ADRENAL INCIDENTALOMA CORTEX DISORDERS ENDOCRINOLOGICAL ASPECTS Dr. Mohan T Shenoy DM trainee in Endocrinology Amrita Institute of Medical Sciences, Kochi NUCLEAR MEDICINE INTERDEPARTMENTAL – 27/8/2015

OUTLINE BACKGROUND CASE HISTORY ADRENAL INCIDENTALOMA – APPROACH ADRENAL CORTEX DISORDERS PHYSIOLOGICAL ASPECTS BIOCHEMICAL ASSAYS / HORMONAL WORKUP RADIOLOGICAL GADGETS TO DIAGNOSIS SURGICAL ASPECTS AND MEDICAL TREATMENT

RESOURCES/ REFERENCES Williams textbook of Endocrinology Campbell textbook of Urology American Journal of Radiology Journal of Clinical Endocrinology and Metabolism European Journal of Endocrinology Best Practice & Research Clinical Endo & Metab

CASE HISTORY August 2015: 55y M working in Gulf referred to AIMS,Kochi Evaluated outside for fever, cough, vague abdominal region pain ; detected to have raised blood pressur hypertension with uncontrolled sugars Recently detected diabetes 6 months duration. Found to have an adrenal mass in CT abdomen.

Evaluated at AIMS FBS 92.9 mg/dl Creat: 1.0 mg/dl Hba1c: 7.2 % Corrected Ca- 8.8 ONDST: S. Cortisol: 2.4 ug/dl DHEA-S : 47.00 ug/dl (100-420) Metanephrines-Urine: 295.62 ug/24hrs (<350ug/24hrs) Nor MN Urine: 1071.43 ug/24hrs (<600 ug/day). Date S. Na+ S. K+ 28/814 130.5 3.4 28/8/14 132.7 3.0

Endocrine Causes of Hypertension Acromegaly Hyperparathyroidism Thyrotoxicosis Glucorticoid – suppressible hyperaldosteronism Pheochromocytoma Cushing's syndrome Primary hyperaldosteronism (Conn's syndrome) Congenital adrenal hyperplasia due to 11 Beta hydroxylase or 17 alpha hydroxylase deficiency

DD for Hypertension + Hypokalemia Renovascular disease Cushing’s syndrome Primary aldosteronism Renin secreting tumors

Cross Sectional Anatomy Retroperitoneal organ – Normally : 3 cm × 6 mm Gerota’s fascia : connect gland to upper pole of kidney

ADRENAL ZONES Cortex derived from embryonic mesoderm, secreting steroid hormone Medulla derived from neurectoderm, secreting catecholamines

NORMAL ADRENAL ABNORMAL ADRENALS ATROPHY HYPERPLASIA

Adrenal incidentaloma - Introduction “Serendipitously discovered adrenal mass lesion > 1 cm by radiologic examinations – CT/MRI in the absence of symptoms or clinical findings suggestive of adrenal disease” Demonstration : Unilateral/ bilateral enlarged unusual shape (?bulky) Recent study : report prevalence from high resolution scanner CT abdomen = 4.4% Two relevant questions - Is it malignancy ? - Is it functioning ?

Adrenal disorders Cushing syndrome Hyperaldosteronism CAH Pheochromocytoma CAH Adrenal tumours Hypoaldosteronism Pseudohypoaldosteronism Adrenal insufficiency

ADRENAL INCIDENTALOMA ADRENAL CORTEX ADRENAL MEDULLA Adenoma Pheochromocytoma Nodular hyperplasia Ganglioneuroma Ganglioneuroblastoma Carcinoma Hemorrhage Metastasis OTHER ADRENAL MASSES Adrenal Cyst, Myelolipoma, Neurofibroma Hematoma, Hamartoma, Teratoma Xanthomatosis, Amyloidosis Granulomatosis (TB, Histo) METASTASES Breast, Lung, Colon Lymphoma, Leukemia PSEUDOADRENAL MASSES Arising from KIDNEY, PANCREAS, SPLEEN, LYMPH NODES, SARCOMA, GREAT VESSELS Technical artefacts

PHYSIOLOGY

BIOCHEMISTRY

BILATERAL ADRENAL MASSES Studies : 887 and 202 cases (with adrenal incidentaloma) - bilateral 10-15% One adrenal mass : non-functioning cortical adenoma Contralateral adrenal mass : hormone secreting +++ All patients with bilateral adrenal masses should be screened for adrenocortical hyper/hypo function +++

