Adrenal Incidentaloma

Practice Essentials

Adrenal masses are often discovered incidentally and are then termed adrenal incidentalomas (AIs). They are often discovered after an imaging procedure is performed that is unrelated to the adrenal gland. Usually, the patient has no signs of hormonal excess or obvious underlying malignancy. Incidence has been increasing proportionally to the use of radiographic imaging, as shown in the images below.^[1] Less commonly, AIs are discovered as part of the clinical workup for suspected adrenal disease (eg, Cushing syndrome). (See Workup, as well as Clinical Presentation.)

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Left adrenal mass discovered incidentally.

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Close-up of the left adrenal incidentaloma from the above image.

The differential diagnosis of AIs includes many primary, metastatic, benign, and malignant entities, most of which are not discussed at length here. (See Diagnosis)

Adrenal cortical adenoma is a common benign tumor arising from the cortex of the adrenal gland. It commonly occurs in adults, but it can be found in persons of any age. Adrenal cortical adenomas are not considered to have the potential for malignant transformation (see the images below).

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Homogeneous, well-defined, 7-HU ovoid mass is seen in the right adrenal gland; this finding is diagnostic of a benign adrenal incidentaloma.

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Homogeneously enhancing ovoid mass is seen in the left adrenal gland.

Because adrenal metastases may be found in as many as 25% of patients with known primary lesions, radiologists frequently face the task of determining whether an adrenal mass is benign or malignant. The question can directly affect the clinical management of the case. For instance, the workup for an otherwise resectable lung cancer may reveal the presence of an adrenal mass and suggest the possibility of metastatic disease. (See Workup.)

The treatment for a hormonally active (functional) adrenal tumor is surgery. The treatment for a malignancy depends on the cell type, spread, and location of the primary tumor.^[2] Nonfunctional adrenal cortical adenomas are not premalignant, and surgical excision is not indicated. (See Treatment and Management.)

Signs and symptoms of adrenal incidentaloma

Pheochromocytomalike symptoms include episodic attacks, palpitations, sweats, headaches, and abdominal pain, as well as labile hypertension. Pheochromocytomas should be considered in all AI cases because they are more common than previously thought, the diagnosis is often overlooked, and a failure to recognize them may lead to patient death.

Primary hyperaldosteronism includes hypertension and unprovoked hypokalemia. However, more patients are being identified who have normal potassium levels.

Patients with adrenal carcinoma report weight loss. Virilization is reported in women (for androgen-secreting tumors), and feminization in men (for estrogen-secreting tumors).

Cushing syndrome (reflecting cortisol-secreting adenomas) includes weight gain, weakness, depression, and bruising.

Workup in adrenal incidentaloma

Biochemical tests used in the assessment of AIs include evaluation of the following:

• Pheochromocytoma - Urine-free and plasma-free metanephrines
• Primary aldosteronism - Plasma aldosterone-to-renin ratio
• Adrenocortical carcinoma - Urine 17-ketosteroids
• Cushing or "silent" Cushing syndrome - Overnight 1-mg dexamethasone test

The imaging modalities of choice in the evaluation of an adrenal mass are computed tomography (CT) scanning, magnetic resonance imaging (MRI), and positron-emission tomography (PET) scanning.

Adrenal fine-needle aspiration (FNA) helps to identify metastatic, systemic, and hemorrhagic disease of the adrenal glands. It cannot distinguish between benign and malignant primary adrenal tumors and should be used only when an AI cannot be diagnosed clinically or hormonally.^[3]

Management

Conditions that do not warrant surgery include bilateral adrenal diseases such as corticotropin-dependent Cushing disease and bilateral hyperaldosteronism. Nonfunctional (hormonally silent) adrenal cortical adenomas are not premalignant, and surgical excision is not indicated.

The treatment for a hormonally active adrenal tumor is surgery. The treatment for a malignancy depends on the cell type, spread, and location of the primary tumor.^[2]

No randomized trials have compared laparotomy versus laparoscopic adrenalectomy; however, abdominal laparotomy is preferred for bilateral disease, large masses (>10 cm), possible malignant disease, and pheochromocytoma.

