1. Resident Conference Presented by Rachel Dunagin, M.D. November 15, 2005

2. Case Presentation  CC: Chronic Cough  Mr. DW, a 74yo WM, presented to PHD for direct admission by PCP: abnormal finding on imaging.  HPI: He complains of a cough  Productive of white mucus  Duration: past several months  3-4 wks PTA developed “pneumonia” – treated with Levaquin by PCP; febrile to 102  CXR was done at the time the antibiotic was prescribed and read as normal

3. Case Presentation  2d PTA returned to PCP office for routine physical exam  Patient continued to complain of “nagging” cough  Especially pronounced after meals  Productive of white mucus  Denied fever/chills  PCP ordered CT chest

4. Patient History  PMHx:  Cough 3/05 thru present (6/05)  HTN  Arthritis  Superficial “clot” of LE 2001  PSHx:  Left ear surgery  Appendectomy  All:  NKDA  Meds:  Lotensin/HCTZ 20/12.5  Benzepril 20  Aspirin 81  Tums  Flaxseed Oil  Vitamin E  Claritin D.  SocHx:  Married with 4 kids  Retired from DISD  Denies tobacco or drugs  Rare Etoh  FamHx:  sister/brother/mom-HTN  dad-CVA  ROS:  Weight loss (5 pounds in 3wks)  Decreased appetite  Edema BLE  Cough  otherwise negative

5. Physical Exam  Vital Signs: stable, afebrile  HEENT: NC/AT, pupils equal and reactive, EOMI, nares patent, OP clear  Neck: supple, no JVD, no LAD, no thyromegaly  Heart: RRR, no m/g/r  Lungs: CTAB, no w/c/r  Abd: soft, NT/ND, NABS, no HSM  Ext: 1+ edema LLE, trace RLE, 2+ pulse, neg Homan’s sign

6. Labs (from PCP’s office)  Na 142 K 4.1 Cl 103 Bicarb 26 BUN 22 Cr 1.6 Glc 138 Ca 9.4 TP 7.1 Alb 4.1 Glob 3 AlkP 78 AST 22 ALT 14 TB 0.7  WBC 6.4 Hgb 14.2 Hct 41.8 MCV 96 Plt 239  TSH 2.35  TG 120 Chol 181 HDL 43 LDL 114  EKG NSR 74 + PVC, no Q waves or ST changes  UA: negative  Imaging report

7. CT Chest: done 1 day prior to admission

8. Report of CT Chest: -clot in right superior pulmonary artery -& in second order branches of upper & lower lobes. -No left- sided pulmonary emboli are appreciated. Upon Admission CT Angio done: -filling defects seen within the right upper and lower lobe pulmonary arteries with extension into the second order branches as seen previously. - & filling defect within a segmental branch supplying the left lower lobe. 3 Pulmonary Emboli 3 Pulmonary Emboli

9. 30.6 HUs

10. A low density mass measuring approximately 3 cm in diameter is noted. The CT attenuation is approximately 28 Hounsfield units. Adrenal adenoma would be a possibility but cannot be confirmed.

11. Adrenal Incidentaloma: Introduction  What is an adrenal incidentaloma and why should we care?  Definition: “Clinically inapparent adrenal mass detected through imaging for non-adrenal disease”  First described approx 20 years ago

12. Is it common?  Based on autopsy reports, adrenal masses are AMONG THE MOST common tumors in humans  Found in ~3% of 50 year olds  Found in up to 10% of elderly patients  Advances in imaging (including CT, MRI, US) may reveal even higher numbers

13. So…is it time to panic ?

14.  NO  NO …Most adrenal masses cause no serious health problems  Approx 1 of every 4000 is malignant

15. Trivia: W hich adrenal is affected more frequently?  US studies show right adrenal more often affected  Likely because of better ultrasound visualization of right adrenal gland  Autopsy and CT studies show both adrenal equally affected

16. Outline  Causes, Prevalence, Natural History  Diagnostic Evaluation  Treatment, Follow-up  Bottom Line for the PCP  Conclusion of Case Presentation

