Medical and Surgical Evaluation and Treatment of Adrenal ... · Adrenal Incidentaloma J Clin...

Medical and Surgical Evaluation and Treatment ofAdrenal Incidentalomas

Martha A. Zeiger, Stanley S. Siegelman, and Amir H. Hamrahian

Department of Surgery, Endocrine Surgery Section (M.A.Z.), and Department of Radiology (S.S.S.), JohnsHopkins University School of Medicine, Baltimore, Maryland 21287; and Department of Endocrinology,Diabetes, and Metabolism (A.H.H.), Cleveland Clinic, Cleveland, Ohio 44120

Introduction: Adrenal incidentalomas are detected in approximately 4% of patients undergoinghigh-resolution abdominal imaging studies. The majority of adrenal incidentalomas are benign,but careful evaluation of all patients is warranted to be certain that primary adrenocortical car-cinoma and functional adenomas are not missed.

Methods: The diagnostic approach in patients with adrenal incidentalomas should focus on twomain questions: whether the lesion is malignant, and whether it is hormonally active. Radiologicalevaluation including noncontrast and contrast computed tomography attenuation values ex-pressed in Hounsfield units is the best tool to differentiate between benign and malignant adrenalmasses. All adrenal tumors with suspicious radiological findings, most functional tumors, and alltumors more than 4 cm in size that lack characteristic benign imaging features should be surgicallyexcised. All patients should undergo hormonal evaluation for subclinical Cushing’s syndrome andpheochromocytoma, and those with hypertension should also be evaluated for hyperaldosteron-ism. Combined 1-mg dexamethasone suppression test, plasma metanephrines, and aldosterone/plasma renin activity measurements (if hypertensive) are reasonable initial hormonal evaluations.

Results: Annual biochemical follow-up of most patients with adrenal incidentalomas, especially ifthe tumor is more than 3 cm in size, for up to 5 yr may be reasonable. Patients with adrenal massesless than 4 cm in size and a noncontrast attenuation value of more than 10 Hounsfield units shouldhave a repeat computed tomography study in 3–6 months and then yearly for 2 yr. Adrenal tumorswith indeterminate radiological features that grow to at least 0.8 cm over 3–12 months may beconsidered for surgical resection. (J Clin Endocrinol Metab 96: 2004–2015, 2011)

An adrenal incidentaloma is defined as an adrenal le-sion that is discovered when a radiological study is

performed for indications other than suspected adrenaldisease. This definition should exclude patients undergo-ing imaging studies as part of staging and workup of anunderlying malignancy unless the radiological features areconsistent with a benign lesion, and patients who hadmedical history or physical exam that was inadequate butthat would have led to a suspicion of an underlying adrenaldisorder if taken or performed (1, 2).

The prevalence of adrenal incidentalomas based on re-ports summarizing the result of 25 autopsy studies is about

6% (1, 3, 4). The mean prevalence of adrenal incidenta-lomas using high-resolution computed tomography (CT)scans is about 4%, close to the percentage reported inautopsy series (5, 6). The prevalence of adrenal inciden-talomas increases with age; it is less than 1% in patientsyounger than 30 yr of age and up to 7% in patients overage 70 (3, 4, 7). In a comprehensive review by Cawood etal. (2), the authors argue that many series in the literaturerepresent an overestimation of malignant lesions and func-tional adrenal tumors for a variety of reasons, such as:inclusion of surgical series with patients who had signif-icant clinical findings; inclusion of patients with suspi-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2011 by The Endocrine Societydoi: 10.1210/jc.2011-0085 Received January 11, 2011. Accepted May 6, 2011.First Published Online June 1, 2011

Abbreviations: APA, Aldosterone-producing adenoma; ARR, aldosterone to renin ratio; CT,computed tomography; FNA, fine-needle aspiration; HPA, hypothalamic-pituitary-adrenal;HU, Hounsfield units; POB, phenoxybenzamine; PRA, plasma renin activity; SCS, subclinicalCushing’s syndrome.

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cious radiological features; exclusion of those with benignimaging studies; small sample size; inclusion of a patientpopulation who were referred to tertiary centers; exclu-sion of patients with small tumors; inclusion of patientswith a history of cancer or suspicion of malignancy; usageof ultrasonography for tumor detection; and finally, meth-odological error in reporting tumor prevalence (2).

