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Thyroid Nodules and Nothing to disclose Endocrine Incidentalomas UCSF Primary Care Update Hawaii April 10, 2014

Elizabeth J. Murphy, MD, DPhil Professor of Clinical Medicine University of California, San Francisco Chief, Division of San Francisco General Hospital

Radiology report Adrenal Incidentalomas

58 yom with hypertension and vague . 6% (1-32%)of individuals have adrenal abdominal pain gets a CT that shows an on autopsy1 incidental 2.5 cm adrenal nodule. Dedicated . 4% of individuals have adrenal adrenal CT recommended. incidentalomas on CT . Prevalence increases with age Do you need the extra CT? o < 1% age < 30 o 7% age > 70 Anything to worry about? 3-10 million Americans!

1 Kloos et al. Incidentaly discovered adrenal masses. Endocr Rev 1995;16:460. 4

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Common Adrenal Masses Why Adrenal Specific CT 1. Thin cuts (2-3 mm) through the adrenals . Adrenalocortical 90+% which are quite small. . 5% 2. Determine pre contrast Hounsfield Units (HU) . Adrenalocortical <5%? • HU < 10-15 very specific for benign adenoma . Metastatic Lesion 2.5% 3. Determine % washout of contrast • Washout % > 60 is very specific for benign adenoma Incidence of carcinoma 3000/year Corresponding prevalence 1/1000 (0.1%) Prevalence really 5%?

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Adrenal Nodule – Imaging Mansmann et al, Endocrine Reviews, 2004, 25:309-340)

. Concerning features

o Hemorrhage, Calcification, Necrosis

o no fat (high HU) . Concerning size

o > 4 cm : 70% malignant (excluding adrenal myelolipomas and )

o > 6 cm : 85% malignant

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Radiology report What to do?

58 yom with hypertension and vague abdominal pain gets a CT that shows an 1) Wish you hadn’t ordered the original CT in incidental 2.5 cm adrenal nodule. Dedicated the first place. adrenal CT recommended. 2) Be thankful everything is good and tell the patient it’s nothing to worry about. IMPRESSION: 3) Wish you hadn’t gone to that CME course in Hawaii as now you know #2 isn’t correct 1.3 cm nodule in the left adrenal gland. This and you have more work ahead. has Hounsfield units and enhancement characteristics consistent with a benign adrenal adenoma. No additional follow-up is recommended.

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Adrenal Gland - Hormones Adrenal Gland - Hormones

. Catacholamines (Medulla) . Catacholamines (Medulla)

o Pheochromocytoma o Pheochromocytoma . Mineralocorticoids (aldosterone/glomerulosa) . Mineralocorticoids (aldosterone/glomerulosa)

o Aldosterone secreting adenoma o Aldosterone secreting adenoma 1+ %? o Adrenal hyperplasia o Adrenal hyperplasia

o Adrenal carcinoma o Adrenal carcinoma . Glucocorticoids (cortisol/fasiculata) . Glucocorticoids (cortisol/fasiculata)

o Adrenal adenoma o Adrenal adenoma 5- %?

o Adrenal carcinoma o Adrenal carcinoma

o Bilateral hyperplasia o Bilateral hyperplasia . Androgens (DHEA/reticularis) . Androgens (DHEA/reticularis)

o Adrenal carcinoma o Adrenal carcinoma

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Common Adrenal Masses Hormonal Evaluation

. Adrenalocortical Adenoma 90+% . Everyone:

o Aldosterone secreting 1%? o Dexamethasone suppression test • 1 mg dex at 11-MN night before with 8 am cortisol o Cortisol secreting 5%? • Cortisol > 5 mcg/dl is abnormal . Pheochromocytoma 5% o Fractionated urinary metanepharines and . Adrenalocortical Carcinoma < 5%? catecholamines or plasma metanepharines . Metastatic Lesion 2.5% . If Hypertension

o Hyperaldo screening test with morning plasma aldosterone and plasma renin activity

• Ratio > 20 AND aldo > 15 consider hyperaldo

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Endocrine Referral Primary Hyperaldosteronism - Etiologies 66 yow with DM2, HTN on a beta-blocker, HCTZ, and amlodipine. Got aldo and renin because K  Steady rise in prevalence (5-10% of hypertensive was 3.4. Elevated ratio. Abdominal CT with 1.4 patients?) cm adenoma on left. Please assist in referral to surgery.  Adrenal adenoma (75%) LABS  usually very small tumors Aldo 4  treat/cure with surgical resection PRA 0.1  Bilateral adrenal hyperplasia (25%) Aldo/PRA ratio: 40 H (nl < 20)  treat medically with aldosterone antagonist (spironolactone or Patient with hypoaldo, hyporenin state due to eplerenone) age and DM2. Ratio is high (low renin). Aldo  Adrenal carcinoma (rare %) is not high. Now there is the need to w/u the  very, very poor prognosis, more often secrete DOC, mineralocorticoid excess least of concerns incidental nodule.

