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Management of adrenal incidentaloma
Darko Kastelan
To cite this article: Darko Kastelan (2011) Management of adrenal incidentaloma, Expert Review of Endocrinology & Metabolism, 6:6, 811-817, DOI: 10.1586/eem.11.75
To link to this article: http://dx.doi.org/10.1586/eem.11.75
Published online: 10 Jan 2014.
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EXPERT REVIEWS
Management of adrenal incidentaloma
Expert Rev. Endocrinol. Metab. 6(6), 811-817 (2011)
Darko Kastelan
School of Medicine, University of Zagreb, Zagreb, Croatia and Department of Endocrinology, University Hospital Zagreb, Zagreb, Croatia Tel .: +38 512 376 036 Fax: +38 512 376 036 dkastelan@inet.hr
The term adrenal incidentaloma covers a wide spectrum of adrenal pathologies sharing the method of discovery. The management of adrenal incidentaloma is controversial, and clinicians should determine whether the patient’s health is affected by the presence of a tumor. Critical points in management include differentiating benign from malignant and hormonally active from nonfunctional adrenal masses. The probability of malignancy is related to tumor size and imaging phenotype. Masses smaller than 4 cm in diameter that exhibit low attenuation by unenhanced CT scan and rapid contrast washout by delayed contrast-enhanced CT scan are probably benign. All patients with adrenal incidentaloma should undergo biochemical evaluations for pheochromocytoma and subclinical or overt Cushing’s syndrome, and hypertensive patients should undergo biochemical testing for hyperaldosteronism. Laparoscopic adrenalectomy is the treatment of choice in all hypersecretory tumors. If adrenocortical carcinoma is suspected, an open adrenalectomy is recommended. Patients who are not candidates for surgical resection of the tumor should be monitored radiographically for 2 years, and hormonal follow-up should be performed annually for 4 years.
KEYWORDS: adrenal incidentaloma · adrenocortical carcinoma · laparoscopic adrenalectomy · pheochromocytoma · primary aldosteronism · subclinical Cushing’s syndrome
Adrenal incidentaloma is an adrenal tumor dis- covered inadvertently during radiologic evalua- tion for other clinical conditions unrelated to the adrenals. Most experts agree that the definition should exclude patients undergoing diagnostic work-up or staging for cancer.
The term adrenal incidentaloma covers a wide spectrum of adrenal pathologies sharing the same method of discovery. The discov- ery of these tumors is a byproduct of modern technology; the widespread use of imaging pro- cedures in routine clinical practice has led to more frequent detection of these tumors, mak- ing their management a challenge of growing importance in modern endocrinology.
A number of autopsy studies have examined the frequency of adrenal masses. Grumbach et al. found adrenal tumors in 3% of persons over the age of 50 years [1]. In a report of 25 stud- ies with more than 85,000 autopsies, the overall prevalence of adrenal tumors was 5.9% (range: 1-32) [2]. In clinical studies, the prevalence of adrenal incidentaloma is strongly associated with age, with a frequency of 0.2% in patients under 30 years of age that increases to 7% in patients over 70 years of age [2-4]. This is partly
a reflection of the higher number of imaging procedures performed in older people.
The management of adrenal incidentaloma is controversial, and clinicians should determine whether the patient’s health is affected by the pres- ence of the tumor. Accordingly, major issues that need to be addressed include differentiating malig- nant from benign as well as hormonally active from inactive adrenal masses, which is critical for optimal treatment (conservative vs surgical).
The purpose of this article is to give practical recommendations for the management of adrenal incidentaloma in everyday clinical practice based on published data and clinical experience.
Causes of adrenal incidentaloma
There are a number of clinical disorders that should be considered in the differential diagno- sis of adrenal incidentaloma (Box 1; FIGURE 1) [5]. The vast majority of adrenal incidentalomas are benign cortical adenomas [6-9]. Nevertheless, adrenal carcinoma is of great clinical concern due to its high mortality rate. In a survey of 1004 adrenal incidentaloma patients in Italy, 85% had adrenal adenoma, whereas 5% had adrenal carcinoma or metastases [8].
Box 1. Causes of adrenal incidentaloma.
