Surgery for Disorders of the Adrenal Gland

Alexander Kutikov, MD and Robert G. Uzzo, MD

written for www.urologymatch.com:

http://www.urologymatch.com/adrenalectomy

Fox Chase Cancer Center Philadelphia, PA www.foxchase.org Background

The adrenal glands serve a critical function in physiological homeostasis. Surgical indications for adrenalectomy vary from resection of benign and malignant neoplasms to surgical elimination of functional adrenal tissue in cases where excess adrinocorticotropic hormone (ACTH) levels cannot be controlled through other means. In order to avoid

overtreatment and minimize risks, the adrenal surgeon must be familiar with adrenal physiology, adrenal neoplasm biology, retroperitoneal anatomy, and nuances of adrenal imaging. Furthermore, he/she also must be a full-fledged participant in multi-disciplinary care of these often complex patients. This overview provides a summary of the main surgical indications for adrenalectomy, summarizes the clinical approach to evaluating incidental adrenal masses, and reviews perioperative considerations in patients with adrenal disease.

Surgical Indications Suspicion of Malignancy The vast majority (>85%) of incidentally-discovered adrenal lesions prove to be benign adenomas 1,2. Indeed, adrenocortical carcinomas (ACC) are exceedingly rare with an incidence of approximately 1 per million 3-5. Differentiation between the two lesions is critical and pivots on 3 factors: (1) size, (2) imaging characteristics, and (3) growth kinetics. Median diameter of incidentally-discovered adrenal lesions is 3cm 6. Lesions 6cm must be resected regardless of imaging characteristics, since >30% will prove malignant 7. Definitive diagnosis of asymptomatic

myelolipoma denoted by radiographic presence of macroscopic fat is the one general exception to this rule 8. Incidental adrenal lesions 4cm require thorough metabolic evaluation and follow-up imaging; however, routine resection is unnecessary 9,10. Lesions between 4 and 6 cm in size are malignant in approximately 6% of cases, and most experts suggest resection in individuals who are at an acceptable risk for surgery 1,2,6,11,12. Indeed, this 4 cm threshold has been reported to afford a 93% sensitivity and 42% specificity for diagnosis of malignant adrenal lesions 6. Every surgeon that tackles adrenal disease must be fluent in radiographic evaluation of adrenal pathology. Large, heterogeneous, poorlycircumscribed masses should immediately raise suspicion; however, most adrenal lesions are small, homogeneous, and have regular contours 13. Indeed, attention to radiographic detail is especially important for non-functional lesions 4 cm that do not meet size criteria for resection. In addition to assessment of size, homogeneity, and contours, imaging affords determination of lesion density. Adenomas are differentiated from other lesions by assessment of intra-cytoplasmic lipid content. Non-contrast computed tomography (CT) affords near 100% specificity for diagnosis of adrenal adenomas 14. Indeed essentially all lesions that exhibit attenuation of <10 HU on unenhanced CT are adenomas 9. The sensitivity of this 10 HU

radiographic cutoff, however, is imperfect, and some 30% of adrenal adenomas will register attenuation above this level 15-17. Such lesions are deemed indeterminate; however, the majority of these lipid-poor adenomas that exhibit a density above 10HU can still be differentiated from other adrenal pathology using the so-called washout imaging technique. Lesions that lose more than 40-60% of gained enhancement on delayed contrast-enhanced CT imaging (i.e. those that washout) should be managed as adenomas, since specificity of this technique approaches 100% 15-18. Magnetic resonance imaging also can be useful for characterizing adrenal neoplasms. Using opposed phase chemicalshift strategies, intracellular fat content of the adrenal lesions can be gauged 19. Loss of signal intensity on out-of-phase sequences when compared to in-phase images demonstrates abundance of cytoplasmic lipid and identifies the lesion as an adenoma 13,20. Although MR chemical-shift imaging is arguably superior to unenhanced CT in characterizing indeterminate lesions 21,22, CT washout studies are the gold standard imaging technique in characterizing lipid-poor adenoma19,23-25. Indeed, MR-based washout techniques are not clinically useful, since gadolinium contrast agents do not possess the dose-dependent signal intensity properties that are inherent in iodinated contrast agents (i.e. gadolinium contrast agents do not washout) 19. Malignant transformation of adrenal incidentalomas has been estimated at 1 in 1000 7, and current recommendations suggest that all adrenal lesions that