17. Prevalence  At autopsy, <1% in patients <30 years old ~3% in 50 year olds Up to 10% in elderly  Women > Men ? if this reflects sex differences in undergoing imaging procedures

18. Causes  Benign Adrenocortical Masses  Pheochromocytoma  Adrenocortical carcinoma  Metastases  Other

19. Benign Adrenocortical Masses (Adenoma)  Do not degenerate into malignant lesions  Incidence increases with age  Its small size makes it difficult to differentiate from focal hyperplasia and accessory cortical nodules

20. Benign Adrenocortical Masses (Adenoma)  Higher incidence in patients with congenital adrenal hyperplasia (82% in homozygous, 45% in heterozygous)  Size variable: 1.4 – 9cm with mean of 3.3 cm  Majority are non-hypersecretory, but 5- 47% secrete cortisol and 1.6-3.3% secrete mineralcorticoids. Extremely rarely secrete androgens/estrogens

21. Pheochromocytoma  Catecholamine-producing tumor  Hypersecretion of norepinephrine, epinephrine and dopamine  Classic Triad: episodic headache, diaphoresis, and palpitations (tachycardia/anxiety)  Half have paroxysmal hypertension, most of the rest have what appears to be essential hypertension.

22. Pheochromocytoma  May see encephalopathy, retinopathy and proteinuria associated with malignant hypertension  When associated with MEN2 syndrome  1/2 have symptoms  1/3 have hypertension

23. Pheochromocytoma: Other Symptoms  Pallor  Orthostatic hypotension  Visual blurring  Papilledema  Weight loss  Polyuria  Polydipsia  Increased erythrocyte sedimentation rate (ESR)  Psychiatric disorders  Dilated cardiomyopathy  Hyperglycemia  Insulin resistance  Impaired glucose tolerance  Type 2 diabetes mellitus

24. Pheochromocytoma  Account for 1.5 – 33% of incidentalomas  Mayo Clinic reviewed 40,078 autopsies between 1928 and 1977  Pheochromocytoma found in 0.13%  Only diagnosed in 24% while alive  Histology: large pleiomorphic chromaffin cells  10-13% are malignant  However no widely accepted pathological criteria to differentiate benign from malignant exists.  Thus, metastases are the only irrefutable proof of malignancy

25. Pheochromocytoma  90% located in adrenal glands  10% in paraaortic sympathetic chain, aortic bifurcation, and urinary bladder.  Bilateral in 10% of pts (esp in familial pheochromocytomas associated with MEN IIA and IIB)

26. Adrenocortical carcinoma  Rare  Incidence is 0.6 – 2 cases per million per year  Interestingly, Southern Brazil’s incidence is 10x higher (reasons unknown).  Represents 0.02 -0.2% of all cancer- related deaths  Bimodal age distribution: 1 st and 5 th decades  Functional or nonfunctional  Functional tumors: Females > Males  Nonfunctional tumors: Males > Females

27. Functional Tumors  Androgen-secreting tumors resulting in virilization - commonly in kids (84%), less in adults (<10%)  Estrogen-secreting tumors resulting in feminization are rare (<10%)  Hypercortisolism resulting in Cushing’s syndrome (45% adults vs 6% kids) or mixed Cushing-virilizing syndrome (25% adults)  Isolated primary mineralcortisolism – rare (<10%)

28. Adrenocortical Carcinoma  Prognosis – poor; mean survival = 18 months  Based on extent of disease, not impacted by sex or functional status  Common Symptoms of Non-functional tumors: weight loss, weakness, anorexia, nausea, emesis, severe abdominal gas, and myalgia  Abdominal pain + palpable tumor = advanced disease  Fever = tumor necrosis, hemorrhage, or opportunistic infection

29. Metastases  75% of incidentalomas in cancer patients are metastatic lesions.  Virtually any primary can be origin  Large proportion from lymphoma, lung cancer (35%) and breast cancer (39%)  Melanoma, leukemia, kidney and ovarian cancer also common  Review of 1000 consecutive autopsies of patients with carcinoma, adrenal glands involved 27% of cases.