Hyperfunctioning tumors
· Adenoma
· Primary hyperaldosteronism
· Cushing’s syndrome
· Masculinizing/feminizing tumor
· Nodular hyperplasia
· Congenital adrenal hyperplasia
Nonfunctioning tumors
· Pheochromocytoma
· Cyst
· Lipoma
· Myelolipoma
· Ganglioneuroma
· Hemangioma
Malignant tumors
· Adrenocortical carcinoma
· Malignant pheochromocytoma
· Lymphoma
· Metastatic tumor
· Ganglioneuroblastoma
· Angiosarcoma
Other causes & false images
· Lymph node
· Renal mass
· Pancreatic mass
· Developmental defect
· Gastric diverticulum
· Technical artifact
Adapted from [3].
Bilateral adrenal incidentalomas account for up to 15% of all adre- nal incidentalomas; likely diagnosis is bilateral cortical adenoma. Less commonly, bilateral incidentalomas represent adrenocortico- tropic hormone (ACTH)-independent macronodular hyperplasia, micronodular hyperplasia, congenital adrenal hyperplasia or meta- static spreading of the primary cancer [10,11]. A study by Vassiliadi et al. suggests that bilateral adrenal incidentalomas are more commonly associated with subtle autonomous cortisol secretion [11].
Pheochromocytoma
Approximately 5% of adrenal incidentalomas are pheochromo- cytomas [6,8], a condition that is commonly associated with par- oxysms of hypertension, sweating, headache and palpitations. Approximately half of the pheochromocytoma cases detected as adrenal incidentaloma are clinically silent, but are also associated with significant morbidity and mortality [12,13].
Imaging studies can be helpful in determining if an adrenal mass is a pheochromocytoma. Pheochromocytomas usually exhibit increased attenuation on unenhanced computed tomography (CT), delayed-contrast washout on enhanced CT and high signal inten- sity on T2-weighted MRI [14,15]. However, approximately a third of these tumors have no characteristic imaging phenotype [16].
The measurement of fractionated metanephrines in urine or free metanephrines in plasma represents a reliable biochemical test for screening patients for pheochromocytoma [17,18].
Subclinical Cushing’s syndrome
Subclinical Cushing’s syndrome is characterized by autonomous cortisol secretion in patients lacking the typical physical signs of hypercortisolism. It is present in 5-20% of patients with adre- nal incidentaloma depending on the diagnostic criteria used in different studies [1,3,8,19].
The criteria for diagnosing this condition are controversial, and presently there is no consensus on a gold standard for the diagno- sis. Some tests of the hypothalamic-pituitary-adrenal (HPA) axis, such as measurement of urinary free cortisol, do not have sufficient sensitivity to detect mild cortisol excess. Blunting of the circadian rhythm of cortisol, low to undetectable ACTH levels and low dehy- droepiandrosterone sulfate levels have been frequently reported in patients with subclinical Cushing’s syndrome [20-22]. Nevertheless, adrenal autonomy is probably best assessed by the overnight dex- amethasone suppression test (1 mg), which has been widely used to diagnose subtle cortisol hypersecretion. However, different cut- off values to define cortisol suppression have been used in various studies. The NIH state-of-the-science conference panel on adrenal incidentaloma recommended a threshold of 5 µg/dl (138 nmol/l) to define adequate cortisol suppression [1]. Recently, lower cut-off val- ues have been suggested by some authors [23,24], thereby increasing the detection of the disease. A cut-off point of 1.8 µg/dl (50 nmol/l) has better sensitivity but lower specificity as compared with the 5 ug/dl limit, which may increase the rate of false-positive results. To settle this controversy, most of the experts recommend that at least two tests of the HPA axis should be abnormal to qualify a patient for subclinical Cushing’s syndrome [6,8,25].
A critical issue in patients with subclinical Cushing’s syndrome is whether the patients are at increased risk of poor health outcomes and the probability of progression to overt Cushing’s syndrome. A number of studies reported that slight hypercortisolism observed in these patients may be associated with increased frequency of hyper- tension, obesity, hyperlipidemia, insulin resistance and impaired glucose tolerance [26-28]. A study by Tauchmanovà et al. reported increased cardiovascular risk profiles and increased frequency of atherosclerotic plaques in patients with subclinical Cushing’s syn- drome [29]. Few studies have demonstrated lower bone mineral densities in patients with adrenal incidentaloma, compared with values in healthy controls [30,31]. Despite the observed association between subclinical Cushing’s syndrome and metabolic syndrome, evidence of increased mortality in these patients is lacking.