The distributions of the pathological origins of adrenalincidentalomas vary with regard to several clinically im-portant factors, including cancer history and tumor size.Among patients with cancer (most commonly carcinomasof the lung, breast, kidney, and melanoma), up to threefourths of incidentalomas are metastases (4, 8). In con-trast, the lack of a primary cancer site in a patient with atrue adrenal incidentaloma would make the diagnosis of ametastatic lesion very unlikely. In such cases, primary ad-renocortical carcinoma would be a more common etiologyfor a malignant adrenal tumor (9, 10).

When clinicians face an adrenal incidentaloma, thereare mainly two questions that need to be answered: 1) isthe lesion malignant, and if so, is it a primary or a meta-static tumor; and 2) is it functional. Patients with an ad-renal incidentaloma should undergo a thorough clinicalevaluation. The history and physical exam should beaimed at excluding a functional tumor or an underlyingmalignant disease.

Hormonal Evaluation

All patients with an adrenal incidentaloma should be eval-uated for autonomous cortisol secretion referred to as sub-clinical Cushing’s syndrome (SCS), pheochromocytoma,and (if hypertensive) hyperaldosteronism. In most pa-tients, a combination of 1-mg dexamethasone suppressiontest (DST), plasma metanephrines, along with aldosterone

and plasma renin activity (PRA) mea-surements (if hypertensive) is a reason-able initial hormonal workup. Furtherhormonal evaluation is based on clini-cal and radiological findings.

Adrenal Imaging

With modern CT scanners, both adre-nal glands are now easily recognized.On rare occasions, it is even possible todistinguish between cortex and medullaon CT scans (Fig. 1, A and B). The threemost important imaging criteria to dis-tinguish between benign and malignantadrenal lesions are: 1) size of the lesion;2) the CT attenuation value on an un-

enhanced CT scan; and 3) the pattern of enhancement anddeenhancement (so-called “washout”).

Adrenal tumor sizeAdrenal tumor size is an important determinant to help

differentiate adrenal adenomas from nonadenomas; themajority of tumors less than 3 cm are benign, and themalignant adrenal lesions are generally more than 6 cm insize (11–20). Different cutoff values ranging from 4–6 cmhave been proposed for surgical resection of adrenalmasses (12, 17, 18, 20–24). The risk of malignancy in-creases significantly with tumor size greater than 4 cm, andtherefore, in the authors’ opinion, all adrenal incidenta-lomas more than 4 cm in size that lack characteristic be-nign radiological features should be surgically removed,regardless of whether or not they are functional (19, 21,25). At the same time, the risk of malignancy in a 5-cmhomogenous adrenal mass with noncontrast attenuationvalue of less than 10 Hounsfield units (HU) is close to 0%(12, 15, 26–33). The noncontrast CT attenuation coeffi-cient expressed in HU is superior to adrenal size in differ-entiating between benign and malignant adrenal tumors(12, 15, 26, 28, 30, 33, 34).

Lack of change in the size of an adrenal mass has alsobeen proposed as an indicator of the benign nature of anadrenal tumor (20, 35). However, follow-up of patientswith nonfunctioning adrenal masses suggests that 5 to25% of adrenal masses increase in size by at least 1 cm (20,36–38). Furthermore, there are reports of cases of adrenalmetastases with no change in CT appearance over a periodof 36 months (10, 27). In a recent study by Pantalone et al.(10) reporting on 75 surgically resected adrenal masseswith at least two imaging studies 3 to 12 months apart, achange in tumor size of 0.8 cm provided the highest com-

FIG. 1. A, Enhanced CT of normal right adrenal gland to illustrate distinction betweenadrenal cortex and medulla. The outer two layers of cortex enhance more avidly than thecentral layer of the medulla, revealing the “sandwich-like” nature of normal adrenal limbs. B,Enhanced CT of left adrenal gland in a different patient. The outer layers of cortex enhanceto a greater degree than the centrally located adrenal medulla.

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bined sensitivity (60%) and specificity (84.6%) for thedifferentiation of a benign vs. a malignant adrenal mass.The authors could not find any adrenal size cutoff valuethat would provide 100% sensitivity or specificity toconfirm or exclude malignancy. Therefore, change intumor size should be used in conjunction with otherimaging and clinical characteristics when consideringsurgical resection (10).