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Effect of Antihypertensives on Aldo-Renin Ratio Confirmatory Tests for Hyperaldo

Confirmatory testing DIAGNOSING ENDOCRINE DISORDERS

 Screening test is elevated Aldo/PRA ratio 1. Discern a clinical syndrome  Confirmatory Tests 2. Make the biochemical diagnosis of hormone excess  24 hour urine aldosterone testing after a salt load or deficiency  Saline suppression test  Fludracortisone suppression test 3. Determine the etiology of the hormone excess or  Captopril (ACE-I) challenge test deficiency  Problems with Testing in Hypertensive Patients 4. Consider appropriate imaging to localize the site of  Stopping BP meds pathology  Massive salt loading  Testing is really difficult….  Once confirmed need to consider need for adrenal vein sampling

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Adrenal Gland Biopsy Radiology report Per radiology recommendation you send the 58 yom with hypertension and vague abdominal pain patient to IR for FNA of the adrenal lesion. gets a CT that shows an incidental 2.5 cm adrenal You get called the day of the procedure by nodule. Dedicated adrenal CT recommended. radiology who tells you the patient coded and died during the procedure. You have to call IMPRESSION: the patient’s wife to explain what happened. Indeterminate 15 mm nodule in left adrenal gland. For further evaluation a biopsy is recommended if clinically indicated. What did happen??? (findings section: HU 32, washout 9%)

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Pheochromocytoma/

 Rule of 10s: 10% bilateral, 10% extra-adrenal, 10%  Typically present with pain and are very large malignant, 10% genetic >25% genetic  Invasive  Associated Genetic Syndromes:  Can secrete a lot of different hormones  Multiple Endocrine Neoplasia 2 (RET)  Cortisol  Familial Paraganglioma Syndrome (SDHA, SDHB, SDHC, SDHD, SDHAF2)  Deoxycorticosterone (mineralocorticoid)  Von Hippel-Lindau Syndrome (VHL)  Androgens (Testosteron, Dehydroepiandrosterone (DHEA-S))  Neurofibromatosis Type 1 (NF1)  Can have Cushings, huirsuitism, virulization  TMEM127  Very poor prognosis  Pheo Crisis/HTN Crisis/Catecholamine Storm

 NEVER EVER (hardly ever) BIOPSY AN ADRENAL MASS

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Frequency of Follow-up Imaging Algorithm for for Benign Lesion (< 10 HU) adrenal incidnetalomas (one of many) . Never . Once in 6-12 months (may reassure the physician and the patient) Zieger et al, JCEM . At 6, 12, and 24 months 96:2004-2015, 2011.

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Case Pituitary Incidentaloma

. 34 yow with worsening migraine HA and gets an MRI. She was noted to have an • (50-90%) incidental 6 mm pituitary adenoma. What • now? • Rathke’s cleft cyst • Other primary tumors in the pituitary • Metastases

Pituitary Incidentaloma • 11% prevalence on data • 10% prevalence on MRI (10-38%)

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ANTERIOR PITUITARY PITUITARY GLAND: Sagittal View . Testing for Hypofunction

o History and exam

o Laboratory testing if suspicion - test end- organ function as basal levels of pituitary hormones are often normal in hypopituitarism . Testing for Hyperfunction

o History and exam

o Laboratory testing for everyone – often dynamic GH ACTH ADH testing with suppression tests TSH LH, FSH

Pituitary Hypofunction Pituitary Hyperfunction

. GH (rarely tested) . Prolactin level (most common) o IGF-1 level . IGF-1 o GH stimulation test (insulin induced hypoglycemia) . Gonadotrophs (FSH/LH) o Low Testosterone level without elevated LH

o Amenorrhea in a young woman or lack of FSH elevation in a post-menopausal woman (estradiol not useful) . TSH o good history and exam for o Low free T4 level without elevated TSH . ACTH o Cosyntropin (synthetic ACTH) stimulation test