Evolution from subclinical to overt Cushing’s syndrome has rarely been observed [32-34]. Conversely, in some patients there is spontaneous normalization of the HPA axis during the follow-up period [32].
Primary aldosteronism
Approximately 1% of patients with adrenal incidentaloma may have primary aldosteronism. The classical form of the disease is associated with refractory hypertension and hypokalemia.
However, most patients with primary aldosteronism do not have hypokalemia [35].
Screening for excess aldosterone secretion should be performed in hypertensive patients with adrenal incidentaloma. The widely accepted screening test is the ratio of plasma aldosterone to plasma renin activity, with a sensitivity and specificity of 90 and 91%, respectively, if the ratio of plasma aldosterone to plasma renin activity is greater than 30 in association with a plasma aldosterone of more than 20 ng/dl [36]. If the screening is positive, the pres- ence of autonomous aldosterone secretion should be confirmed by a saline suppression test. Failure to suppress aldosterone below 10 ng/dl confirms primary aldosteronism [37]. Before considera- tion of treatment options, it is critical to make the distinction between aldosterone-producing adenoma and primary adrenal hyperplasia by bilateral adrenal venous sampling.
Sex hormone-secreting tumors
Routine measurement of androgens or estrogens is warranted only in patients with characteristic clinical manifestations, such as hir- sutism, virilization, gynecomastia, decreased libido or testicular atrophy. Congenital adrenal hyperplasia is another rare cause of unilateral or bilateral adrenal incidentalomas.
Detection of malignancy
A pooled analysis of 26 studies revealed that the frequency of adrenocortical carcinoma (ACC) is less than 5% of all adrenal incidentalomas [34]. However, because of the poor prognosis of these tumors, assessing the risk of malignancy in patients with adrenal incidentaloma is of crucial importance. Therefore, the major goal of adrenal incidentaloma management is to identify all patients with adrenal malignancy. The probability of malig- nancy is related primarily to tumor size and CT or MRI char- acteristics (shape, margins, unenhanced CT attenuation value and contrast washout).
A tumor size cut-off of 4 cm has been found to differentiate benign from malignant tumors with the highest sensitivity [38]. However, as during the early phase of the clinical course the ACC diameter could be less than 4 cm, a close imaging follow- up 3-6 months after the initial diagnosis is mandatory to avoid misdiagnosis. A study by Pantalone et al. has shown that change in adrenal tumor size was a significant predictor of malignancy [39]. A growth cut-off value of 0.8 cm had the highest sensitivity and specificity of 72 and 81.1%, respectively.
Adrenal adenomas are commonly homogenous round masses with smooth margins. They are usually lipid-rich, resulting in low attenuation on unenhanced CT. On delayed contrast-enhanced CT, adenomas are characterized by rapid contrast washout of more than 50% 10 min after administration [40]. ACCs typically exhibit high attenuation values (>10 Hounsfield unit [HU]) and slower contrast washout than adenomas. Several studies indicated that noncontrast HU is superior to tumor size in differentiat- ing benign from malignant masses [41,42]. Up to 30% of adre- nal adenomas are lipid-poor and may be indistinguishable from nonadenomas on unenhanced CT. Nevertheless, they exhibit the same contrast washout as lipid-rich adenomas on enhanced CT,
A
B
C
which enables their distinction from nonadenomas [42]. Upon MRI, adenomas exhibit loss of signal on out-of-phase images compared with in-phase images [40].
Hormone measurement is of limited utility for predicting malignancy. Nevertheless, detailed hormonal evaluation in patients suspected of having ACC is warranted because any hor- mone abnormality identified before the treatment could serve as a tumor marker during postoperative follow-up. Approximately two-thirds of all ACCs are hormonally active, whereas a third are nonfunctioning tumors.
Adrenal metastases are rarely found in patients without history of malignant disease. Carcinomas of the lung, breast and kidney, as well as melanomas and lymphomas, frequently metastasize to the adrenal glands. Adrenal metastases are commonly bilateral and could be associated with adrenal insufficiency [43].