Adrenal protocol CT scanAn adrenal protocol is used to further assess a newly

discovered adrenal lesion. It consists of unenhanced im-ages, images obtained 1 min after iv injection of contrastmedia, and imaging after a 10- to 15-min delay (Figs. 2 and3). In a study by Hamrahian et al. (12) looking at 299adrenal masses, a noncontrast CT of less than 10 HU or acombination of no more than 4 cm adrenal mass size anda noncontrast CT scan with no more than 20 HU had a100% specificity in the identification of benign adrenaltumors (Fig. 4).

A relative or absolute percentage deenhancement of 40and 60% in 10 or 15 min, respectively, is an excellentmeans of distinguishing between adenomas and metasta-ses. Pheochromocytomas, however, may mimic adenomas

(Figs. 2 and 3) (39). Caoili et al. (40) characterized 127adrenal masses and reported the criteria for benign lesionsof less than 10 HU on unenhanced CT scan and absolutepercentage enhancement washout of at least 60% was98% sensitive and 92% specific. Some adrenal lesionssuch as myelolipomas have characteristic CT scan findingswith HU often below !40 (Fig. 5).

Subclinical Cushing’s Syndrome

The first reports on SCS were published by Beierwaltes etal. (41) in 1973 and subsequently by Charbonnel et al. (42)in 1981. The authors suggested that the adrenal tumorsproduced autonomously small amounts of cortisol, insuf-ficient to result in the typical clinical manifestations ofCushing’s syndrome, but enough to suppress ACTH. Thiswould result in decreased stimulation of the contralateraladrenal gland and lack of iodocholesterol uptake, whichwould increase after ACTH administration.

Most studies report a prevalence of 5–24% for SCS inpatients with adrenal incidentalomas. This broad range islikely the result of differences in the diagnostic criteria thathave been used (4, 7, 22, 43–46). Young (1) reported a

FIG. 2. An 80-yr-old man had a chest x-ray before planned surgery for carpal tunnel syndrome. A questionable nodule was noted in the rightlower lobe. A lesion of the left adrenal was noted on chest CT. The lesion did not meet criteria for an adrenal adenoma. Biopsy showed metastaticmelanoma. Subsequently more careful questioning of the patient disclosed a history of resection of melanoma from his left arm 8 yr earlier. A,Unenhanced CT scan lesion measures 40 HU. B, One minute after iv injection of contrast media, lesion measures 72 HU. C, Fifteen minutes afterinjection, lesion measures 60 HU. Enhancement, 32 HU; deenhancement, 12 HU; percentage deenhancement, 37.5%; hence, lesion is not anadenoma.

FIG. 3. A 25-yr-old woman hospitalized with severe abdominal pain and constipation was incidentally diagnosed with an enhancing right adrenalmass. Urine and serum metanephrines were significantly elevated. Subsequent questioning disclosed that the patient was usually normotensive,but she had recently experienced numerous episodes with recorded blood pressures above 200 mm Hg systolic, and she also reported severalpanic attacks associated with palpitations and dizziness. A 2.7-cm pheochromocytoma was resected. A, Unenhanced CT scan. Right adrenal gland,anteromedial to the kidney, medial to the liver, and lateral to the right crus of the diaphragm was replaced by soft tissue mass. CT attenuation was41 HU. B, Enhanced CT scan, 1 min after injection of iv contrast. Adrenal lesion enhances to 153 HU. C, Delayed scan 15 min after injection of ivcontrast. Adrenal lesion deenhances to 74 HU; enhancement, 112 HU; deenhancement, 79 HU; percentage or washout, 70.5%.

2006 Zeiger et al. Adrenal Incidentaloma J Clin Endocrinol Metab, July 2011, 96(7):2004–2015

prevalence of about 5% after summarizing the data onover 2000 patients from 13 different studies. This per-centage is closer to our clinical experience and a recentcritical review of the literature (2, 7).

