no treatment (2, 3, 4, 5, 6).Given the relatively low prevalence of functionaland malignant lesions, diagnostic tests for adrenalPublished by Bioscientifica Ltd.Downloaded from Bioscientifica.com at 05/14/2021 09:45:05AMvia free access
European Journal of EndocrinologyClinical StudyD Kastelan and othersincidentaloma need to have high sensitivity andspecificity in order to capture all the clinically importantadrenal lesions and to avoid a high rate of false positiveresults. Guidelines for the management of adrenalincidentalomas suggest multiple repetitions of radiological and biochemical tests. Patients who are notcandidates for surgery should undergo re-imaging 3–6months after the initial diagnosis and then annually forthe next 1–2 years. Furthermore, annual biochemicalfollow-up is advised for up to 4–5 years after the establishment of the diagnosis (3, 7, 8). However, given the lowprobability of the transformation of a benign andnon-functional adrenal mass to a malignant or functionalone (2), the routine application of the current strategies islikely to result in a number of unnecessary biochemicaland radiological investigations. Such an approach is costlyand it does not take into account harmful consequences ofdiagnostic evaluation such as patients’ anxiety associatedwith repeated clinical visits and a high rate of false positiveresults leading to further testing or unnecessary adrenalectomy. Moreover, radiation exposure associated withrepeated CT imaging increases the risk of fatal cancer (2).The described problems appear to call for the reconsideration of the current practices in the management ofadrenal incidentalomas. Therefore, in the present study weanalysed the clinical course of patients with adrenalincidentaloma. Based on our results and on the resultsfrom existing literature, we provide a critical review of thecurrent follow-up strategy for adrenal incidentaloma. Wesuggest its reconsideration in order to avoid unnecessary,costly and sometimes harmful diagnostic work-up.Subjects and methodsPatientsThe study population comprised 319 consecutive patients(111 males, 208 females: median age 58 (25–86) years) whowere referred to the Department of Endocrinology,University Hospital Zagreb, between January 2008 andJune 2013.In all the study subjects, adrenal tumor was diagnosedby the unenhanced CT. Adrenal tumors characterised bythe attenuation value of %10 Hounsfield units (HU) wereconsidered as benign adrenocortical adenomas. Theclinical indication for the CT image that led to thediagnosis of adrenal mass included acute abdominal pain(21.3%), various gastrointestinal tract disorders (20.4%),renal colic and other urinary tract disorders (26.9%),abdominal infection (6.3%), pulmonary diseases (3.4%)Clinical management of adrenalincidentaloma173:2276and a group of other less frequent indications, whichaccounted for 11.0% of the cases. In 10.7% of the patients,adrenal incidentaloma was discovered by abdominalultrasound during a regular check-up, and then it wasconfirmed by CT. Patients with a history of a malignantdisease within 10 years before entering the study wereexcluded from the analysis. The study was approved by theLocal Ethics Committee.Hormone assaysAll the laboratory analyses were performed using standardassays. Serum cortisol, free urinary cortisol, plasmaadrenocorticotropin (ACTH) and DHEAs were measuredwith electrochemiluminescence immunoassay (Roche).HPLC (Chromsystems, Munich, Germany) was used forthe measurement of urinary metanephrine and normetanephrine. Plasma renin activity and aldosterone wereassessed in hypertensive patients using RIA kits (SorinBiomedica, Saluggia, Italy). Androstendione and 17-OHPwere measured by ELISA (DRG, Marburg, Germany),whereas testosterone was determined by chemiluminescent immunoassay using the VITROS ECi immunodiagnostic system (Ortho Clinical Diagnostics,Rochester, NY, USA). Hormone reference values wereprovided by the manufacturer.Imaging studiesIn the study, all the CT data were evaluated by a singleradiologist (M K). Initial CT scanning was done ondifferent scanners available in various medical institutionsin Croatia, including ours. However, in all the patients atleast one CT scan was