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Although by definition the clinically inapparent adrenal masses appear "nonfunctioning," on the basis of clinical and essential laboratory findings more and more investigators have shown that a high percentage of them may be subclinical^ functioning and/or associated with other metabolic abnormalities. In a multicenter, retrospective evaluation of 1096 patients with adrenal incidentaloma, the work-up revealed that 9.2% had subclinical Cushing's syndrome, 4.2% had pheochromocytoma, and 1.6% had clinically unsuspected aldosteronomas.22

Rossi and colleagues10 followed prospectively 50 consecutive patients with clinically inapparent adrenal masses. Detailed hormonal investigation found 12 (24%) of 50 to have subclinical Cushing's syndrome defined as abnormal response to at least two standard tests of hypothalamus-pituitary-adrenal axis function in the absence of clinical signs of Cushing's syndrome. In the same study, 92% of patients had hypertension, 50% obesity, 42% type 2 diabetes mellitus, and 50% abnormal serum lipid concentration. The clinical and hormonal features improved in all patients treated by adrenalectomy but were unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months).

All 13 patients who had resection of truly nonfunctioning adenomas because of large size had improved clinically to such an extent that antihypertensive and antidiabetic therapy was reduced or discontinued. All the improvements persisted during the follow-up.

Another multicenter study12 of 64 consecutive patients with clinically inapparent adrenal masses found a higher than expected prevalence of abnormal glucose tolerance in 39 patients (61%). The same authors,35 following 62 consecutive patients with clinically inapparent adrenal masses, found abnormal glucose tolerance in 66%.

Midorikawa and coworkers,11 studying 15 patients with clinically inapparent adrenal masses (4 with subclinical Cushing and 11 with truly nonfunctioning tumors), found a high prevalence of altered glucose tolerance and insulin resistance. Adrenalectomy reversed insulin resistance in all patients with subclinical functioning and truly nonfunctioning adrenal adenomas.

Terzolo and associates8 followed 41 patients with clinically inapparent adrenal masses (12 with subclinical Cushing's syndrome) and compared them with 41 controls. They found that the 2-hour postchallenge glucose was significantly higher in patients than in controls. Similarly, both systolic and diastolic blood pressures were higher in patients. The calculated whole-body insulin sensitivity index (derived from the oral glucose tolerance test) was significantly reduced in the patients. They concluded that patients with these tumors (subclinically functioning or nonfunctioning)

display some features of the metabolic syndrome such as impaired glucose tolerance, increased blood pressure, and high triglyceride levels.

Garrapa and colleagues13 evaluated body composition and fat distribution, as measured by dual-energy x-ray absorptiometry (DEXA), in women with nonfunctioning clinically inapparent adrenal masses and in women with Cushing's syndrome compared with healthy controls matched for age, menopausal status, and body mass index. Women with clinically inapparent adrenal masses had larger waist circumference, reflecting intra-abdominal fat. The blood pressure was higher in patients with these tumors than controls, and 50% of patients were hypertensive. High-density lipoprotein (HDL) cholesterol levels and triglyceride mean values were also higher in patients with clinically inapparent adrenal masses than in controls. If central fat deposition, hypertension, and low HDL are important risk factors for cardiovascular disease, then patients with clinically inapparent adrenal masses, whether subclinically functioning or nonfunctioning, are at higher risk than the general population for cardiovascular disease.

Chiodini and coworkers14 performed a longitudinal study evaluating the rate of spinal and femoral bone loss levels in 24 women with clinically inapparent adrenal masses. They were divided into two groups on the basis of the median value of urinary Cortisol excretion. The group with higher Cortisol values (subclinical Cushing levels) had more lumbar trabecular bone loss than those with low Cortisol secretion (not hypersecreting tumors).

Therefore, the "cavalier" attitude toward clinically inapparent adrenal masses should be changed. These tumors are at an intermediate stage, between normal and pathologic. They should be screened to rule out (1) subclinical Cushing's syndrome, (2) subclinical pheochromocytoma, (3) subclinical primary aldosteronism, and (4) adrenal carcinoma (primary or solitary metastasis).