Diagnosis of SCSIn the largest study of patients with adrenal incidenta-

loma, a combination of a positive 1-mg DST and lowACTH was the most common biochemical abnormality inpatients with SCS (19). Comparing patients with unilat-eral and bilateral adrenal iodomethyl-norcholesterol up-take, the 1-mg DST and morning serum ACTH levels weresuperior to 24-h urinary free cortisol in differentiatingbetween the two groups (47). Despite the lack of a single“gold standard” test to diagnose SCS, the authors considera combination of the 1-mg DST and plasma ACTH levelas the best diagnostic tool for evaluation of patients sus-pected to have SCS (20, 21, 48). Others have advocateddifferent test combinations, including 1-mg DST, 24-h uri-nary free cortisol, and plasma ACTH level (49, 50).

There has been disagreement among authors about thebest cortisol cutoff value for the diagnosis of SCS, andcortisol levels ranging from 27.6 to 138 nmol/liter (1 to 5!g/dl) have been proposed (20, 22, 46, 51–53). In a studyby Barzon et al. (54), all patients with plasma cortisolgreater than 138 nmol/liter after 1-mg DST had only up-take on the side of the adenoma during adrenal scintigra-phy. Based on these results, and because the 1-mg DST hasthe highest impact in both diagnosing SCS and subsequentsurgical decisions, the authors recommend using 138

nmol/liter as the cortisol cutoff value during 1-mg DST (1,20, 21). Using lower cutoff values for cortisol after 1-mgDST would result in an increased test sensitivity but lowerspecificity (49). With the availability of further prospec-tive studies to better define the value of a surgical approachin patients with SCS, using lower cortisol cutoff valuesafter 1-mg DST may be indicated. Based on limited data,the late-night salivary cortisol should not be used as aninitial screening test in patients suspected to have SCS (55).Despite potential usefulness of adrenal scintigraphy fordiagnosis of SCS in patients with adrenal incidentalomas,the lack of widespread availability and the time requiredto complete the test limit its usage (56, 57).

Treatment of SCSStudies on the natural history of SCS are limited, and

long-term morbidity and mortality data are still lacking(45, 52, 58). In a study by Vassilatou et al. (59) among 77patients with an adrenal incidentaloma who were fol-lowed for a mean duration of 62 months, only two patientsdeveloped Cushing’s syndrome, and neither of these hadSCS. With regard to developing SCS in a nonfunctioningadenoma, Barzon et al. (60) followed 130 patients with anadrenal incidentaloma, and the estimated cumulative riskof developing SCS at 1 and 5 yr was 3.8 and 6.6%, re-spectively. Most studies have reported a higher prevalenceof hypertension, obesity, insulin resistance, dyslipidemia,and osteoporosis in patients with SCS (22, 52, 53, 61–66).There is growing evidence for the deleterious effects ofexcess cortisol on bone in patients of both sexes with SCS.A high prevalence of vertebral fractures (43 to 72%) hasbeen reported in patients with subclinical hypercortiso-lism (67–69). A possible role of glucocorticoid receptorpolymorphism in determining metabolic and bone com-plications in patients with adrenal incidentaloma has re-cently been suggested (70).

The decision to operate should take into account thepresence of the metabolic consequences of cortisol excess,as well as the severity of the hypothalamic-pituitary-ad-renal (HPA) axis abnormality. In general, the more severethe abnormality of the HPA axis, the more likely the pa-tient would benefit from surgery. In a recent retrospectivestudy of 41 patients with adrenal incidentaloma and SCS,there was a significant improvement in blood pressure andfasting blood glucose in patients who underwent surgery,but a worsening of blood pressure and fasting blood glu-cose in those who chose to be managed conservativelyduring a follow-up period of 18–48 months (71). Until theresults of prospective studies are available, a reasonablestrategy may be to consider adrenalectomy for youngerpatients and those with new onset or a worsening of un-

FIG. 4. A 40-yr-old man with long history of hypertension had a CTscan to evaluate for renal calculi because of microscopic hematuria.Lesion in right adrenal gland was discovered incidentally. More carefulevaluation then revealed evidence of hypokalemia and elevated serumaldosterone. Bilateral adrenal vein sampling showed elevated valuesfrom the right side. A 1.8-cm adenoma was resected. Unenhanced CTscan is shown. Cross-sectional image shows aldosteronoma arisingfrom the posterior inferior aspect of the medial limb of the rightadrenal. Attenuation was !10 HU, establishing the lesion as anadenoma.


derlying comorbidities such as diabetes mellitus, hyper-tension, obesity, or osteoporosis (1, 21, 72).

