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8.1 What Does “Adrenal Incidentaloma” Mean?

Adrenal incidentalomas are adrenal masses discovered by chance while performing imaging studies for reasons other than the suspicion or follow-up of adrenal diseases [1]. Per se, the term adrenal incidentaloma does not identify a precise diagnosis; rather, it is an umbrella definition encompassing many different tumor types.

8.2 How Often Will I Find an Adrenal Incidentaloma in My Practice?

According to the most recent radiological studies [2,3,4], the frequency of adrenal masses ranges from 1.4% to 7.3% in the general population. Similarly, autopsy studies reported a prevalence of adrenal masses of about 2%, ranging from 1% to 8.7% [1]. This variability is partially due to the differences in the age of the selected populations, since the prevalence of adrenal incidentalomas increases with age, approximating 10% in patients older than 80 years. However, it should be kept in mind that, although adrenal tumors are uncommon in young people and very rare in children and adolescents, in these patients the masses are more frequently hormone-secreting and malignant [1]. Therefore, the first lesson to draw from these epidemiological data is that in most cases we will manage elderly patients, often affected by several comorbid conditions, while in few cases we will deal with patients <40 years of age, but this context should ring an alarm bell in our mind.

8.3 What Type of Adrenal Tumor Can Be Found Incidentally?

Adrenal masses can be classified as follows [5]:

  1. 1.

    Adrenal adenomas and macronodular bilateral adrenal hyperplasia;

  2. 2.

    Other benign lesions (myelolipomas, cysts, hematomas, other);

  3. 3.

    Adrenocortical carcinomas (ACC);

  4. 4.

    Other malignant tumors (metastases, sarcomas, lymphoma);

  5. 5.

    Pheochromocytomas.

The majority of these lesions are benign (Table 8.1) [1, 6]; however, malignant or hormonally active adrenal lesions are associated with poor prognosis if not promptly identified and correctly treated. For this reason, determining whether the discovered mass has the potential to be malignant is of paramount importance [1].

Table 8.1 Comparison between frequencies of adrenal incidentaloma types based on clinical studies (hormonal and radiological work-up) and surgical studies (patients who underwent adrenalectomy)
Full size table

8.4 What Should I Do Next After Discovering an Adrenal Incidentaloma?

According to the guidelines of the European Society of Endocrinology (ESE) and European Network for the Study of Adrenal Tumors (ENSAT) [1], when an adrenal mass is discovered, clinicians should evaluate and define:

  1. 1.

    Risk of malignancy;

  2. 2.

    Hormonal activity.

The risk of malignancy and the hormonal excess should be evaluated simultaneously.

8.4.1 Risk of Malignancy

Malignancy is reported in 5–8% of patients with adrenal incidentalomas [5]. In a population-based study, the most common etiology in the category of malignant adrenal tumors was adrenal metastases (86%), while only 3.6% were ACC [3]. Nonetheless, ACC is the most frequent malignant adrenal tumor reported in endocrine case series and recent studies demonstrated that 38–44% of ACC present as incidentalomas [7, 8].

The malignant potential is influenced by both (a) patient and (b) tumor characteristics. Since no parameter can confirm or exclude by itself the malignant nature of the lesion, the evaluation should consider globally the following features.

  1. (a)

    Features influencing the “a priori” risk of malignancy [5]

    • Young age: adrenal incidentalomas are uncommon in children and adolescents and usually show an increased malignant potential in this population.

    • Constitutional symptoms: low-grade fever, fatigue, weight loss.

    • History of extra-adrenal malignancies or genetic syndromes associated with increased cancer risk (ACC or pheochromocytoma).

  2. (b)

    Imaging characteristics of the lesion [1]

    Non-contrast computed tomography (CT) is recommended as the first imaging modality, if not yet performed. This examination provides data about size, lipid content and homogeneity of the lesion. A key element is the evaluation of the mass density expressed in Hounsfield units (HU), because low HU values reflect high lipid content, and benign lesions are usually homogeneous and lipid-rich. Combining the characteristics of size, density and homogeneity, the ESE/ENSAT guidelines summarize the recommendations for different scenarios:

    • The adrenal mass is homogenous and ≤ 10 HU: benign lesion, no additional imaging is required after exclusion of hormonal excess.

    • Tumor size ≥4 cm and HU >20, or mass is heterogeneous: a malignant lesion should be suspected. In these cases, surgery is usually recommended after completing staging procedures (i.e., chest CT or 18F-FDG positron emission tomography [PET]/CT).

    • Cases that do not fit any of the previous categories need a multidisciplinary approach with an expert team. The team should consist of staff qualified for the management of adrenal tumors, and should comprise a radiologist, an endocrinologist and a surgeon. The options include proceeding immediately to another imaging test (i.e., FDG PET/CT or MRI) or follow-up imaging after 3–6 months, or proceeding swiftly to surgery, and the choice depends on patient’s age, history, clinical presentation, and imaging characteristics.

8.4.2 Hormonal Activity

Based on expert consensus, the evaluation of hormonal activity is indicated when adrenal tumor size is at least 1 cm or in the presence of clinical signs and symptoms suggestive for hormonal excess [1].

Studies show that up to 30–50% of adrenal lesions are responsible for hormone excess, often associated with increased cardiometabolic morbidity and mortality [2, 9,10,11,12,13].

A careful history should be collected and a physical examination focused on potential signs of overt hormone excess should be performed in all patients.

The evaluation of hormonal activity includes: (a) cortisol; (b) free plasma or urinary fractionated metanephrines; (c) aldosterone/renin ratio; (d) sex steroids and precursors of steroidogenesis.

