Management of Adrenal Incidentalomas

Adrenal incidentalomas have been described as a disease of modern technology [1] but they are not new; they are only increasingly recognized during life [2]. By definition, adrenal incidentalomas are discovered inadvertently in the course of workup or treatment of clinical conditions that are not related to suspicion of adrenal disease [3]. The unexpected discovery of an adrenal incidentaloma raises challenging questions for physicians and causes uncertainty and doubt in their patients. To address the uncertainty associated with adrenal incidentalomas, clinicians need to know the options for assessment and treatment of these masses with respect to their malignant potential and functional status.

The management of a specific disease should be guided by evidence-based demonstration of its efficacy, but for adrenal incidentalomas we only have low levels of evidence generated by case-control studies, case series, or expert opinions. The matter is complicated by the fact that adrenal incidentaloma is not a uniform disease; rather, the term adrenal incidentaloma includes a spectrum of different types of lesions arising from the adrenal glands or extra-adrenal tissues. Thus, the management greatly differs among the various lesions [4]. Data from the Italian survey on a series of 380 patients submitted to adrenalectomy demonstrated that adrenocortical adenoma is the most frequent type among adrenal incidentalomas, accounting for approximately 50% of cases. Also adrenocortical carcinoma (ACC) and pheochromocytoma (PHEO) were well represented in this surgical series with an observed frequency of 12% and 11%, respectively [5]. These figures overestimated the real prevalence of such tumors because these patients were recommended surgery. In series enrolled in Endocrinology or Internal Medicine departments, adrenocortical adenoma is by far the most frequent type of adrenal incidentaloma and in the Authors’ experience, the frequency of ACC and PHEO drops down to 1-2% (unpublished observation). Two basic questions should be answered before trying to outline some recommendations for the management of adrenal incidentalomas:

Which types of adrenal incidentaloma may cause harm to the patient? Can we effectively recognize and treat these types of adrenal incidentaloma?

We have to consider that appropriate management of adrenal incidentalomas is a growing public health challenge since the serendipitous detection of an adrenal mass increases with age and is expected to rise in populations that are getting older and may have widespread access to ever improving radiological techniques [1].

There are no doubts that ACC may significantly affect patients’ health and there is sufficient evidence to recommend surgery whenever possible. MacFarlane has reported that patients with untreated ACC have a median survival of 3 months [6] while complete surgical resection continues to be the treatment of choice for ACC and a margin-free resection is a strong predictor of long-term survival [7]. The suspicion of ACC is raised by radiologic criteria and finally verified by histopathology; fine-needle biopsy (FNB) is currently not indicated for the diagnosis of primary ACC because of poor differentiation from adenoma and safety issues [7] [8]. The risk of ACC is related to the mass size, even if the correlation is far from perfect. In the multicentric Italian experience, a cut-off at 4 cm had the highest sensitivity to differentiate ACC from benign lesions. The positive predictive value, however, was low because benign lesions were greatly exceeding ACC at any size [5]. Despite that only a limited number of patients with ACC has been included in imaging studies, current criteria suggestive of a benign adenoma include attenuation values <10 Hounsfield units (HU) on unenhanced computerized tomography (CT) and <30 HU on enhanced scans. Tumors with >10 HU include lipid-poor adenoma, PHEO, metastasis, and ACC [4] [8].

It is also conceivable that PHEO can lead to significant morbidity and mortality, particularly if it remains undiagnosed. An increasingly greater number of PHEOs are clinically silent: in large multi-institutional series of adrenal incidentalomas collected in Italy and Sweden, approximately 50% of the patients bearing incidental PHEO were normotensive or had stable low-grade hypertension that was indistinguishable from essential hypertension [5] [9]. Since nearly one third of all PHEOs show a nonspecific appearance at the imaging studies, it is mandatory to perform an appropriate biochemical screening in every patient with an adrenal mass. Screening is of utmost importance whenether FNB or surgical removal of the mass is programmed [10]. Prompt surgical resection remains the standard curative modality after specific preparation of the patient because up to 80% of patients with unsuspected PHEO who underwent surgery or anesthesia have died [8] [10]. The diagnostic approach to PHEO is addressed in a specific chapter of this issue.