Screening for Subclinical Cushing's Syndrome

Patients with subclinical Cushing's syndrome have none of the signs and symptoms of the typical Cushing's syndrome (e.g., plethora, moon face, central obesity, easy bruising, proximate muscle weakness, acne, osteoporosis). The frequency of subclinical Cushing's syndrome among patients with adrenaloma ranges from 12% to 24%.10'36

Depending on the amount of glucocorticoids secreted, the clinical significance of subclinical Cushing's syndrome ranges from slightly attenuated diurnal Cortisol rhythm to atrophy of the contralateral adrenal gland, a dangerous condition after unilateral adrenalectomy if appropriate therapeutic measures are not taken early enough.37

The best screening test for autonomous Cortisol secretion is the short dexamethasone suppression test. A 2- or 3-mg dose is better than the usual 1-mg dose to reduce false-positive results. A suppressed serum Cortisol (<3 pg/dL or 80 nmol/L) excludes Cushing's syndrome. A serum Cortisol greater than 3 pg/dL requires further investigation, including a confirmatory high-dose dexamethasone suppression test (8 mg), corticotropin-releasing hormone test, and analysis of diurnal Cortisol rhythm. If serum Cortisol concentrations are not suppressible by high-dose dexamethasone, the diagnosis of subclinical Cushing's syndrome is established. Another suggested test is the growth hormone response to growth hormone-releasing hormone. A blunted growth hormone release might prove a sensitive and early sign of subclinical Cushing's syndrome.8 As already discussed, glucose tolerance is altered in patients with clinically inapparent adrenal masses (with and without subclinical Cushing), and a glucose tolerance test is recommended in patients with clinically inapparent adrenal masses.1012'38 Finally, bone mineral density of the spine should be performed to detect reduced bone mass in patients with subclinical Cushing's syndrome.14

Adrenal scintigraphy with 131I-6p-iodomethylnorcholes-terol (NP-59) can reveal a "functioning" but not "hypersecretory" tumor when there is an uptake of the nucleotide in the tumor site and no uptake in the contralateral suppressed gland. Some authors39'40 suggested a significant positive correlation between abnormal cortical secretion and NP-59 uptake, making NP-59 scanning a cost-effective diagnostic tool for evaluating clinically inapparent adrenal masses. Others15 found it cumbersome because it requires several days to obtain the images and it is unable to take up NP-59 in the presence of hemorrhage or inflammation; they recommend no routine use of NP-59 scanning.

Screening for Subclinical Pheochromocytoma

The typical patient with pheochromocytoma is hypertensive and may have paroxysmal hypertension and related symptoms (headache, hypertensive crisis, sweating, and cardiac arrhythmias). The proposed term subclinical pheochromocytoma refers to the totally asymptomatic clinically inapparent adrenal masses that histologically proves to be a pheochromocytoma. In several series of clinically inapparent adrenal masses, the frequency of pheochromocytomas ranges from 10% to 40%.3133 Although the percentage of asymptomatic pheochromocytomas among patients with nonfunctioning adrenal tumors is relatively high, most test positive on hormonal evaluation, which is a measurement of 24-hour urinary metanephrines and VMA or fractionated urinary catecholamines. In the National Italian Study Group, 27 patients (3.4% of the total patients with incidentaloma) were found to have pheochromocytoma; 24-hour urinary catecholamine and VMA concentrations were elevated in 86% and 4.6% of patients, respectively,22 indicating that a combination of tests is more useful clinically than an individual test. The efficacy of single-voided ("spot") urine metanephrine and normetanephrine assays for diagnosing pheochromocytoma has been documented. Such tests may avoid the inconvenience of 24-hour urine collection.41

There is no indication for routine use of 131I-meta-iodobenzylguanidine (I-MIBG) scintigraphy in the evaluation of an adrenaloma unless catecholamine and urinary metabolites are elevated.

Because there are cases of clinically inapparent adrenal masses that preoperatively had negative urinary VMA, metanephrines, and MIBG scanning but that intraopera-tively behaved (with later histologic proof) as pheochromocytomas, prophylactic measures should always be taken (e.g., arterial line, immediate access to intravenous nitro-prusside [Nipride]) during surgery.

Screening for Subclinical Primary Aldosteronism

The typical primary aldosteronism is characterized by hypertension with hypokalemia, elevation of plasma aldosterone, and suppressed plasma renin activity. Subclinical primary aldosteronism describes the patient with adrenaloma who is normotensive or hypertensive with normokalemia. More than 40% of patients with primary aldosteronism are normokalemic; therefore, the previously recommended measurement of potassium as the only test to rule out primary aldosteronism in the case of clinically inapparent adrenal masses should be abandoned.42 Instead, a detailed, time-consuming evaluation is necessary, especially in all hypertensive patients, to rule out primary aldosteronism, which may be the cause of hypertension in up to 15% of these patients.43,44 In a normotensive patient with a serum potassium level greater than 3.9 nmol/L, no further hormonal evaluation is necessary. The screening for subclinical primary aldosteronism should include, in addition to serum potassium, the upright aldosterone level to plasma renin activity (PRA) ratio, since a single value of aldosterone may be normal. Patients with two or more samples with a positive aldosterone-PRA ratio (>40) should undergo the fludrocortisone suppression test (0.4 mg every day for 4 days) or the acute saline suppression test (2 L of 0.9% NaCl solution infused intravenously over 4 hours) to confirm the diagnosis. Bilateral adrenal venous sampling with measurements of aldosterone and Cortisol levels is the necessary next step to lateralize and determine the subtype of primary aldosteronism to identify the patient who will be cured through surgery.

