Adrenal adenoma

An adrenal adenoma is a benign neoplasm of the adrenal cortex, generally slow growing, that arises from differentiated cortical cells and, in most cases, is identified incidentally during imaging examinations performed for other indications. Clinically, it is the most common cause of an adrenal mass and the prototype of lesions with radiological features of benignity. However, it is not a uniform entity: a substantial proportion of adenomas are nonfunctioning, whereas others may secrete hormones overtly or subtly, with cardiovascular and metabolic effects even when symptoms are mild.

The importance of adrenal adenoma arises from the need to distinguish three dimensions that guide management: the probability of malignancy, which is generally low when imaging findings are typical; hormonal function, involving cortisol, aldosterone and, more rarely, other steroids; and the clinical relevance of hormone secretion, which may manifest as comorbidities potentially attributable to low-grade hormonal excess. Modern assessment is therefore an integrated process combining the clinical phenotype, endocrine biochemistry and radiological criteria, with the aim of avoiding both overtreatment and delays in recognizing higher-risk forms.

Adrenal adenomas are extremely common in contemporary clinical practice, particularly because of the increasing use of abdominal CT and MRI. Their estimated prevalence in the general population increases with age and is particularly high among older individuals, in whom the probability of incidentally detecting an adrenal lesion rises as a combined result of comorbidities, greater access to diagnostic imaging and an increase in cortical hyperplastic or nodular changes associated with ageing of the gland. In autopsy and radiological studies of unselected populations, adrenal masses compatible with adenomas account for the predominant proportion of incidental lesions.

From a clinical and epidemiological perspective, it is useful to distinguish the frequency of nonfunctioning adenomas from that of adenomas with autonomous hormone secretion. Most belong to the first group, but a non-negligible proportion exhibit low-grade cortisol secretion, now conceptualized as a spectrum of autonomous cortisol secretion that may be associated with hypertension, diabetes or lipid metabolism abnormalities even in the absence of overt features of Cushing syndrome. This intermediate area is crucial because it shifts attention from the organ to the patient: clinical relevance depends on comorbidities, physiological reserve and the duration of exposure to a nonphysiological glucocorticoid signal.

Several factors increase the likelihood of detecting an adrenal adenoma and, more importantly, a clinically significant adenoma. Advanced age is the most robust determinant, whereas the presence of hypertension, diabetes, visceral obesity and metabolic syndrome is more frequently associated with autonomous cortisol secretion. This relationship may be bidirectional: on the one hand, these conditions increase the likelihood that imaging will be performed; on the other, even mild chronic cortisol excess may contribute to their onset or treatment resistance. In parallel, hypertension associated with hypokalemia or characterized by severity and treatment resistance should always raise suspicion of an aldosterone-producing adenoma.

Iodine status and specific medications are not epidemiological drivers of adrenal adenoma, unlike the situation in certain thyroid diseases, but some clinical contexts increase the probability that an adrenal lesion will be relevant. A history of extra-adrenal malignancy alters the pretest probability and requires greater interpretative caution, although an adrenal mass in a patient with cancer may still be a benign adenoma. Similarly, osteoporosis, fragility fractures, sarcopenia and clinical frailty may indicate chronic glucocorticoid exposure, even when the biochemical excess is modest.

Finally, the functional epidemiology of adrenal adenomas is influenced by the sensitivity of endocrine tests and the thresholds used. More attentive diagnostic strategies reveal phenotypes that were previously underestimated, particularly mild autonomous cortisol secretion. The frequency of clinically relevant adrenal adenoma is therefore not a static figure, but depends on the operational definition, the quality of the diagnostic work-up and the population context, with direct implications for management and communication of risk to the patient.

An adrenal adenoma results from clonal proliferation of cortical cells, often with preservation of differentiated characteristics that account for its typical radiological appearance and, in some subtypes, its ability to produce steroids. Under physiological conditions, adrenocortical steroidogenesis is regulated mainly by ACTH in the zona fasciculata and zona reticularis, and by the renin-angiotensin system and potassium in the zona glomerulosa. Adenomas lie along a continuum in which proliferation may occur without hormone hypersecretion or may be accompanied by partially autonomous secretion that escapes feedback mechanisms to varying degrees.

