Adrenal Incidentaloma and Pituitary Incidentaloma/Tumors

Adrenal Incidentaloma

Objectives Definition Epidemiology/Statistics Etiology Biochemical work up Treatment

Definition Adrenal mass > or = 1cm Discovered incidentally Asymptomatic

Epidemiology and Statistics Prevalence 4-6% Increases with increasing age 0.2 % between 20-29 years of age 7% in patients over 70 years of age

Etiology Adrenal adenoma Adrenocortical carcinoma Myelolipoma Pheochromocytoma Adrenal cyst Adrenal hemorrhage Adrenal metastasis Infection Infiltrative disease ACTH-independent MMAD ACTH-dependent Cushing’s Congenital adrenal hyperplasia

Question 1 A 45 y/o healthy woman undergoes emergent abdominal imaging after an automobile accident and was found to have a 6.3 cm right adrenal mass. The results of basic chemistry and hematology tests are normal. Which of the following is the best evaluation plan for this patient? A. Chest CT, morning serum cortisol, repeat imaging in 3 months B. 1 mg dexamethasone suppression test, 24-hour urine metanephrines and catecholamines, surgical consultation C. Paired plasma renin and aldosterone, 8 AM serum cortisol, repeat abdominal imaging in 6 months D. No hormonal evaluation, surgical consultation

Evaluation 2 questions: Is it functioning? Is it malignant?

Evaluation (cont’d) Functional status 10 – 15% functional Hormonal evaluation Subclinical Cushing’s syndrome Pheochromocytoma Primary aldosteronism

Evaluation for hormonal function Subclinical Cushing’s syndrome Low dose 1mg overnight dexamethasone suppression test Normal: cortisol suppresses < 5 mcg/dL Sensitivity 89%, specificity 98% Endo Soc. recommended cut point 1.8 mcg/dL – sens 95%, spec 80% Test of choice for adrenal incidentaloma Autonomy 24-hour urine free cortisol Hypersecretion 24 hr UFC > 4x upper normal limit May miss subclinical Cushing’s or Cushing’s in renal failure Midnight salivary cortisol Midnight serum cortisol

Evaluation for hormonal function (cont’d) Subclinical Cushing’s syndrome (cont’d) Pseudo-Cushing’s Stress Morbid obesity Psychiatric illness (MDD, anxiety, anorexia/bulimia) Alcoholism (rare) Glucocorticoid resistance Uncontrolled DM Elevated cortisol-binding globulin (estrogen, pregnancy, hyperthyroidism) Drugs that increases dexamethasone metabolism (rifampin, phenytoin, phenobarbital, alcohol)

Evaluation for hormonal function Pheochromocytoma Urine metanephrines and catecholamines Sensitivity 91%, specificity 98% Screen cases with low suspicion Serum fractionated metanephrines and catecholamines Sensitivity 96-100%, specificity 85-95% High false positive rate High suspicion Imaging over-rules biochemical testing Early, asymptomatic pheo may have negative hormonal testing

Evaluation for hormonal function (cont’d) Pheochromocytoma (cont’d) Conditions that may interfere with test results Meds – discontinue at least 2 weeks Tricyclic antidepressants Levodopa Drugs containing adrenergic receptor agonists (decongestants, appetite suppressants) Amphetamines Buspirone and most psychoactive agents Prochlorperazine Reserpine Acetaminophen Increased endogenous catecholamines: physiologic stress, alcohol or clonidine withdrawal

Evaluation for hormonal function (cont’d) Primary aldosteronism – performed if pt has HTN Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) PAC/PRA > 20 and PAC > 15 ng/dL Confirmation test Saline infusion PAC > 10 ng/dL Oral salt loading 24 hr urine aldosterone > 12 mcg and 24 hr urine Na > 200 mEq Catopril suppression Fludrocortisone suppression Adrenal vein sampling

Evaluation for hormonal function (cont’d) Primary aldosteronism (cont’d) Agents that markedly affect ARR – withdraw at least 4 weeks Spironolactone, eplerenone All diuretics Liquorice products (chewing tobacco, confectionary licorice) If ARR is non-diagnostic off the above agents, consider withdrawing other anti-HTN meds for 2 weeks and repeat test

Evaluation for hormonal function (cont’d) Primary aldosteronisim (cont’d) Drugs that minimally affect ARR Verapamil Hydralazine Alpha-adrengeric blockers – prazosin, doxazosin, terazosin Drugs that can falsely suppressed ARR ARB, ACE I, diuretics, aldosterone receptor antagonists - increase PRA Drugs that can falsely elevated ARR Beta blocker, central alpha 2 agonist (clonidine, methyldopa), NSAIDS – suppresses renin release