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Anatomy

The adrenal glands are located in the perirenal space near the upper pole of each kidney. Their appearance varies: they may be shaped like the letter H, L, Y, T, or V. Typically, they are less than 4 cm in length and less than 1 cm in width.

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Pathophysiology

The biochemical mechanisms depend on the underlying cell type. The cellular mechanisms for primary adrenocortical tumorigenesis are just beginning to be understood.

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Etiology

Some studies report an association with chromosomal and genetic abnormalities (genes coding for p53 and p57). Tumor markers are also present in other syndromes. The multiple endocrine neoplasia (MEN1) gene is linked to multiple endocrine neoplasia type 1. The aldosynthase/11-beta hydroxylase hybrid gene is associated with glucocorticoid-remediable hyperaldosteronism.

Another very rare cause of Cushing syndrome is adrenal-dependent macronodular hyperplasia associated with extremely large adrenal glands.

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Epidemiology

Adrenal incidentalomas (AIs) are a common finding on cross-sectional abdominal images. In about 1-5% of all cases, abdominal computed tomography (CT) scans that are obtained for reasons other than the evaluation for possible adrenal neoplasm demonstrate an adrenal mass; most of these are AIs. The autopsy prevalence for AIs is 2-9% (see Table 1).

Table 1. Prevalence of AIs

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See Table

Approximately 1-10% of CT scans and magnetic resonance images (MRIs) detect AIs that are 5 mm or larger. An Italian study of incidentally discovered AIs among subjects undergoing chest CT scan found that the prevalence of AIs was approximately 4%.^[9]

The most important hormonally silent AI is pheochromocytoma. They are present in approximately 1 in 1000 autopsies. If the prevalence of AIs is 10-100 in 1000, then 1-10% of AIs are pheochromocytomas, as noted in the image below.

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Adrenal incidentaloma and disease type.

A study by Falhammar et al of 94 cases of pheochromocytoma, as encountered at a single center, determined that 64% were identified as incidentalomas, while 32% were found in patients suspected of having a pheochromocytoma. In another 4% of cases, patients were screened for the lesion because they were known to have MEN2A.^[10]

Demographic distribution for AI

Prevalence increases with age; the rate is less than 1% for patients younger than 30 years and is 7% for patients 70 years or older. Evidence suggests that the incidence in teenage girls is slightly higher than that of teenage boys, but no sex-related predilection is found in adults. AI prevalence is higher in white than in black people and in obese, diabetic, and hypertensive patients.^[11]

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Prognosis

Generally, the prognosis is excellent, but it depends on the type of underlying adrenal disease.

Approximately 85% of AIs are nonfunctional (hormonally silent) and benign. The other 15% of AIs are either functional (hormonally active) or malignant and require further evaluation and treatment to avoid medical complications.^{[12, 13, 14]}

Patients with a previous history of cancer have a clinical course dictated by the primary tumor. Patients with adrenal cortical carcinomas have poor clinical outcomes, usually a 2- to 5-year 50% overall survival rate.

Approximately 3-7 percent of AIs prove to be pheochromocytomas.^{[12, 13, 15]} Pheochromocytomas may result in substantial complications, including death if not recognized. A 1981 series reported that less than one quarter of pheochromocytomas found post mortem were diagnosed ante mortem.^[16] More than 90% of these patients had characteristic symptoms suggesting the unrecognized tumors were not silent. Many of the patients died of causes possibly related to the pheochromocytoma. Approximately 29% died unexpectedly during surgery, 27% died from cardiovascular causes, and 17% died from cerebrovascular causes.

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Patient Education

If pertinent, patients should know the signs and symptoms of adrenal insufficiency. Clinical clues include nausea, abdominal pain, fever, and diarrhea.

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History

Evidence of hormonal excess should be sought.

Pheochromocytomalike symptoms include episodic attacks, palpitations, sweats, headaches, and abdominal pain, as well as labile hypertension. Pheochromocytomas should be considered in all adrenal incidentaloma (AI) cases because they are more common than previously thought, the diagnosis is often overlooked, and a failure to recognize them may lead to patient death.

Primary hyperaldosteronism includes hypertension and unprovoked hypokalemia. However, more patients are being identified who have normal potassium levels.