are not resected should be reimaged at 6, 12, and as possible 24 months following diagnosis 2,9. Approximately 5% to 9% of adrenal masses grow at least 1 cm in diameter upon interval follow-up 7,26, and such growth has been suggested as a trigger for resection 2. Nevertheless, patients who are taken to the operating room due to interval growth of an adrenal lesions must be candidly counseled that the chances of uncovering malignant pathology are extremely low 2. Functional Adrenal Mass As a general rule, all adrenal lesions that exhibit metabolic hyperactivity require resection. Indeed metabolic testing is recommended for all adrenal incidentalomas, since over 11% will show metabolic activity upon evaluation
9

. Cortisol-producing adenomas are found in 5.3% of cases, while

aldosteronomas are uncovered in approximately 1% of patients with incidentally-discovered adrenal lesions. Furthermore, some 5.1% of incidentalomas will prove to be pheochromoctyomas 1,2. Isolated Adrenal Metastasis A wide range of malignancies metastasizes to the adrenal gland 27,28. In fact, retrospective series reveal that in patients with history of previous malignancy, 50% of new adrenal lesions prove metastatic 28,29. Isolated

metastases to the adrenal are at times resected; however, such cases require a thoughtful multidisciplinary approach 28,30-34.

Cushings Syndrome In addition to treatment of ACTH-independent Cushings Syndrome such as resection of cortisol-producing adrenal adenoma, the adrenal surgeon is at times called upon to treat patients with ACTH-dependent conditions. For instance, transsphenoidal surgical resection fails in 20 to 40% of patients with Cushings Disease 35,36. In addition, relapse is seen in up to 25% of patients whose resection of an ACTH-producing pituitary adenoma is initially deemed successful37. When at least one attempt at neurosurgical correction has failed, bilateral adrenalectomy may be considered by the multi-disciplinary team treating the patient. Although rapid resolution of hypercortisolism can be expected, the adrenal surgeon must council the patient regarding life-long need for both glucocorticoid and mineralocorticoid replacement and a 10 to 30% chance of developing the Nelson-Salassa syndrome (aka Nelson syndrome) 3841

. The syndrome is characterized by complications such as ocular chiasm

compression, oculomotor deficiencies, and rarely a rise in intracranial pressure, due to progressive growth of the pituitary adenoma in the absence of appropriate glucocorticoid feedback 41. Also, one is wise to warn the patient

regarding the remote possibility of leaving residual functional adrenal tissue at the time of the bilateral adrenalectomy 42. Approximately 10% of Cushings Syndrome is caused by ectopic secretion of ACTH by malignant tissues 43. Although resection of the primary ACTH-producing tumor is ideal, such approach is possible in only ~10% of patients 44. Indeed, bilateral adrenalectomy is a therapeutic option in the appropriately-selected patient 43. Work-Up of Adrenal Incidentaloma A metabolic evaluation is necessary for all adrenal incidentalomas, since over 10% are metabolically active 9. Hypersecretion of cortisol, and catecholamines should be evaluated in all-comers, while aldosterone hypersecretion only needs to be ruled out in those with history of hypertension 2,9. The adrenal surgeon should have a low-threshold in recruiting expertise from endocrine specialists. Such consultation is especially important when initial first-line testing returns positive results, since confirmatory testing is often sophisticated. Initial Evaluation for Hypercortisolism Approximately 5-8% of adrenal masses will exhibit cortisol hypersecretion (aka ACTH independent Cushings Syndrome) upon work-