Back to Question 1 A 45 y/o healthy woman undergoes emergent abdominal imaging after an automobile accident and was found to have a 6.3 cm right adrenal mass. The results of basic chemistry and hematology tests are normal. Which of the following is the best evaluation plan for this patient? A. Chest CT, morning serum cortisol, repeat imaging in 3 months B. 1 mg dexamethasone suppression test, 24-hour urine metanephrines and catecholamines, surgical consultation C. Paired plasma renin and aldosterone, 8 AM serum cortisol, repeat abdominal imaging in 6 months D. No hormonal evaluation, surgical consultation

Question 2 A 45-year-old man is diagnosed with a 1.5 cm left adrenal mass on abdominal/pelvic CT to evaluate abdominal pain. The lesion has attenuation value of 3 HU pre-contrast, 40 HU immediately after contrast administration, and 15 HU at 10 minutes post-contrast. The adrenal mass is likely A. Pheochromocytoma B. Adrenocortical carcinoma C. Metastatic lesion D. Adrenal adenoma

Question 3 41 y/o F with h/o HTN, who presented with abdominal pain and found to have a 3 cm L adrenal mass on abdominal CT. F/u MRI shown below. T1W MRI T2W MRI

Question 3 (cont’d) Your differential diagnoses include all of the following except A. Pheochromocytoma B. Adrenocortical carcinoma C. Metastatic malignancy D. Adrenal adenoma

Imaging differences between malignant and benign lesions Size > 4 cm Irregular, calcifications Inhomogenous High attenuation on non-contrast studies > 10 HU Highly enhanced with contrast, slower washout (< 50% at 10 min) Isointensity with liver on T1W and hyperintense on T2W MRI images No signal loss on out-of-phase chemical shift MRI Size < 4cm Round, smooth contour Homogeneous Low attenuation on non-contrast studies <10 HU Limited enhancement with contrast and earlier washout of contrast Isointensity with liver on both T1W and T2W MRI images Lose signal on out-of-phase chemical shift MRI

Back to Question 2 A 45-year-old man is diagnosed with a 1.5 cm left adrenal mass on abdominal/pelvic CT to evaluate abdominal pain. The lesion has attenuation value of 3 HU pre-contrast, 40 HU immediately after contrast administration, and 15 HU at 10 minutes post-contrast. The adrenal mass is likely A. Pheochromocytoma B. Adrenocortical carcinoma C. Metastatic lesion D. Adrenal adenoma

Back to Question 3 41 y/o F with HTN who presented with abdominal pain and found to have a 3 cm L adrenal mass on abdominal CT. F/u MRI shown below. T2W MRI T1W MRI

Back to Question 3 Your differential diagnoses include all of the following except A. Pheochromocytoma B. Adrenocortical carcinoma C. Metastatic malignancy D. Adrenal adenoma

CT-guided adrenal biopsy Rarely indicated Can’t distinguish benign from malignant cortical tissues Helpful if metastasis or infection Rule out pheochromocytoma prior to biopsy

Treatment Lesion > 6 cm or functioning and no evidence of metastases  surgical resection Lesion < 4 cm and non-functioning Repeat scans in 3-6, 12, and 24 months Repeat hormonal testing annually for 4 years If lesion is 4-6 cm or is enlarging by 1cm or more  consider removal

Question 4 36 y/o woman was found incidentally to have a 3-cm right adrenal mass. The left adrenal gland is very small. Gained approximately 22 lb over the past 18 months Diagnosed with impaired glucose tolerance P/E showed central obesity, proximal muscle weakness, and wide violaceous striae 1mg DST – plasma cortisol 12 mcg/dL 24-hr urine free cortisol - 3x the normal upper limit for daily excretion Serum ACTH is < 5 pg/mL The patient undergoes laparoscopic right adrenalectomy During the first 24 hours after surgery experiences hypotension and nausea.

Question 4 (cont’d) Which of the following is the most appropriate management at this time? A. Surgery to explore for retroperitoneal bleeding B. Emergent CT scan of abdomen and retroperitoneum C. Evaluation to insure that the correct adrenal gland was resected D. Administer hydrocortisone, 100mg IV q8 hrs

NEJM 2007; 356:601-610

Pituitary Incidentaloma/Tumors

Objectives Definition and classification of pituitary incidentaloma Causes of pituitary incidentaloma Review of anterior and posterior pituitary hormones Biochemical evaluation Treatment and follow-up

Pituitary incidentaloma Previously unrecognized lesion in the pituitary Prevalence up to 10% Classification Microadenoma < 10 mm Macroadenoma > 10 mm More likely to cause visual and hormonal abnormalities