30. Other Etiologies  Adrenal Myelolipoma  Ganglioneuromas  Adrenal Hyperplasia  Hematomas  Angiomyelolipomas  Malignant Epithelial Carcinoma  Epithelioid Angiosarcoma  Neurinoma

31. FIG. 1. Top, Distribution of diagnosis by tumor size. Data from eight studies with 103 diagnoses determined by histology (35 40 41 47 53 55 72 73 ). Bottom, Distribution of 380 clinically inapparent adrenal masses by histological confirmed diagnosis. [Reproduced with permission from F. Mantero et al.: J Clin Endocrinol Metab 85:637–644, 2000 (60 ). © The Endocrine Society.]

32. Natural History  Large clinically inapparent adrenal masses (> 6cm)  25% = adrenal cortical carcinoma, thus poor outcomes (less than 50% 5 year survival)  treated surgically  Nonfunctioning adrenal masses  5-25% increase in size by at least 1 cm.  Risk of malig = 1/1000  Up to 20% develop hormone overproduction  Masses > 3 cm more likely to develop hyperfunction  Transformation rate of small (<3cm) nonfunctioning masses is low.

33. Diagnostic Evaluation 2 Main Questions 1.Hormonally active or nonfunctioning? 2.Malignant or benign?

34. Detailed Endocrine Evaluation  Goal: determine if patient has pheochromocytoma, subtle glucocorticoid excess, primary aldosteronism, virilizing or feminizing tumors.  History of or episodic hypertension, tachycardia, profuse sweating  Hirstuism, striae, central obesity, gynecomastia

35. Specific Hormonal Evaluation  Subclinical Hypercortisolism (5-47% of adrenal incidentalomas):  Overnight 1mg dexamethasone suppression test  Normal individual, 0800 serum cortisol concentration is suppressed to <139.75nmol/L (<5μg/dL).  >10 μg/dL are suggestive of Cushing’s syndrome  Levels inbetween are equivocal

36. Specific Hormonal Evaluation  Hyperaldosteronism (1.6-3.8% of adrenal incidentalomas):  If patient has HTN, check serum K and plasma aldosterone concentration:plasma renin activity ratio  Historically, spontaneous hypokalemia (<3.5mmol/L) was hallmark of primary aldosteronism in hypertensive pts.  But NORMOkalemic primary aldosteronism appears at frequency 7-38% higher than previously thought (Bravo 1994, Stowasser 2001 & 2003)

37. Specific Hormonal Evaluation  Of 90 normokalemic patients with adrenal incidentaloma and HTN, at least 5.5% were found to have primary aldosteronism (Bernini 2002)  If Aldosterone(μg/dL):Renin(μg/mL/hr) > 30 & plasma aldosterone concentration is >0.5nmol/L – highly suggestive of autonomous aldosterone production

38. Specific Hormonal Evaluation  Note patients with kidney failure and those on Beta blockers and antisympathetic agents that may result in false positives by reducing plasma renin levels, or calcium channel blockers that may increase plasma renin and decrease aldosterone.  Additional Tests: 25mg Captopril Test, Salt- loading tests, or fludrocortisone suppression test confirm the diagnosis; Elevated level urinary excretion of methyloxygentaed cortisol metabolites (18- hydroxycortisol and 18-oxo-cortisol).

39. Specific Hormonal Evaluation  Pheochromocytoma:  Elevated 24hr urinary excretion of free catecholamines (norepinephrine and epinephrine) or catecholamine metabolites [vanillylmandelic acid (VMA) and total metanephrines]

40. Specific Hormonal Evaluation  Plasma free metanephrines (normetanephrine and metanephrine) have good specificity and sensitivity and are recommended screening tests; however plasma catecholamines are not recommended due to poor sensitivity and specificity leading to false positives  Caution: Acetaminophen use interferes with assays of plasma free metanephrines, results in false-positive tests  Other possible tests: pharmacologic testing with glucagon or clonidine