From an etiological perspective, most adenomas are sporadic. However, current understanding recognizes that specific molecular alterations may promote both growth and hormone secretion. Alterations that enhance cAMP-PKA signaling and steroidogenesis have been described in cortisol-secreting adenomas, resulting in inappropriate cortisol production and suppression of the hypothalamic-pituitary-adrenal axis. In aldosterone-producing adenomas, variants that alter membrane ion homeostasis and intracellular signaling increase aldosterone production and promote a phenotype of mineralocorticoid-mediated hypertension. These mechanisms explain why some lesions are biochemically active while remaining histologically benign.

The pathophysiology of an adenoma therefore depends on its functional status. A nonfunctioning adenoma may be clinically silent and become relevant mainly because malignancy or dimensional progression must be excluded. By contrast, an adenoma with autonomous cortisol secretion may cause chronic glucocorticoid exposure that, even when it does not produce the classic features of Cushing syndrome, alters fat distribution, vascular tone, insulin sensitivity, immune modulation and bone turnover. The resulting risk profile is often dominated by hypertension, diabetes or prediabetes, dyslipidemia, muscle frailty and reduced bone mineral density, with an effect that tends to increase with age and duration of exposure.

In aldosterone-producing adenomas, the pathophysiology is centered on volume expansion and cardiovascular remodeling. Excess aldosterone increases renal sodium reabsorption and potassium and hydrogen ion excretion, promoting hypertension that is often more severe, a tendency toward hypokalemia and target-organ damage mediated by profibrotic and proinflammatory effects on the heart and blood vessels. Even when serum potassium is within the normal range, mineralocorticoid signaling may be clinically active, making biochemical recognition essential for reducing the long-term risk of cardiovascular events.

An important additional element concerns the relationship between lesion size, imaging and biology. Typical adenomas often contain variable amounts of intracellular lipid, which reduce attenuation on unenhanced CT and account for the ability of chemical shift MRI to demonstrate signal loss on opposed-phase images. Lipid-poor adenomas are more challenging because they may be radiologically indeterminate despite being benign and may require dynamic criteria, such as contrast-medium washout, or additional imaging techniques for reliable characterization.

Finally, the pathophysiology of an adenoma should not be interpreted solely as a property of the lesion, but as the interaction between hormone secretion, individual susceptibility and organ reserve. Two patients with similar levels of secretion may experience different clinical effects depending on age, comorbidities and frailty. This principle is central to current management, which is not limited to treating the mass but aims to reduce cardiometabolic risk and target-organ complications when hormone secretion, even if mild, is plausibly causal or contributory.

The clinical manifestations of an adrenal adenoma depend primarily on its hormonal activity and, secondarily, on mass effect, which is uncommon in small and medium-sized adenomas. Many patients are asymptomatic and come to medical attention because a CT or MRI performed for abdominal pain, urinary stones, oncological follow-up or other indications identifies an adrenal lesion compatible with an adenoma. In such cases, the clinical picture must be reconstructed retrospectively by looking for signs and comorbidities that may suggest previously unrecognized autonomous hormone secretion.

On medical history, a nonfunctioning adenoma generally causes no specific symptoms. However, the clinical history may reveal recently developed or increasingly difficult-to-control hypertension, worsening glycemic control, central weight gain, easy fatigability, loss of proximal muscle strength, insomnia and mood disturbances. Although these findings are not pathognomonic, they become relevant when part of a pattern consistent with autonomous cortisol secretion, especially when accompanied by osteoporosis, fragility fractures or recurrent infections suggesting a chronic glucocorticoid effect.

When the adenoma produces aldosterone, the history may include muscle cramps, episodic weakness, polyuria and nocturia, particularly when hypokalemia is substantial. However, the clinical picture is often dominated by severe or resistant hypertension and signs of target-organ damage, such as left ventricular hypertrophy or microalbuminuria. It is important to remember that many patients do not have spontaneous hypokalemia and that the clinical presentation may therefore be poorly suggestive unless active suspicion is maintained on the basis of the blood pressure profile and family cardiovascular history.

