1. Adrenal and Pituitary Incidentaloma Gita Majdi, PGY5 Endocrinology, MD, MRCP (UK), FRCPC, ABIM

2. Objectives: 1- To discuss the Hormonal evaluation and assessment of malignant potential of Adrenal incidentaloma 2- to discuss the initial evaluation and follow up for pituitary incidentaloma

3. Case: A 68-year-old woman is incidentally found to have a left adrenal mass, 2.8 cm in diameter, on abdominal computed tomography that was ordered to evaluate right lower abdominal discomfort (which has since resolved). Her medical history is notable only for hypertension that has been well controlled with hydrochlorothiazide, at a dose of 25 mg daily. She reports no sweating, palpitations, headache, weight gain, or proximal muscle weakness. Her physical examination is unremarkable. How should she be evaluated?

4. Definition: An adrenal “incidentaloma” is an adrenal mass, generally 1 cm or more in diameter, that is discovered during a radiologic examination performed for indications other than an evaluation for adrenal disease. This definition excludes cases in which a symptomatic adrenal- dependent syndrome is “missed” because of a superficial interview or physical examination. The widespread use of abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) has resulted in the clinical dilemma of the adrenal incidentaloma.

5. Incidence In a report on 25 studies, the overall frequency of adrenal adenomas in 87,065 autopsies was 6% (range, 1 to 32). Abdominal CT yields similar findings; reported a prevalence of adrenal incidentaloma of 4%. The prevalence of adrenal adenomas increases with increasing age: the probability of finding an unsuspected adrenal adenoma on abdominal CT in a patient between 20 and 29 years of age would be approximately 0.2%, as compared with approximately 7% in a patient over 70 years of age.

6. Adrenal Incidentaloma: AACE/AAES Adrenal Incidentaloma Guidelines, Endocr Pract. 2009 Definition of adrenal incidentaloma: detecting an otherwise unsuspected adrenal mass on radiologic imaging The definition of incidentaloma excludes patients undergoing imaging procedures as part of staging and work-up for cancer. Incidence: 8.7% incidence reported in autopsy series

7. Evaluation of Adrenal Incidentaloma 3 questions need to be addressed: (1) Is the tumor hormonally active? (2) Does it have radiologic characteristics suggestive of a malignant lesion? (3) Does the patient have a history of a previous malignant lesion? The patient should be tested for evidence of hypercortisolism, aldosteronism (if hypertensive), and the presence of a pheochromocytoma.

8. Causes of Adrenal Incidentaloma A summary of the literature revealed that approximately : 80% of patients with incidentalomas had a nonfunctioning adenoma, 5% had subclinical Cushing syndrome (SCS), 5% had a pheochromocytoma, 1% had an aldosteronoma, <5% had an adrenocortical carcinoma (ACC), 2.5% had a metastatic lesion; the remaining incidentalomas were ganglioneuromas, myelolipomas, or benign cysts

13. Algorithm for confirmation of primary aldosteronism. APA = aldosterone-producing adenoma AVS = adrenal venous sampling; CT = computed tomography PAH = primary adrenal hyperplasia.

15. Pheochromocytoma (Panel A), A heterogeneous (vascular), contrast- enhanced, right adrenal mass, 4.5 cm in diameter (Panel A, arrow). The unenhanced CT attenuation was 40 Hounsfield units, and the contrast-medium washout was less than 50% at 10 minutes Benign Cortical Adenoma (Panel B) The unenhanced CT density (–10 Hounsfield units) and the contrast-medium washout of more than 50% at 10 minutes Adrenocortical Carcinoma (Panel C). A heterogeneous, contrast-enhanced, left adrenal mass (Panel C, arrow), 7.5 cm by 5.5 cm by 6.5 cm, The unenhanced CT attenuation was greater than 10 Hounsfield units, and the contrast-medium washout at 10 minutes was below 50%.

16. On abdominal CT in a 63-year-old man with a history of colon cancer, a mass, 1.0 cm in diameter, was found in the left adrenal gland (Panel A, arrow); an image obtained 3 months later shows marked growth of the mass (3 cm in diameter) (Panel B, arrow). After biochemical testing had ruled out pheochromocytoma, a diagnosis of metastatic colon cancer was confirmed on CT- guided fine-needle aspiration biopsy. On initial CT performed to evaluate nephrolithiasis in a 66-year- old man, a right adrenal mass, 1.7 cm by 1.3 cm (Panel C, arrow), was incidentally discovered. Two years later (after prostate cancer had been diagnosed), CT revealed that the right adrenal mass had enlarged (2.6 cm by 2.4 cm) (Panel D, arrow). Repeated CT after an additional 2 years of follow-up showed further growth of the mass (3.2 cm by 2.9 cm) (Panel E, arrow); another follow-up scan obtained 1 year later (i.e., 5 years after the mass was initially noted) showed further enlargement of the mass (3.8 cm by 3.3 cm) (Panel F, arrow). Patient developed HTN and DM later, Workup and surgery: pheochromocytoma On abdominal CT in a 69-year-old woman with pulmonary symptoms, a slightly thickened right adrenal gland was found (Panel G, arrow). Two years later, an image obtained to evaluate right upper quadrant abdominal pain showed a right adrenal mass, 8.0 cm by 6.5 cm by 6.0 cm (Panel H, arrow).