Patients with adrenal carcinoma report weight loss. Virilization is reported in women (for androgen-secreting tumors), and feminization in men (for estrogen-secreting tumors).

Cushing syndrome (reflecting cortisol-secreting adenomas) includes weight gain, weakness, depression, and bruising.

Evidence of systemic disease, such as carcinoma, amyloidosis, or granulomatous disease, may be present. Often, no clinical clues can be found and other information is needed for diagnosis.

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Physical Examination

Vital signs may include findings of high blood pressure, postural hypotension, and tachycardia. A fundi feature is hypertensive retinopathy. Skin findings include hirsutism and striae. General signs include central obesity and gynecomastia.

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Approach Considerations

Adrenal insufficiency should be the first consideration, especially with bilateral adrenal incidentalomas (AIs). A corticotropin test with 60-minute cortisol levels helps rule out the diagnosis. If found, suspect granulomatous disease, hemorrhage, or lymphoma. A 21-hydroxylase deficiency can also be diagnosed with a 60-minute post-corticotropin plasma 17-hydroxyprogesterone level.

The diagnosis should be confirmed with a second test. According to guidelines issued by the American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine Surgeons (AAES) in 2009 for the management of AIs, a 2-day low-dose dexamethasone suppression test is a suitable second test.^[17] Other possible tests include a urinary free cortisol test, a urinary metanephrine–to–creatinine ratio, or a renin-to-aldosterone ratio. If a hormonal excess is found, surgical removal is usually indicated.

If no hormonal excess is found and the corticotropin test results were unremarkable, fine-needle aspiration (FNA) helps distinguish between adrenal and metastatic disease.

Adrenal cortical adenoma can be diagnosed with a high degree of accuracy: the specificity of imaging studies ranges from 95-99%, and the sensitivity is greater than 90%. These impressive percentages are a result of the relatively high prevalence of AIs in the general population and the extensive radiologic research with imaging methods, primarily computed tomography (CT) and magnetic resonance imaging (MRI).

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed to detect and evaluate the performance of plasma-free metanephrine and normetanephrine in the differential diagnoses of adrenal incidentaloma. The method was validated and found to be rapid, reliable, and accurate.^[18]

The adrenal gland is the fourth most common site of metastasis, and adrenal metastases may be found in as many as 25% of patients with known primary lesions. Therefore, radiologists frequently face the task of determining whether an AI is benign or malignant. The question can directly affect the clinical management of the case. For instance, the workup for an otherwise resectable lung cancer may reveal the presence of an adrenal mass and suggest the possibility of metastatic disease.

A study by Schmitz et al concluded that using real-time polymerase chain reaction (PCR) analysis to measure microRNA (miRNA) expression of miR-675 and miR-335 helps to differentiate adrenocortical carcinomas from adrenocortical adenomas.^[19]

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Biochemical Testing

If clinical evidence manifests, perform diagnostic hormonal testing (see Table 2). Because adrenal incidentalomas (AIs) may be hormonally silent, biochemical screening is warranted.

Table 2. Evaluation of AI Syndromes

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See Table

Cushing syndrome

Most frequently, cortisol produces subclinical Cushing syndrome. This occurs when the AI autonomously secretes cortisol at levels high enough to suppress corticotropin but too low to produce Cushing stigmata.

Patients do not have increased rates of hypertension or diabetes mellitus, but they may have features of metabolic syndrome, including hypertension, dyslipidemia, and impaired glucose tolerance. Patients may have reduced bone density and osteoporosis.^{[20, 21, 22]}

Because urinary free cortisol levels may be within the reference range, a 1-mg overnight dexamethasone suppression test is needed to diagnose subclinical Cushing syndrome.

Pheochromocytoma

Pheochromocytomas should be considered in all AI cases because they are more common than previously thought, the diagnosis is often overlooked, and a failure to recognize them may lead to patient death. AACE/AAES 2009 guidelines recommend this diagnosis be confirmed by a measurement of plasma fractionated metanephrines and normetanephrines or 24-hour total urinary metanephrines and fractionated catecholamines (or both plasma and urine studies).^[17]

Assume all AIs have a pheochromocytoma until proven otherwise, especially when paroxysmal hyperadrenergic symptoms are present.

