Medical management of adren al gland disease -

부신우연종 정의 우연히 발견된 부신 종양 크기 > 1cm? Potentially lethal, timely adrenalectomy Pheochromocytoma ( ) adrenal cortical carcinoma Cushing ( steroid replace)

2% (1.0 ~ 8.7%),, CT - : 4%, (60-79): 10%

(Clinical studies) Types Average (%) Range (%) Adenoma 80 33 ~ 96 Non-functioning 75 71 ~ 84 Cortisol-secreting 12 1.0 ~ 29 Aldosterone-secreting 2.5 1.6 ~ 3.3 Pheochromocytoma 7.0 1.5 ~ 14 Carcinoma 8.0 1.2 ~ 11 Metastasis 5.0 0 ~ 18 European J of Endocrinology (2011) 164:851-870

(Surgical studies) Types Average (%) Range (%) Adenoma 55 49 ~ 69 Non-functioning 69 52 ~ 75 Cortisol-secreting 10 1.0 ~ 15 Aldosterone-secreting 6.0 2.0 ~ 7.0 Pheochromocytoma 10 11 ~ 23 Carcinoma 11 1.2 ~ 12 Myelolipoma 8.0 7.0 ~ 15 Cyst 5.0 4.0 ~ 22 Ganglioneuroma 4.0 0 ~ 8.0 Metastasis 7.0 0 ~ 21 European J of Endocrinology (2011) 164:851-870

SMC (n=282) Tumor size (cm) 2.31 ± 1.38 Tumor volume (cm 3 ) 16.84 ± 53.87 Number of tumors/patient 1.12 ± 0.37 Number of patients with multiple 32(11.3%) tumors Location of the tumor Hounsfield units (HU) 11.90 ± 21.40 Follow-up duration (months) 15.33 ± 17.99 Concomitant disease Diabetes mellitus Hypertension Extra-adrenal malignancy Left:56.0%, Right:36.5%, Both:7.5% 46 (16.3%) 108 (38.3%) 81 (28.7%) Cho YY et al. KJIM 2013

SMC Clinical studies (N=282) Non-functioning tumor Adenoma Adrenal cancer Adrenal metastasis Adrenal lipoma Adrenal cyst Functioning tumor Subclinical Cushing s synd Pheochromocytoma Primary hyperaldosteronism 243 (86.2%) 220 (78.0%) 2 (0.7%) 1 (0.4%) 8 (2.8%) 12 (4.3%) 39 (13.8%) 28 (9.9%) 6 (2.1%) 5 (1.8%) Surgical studies (n=45) Cortical adenoma Pheochromocytoma Ganglioneuroma Cortical carcinoma Metastatic Ca Others* 25 (55.5%) 7 (15.6%) 3 (6.7%) 2 (4.4%) 1 (2.2%) 7 (15.6%) Data are presented as number (percent). *Others include lipomas, pseudocysts and cavernous lymphangiomas. Cho YY et al. KJIM 2013

Analysis of the risk factors of functional adenoma N=282 OR 95% CI P value Female 3.386 1.611 7.117 0.0013 Age 0.989 0.957 1.023 0.5282 BMI (kg/m 2 ) 1.007 0.899 1.129 0.9001 Tumor size (cm) 1.049 0.817 1.348 0.7073 Tumor number 0.590 0.105 3.337 0.5509 Tumor location Right to left Bilateral to left N o n - c o n t r a s t attenuation HU > 10 0.905 5.418 0.415 1.973 0.595 49.324 0.8011 0.1338 2.806 1.231-6.397 0.0141 Cho YY et al. KJIM 2013

CT : MRI, Scintigraphy, PET/CT : 24h fractionated MNs, plasma free MNs : 1mg dexamethasone suppressio n test (DST), 24h cortisol, ACTH, DHEA-s,, : Aldosterone/renin ratio, serum K

pheochromocytoma chromaffin cell ( ) Extramedullary pheochromocytoma catecholamin e-secreting paraganglioma: ~10% : 0.1%,,, (40~60%)

