Insights on the Natural History of Adrenal Incidentalomas

Abstract

The adrenal incidentaloma is possibly the most common adrenal disorder encountered in everyday practice because extensive use of high-resolution cross-sectional imaging frequently leads to the incidental finding of an adrenal tumor (1). These clinically inapparent tumors are called adrenal incidentalomas to highlight their unexpected discovery through a diagnostic work-up done for reasons unrelated to previous suspicion of adrenal disease. Studies show that an adrenal incidentaloma is found in 4% to 5% of abdominal computed tomography scans (1, 2), and because of technological improvements in imaging, this frequency is expected to increase in the near future. The natural history of adrenal incidentalomas is still incompletely understood, and this important knowledge gap hinders appropriate patient care. It is reassuring that most of these tumors are benign (1, 2); however, molecular studies support the concept of multistep adrenocortical tumorigenesis, and an evolution from benign cortical adenoma to adrenal carcinoma has been reported (3). Moreover, adrenal adenomas can harm patients through their ability to secrete cortisol autonomously (4). In principle, this subclinical condition of mild cortisol excess may represent a preliminary stage of overt Cushing syndrome. In this context, Elhassan and colleagues (5) strive to provide meaningful information about several key aspects of the natural history of adrenal incidentalomas: risk for tumor growth and possible malignant transformation, risk for clinically overt hormone excess, and risk for morbidity and mortality associated with autonomous cortisol secretion. They did a careful meta-analysis of the literature, which is heterogeneous regarding the definition of adrenal incidentaloma and, more important, the definition of autonomous cortisol secretion and ascertainment of outcomes of interest. The first finding of the present study is that tumor growth was limited to a few cases and usually involved an insignificant change in sizegrowth was 10 mm or more in only 2.5% of caseswhereas malignant transformation was never observed. Cortisol autonomy was tied to increased risk for growth. These results robustly confirm, thanks to a comprehensive analysis of the available evidence, what was previously envisaged (6). The novel piece of information is that the chance of growth over time is reduced in larger tumors. Therefore, the outcome of this meta-analysis strongly supports guidelines from the European Society of Endocrinology and European Network for the Study of Adrenal Tumors (ESE/ENSAT) that recommend against further follow-up imaging for masses smaller than 4 cm with clear benign features on imaging (7). This meta-analysis should end controversy about the need for routine follow-up imaging (8). As the ESE/ENSAT guidelines indicate, an area of uncertainty exists for masses larger than 4 cm given the low number of such tumors included in follow-up studies (7). However, the present results also seem reassuring for this subset of tumors that represent fewer than 10% of adrenal incidentalomas. The second finding of the present study is that risk for overt Cushing syndrome was virtually absent, although clinically inapparent cortisol autonomy ensued in 4.3% of patients with nonfunctioning tumors. Again, this confirms and extends previous knowledge (6) and shows clearly that autonomous cortisol secretion is not a preliminary stage of overt Cushing syndrome. This finding fits well with the reported difference in molecular pathogenesis between adrenal adenomas associated with subclinical versus overt cortisol excess (9). The value of repeating hormone work-up during follow-up of patients with adrenal incidentalomas remains a matter of contention (8), and the present finding validates the advice of the ESE/ENSAT guidelines against further work-up in patients with nonfunctioning tumors (7). Although these guidelines suggest reassessment in patients with autonomous cortisol secretion who have associated comorbid conditions, the present results seem to further limit the role of hormone testing. It has to been argued, however, that we presently do not know whether the development of autonomous cortisol secretion during follow-up is tied to clinical consequences (4, 6). The third and most novel finding of the present study is that both patients with nonfunctioning tumors and those with tumors causing autonomous cortisol secretion had at baseline, and developed during follow-up, comorbid conditions and incident cardiovascular events. Because these conditions are potentially linked to cortisol excess, it may be surprising that patients with nonfunctioning tumors are also affected, albeit at a lower rate than those exposed to autonomous cortisol secretion. To what extent this represents ascertainment bias is presently unknown because patients with diseases are more likely to have imaging tests that may detect an adrenal incidentaloma. Alternative explanations could be found in the concept of reverse causality, implying that the metabolic syndrome or diabetes is promoting adrenal tumor development (10), or in the concept of a continuum of cortisol secretion from normal to autonomous that escapes precise categorization because of the limitations of endocrine tests. Consequently, tumors labeled as nonfunctioning may also retain the ability to secrete cortisol in lower levels of excess. Elhassan and colleagues (5) did not find any association between varying degrees of cortisol autonomy and cardiovascular disease, and they found that risk for death from any causeand from cardiovascular disease in particularwas similar between patients with nonfunctioning tumors and those with cortisol-secreting tumors. Evidence suggests, however, that a greater degree of cortisol autonomy, heralded by higher cortisol levels after overnight dexamethasone suppression, is linked to increasing cardiovascular risk (4, 6, 7), although we need more evidence to understand what level of cortisol autonomy is tied to clinical consequences. Answering this question is key to developing adequate decision-making strategies concerning the choice between surgery and conservative management for patients with adrenal incidentalomas. Elhassan and colleagues (5) have provided important insights on the natural history of adrenal incidentalomas that help in solving controversy and informing practice. Further studies are needed to associate results of endocrine work-up with clinical phenotyping and to define patient-centered outcomes for optimal treatment of such a common endocrine disorder.