Exclude the presence of pheochromocytoma prior to performing a fine-needle aspiration (FNA) biopsy on the AI.

Primary aldosteronism

Primary aldosteronism is a less compelling, but nevertheless important, diagnosis. The test of choice is an upright plasma aldosterone–to–renin ratio. A plasma aldosterone concentration–to–plasma renin activity ratio greater than 30 and a plasma aldosterone concentration of greater than 0.5 nmol/L (18 ng/dL) are suggestive of primary aldosteronism.^[23]

Hyperaldosteronism is usually identified by suppressed upright plasma renin levels and concomitant elevated plasma aldosterone levels.

Abnormalities of other secreted hormones

Other secreted hormones can include estrogens, androgens, and 17-hydroxyprogesterone. They are associated with AIs, carcinomas, and hyperplasia. They often manifest clinically and therefore do not require presumptive screening.

Bilateral adrenal masses

Bilateral AIs should always raise the possibility of hemorrhage, especially in patients with coagulopathies or those on anticoagulant therapy. Clinical symptoms include flank pain, nausea and vomiting, fever, and hypotension. Diagnosis can be made with a rapid corticotropin stimulation test demonstrating decreased cortisol reserve.

Bilateral AIs usually suggest certain systemic diseases that can produce adrenal insufficiency. They should be recognized early. Fungal or tuberculosis infection may be present. Granulomatous diseases (eg, histoplasmosis, tuberculosis) are characteristically homogeneous and may show calcifications.

In a patient with primary hyperaldosteronism, bilateral AIs suggest bilateral adrenal hyperaldosteronism (idiopathic hyperaldosteronism). Confirm this by adrenal venous sampling to demonstrate bilateral plasma aldosterone secretion. Long-standing, corticotropin-dependent Cushing syndrome may result in large AIs.

A retrospective study by Li et al of 1941 patients with AIs found that the proportion of subclinical Cushing syndrome was greater greater in patients with bilateral incidentalomas than in other subjects (18.6% vs 7.1%, respectively).^[24]

A 21-hydroxylase deficiency can produce unilateral AIs, but bilateral AIs are more common. To recognize this, measure the level of corticotropin-stimulated plasma 17-hydroxyprogesterone.^[25]

Most metastatic disease to the adrenal gland is unilateral, but lymphoma may be bilateral and can cause adrenal insufficiency.

Adrenal myelolipoma, although a benign tumor, can sometimes grow to a large size (>6 cm), causing mass effect and requiring surgery. This tumor is composed of mature fat and interspersed hematopoietic elements that resemble bone marrow. On CT imaging, the presence of large amounts of macroscopic fat in an adrenal mass is diagnostic of a myelolipoma.^[26]

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Computed Tomography, Magnetic Resonance Imaging, and Other Modalities

The presence of intracytoplasmic lipid is fairly specific for adrenal cortical adenomas: approximately 70% of all adrenal cortical adenomas have a high percentage of intracytoplasmic lipid, whereas the remaining 30% do not. Other processes, such as metastasis, hemorrhage, and other primary adrenal neoplasms, have distinctly different imaging characteristics.

This unique characteristic allows clinicians to distinguish adenomas from other processes that affect the adrenal gland, by using imaging techniques that demonstrate lipid. The major exception is clear cell carcinoma of the kidney, which contains an abundance of intracytoplasmic lipid; when these metastasize to the adrenal gland, their appearance can be identical to that of a lipid-rich adenoma. Note that on CT scans and MRIs, the appearance of intracytoplasmic lipid is different from that of macroscopic fat, as in the case of a myelolipoma.

The modalities of choice in the evaluation of an adrenal mass are CT, MRI, and positron-emission tomography (PET). CT scanning is preferred because it is more cost-effective than MRI to delineate size, shape, and appearance. MRI is as effective as CT scanning for distinguishing benign from malignant lesions and is superior for detecting pheochromocytomas. A benign incidentaloma has a T2-weighted intensity similar to liver tissue.