41. Pheochromocytoma Upper Reference Limit Sensitivity (%)Specificity (%) Plasma (nmol/d) Free metanephrines 0.3 (0.6) 1 9982 Catecholamines0.5 (2.9) 2 9272 Urine (µmol/d) Fractionated metanephrines 9745 Female0.7 (1.7) 1 Male1.2 (3.0) 1 Catecholamines0.1 (0.5) 2 9175 Total metanephrines 68889 VMA407786 1 Metanephrine (Normetanephrine) 2 Epinephrine (Norepinephrine)

42. Wait.. What was this about Clonidine and Glucagon?  Clondine Suppression Test  Clonidine, a central alpha-2 agonist, normally suppresses sympathetic nervous system activity, but does not decrease catecholamine secretion from pheochromocytoma  If plasma norepinephrine levels decrease >50% or to less than 2.96nmol/L after clonidine = normal response.  If remains consistently elevated before and after clonidine, indicates pheochromocytoma.  False-positives if on diuretics or tricyclic antidepressants  Serious complication: hypotension

43. Wait.. What was this about Clonidine and Glucagon?  Glucagon Stimulation Test  Used when high plasma levels of normetanephrine or metanephrine and normal to slightly elevated plasma catecholamine levels  Give 1-2mg IV glucagon, after 2 minutes > 3x increase in norepinephrine indicates pheochromocytoma with high specificity, simultaneous increase in blood pressure may occur.  Test is not sensitive, thus negative result does not exclude the diagnosis  Serious complication: hypertensive crisis, so only done with experience operator

44. Specific Hormone Evaluation  Sex Hormone-secreting Masses:  Benign adenomas rarely secrete sex hormones, so routine evaluation of testosterone and estradiol is not recommended in patients with adrenal masses  Exception = Clinically suspected virilizing or feminizing tumor or if adrenocortical carcinoma is suspected based on radiology or history

45. Imaging  CT  MRI  US

46. CT  Lesions <4cm usually benign  Adrenal adenomas  small, homogeneous, well-defined lesions with clear margins, constant in size  contain large amount intracytoplasmic lipid  allows a quantitative evaluation by measurement of the attenuation value of the lesions (expressed as Hounsfield units)  usually have < 18 HUs on noncontrast CTs.  100% Specificity with 68-89% sensitivity at 20-21 HUs.  Conclusion of several studies, no further w/u necessary if < 10 HUs (suggests lipid-rich adrenal adenoma)

47. CT  The problem: Lipid-poor adenomas represent 10-40% of adenomas  They have a higher attenuation value than lipid-rich adenomas  Therefore, not all adenomas can be characterized using non-contrasted CT  Solution: 3-minute delayed contrast CT using thresholds between 64 and 70HUs to differentiate adenoma from nonadenoma  Washout Method – calculate % enhancement washout after 10-15min delay. If relative washout is >40-50% = highly suggestive of benign mass (sensitivity 96%, specificity 100%), is lower relative washout value suggests malignancy.

48. FIG. 4. Radiological panel of an adrenal cortical adenoma. Findings in a 66-yr-old woman with a history of breast cancer. Panels A and B demonstrate the use of CT for calculation of the relative enhancement washout. A, The contrast-enhanced CT shows a left-sided 1.5-cm adrenal mass (arrow) with a mean attenuation of 32.9 HU. B, On the 12-min delayed image, the attenuation of the left adrenal (arrow) is 12.9 HU. The relative enhancement washout is calculated using the following equation: percentage of relative enhancement washout = (1 – delayed enhanced HU value/initial enhanced HU value) x 100. With a relative washout of (1 – 12.9 /32.9) x 100 = 61%, the delayed enhanced CT is indicative of an adrenal adenoma (196 215 )

49. CT (cont)  Lesions >6cm more likely to be malignant – consider surgery  Pheochromocytomas  Rounded or oval masses, density similar to liver on noncontrast CT

50. CT (cont)  Larger lesions show cystic component due to central necrosis or hemorrhage  10% have calcification  Are hypervascular, so have intense enhancement with contrast.  CT Sensitivity = 93-100%  However, nearly 1/3 show nonspecific appearance that may overlap with adrenocortical carcinoma