up 1,7. In clinical practice, after exogenous steroid use is ruled-out, 3 main tests are employed: (1) the overnight low-dose dexamethasone suppression test (OST), (2) the late-night salivary cortisol test, and (3) the 24-hour urinary-free cortisol evaluation (UFC). In general, all three tests provide relatively equivalent test characteristics 45; however, some reports and guidelines suggest that the UFC may not be appropriate for screening patients with adrenal incidentaloma due to inferior sensitivity 46-48. Again, if this first-line testing is positive, consultation with endocrinology is advised. Initial Evaluation for Hyperaldosteronism Hyperaldosteronism (aka Conns syndrome) stemming from an adrenal mass is exceedingly rare, as the condition is found in only ~1% of adrenal incidentalomas 1,49. Some evidence does exist, however, that up to 5% of patients with newly diagnosed hypertension will be found to have an alodosterone-secreting adenoma upon work-up50. Therefore, all patients with history of hypertension who are found to have an adrenal incidentaloma should be tested for aldosterone hypersecretion. First-line screening consists of obtaining a morning plasma aldosterone to renin ratio (ARR). In the setting of an aldosterone level of 15 ng/mL, an ARR of 20 is suggestive of Conns syndrome. Confirmatory testing is mandatory and should involve

endocrinologic experts49,51. Although beyond the scope of this chapter, adrenal vein sampling is often advisable 52. Initial Evaluation for Catecholamine Hypersecretion Approximately 5% of patients with adrenal incidentaloma will prove to have pheochromocytoma 2. Indeed, pheochromocytoma must be ruled out in all patients with adrenal mass, even in those in whom metastases are strongly suspected 53. Arguments that the work-up can be omitted in patients with masses that exhibit a density less than 10HU are weakened by isolated reports of rare low-density pheochromocytomas that possess an unenhanced attenuation of <10HU and demonstrate brisk contrast washout 54,55. Clinical first-line testing for pheochromocytoma should include either free fractionated plasma metanephrines or 24-hour urinary fractionated metanephrine levels 56,57. Although there is currently a debate regarding which test is superior, both evaluations afford excellent sensitivity and specificity 2,58. As already stressed, endocrinological expertise is invaluable in patients in whom first-line testing is positive. Follow-up Metabolic Testing Experts suggest that all patients with adrenal incidentaloma who have an initially negative metabolic work-up receive annual metabolic screening for

3 to 4 years following diagnosis9. Nevertheless, the percentage of patients who will develop de-novo metabolic activity is small (~2%) 7. Perioperative Considerations By and large, periooperative care of patients undergoing adrenalectomy is routine. Although recent data suggest that biochemical adrenal insufficiency following adrenalectomy may be common (up to 22%), clinically significant adrenal insuffiency appears to be rare. Albeit rare, it is possible, and a high index of suspicion is mandatory. Patients with Cushing Syndrome in whom the contralateral gland can be suppressed are at an especially high risk and should be monitored closely 46. Prior to bilateral adrenalectomy, proactive therapy must be appropriately instituted, since Addisonian crises may result in death59. Patients undergoing resection of pheochromocytoma also require thoughtful perioperative management. Thought leaders recommend that all

patients with pheochromocytoma undergo pre-operative catecholamine blockade, regardless of the severity of symptomatology 60. Indeed today perioperative mortality rates in patients with pheochromocytoma are less than 3% 61. In contrast, prior to routine perioperative blockade, mortality rates as high as 50% were reported62.