HORMONAL ASSAYS AND CUTOFFS S. ACTH: Electrochemiluminescence: To be collected in chilled tube. Transport in ice Refrigerated centrifugation. Store freezed. susceptible to degradation by peptidases S. Cortisol: Chemiluminescence : Plasma Renin Activity: Plasma Aldosterone concentration:

Statistics (The Mayo clinic 1985 – 1990) Radiology : 61,054 Abd CT : (3.4% = 2,066 cases) 2,066 cases - 50% metastasis cancer - 25% other known lesions - 7.5% symptomatic tumors - 16.5% incidental (include nodules < 1cm) Overall incidental adrenal tumor (> 1cm) = 0.4 %

STATISTICS FROM NIH Autopsy : 739 cases (adrenal masses 2 mm-4 cm) 85 percent of the masses were non-functioning. 9 percent secreted sufficient cortisol to produce subclinical Cushing's syndrome 4 percent were pheochromocytomas (<50% of which caused hypertension). 2 percent were aldosteronomas.

UNILATERAL ADRENAL MASS FUNCTIONAL NON- FUNCTIONAL Adrenal adenoma Adrenal carcinoma Pheochromocytoma Ganglioneuroma Myelolipoma Hyperplasia : “looks like” /”bulky” Hemorrhage Metastasis

BILATERAL ADRENAL MASS CAUSES FUNCTIONAL NON- FUNCTIONAL ACTH-dependent Cushing’s Infections : TB, fungus cortical adenoma - Conn’s : hyperplastic variety infiltrative disease of adrenal gl (lymphoma Micronodular adrenal disease pheochromocytoma Replacement: amyloidosis Myelolipoma ACTH-independent bilateral macronodular adrenal hyperplasia Hemorrhage congenital adrenal hyperplasia Metastasis

CUSHING SYNDROME

CORTISOL EXCESS SECRETION NORMAL AXIS LIDDLE’S SIGN

TYPES OF CUSHING’s

CLASSIFICATION ACTH dependent ACTH independent "Normal” or high ACTH Normal ACTH 20-80 pg/ml Blood collected at ACTH Nadir – around midnight Values correlate with tumour size when ACTH arise from pituitary Source of ACTH may be extrapituitary Low ACTH levels Usually, adrenal origin of disease Circadian rhythm lost Paradoxical response may be seen

BIOCHEMICAL TESTS

Dexamethasone suppression test Overnight- 1mg at 11 pm, 8 am cortisol<1.8mcg LDDST – 0.5mg 6h 48 hours – 8 am <1.8 HDDST – 8, 16 and 32mg – for larger pituitary adenoma and differentiating Ectopic ACTH production – Bronchial carcinoids- cutoff 1.8mcg 8 mg Infusion - Cut off 1.8mcg

Varying degrees of sensitivity and specificity In hyperfunction, high hormone levels -> Circadian fluctuation of hormones are lost ; Even am-pm reversal Varying degrees of sensitivity and specificity Vary from lab to lab, batch to batch of reagents Hence, one method can not be totally relied upon Usually combination of more than one method used

PSEUDO CUSHING STATES

URINE FREE CORTISOL Measures cortisol that is not bound to CBG. Therefore, unlike serum cortisol, which measures both CBG-bound and free hormone, UFC is not affected by conditions and medications that alter CBG. Useful in pregnant pts, Cyclical Cushing’s, pts on antiepileptics. Because most of cortisol secreted during any 24-hour period is usually between 4 AM and 4 PM, subtle increases in night time cortisol secretion may not be detected in standard 24-hour urine free cortisol measurements. It also requires an adequate urine collection that must be verified with a measurement of urinary creatinine.

Late-night salivary cortisol Ask patient to collect a saliva sample on two separate evenings between 2300 and 2400h. Saliva is collected either by passive drooling into a plastic tube or by placing a cotton pledget (salivette) in the mouth and chewing for 1–2 min. Normal < 145ng/dl (4nmol/L) Sensivity: 92-100% , specificity 93-100% In US- ELISA/LC-MS/MS.

