General and Radiographic Workup and Adrenal Incidentaloma

The general diagnostic approach to adrenal lesions is usually based on three pillars: clinical suspicion, targeted imaging modalities, and hormonal evaluation. While history and clinical examination may provide a basis for suspicion, radiographic and hormonal evaluation should be conducted in order to categorize the lesion as likely benign or not and biochemically active or not. Clinical diagnosis and hormonal testing may require additional imaging prior to definitive treatment planning should the initial imaging be inconclusive. Prior to discussing the biochemical testing for a specific diagnosis, it is imperative to cover the available radiographic imaging and its utility in the assessment of the adrenal lesion.

Radiographic studies play a crucial role not only in detection of adrenal lesions but also in characterizing these lesions as adenoma or suspicious for malignancy. Computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scan are usually the three imaging modalities that detect adrenal abnormality. Each of the modalities specifically exploit different physiologic principles necessary in the diagnosis of adrenal masses: identification of intracellular lipid concentration in a mass, percent washout or, and the metabolic activity. First of all, the size itself may be quite informative. If the lesion in question is seen on imaging as larger than 4 cm in diameter, the likelihood of malignancy is increased and intervention may be indicated simply based on the size criteria alone. The rate of growth of the adrenal mass may also be informative, as benign adenomas will grow slower than malignant tumors. As with any other tumors, consistency (cystic versus solid), shape, and contour of the tumor may be helpful, with benign lesions appearing smoother and better circumscribed compared to malignant tumors.

Among all modalities, the noncontrasted phase of CT is likely to be the most informative. In the case of attenuation of less than 10 Hounsfield units (HU) the probability of malignancy is minimal and the patient most likely has an adrenal adenoma. If, however, attenuation of the adrenal gland on unenhanced imaging is greater than 10 HU, the index of suspicion for malignancy should be higher, and further radiographic workup should be performed. Should the patient have sufficient renal function, enhanced CT with a calculated washout will help differentiate lipid-poor adenomas from potentially more ominous lesions. A vast majority of adrenal adenomas have HU less than 10 while most carcinomas exhibit HU greater than 30 on unenhanced CT. Of note, lipid-poor adenomas can also have values higher than 10 HU, indicating that many lesions with HU >10 are still benign. Therefore an adrenal protocol CT (or alternatively MRI) is recommended.

Contrast-enhanced CT, MRI, or PET can help distinguish between benign and malignant lesions. In the case of the adrenal mass protocol CT, a noncontrasted phase is followed by contrasted phase and a 10- to 15-minute delay. In studies evaluating the rate of the enhancement loss at specific time intervals (contrast washout) the adenomatous lesions washed much faster when compared to nonadenomatous or malignant lesions. Some have demonstrated that the washout was observed at as early as 3 minutes. Typically, over 50% of washout of contrast on 10-minute delayed CT is diagnostic of an adenoma. Occasionally, when CT scan is indeterminate it is appropriate to utilize chemical shift MRI to further categorize the lesion. Chemical shift MR imaging detects presence of a lipid within an organ and is regarded as a sensitive method for differentiating adenomas from metastases. Typically, MR imaging is more costly and time consuming when compared to the ease of CT and is therefore utilized less often. Lastly, PET scan (using fluorine-18 fluorodeoxyglucose or FDG) can be helpful in selected cases to identify the metabolic activity and exploring the differences of lower activity of benign tumors versus more metabolically active malignant lesions based on glucose utilization and differential FDG uptake. Additional PET agents are becoming useful in further workup and differentiation of adrenal masses.

Ultimately, the radiographic portion of the adrenal workup will guide the index of suspicion for benign or malignant etiology. Metabolic workup will ultimately provide a more definitive diagnosis. Occasionally, however, the definitive diagnosis is only possible after surgical removal.

Hyperaldosteronism

Aldosterone-producing adenomas (APAs) constitute approximately 2% of incidentally discovered adrenal masses. While often nonspecific, symptoms can range from muscle cramping, weakness, headaches, and polydipsia associated with polyuria. Patients with APA may have hypertension that is refractory to treatment by multiple (usually three) antihypertensive medications. In addition, some, but not all, may exhibit hypokalemia (usually serum potassium <3.5 mEq/L) and hypernatremia.

Identification of an adrenal mass in a hypertensive patient presenting with refractory hypertension or hypertension requiring several types of medication usually leads to further workup for APA. The diagnosis of APA or hyperaldosteronism itself consists of a two-step approach with screening and confirmatory testing. First, the calculated ratio of plasma aldosterone concentration (PAC ng/dL) to plasma renin activity (PRA ng/mL) is performed. To increase the specificity further, PAC to aldosterone renin ratio (ARR) can be obtained. Since the levels of renin and aldos­terone may be affected by numerous medications, it is important that the screening test is conducted properly. Several types of medications that are mineralocorticoid receptor blockers such as spironolactone and eplerenone must be stopped 4–6 weeks prior to screening. When drawing blood samples for suspicion of APA, the ARR is the most sensitive test. The labs should be drawn in the morning after the patient has been out of bed for over 2 hours and seated for 5–15 minutes.