Alpha-blockade with or without alpha-methyltyrosine an inhibitor of catecholamine biosyntheis is the most widely recommended pre-operative regimen60. Calcium channel blockade for patients with mild symptomatology also has been popularized by some authors63. In addition to catecholamine blockade, some experts recommend routine pre-operative cardiac evaluation that includes echocardiography to exclude presence of catecholamine-induced cardiomyopathy 64. Furthermore, establishment of an adequate intravascular

volume is paramount. Patients are encouraged salt and fluid intake, once catecholamine blockade is started, and some institutions pre-admit patients a day prior to surgery for aggressive intravenous fluid administration61. In the post-operative period, the patient must be monitored for hypotension and hypoglycemia. The former can be due to lasting effects of the pre-operative blockade, while the latter is caused by inhibition of insulin release during a high catecholamine state62,64. Indeed, some centers monitor patients overnight in the intensive care unit following surgery for pheochromocytoma61.

Robert G. Uzzo, M.D., F.A.C.S. G. Willing "Wing" Pepper Chair in Cancer Research Professor and Chairman, Department of Surgery Fox Chase Cancer Center

Alexander Kutikov, MD Assistant Professor of Urologic Oncology Department of Surgical Oncology Fox Chase Cancer Center

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REFERENCES:
1. Young WF, Jr.: Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29:159-85, x, 2000 2. Young WF, Jr.: The Incidentally Discovered Adrenal Mass. N Engl J Med 356:601-610, 2007 3. Aubert S, Wacrenier A, Leroy X, et al: Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 26:1612-9, 2002 4. Fassnacht M, Allolio B: Clinical management of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 23:273-89, 2009 5. Roman S: Adrenocortical carcinoma. Curr Opin Oncol 18:36-42, 2006 6. Mantero F, Terzolo M, Arnaldi G, et al: A Survey on Adrenal Incidentaloma in Italy, 2000, pp 637-644

7. Barzon L, Sonino N, Fallo F, et al: Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 149:273-285, 2003 8. Han M, Burnett AL, Fishman EK, et al: The Natural History and Treatment of Adrenal Myelolipoma. The Journal of urology 157:1213-1216, 1997 9. Grumbach MM, Biller BMK, Braunstein GD, et al: Management of the Clinically Inapparent Adrenal Mass ("Incidentaloma"). Ann Intern Med 138:424-429, 2003 10. Cicala MV, Sartorato P, Mantero F: Incidentally discovered masses in hypertensive patients. Best Practice & Research Clinical Endocrinology & Metabolism 20:451-266, 2008 11. Barry MK, van Heerden JA, Farley DR, et al: Can Adrenal Incidentalomas Be Safely Observed? World Journal of Surgery 22:599-604, 1998 12. Thompson GB, Young Jr WF: Adrenal incidentaloma. Current Opinion in Oncology 15:84-90, 2003 13. Korobkin M, Giordano TJ, Brodeur FJ, et al: Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 200:743-7, 1996 14. Hamrahian AH, Ioachimescu AG, Remer EM, et al: Clinical Utility of Noncontrast Computed Tomography Attenuation Value (Hounsfield Units) to Differentiate Adrenal Adenomas/Hyperplasias from Nonadenomas: Cleveland Clinic Experience. J Clin Endocrinol Metab 90:871-877, 2005 15. Szolar DH, Korobkin M, Reittner P, et al: Adrenocortical Carcinomas and Adrenal Pheochromocytomas: Mass and Enhancement Loss Evaluation at Delayed Contrast-enhanced CT. Radiology 234:479-485, 2005 16. Korobkin M, Brodeur FJ, Francis IR, et al: CT time-attenuation washout curves of adrenal adenomas and nonadenomas. Am. J. Roentgenol. 170:747-752, 1998 17. Pena CS, Boland GWL, Hahn PF, et al: Characterization of Indeterminate (Lipid-poor) Adrenal Masses: Use of Washout Characteristics at Contrastenhanced CT. Radiology 217:798-802, 2000 18. Heinz-Peer G, Memarsadeghi M, Niederle B: Imaging of adrenal masses. Curr Opin Urol 17:32-8, 2007 19. Hussain HK, Korobkin M: MR imaging of the adrenal glands. Magn Reson Imaging Clin N Am 12:515-44, vii, 2004 20. Namimoto T, Yamashita Y, Mitsuzaki K, et al: Adrenal Masses: Quantification of Fat Content with Double-Echo Chemical Shift In-Phase and Opposed-Phase FLASH MR Images for Differentiation of Adrenal Adenomas. Radiology 218:642-646, 2001 21. Israel GM, Korobkin M, Wang C, et al: Comparison of Unenhanced CT and Chemical Shift MRI in Evaluating Lipid-Rich Adrenal Adenomas. Am. J. Roentgenol. 183:215-219, 2004