performed at the Department ofRadiology, University Hospital Centre Zagreb, using theSomatom Sensation 40 (Siemens, Erlangen, Germany) andLightSpeed Ultra 8 (GE Healthcare, Little Chalfont, UK) CTscanners with a slice thickness of 1.5 mm or 2 mm.Study protocolDuring the study period, a total of 319 patients diagnosedwith adrenal incidentaloma were included in the baselineanalysis. The data of 174 patients were available for thefinal analysis, which was done 24 months after enteringthe study. The patient flowchart is presented in Fig. 1.Subclinical Cushing’s syndrome (SCS) was definedby the presence of plasma cortisol level O83 nmol/l after1 mg overnight dexamethasone suppression plus eitherelevated urinary cortisol (O379 nmol/24 h) or lowwww.eje-online.orgDownloaded from Bioscientifica.com at 05/14/2021 09:45:05AMvia free access
D Kastelan and othersClinical StudyUnilateraladrenalectomyn 77Lost to follow-upn 32Continued follow-updue to contralateral massn 13Final visit(24 months of follow up)n 174Figure 1Patient flowchart.European Journal of Endocrinology173:2277but with otherwise benign CT phenotype refused surgeryand were included in the follow-up group.Study populationn 319Follow-up 24 monthsn 49Clinical management of adrenalincidentalomaACTH (!2.2 pmol/l). All the patients were evaluated forthe presence of hypertension, dyslipidemia, osteoporosisand diabetes mellitus/impaired glucose tolerance. Hypertension was defined as the use of anti-hypertensive drugsor blood pressure O140/90 mmHg. Dyslipidemia wasdefined as the use of anti-lipemic drugs or abnormal levelsof cholesterol (O6.5 mmol/l) and tryglicerides(O1.69 mmol/l). Osteoporosis was defined as bonemineral density T-score %K2.5 on lumbar spine, femoralneck or total hip. Diabetes was defined as fasting plasmaglucose R7 mmol/l or as plasma glucose O11.1 mmol/l2 h after a 75-g oral glucose load. Impaired glucosetolerance was defined as fasting plasma glucose between5.6 and 6.9 mmol/l or as plasma glucose between 7.8 and11.1 mmol/l 2 h after a 75-g oral glucose load.According to the Croatian guidelines for the management of patients with adrenal incidentaloma (9), surgerywas considered in the patients with functional tumors ormasses larger than 4 cm or masses exhibiting imagingcharacteristics suspected of malignancy. In the case of theSCS, a unilateral laparoscopic adrenalectomy was performed in all the patients younger than 50 years of age, aswell as in those over 50 with comorbidities that could beattributed to cortisol excess. No surgery was required in theother patients, and in their case biochemical work-up andunenhanced CT were repeated 6 and 24 months after theinitial diagnosis. Adrenal lesions that did not show anincrease in size O10 mm during 24 months of the followup were considered benign. Eleven patients with adrenalmasses larger than 4 cm (median 45 mm, range 40–55 mm)Statistical analysisStatistical analysis was performed using SPSS 14.0 (SPSS).A P!0.05 was considered to be significant. For simultaneous testing, an adjustment of P values using Bonferronicorrection was performed. The normality of the distributions was tested using the Kolmogorov–Smirnov test.The data were expressed as the median and range. For thecomparison between the groups of data, the Mann–Whitney test was used for the numerical variables and thec2 test for the categorical ones. The analysis of the repeatedsamples was done by the Wilcoxon and Friedman tests.MedCalc version 2.0 was used for the analysis of specificityand sensitivity, as well as for the calculation of 95% CI(www.medcalc.org/calc/diagnostic test.php).ResultsAmong the 319 patients examined, 248 had unilateraladrenal masses, and both glands were affected in 71patients. The median size of the tumors was 25 (10–176)mm. Overall, 221 (69.3%) patients had hypertension, 89(27.9%) had glucose intolerance or type 2 diabetes, 141(44.2%) had dyslipidemia and 20 (6.3%) had osteoporosis.In 238 (74.6%) patients, the clinical diagnosis wasa benign non-functional tumor, 17 (5.3%) patients hadpheochromocytoma, 11 (3.4%) had adrenocortical carcinoma, 3 (1%) patients had adrenal metastases whereas onepatient had extragastrointestinal stromal tumor. Forty-nine(15.4%) patients