A 68-year-old woman was referred to an Endocrinologist by her primary care physician after a 1.5 cm adrenal mass was incidentally noted on an abdominal CT urogram of the abdomen performed for the work-up of persistent hematuria. It measured 3 Hounsfield units before contrast was given, consistent with adrenal adenoma.

The patient’s past medical history was significant for hypertension controlled on a single anti-hypertensive agent, hyperlipidemia, and osteopenia. Upon further questioning the patient noted that she had gained 25 pounds in the previous 18 months. She had undergone menopause at 50 years of age.

On physical exam the patient was well appearing and obese. Her blood pressure was 158/88 mmHg and her pulse was 80 beats/min. She had no scalp hair loss, hirsutism, or acne. She did have an increase in the size of her dorsocervical fat pad. Cardiovascular exam revealed regular heart rate and rhythm, with no extra heart sounds. Lung exam was clear to auscultation with no wheezes. Abdomen was obese and soft. She did not have abdominal striae, lower extremity edema, or proximal muscle weakness or wasting.

Biochemical work-up revealed a fasting glucose of 78 mg/dl, creatinine if 0.7 mg/dl, BUN of 16 mg/dl, AST 19 U/l, and ALT of 15 U/l. The patient’s late afternoon serum cortisol level was 6.5 mcg/dl, ACTH was <10 pg/ml and DHEA-S was 31 mcg/dl (normal 35–430 mcg/dl). Midnight salivary free cortisol concentrations were 1.4 nmol/l and 1.6 nmol/l (normal range <0.3–4.3 nmol/l). Serum cortisol concentration after a 1 mg dexamethasone suppression test was 6.1 mcg/dl. 24-h urine free cortisol levels were 55 mcg/24 h and 32 mcg/24 h (normal <50 mcg/24 h). Serum aldosterone was 7.0 ng/dl and renin was 0.40. Serum catecholamine and 24-h urine catecholamine levels were normal.

Based on the partial serum cortisol suppression after 1 mg dexamethasone and mild elevation in urinary-free cortisol in the setting of a suppressed plasma ACTH concentration, the diagnosis of subclinical hypercortisolism was made. Treatment options were discussed with the patient including surgical removal of the adenoma or conservative management. The patient opted for conservative management with serial imaging and biochemical evaluation.

Incidentally identified adrenal nodules, adrenal “incidentalomas,” are becoming more commonly identified as the frequency of abdominal imaging has increased. An incidentaloma is defined as an adrenal mass of 1 cm or greater identified on imaging performed for indications other than the work-up or diagnosis of diseases of the adrenal gland [1].

Autopsy data report an overall prevalence of 1.0–8.7 % (mean 2.0 %). Prevalence varies significantly with age, with fewer than 1.0 % of patients less than 30 years of age having incidentalomas compared to 7.0 % of patients over 70 years of age [2]. The greatest rates of incidence appear to be in the fifth to seventh decades of life. Prevalence of incidentalomas identified by CT appears similar to autopsy data, with reports of <1.0 % prevalence to as great as 4.4 %. Some authors argue that the prevalence of incidentaloma on CT scan is increasing as these imaging techniques improve [2].

Malignant disease is always a concern in patients with adrenal incidentaloma. Adrenal cortical carcinoma (ACC) and metastatic disease comprise the majority of malignant disease in these patients. In populations with no history of cancer, two-thirds of clinically inapparent adrenal lesions are labeled benign [3]. To date there is no evidence suggesting that benign adenomas degenerate into malignant lesions [4].

ACC is rare, with an estimated incidence of 0.6–2 cases per million in the general population. In one case series ACC was found in 4.7 % of incidentally found adrenal masses [1]. The prevalence of ACC in incidentalomas may increase with size, with the greatest frequency in masses greater than 6 cm in diameter [4]. Metastatic disease is identified in approximately 2 % of incidentally identified adrenal masses, with the most commonly identified primary sites being breast, lung, lymphoma and melanoma [1, 4]. Most patients with adrenal metastases have a known primary malignancy and widespread disease.