The diagnostic value of fine-needle biopsy is rarely informative and confers the risk of potentially threatening complications, such as hemorrhage, pneumothorax, formation of an adrenal abscess, hypertensive crisis due to misdiagnosed pheochromocytoma and tumor metastases along the needle track [44-47]. Therefore, at present, the only accepted indication for fine-needle biopsy of adrenal masses is a suspected metastasis in a patient in whom the result would affect the therapeutic approach.
Management of adrenal incidentaloma
A flow chart for the management of adrenal incidentaloma is shown in FIGURE 2 [48]. The treatment decision should be based on
Adrenal incidentaloma
Hormone and metanephrine test
Unenhanced CT
- Overnight dexamethasone test (1 mg)
- Tumor size
- Appearance (shape, margins)
- Metanephrine and normetanephrine plasma/urine
- Attenuation value (HU)
- Hemorrhage, necrosis
Hypertension
Contrast-enhanced CT
- Aldosterone:PRA ratio
- Contrast washout
Hyperfunctioning tumor
Size ≥4 cm Suspicion of malignancy
Adrenalectomy
Nonfunctioning tumor
Size <4 cm Attenuation <10 HU Rapid contrast wash-out
Follow-up
- Hormone evaluation (annually for 4 years)
- CT/MR (3-6, 24 months)
CT: Computed tomography; HU: Hounsfield unit; MR: Magnetic resonance; PRA: Plasma renin activity.
the imaging phenotype of the tumor and the presence of excess hormones. Our recent study demonstrated the impaired quality of life in patients with adrenal incidentaloma, which may also be taken into account when considering treatment options [49].
All hypersecretory tumors, nonfunctional tumors with a diam- eter of more than 4 cm and masses exhibiting imaging pheno- types suspected of malignancy should be considered for surgery. A laparoscopic approach is the method of choice unless ACC is suspected, in which case open adrenalectomy is recommended.
In patients with smaller tumors without hormone excess, fur- ther follow-up is mandatory. Radiographic evaluation is recom- mended 3-6 months after the diagnosis, and then annually for the next 1-2 years. The most commonly used imaging modality is CT. Current practice of management of adrenal incidentaloma consists of two to three follow-up scans, and a recent study has shown that corresponding radiation exposure confers a risk of fatal cancer that is similar to the risk of adrenal incidentaloma becoming malignant [50]. Therefore, to reduce radiation exposure, follow-up imaging, particularly in younger patients, is best com- pleted with MRI or even ultrasound. Compared with CT or MRI, ultrasound has a lower sensitivity in detecting adrenal tumors and is not effective in distinguishing benign from malignant lesion [51,52]. However, it is a reliable method in evaluating tumor size and its growth with time [52]. A hormone assessment should be performed at the time of diagnosis and then annually for 4 years. Clinically relevant hormone hypersecretion is exceptionally rare in normotensive patients with adrenal incidentalomas <1 cm in diameter. Accordingly, these patients probably require no hormonal evaluation. Patients with tumor sizes remaining stable for 2 years who do not develop hormonal hypersecretion over 4 years probably do not need further follow-up [4,48,53,54].
The management of patients with sub- clinical Cushing’s syndrome is contro- versial, as no long-term data are available to guide the decision between medical and surgical therapy for these patients. The critical issue is whether surgical resection is able to reverse features of mild hypercortiso- lism. Several studies reported improvement in cardiovascular risk factors in patients with subclinical Cushing’s syndrome after adrenalectomy [55-57]. Toniato et al. followed up 45 patients with subclinical Cushing’s syndrome for 2-17 years who were randomly selected for surgery or con- servative management [56]. They reported that diabetes, hypertension, hyperlipidemia and obesity normalized or improved in a substantial proportion of patients in the surgical group, whereas some worsen- ing was noted in conservatively managed patients. Chiodini et al. carried out a retro- spective study in which 108 patients with
adrenal incidentaloma, 41 of whom had subclinical Cushing’s syndrome, were followed up for 18-48 months [57]. Weight, blood pressure and glucose levels improved more frequently in patients with subclinical Cushing’s syndrome who underwent adrenalectomy (n = 25) compared with those treated conserva- tively (n = 16). Conversely, a study by Giordano et al. showed no clinical improvement in patients with subclinical Cushing’s syndrome who underwent surgery [27].