Perioperative management of patients with SCSPatients with Cushing’s syndrome or SCS have ade-

quate circulating glucocorticoids and therefore do not re-quire glucocorticoid therapy during surgery. Such patientscan safely undergo surgical resection of their tumor, havetheir cortisol levels measured in the morning of postop-erative d 1, and then be started on hydrocortisone 30 mgin the morning and 10 mg in the early afternoon until theresult of the cortisol level becomes available (73). Thiswould provide an early and accurate evaluation of surgicalsuccess in patients with underlying Cushing’s syndrome orSCS. Another approach would be to cover all patients withglucocorticoids perioperatively and evaluate their HPAaxis at a later date (71, 74).

Pheochromocytoma

A prevalence of 1.1–11% for pheochromocytomas in pa-tients with adrenal incidentalomas has been reported, but

it is probably closer to 3% (2, 7, 75, 76).In approximately 4–14% of patientswith a pheochromocytoma, the tumoris discovered incidentally and up to50% of patients with incidentally dis-covered pheochromocytoma may benormotensive (3, 20, 77).

Pheochromocytomas are usually wellcircumscribed on CT scan and mostlyinhomogeneous due to areas of cysticchanges and hemorrhage. They exhibitincreased vascularity with marked en-hancement during contrast studies (Fig.3). A noncontrast CT of less than 10 HUmakes the diagnosis of pheochromocy-tomaextremelyunlikely (12,34,78–83).One cannot distinguish benign from ma-lignant pheochromocytomas on CT scanunless there is obvious local tumor inva-sion or evidence of metastasis. A high sig-nal intensity on T2-weighted magneticresonance imaging ishighlycharacteristicfor pheochromocytomas, but its absencedoes not rule out such diagnosis (84).

Biochemical evaluationThere is a lack of consensus on the

best initial diagnostic test for the eval-uation of pheochromocytomas in pa-tients with adrenal incidentalomas (1,

85–91). Both plasma and 24-h urinary metanephrines arereasonable initial screening methods for such patients.From a practical standpoint, normal plasma metaneph-rine rules out a diagnosis of pheochromocytoma in almostall patients except the very rare dopamine-secreting tumorand avoids the deadly consequences of a missed diag-nosis (88). Accordingly, the authors favor plasma meta-nephrines as the first-line diagnostic test due to its ex-cellent diagnostic sensitivity and convenience (21, 88,92). Patients with elevated plasma metanephrineswithin three to four times the upper limit of normal needto proceed further with measurement of 24-h urinemetanephrines (91, 93).

Perioperative managementAll patients with pheochromocytoma should be treated

with an "-adrenoceptor antagonist for at least 1–2 wkbefore surgery (94–96). Phenoxybenzamine (POB) is along-acting, nonspecific "-adrenergic antagonist that isusually started at 10 to 20 mg/d, with further adjustmentuntil hypertension is controlled or the patient developsside effects, which may include stomach upset, nausea,

FIG. 5. A, A 62-yr-old female evaluated for abdominal pain was noted to have a 5-cm rightadrenal mass. The lesion had attenuation values in the range of !30 HU, indicating fatcontent. Myelolipoma was resected. Gallstones are noted incidentally. B, A 59-yr-old femalewith a history of stage 1 carcinoma of the endometrium with postoperative follow-up exam.Laparoscopic adrenalectomy revealed an organizing hematoma without evidence of tumor.Coronal reconstruction of images obtained 1 min after injection of iv contrast shows a 6-cmleft adrenal mass with peripheral enhancement and low attenuation center. C and D, Cross-sectional image shows a 4.5-cm mass posterolateral to the inferior vena cava, consistent witha well-differentiated ganglioneuroblastoma. Coronal reconstruction shows lesion with focusof calcification inferiorly. (The study was done without iv contrast material because of ahistory of severe allergy.)


stuffy nose, drowsiness, sexual problems in males (e.g.trouble ejaculating), and weakness (95). POB may be as-sociated with significant orthostatic hypotension, reflextachycardia, and prolonged postoperative hypotension,and it is expensive (97). A selective postsynaptic "1-ad-renergic antagonist such as doxazosin is less costly andusually does not result in reflex tachycardia (87). It shouldbe administered at bedtime at 1 to 2 mg/d to avoid signif-icant orthostatic hypotension, with a gradual increase indosage to 8–12 mg/d at bedtime as tolerated. In the au-thors’ experience, POB provides better "-blockade andcontrol of paroxysmal hypertension but with increasedside effects, which may be prohibitive in some patients(98). The choice of "-blocker often ultimately depends onthe level of comfort of the medical team (including theendocrinologist, surgeon, and anesthesiologist) with aparticular medication.