The adrenal glands are a common site of metastasis (MET) from several tumors: lung cancer, breast cancer, kidney cancer and melanoma are the most frequent causes. There are conflicting data on the rate of adrenal METs in patients with extra-adrenal malignancy because the figure ranged from 32 to 73% in different series [8] [11]. The morphological CT imaging features of METs are nonspecific and FNB may be helpful in patients with a history of extra-adrenal cancer, no other sign of MET, and a heterogeneous adrenal mass with >20 HU, after exclusion of PHEO [4]. When an extra-adrenal malignancy is not obvious, search of the primary tumor should be undertaken; total body scan and adrenal FNB are reasonable in this context. In only a limited number of cases, an effective treatment of adrenal MET is available; however, the diagnosis of adrenal MET may change the therapeutic approach and has important implications on the clinical history of a cancer patient.

Based on the available scientific evidence, therefore, two major recommendations should be made for the management of adrenal incidentalomas:

To identify either primary (ACC) or secondary (MET) malignancy. To rule out PHEO.

Radiologic evaluation is key to this process and magnetic resonance imaging (MRI) is as effective as CT in distinguishing benign from malignant lesions and is increasingly used in this context [4]. Endocrine testing is necessary to exclude PHEO because this tumor may remain undiagnosed after imaging studies. Surgery is the appropriate therapeutic measure of either ACC and PHEO while treatment of MET depends on different clinical circumstances. Many other lesions, either neoplastic or not, may present as an adrenal incidentaloma that may be dealed with following specific algorithms. The first steps in the diagnostic and therapeutic approach to adrenal incidentalomas are outlined in [Fig. 1].

Fig. 1 Management approach to adrenal incidentaloma. PHEO, pheochromocytoma; ACC, adrenocortical cancer; MET, metastasis; FNB, fine-needle biopsy; PET, positron emission tomography.

In most cases, the adrenal mass displays the typical feautures of an adrenocortical adenoma (small size, round or oval shape with smooth margins, hypodensity with rapid washout of i.v. contrast or signal drop on chemical shift MRI [4] [8]) and the biochemical screening for PHEO is negative. We recommend surgery for any adrenal mass larger than 4 cm even if the CT appearance is benign, irrespective of functional status. By definition, the patients bearing incidentally detected adrenal masses should not show signs and symptoms of overt glucocorticoid, mineralocorticoid, or adrenal sex hormone excess. However, a previously unrecognized endocrine syndrome may be diagnosed after the serendipitous discovery of an adrenal mass; in such cases, the specific guidelines for treatment of that condition should be followed. The major issues to be addressed in formulating a management plan for clinically inapparent adrenocortical adenomas are the following ones:

To evaluate for primary aldosteronism (PAL). To evaluate for subclinical Cushing's syndrome (SCS).

The diagnostic and therapeutic management of adrenal incidentalomas presumed to be adrenocortical adenomas after imaging evaluation is outlined in [Fig. 2]. In a hypertensive patient bearing an adrenal adenoma it may be recommended to screen for PAL by measuring serum potassium and a plasma aldosterone concentration-plasma renin activity ratio, even if controversy exists on the cutoff values to ascertain the diagnosis [12]. While PAL is being diagnosed with such an increased frequency among hypertensive patients to claim that there is an epidemic [13], aldosterone-producing adenoma remains a rare diagnosis among adrenal incidentalomas. Adrenalectomy is an option for an individual with hypertension and an aldosterone-producing adenoma [3]. The reader is referred to the specific chapter of this issue for a comprehensive review of PAL.