Screening for Adrenal Carcinoma

The risk of a clinically inapparent adrenal mass harboring a primary carcinoma of the adrenal is very low.45 The annual incidence of the latter has been estimated to range from 1 case per 600,000 to 1 case per 1.6 million persons. Its prevalence is approximately 0.0012% 46 In contrast, metastatic carcinoma to the adrenal is a common finding in patients with lung, breast, colon, and other extra-adrenal malignancies. In published series of surgically resected adrenalomas, the frequency of histologically confirmed primary adrenal carcinoma ranges from 4.2% to 25%.7 The frequency of adrenal metastasis from lung cancer at autopsy ranges from 17% to 38%. In patients with adrenal mass in the setting of extra-adrenal malignancy, the probability of this mass being metastatic ranges from 32% to 73%.5-33'47

SIZE OF TUMOR

The size of a clinically inapparent adrenal mass is frequently used to predict potential malignancy and the need for surgery. Although most clinically treated adrenal malignancies are discovered when they are larger than 6 cm in diameter, several reports have described very large tumors that never metastasized and small adrenal tumors that did (Fig. 67-2). In several series, adrenocortical carcinomas with a maximum diameter of 3 cm or less have been described.15'33'37'47

The size of a clinically inapparent adrenal mass as reported on a CT scan is usually smaller than the size reported on the histology report. This underestimation ranges from 16% to 47%.48 In an analysis of the CT and histology reports

Subclinical Cushing

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FIGURE 67-2. This larger than 6 cm, clinically inapparent adrenal mass was suspicious for malignancy on CT scan (A) but histologically was proved a benign cortical tumor (B).

of 76 patients with various diseases, we found48 that the mean estimated diameter of the adrenal tumor was 4.64 cm on the CT report when the real size (pathology report) was 5.96 cm. Further analysis of different CT scans revealed a consistent underestimation in all groups. In the group of adrenal tumors with a maximum diameter of less than 3 cm, the mean diameter reported on CT was 2.32 cm in contrast to the true histologic size of 3.63 cm (P < 0.001). We therefore proposed the formula

to correct the underestimated CT size so as to use the size criterion more accurately.48

A recent study49 showed that the above "Linos formula" turned out to be significantly more accurate than direct radiologic measurements in predicting the real pathologic size of the tumor.

IMAGING

In addition to assessing distant metastasis and tumor size, imaging studies may suggest malignancy. On a CT study, one may see a irregular, blurred, heterogeneous tumor with areas of necrosis; such lesions are suggestive of malignancy, especially if enlarged lymph nodes or local invasion is also detected.49

On MRI studies, one should look for heterogeneously increased, early T2-weighted signal, weak and late enhancement after gadolinium injection, or an intravascular signal identical to the tumor signal. When NP-59 scintigraphy is available, the lack of (or very weak) uptake in the tumor and normal contralateral uptake is suspicious for malignancy. Positron emission tomography (PET) can be used following the administration of 2-deoxy-2[18F]-fluoro-d-glucose (18F-FDG). The l8F-FDG PET scan is a useful tool confirming isolated metastases and selecting patients for adrenalectomy. It has been used in studies to distinguish between primary and metastatic adrenal lesions, especially in patients with other primary malignancies (Fig. 67-3).50

FINE-NEEDLE ASPIRATION

Fine-needle aspiration (FNA) biopsy of a clinically inapparent adrenal mass has a limited role. It is useful in cases of coexistent extra-adrenal carcinoma (usually lung cancer) to confirm the radiologic evidence of adrenal metastasis.

In a study by Silverman and coworkers,51 3 of 33 FNA specimens that contained "benign" adrenal tissue were later proved to be malignant. Each malignant lesion was smaller than 3 cm in diameter. In 14 patients in whom the FNA was nondiagnostic, two masses proved to be malignant. Generally, FNA cannot differentiate cortical adenoma from carcinoma because it cannot detect invasion of the tumor into the capsule.

Although it has been suggested that FNA is useful in the differential diagnosis of a cystic adrenal mass, we strongly object to such practice because cystic pheochromocytomas are prevalent. Diagnostic puncture of such a lesion (or of a rare cystic echinococcal parasitic cyst) can be harmful to the patient. The possibility of seeding a malignant adrenal neoplasm in the retroperitoneum is an additional reason that FNA should be discouraged.

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