A study by Kuzu et al suggested that when T2-weighted MRI studies reveal AIs to be hypointense or isointense, as well as when out-of-phase MRI sequences reveal signal loss, routine biochemical screening for pheochromocytomas may not be necessary. While 13 out of 28 AIs that showed hyperintensity on T2-weighted MRIs were found to be pheochromocytomas, with all 13 not showing signal loss on out-of-phase sequences, none of the hypointense or isointense AIs, and none that demonstrated signal loss on out-of-phase sequences, were determined to be pheochromocytomas. The study included 300 AIs in 278 consecutive patients.^[27]

PET scanning with 18-fluorodeoxyglucose (FDG) can be helpful in patients with a prior history of malignancy or those in which CT densitometry or washout analysis is inconclusive or suggestive for malignancy.^{[11, 28, 29]}

To see complete information, Adrenal Adenoma Imaging.

Mass size is an important predictive characteristic. A smooth homogeneous lesion smaller than 4 cm with a low attenuation value (Hounsfield units) is usually benign. A larger inhomogeneous lesion with irregular borders and a higher attenuation score should be considered for malignancy.

The cutoff criterion for suspicion of malignancy ranges from 3-6 cm in diameter. The best hope for a surgical cure is a lower cutoff, but this means a greater number of benign tumors are unnecessarily removed. A 4-cm cutoff is estimated to result in an acceptable ratio of 1 cancerous to 8 benign tumors, as in the image below.^[30]

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Characteristics of adrenal masses and their malignant potential.

Plain radiography, tomography, and ultrasonography are less sensitive and are used less frequently since the advent of CT scanning and MRI. Ultrasonography has a role in the evaluation of a potential adrenal incidentaloma (AI) in infants, but no appearance is specific for benign AI.^{[31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]}

Other scanning techniques include iodine-131 metaiodobenzylguanidine (MIBG) for pheochromocytoma and iodine-131-6-b-iodomethylnorcholesterol (NP-59 cholesterol) for adrenocortical lesions; however, these tests are not widely available, and data on their clinical usefulness is insufficient.

A prospective cohort study of AIs in an unselected population undergoing radiological examination by Muth et al found that 6.6% of patients with AIs had surgery, and benign hormone-producing tumors were found in 3.1%.^[42] Repeated CT scanning and hormone evaluation after 2 years resulted in no significant increase in the sensitivity for diagnosis of malignant or hormone producing tumors.

Imaging features of pheochromocytomas

Pheochromocytomas vary in size, consistency, and margins. They can be bilateral; they are strongly enhanced with contrast; and they show high signal intensity on T2-weighted images, owing to their vascularity.

A multicenter, retrospective study by Canu et al evaluating the CT-scan characteristics of pheochromocytomas suggested that when assessing an adrenal incidentaloma, a lesion with an unenhanced attenuation value of 10 HU or less need not be biochemically tested to determine if it is a pheochromocytoma. The investigators based their recommendation on the fact that out of 376 pheochromocytomas reviewed, none had an unenhanced attenuation value below 10 HU, and only 2 (0.5%) had a value of exactly 10 HU.^[43]

A literature review by Buitenwerf et al came to the same conclusion as the Canu study with regard to unenhanced attenuation values of adrenal incidentalomas.^[44]

Imaging features of adrenal carcinomas

Adrenal carcinomas are often larger than 6 cm in diameter, with an irregular margin. They are unilateral, sometimes with local invasion and lymphadenopathy and metastases. Adrenal carcinomas demonstrate a soft-tissue inhomogeneous density on CT scans, which enhances with contrast. They have an intermediate increased intensity on T2-weighted MRIs. Myelolipomas show characteristic images of fat. Hemorrhage shows characteristic images of blood.