Etiology of incidentaloma Pituitary adenoma Pituitary hyperplasia Pituitary carcinoma Craniopharyngioma Meningioma Lymphocytic hypophysitis Rathke’s cleft cyst Germinoma Primary CNS lymphoma Metastasis AVM

Pituitary incidentaloma (cont’d) Functional status Hyposecretion Hypersecretion Non-functioning Mass effect Headache Visual field deficits (bitemporal hemianopsia) Cranial nerve III, IV, VI palsy - diplopia

Hypopituitarism Decreased secretion of one or more anterior pituitary hormones (ACTH, GH, FSH, LH, TSH, prolactin) Panhypopituitarism – deficiency of all pit hormones Partial – deficiency of some pit hormones Isolated – deficiency of only one pit hormone Diagnosis can’t be make by measuring pituitary hormones Overlap between normal and hypopituitary ranges Hormone present not bioactive

Hypopituitarism Central adrenal insufficiency Abnormality in CRH or ACTH production  decreased cortisol Fatigue, weakness, anorexia, weight loss, lightheadedness, orthostatic hypotension, nausea/vomiting, hyponatremia Different from primary AI – ACTH not elevated - no hyperpigmentation Aldosterone secretion normal - no hyperkalemia Dx - morning fasting serum cortisol < 3 mcg/dL – highly suggestive of AI > 15 mcg/dL – normal > 3 < 15 mcg/dL  further testing

Hypopituitarism Central AI (cont’d) Cosyntropin stimulation test – Not useful in acute setting (normal until adrenals atropy – weeks to months) Insulin tolerance test – gold standard Hypoglycemia stimulates entire HPA axis Contraindicated in elderly, CV disease, seizures Medic alert bracelet Glucocorticoid replacement Sick day coverage Stress dose coverage

Question 5 A 50 y/o man who presented with new onset headache and was subsequently diagnosed with a 1.5 cm pituitary mass. Fasting morning serum cortisol is 5 mcg/dL, FT4 0.6 ng/dL (0.79 to 2.35), TSH 1.2 mIU/L (0.47 to 4.68), total testosterone 120 ng/dL (132 to 813), FSH 2 mIU/ml, LH 3 mIU/ml, IGF-1 70 ng/mL (109 to 284), prolactin 15 ng/mL (3.7 to 17.9). The best next step is A. Start levothyroxine replacement B. Start testosterone replacement C. Perform Cosyntropin stimulation test D. Start human growth hormone replacement

Hypopituitarism Central hypothyroidism Symptoms and signs – same as primary hypothyroidism except goiter Dx - low FT4 and low or inappropriately normal TSH LT4 replacement Treat AI before starting LT4 as LT4 increases cortisol metabolism  adrenal crisis Follow FT4 level, goal FT4 mid normal range

Back to question 5 A 50 y/o man who presented with new onset headache and was subsequently diagnosed with a 1.5 cm pituitary mass. Fasting morning serum cortisol is 5 mcg/dL, FT4 0.6 ng/dL (0.79 to 2.35), TSH 1.2 mIU/L (0.47 to 4.68), total testosterone 120 ng/dL (132 to 813), FSH 2 mIU/ml, LH 3 mIU/ml, IGF-1 70 ng/mL (109 to 284), prolactin 15 ng/mL (3.7 to 17.9). The best next step is A. Start levothyroxine replacement B. Start testosterone replacement C. Perform Cosyntropin stimulation test D. Start human growth hormone replacement

Hypopituitarism (cont’d) Hypogonadotropic hypogonadism Men Decreased libido, infertility Low total testosterone and low or inappropriately normal FSH/LH Testosterone replacement (gonadotropins if desire fertililty) Women Amenorrhea, infertility Low estradiol and low or inappropriately normal FSH/LH No data on estrogen/progestin replacement in reproductive-age women – recommend to replace Gonadotropins if desire fertility

Hypopituitarism (cont’d) Growth hormone deficiency Dx - Low IGF-1 Low IGF-1 caveats Fasting, anorexia, malnourishment Poorly controlled DM Exogenous estrogen Liver disease Confirmation tests Insulin tolerance test Arginine-GHRH stimulation test (GHRH no longer available in the U.S.) Glucagon stimulation test HGH replacement Improves BMD and body composition; does not decrease weight Contraindicated – active cancer Follow IGF-1 level

Hormonal hypersecretion Lactotroph (prolactinoma) – 50-60% Gonadotroph (nonfunctioning) – 15-45% Somatotroph (acromegaly) – 10-20% Corticotroph (Cushing’s disease) – 10-15% Thyrotroph (Hyperthyroidism) – 1%