Calcium channel blockers may be used to control hy-pertension or tachycardia or may be used in those patientswho cannot tolerate "-blockade (87, 99). Only after ad-equate "-blockade may patients be started on a #-blockersuch as metoprolol or atenolol to control persistent tachy-cardia or arrhythmias (21, 95). "-Methyltyrosine (mety-rosine), a tyrosine hydroxylase inhibitor responsible forthe rate-limiting step in catecholamine synthesis, maybe used in association with an "-adrenergic antagonistin patients with hemodynamic instability before surgeryand may be associated with less intraoperative hemo-dynamic instability compared with use of an "-blockeralone (100, 101).

With advances in surgical techniques and minimallyinvasive surgery, most tumors can now safely and suc-cessfully be resected laparoscopically (102). All patientsshould have their biochemical evaluation reassessed a fewweeks after surgery, with further assessment intervalsbased on the overall clinical picture. Because there are nodefinitive diagnostic criteria for malignancy, patients withan apparently benign pheochromocytoma should be fol-lowed annually for at least 5 yr and then intermittentlyafterward (103, 104).

Primary Aldosteronism

All patients with an adrenal incidentaloma who have hy-pertension should be screened for primary aldosteronism(44). It is important to note that patients with an aldoste-rone-producing adenoma (APA) may be normokalemic,and therefore a normal serum K should not precludefurther evaluation (105, 106). The estimated prevalenceof an APA among patients with adrenal incidentalomais less than 1%, but a prevalence as high as 2% has been

suggested by some (3, 5, 7, 19, 75, 107–109). APA areoften small (usually "2 cm in diameter) on CT scan(Fig. 4) (110).

Diagnosis of primary aldosteronismSince its introduction in 1983 by Hiramatsu et al. (111)

and, despite its shortcomings, measurement of plasma al-dosterone to renin ratio (ARR) is the best initial test for theevaluation of primary aldosteronism (44, 106, 111). Arange of ARR cutoff values from 20 to 100, where plasmaaldosterone and renin activity are measured in nanogramsper deciliter and nanograms per milliliter per hour, re-spectively, is used in different institutions before proceed-ing with confirmatory tests (7, 19, 44). The sensitivity ofthe assay (level of detection) for PRA can have a significantimpact on ARR (112). A PRA of 0.1 ng/ml!h, even in thepresence of a serum aldosterone of only 5 ng/dl, will resultin an ARR of 50. Therefore, the plasma aldosterone levelneeds to be considered when evaluating the ARR. A serumaldosterone level below 0.25 nmol/liter (9 ng/dl) makes adiagnosis of primary aldosteronism highly unlikely (113,114). On the contrary, requiring an aldosterone level of0.42 nmol/liter (15 ng/dl) as an additional criterion priorto proceeding with confirmatory tests will miss some pa-tients with primary aldosteronism (114). From a practicalstandpoint, ARR may be measured at the time of an initialpatient visit. However, borderline values should be re-peated: 1) after correcting hypokalemia; 2) while the pa-tient is on salt restriction; 3) in the morning in a sittingposition; and 4) after resting for at least 15 min beforeproceeding with confirmatory tests (44, 91).

Patients with an elevated ARR should proceed with aconfirmatory test such as the salt loading test or salinesuppression test (44, 115). Patients may be treated with anon-dihydropyridine calcium channel blocker (verapamilslow release) as a single agent or in combination with"-adrenergic blockers (e.g. doxazosin, to be given at bed-time) and hydralazine for blood pressure control whileundergoing confirmatory biochemical evaluation (44).Proceeding with salt loading in some patients with severeuncontrolled hypertension and significant hypokalemiamay be unsafe and unnecessary.