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Fine-Needle Aspiration

Adrenal FNA helps identify metastatic, systemic, and hemorrhagic disease of the adrenal glands. It cannot distinguish between benign and malignant primary adrenal tumors and should be used only when adrenal incidentaloma (AI) cannot be diagnosed clinically or hormonally.^[3]

Use CT scanning to guide a 23- or 25-gauge needle into the left or right adrenal gland. If a metastatic lesion is found, initiate a search for the primary cancer. If adrenal tissue is found, consider surgical removal. Pheochromocytoma should always be excluded before performing FNA biopsy to avoid the potential for a hypertensive crisis.^[45]

In a study on the sensitivity of percutaneous adrenal biopsy in the detection of malignant adrenal neoplasms, Mazzaglia and Monchik concluded that such biopsies are not diagnostically useful in patients with isolated AIs.^[46] Reporting on 163 adrenal biopsies, including 30 performed on isolated AIs, the investigators found the negative predictive value of percutaneous biopsy to be too low for use in ruling out malignancy in isolated AIs. The results also indicated that biopsy is valuable for diagnosing metastatic carcinoma in cases of nonadrenal primary malignancy.

Histologic findings are based on the AI cell type.

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Approach Considerations

The two main concerns with regard to an adrenal incidentaloma (AI) are (1) whether it is hormonally active (functional) and (2) whether it is malignant. Correlation with the clinical presentation and, if necessary, serum chemical and urinalysis results should be used to determine whether an adrenal cortical adenoma is functional.^[47] Benign adrenal cortical adenomas are commonly smaller than 6 cm in diameter on initial presentation, but they may be larger.^[48]

No specific medical therapy is required except treating the underlying disease.

Nonsurgical treatment

Conditions that do not warrant surgery include bilateral adrenal diseases such as corticotropin-dependent Cushing disease or bilateral hyperaldosteronism. Nonfunctional (hormonally silent) adrenal cortical adenomas are not premalignant, and surgical excision is not indicated.

The AACE/AAES 2009 guidelines add that patients with bilateral idiopathic hyperaldosteronism (IHA) who cannot or choose not to receive surgical treatment should be managed with selective and nonselective mineralocorticoid receptor blockers.^[17]

Surgical treatment

The treatment for a hormonally active adrenal tumor is surgery. The treatment for a malignancy depends on the cell type, spread, and location of the primary tumor.^[2]

No randomized trials have compared laparotomy versus laparoscopic adrenalectomy; however, abdominal laparotomy is preferred for bilateral disease, large masses (>10 cm), possible malignant disease, and pheochromocytoma. Fiberoptic laparoscopy is used for visualization, biopsy, and removal. A transthoracic approach is faster than fiberoptic laparoscopy but has a longer postoperative recovery period.

Other experimental approaches, including a laparoscopic robot and augmented-reality visualization of the surgical field, have been described.

Treatment of metastatic disease

Metastatic disease is managed according to the type of primary cancer. Adrenal disease should be removed if the diameter is greater than 6 cm. Otherwise, follow up with repeat computed tomography (CT) scans at periodic intervals.

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Complications

Patients are prone to adrenal insufficiency once the cortisol-secreting tumor is removed. This postoperative adrenal insufficiency is caused by corticotropin suppression and adrenal cortical atrophy of the contralateral adrenal gland, described in the image below.

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Pituitary-adrenal axis and cortisol-secreting adrenal mass.

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Consultations

An endocrinologist should be consulted to review the results of endocrine testing.

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Long-Term Monitoring

For patients who do not have an adrenalectomy, follow-up is designed to detect interval changes in tumor size or the development of hormonal overproduction. Most adrenal lesions remain unchanged or decrease in size, whereas 5-25% enlarge. Repeat CT scanning at 6-12 months is recommended, and for lesions that do not increase in size, further testing is generally not warranted.^{[49, 14]}

Annual biochemical evaluation of most patients with adrenal incidentalomas (AIs) for as long as 5 years may be reasonable, especially if the tumor is larger than 3 cm in size.^[50] Patients with adrenal masses smaller than 4 cm who have a noncontrast attenuation value of more than 10 Hounsfield units should have repeat CT scanning in 3-6 months and again annually for 2 years. Any tumors with indeterminate features on radiology that grow to at least 0.8 cm over 3-12 months may be considered for surgical resection.

Overnight 1-mg dexamethasone suppression testing, a renin-to-aldosterone ratio, and urinary catecholamine and metabolite measurements can be performed yearly or more frequently if clinically indicated. After several years, this testing can probably be discontinued.

Hypercortisolism (especially subclinical) is the most likely hormonal disorder to develop in the follow-up period and is subclinical in most cases.