Question 6 32 y/o M who presented with several weeks of visual field deficits. Work up revealed 2.5 cm prolactin secreting pituitary adenoma, which extends into the suprasellar space, compressing the optic chiasm. The best treatment option after a complete ophthalmologic evaluation is A. Starting cabergoline or bromocriptine treatment B. Start octreotide LAR 30mg SQ monthly C. Refer for radiosurgery D. Refer for transphenoidal surgery

Question 7 34 y/o female who was found to have a 1 cm prolactinoma during infertility work up. She wishes to conceive soon. The best next step is A. Start bromocriptine 2.5 mg daily B. Start cabergoline 0.25 mg weekly C. Start octreotide LAR 30mg SQ monthly D. Referral to neurosurgery for pituitary mass resection

Hormonal hypersecretion Men Gynecomastia ED Infertility Osteopenia/osteoporosis Mass effect Prolactinoma Women : Hirsutism Galactorrhea Menstrual irregularity Infertility Osteopenia/osteoporosis Mass effect Prolactin > 200 ng/mL - prolactin-secreting tumors Stalk effect Hook effect

Hormonal hypersecretion Prolactinoma (cont’d) Conditions that can cause hyperprolactinemia Pregnancy Stress Exercise Food Nipple stimulation Intercourse Postpartum Estrogen therapy

Hormonal hypersecretion Prolactinoma (cont’d) Treatment Dopamine agonist – bromocriptine or cabergoline Bromocriptine - drug of choice in women desiring pregnancy Cabergoline - better tolerated and better efficacy Start low and titrate slowly to avoid side effects Indications for surgery Unable to tolerate or unresponsive to medical treatment Pituitary apoplexy

Back to question 6 32 y/o M who presented with several weeks of visual field deficits. Work up revealed 2.5 cm prolactin secreting pituitary adenoma, which extends into the suprasellar space, compressing the optic chiasm. The best treatment option after a complete ophthalmologic evaluation is A. Starting cabergoline or bromocriptine treatment B. Start octreotide 30mg LAR SQ monthly C. Refer for radiosurgery D. Refer for transphenoidal surgery

Back to question 7 34 y/o female who was found to have a 1 cm prolactinoma during infertility work up. She wishes to conceive soon. The best next step is A. Start bromocriptine 2.5 mg daily B. Start cabergoline 0.25 mg weekly C. Start octreotide LAR 30mg SQ monthly D. Referral to neurosurgery for pituitary mass resection

Hormonal hypersecretion Cushing’s disease Increased ACTH production  increased cortisol Most common cause of endogenous Cushing’s syndrome Specific symptoms and signs of Cushing’s syndrome Central obesity Proximal muscle weakness Wide (>1 cm), purple striae Spontaneous ecchymosis Hypokalemia Osteopenia/osteoporosis

Hormonal hypersecretion Cushing’s disease (cont’d) 24 hr UFC, 1mg DST, salivary cortisol, MN serum cortisol Confirmation test Conditions that can cause pseudoCushing’s ACTH > 15 mcg/dl Differentiate from ectopic Cushing’s syndrome 8 mg DST CRH stimulation test Inferior petrosal sinus sampling (IPSS)

Hormonal hypersecretion Cushing’s disease (cont’d) Treatment Transphenoidal surgery (TSS) is primary treatment Better outcome with high volume surgeons/hospitals Radiotherapy or radiosurgery Ketoconazole, mitotane, octreotide, etomidate, metyrapone, aminoglutethemide, pasreotide, cabergoline, and mifepristone

Hormonal hypersecretion TSH-Secreting Adenoma Rarest, 0.5 – 1% Symptoms of hyperthyroidism Elevated FT4 and inappropriately normal or elevated TSH Treatment TSS is primary treatment Octreotide, lanreotide, dopamine agonist Radiotherapy or radiosurgery

Question 8 The best screening test for acromegaly is A. Insulin-like growth factor 1 B. Human growth hormone C. Oral glucose tolerance test with measurement of human growth hormone D. Insulin tolerance test with measurement of human growth hormone

Question 9 42 y/o man is evaluated for a 12 month history of decreased libido, increased sweating, arthritis, and occasional headaches. Initial hormonal evaluation showed normal TSH, FT4, cbc, and comprehensive metabolic panel. Testosterone 120 ng/dL. Further testing revealed FSH 3, LH 3, prolactin 30, IGF-1 500 ng/mL, GH 8 ng/mL. GH was 3, 5, and 5 ng/ml at 30, 60, and 90 minutes during a 75 gm oral glucose tolerance test, suggesting acromegaly. Pituitary MRI showed a 1.5 cm pituitary mass within the sella turcica.

