Adrenal incidentaloma: what to investigate

A 62-year-old woman has an abdominal CT scan to investigate pain in her right flank. The pain was from a small kidney stone, which has already passed. At the end of the report, however, a line appears that nobody asked for: "2.3 cm nodule in the left adrenal gland". She has hypertension, type 2 diabetes and arrives at the office with a simple, anxious question: "Is this cancer?"

The nodule found by chance in the adrenal gland, called an adrenal incidentaloma, has become a routine encounter in clinical practice. The more imaging tests are done, the more of these nodules appear. Most are benign and produce no hormone at all, but a small portion hides a malignant tumor, a pheochromocytoma or autonomous hormone production that weighs on cardiovascular and metabolic health.

The reasoning in the face of this finding revolves around two questions: is the nodule benign or malignant, and does it function or not function. This text shows how guidelines and cohorts from several countries answer these questions, which tests enter the initial investigation and how to decide on follow-up without burdening the patient with unnecessary tests.

Key points

• An adrenal incidentaloma is a nodule found on imaging done for another reason, usually 1 cm or larger.
• The vast majority are benign adenomas without hormone production, but investigation of malignancy and of function applies to all.
• Density on unenhanced CT is the main tool for separating a fat-rich adenoma from an indeterminate lesion.
• The 1 mg dexamethasone suppression test, metanephrine measurement and, in hypertensive or hypokalemic patients, the aldosterone/renin ratio form the core of the hormonal evaluation.
• A homogeneous nodule with low density on unenhanced CT does not require imaging follow-up according to the most recent European guideline.

What an adrenal incidentaloma is

An adrenal incidentaloma is an adrenal mass discovered on an imaging test done for a reason unrelated to adrenal disease. The guideline from the Korean Endocrine Society defines the finding this way and notes that nodules smaller than 1 cm generally do not fall under the definition, with further investigation recommended for lesions larger than 1 cm without signs of hormone excess (Lee et al., 2017).

The definition therefore excludes the patient who was already having imaging for suspected adrenal disease, such as someone investigating hypertension with hypokalemia or signs of Cushing. It also excludes, in most guidelines, the patient with cancer undergoing staging, because in that patient the probability of metastasis changes the whole reasoning. A review of the recommendations of the European Society of Endocrinology aimed at radiologists highlights precisely these special situations, such as bilateral incidentalomas, patients with cancer outside the adrenal gland, the young and the elderly (Sahdev et al., 2017).

Why the term matters

The name "incidentaloma" carries an important message: the finding was not sought. This means the pretest probability of serious disease is low, and that every test ordered from then on must be weighed against the risk of a diagnostic cascade. Anyone who understands pretest probability avoids both dismissing the finding and endless investigation.

How often the finding appears

The frequency of incidentaloma depends on age and type of test. A review on the topic gathers autopsy data showing a prevalence of less than 1 in 100 in the young, about 3 in 100 in middle-aged adults and more than 15 in 100 above age 70, and, in imaging studies, 2 to 4 in 100 in middle age, reaching more than 10 in 100 from age 70 onward (Ceccato et al., 2021).

A systematic review on imaging notes that adrenal masses appear by chance in 5 in 100 CT scans, and that in the United States alone 81 million CT scans were performed in 2013 and 2014 (Dinnes et al., 2016). The volume of tests turns an individually rare finding into a public health problem.

What routine data show

A study from a large UK teaching hospital reviewed 479,945 imaging reports made between 2015 and 2019 and identified adrenal lesions in 1.2 per 100 exams, with a frequency of 3.0 per 100 on abdominal CT scans (Hanna et al., 2022). In the same study, the number of exams grew by 7.7 per 100 per year, and the number of exams with an incidentaloma grew by 14.7 per 100 per year.

The most troubling finding came later. Only 394 of the 4097 patients with an incidentaloma, or 9.6 per 100, had a referral to endocrinology recorded within 90 days, and older patients were referred less often (Hanna et al., 2022). The finding is in the report, but the reasoning does not always happen.