After the initial plasma levels of aldosterone and renin are obtained, further testing is done by salt loading. This can be performed by measuring 24-hour urinary aldos­terone levels after either consuming one teaspoon of salt with the addition of salty foods for a period of 72 hours or by saline suppression testing where isotonic saline is infused at 300–500 mL/h for a total of 4 hours. Extra caution should be exercised in patients with heart failure, severe hypertension, and those who are already taking multiple antihypertensive medications. Failure to suppress 24-hour aldosterone levels to normal levels after the salt loading confirms diagnosis of primary aldosteronism.

Finally, after the diagnosis of primary aldosteronism based on clinical and laboratory tests, the treatment plan is paramount. While cross-sectional imaging (usually with CT) is quite helpful in defining the location of the adrenal nodule, adrenal vein sampling (AVS) is mandatory for lateralizing the disease and distinguishing between unilateral and bilateral processes. This is done to avoid subjecting the patient to erroneous removal of a nonfunctioning adenoma on the wrong side, while the micronodular hyperplasia of the adrenal (not readily seen on cross-sectional imaging) may be producing the aldosterone. The most optimal setting to perform AVS is in the morning and in the fasting state. Failure to lateralize with the use of AVS may lead to improper surgical or medical treatment of APA. One study in particular showed that when CT alone was utilized to establish laterality without AVS, 25% of patients underwent unnecessary or inappropriate adrenalectomy.

When the decision to operate has been made, preoperatively patients should be started on a mineralocorticoid receptor antagonist. This approach not only corrects the preoperative hypokalemia but also controls the hypertension. Finally, while working on the diagnosis of primary aldosteronism, we must also be aware that secondary aldosteronism may be seen in patients with renal artery stenosis, malignant hypertension, pregnancy, heart failure, and cirrhosis.

Cushing’s Syndrome

Cushing’s syndrome is characterized by glucocorticoid excess and exhibits the typical signs and symptoms of hypercortisolism. From a careful history of the patient the following can be elicited: fatigue, sleep disturbances, depression, weight gain, hypertension, and easy bruising. On physical exam patients present with central obesity, facial plethora, thinned skin, acne, striae, hirsuitism, and proximal muscle weakness and wasting. Since the most common cause of glucocorticoid excess is usually from exogenous steroid intake, thorough investigation by the physician should be done to rule out potential iatrogenic sources of cortisol excess.

While clinical diagnosis is an integral part of the Cushing’s syndrome diagnosis, biochemical evaluation is paramount and involves screening and confirmatory testing. There are three simple screening tests that can be used for early suspicion of hypercortisolemia. The first of these tests is the late-night salivary cortisol test used for screening Cushing’s syndrome. A specimen of saliva is collected at bedtime in patients with a regular sleep pattern and tested in a laboratory. The sensitivity and specificity for diagnosing Cushing’s syndrome approaches 90–95% if the nighttime cortisol levels are elevated. Alternatively, the overnight 1-mg dexamethasone suppression test (DST) is used. This test is performed by administering 1 mg of dexamethasone at 11 p.m. and testing for plasma cortisol levels the following morning at 8 a.m. The DST is also used to differentiate between Cushing’s syndrome and Cushing’s disease (when 8 mg of dexamethasone is used). The third screening tool is the 24-hour urinary free cortisol (UFC) level. Any of the above three tests must be done in a systematic and timely fashion to be accurate and avoid false results or erroneous diagnosis.

Once elevated levels of cortisol are demonstrated in the setting of Cushing’s syndrome (and Cushing’s disease is appropriately ruled out), proper preoperative planning is crucial. Patients with diabetes and hypertension must be managed appropriately. Because of possible immunosuppression as a result of long-standing elevated levels of cortisol, care must be taken with prophylactic preoperative antibiotics. Due to long-standing suppression of the hypothalamic pituitary axis, imaging may depict a contralateral adrenal gland that is atrophied. In all cases, a stress dose of steroids should be administered preoperatively with a careful taper.

Pheochromocytoma

Patients who present with severe, episodic hypertension, palpitations, tachycardia, anxiety attacks, weight loss, sweating and facial flushing on physical exam should be suspected to have pheochromocytoma. The patient’s family history is also important as pheochromocytoma does not only occur sporadically but can be inherited or associated with several genetic syndromes, such as von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type II (MEN), familial paraganglioma syndrome, neurofibromatosis (NF-1), and succinate dehydrogenase deficiency syndrome of subunits B, C, or D (SDHB, SDHC, or SDHD).

