1. Introduction
The most common endocrine-related incidentalomas are located in the adrenal, thyroid and pituitary glands [
1,
2]. Due to improvement in radiological techniques and early detection of diseases, the increase in prevalence of endocrine-related incidentalomas is expected to continue [
3]. Specifically, adrenal incidentalomas are mass lesions detected on imaging performed for another clinical reason different to suspicion of adrenal disease [
4].
It is known that multiple endocrine neoplasia syndrome type 1 (MEN1) is related to the presence of adenomas in multiple locations, but the presence of endocrine-related adenomas in patients without MEN1 syndrome has not been reported, probably due to their benign behavior or lower prevalence [
5]. In contrast, several case reports in the literature only reflect the presence of endocrine-related adenomas along with malignant neoplasms or with unusual hormone secretion [
6,
7,
8,
9,
10,
11].
Adrenal incidentalomas are reported in approximately 4.2% of imaging studies, and their prevalence reaches about 6–7% in autopsies. Their prevalence is age-related; specifically, it is about 0.2% in patients younger than 30 years and increases up to 7% in patients older than 70 years [
12]. Despite an adrenal incidentaloma being usually asymptomatic, an appropriate hormonal evaluation is necessary, since up to 55% can present with excess hormone secretion [
2,
4]. Specifically, mild autonomous cortisol secretion (MACS) is the most common hormonal finding, being observed in approximately 30% of adrenal incidentalomas [
13]. It has been previously named subclinical hypercortisolism due to the presence of excess biochemical cortisol in the absence of classic clinical features of Cushing syndrome [
2,
4], but it has been related to the presence of metabolic comorbidities or impaired control [
1].
Cortisol secretion has been previously associated with impaired cell proliferation, suggesting that hypercortisolism could be directly related to increased prevalence of benign and malignant lesions [
14,
15,
16]. Other studies, in contrast, have suggested that cortisol-related systemic alterations (in blood vessels and circulation) could alter the histological characteristics of different glands, contributing to the presence of adenomas in different locations [
17]. Furthermore, the dose-dependent effects of cortisol on cell proliferation have been reported in vitro: specifically, cortisol may increase mitosis, cell migration and cytokines release, which increases tumor proliferation in head and neck cancers [
14]. Additionally, chronic cortisol secretion produce functional epigenomic changes, which can induce specific cell phenotypes that have been related to several diseases including cancer [
18]. Furthermore, its effects might be tissue-specific; for example, an antiproliferative effect has been described in bone cells, which affects both healthy cells (in consequence producing osteoporosis) [
19,
20] and osteosarcoma cells, avoiding tumor spread and metastasis [
21].
In addition to these controversial results, cortisol secretion has been associated with increased cardiovascular risk. Specifically, the prevalence of cardiovascular outcomes is three times higher in patients with MACS than in patients with NFAIs [
22]. Current European clinical guidelines suggest individualizing surgical management depending on cortisol levels and the clinical evolution of comorbidities [
2,
4], but the presence of other lesions, including benign tumors such as endocrine-related adenomas, is not considered. In this context, we aimed to determine the prevalence of other endocrine-related adenomas in patients with adrenal incidentalomas and to compare the clinical characteristics, including metabolic comorbidities and mortality, depending on the presence of MACS.
4. Discussion
Current clinical practice entails the improved performance of numerous imaging techniques, resulting in increased diagnoses of incidental lesions, especially endocrine-related adenomas. In this context, adrenal incidentalomas represent a particularly important entity due to the possible presence of cortisol secretion and its related effects on morbidity and mortality. The prevalence of adrenal incidentalomas varies depending on age and the studied population. Imaging-based studies have reported an age-related prevalence, specifically in the range of 4–7% among people older than 40 years and up to 5–10% in patients older than 70 years [
24]. Autopsy series report prevalence of about 7% [
25]. Due to their relatively high prevalence in imaging studies, adrenal incidentalomas are a frequent consultation for endocrinologists.
In this context, our study aimed to report some clinical characteristics of patients with NFAIs and MACS, especially focusing on the prevalence of other endocrine-related adenomas. To the best of our knowledge, this is the first specific report of endocrine-related adenomas in a cohort of patients with adrenal incidentalomas.
As in our study, earlier reports have described a median age of adrenal incidentaloma diagnosis of 62 years old [
26]. Nevertheless, we found that adrenal incidentalomas were more prevalent in men, in contrast to previous reports, in which a slightly increased prevalence in women (55%) has been reported [
26]. Additionally, we observed a higher prevalence of MACS (30%) compared with that of other studies (20%) [
27,
28] but similar to other population-based reports (37%) [
26]. Additionally, an increased number of bilateral lesions was observed in our study (21.7%) compared with that in earlier reports in the literature (4.5%) [
26]. Differences across studies may be justified due to the different definitions of MACS employed and the different designs of the studies.