What the nodule usually is

The distribution of diagnoses is the basis of any reasoning about the incidentaloma. The numbers vary between cohorts, but the overall picture is stable: the vast majority are non-functioning adenomas, and a minority carry disease that changes management.

Data from large cohorts

A Polish cohort with 2005 patients and 2498 tumors showed that 83.1 per 100 tumors were hormonally inactive, with autonomous cortisol secretion present or suspected in 6.6 per 100, pheochromocytoma in 4.7 per 100, hyperandrogenism in 3.1 per 100 and primary hyperaldosteronism in 2.4 per 100 (Cyranska-Chyrek et al., 2019). In the same cohort, hypertension was present in 76.6 per 100 patients, which recalls how often the incidentaloma appears on ground of cardiovascular risk.

The Korean prospective COAR study, with 1005 patients assessed by CT, found 83.3 per 100 non-functioning nodules, 4.4 per 100 with subclinical hypercortisolism, pheochromocytoma in 6.0 per 100 and primary aldosteronism in 6.1 per 100 (Ahn et al., 2018).

The guideline synthesis

The Korean guideline compiled the literature and presents averages of 6.2 per 100 for pheochromocytoma, 8.1 per 100 for Cushing syndrome, including forms without symptoms, 3.9 per 100 for hyperaldosteronism and 2.6 per 100 for malignant tumors, adding adrenocortical carcinoma and metastases (Lee et al., 2017). The ranges are wide, and that is information too: the population seen at each service changes the probability of each diagnosis.

Diagnosis	Polish cohort (2005 patients)	Korean COAR cohort (1005 patients)	Korean guideline average
No hormonal function	83.1 per 100 tumors	83.3 per 100	not reported as an average
Autonomous cortisol secretion	6.6 per 100	4.4 per 100	8.1 per 100
Pheochromocytoma	4.7 per 100	6.0 per 100	6.2 per 100
Primary aldosteronism	2.4 per 100	6.1 per 100	3.9 per 100
Malignant	not reported as a total	not reported as a total	2.6 per 100

Table sources: Cyranska-Chyrek et al., 2019; Ahn et al., 2018; Lee et al., 2017.

The reasoning that arises from this table is that of the base rate at diagnosis: before any test, the non-functioning adenoma is the most likely hypothesis, but the minorities are serious enough to justify standardized investigation.

First question: benign or malignant

Imaging answers the question about malignancy. In practice, it does so through three features: size, density and behavior after contrast.

Size

Size is the simplest piece of data and one of the heaviest. The Korean guideline lists a nodule of 4 cm or more among the signs of malignancy and recommends considering surgery in incidentalomas larger than 4 cm, regardless of hormonal function (Lee et al., 2017). In the Polish cohort, the risk of malignancy in tumors larger than 6 cm reached 37.7 per 100 (Cyranska-Chyrek et al., 2019).

Size, however, does not decide on its own. Small nodules can be malignant, and large nodules can be adenomas. The authors of the COAR study observed that Korean incidentalomas were smaller and suggested that a lower size cutoff might be needed to detect adrenocortical carcinoma in that population (Ahn et al., 2018).

Density on unenhanced CT

The typical adenoma is rich in intracellular fat, and fat lowers the density measured in Hounsfield units (HU). For this reason, unenhanced CT is the initial exam recommended by the Korean guideline, which lists a density of 10 HU or more among the signs of malignancy (Lee et al., 2017).

The systematic review by Dinnes and colleagues gathered 37 studies and concluded that, with limited data, a density above 10 HU has high sensitivity for malignancy, meaning masses with 10 HU or less are unlikely to be malignant (Dinnes and colleagues, 2016). The same authors warn that most studies were small and at high or uncertain risk of bias, and that the evidence for each imaging test on its own is still insufficient.

The 2023 European guideline went a step further. According to the review by Park and colleagues, a homogeneous adrenal mass with 10 HU or less on unenhanced CT does not need imaging follow-up, whatever its size (Park and colleagues, 2023).