Catecholamine metabolism Tyrosine Catecholamines Dopamine MAO,COMT Metabolites Homovanillic acid(hva) DBH Norepinephrine COMT Normetanephrine PNMT Epinephrine COMT Metanephrine MAO MAO Vanillylmandelic acid(vma)

PNMT - phenylethanolamine N-methyltransferase COMT - catechol-o-methyltransferase; SULT1A3 (GI tract) - monoamine-preferring sulfotransferase. Fractionated metanephrines Total Metanephrines

24,, metanep hrine (MN), normetanephrine (NM), vanillymandelic acid (VMA) (specificity ) Total metanephrines: free & conjugated (MN) + free & conjung ated (NM), Fractionated metanephrines: metanephrine, normetane phrine, free & conjugated, Free metanephrines: free metanephrine, free normet anephrine, plasma False positive test Levodopa, labetalol, sympathomimetics, tricyclic antidepressant

24 MN & NM Pheochromocytoma Control group Healthy (n=103) (n=294) Volunteers (n=49) Metane- Males 875 (39-9599) 104 (43-308) 118 (45-225) phrine Females 238 (42-8168) 83 (38-183) 61 (26-193) (µg/day) P-value <0.001 <0.001 <0.001 Normeta- Males 1524 (206-21550) 248 (74.9-600)* 131 (67-356) nephrine Females 1643 (268-21600) 224 (88-558)* 104 (37-237) (µg/day) P-value NS 0.008 0.067 Median (2.5 th 97.5 th %ile), * p < 0.05 vs. healthy volunteers Sohn SY et al. Endocrine J 2012

24 MN & NM cut-off Cut-off values Sensitivity, % (n/n) Specificity, % (n/n) Either MN or NM above the cut-off value MN >174 µg/day or NM > 48 90.2% (46/51) 77.8% (123/158) 5.5 µg/day in males MN > 174 µg/day or NM > 4 85.5 µg/day in females 88.5% (46/52) 94.1% (128/136) 89.3% (92/103) 85.4% (251/294) Either MN or NM above the cut-off value MN > 229.5 µg/day or NM > 502 µg/day in males MN > 174 µg/day or NM > 4 71 µg/day in females 96% (49/51) 88.6% (140/158) 98.1% (51/52) 94.1% (128/136) 97.1% (100/103) 91.2% (268/294) Sohn SY et al Endocrine J 2012

Diagnostic cut-off Men Women JCEM 1993 Clinical Endo 2007 Metanephrine (ug/day) 230 174 400 302 Normetanephrine (ug/day) 502 471 900 733 Previous SMC metanephrine, normetanephrine Metanephrines : 45-290 ug/day (M: 45.4-225, F: 25.7-193) Normetanephrines : 82-500 ug/day (M: 66.7-356, F: 37-237) Based on 2.5%~ 97.5% ranges from 51 healthy volunteers From 49 healthy Korean volunteers Pediatric endocrine testing. Nichols Institute, 1993:30

False negative test ( ) ( 97.5 th percentile ) Total : 5/103 (5% ) Male : 2/51 (4%) 14418414 ( 0) 16511551 ( 0) Female : 3/52 (6%) 17804513 ( o) 04193918 ( o) 14592819 ( o) Sex/age symptom U-MN U-NM Tumor size Others MN<290 and NM<500 M/61 incidental 176 193 7.0cm paraganglioma M/25 Genetic w/u 143 425 2.4cm Known VHL MN<290 and NM<500 F/38 Genetic w/u 85 312 2cm Known VHL F/42 r/o recur 122 486 2cm MEN2 F/60 Incidental (E GC Op) 208 258 1.4cm

False negative test ( ) ( diagnostic cut off ) Total : 3/103 (3% ) Male : 2/51 (4%) 14418414 ( 0) 16511551 ( 0) Female : 1/52 (2%) 17804513 ( o) 04193918 ( o) 14592819 ( o) Sex/age symptom U-MN U-NM Tumor size Others Men: MN<230 and NM<502, Women: MN<174, NM<471 M/61 incidental 176 193 7.0cm paraganglioma M/25 Genetic w/u 143 425 2.4cm Known VHL Men: MN<230 and NM<502, Women: MN<174, NM<471 F/38 Genetic w/u 85 312 2cm Known VHL F/42 r/o recur 122 486 2cm MEN2 F/60 Incidental (E GC Op) 208 258 1.4cm