A recent metanalysis described a thyroid nodule prevalence of 24.83% in the general population, and the prevalence has increased during the last ten years, especially in women (36.5%1) compared with men (23.47%) [
29]. Furthermore, in the metanalysis, obesity was correlated with the prevalence of thyroid nodules [
29]. This finding was not observed in our cohort.
In this line, previous studies have described a significantly increased prevalence of thyroid nodules in patients with Cushing syndrome [
30], especially in Cushing disease (60%) [
30] compared with adrenal Cushing syndrome (25–30%) [
31], but no increase has been observed in patients with NFAIs [
30]. Based on this, it has been hypothesized that an unknown factor may affect both adrenal and thyroid glands when cortisol secretion is increased [
32]. In this study, we did not evaluate patients with adrenal Cushing syndrome, but in our cohort, we did not observe significant differences in the prevalence of thyroid nodules in patients with MACS of NFAIs.
Remarkably, we observed increased metabolic comorbidities in patients with MACS, thyroid adenomas and adenomas in other locations. Similarly, previous studies have described an increased prevalence of adrenal incidentalomas in elderly patients, which has been associated with increased arteriopathy of adrenal capsule arteries [
17]. Additionally, a higher prevalence of adrenal incidentalomas has been also reported in patients with hyperthyroidism, type 2 diabetes and hypertension [
25,
32,
33]. Moreover, MACS has been associated with other metabolic comorbidities including insulin resistance, obesity and metabolic syndrome [
34,
35,
36]. These relations are clearly observed in this study, specifically in the cohort of patients with thyroid adenomas and adenomas in other locations. The specific underlying mechanism is unknown, but altered inflammation, cytokine release, decreased plasma nitrate/nitrite concentrations and altered microcirculation have been proposed [
37,
38,
39,
40]. Furthermore, it has been also suggested that chronic cortisol excess is associated with impaired brain blood flow, which might affect the brain microenvironment and as a consequence produce impaired cognitive function [
41]. In our cohort, patients with thyroid adenomas and adenomas in other locations presented with increased prevalence of cerebrovascular complications, but other clinical conditions such as dementia were not considered. Furthermore, MACS was independently associated with increased mortality as previously reported [
42].
Regarding pituitary adenomas, these are a diverse group of tumors arising from the pituitary gland; specifically, an overall estimated prevalence of pituitary adenomas of 16.7% has been reported (14.4% in autopsy studies and 22.5% in imaging studies) [
43]. Historically, these tumors have been classified according to size and divided into microadenomas (maximal tumor diameter < 1 cm) and macroadenomas (maximal tumor diameter ≥ 1 cm). Due to the small size of many pituitary lesions, the fact that many are nonfunctioning pituitary adenomas or that they might present with a very mild hormone secretion, it is a challenge to accurately measure the real prevalence of pituitary adenomas in the general population [
43]. Chrisoulidou et al. described a prevalence of 8% of pituitary adenomas in patients with adrenal incidentalomas [
44]. In contrast, the prevalence rate in our cohort was almost half (4.1%). Similarly, MACS was not associated with the presence of pituitary adenomas [
44]. Despite this, it has been described that almost 23% of patients with adrenal incidentaloma present an alteration in the pituitary gland morphology, suggesting that an altered mechanism could affect cell proliferation on both glands.
A parathyroid adenoma is a benign tumor of the parathyroid gland that generally causes hyperparathyroidism. It is usually diagnosed when patients present with hypercalcemia; specifically, a single parathyroid adenoma is responsible for 80–85% of hyperparathyroidism, double adenomas are observed in 4–5% of cases and parathyroid hyperplasia in 10–12% of patients. Additionally, parathyroid carcinomas are very rare causes of hyperparathyroidism and account for less than 1% of the disease cause [
45,
46].
We did not find in the literature specific reports about parathyroid adenomas and adrenal incidentalomas apart from studies in patients with MEN1 or MEN1-like syndromes. Although parathyroid adenomas are not uncommon, these lesions can be frequently missed due to their small size [
47]. As previously described, hypercalcemia is frequently the leading sign for diagnosing these adenomas and is associated with several clinical outcomes, including increased cardiovascular risk and mortality. Specifically, hyperparathyroidism is associated with a higher incidence of hypertension, left ventricular hypertrophy, heart failure, cardiac arrhythmias and valvular calcific disease, which may contribute to higher cardiac morbidity and mortality [
48]. In our cohort we did not observe an increased prevalence of metabolic comorbidities or mortality, probably due to an appropriate, early clinical and surgical management of the primary hyperparathyroidism.
This study has some limitations. First, the retrospective nature of the study is accompanied by an intrinsic risk of bias and missing data. Additionally, we did not include patients with overt cortisol secretion, which could have allowed us to compare differences across different degrees of cortisol secretion. We did not specifically analyze hormone levels in pituitary or parathyroid adenomas. Finally, only endocrine-related adenomas were included in the analysis, and other benign lesions were not included in the analysis. In contrast, the most important strength of this study is the large number of well-characterized patients with adrenal incidentalomas and the novelty of the findings.