Washout and MRI

When the unenhanced density is greater than 10 HU, the lesion is called indeterminate and other tools come into play. Contrast-enhanced CT with a delayed phase measures how much of the contrast leaves the lesion, the so-called washout. The Korean guideline considers an absolute washout below 60 per 100 or a relative washout below 40 per 100 a sign of malignancy (Lee and colleagues, 2017). An imaging review notes that the protocol with a 15-minute delayed phase has the highest diagnostic accuracy and that chemical shift MRI helps identify fat within the lesion (Albano and colleagues, 2019).

The same review points out that diffusion on MRI does not help differentiate adrenal lesions and that nuclear medicine has a role in specific situations (Albano and colleagues, 2019). Functional imaging is not the first step for the common incidentaloma.

When the fat disappears

The lipid-poor adenoma is a possible diagnosis within the indeterminate lesion. In the Polish cohort, the lipid-poor appearance on CT was the strongest predictor of hormonal activity and also the factor that most increased the risk of malignancy (Cyranska-Chyrek and colleagues, 2019). A lesion that does not behave like a typical adenoma deserves a team discussion.

Second question: does the nodule function

Hormonal investigation applies to every patient with an incidentaloma, even without symptoms. The reasoning is that many functioning forms are silent, and some, such as pheochromocytoma, can bring acute risk during procedures.

Cortisol: the 1 mg dexamethasone test

The Korean guideline recommends the overnight 1 mg dexamethasone suppression test for all patients with an incidentaloma (Lee and colleagues, 2017). The proposed interpretation uses three ranges: a cortisol of 1.8 µg/dL (50 nmol/L) or less rules out autonomous secretion; 1.9 to 5.0 µg/dL suggests possible autonomous secretion; and above 5.0 µg/dL is considered evidence of autonomous secretion.

The 2023 European guideline simplified the cutoff. In patients without signs of overt Cushing syndrome, a post-dexamethasone cortisol above 50 nmol/L (more than 1.8 µg/dL) should be considered mild autonomous cortisol secretion (Park and colleagues, 2023). The same review recommends reassessing comorbidities possibly linked to cortisol excess, such as hypertension and diabetes, to weigh the possible benefit of surgery.

The other cortisol tests disappoint

It is tempting to add other tests to "confirm" the result. A Norwegian study of 165 patients with an incidentaloma showed that late-night salivary cortisol poorly discriminated nonfunctioning adenomas from autonomous secretion, with 23 false positives out of 63 and 38 false negatives out of 69 (Ueland and colleagues, 2020). Dehydroepiandrosterone sulfate had a sensitivity of 58 per 100 and a specificity of 80 per 100 at the recommended cutoff.

The authors concluded that neither dehydroepiandrosterone sulfate, nor nighttime salivary cortisol, nor 24-hour urinary free cortisol helped separate the two groups, and that the prolonged low-dose test added no information to the overnight 1 mg test (Ueland and colleagues, 2020). In the Korean COAR study, raised urinary free cortisol also had very low sensitivity (Ahn and colleagues, 2018).

Pheochromocytoma: metanephrines

The Korean guideline recommends measuring plasma metanephrines or fractionated metanephrines in a 24-hour urine sample in all patients with an incidentaloma (Lee and colleagues, 2017). The reason is clear: an undiagnosed pheochromocytoma can cause a severe hypertensive crisis during surgery, anesthesia or other procedures.

This "all", however, has been under discussion. A review in question-and-answer format cites a European study in which only 2 of 376 patients with pheochromocytoma had a density below 10 HU, which led the authors to consider it reasonable to skip biochemical screening for pheochromocytoma in an incidentaloma of 10 HU or less (Ceccato et al., 2021). A Finnish study with 5-year follow-up of fat-rich adenomas reached the same suggestion for lesions under 10 HU (Schalin-Jäntti et al., 2015).