The AACE/AAES 2009 guidelines state that a patient who has undergone a resection due to a pheochromocytoma should receive long-term follow-up because the recurrence rate is 10-15%.^[17]

A study by Leboulleux et al found that 18-fluorodeoxyglucose (FDG) uptake occurred in 14-29% of patients within 24 months after adrenalectomy in patients with adrenocortical carcinoma.^[51] The uptake is considered transient and is not suspicious for malignancy.

Primary hyperaldosteronism or catecholamine excess is rarely observed during follow up.

Adrenal insufficiency may occur with bilateral adrenal disease such as lymphoma or hemorrhage.

Hypocortisolism may also occur as a result of corticotropin deficiency from a cortisol-secreting adenoma that is causing contralateral adrenal atrophy. The postoperative course for these patients is prolonged physiologic cortisol replacement.

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Guidelines Summary

Diagnosis

Guidelines issued in 2009 by the American Association of Clinical Endocrinologists (AACE) and American Association of Endocrine Surgeons (AAES) for the management of adrenal incidentalomas recommend that evaluation of patients with an adrenal incidentaloma include clinical, biochemical, and radiographic testing for the following^[17] :

• Hypercortisolism
• Aldosteronism (if hypertensive)
• Pheochromocytoma or a malignant tumor

The simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. Salivary cortisol, dexamethasone suppression, and urine free cortisol testing can be used if clinical suspicion is high (eg, in patients with hypertension, obesity, diabetes mellitus, or osteoporosis).

Primary aldosteronism is confirmed by lack of aldosterone suppression on a 24-hour urine study with salt loading.

To determine the incidentaloma subtype, high-resolution CT scanning should be performed in all patients. In addition, adrenal venous sampling should be performed in most patients older than 40 years.

Clinical practice guidelines for adrenal incidentaloma management issued in 2016 by the European Society of Endocrinology, in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT), include the following diagnostic recommendations^[52] :

• That clinicians aim to establish if an adrenal mass is benign or malignant at the time of initial detection
• That all adrenal incidentalomas undergo an imaging procedure to determine if the mass is homogeneous and lipid-rich and therefore benign; for this purpose, the use of noncontrast CT scanning is recommended
• That every patient with an adrenal incidentaloma undergo careful assessment, including clinical examination, for symptoms and signs of adrenal hormone excess
• That all patients with adrenal incidentalomas undergo a 1-mg overnight dexamethasone suppression test to exclude cortisol excess
• That post-dexamethasone serum cortisol levels between 51 and 138 nmol/L (1.9-5.0 µg/dL) be considered evidence of possible autonomous cortisol secretion and that post-dexamethasone cortisol levels of over 138 nmol/L (over 5.0 µg/dL) be taken as evidence of autonomous cortisol secretion
• That pheochromocytoma be excluded by measurement of plasma-free metanephrines or urinary fractionated metanephrines
• That in patients with concomitant hypertension or unexplained hypokalemia, the aldosterone/renin ratio be used to exclude primary aldosteronism
• That sex hormones and steroid precursors be measured in patients with clinical or imaging features suggestive of adrenocortical carcinoma
• That if the adrenal mass is indeterminate on noncontrast CT scan and the results of the hormonal workup do not indicate significant hormone excess, three options be considered by a multidisciplinary team acknowledging the patient’s clinical context: immediate additional imaging with another modality, interval imaging in 6-12 months (noncontrast CT or MRI scan), or surgery without further delay

For evaluation of possible adrenocortical carcinomas, the 2012 European Society for Medical Oncology (ESMO) guidelines utilize the 2005 proposed diagnostic workup of ENSAT. The guidelines note that although the evidence level for this workup is low, the diagnostic accuracy is high. The recommended workup includes the following tests.^[53]

Hormonal work-up

These studies include the following:

• Glucocorticoid excess (minimum 3 of 4 tests)
• Dexamethasone suppression test (1 mg, 23:00 h)
• Excretion of free urinary cortisol (24 h urine)
• Basal cortisol (serum)
• Basal adrenocorticotropic hormone (ACTH) (plasma)

Sexual steroids and steroid precursors

These studies include the following:

• Dehydroepiandrosterone-S (serum)
• 17-OH-progesterone (serum)
• Androstenedione (serum)
• Testosterone (serum)
• 17-beta-estradiol (serum, only in men and postmenopausal women)
• 24-hour urine steroid metabolite examination

Mineralocorticoid excess

These studies include the following:

• Potassium (serum)
• Aldosterone/renin ratio (only in patients with arterial hypertension and/or hypokalemia)

Catecholamine excess

These studies include the following:

• Normetanephrine, metanephrine, and methoxytyramine (plasma)
• Alternatively: fractionated metanephrine excretion (24-h urine)

Imaging

These studies include the following:

• CT or MRI scan of abdomen and CT thorax scan
• Bone scintigraphy (when suspecting skeletal metastases)
• Fluorodeoxyglucose-PET (FDG-PET) scan (optional)
• MIBG scintigraphy, DOTATATE-PET scan, or dopa/dopamine PET scan if pheochromocytoma is proved 

Staging

The National Comprehensive Cancer Network (NCCN) guidelines recommend staging adrenal cancer according to the 7^th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.^[54]  However, the European Society of Medical Oncology (ESMO) recommends the 2009 European Network for the Study of Adrenal Tumors (ENSAT) tumor/node/metastasis (TNM) system^[55] over the AJCC system.^[53]

Treatment

AACE/AAES guidelines treatment recommendations include the following^[17] :

• Surgical resection should be reserved for those with worsening hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis
• In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is preferred over open approaches
• Patients with bilateral idiopathic hyperaldosteronism (IHA) should be managed with selective and nonselective mineralocorticoid receptor blockers
• Open adrenalectomy should be performed if adrenocortical carcinoma is suspected

For patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection, the guidelines recommend radiographic reevaluation at 3-6 months and then annually for 1-2 years. Hormonal evaluation should be performed annually for 5 years.

The NCCN guidelines for the treatment of adrenal carcinoma include separate recommendations for localized and metastatic disease. Recommendations for localized disease are as follows^[56] :

• Resection of primary tumor and adjacent lymph nodes
• Open adrenalectomy recommended
• External-beam radiation therapy and adjuvant mitotane may be considered in patients at high risk for recurrence

NCCN treatment recommendations for metastatic disease are as follows^[56] :

• Observation for clinically indolent disease with imaging and biomarkers (if functional) every 3 months
• Resection of primary tumor and metastases if more than 90% removable, particularly if functional
• Systemic therapy, preferably within a clinical trial

The ESMO guidelines recommendations include the following^[53] :

• Open surgery with transperitoneal access for stages I-III when complete resection is possible
• Laparoscopic adrenalectomy only for selected patients with small tumors and no evidence of invasiveness or adrenal incidentalomas
• Margin-free complete resection of locally advanced adrenocortical carcinomas may require resection of parts of adjacent organs
• Re-resection of adrenocortical carcinomas for recurrence if margin-free resection is possible and the time to recurrence has been over 12 months
• Adjuvant mitotane therapy in patients with incomplete/R1 or Rx resection and/or Ki67 expression in 10% or less of neoplastic cells
• For bone metastasis, palliative radiotherapy is an option; arterial chemoembolization and radiofrequency ablation may be beneficial in selected patients

The aforementioned clinical practice guidelines for adrenal incidentaloma management issued in 2016 by the European Society of Endocrinology, in collaboration with ENSAT, include the following surgical recommendations^[52] :

• That adrenalectomy be considered the standard of care for unilateral adrenal tumors with clinically significant hormone excess
• That surgery not be performed in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies
• That laparoscopic adrena­lectomy be performed in patients with unilateral adrenal masses with radiologic findings suspicious of malignancy and a diameter of 6 cm or less, but without evidence of local invasion
• That open adrenalectomy be performed for unilateral adrenal masses with radiologic findings suspicious of malignancy and signs of local invasion
• That perioperative glucocorticoid treatment be administered at major surgical stress doses as recommended by guidelines, in all patients undergoing surgery for an adrenal tumor in which there is evidence of (possible) autonomous cortisol secretion; ie, in patients who do not suppress to less than 50 nmol/L after 1 mg dexamethasone overnight.

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