were diagnosed with benign functionaltumors, 36 of which had SCS, 12 had primary hyperaldosteronism and one patient had an excess of androgens (Table 1).Of the 77 patients (24.1%) who underwent unilateraladrenalectomy, 37 had adrenal adenoma or hyperplasia,11 had adrenocortical carcinoma, 17 had pheochromocytoma, three were diagnosed with hemangioma, threewith myelolipoma, three with adrenal metastasis, twopatients had cysts of the adrenal gland and one patienthad extragastrointestinal stromal cell tumor.CT characteristics of adrenal tumorsTumor density was evaluated in 310 patients with 379adrenal masses, whereas for nine patients no tumorattenuation values were reported by the radiologist. In 291cases of adrenal mass the attenuation value on unenhancedCT was %10 HU, whereas in 92 of them it was O10 HU. Thewww.eje-online.orgDownloaded from Bioscientifica.com at 05/14/2021 09:45:05AMvia free access
D Kastelan and othersClinical diagnosis in patients with adrenal incidenta-loma.European Journal of nal adenomaSCSPHAAndrogensOther benign omocytomaCarcinomaFunctionalNon-functionalOther malignantmassesMetastasesEGISTNo.278primary hyperaldosteronism compared to those with SCSor pheochromocytoma with the values of 19 (10–42),40 (10–72) and 55 (16–90) mm (P!0.001) respectively.Size median(range)231 (72.4%) 25.5 (10–61)46 (14.4%)33121173:210 (3.1%)40 (10–72)19 (10–42)––17 (5.3%)11 (3.5%)55 (16–90)75 (45–176)4 (1.3%)68.5 (49–110)3132315631SCS, subclinical Cushing’s syndrome; EGIST, extragastrointestinal stromaltumor; PHA, primary hyperaldosteronism.attenuation value of O10 HU was associated with a largertumor size (32 (10–176) vs 24 (10–120) mm; P!0.001).In addition, the patients with attenuation values of O10 HUwere more likely to undergo adrenalectomy (55.0 vs 12.7%;P!0.001) and were more likely to have a functional tumor(40.3 vs 17.2%; P!0.001).The tumor attenuation value was O10 HU in all thepatients with adrenocortical carcinoma, adrenal metastasis or pheochromocytoma. The ROC curve analysis, whichinvolved only those patients with confirmed adrenalhistology, showed that the specificity of the adrenaltumor attenuation value of %10 HU to rule out malignantadrenal mass or pheochromocytoma was 100%, with thesensitivity of 65% (positive predictive value 100%,negative predictive value 67%, AUCZ0.924, PZ0.03, CI0.863–0.986; Fig. 2). With regard to tumor size, adrenalmasses in patients with adrenocortical carcinoma, metastasis and pheochromocytoma were significantly largercompared to those with benign lesions (Table 1). The cutoff of %4 cm had 91% specificity and 31% sensitivity(positive predictive value 82%, negative predictive value48%, AUCZ0.736, PZ0.05, CI 0.605–0.859; Fig. 2) to ruleout malignant tumor or pheochromocytoma.As for the hormonally active adrenal masses, the sizeof the tumor was significantly lower in patients withSubclinical Cushing’s syndromeTable 2 compares the demographic and clinical characteristics of patients with SCS as opposed to those withnon-functional adenomas. Thirty-six patients hadhormonal characteristics of SCS, which was found to bemore common among those with bilateral adrenal tumors(21.1 vs 8.4%; P!0.001). All of the patients with SCS hadcortisol levels O83 nmol/l in overnight 1 mg dexamethasone test; 34 (94.4%) had ACTH levels !2.2 pmol/l,whereas 9 (25%) patients had elevated urinary freecortisol. Overall, 26 (72.2%) patients with SCS hadhypertension, 12 (33.3%) had glucose intolerance ortype 2 diabetes, 16 (44.4%) had dyslipidemia, and 3(8.3%) had osteoporosis. No differences were establishedbetween the patients with SCS and those with nonfunctional adenomas with regard to the BMI and waistcircumference, or to the frequency of hypertension, type 2diabetes, dyslipidemia or osteoporosis. However, patientswith SCS had larger tumors compared to those withnon-functional adenomas (44 (17–72) vs 25.5 (10–61)mm; P!0.001).ROCs for multiple surrogates, gold standard .400.60False positive rate0.80SensitivityTable 1Clinical management of adrenalincidentalomaTrue positive rateClinical Study01.00Figure 2Value of the tumor size and tumor density for distinguishingbenign adrenal masses from malignant tumors andpheochromocytomas.www.eje-online.orgDownloaded from Bioscientifica.com at 05/14/2021 09:45:05AMvia free access