Aldosterone: aldosterone/renin ratio

The Korean guideline recommends the aldosterone/renin ratio in patients with an incidentaloma who also have hypertension or hypokalemia (Lee et al., 2017). The review by Ceccato et al. notes that the result depends on appropriate suspension of medications that interfere with the test, and suggests urinary metanephrines, the aldosterone/renin ratio and cortisol after 1 mg of dexamethasone in all patients with an incidentaloma (Ceccato et al., 2021).

This point illustrates a lesson about how to choose tests and approaches: the same test has different value depending on the clinical context in which it is ordered.

The nodule grows

The fear of growth underpins many long follow-ups. The Korean guideline cites a risk of size increase of 6 in 100 at 1 year, 14 in 100 at 2 years and 29 in 100 at 5 years, and recommends periodic imaging and hormone checks for the nonfunctioning nodule of 4 cm or less (Lee et al., 2017).

What long follow-ups say

The Finnish study followed 69 fat-rich incidentalomas, all under 40 mm and under 10 HU, for 5 years (Schalin-Jäntti et al., 2015). Mean growth was 1 mm, the largest increase was 8 mm, in a tumor that proved to be a cortical adenoma at surgery, and 97 in 100 of the re-evaluated masses kept a density below 10 HU. No patient developed clinically relevant growth or new subclinical hypercortisolism.

An Italian study with 277 patients and 355 adenomas showed a mean diameter of 18.7 mm and a mean density of 0.8 HU on the first CT, with no change on early scans between 12 and 36 months (Ceccato et al., 2021). The largest differences appeared after at least 60 months, with a mean increase of 2 mm in diameter, and fat-poor adenomas showed less cortisol suppression and more growth over time.

How this changed the guidelines

These data help explain why the 2023 European guideline skips imaging follow-up for the homogeneous nodule of 10 HU or less (Park et al., 2023). For autonomous cortisol secretion, the same review describes the recommendation to reassess comorbidities periodically and refer to an endocrinologist if they appear or worsen.

Follow-up without criteria has a cost. Each extra CT adds radiation, anxiety and new incidental findings. This is the territory of overdiagnosis, where the pursuit of absolute safety produces real harm.

Special situations

Some situations change the pretest probability and require reasoning different from the standard.

Bilateral nodules

The review of the European guideline proposes thinking about bilateral incidentalomas in four groups: macronodular bilateral hyperplasia, bilateral adenomas, two similar masses that do not look like adenoma and two masses that differ from each other (Park et al., 2023). Each group opens its own differential, which includes hyperplasia, metastases, infections and infiltration.

Young patients and pregnant women

The review by Park et al. highlights that the 2023 European guideline supports a more active surgical approach to indeterminate masses in patients under 40 years of age and in pregnant women (Park et al., 2023). In young people, the incidentaloma is less frequent, and the probability of a relevant lesion within the group of findings is proportionally higher.

Patient with known cancer

In a patient with a neoplasm outside the adrenal gland, a new adrenal mass may be a metastasis. The review for radiologists notes that this scenario has its own recommendations within the European guideline (Sahdev et al., 2017). The reasoning in this case is closer to oncologic staging than to the classic incidentaloma.

Building the reasoning step by step

The reasoning when facing an incidentaloma can be organized into a short sequence. It does not replace the local guideline, but it helps avoid forgetting any question.

1. Confirm that it is an incidentaloma: the imaging was done for another reason, the nodule is 1 cm or larger and there is no known cancer that changes the context.
2. Look for signs and symptoms of hormonal excess: Cushing, adrenergic crises, difficult hypertension, hypokalemia, virilization.
3. Assess the imaging: size, homogeneity and unenhanced density; if greater than 10 HU, consider washout or MRI.
4. Request baseline hormonal evaluation: 1 mg dexamethasone suppression test, metanephrines and, if hypertension or hypokalemia, aldosterone/renin ratio.
5. Decide as a team when the lesion is indeterminate, large or functioning.
6. Define follow-up proportional to risk, without repeating tests out of habit.