On physical examination, mild and nonspecific signs may be found in patients with low-grade cortisol excess, including visceral adiposity, hypertension, more fragile skin or easy bruising, reduced proximal muscle mass and, in some cases, signs of osteoporosis or vertebral pain caused by compression fractures. In patients with primary aldosteronism, cardiovascular assessment is central, with attention to blood pressure, signs of volume overload and the presence of complications. In patients without hormone secretion, the physical examination is often normal, and the clinical focus shifts to correct interpretation of imaging and risk stratification.

Mass effect causing pain, a sensation of fullness or compression is unusual in typical adenomas and should prompt reconsideration of the diagnosis when the lesion is large or atypical. Rapid growth or the development of unexplained systemic symptoms also requires caution, because these findings are more consistent with nonadenomatous lesions. In this sense, the clinical presentation of adrenal adenoma is often a presentation of comorbidities and risk rather than direct symptoms, requiring a medical approach capable of linking apparently common findings to a possible underlying endocrine driver.

Suspicion of an adrenal adenoma most often arises from imaging rather than from the clinical presentation, but proactive reasoning is essential to identify cases in which the lesion is functionally relevant. An adrenal mass with features of benignity, particularly a homogeneous appearance and low attenuation on unenhanced CT, strongly suggests an adenoma. However, the immediate clinical question is not only “what is it?” but also “what does it do?” An adenoma may be silent or may autonomously produce hormones, potentially causing a chronic comorbidity that benefits from etiological assessment.

Autonomous cortisol secretion should be suspected in the presence of hypertension, diabetes or impaired glucose tolerance, visceral obesity, osteoporosis, fragility fractures or sarcopenia, particularly when these conditions are more severe than expected, difficult to control or occur together. An otherwise unexplained profile of clinical frailty, with reduced resilience to stress and slow recovery from intercurrent illnesses, may also be consistent with chronic glucocorticoid signaling, even in the absence of classic stigmata.

An aldosterone-producing adenoma should be suspected in patients with resistant hypertension, severe hypertension of relatively early onset, hypertension associated with spontaneous or diuretic-induced hypokalemia, and disproportionate cardiovascular target-organ damage. In these situations, recognizing a mineralocorticoid driver is decisive because it enables targeted treatment, often with improved blood pressure control and a reduction in long-term cardiovascular risk.

It is equally important to recognize when the hypothesis of an adenoma should be questioned. Heterogeneous lesions with irregular margins, high attenuation on unenhanced CT, rapid growth or large dimensions require broader assessment, because the objective is to avoid missing alternative diagnoses that require a different approach. Clinical suspicion should therefore lead to a structured diagnostic process that confirms radiological benignity, defines hormonal function and quantifies the clinical relevance of any autonomous secretion, avoiding a uniform approach in patients with markedly different risk profiles.

The diagnosis of an adrenal adenoma is an integrated process combining imaging criteria for characterization of the mass with endocrine assessment to define its functional status. The first objective is to determine whether the lesion has features consistent with benignity. Unenhanced CT is a central tool because low attenuation, particularly when consistent with intracellular lipid content and a homogeneous appearance, significantly reduces the probability of malignancy. When attenuation is not low or the lesion is radiologically indeterminate, second-level techniques become important, including CT assessment of contrast-medium washout or chemical shift MRI, which exploits the presence of intracellular lipid to distinguish adenomas from many nonadenomatous lesions.

In parallel, endocrine assessment should not be guided by intuition but by a rational algorithm. According to the European Society of Endocrinology and ENSAT guidelines for the management of adrenal incidentalomas, the initial work-up aims to exclude clinically relevant hormone excess and identify patients in whom mild autonomous cortisol secretion may contribute to cardiometabolic comorbidities.