22. Haider MA, Ghai S, Jhaveri K, et al: Chemical Shift MR Imaging of Hyperattenuating (>10 HU) Adrenal Masses: Does It Still Have a Role? Radiology 231:711-716, 2004 23. Caoili EM, Korobkin M, Francis IR, et al: Delayed Enhanced CT of LipidPoor Adrenal Adenomas. Am. J. Roentgenol. 175:1411-1415, 2000 24. Park BK, Kim CK, Kim B, et al: Comparison of Delayed Enhanced CT and Chemical Shift MR for Evaluating Hyperattenuating Incidental Adrenal Masses. Radiology 243:760-765, 2007 25. Boland GW, Blake MA, Hahn PF, et al: Incidental adrenal lesions: principles, techniques, and algorithms for imaging characterization. Radiology 249:756-75, 2008 26. Libe R, Dall'Asta C, Barbetta L, et al: Long-term follow-up study of patients with adrenal incidentalomas. Eur J Endocrinol 147:489-494, 2002 27. Bullock WK, Hirst AE, Jr.: Metastatic carcinoma of the adrenal. Am J Med Sci 226:521-4, 1953 28. Lenert JT, Barnett CC, Kudelka AP, et al: Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 130:1060-1067, 2001 29. Frilling A, Tecklenborg K, Weber F, et al: Importance of adrenal incidentaloma in patients with a history of malignancy. Surgery 136:1289-96, 2004 30. Tanvetyanon T, Robinson LA, Schell MJ, et al: Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J Clin Oncol 26:1142-7, 2008 31. Mercier O, Fadel E, de Perrot M, et al: Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer. J Thorac Cardiovasc Surg 130:136-40, 2005 32. Collinson FJ, Lam TK, Bruijn WM, et al: Long-term survival and occasional regression of distant melanoma metastases after adrenal metastasectomy. Ann Surg Oncol 15:1741-9, 2008 33. Mittendorf EA, Lim SJ, Schacherer CW, et al: Melanoma adrenal metastasis: natural history and surgical management. Am J Surg 195:363-8; discussion 368-9, 2008 34. O'Malley RL, Godoy G, Kanofsky JA, et al: The necessity of adrenalectomy at the time of radical nephrectomy: a systematic review. J Urol 181:2009-17, 2009 35. Pivonello R, De Martino MC, De Leo M, et al: Cushing's Syndrome. Endocrinol Metab Clin North Am 37:135-49, ix, 2008 36. Newell-Price J, Bertagna X, Grossman AB, et al: Cushing's syndrome. Lancet 367:1605-17, 2006 37. Patil CG, Prevedello DM, Lad SP, et al: Late recurrences of Cushing's disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab 93:358-62, 2008