Fig. 2 Management approach to clinically inapparent adrenal adenoma. APA, aldosterone-producing adenoma; SCS, subclinical Cushing's syndrome

However, the most controversial topic is how to screen for and treat SCS. The first uncertainty concerns demonstration of SCS, or “subclinical autonomous glucocorticoid hypersecretion” as this condition was defined at the recent National Institutes of Health (NIH) state-of-the-science conference [3]. The term preclinical Cushing's syndrome is not completely accurate since the evolution towards clinically overt hypercortisolism does occur rarely, if ever [2] [14] [15] [16] [17]. The pathophysiology of this endocrine disorder is straightforward: the adrenal adenoma secretes cortisol autonomously, in a way that is not fully restrained by pituitary feedback, and possibly in excess. However, the diagnostic process of SCS may prove to be challenging for either biological or methodological reasons.

First, the degree of hypercortisolism only minimally to slightly exceeds the physiological daily production rate of cortisol and is distributed continuously among different patients, because there is a spectrum of variability from non-functioning adenoma to autonomous cortisol-producing adrenocortical adenoma [3] [17]. As a consequence, a number of different alterations in the endocrine tests aimed at assessing the function of the hypothalamic-pituitary-adrenal (HPA) axis may be found in such patients [14] [17] [18] [19].

Second, the study of SCS is pursued by means of the standard biochemical tests used in the screening of Cushing's syndrome that are ill-suited to assessing patients who have only aspecific signs of hypercortisolism, if any, and very mild degrees of cortisol excess [15] [20]. The insufficient sensitivity of urinary free cortisol to recognize slight cortisol excess [21] and the technical problems with measurement of reduced ACTH concentrations to demonstrate functional autonomy of adrenocortical adenoma [22] are well known. Dexamethasone suppression tests have been extensively employed to screen for SCS in patients with adrenal incidentaloma but results of different studies are not readily comparable since various amounts of dexamethasone and different thresholds of suppression have been used [15].

It is therefore hardly surprising that the criteria for qualifying SCS are controversial [2] [15] [17]. The analysis of the relevant literature should be done taking into consideration that various endocrine algorithms (testing methods) with disparate thresholds have been used across different series that are also heterogeneous as to sample size and inclusion criteria [2] [3] [4] [5] [8] [14] [15] [16] [17] [18] [19] [23] [24] [25] [26]. The bottom line is that we presently do not have sufficient evidence to define a gold standard for the diagnosis of SCS. To provide a standard, the NIH state-of-the-science conference panel recommended the 1-mg dexamethasone suppression test to screen for autonomous cortisol secretion with the traditional threshold of 5 μg/dL (138 nmol/L) to define adequate suppression [3]. However, some experts have proposed to use lower cutpoints to increase the detection of subclinical hypercortisolism [27]. However, specificity decreases when lower post-dexamethasone cortisol thresholds are used, which may result in more false positive test results; thus, other authors have suggested to employ high-dose dexamethasone tests (3 or even 8 mg) since the diagnosis of pituitary Cushing's syndrome is not a consideration [1] [17]. At present, there is insufficient evidence to solve this controversy. It has also been advocated that a positive suppression test should be confirmed by other tests, but it remains unclear what is the most appropriate biochemical evaluation of silent cortisol excess [3]. The current uncertainty on what strategy is best suited to detect adrenocortical autonomy might be solved by finding at what point cortisol excess does lead to clinical morbidity or, in other terms, by finding which endocrine alteration is correlated with a particular phenotype that may cause harm to the patient. However, it is presently unclear whether and how SCS may affect patients’ health [2] [3] [4] [15] [16] [17] [28].

A critical issue is whether SCS may predispose to diseases such as arterial hypertension, obesity, or diabetes that are classical features of full-blown endogenous hypercortisolism [21] and cluster in the metabolic syndrome [29]. This is biologically plausible since many patients with clinically inapparent adrenocortical adenoma can be exposed to a chronic, albeit slight, cortisol excess [2] [15] [17] [26] [30]. There are indeed data indicating that some patients with subtle hypercortisolism may develop metabolic derangements, including insulin resistance, that may predispose to atherosclerosis and relevant cardiovascular complications [3] [30]. Interestingly, alterations in glucose metabolism and reduced insulin sensitivity are not restricted to patients with SCS; however, they are more marked in such patients than in those harboring nonfunctioning adenoma [31] [32] [33] [34].