51. MRI  Malignant masses  Denser than benign masses because of higher fluid content  Therefore appear brighter on T2-weighted images  Useful in staging adrenal carcinomas  Especially extent of infiltration into IVC  Pheochromocytomas  Low T1 and bright T2 signal intensities  Central necrosis  Metastases  Hypointense compared to liver on T1-weighted images and hyperintense on T2-weighted images  Strong contrast enhancement with delayed washout after paramagnetic contrast injection

52. CT vs MRI  Trials comparing noncontrast MRI to combined non-contrast/contrast CT found superior, similar and inferior MRI test performance, depending on which technique was used (chemical-shift MRI, adrenal mass to reference organ ratio, etc) McNicholas 1995, vanErkel 1994, Krestin 1991, Schwartz 2000

53. CT vs MRI  Studies on qualitative comparison of test accuracy concluded that combined noncontrast/contrast MRI was superior to both combined noncontrast/contrast CT and noncontrast MRI alone. Krestin 1991

54. Ultrasound  Operator dependent  Compounding factors: obesity, overlying gas  Decreased sensitivity compared to CT/MRI

55. Ultrasound  1995 Suzuki reported series of 61 patients with adrenal masses  US correctly identified all adrenal tumors > 3cm  Identified 65% of masses < 3cm  CT/MRI identified 100%  Usefulness: follow-up benign lesions  On the horizon: EUS

56. Fine Needle Aspiration  Performed under CT or US guidance  Based on review of 8 studies investigating the test performance for FNA to diagnose adrenal masses:  Sensitivity 81-100%  Specificity 83-100% to diagnose malignancy  Higher sensitivity and accuracy if mass > 3 cm or needle > 19 gauge

57. Fine Needle Aspiration  No conclusions of risk of needle-track metastases from FNA biopsy of adrenal carcinoma can be drawn from present studies.  In total, 36 complications (4%) have been reported on 888 adrenal mass biopsies, including 26 complications that were potentially serious and 9 patients (1%) requiring in-hospital treatment.  Wide range of biopsy technique, incomplete/unclear reporting, and small study sizes make it difficult to evaluate the risk of biopsies.

58. Fine Needle Aspiration  May be useful in the diagnostic evaluation of patients with a history of malignancy (particularly lung, breast and kidney) and a suspicious adrenal mass on imaging (particularly if heterogeneous and >20HUs)  May be useful in the diagnostic evaluation of patients with a history of malignancy (particularly lung, breast and kidney) and a suspicious adrenal mass on imaging (particularly if heterogeneous and >20HUs).  Pheochromocytoma MUST be ruled out before FNA attempted due to potential of life-threatening hypertensive crisis

59. Surgery or NonSurgical Management?  Functional Lesions  Glucocorticoids, Mineralcorticoids, Adrenal sex hormones, Catecholamines  Confirmed biochemically  Adrenalectomy – Treatment of Choice  Or medical therapy  Inhibitors of adrenal cortical steroid hormone biosynthesis (ie in patients with Cushing syndrome who are poor surgical candidates)  Aldosterone antagonists for aldosterone- secreting tumors.

60. Surgery or NonSurgical Management?  Nonfunctional Lesion  Management is not straightforward  Silent Pheochromocytoma: high risk for hypertensive crisis thus should undergo adrenalectomy  Next question – Benign vs Malignant

61. Benign vs Malignant: A Question of Size  > 6cm: Excise the lesion  < 4 cm: low risk, unlikely to have malignant potential, not resected  Lesions between 4 and 6 cm, either close follow-up or adrenalectomy  Adrenalectomy strongly considered if rapid growth rate, decreased lipid content on imaging or other imaging findings suggestive of malignancy

62. Follow-up  Most adrenal lesions remain stable, but 5-25% enlarge and 3-4% decrease in size  Imaging – if not excised, lesion should be re- evaluated with CT in 6-12 months  If does not increase in size, no data to support further imaging.  Hormone excess may develop in up to 20% of patient during follow-up but is unlikely in patients smaller than 3cm.  Cortisol hypersecretion is the most common and is usually subclinical  Risk for tumor hyperfunction plateaus after 3-4 years

64. Bottom Line from NIH Conference  All patients with an incidentaloma should have a 1-mg dexamethasone suppression test and measurement of plasma free metanephrines.  Patients with hypertension should also undergo measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio.  A homogeneous mass with a low attenuation value (<10 HUs) on computed tomography is probably a benign adenoma.