38. Chow JT, Thompson GB, Grant CS, et al: Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. Clin Endocrinol (Oxf) 68:513-9, 2008 39. Vella A, Thompson GB, Grant CS, et al: Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 86:1596-9, 2001 40. Lacroix A: Evaluation of bilateral laparoscopic adrenalectomy in adrenocorticotropic hormone-dependent Cushing's syndrome. Nat Clin Pract Endocrinol Metab 4:310-1, 2008 41. Assie G, Bahurel H, Coste J, et al: Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab 92:172-9, 2007 42. Kemink L, Hermus A, Pieters G, et al: Residual adrenocortical function after bilateral adrenalectomy for pituitary-dependent Cushing's syndrome. J Clin Endocrinol Metab 75:1211-4, 1992 43. Porterfield J, Thompson G, Young W, et al: Surgery for Cushings Syndrome: An Historical Review and Recent Ten-year Experience. World Journal of Surgery 32:659-677, 2008 44. Aniszewski JP, Young Jr WF, Thompson GB, et al: Cushing Syndrome Due to Ectopic Adrenocorticotropic Hormone Secretion. World Journal of Surgery 25:934-940, 2001 45. Elamin MB, Murad MH, Mullan R, et al: Accuracy of diagnostic tests for Cushing's syndrome: A systematic review and metaanalyses. Journal of Clinical Endocrinology & Metabolism 93:1553-1562, 2008 46. Tsagarakis S, Vassiliadi D, Thalassinos N: Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. J Endocrinol Invest 29:471-82, 2006 47. Mitchell IC, Auchus RJ, Juneja K, et al: "Subclinical Cushing's syndrome" is not subclinical: improvement after adrenalectomy in 9 patients. Surgery 142:900-5; discussion 905 e1, 2007 48. Nieman LK, Biller BM, Findling JW, et al: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:1526-40, 2008 49. Young WF: Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 66:607-18, 2007 50. Rossi GP, Bernini G, Caliumi C, et al: A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48:2293-300, 2006 51. Mulatero P, Stowasser M, Loh K-C, et al: Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents. J Clin Endocrinol Metab 89:1045-1050, 2004 52. Young WF, Stanson AW, Thompson GB, et al: Role for adrenal venous sampling in primary aldosteronism. Surgery 136:1227-35, 2004 53. Tsvetov G, Shimon I, Benbassat C: Adrenal incidentaloma: clinical characteristics and comparison between patients with and without extraadrenal malignancy. J Endocrinol Invest 30:647-52, 2007

54. Blake MA, Krishnamoorthy SK, Boland GW, et al: Low-Density Pheochromocytoma on CT: A Mimicker of Adrenal Adenoma. Am. J. Roentgenol. 181:1663-1668, 2003 55. Blake MA, Kalra MK, Sweeney AT, et al: Distinguishing Benign from Malignant Adrenal Masses: Multi-Detector Row CT Protocol with 10-Minute Delay. Radiology 238:578-585, 2005 56. Pacak K, Eisenhofer G, Ahlman H, et al: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3:92-102, 2007 57. Grossman A, Pacak K, Sawka A, et al: Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci 1073:332-47, 2006 58. Eisenhofer G, Siegert G, Kotzerke J, et al: Current Progress and Future Challenges in the Biochemical Diagnosis and Treatment of Pheochromocytomas and Paragangliomas. Horm Metab Res 40:329-337, 2008 59. Asari R, Scheuba C, Kaczirek K, et al: Estimated Risk of Pheochromocytoma Recurrence After Adrenal-Sparing Surgery in Patients With Multiple Endocrine Neoplasia Type 2A. Arch Surg 141:1199-1205, 2006 60. Pacak K: Preoperative Management of the Pheochromocytoma Patient. J Clin Endocrinol Metab 92:4069-4079, 2007 61. Lenders JW, Eisenhofer G, Mannelli M, et al: Phaeochromocytoma. Lancet 366:665-75, 2005 62. Pacak K, Linehan W, Eisenhofer G, et al: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Annals of Internal Medicine 134:315 - 329, 2001 63. Ulchaker JC, Goldfarb DA, Bravo EL, et al: SUCCESSFUL OUTCOMES IN PHEOCHROMOCYTOMA SURGERY IN THE MODERN ERA. The Journal of urology 161:764-767, 1999 64. Kinney MAO, Narr BJ, Warner MA: Perioperative management of pheochromocytoma. Journal of Cardiothoracic and Vascular Anesthesia 16:359369, 2002