Preoperative and surgical managementThe majority of patients with primary aldosteronism

need to proceed with bilateral adrenal venous sampling toconfirm the presence of a unilateral source for hyperaldo-steronism. The approach in patients with a well-definedadrenal adenoma more than 1 cm in size and a normalcontralateral adrenal gland is somewhat controversial(91). Although in some institutions almost all patientswith primary aldosteronism undergo adrenal vein sam-


pling, others may proceed with surgery in patients with anisolated well-defined adrenal nodule more than 1 cm insize (106, 116, 117). Some experts recommend adrenalvein sampling in all patients with primary aldosteronismolder than 40 yr due to the increased prevalence of adrenalincidentaloma in such a population (118).

Adrenalectomy in patients with a documented uni-lateral source of primary aldosteronism is more costeffective compared with lifelong medical therapy. Med-

ical therapy with mineralocorticoid receptor antago-nists should be reserved for those who are unable orunwilling to undergo surgery (44). Laparoscopic adre-nalectomy compared to an open procedure is associatedwith a shorter hospital stay, fewer complications, andfaster recovery. Resection of the adrenal tumor in apatient with APA will result in resolution of hypokale-mia and improvement in hypertension in almost allpatients.

Postoperative managementPotassium supplementation and mineralocorticoid re-

ceptor antagonists should be stopped on postoperative d1, and there should be close monitoring of serum potas-sium. A temporary state of hypoaldosteronism may alsodevelop in some patients with primary aldosteronismpostoperatively. In the majority of cases, this conditioncan be managed by increasing salt intake. Rarely, treat-ment with fludrocortisone 0.1 mg/d for several weeks maybe required (119, 120).

Fine-Needle Aspiration (FNA)

Image-guided FNA of an adrenal tumor occasionally maybe helpful in the diagnostic evaluation of patients with a

TABLE 1. The prevalence of some of the commonunderlying etiologies in patients with a true adrenalincidentaloma

Etiology PrevalenceAdrenal cortical tumors

Nonfunctional adenoma 85 (71–93)Subclinical Cushing’s syndrome 6.4 (4.4–8.3)

Conn’s syndrome 0.6 (0–1.2)Adrenocortical carcinoma 1.9 (0.8–3)

Adrenal medullary tumorsPheochromocytoma 3.1 (1.8–4.3)

Metastasis 0.7 (0–1.4)Others "5

In patients with a history of cancer or clinical features suggestive of anunderlying adrenal etiology have been excluded. Data are expressed aspercentage (range).

TABLE 2. Laboratory evaluation of patients with adrenal incidentaloma with pre- and postoperative management

Suspecteddiagnosis

Screeningtest

Confirmatorytest

Preoperativemanagement

Postoperativemanagement

SCS 1-mg DST Low plasma ACTH andDHEAS wouldfurther support thediagnosis. Additionaltests of HPA axismay be consideredin some patients butusually is not needed

Treat comorbidities suchas DM, HTN andosteoporosis and/orvertebral fractures ifpresent

No glucocorticoid coverageperioperatively. Measuremorning cortisol on POD1 and starthydrocortisone untilcortisol level is available.Alternatively, may coverwith glucocorticoids andevaluate HPA axis lateron

Pheochromocytoma Plasma metanephrines 24-h urinemetanephrines.Clonidinesuppression test.MRI may beconsidered in someselected cases

"!Blocker #/!#!blocker #/!calcium channelblocker. Additionalimaging studies asclinically indicated.

Monitor blood pressureand glucose levels.Intravenous fluid to treathypotension. Discontinueor adjustantihypertensive therapy.

Primaryaldosteronism

Plasma ARR Repeat thelevel in the morningif ARR borderlinebased on the cutoffused by a particularlab

Salt loading test.Intravenous salineinfusion. Captoprilchallenge test.

Control HTN #/!aldosterone receptorblocker. Correcthypokalemia.

Hold mineralocorticoidreceptor blocker andpotassium supplement,and monitor bloodpressure and serumpotassium closely. Adjustantihypertensive drugs.Measure plasmaaldosterone and PRA.

All patients should be evaluated for subclinical Cushing’s syndrome, pheochromocytoma, and if hypertensive, primary aldosteronism. MRI,Magnetic resonance imaging; DHEAS, dehydroepiandrosterone sulfate; DM, diabetes mellitus; HTN, hypertension; POD, postoperative day 1.


history of cancer (particularly lung, breast, kidney, andmelanoma), no other signs of metastasis, and an adrenalmass with noncontrast CT attenuation value more than 10HU and a CT examination showing less than 60% abso-lute deenhancement. To avoid the potential for a hyper-tensive crisis, pheochromocytoma should always be ex-cluded before FNA of an adrenal mass is attempted (121).FNA should not be considered in the diagnostic approachof a tumor suspected to be an adrenocortical carcinomabecause it may not be informative and may be hazardousdue to the potential for tumor seeding (18, 23).