Other essential investigations 1. FBS , PPBS / GTT. 2. FLP 3. Ca Profile ( Fasting Ca, P, ALP,Albumin, Urine calcium creatinine ratio). 4. AST, ALT. 5. SE (Na, K, HCO3) 6. CXR PA 7. X-ray spine and hip/DEXA. 8. RFT. 9. ECG, Echo

ENDOGENOUS HYPERCORTISOLISM

Diagnostic approach Two measurements At least two first line tests are done – Salivary, LDDST, urinary cortisol Urine cortisol x 3 times Diagnosis confirmed if two tests confirmed When discordant, repeat the test When results normal, Cushings unlikely

Central-peripheral gradient LOCALISATION CRH stimulation 1ug/kg single dose Positive response - 100% rise ACTH, - 50% in S. cortisol over baseline Central-peripheral gradient inf petrosal : peripheral <1.4: 1 - ECTOPIC

Primary aldosteronism

Aldosterone secretion Inducing factors Inhibitors Angiotensin II Potassium ACTH Dopamine ANP Heparin Aldosterone secretion occur only in zona glomerulosa as the enzyme aldosterone synthase is expressed only in this region

Diagnostic and therapeutic approach to primary aldosteronism Hoorn, E. J. et al. (2010) A case of primary aldosteronism revealed after renal transplantation Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.158

PRA/PAC Time : 0800-1000 hrs Paired plasma aldosterone concentration Correct hypokalemia if present Avoid : (6 wks) Spironolactone, eplerenone Renin inhibitor Amiloride

Pheochromocytoma 3-10% incidentalomas prove to be pheochromocytomas. Screening for pheochromocytoma is mandatory in all cases because high rate morbidity and mortality. It is symptomatic up to 15% of case. Screening test is measurement of plasma free metanephrines or 24 hr urine metanephrine . Plasma free metanephrines is 99% sensitive. Not very specific 85-89%

- Is it malignancy ? - Is it functioning ? Two questions - Is it malignancy ? - Is it functioning ? IS IT FUNCTIONAL? Hormonal hypersecretion most likely in mass at least 3 cm in diameter. Occurs mostly within first 3 years after diagnosis. 6% - 20% of incidentalomas: hormonal abnormality.

RADIOLOGICAL ASSESSMENT

CT scan Abdomen Density (black is less dense) Spectrum : Air -black, Bone-white Hounfield scale is a semiquantitative method of measuring x-ray attenuation Typical precontrast HU values adipose tissue = -20 to – 150 HU kidney = 20 to – 150 HU If adrenal mass < 10 HU on unenhanced CT (ie, has density of fat) likelihood benign adenoma 100 %

DICTUMS on Size and Imaging phenotype The National Italian Study Groups - 4 cm cutoff - sensitivity 93 % - specificity 76 % Imaging phenotype does not predict hormone function, it can predict underlying pathology, and surgical resection

Evaluate for malignancy Primary adrenal carcinoma : quite rare Others : - metastasis (particularly lung) Evaluate : size and imaging characteristics (imaging phenotype)

Fine-needle aspiration biopsy Cannot distinguish a benign adrenal mass from the rare adrenal carcinoma Thus; FNA biopsy - indicated a suspicion of cancer outside the adrenal gland - staging evaluation for a known cancer - not useful routine evaluation

Imaging phenotype MRI or CT Characteristics of the mass (benign tumor) 3-5 mm. cuts : predict histological type of adrenal tumor Characteristics of the mass example ; lipid-rich nature of cortical adenomas (benign tumor)

Contrast-enhanced CT Adenoma : rapid contrast medium washout Non-adenoma : delayed washout 10 mins after administration of contrast Adenoma : absolute contrast media washout > 50 % ( 100% sensitivity & specificity) if compared with carcinomas, metastasis or pheochromocytoma

Size The maximum diameter is predictive of malignancy Important : if the smaller is at the time of diagnosis, the better overall prognosis Adenocortical carcinomas - significantly asso. with mass size - 90% > 4 cm

CT scan in AMRITA (Adrenal Protocol)

MRI Although CT : primary adrenal imaging MRI has advantages in certain clinical situations Several MRI equipments Conventional spin-echo MRI (Initial) - T1 and T2 weighted Distinguish benign adenomas from malignancy and pheochromocytoma

Gadolinium-DPTA-enhanced MRI Adenoma : mild enhancement and rapid washout of contrast Malignancy : rapid and marked enhancement and a slower washout pattern

Chemical shift imaging (CSI) MRI Lipid sensitive imaging: Works on the principle that hydrogen protons in water, lipid molecules have alignment issues. Chemical shift technique 1. In-phase : water & lipid are aligned : signal intensity high 2. Out of phase: opposite from each other: signal intensity low Interpretation: Benign adrenal cortical adenoma : lose signal on out-of-phase images, but appear relatively bright on in-phase images

Imaging characteristics

Benign adenoma Benign cortical adenoma Round & homogenous density < 4 cm, unilateral Low unenhanced CT attenuate values (<10HU) Isointensity with liver on both T-1 & T-2 (MRI) Chemical shift : lipid on MRI Rapid contrast washout (10 min) Absolute contrast washout >50%