Diagnostic assessment of adrenal adenoma

• Radiological characterization: definition of criteria of benignity using unenhanced CT and, when necessary, additional techniques for indeterminate lesions, integrating morphology, homogeneity and contrast-enhancement behavior.
• Cortisol assessment: low-dose dexamethasone suppression testing as the cornerstone for identifying autonomous secretion and estimating its possible clinical relevance in relation to comorbidities.
• Targeted aldosterone screening: assessment of the aldosterone-to-renin ratio in patients with hypertension, especially when hypokalemia or features of severity and treatment resistance are present, because identification of a mineralocorticoid phenotype changes the therapeutic strategy.
• Exclusion of alternative diagnoses when indicated: extension of the diagnostic work-up in the presence of atypical imaging, lesion growth, a history of cancer or inconsistency between the clinical presentation and test results, using a multidisciplinary approach for complex decisions.

A clinically crucial point is distinguishing a radiologically benign lesion from an indeterminate lesion. In a typical adenoma that is homogeneous and has low attenuation on unenhanced CT, attention is focused on hormonal function and individual risk. In lipid-poor lesions or lesions with higher attenuation, washout CT may improve diagnostic accuracy, whereas chemical shift MRI is particularly useful when radiation exposure should be avoided or CT findings are inconclusive. In selected contexts, additional techniques such as PET with metabolic tracers may be considered, particularly when the pretest probability of malignancy is higher, but interpretation must remain anchored to the clinical context and pre-examination probability.

The biochemical diagnosis of autonomous cortisol secretion requires cautious interpretation. The glucocorticoid signal may be modest, variable and influenced by medications or intercurrent conditions, and its clinical relevance should be inferred by integrating the results with potentially attributable comorbidities. In primary aldosteronism, screening should be followed by confirmation and, where appropriate, lateralization procedures to distinguish unilateral secretion from bilateral disease, because this distinction radically determines the choice between surgery and medical therapy.

One frequently misunderstood issue is the role of biopsy. In the assessment of adrenal masses, biopsy is not routinely used to distinguish an adenoma from an adrenocortical carcinoma and may be misleading or hazardous, in addition to providing no reliable information on hormonal function. Biopsy may be justified only in selected scenarios, typically when there is a history of extra-adrenal malignancy and the result would alter the oncological strategy. Even then, it should be considered only after excluding diagnoses that would make the procedure dangerous or inappropriate and after multidisciplinary evaluation.

Ultimately, the diagnosis of adrenal adenoma is not merely a radiological label, but a clinical assessment that identifies a lesion as probably benign, defines its endocrine function and establishes whether and to what extent that function may contribute to cardiometabolic risk and frailty. This step makes it possible to implement personalized treatment and follow-up proportionate to the actual risk.

The classification of adrenal adenomas is primarily functional and radiological, because these two dimensions determine therapeutic indications and the intensity of follow-up. From a functional perspective, the first distinction separates nonfunctioning adenomas from secreting adenomas. Nonfunctioning adenomas are those in which there is no evidence of clinically significant hormone excess. However, this definition requires accurate initial endocrine assessment because mild autonomous cortisol secretion may be clinically important despite the absence of the classic phenotype.

A second category includes adenomas with autonomous cortisol secretion along a spectrum. In its most evident form, glucocorticoid excess is associated with the signs and symptoms of Cushing syndrome. More commonly, however, the presentation is subtle and becomes apparent through cardiometabolic and skeletal comorbidities. In this setting, severity is not measured solely by a laboratory value, but by the combination of biological exposure and patient vulnerability, namely the effects on blood pressure, glycemia, weight, bone and muscle.

Aldosterone-producing adenomas form a separate category because of their pathophysiology and therapeutic implications. In these forms, the central clinical feature is mineralocorticoid-mediated hypertension, with a long-term risk of cardiovascular and renal damage. Severity may be substantial even when hypokalemia is not marked, because risk is driven more by blood pressure burden and target-organ remodeling than by a single electrolyte measurement.