D Kastelan and othersClinical StudyTable 2Clinical management of adrenalincidentalomaClinical characteristics of patients with SCS and non-functional adenomas. Data are presented as median (range) orpercentage.VariableAgeGender (F/M)Tumor sizeWeightBMIWaistHOMA glucoseintoleranceSCS (nZ36)57 (38–76)27/944 (17–72)79.7 (45–169.5)31.5 (18–56)106 (87–119)2.1 (0.7–9.4)26 (72.2%)3 (8.3%)16 (44.4%)12 (33.3%)NFA (nZ231)P0.24559 (32–86)0.671124/73!0.00125.5 (10–61)0.38280 (44–130)0.08929.1 (17–46.5)0.25199 (78–129)0.7701.7 (0.4–30.3)0.538132 (57.1%)0.50928 (12.1%)0.987103 (44.5%)0.09231 (13.4%)173:2279enlargement. Moreover, a tumor size decrease of O10 mmwas found in 12 (6.9%) patients.With regard to tumor function, no changes either inmetanephrines and normetanephrines or in the activity ofrenin–aldosterone axis were observed during the followup. Five patients developed SCS but without any clinicalrelevance. Hence, these patients did not undergo surgery.On the other hand, one patient developed SCS togetherwith metabolic worsening and was considered for surgery.In that patient, the change of the hormonal profile wasnot associated with a tumor size increase. None of thepatients developed overt Cushing’s syndrome during thefollow-up period. Eight of the 14 patients with baselineSCS showed improvement of the hormonal profile and didnot fulfil the criteria for SCS on the final visit.NFA, non-functional adenoma; SCS, subclinical Cushing’s syndrome;HOMA, homeostasis model assessment.European Journal of EndocrinologyDiscussionTwenty-two patients with SCS underwent unilateraladrenalectomy. Patients with SCS who underwent surgicalresection of the tumor had a larger tumor size (P!0.001)and tended to have more hypertension (PZ0.02)compared to those who did not need surgery. Nodifference in the prevalence of diabetes, osteoporosis anddyslipidaemia were found between the two groups ofpatients (Table 3). Biochemical work-up performed 6months after the surgery showed significantly lower1-mg dexamethasone cortisol concentrations (39 vs137.5 nmol/l; P!0.01), lower urinary free cortisol levels(178 vs 311.5 nmol/dU; PZ0.01) and higher ACTHconcentrations (1.55 vs 0.8 pmol/l; PZ0.03). Postoperatively, patients with SCS had a lower body weight (81.5(45–128) vs 86.7 (45–135) kg; PZ0.01) and a lower BMI(31.1 (18–53.3) vs 33.4 (18–56) kg/m2; PZ0.02) thanbefore the operation. No differences were found in theblood glucose level and lipid profile, whereas in 15 out of22 patients the remission of the disease was associatedwith improved blood pressure, including cured hypertension in four patients (PZ0.006).The widespread use of imaging techniques results in thefrequent detection of adrenal tumors among the generalpopulation. Although in most cases adrenal masses arebenign, they represent an important clinical concern due tothe risk of malignancy and possible hormonal hyperfunction. The present study involved 319 patients with adrenalmasses, 74.6% of which turned out to be benign nonfunctional tumors. In the study group, nearly 5% of thepatients were diagnosed with adrenal carcinoma or adrenalmetastasis from extraadrenal tissues, whereas another 5% ofthe patients had pheochromocytoma. Our findings are inline with the data of the previous studies that reported onthe etiology of adrenal incidentalomas (10, 11).SCS was the most common functional
Lost to follow-up n 32 Continued follow-up due to contralateral mass n 13 Study population n 319 Final visit (24 months of follow up) n 174 Figure 1 Patient flowchart. European Journal of Endocrinology Clinical Study D Kastelan and others Clinical managem
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
Dr. Sunita Bharatwal** Dr. Pawan Garga*** Abstract Customer satisfaction is derived from thè functionalities and values, a product or Service can provide. The current study aims to segregate thè dimensions of ordine Service quality and gather insights on its impact on web shopping. The trends of purchases have
Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. 3 Crawford M., Marsh D. The driving force : food in human evolution and the future.
