Surgery for Disorders of the Adrenal Gland
Alexander Kutikov, MD and Robert G. Uzzo, MD
Fox Chase Cancer Center
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.
Suspicion of Malignancy
The vast majority (>85%) of incidentally-discovered adrenal lesions prove to be benign adenomas1,2. Indeed, adrenocortical carcinomas (ACC) are exceedingly rare with an incidence of approximately 1 per million3-5. 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 3cm6. Lesions ≥6cm must be resected regardless of imaging characteristics, since >30% will prove malignant7. Definitive diagnosis of asymptomatic myelolipoma – denoted by radiographic presence of macroscopic fat – is the one general exception to this rule8. Incidental adrenal lesions ≤4cm require thorough metabolic evaluation and follow-up imaging; however, routine resection is unnecessary9,10. 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 surgery1,2,6,11,12. Indeed, this 4 cm threshold has been reported to afford a 93% sensitivity and 42% specificity for diagnosis of malignant adrenal lesions6.
Every surgeon that tackles adrenal disease must be fluent in radiographic evaluation of adrenal pathology. Large, heterogeneous, poorly-circumscribed masses should immediately raise suspicion; however, most adrenal lesions are small, homogeneous, and have regular contours13. 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 adenomas14. Indeed essentially all lesions that exhibit attenuation of <10 HU on unenhanced CT are adenomas9. The sensitivity of this 10 HU radiographic cutoff, however, is imperfect, and some 30% of adrenal adenomas will register attenuation above this level15-17. 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 chemical-shift strategies, intracellular fat content of the adrenal lesions can be gauged19. 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 adenoma13,20. Although MR chemical-shift imaging is arguably superior to unenhanced CT in characterizing indeterminate lesions21,22, 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 10007, and current recommendations suggest that all adrenal lesions that are not resected should be reimaged at 6, 12, and as possible 24 months following diagnosis2,9. Approximately 5% to 9% of adrenal masses grow at least 1 cm in diameter upon interval follow-up7,26, and such growth has been suggested as a trigger for resection2. 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 low2.
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 evaluation9. 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 pheochromoctyomas1,2.
Isolated Adrenal Metastasis
A wide range of malignancies metastasizes to the adrenal gland27,28. In fact, retrospective series reveal that in patients with history of previous malignancy, 50% of new adrenal lesions prove metastatic28,29. Isolated metastases to the adrenal are at times resected; however, such cases require a thoughtful multidisciplinary approach28,30-34.
In addition to treatment of ACTH-independent Cushing’s 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 Cushing’s Disease35,36. 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)38-41. 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 feedback41. Also, one is wise to warn the patient regarding the remote possibility of leaving residual functional adrenal tissue at the time of the bilateral adrenalectomy42.
Approximately 10% of Cushing’s Syndrome is caused by ectopic secretion of ACTH by malignant tissues43. Although resection of the primary ACTH-producing tumor is ideal, such approach is possible in only ~10% of patients44. Indeed, bilateral adrenalectomy is a therapeutic option in the appropriately-selected patient43.
Work-Up of Adrenal Incidentaloma
A metabolic evaluation is necessary for all adrenal incidentalomas, since over 10% are metabolically active9. 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 hypertension2,9. 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 Cushing’s Syndrome) upon work-up1,7. 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 characteristics45; however, some reports and guidelines suggest that the UFC may not be appropriate for screening patients with adrenal incidentaloma due to inferior sensitivity46-48. Again, if this first-line testing is positive, consultation with endocrinology is advised.
Initial Evaluation for Hyperaldosteronism
Hyperaldosteronism (aka Conn’s syndrome) stemming from an adrenal mass is exceedingly rare, as the condition is found in only ~1% of adrenal incidentalomas1,49. 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 Conn’s syndrome. Confirmatory testing is mandatory and should involve endocrinologic experts49,51. Although beyond the scope of this chapter, adrenal vein sampling is often advisabl 52.
Initial Evaluation for Catecholamine Hypersecretion
Approximately 5% of patients with adrenal incidentaloma will prove to have pheochromocytoma2. Indeed, pheochromocytoma must be ruled out in all patients with adrenal mass, even in those in whom metastases are strongly suspected53. 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 washout54,55.
Clinical first-line testing for pheochromocytoma should include either free fractionated plasma metanephrines or 24-hour urinary fractionated metanephrine levels56,57. Although there is currently a debate regarding which test is superior, both evaluations afford excellent sensitivity and specificity2,58. 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.
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 closely46. 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 symptomatology60. 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 cardiomyopathy64. 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
Associate Professor of Urologic Oncology
Department of Surgical Oncology
Fox Chase Cancer
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