From a radiological perspective, classification distinguishes adenomas with classic features of benignity from indeterminate lesions. A typical adenoma is homogeneous and often has a low attenuation value on unenhanced CT. Adenomas with low lipid content require additional criteria and may fall into the indeterminate group, in which the strategy is based on dynamic imaging, comparison over time and the clinical context. Within this dimension, severity is related to the probability of malignancy and the need to avoid missing alternative diagnoses.

Finally, classification must include the dimension of clinical relevance. A small, radiologically benign and nonfunctioning adenoma in a young patient without comorbidities has a different significance from the same lesion in an older patient with frailty, resistant hypertension and diabetes. This is why modern management moves beyond rigid categories and adopts integrated stratification aimed at reducing actual risk and maximizing the expected clinical benefit.

Treatment of an adrenal adenoma depends on two key questions: whether the lesion is functioning and whether it is suspicious for malignancy or unfavorable progression. In radiologically benign, nonfunctioning adenomas, the most appropriate strategy is often conservative, with follow-up proportionate to risk. The objective is to avoid unnecessary interventions and minimize exposure to repeated imaging and redundant diagnostic pathways, without overlooking situations in which hormone secretion or lesion biology may alter prognosis.

When autonomous cortisol secretion is present, treatment must be patient-centered. In cases of overt glucocorticoid excess, treatment generally tends toward surgery when secretion is unilateral and the clinical profile permits it. In mild autonomous cortisol secretion, the decision is more complex and requires assessment of whether comorbidities such as hypertension, diabetes, visceral obesity or osteoporosis are plausibly sustained by the cortisol-secreting lesion and whether removing it may improve outcomes. Personalization is essential in this setting: not all patients obtain the same benefit, and the risk-benefit balance varies according to age, frailty and comorbidity burden.

For aldosterone-producing adenomas, the strategy depends on lateralization of secretion. When production is unilateral, adrenalectomy may provide causal control of the hormonal driver and significantly reduce blood pressure burden and cardiovascular risk. When secretion is bilateral or surgery is not indicated, medical treatment with mineralocorticoid receptor antagonists becomes the cornerstone, with careful dose titration and monitoring of potassium and renal function. In this context as well, treatment is not merely a matter of controlling blood pressure, but of reducing the target-organ effects of aldosterone signaling.

Surgery is also indicated when the lesion does not have typical features of benignity or when findings increase the probability of nonbenign behavior, such as significant growth over time, large size associated with nonreassuring imaging or suspicious morphological characteristics. In these cases, the decision should be multidisciplinary, integrating radiology, endocrinology and surgery, because the benefit of timely intervention may be substantial when the pretest probability of malignancy is increased.

A cross-cutting therapeutic issue concerns perioperative and postoperative management in cortisol-secreting forms. Suppression of the hypothalamic-pituitary-adrenal axis may require glucocorticoid support and monitoring of recovery of residual adrenal function. Even in mild autonomous cortisol secretion, the risk of relative postoperative adrenal insufficiency should not be underestimated, because adaptation of the axis may take time and safe management reduces complications and hospital admissions.

Finally, treatment always includes management of comorbidities. Blood pressure control, metabolic optimization, prevention and treatment of osteoporosis, restoration of muscle function and reduction of cardiovascular risk are integral components of care. In many patients, particularly those with autonomous cortisol secretion, clinical benefit derives both from correction of the endocrine driver and from comprehensive intervention on lifestyle and treatment of comorbidities within a coordinated and continuous care pathway.

Follow-up of an adrenal adenoma should be proportionate to risk and guided by radiological and functional criteria. When the lesion has clear features of benignity and there is no evidence of clinically relevant hormone secretion, the objective is to avoid unnecessary repeated investigations, reducing radiation exposure, patient anxiety and diagnostic cascades. In this setting, clinical surveillance focuses primarily on recognizing changes in comorbidities that may warrant targeted endocrine reassessment.

For indeterminate lesions that are not surgically removed, interval imaging may be indicated to document stability and reduce uncertainty. The choice of technique depends on the clinical context, age and risk profile, and lesion growth should be interpreted in a clinically meaningful manner, distinguishing minimal variation from dimensional increases consistent with significant biological progression. Radiological follow-up should not replace clinical judgment: stability and benign features reinforce the diagnosis of adenoma, whereas growth or a change in appearance requires reassessment.