Bilateral Adrenal Lesions

Adrenal incidentalomas are bilateral in less than 15% ofcases (60, 122). The most common underlying etiologies in-clude metastatic disease, congenital adrenal hyperpla-sia, bilateral cortical adenomas/hyperplasia, bilateralpheochromocytomas, or infiltrative diseases (1) (Tables 1and 2). Measurement of cortisol precursors such as 17-hydroxyprogesterone during a cortrosyn stimulation testshould be considered to rule out congenital adrenalhyperplasia.

Long-Term Follow-Up ofPatients with AdrenalIncidentalomas

The optimal duration of biochemicalfollow-up for patients with adrenal in-cidentalomas is unknown. Excess hor-mone secretion may develop in up to20% of patients with previously non-functional adrenal tumors during fol-low-up (37, 38, 123). The transforma-tion rate of nonfunctional adrenalmasses to functional tumors seems to behigher in adrenal masses greater than 3cm in size (38). The National Institutesof Health consensus statement includedrecommendations for limited follow-uponly for nonfunctional adenomas ofless than 3 cm with no specific recom-mendations (20). Until data from largeprospective studies are available, an-nual biochemical follow-up for up to 5yr may be reasonable for patients withadrenal incidentalomas, especially ifthe tumor is more than 3 cm in size (20,21, 37, 45).

The most appropriate radiologicalfollow-up of a nonfunctional adrenalmass is unknown. Although some au-thors recommend no routine follow-up

of adrenal incidentalomas with a noncontrast attenuationvalue no greater than 10 HU, a one-time follow-up scan in6–12 months may be reassuring to the physician and thepatient (2, 12, 40, 124). Frequent adrenal imaging is as-sociated with additional cost, anxiety, and exposure toradiation, which may theoretically induce cancer at anestimated rate similar to the chance of developing adrenalmalignancy (2). Patients with adrenal masses less than 4cm in size and a noncontrast attenuation value more than10 HU should have a repeat CT study in 3–6 months andthen yearly for 2 yr. There is no good evidence supportingcontinued radiological surveillance if the follow-up imag-ing studies show no change in the adrenal tumor size (20).Surgical excision may be considered for tumors with in-determinate radiological features that grow at least 0.8 cmover 3- to 12-month follow-up (10).

Summary

The diagnostic approach in patients with adrenal inciden-talomas should focus on two main questions: 1) whetherthe lesion is malignant; and 2) whether it is hormonally

FIG. 6. Algorithm depicting the recommended evaluation and treatment of patients with anadrenal incidentaloma.


active (Fig. 6). Radiological evaluation including noncon-trast CT attenuation value expressed in HU is the best toolto differentiate between benign and malignant adrenalmasses. All adrenal tumors with suspicious radiologicalfeatures, most functional tumors, and all tumors morethan 4 cm in size that lack characteristic benign imagingfeatures should be removed. All patients should undergohormonal evaluation for SCS and pheochromocytoma,and those with hypertension should also be evaluated forprimary hyperaldosteronism. Annual biochemical fol-low-up of most patients with an adrenal incidentaloma(especially if the tumor is more than 3 cm in size) for up to5 yr may be reasonable. Patients with adrenal masses lessthan 4 cm in size and a noncontrast attenuation valuegreater than 10 HU should have a repeat CT study in 3–6months and then yearly for 2 yr. Adrenal tumors withindeterminate radiological features that grow at least 0.8cm over 3–12 months should be considered for surgicalresection once other imaging and clinical characteristicshave been taken into consideration.

Acknowledgments

Address all correspondence and requests for reprints to: Dr.Martha Zeiger, M.D., Chief of Endocrine Surgery, The JohnsHopkins University School of Medicine, Blalock 606 600 NWolfe Street, Baltimore, Maryland 21287. E-mail: [email protected].

Disclosure Summary: The authors have nothing to disclose.

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