18. Recommendation: Thorough history and a physical examination Lab: 1-mg overnight dexamethasone suppression test, collect a 24-hour urinary specimen for measurement of fractionated metanephrines and catecholamines, and (because she has hypertension) measure the plasma aldosterone concentration and plasma renin activity. If the results of the initial hormonal testing are consistent with autonomous hormone secretion, unilateral laparoscopic adrenalectomy should be considered. The adrenal imaging should be reviewed with a radiologist. If the imaging phenotype suggests infection or metastatic disease, CT-guided fine-needle aspiration biopsy should be considered (after biochemical testing to rule out pheochromocytoma). If the results of hormonal testing are normal and the imaging features are consistent with benign disease, repeat the imaging studies at 6, 12, and 24 months and repeating the hormonal evaluation yearly for 4 years, even though there are no data from large, long-term studies to support these recommendations. Although the data are also scarce to suggest when surgery is necessary, consideration of adrenalectomy if the adrenal mass is 4 cm or greater in diameter or if the mass enlarges by 1 cm or more during the period of observation, or if evidence of autonomous hormonal secretion develops.

19. Pituitary Incidentaloma Definition: “pituitary incidentaloma” refers to a previously unsuspected lesion that is detected on an imaging study performed for reasons other than pituitary symptoms or disease. Epidemiology: Frequency of incidentally discovered signal abnormalities (<10 mm) varies among studies from 4 to 20 percent by CT and 10 to 38 percent by MRI.

21. In one study of 61 incidentally discovered sellar masses found among 1000 unselected autopsy specimens: there were 37 Rathke’s cleft cysts, 18 pituitary adenomas, 2 hyperplasia, 2 infarction, and 2 hemorrhage.

23. Pituitary adenomas are a common finding. Review of 29 autopsy studies that included over 18,000 pituitary glands showed: 1. The frequency of pituitary adenomas was approximately 10 percent 2.Nearly all of the adenomas were microadenomas (<10 mm). 3.The frequencies were similar for men and women, and across age groups in adults.

24. Natural History In a systematic review and meta-analysis of studies that included 865 patients with incidentally discovered, non functioning sellar masses, those ≥10 mm were approximately four times more likely to experience growth during follow-up than those <10 mm (incidence 12.5 versus 3.3 per 100 person-years, respectively)

29. Lesions 10 mm or larger These lesions should be evaluated as a symptomatic sellar mass of similar size. Vision should be evaluated clinically and by formal testing of acuity and fields. Patients undergo clinical and biochemical evaluation for both hormone hypersecretion and hypopituitarism. For hypersecretion: prolactin, insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and alpha subunit, and 24-hour urine free cortisol.

30. Patients with pituitary adenomas resulting in hormonal hypersecretion (eg, hyperprolactinemia, acromegaly, or Cushing's disease) should be treated as other patients with these disorders. For patients with gonadotroph adenomas and other clinically nonfunctioning lesions causing visual impairment or other neurologic symptoms, transsphenoidal surgery is the treatment of choice for initial therapy.

31. For patients with adenomas less than 20 mm without clinically important hormonal hypersecretion and no visual or other neurologic abnormalities, recommendation is careful observation. The patient should be monitored for size of the mass, visual changes, and hormonal hypersecretion in six and 12 months, then annually for several years, and perhaps less frequently thereafter. Hormonal hyposecretion should be treated by appropriate replacement.

32. Lesions less than 10 mm Patients with smaller lesions should be evaluated clinically for hormonal hypersecretion and biochemically for any hypersecretion suspected clinically. No evaluation for hormonal hyposecretion or visual abnormalities is necessary.

34. Source: AACE/AAES Adrenal Incidentaloma Guidelines, Endocr Pract. 2009;15 The Incidentally Discovered Adrenal Mass, William F. Young, Jr., M.D. NEJM 2007; 356:601-610 February 8, 2007February 8, 2007 CHEP Guideline 2014 Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline 2011, Journal of Clinical Endocrinology & Metabolism, 96(4):894–904, 2011. Am Fam Physician. 2013 Sep 1;88(5):319-327. UpToDate