Where the reasoning usually fails

The most common failure is not the wrong test, but the missing test. The British study showed that fewer than 1 in 10 patients with an incidentaloma had a documented referral within 90 days (Hanna et al., 2022). Recording the finding and the plan in the medical record is part of the diagnosis, and this care with the organization of clinical reasoning in the medical record keeps the finding from being lost.

The opposite failure is the cascade. Ordering MRI, PET and biopsy for a 1.5 cm nodule with negative density exposes the patient to risks with no gain. The Korean and European guidelines converge on the idea that low density on unenhanced CT already answers the malignancy question in most cases (Lee et al., 2017).

Back to the patient in the case

The 62-year-old patient has a 2.3 cm nodule. The next step is to review the CT: if the nodule is homogeneous and has a density of 10 HU or less, the hypothesis of a benign adenoma becomes very strong, and the European guideline does not require imaging follow-up (Park et al., 2023). If the density is higher, the lesion is indeterminate and deserves washout, MRI or team discussion.

She has hypertension and diabetes, which makes testing for autonomous cortisol secretion especially relevant, because these comorbidities may be related to the hormonal excess. Hypertension also indicates the aldosterone/renin ratio, and metanephrines are included in the evaluation according to the guideline adopted.

The answer to the question "is this cancer?" depends on these steps, but the initial conversation can already be reassuring. Based on the cohorts, the most likely hypothesis is a nonfunctioning adenoma, and the investigation exists to confirm this hypothesis and find the minority who need another approach. Communicating diagnostic uncertainty with honest numbers is part of care.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code.

The limits of use of the game are described on the NEXO Economy page. If you research clinical reasoning teaching, the page for Researchers explains how to get in touch. Professionals who write or review cases find information in Curator and in Creators, and institutions can learn about the proposal on the for partnerships page. Training differential diagnosis with clues and searching for the right ICD-10 code complete this practice.

Frequently asked questions

Does every adrenal incidentaloma need hormonal investigation?

Guidelines recommend hormonal evaluation for all patients with an incidentaloma, even without symptoms, because many functioning forms are silent. The 1 mg dexamethasone test is recommended for everyone, metanephrines are part of most protocols, and the aldosterone/renin ratio is indicated in hypertensive or hypokalemic patients (Lee et al., 2017).

Can a nodule with less than 10 HU be cancer?

It is unlikely. The systematic review by Dinnes et al. suggests that masses with 10 HU or less are rarely malignant, although with limited evidence (Dinnes et al., 2016). The 2023 European guideline considers a homogeneous mass with 10 HU or less benign enough to skip imaging follow-up (Park et al., 2023).

Why is measuring cortisol in urine not enough?

Because urinary free cortisol has low sensitivity for mild autonomous secretion. In the Norwegian study, neither 24-hour urinary cortisol nor late-night salivary cortisol separated the groups well (Ueland et al., 2020), and in the Korean study the sensitivity of raised urinary cortisol was very low (Ahn et al., 2018).

Will the nodule grow over time?

It may grow a little. In the 5-year Finnish follow-up, mean growth was 1 mm (Schalin-Jäntti et al., 2015), and in the Italian study the mean increase after at least 60 months was 2 mm (Ceccato et al., 2021). Significant growth changes management and should lead to a new evaluation.

Who should follow the patient?

It depends on the finding. Indeterminate, large or functioning nodules should be discussed with endocrinology and, when indicated, in a multidisciplinary team, as the European guideline stresses (Park et al., 2023). The British data on low referral show that the biggest risk is the finding being left without an owner (Hanna et al., 2022).

Take-home messages

• Adrenal incidentaloma is common and grows with the volume of imaging exams.
• Most are non-functioning adenomas, but malignancy and hormone production must be evaluated in everyone.
• A density of 10 HU or less on unenhanced CT is the main clue to benignity.
• The 1 mg dexamethasone test is the central exam for autonomous cortisol secretion.
• Metanephrines and the aldosterone/renin ratio complete the evaluation according to the context and the guideline adopted.
• Follow-up should be proportional to risk, and the finding cannot be left without a recorded plan.

References

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