Size and imaging characteristics can be used to help distinguish benign from malignant lesions. A diameter of greater than 4 cm has a 90 % sensitivity for detection of ACC, but only 24 % of lesions larger than 4 cm are malignant [5]. Retrospective analyses suggest that benign adenomas range in size from 1.0 to 9.0 cm in diameter, with a mean diameter of 3.3–3.5 cm [3]. Benign lesions are typically lipid rich, which results in a hypodense lesion on CT with low Hounsfield units, typically less than 10. Pheochronocytoma and malignant disease (both ACC and metastases) are lipid poor lesions and thus have high Hounsfield units, often greater than 25 [1]. Additionally, on delayed contrast-enhanced CT, adenomas show rapid washout (greater than 50 % at 10 min) while nonadenomas show delayed washout (less than 50 % at 10 min) [6].

The vast majority of incidentally identified adrenal nodules are benign adenomas and most are non-functional [7]. Work-up of these nodules should focus on finding the few that are hormonally active. This should include a careful history and physical exam focusing in particular on possible signs of hypercortisolism, elevated catecholamines, hyperaldosteronism, and hyperandrogenism. Biochemical testing should focus on evaluation for pheochromocytoma, subclinical hypercortisolism, and hyperaldosteronism. Hormonal work-up should be performed regardless of imaging phenotype or lesion size [1]. Incidental adenomas that secrete androgens or estrogens are quite rare and biochemical testing need only be performed if signs and symptoms are present [4].

Plasma free metanephrines have high sensitivity and are simpler to perform than 24-h urine testing and thus are an excellent initial test for the identification of pheochromocytoma [8]. Confirmatory testing in the form of a 24-h urine fractionated metanephrines and normetanephrines should be performed if the initial screening test is positive. Estimates of the frequency of pheochromocytoma in patients with adrenal incidentaloma are variable. Retrospective analyses report a prevalence of 1.5–23 % [4]. Most estimate that approximately 5 % of adrenal incidentalomas are clinically silent pheochromocytoma [1].

The initial screening test for adrenal hypercortisolism should include a 1 mg overnight dexamethasone suppression test. There is on-going debate regarding the appropriate cut-off for this test, though a serum cortisol concentration at 8 am of >5 mcg/dl is currently considered consistent with autonomous cortisol production [1, 4, 8]. A post-dexamethasone serum cortisol concentration of >5 mcg/dl will identify hypercortisolism with a specificity of 83–100 % but a sensitivity of only 44–58 %. Thus, one might adopt the lower serum cortisol cut-off of >1.8 mcg/dl after 1 mg overnight dexamethasone suppression, which is used in the diagnosis of overt Cushing’s syndrome, if the clinical suspicion for hypercortisolism is high. This cut-off will identify hypercortisolism with a sensitivity of 75–100 %, but with a specificity of only 67–72 %. A serum cortisol level of >5 mcg/dl after 1 mg overnight dexamethasone suppression should trigger confirmatory testing which will be discussed later in this chapter. Approximately 5 % of incidentalomas secrete cortisol [4].

Work-up for hyperaldosteronism should only be performed in patients with hypertension [1]. While many patients with hyperaldosteronism have hypokalemia, normokalemic hyperaldosteronism is much more common than previously thought. Thus, serum potassium cannot be used for screening in these patients. Plasma aldosterone to plasma renin activity ratio is recommended for screening. If this ratio is elevated confirmatory testing should be performed [9]. Approximately 1 % of incidentalomas secrete aldosterone.

There is little prospective data regarding the follow-up of patients with adrenal incidentalomas. Retrospective studies suggest that the majority of patients will not experience significant growth of their benign appearing incidentaloma or new hyperfunction up to 10 years after initial identification of a nodule [10]. In contrast, one case series of nine patients who underwent serial imaging with pheochromocytoma and adrenal cortical carcinoma suggest that these masses grow at a rate of 1.0 cm/year and 2.0 cm/year, respectively [1]. However, the majority of adrenal masses that grow have benign pathology when surgically removed.