Question 9 (cont’d) The next best treatment is A. Bromocriptine B. Cabergoline C. Octreotide D. Pegvisomant E. Neurosurgery referral for transphenoidal surgery

Hormonal hypersecretion Acromegaly Increased GH production  increased IGF-1 Clemmons DR et al, JCEM 2003

Hormonal hypersecretion Acromegaly (cont’d) Best screening test is serum IGF-1 Confirmed with OGTT Failure of GH suppression to < 1 ng/mL Pitfalls in IGF-1 levels Low – Fasting, anorexia, malnourishment Poorly controlled DM Exogenous estrogen Liver disease High Pregnancy, adolescent/puberty, hyperthyroidism

Hormonal hypersecretion Acromegaly (cont’d) Screening for co-morbidities Colonoscopy, fasting glucose and A1c, EKG Sleep test if symptoms/signs of OSA present Treatment Transphenoidal sinus surgery is primary treatment Octreotide, lanreotide, pegvisomant, dopamine agonist Radiotherapy or radiosurgery

Back to question 8 The best screening test for acromegaly is A. Insulin-like growth factor 1 B. Human growth hormone C. Oral glucose tolerance test with measurement of human growth hormone D. Insulin tolerance test with measurement of human growth hormone

Back to question 9 42 y/o man is evaluated for a 12 month history of decreased libido, increased sweating, arthritis, and occasional headaches. Initial hormonal evaluation showed normal TSH, FT4, cbc, and comprehensive metabolic panel. Testosterone 120 ng/dL. Further testing revealed FSH 3, LH 3, prolactin 30, IGF-1 500 ng/mL, GH 8 ng/mL. GH was 3, 5, and 5 ng/ml at 30, 60, and 90 minutes during a 75 gm oral glucose tolerance test, suggesting acromegaly. Pituitary MRI showed a 1.5 cm pituitary mass within the sella turcica.

Back to question 9 (cont’d) The next best treatment is A. Bromocriptine B. Cabergoline C. Octreotide D. Pegvisomant E. Neurosurgery referral for transphenoidal surgery

Question 10 40 y/o F with new onset headache and visual field deficits who was found to have a 2 cm pituitary mass. Hormonal work up including 1mg dexamethasone suppression test, 24 hr urine free cortisol, TSH, FT4, IGF1 were normal. 8 am serum cortisol was 18 mcg/dl. Prolactin level was 35 and on repeat was 37, with 1:10 dilution was 4, and 1: 100 dilution was 0.4. Ophthalmologic evaluation confirmed visual field defects. The next best step is A. Start bromocriptine 2.5mg daily B. Start cabergoline 0.25 mg weekly C. Observation with repeat pituitary MRI in 3-6 months D. Neurosurgery referral

Nonfunctioning pituitary adenoma Gonadotroph adenoma Mass effect Hypopituitarism Treatment TSS is primary treatment If no mass effect and no hypopituitarism  observation with repeat MRI q6 months for 2 years, then yearly.

Back to question 10 40 y/o F with new onset headache and visual field deficits who was found to have a 2 cm pituitary mass. Hormonal work up including 1mg dexamethasone suppression test, 24 hr urine free cortisol, TSH, FT4, IGF1 were normal. 8 am serum cortisol was 18 mcg/dl. Prolactin level was 35 and on repeat was 37, with 1:10 dilution was 4, 1:100 dilution was 0.4. Ophthalmologic evaluation confirmed visual field defects. The next best step is A. Start bromocriptine 2.5mg daily B. Start cabergoline 0.25 mg weekly C. Observation with repeat pituitary MRI in 3-6 months D. Neurosurgery referral

Summary Adapted from Uptodate

Summary Hormonal evaluation 1mg DST and/or 24 hr urine free cortisol If suspect adrenal insufficiency Morning fasting serum cortisol IGF-1 TSH, FT4 Prolactin FSH/LH panel and estradiol or testosterone Serum osmolality, urine osmolality, urine Na – if suspect DI

References 1. Young, WF “The Incidentally discovered adrenal mass.” NEJM 2007; 356:601-610 2. The diagnosis of Cushing’s syndrome: An Endocrine society clinical practice guideline, JCEM 2008; 93: 1526-1540 3. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine society clinical practice guideline, JCEM 2008; 93: 3266-3281 4. Guidelines for acromegaly management: an update. JCEM 2009;94:1509-1517. 5. Clemmons DR et al, JCEM 2003; 88: 4759-67 6. MKSAP 12 and 14 7. Up to date