Adrenal Incidentaloma Workup

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. ^[18] 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. ^[19]

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. ^[20]

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 (Open Table in a new window)

 

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. ^{[21, 22, 23]}

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). ^[18]

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. ^[24]

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). ^[25]

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. ^[26]

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. ^[27]

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. ^[28]

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, 29, 30]}

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. ^[31]

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. ^{[32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]}

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%. ^[43] 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. ^[44]

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. ^[45]

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.

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. ^[46]

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. ^[47] 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.