However, caution should be taken in generalizing results from series gathered in academic centers: referall bias is an obvious issue since these studies are not population-based and there is the potential for confounding due to their case-control design. The complexity of an accurate matching between patients and controls for the many factors that may affect cardiovascular risk should be also disclosed [30]. Moreover, the prove of an association should not imply a cause and effect relationship. An alternative hypothesis that adrenal incidentaloma may itself be an unrecognized manifestation of the metabolic syndrome could not be ruled out [35]; however, a causal link between SCS and insulin resistance is the most plausible explanation for the available data [3] [30]. Osteoporosis is another established consequence of overt cortisol excess [21], but data on bone mineral density in patients with clinically inapparent adrenocortical adenoma are controversial [36] [37] [38].

The management of patients with SCS presents vexing problems. It is tempting to speculate that SCS represents a very mild variant of the syndrome of endogenous glucocorticoid excess sharing similar target organ damages and long-term complications with the full-blown variant. Even if progression to overt glucocorticoid excess is rare, SCS has the potential to carry an adverse prognosis since it may contribute to develop the phenotype of insulin resistance, thus portending to atherosclerosis and relevant cardiovascular complications. However, there is not evidence-based demonstration of the long-term complications of incidentally discovered adrenocortical adenomas and, consequently, the management of such tumors remains largely empirical [30]. Identification of patients with SCS may provide an opportunity for early treatment but it is unclear whether a precocious diagnosis and treatment is more effective in paucisymptomatic patients and whether the beneficial effects justify the costs incurred [1] [30]. Recent refinements in the field of minimally invasive surgery have rendered adrenalectomy a more tantalizing and easy-to-perform procedure. However, data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenocortical adenomas. It is important to remember that patients with subclinical hypercortisolism should receive perioperative glucocorticoids after removal of the functioning mass because they are at risk for hypoadrenalism [3].

While adrenalectomy has been demonstrated to correct the HPA axis abnormalities, its effect on long-term patient outcome and quality of life is unknown [1] [3] [4]. Until the risks and benefits of surgical removal of silent hyperfunctioning adrenocortical adenomas will be elucidated, we should likely elect to surgery patients with SCS who display diseases potentially attributable to cortisol excess that are of recent onset, or are resistant to medical intervention, or are rapidly decompensating [1] [17] [30]. This strategy is based purely on pragmatism and not evidence. Patients who are not candidates to surgery (possibly the majority) should be enrolled in a program of regular and careful follow up to detect, treat and control hypertension, diabetes, dyslipidemia and the other manifestations of the metabolic syndrome [30]. The limited and incomplete evidence available precludes making any stringent recommendation for periodic hormonal testing and repeat imaging evaluation for follow-up purposes. However, a repeat CT after three to six months from diagnosis should be recommended to recognize a rapidly growing mass whose malignant potential has escaped detection by the first imaging study.

Additional research is needed to guide practice and it is of primary importance the establishment of prospective studies to appraise the natural history and long-term morbidity of clinically inapparent adrenocortical adenomas. Further, the results of surgery in terms of risk, cost and outcome should be compared with the other possible interventions, including life-style changes and pharmacological therapy. The management of clinically inapparent adrenocortical adenoma may have a great deal to do with cardiovascular prevention and an optimal preventive measure should be harmless for patients while (laparoscopic) adrenalectomy has minimal (but not zero) morbidity and mortality. Thus, doing surgery on more people, even a safe procedure, has the potential to cause considerable morbidity [1].

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1 This work was partially supported by grants of the University of Turin (ex-60 % funds).

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