  1. (a)

    Cortisol

    Adrenal cortisol secretion is the most frequent finding; therefore, it is mandatory to exclude autonomous cortisol secretion using the 1-mg overnight dexamethasone suppression test (DEX) [1, 6, 14]. This test assesses the normal function of the hypothalamus-pituitary-adrenal (HPA) axis feedback. Serum cortisol is evaluated in the morning at 8.00 am, after the patient has taken 1 mg of dexamethasone between 11.00 p.m. and midnight the previous night. A value of ≤50 nmol/L (≤ 1.8 μg/dL) may be regarded as physiologic, excluding cortisol excess and reflecting normal HPA axis suppression. Recently, the prevalent opinion is that DEX results should be considered as a continuous rather than a categorical variable; however, defining a cut-off is useful for distinguishing between functioning and non-functioning adenomas. Values above 50 nmol/L should be considered indicative of mild autonomous cortisol secretion (MACS). In these cases, the diagnosis should be confirmed with a second DEX test, while additional hormonal tests (late night salivary cortisol, 24-h urinary free cortisol) may be required depending on clinical circumstances, and pituitary disease should be excluded with ACTH level measurement. MACS is not associated with an increased risk of developing an overt Cushing’s syndrome (<1%) [15, 16], but the data have shown that it is associated with increased metabolic and cardiovascular risks [9,10,11,12]. In particular, MACS is associated with increased all-cause mortality, especially in women younger than 65 years [13]. Moreover, some but not all studies found a higher prevalence of osteoporosis and asymptomatic vertebral fractures in patients with MACS [17,18,19], particularly in postmenopausal women [20]. Screening for hypertension, type 2 diabetes mellitus and vertebral fractures are indicated in patients with MACS [1].

  2. (b)

    Free plasma or urinary fractionated metanephrines

    When discovering an adrenal lesion with indeterminate imaging characteristics or in the case of genetic syndromes harboring an increased risk of pheochromocytoma, clinicians should exclude this diagnosis through the measurement of free plasma or urinary fractionated metanephrines. This evaluation is not required when the mass has <10 HU.

    Before any surgery or biopsy, pheochromocytoma should be excluded to prevent a catecholamine crisis and define the best preparation and intraoperative management for the patient.

  3. (c)

    Aldosterone/renin ratio

    This test is indicated for patients with hypertension or unexplained hypokalemia to exclude primary aldosteronism.

  4. (d)

    Sex steroids and precursors of steroidogenesis

    These measurements are indicated in patients whose clinical and imaging characteristics are suggestive for ACC.

Adrenal biopsy should be considered to exclude an adrenal metastasis when this influences patient management. Moreover, it may be useful when rare tumors like adrenal lymphoma or sarcoma are suspected. Otherwise, adrenal biopsy is not part of the standard diagnostic workup of adrenal incidentalomas, because it has low diagnostic accuracy, especially for ACC, and is burdened by possible complications [1, 21]. Before performing an adrenal biopsy, catecholamine excess should always be excluded to avoid cardiovascular crises during the procedure [1].

8.5 Which Treatment?

The decision whether to perform an adrenalectomy or to simply follow up the adrenal incidentaloma over time with clinical, hormonal and imaging assessments should be guided by the patient’s characteristics (i.e.: performance status, age, patient’s preference), the malignant potential and the hormonal activity of the adrenal lesion.

It is of crucial importance that a multidisciplinary expert team evaluates whether or not there is an indication to perform the adrenalectomy [1].

After surgery, patients with DEX test results ≥50 nmol/L are at risk of developing adrenal insufficiency. For this reason, these patients should undergo perioperative glucocorticoid treatment at surgical stress doses and, after surgery, they should be followed by an endocrinologist until recovery of the HPA axis has been documented [1].

8.6 Which Patients Deserve Particular Consideration?

8.6.1 Mild Autonomous Cortisol Secretion

In patients with MACS the indication for surgery should be individualized. Many factors should be taken into account, but age and comorbidities are the main ones. Older people show greater cortisol levels after DEX regardless of comorbidities, and there is evidence that the clinical significance of MACS decreases in patients older than 65 years [13]. For these reasons conservative management is the most frequent choice in older people. The presence of uncontrolled hypertension, diabetes or fragility fractures and evidence of progressive disease, associated with inappropriate end-organ damage, are the features clinicians should consider when evaluating the indication for surgery.

8.6.2 Bilateral Adrenal Incidentalomas

The initial evaluation of bilateral adrenal lesions is the same as used for unilateral one. Bilateral disease can be attributed to:

  • Bilateral macronodular hyperplasia (congenital adrenal hyperplasia should be excluded by measuring 17-hydroxyprogesterone);

  • Bilateral adrenal adenomas;

  • Morphologically similar adrenal masses (non-adenoma);

  • Morphologically different adrenal masses.

Bilateral incidentalomas (especially bilateral macronodular hyperplasia and bilateral adrenal adenomas) are more frequently associated with MACS and both adrenal glands can contribute to cortisol excess. In these patients, surgical management should be individualized and bilateral adrenalectomy should be reserved for those with Cushing’s syndrome due to the high morbidity burden of this procedure.

In patients with large and bilateral metastases replacing the adrenal gland tissue, there is an increased risk of adrenal insufficiency, to be excluded with morning serum cortisol measurement.

8.6.3 Younger People (< 40 Years)

The approach to this population should be more aggressive due to increased risk of malignancy. For this reason, indeterminate adrenal masses should undergo surgical treatment [1].