As this subject is still a matter of debate it seems reasonable to select for surgery younger patients and those with recent worsening of clinical and biochemical parameters of metabolic syndrome [4].
Conclusion
Adrenal masses are not infrequent findings during diagnostic management for other clinical conditions. All patients with adre- nal incidentaloma should undergo thorough clinical, biochemical and radiological evaluation for signs of hormone hypersecretion or malignancy. Laparoscopic adrenalectomy is the treatment of choice in all hypersecretory tumors. If ACC is suspected, open adrenalectomy is recommended. Patients who are not can- didates for surgical resection of tumors should be monitored radiographically for 2 years, and hormonal follow-up should be performed annually for 4 years. In patients with subclinical Cushing’s syndrome, long-term prospective studies are needed to guide optimal disease management.
Expert commentary
The widespread use of imaging procedures in routine clinical prac- tice has led to more frequent detection of adrenal masses, making their management an increasingly important aspect of healthcare.
The management of adrenal incidentaloma is controversial, and clinicians should determine whether the patient’s health is affected by the presence of the tumor. Clear distinction between malignant and benign lesions, as well as between hormonally active and inactive adrenal mass, is critical for optimal treatment.
Pheochromocytoma should be ruled out in all patients. Screening for aldosterone excess should be performed in hyper- tensive patients with adrenal incidentaloma. An overnight 1-mg
dexamethasone suppression test should be performed to detect subtle cortisol hypersecretion. Imaging studies are essential for distinguishing cortical adenomas from carcinoma.
Surgery should be considered in all patients with hypersecretory tumors, nonfunctional tumors with a diameter of more than 4 cm or masses exhibiting imaging phenotypes suspected of malig- nancy. Patients who are not candidates for surgery should be monitored radiographically for 2 years, and hormonal follow-up should be performed annually for 4 years.
Five-year view
Owing to the sparse data available that might help guide the management of adrenal incidentaloma, further studies are needed. In the future, we could expect the establishment of an interna- tional study group with the aim to facilitate the formation of a registry of patients with adrenal incidentaloma. The purpose would be to define the natural history of adrenal incidentaloma and identify patients who are at high risk for developing adrenal carcinoma. Furthermore, prospective clinical trials are needed to define the optimal follow-up strategy and to answer the question of for how long patients with adrenal incidentaloma should be monitored. Finally, comparative studies of quality-of-life out- comes among patients who are conservatively managed and those who are considered for surgery are warranted.
Another important issue that needs to be investigated in the future is the impact of subclinical Cushing’s syndrome on mor- bidity and mortality. Although some reports suggest that adrena- lectomy may benefit patients who have subclinical Cushing’s syn- drome, evidence for this is insufficient and these data should be confirmed in a large prospective trial.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
· The prevalence of adrenal incidentaloma is associated with age, with a frequency of 0.2% in patients under 30 years of age that increases to 7% in patients over 70 years of age.
· Critical points in the management of adrenal incidentaloma include differentiating benign from malignant and hormonally active from nonfunctional adrenal masses.
· The vast majority of adrenal incidentalomas are benign cortical adenomas.
· Approximately 5% of adrenal incidentalomas are pheochromocytomas. Approximately half of the pheochromocytomas detected as adrenal incidentaloma are clinically silent.
· Subclinical Cushing’s syndrome, characterized by autonomous cortisol secretion in patients lacking the typical physical signs of hypercortisolism, is present in 5-20% of patients with adrenal incidentaloma.
· Adrenocortical carcinomas typically exhibit high attenuation values (>10 Hounsfield units) and slower contrast washout than adenomas. In addition, a tumor size cut-off of 4 cm has also been found to differentiate benign from malignant tumors.
. The only indication for fine-needle biopsy of adrenal masses is a suspected metastasis in a patient in whom the result would affect the therapeutic approach.
· Hypersecretory tumors, nonfunctional tumors with a diameter of more than 4 cm and masses exhibiting imaging phenotypes suspected of malignancy should be considered for surgery.
Review
References
Papers of special note have been highlighted as:
· of interest
·· of considerable interest
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