Free form metanephrines Plasma free metanephrines (MN/NM): position ( ) Position supine vs. sitting Resting & supine à high sensitivity & specificit y,

Changes in plasma concentrations after transition from the seated to t he supine position (Darr et al. Clinical Endo 2014) NE E Dopa NM MN Methoxytyramine

Baseline characteristics of patients and h ealthy volunteers (N = 229) Pheochromocytoma (n=28) Control (n=156) Healthy volunteers (n=45) p value c p value d Sex, M/F 15/13 92/64 23/22 NS NS Age (years) a 44.5 (31.5, 56.3) 54.5 (47.0, 64.0) 24.0 (22.0, 25.0) 0.002 <0.001 BMI (kg/m 2 ) a 24.8 (21.8, 27.1) 25.7 (23.0, 27.8) 20.5 (19.0, 23.6) NS <0.001 Tumor size (cm) a 3.5 (2.4, 5.1) 2.0 (1.5, 3.5) b NA 0.005 NA Plasma MN (nmol/l) a 0.56 (0.22, 2.28) 0.20 (0.16, 0.25) 0.21 (0.17, 0.24) <0.001 NS Plasma NM (nmol/l) a 3.12 (0.72, 8.09) 0.42 (0.27, 0.57) 0.39 (0.32, 0.51) <0.001 NS a medians (25 th 75 th %ile). c A comparison of patients with pheochromocytoma vs. control. d A comparison of control vs. healthy volunteers. Prospective study design for 3yrs Kim HJ Endo J 2014

Change of sensitivity & specificity acco rding to diagnostic cut-off plasma free seated MNs Biochemical test Plasma (nmol/l) Upper cut-offs % (95% CI) (n/n) Sensitivity Specificity MN 0.50 53.5% (35.8-70.5) (15/28) 98.1% (94.5-99.3) (153/156) NM 0.90 67.9% (19.3-82.1) (19/28) 96.1% (91.9-98.2) (150/156) MN or NM 85.7% (68.5-94.3) (24/28) 94.2% (89.4-96.9) (147/156) MN 0.33 67.9% (49.3-82.1) (19/28) 89.1% (83.2-93.1) (139/156) NM 0.61 89.3% (72.8-96.3) (25/28) 80.8% (73.9-86.2) (126/156) MN or NM 96.4% (82.3-99.4) (27/28) 75.6% (68.3-81.7) (118/156) Urine (µg/d) MN or NM 96.4% (82.3-99.4) (27/28) 94.2% (82.3-99.4) (147/156) Mayo reference limit: MN 0.50 nmol/l, NM 0.90 nmol/l Screening test easy, low cost, high sensitivity Kim HJ et al. Endo J 2014

Multiple linear regression analysis of in dependent factors associated with seat ed plasma free metanephrines Variables p-value for plasma metanephrine p-value for plasma normetanephrine Sex <0.001 0.014 Age a 0.010 0.239 Hypertension 0.104 0.049 BMI a <0.001 0.017 a Age and BMI were used as a continuous variables Kim HJ et al. Endo J 2014