Adrenocortical carcinoma Irregular shape; High unenhanced CT (>20HU) > 4 cm, unilateral, calcified Inhomogenous density (central necrosis) Evidence of local invasion or metas. Hypointensity compared with liver T-1 and high to intermidiate intensity T-2 MRI High standard uptake value (SUV) on FDG-PET-CT study Delayed contrast washout (10 min) Absolute contrast washout < 50 %

Metastasis Irregular, inhomogenous Bilateral High enhanced CT (>20 HU) Enhancement with contrast Delayed contrast washout (10 min) Absolute contrast washout < 50% Isointensity or slightly less intense than liver T-1 , high to intermediate intensity T-2 MRI (represent water increase)

Others Adrenal cysts Adrenal hemorrhage Myelolipoma Typical adrenal myelolipoma appears as an adrenal mass with fat-containing components. The mass is usually relatively well circumscribed

Pheochromocytoma Increase attenuate on nonenhanced CT (>20HU) Increase mass vascularity High signal intensity on T-2 MRI Cystic and hemorrhage Variable size Delayed contrast washout (<10 min) Absolute contrast washout <50 %

Pheochromocytoma

ALTERNATE IMAGING PET (Positron emission tomography) - Fluoro-2-deoxy-D-glucose (FDG) High sensitivity for detect malignancy However : 16% benign cortical lesions may have FDG-PET uptake - Metomidate (MTO) PET: Lack of MTO – specific to non-adrenal cortical origin (metastasis & pheochromocytoma

Management of adrenal incidentaloma

Therapeutic goals IDENTIFY COMPENSATORY ENLARGEMENT a) Enzyme deficiency b) Excess renin c) Excess ACTH IDENTIFY HORMONE SECRETING TUMORS - Cortisol, Aldosterone, catecholamines, Androgens , IDENTIFY BENIGN and NON-FUNCTIONING LESIONS - Tumors, Infection, hemorrhage 4 . IDENTIFY PRIMARY ADRENAL CANCERS 5. IDENTIFY CANCER METASTATIC TO ADRENAL TISSUE

GUIDELINES IN ADRENAL MASS PET (Positron emission tomography)/FDG-PET and MTO-PET are not recommended (cost and insufficiency data to support their routine use)

24 hr Urine Metanephrines DST/ UFC PAC/PRA History & Examination 24 hr Urine Metanephrines DST/ UFC PAC/PRA Imaging - CT Nonfunctional Benign Size < 4 cm Functional Malignant Size > 4 cm Follow up Surgery

SUMMARY Adrenal incidentalomas should not be ignored. All patients should be evaluated for functional status and malignant potential . History and physical examination are important in the initial assessment.

BIOCHEMISTRY TO PRECEDE RADIOLOGY Pheochromocytoma should be excluded by measuring 24-hour urinary fractionated metanephrines and catecholamines. Subclinical Cushing's syndrome should be ruled out by the 1-mg overnight dexamethasone. Primary aldosteronism. should be screen in patient is hypertensive by a plasma aldosterone-to-plasma renin activity ratio and plasma potassium concentration

Benign cortical adenoma A homogeneous adrenal mass <4 cm in diameter, A smooth border, Attenuation value <10 HU on unenhanced CT, rapid contrast medium washout (eg, >50 percent at 10 minutes) Adrenal carcinoma or metastases irregular shape. inhomogeneous density. high unenhanced CT attenuation values (>20 HU), delayed contrast medium washout (eg, <50 percent at 10 minutes), diameter >4 cm, and tumor calcification.

Suggest surgery for patients with adrenal masses greater than 4 cm in diameter . If there is evidence of metastasis and after excluding pheochromocytoma with biochemical testing, suggest performing a diagnostic CT-guided FNA biopsy .

Recommend surgery: pheochromocytoma, aldosteronoma. Suggest surgery for patients with subclinical Cushing's syndrome who are younger and who have disorders potentially attributable to autonomous glucocorticoid secretion.

Subclinical Cushing’s syndrome, Best Practice & Research Clinical Endocrinology & Metabolism. 2012 In 5–20% of cases, adrenal incidentaloma are responsible for a subtle cortisol overproduction, commonly defined as “subclinical Cushing’s syndrome” (SCS). The standard biochemical tests used to screen for overt Cushing’s syndrome are generally ill-suited. Adrenalectomy or medical management of associated disease has been indicated as therapeutic options due to lack of data demonstrating the superiority of a surgical or non-surgical treatment.

Subclinical Cushing's syndrome and unilateral adrenalectomy? lack of suppression to both an overnight DST) and a two-day high-dose DST. absence of a prospective randomized study candidates for unilateral adrenalectomy ??