Endocrine follow-up is particularly important in adenomas with autonomous cortisol secretion. In these patients, surveillance should include monitoring of comorbidities potentially attributable to cortisol, such as hypertension, glucose abnormalities, lipid profile, body weight and bone health. The objective is not to repeat tests automatically, but to measure clinical effects over time and identify early those who are accumulating cardiometabolic risk or frailty, because this may shift the balance toward more interventional strategies or more intensive medical management.

In patients with primary aldosteronism treated surgically or medically, follow-up focuses on blood pressure control, electrolyte balance and prevention of progression of renal and cardiovascular damage. After adrenalectomy, it is essential to assess the blood pressure response and any residual requirement for antihypertensive medication, because complete resolution of hypertension is not guaranteed in all patients, particularly when hypertension has been present for a long time or when other contributing factors coexist.

After surgery for a cortisol-secreting adenoma, monitoring should include assessment of residual adrenal function and adjustment of glucocorticoid therapy when required, together with evaluation of metabolic and muscular recovery. In many cases, improvement in comorbidities is gradual and takes several months. Effective follow-up therefore supports the patient while the clinical balance is restored, avoiding both iatrogenic hypocortisolism and underestimation of persistent risks.

In summary, follow-up of adrenal adenoma is not a rigid protocol applied identically to every patient, but a pathway tailored to radiological benignity, the hormone secretion profile and individual vulnerability. Well-designed monitoring reduces overdiagnosis while promptly identifying patients who may benefit from targeted treatment and preventive strategies for cardiometabolic and skeletal complications.

The prognosis of an adrenal adenoma is generally favorable, particularly when the lesion is radiologically benign and nonfunctioning. In these cases, the probability of malignant transformation is extremely low, and the clinical effect is related more to appropriate management of the incidentaloma than to an intrinsic risk posed by the adenoma. However, prognosis changes when the lesion is associated with autonomous hormone secretion, because outcomes depend on the duration of exposure and on the ability to reduce cardiometabolic and target-organ risk over time.

The most relevant complications of cortisol-secreting adenomas, even when secretion is mild, are cardiovascular and metabolic. Chronic glucocorticoid exposure may promote hypertension, diabetes, visceral obesity and dyslipidemia, increasing the long-term risk of cardiovascular events. The musculoskeletal system is another major target: reduced muscle mass and strength increase the risk of falls, whereas impaired bone remodeling promotes osteoporosis and fragility fractures. These complications are not sudden but cumulative, and prognosis depends on the ability to recognize and treat them early, with or without surgery according to the patient’s profile.

In aldosterone-producing adenomas, complications are dominated by cardiovascular and renal damage associated with mineralocorticoid-mediated hypertension. In addition to the blood pressure burden, aldosterone may promote remodeling and fibrosis, increasing the risk of atrial fibrillation, ventricular hypertrophy and progression of kidney disease. Targeted surgical or medical treatment improves prognosis by lowering blood pressure and attenuating mineralocorticoid signaling, although complete recovery depends on the duration of the disease and the presence of pre-existing target-organ damage.

Another group of complications is related to treatment. After adrenalectomy for a cortisol-secreting adenoma, transient or more prolonged adrenal insufficiency may occur because the contralateral gland and central axis may require time to recover. This risk explains the need for clinical and biochemical monitoring and cautious management of glucocorticoid replacement. Surgery may also cause general and procedure-specific complications, such as bleeding or infection, which are relatively uncommon in experienced centers but must be considered in the risk-benefit assessment, particularly in frail patients.

Overall, adrenal adenoma is a highly prevalent condition with an often excellent prognosis, but it includes a clinically relevant subgroup in which autonomous hormone secretion, even when mild, acts as a multiplier of cardiometabolic and skeletal risk. The best prognosis is achieved when the initial assessment is accurate, the therapeutic decision is personalized and follow-up is directed toward preventing and treating the comorbidities that truly determine long-term outcomes.