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Pituitary Hyperfunction Pituitary Incidentaloma

. Prolactin level (most common) . Microadenoma < 1 cm . IGF-1 . Macroadenoma ≥ 1 cm . Screening for glucocorticoid excess?? o VF testing if near abutting or compressing the optic nervers or chiasm o Only if clinical suspician . o Dex suppression and not ACTH Follow-up imaging for non-secreting micro- incidentaloma

o Repeat MRI yearly for 3 years and then less frequently

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Case Five things Physicians and Patients Should Question 29 yow comes to your office complaining of amenorrhea, anxiety, weight loss and tremors. You get a TSH which is < 0.01.

You then order a US which shows a 1.2 mm hyperechoic nodule and diffuse increased vascularity.

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Case Thyroid Nodules and

62 yow complains of pain. Spine MRI has . Prevalence of palpable thyroid nodules 4-7% incidental finding of two thyroid nodules. It is . Prevalence of nodules by US 19-67% recommended you get a thyroid US. . Prevalence increases with age . Approximately 5% of nodules are considered malignant on FNA . :

o Differentiated Thyroid Cancer (90%)

• Papillary

• Follicular

o

o Anaplastic Thyroid Cancer

o Other

o 97% 5 year survival

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Case Evaluation

62 yow complains of neck pain. Spine MRI has incidental finding of two thyroid nodules . Check TSH You order a thyroid ultrasound and get back a . Only if suppressed get I-123 nuclear report saying: medicine scan to rule out toxic nodules Diffusely enlarged and heterogeneous thyroid with multiple masses bilaterally which may be consistent which don’t need FNA (the vast majority of with a multinodular goiter. Although no one mass is nodules are cold) more suspicious than the next, malignancy cannot be excluded in any given lesion. Clinical correlation with . Biopsy with FNA all palpable nodules in patient risk factors, physical exam, thyroid function tests, and nuclear is recommended. euthyroid or hypothyroid patients

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Worrisome Things What to FNA?

. Family history of thyroid cancer or history of . Criteria for FNA of incidentally found nodules exposure are in continual flux . On ultrasound: . Many different sets of guidelines out there o Microcalcifications o American Thyroid Association/American o Hypoechoic Association of Clinical Endocrinologists o Hypervascular (internal) o Society of Radiologists in Ultrasound (SRU) o Irregular margins o Kim Criteria o Abnormal lymph nodes

o Size

o Taller than wide

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GUIDELINES

. Kim criteria is any one of the following – Highest sensitivity (7% missed malignant lesions

o marked hypoechogenicity, irregular or microlobulated margins, microcalcifications, or length greater than width. . Society of Radiologists in Ultrasound (SRU)- least accurate

o nodule 1 cm in diameter or larger with microcalcifications

o 1.5 cm in diameter or larger that is solid or has coarse calcifications

o 2 cm in diameter or larger that has mixed solid and cystic components

o nodule that has undergone substantial growth or is associated with abnormal . . AACE- highest specificity (only FNA 26%)

o Nodule 1 cm and hypoechoic

o Any nodule and a hypoechoic nodule with at least one additional feature . American Thyroid Association (ATA)

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New Population Based US Data

Smith-Bindman et al, Jama Internal Medicine, 2013, 173:1788-1795

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Basic Incidentaloma Principles References . Be judicious in your imaging to avoid finding incidentalomas . Endocrine society guidelines Pituitary incidentaloma . Don’t order a thyroid ultrasound for abnormal https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical thyroid function tests %20Practice%20Guidelines/032811_PituitaryIncident_FinalA-2.pdf Primary Aldosteronism . Nodules/adenomas are common in thyroid, http://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Pr pituitary and adrenal actice%20Guidelines/Cushings_Guideline.pdf . Nodules in pituitary and and adrenal need . American Thyroid Association Thyroid evaluation for hormonal secretion. nodule Guideline . NEVER biopsy an adrenal nodule (2009)http://thyroidguidelines.net/revised/taskforce . Hopefully, we will be doing fewer thyroid nodule biopsies in the future

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ENDOCRINE INCIDENTALOMAS . Pituitary

o 10% . Adrenals

o 4-6% . Thyroid

o >50%

Avoid Imaging you don’t need

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