Diagnostic efficacy of seated plasma fr ee MNs according to sex or BMI Biochemical te Upper cut-offs % (95% CI) (n/n) st Sensitivity Specificity Plasma (nmol/l) MN 0.33 67.9% (49.3-82.1) (19/28) 89.1% (83.2-93.1) (139/156) NMN 0.61 89.3% (72.8-96.3) (25/28) 80.8% (73.9-86.2) (126/156) MN or NMN a 96.4% (82.3-99.4) (27/28) 75.6% (68.3-81.7) (118/156) MN Men 0.35 73.3% (48.1-89.1) (11/15) 89.1% (81.1-94.0) (82/92) Women 0.33 61.5% (35.5-82.3) (8/13) 90.6% (81.0-95.6) (58/64) NMN Men 0.64 96.7% (62.1-96.3) (13/15) 84.8% (76.1-90.7) (78/92) Women 0.60 92.3% (66.7-98.6) (12/13) 82.8% (71.8-90.1) (53/64) MN or NMN a 96.4% (82.3-99.4) (27/28) 78.2% (71.1-84.0) (122/156) MN BMI<23 0.43 72.7% (43.4-90.3) (8/11) 74.4% (58.9-85.4) (29/39) BMI 23 0.33 64.7% (41.3-82.7) (11/17) 94.0% (88.2-97.1) (110/117) NMN BMI<23 0.82 72.7% (43.4-90.3) (8/11) 94.9% (83.1-98.6) (37/39) BMI 23 0.69 82.4% (58.9-93.8) (14/17) 91.5% (84.9-95.3) (107/117) MN or NMN a 96.4% (82.3-99.4) (27/28) 87.2% (81.0-91.6) (136/156) Kim HJ et al. Endo J 2014

Free form metanephrines Plasma free metanephrines (MN/NM) Seating position Screening test, rul e out Confirmative test à 24HU fractionated MNs or supine plasma free MNs

( ) 24HU fractionated MNs, Plasma free MNs Seated plasma free MNs - 24HU fractionated MN s Seated plasma free MNs -Screening sensitivity Resting & supine position specificity

Screening of primary aldosteronism ( ) Aldosterone (>10 ng/dl), PRA (plasma ren in activity), ARR (aldosterone renin ratio) > 30, X 2-4 ARB, ACEi, spironolactone, b-blocker,, NS AID (, verapamil, doxazosin)

> 4~6cm: < 3~4cm:. CT. (<10HU, ho mogenous, margin) 17-KS DHEAS: ( ).

? 4년 경과 관찰: 5-20% 크기 1cm 이상 증가, 초기 2년 사이에 size 변화로 악성 발견 adenoma, 0.5-1cm/year >1cm/년, 수술 고려 Adrenal cortical carcinoma: 크기 증가 >2cm/년 양성으로 진단된 경우 악성 전환 위험성 : < 0.1%, renal cell carcinoma, NHL

? 1yr, 2yr, 5yr = 17%, 29%, 47% Pheochromocytoma Primary aldosteronism: very rare Cushing s syndrome Overt Subclinical: most common

Flow chart of follow-up for adrenal incidentaloma SMC data Total cases (N = 147) F/U duration = 23.1 months 16% 78% Tumor diamet er Size : increased > 1cm (n = 0) 1cm (n = 24) Size : no change (n = 115) 0.7% 1.4% Functional change to pheochromocytoma Hormonal statu ( n = s 1) F/U duration = 11 mont hs Operation Operation Cortical adenoma (n = 4 ) Ganglioneuroma (n = 1) Cyst (n = 1) Functional change to SCS (n = 2) F/U duration = 30, 36 m onths Medical F/U 6% Size : decreased (n = 8) Operation Cortical adenoma (n = 2 ) Functioning tumor 2%, Operation 6% Cho YY et al. KJIM 2013 In press

Progression of NFAI to overt Cushing syndrome NFAI SCS Adrenal Cushing - 3.8% after 1year - 6.6% after 5years - 11% after 1year - 26% after 5years Cortisol secretion in AI NIH consensus Panel 2002- clinical inapparent adrenal mass - Repeated hormonal screening annually for at least 4 years - 1mg DST

The Endocrine Society guidelines for the diagnosis of subclinical Cushing s syndrome if two screening tests are abnormal, using urine fr ee cortisol (UFC), late-night salivary cortisol, and/or dexamethasone suppression (1 mg overnight or 2 mg 2-day test) Morning ACTH suppression the dehydroepiandrosterone sulfate (DHEAS) level >> 1mg DST, ACTH, 24HU cortisol, DHEA-s 1mg DST cortisol: 1.8 ~ 5mg/dL,