First, biochemical evidence of the disease is confirmed with testing of plasma free metanephrines. In one study, sensitivity and specificity of this test were 96–100% and 87–92%, respectively. While the plasma free metanephrines is the most sensitive test, care must be taken when collecting these samples. There are numerous pitfalls that may affect the results of the testing ( Table 39.1 ). Usually, patients must have an IV inserted and be placed supine in a quiet room for 30 minutes. Any pain or anxiety may significantly affect the results of the test. Additionally, patients should be instructed to avoid any caffeine intake for at least 24 hours and avoid the medications listed in Box 39.1 . Perhaps, the most important and common medications to remember are acetaminophen, trycyclic anti-depressants and decongestants. Alternatively, (although now used less commonly) 24-hour urine collection for urine metanephrines and vanillylmandelic acid (VMA) testing can be performed. While the test is less sensitive than plasma free metanephrines, it is more specific (VMA specificity 93–97%).

With a high suspicion on clinical exam and confirmation by biochemical workup, the next step in workup of pheochromocytoma is often a combination of anatomic and functional imaging. In the past, contrast enhanced MRI was the preferred method of anatomic imaging in suspected cases of pheochromocytoma for fear of inducing adrenal crisis with the use of iodinated contrast in enhanced CT scanning. Now, however, CT with nonionic iodinated contrast is safe and provides excellent anatomic details. MRI (often bright on T2 sequence) is still a useful imaging modality in patients who have previous allergic responses to contrast mediums, in pregnant women, and in children being scanned. Several functioning radiographic studies such as metaiodobenzylguanidine (MIBG) and various types of PET scans are available. Although the detailed review of every imaging modality for pheochromocytoma is beyond the scope of this chapter, care must be taken in those undergoing MIBG scanning by providing patients with super saturated potassium iodide (SSKI) drops to be taken prior to exposing patient to radioactive iodine (thyroid protective measures).

The importance of preoperative preparation for surgical treatment of pheochromocytoma cannot be overstated. It includes patient compliance, preoperative echocardiogram (to evaluate the cardiac function and rule out cardiomyopathy), and evaluation by anesthesiology team. Medical preparation involves the liberal use of α-adrenergic blockade with phenoxybenzamine 10 mg BID with a slow increase in dose over 2–3 weeks prior to surgical intervention. The recommended dose of phenoxybenzamine starts at 10 mg BID and should be titrated up to as high as 400 mg daily until the patient becomes orthostatic or profound side effects become intolerable (such as tachycardia or nasal congestion). In cases of tachycardia, beta-blockers can be added, but should only be added after the adequate alpha blockade. Metyrosine (α-methyltyrosine) 250 TID to increase to 1.5 g in divided doses can also be used as an adjunct to phenoxybenzamine in preparation for surgery. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthesis cascade. Finally, patients are also encouraged to prepare with adequate fluid and salt intake to volume expand and compensate for the vasoconstrictive effects of pheochromocytomas and intravascular volume depletion.

Adrenal Carcinoma

Adrenocortical carcinoma (ACC) is a rare but aggressive tumor with a poor prognosis. Two-thirds of all ACCs are found to be hormonally active, and approximately 25% are found to be >6 cm on diagnostic imaging. As discussed earlier in this chapter, when an incidentaloma is found with an attenuation of greater than 10 HU on noncontrasted CT, the suspicion for ACC should be present. The suspicion is even greater when the mass is large (>6 cm) or has attenuation of >30 HU on noncontrasted CT. Clinically, patients may complain of flank pain, abdominal discomfort, or pressure with no specific symptoms due to the mass compression of adjacent abdominal structures or organs. Hormonally active tumors may present with symptoms such as virilization, hypercortisolism, or feminization. Therefore, similar to other adrenal masses, evaluation of ACC includes the assessment of hormonal activity. Biochemical workup must include thorough hormonal evaluation prior to surgical intervention as stress steroids may need to be administered preoperatively or repleted postoperatively to prevent adrenal insufficiency or addisonian crisis. On imaging studies, several characteristics of tumors may lead to higher suspicion of malignancy such as irregular tumor shape and enhancement with lack of homogeneous patterning of the tumor due to areas of focal necrosis. If there is a high suspicion for ACC, a metastatic workup is also indicated preoperatively. Preoperative planning involves an assembly of an experienced team of radiologists, surgeons, and anesthesiologists, and a great deal of planning from identifying surgical landmarks (as some tumors may invade surrounding structures or organs) to adequate vascular access and adequate amount of blood products available.

Metastasis to Adrenal

One common pitfall in the workup of an adrenal mass is failure to identify metastasis from a primary tumor. Although primary adrenal masses are most common, adrenals are also a common site of metastasis. Once metastasis is essentially ruled out, different diagnostic practices will guide a step-by-step workup of an adrenal mass (see Fig. 39.1 ). Conversely, a suspicion of metastasis should not preclude one from completion of biochemical interrogation of the adrenal mass. For example, one study evaluated patients with a history of primary tumors and suspected adrenal metastasis and found that as many as 24% of those adrenal masses were pheochromocytoma. This further underscores the importance that any adrenal mass should have a biochemical workup.