65. Bottom Line from NIH Conference  Surgery should be considered in all patients with functional adrenal cortical tumors that are clinically apparent  All patients with biochemical evidence of pheochromocytoma should undergo surgery  Data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas

66. Bottom Line from NIH Conference  Recommendations for surgery based on tumor size are derived from studies not standardized for inclusion criteria, length of follow-up, or methods of estimating the risk for carcinoma. Nevertheless, patients with tumors >6cm usually are treated surgically, while those with tumors <4cm are generally monitored. In patients with tumors between 4 and 6cm, criteria in addition to size should be considered in the decision to monitor or proceed to adrenalectomy

67. Bottom Line from NIH Conference  The literature on adrenal incidentaloma has proliferated in the last several years. Unfortunately, the lack of controlled studies makes formulating diagnostic and treatment strategies difficult. Because of the complexity of the problem, the management of patients with adrenal incidentalomas will be optimized by a multidisciplinary team approach involving physicians with expertise in endocrino- logy, radiology, surgery and pathology. The paucity of evidence-based data highlights the need for well-designed prospective studies.

68. Bottom Line from NIH Conference  Open or laparoscopic adrenalectomy is an acceptable procedure for resection of an adrenal mass. The procedure choice will depend on the likelihood of an invasive adrenal cortical carcinoma, technical issues, and the experience of the surgical team.  In patients with tumors that remain stable on two imaging studies done over at least 6 months apart and do not exhibit hormonal hypersecretion over 4 years, further follow-up may not be warranted. Grumbach, M. M. et. al. Ann Intern Med 2003;138:424-429

69. Mr. DW Labs showed elevated urine catecholamines Cortisol, free, urine34.0 ug/d Epinephrine, urine39 ug/d (H) Dopamine, urine242 ug/d Norepinephrine, urine55 ug/d Metanephrines, urine1,677 ug/d (H) Normetanephrine, urine1,217 ug/d (H)  MRI was done. Diagnosed with Pheochromocytoma  Upon further questioning, denied any elevation of blood pressure, headaches, diaphoresis, palpitations, pallor  Placed on Alpha-blockers. Anti-coagulated for 3 PEs.  Eventually returned to hospital for scheduled Lap Adrenalectomy. No complications. Doing well.

70. References Barzon, Luisa. Risk Factors and Long-Term Follow-Up of Adrenal Incidentalomas. Journal of Clinical Endocrinology and Metabolism 84(2):520-526. Bravo, M. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochormocytoma. Endocrine Review 15:356-368. Grumbach, Melvin. NIH Conference: Management of Clinically Inapparent Adrenal Mass (“Incidentaloma”) Annals of Internal Medicine 138(5): 424- 430. Mansmann, Georg. The Clincally Inapparent Adrenal Mass: Update in Diagnosis and Management Endocrine Reviews 25(2): 309-340. Pacak, K. Recent Advances in genetics, localization, and treatment of pheochromocytoma. Annals of Internal Medicine 134:315-329 Slawik, Marc. Adrenal Incidentaloma. www.endotext.com (ch.20)www.endotext.com Sjoberg, RJ. The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls. Archives of Internal Medicine. 152:1193- 1197. www.vectorpoint.ws/illuspages/panic.html Young, William. The Adrenal Incidentaloma. www.Uptodate.comwww.Uptodate.com

71. End of Show

72. Other: Adrenal Myelolipoma  Benign, composed of fat and hematopoietic tissue  Majority are functionally inactive  Patients asymptomatic, but can become symptomatic if large (pain/ retroperitoneal hemorrhaging)  Slow growing, <5cm  No therapy unless:  rare, large type (can be >5.5kg)  symptomatic  or rapid growing, then surgery is curative.