Impact of surgical intervention Authors (year) Number Type of AI Impact of surgical intervention on cardiometabolic outcomes Erbil (2006) n=11 SCS SBP, DBP 감소/ obesity, DM, dyslipidemia 효과 없음 Mauclere-Denost (2009) n=8 SCS BP(75%), BWt(71%) 호전, A1C(1.1% 감 소), 당뇨약 중단(2/3) (f/u = 12 m) Toniato (2009) n=23 SCS DM(63%), HT(67%), dyslipidemia(38%), obesity(50%) 호전 (f/u = 7.7 yr) Chiodini (2010) n=25 SCS BP, BWt 감소, 혈당 호전 (f/u = 18-48 mo) 대규모의 무작위 대조군 연구 부족

AME position statement (2011) Management of subclinical Cushing s syndrome -, - postoperative steroid repl ace -

Laparoscopic adrenalectomy - debate Postoperative glucocorticoid replace subclinical Cushing s syndrome HPA Morning cortisol, ACTH Rapid ACTH stimulation test

Steroid replacement during perio perative period Minor procedures (local): no extra supplementation Major surgical stress (esophagogastrectomy, open heart op) OP day hydrocortisone 100 mg ivs POD #1 hydrocortisone 50 mg ivs q 6h (for 24 hrs) POD #2-3 hydrocortisone 25 mg ivs q 6h (for 24 ~ 48hrs) POD #4-5 hydrocortisone 25 mg ivs q 12h (for 48 ~ 72hrs) POD #>4-6 Usual dose Arch Surg. 143(12): 1222-1226, 2008

Steroid replacement for surgery taking ex ogenous corticosteroid For minor procedures or surgery under local anesthesia (eg, inguinal hernia repair) à Take usual morning steroid dose à No extra supplementation is necessary For moderate surgical stress (eg, lower extremity revascularization, total joint re placement) à Take usual morning steroid dose à Give 50 mg hydrocortisone intravenously just before the procedure and 25 mg of hydrocortisone every eight hours for 24 hours. Resume usual dose there after. For major surgical stress (eg, esophagogastrectomy, total proctocolectomy, op en heart surgery) à Take usual morning steroid dose à Give 100 mg of intravenous hydrocortisone before induction of anesthesia, and 50 mg every eight hours for 24 hours. Taper dose by half per day to maintenance level. Uptodate 2015

Long term steroid replacement Replacement doses Prednisolone 3.75 ~ 5 mg/day, QD Hydrocortisone 15 ~ 20 mg/day, BID (i.e. Hydrocortisone 10 mg 5 mg) à Clinical symptom and morning ACTH Fludrocortisone (primary AI): 0.05 ~ 0.1 mg/day à plasma renin, K, BP change after standing, edema ( high salt diet replace ) Follow up morning basal cortisol and ACTH Consider stopping steroid replacement and describe PRN steroid, if mor ning basal cortisol 6.5 ug/dl. European Journal of Endocrinology 169: 165 175, 2013

AACE/AAES, 2009 1mg DXT, plasma & urine MNs/catec holamines & PRA/aldo in hypertensi ve patients Annual 5 Monitor ma ss < 4cm Imaging at 3-6m & annually f or 1-2 years AME position 2011 1mg DXT, Urine MNs or plasma free M Ns, PRA/aldo in hypertensive &/or hypo kalemic patients Annual 4 Monitor 2-4 cm mass: 3-6 2cm x, 2cm 호르몬 검사: 매년, 4-5년 동안 CT: 6개월, 12개월, 2년, HU<10, 2cm 1-2

Adrenal mass > 1cm 24HU metanephrines or plasma free metanephrines Consider resection Hx of prior malignancy Fine-needle aspiration Consider resection Adrenocortical hormonal evaluation 1mg DST, 24HU free cortisol, ACTH Renin/aldo, electrolyte (If, HT) Sex steroid (If, virilization), large size: DHEA-s, 17OHP Adrenal imaging (CT) > 6cm < 6cm, > 3cm < 3cm, benign characteristics >20HU Delayed washout Heterogenous mass Irregular borders Consider resection Early washout Repeat scan in 3-6 mo to assess change in size No change. Repeat scan in 1 year