What Causes Adrenal Nodules? Benign & Malignant Reasons

Most adrenal nodules are benign growths that produce no symptoms and get discovered by accident on imaging done for something else. These so-called “incidentalomas” show up on roughly 1 to 4 percent of abdominal CT scans, with the rate climbing steadily as people age.¹ But “benign” does not always mean “harmless,” and a small fraction of adrenal nodules turn out to be cancerous or hormonally active in ways that quietly damage the body. Understanding the full range of causes helps make sense of why your doctor may order follow-up tests even when the initial read looks reassuring.

Non-Functioning Adenomas, the Most Common Cause

The single most frequent type of adrenal nodule is a non-functioning adenoma. These are small, fatty growths in the adrenal cortex that do not secrete meaningful amounts of any hormone. They tend to sit quietly for years, growing slowly or not at all. In one study tracking nearly 400 patients with incidental adrenal nodules over an average of almost seven years, none developed adrenal cancer, and the average growth rate was a barely measurable 0.1 mm per year.² A meta-analysis confirmed this pattern, finding that only about 2.5 percent of benign adrenal adenomas grew by 10 mm or more over an average follow-up of roughly three and a half years, and malignant transformation was never observed.³

On imaging, non-functioning adenomas typically appear lipid-rich, which gives them a characteristic low density on unenhanced CT. That fat content is actually useful diagnostically, because most malignant nodules lack it. Unenhanced CT and a technique called chemical-shift MRI are highly specific for identifying lipid-rich adenomas and distinguishing them from something more worrisome.⁴ Some adenomas are “lipid-poor,” meaning they have less intracellular fat and can look ambiguous on a scan. In those cases, a contrast-enhanced washout CT can usually tell them apart from metastases, though pheochromocytomas and some aggressive cancers can muddy the picture.⁵

Cortisol-Producing Adenomas

Some benign adrenal nodules quietly pump out cortisol on their own, bypassing the brain’s usual signals. When the excess is large enough to cause obvious symptoms like weight gain, high blood sugar, easy bruising, and muscle weakness, the condition is called Cushing’s syndrome. But many cortisol-secreting adenomas produce only a modest surplus, a state sometimes called “mild autonomous cortisol secretion.” Over time, even that low-grade excess can raise blood pressure, thin bones, and worsen metabolic health.

Genetically, cortisol-producing adenomas often trace back to mutations that ramp up an enzyme pathway called protein kinase A (PKA). Researchers have identified specific gene changes, particularly in PRKACA, that lock the PKA signaling pathway into an “always on” state. In one study, these PRKACA mutations appeared in about 37 percent of unilateral adenomas from patients with overt Cushing’s syndrome, but were absent in patients with milder cortisol excess or other adrenal tumor types.⁶ Additional gene variants affecting the broader PKA pathway, including changes in GNAS, PRKAR1A, and several others, have been linked to benign cortisol-producing lesions as well.⁷ For patients, the practical takeaway is that these tumors are not random bad luck in every case; some people carry specific molecular profiles that make their adrenal cells prone to overproduction.

Aldosterone-Producing Adenomas and High Blood Pressure

Aldosterone is the hormone that tells your kidneys to hold onto sodium and release potassium. When an adrenal adenoma pumps out too much of it, the result is a condition called primary aldosteronism, sometimes known as Conn’s syndrome. It is one of the most common treatable causes of resistant high blood pressure, and it often goes unrecognized for years because blood pressure alone does not point to the adrenal glands.

The genetics behind aldosterone-producing adenomas (APAs) have become increasingly clear. Mutations in KCNJ5, a gene encoding a potassium channel, account for roughly 34 to 40 percent of these tumors.⁸ These KCNJ5 mutations are more common in women than men and tend to appear in younger patients who have higher aldosterone levels at diagnosis, suggesting a more aggressive hormonal phenotype.⁸ Additional mutations in ATP1A1 and ATP2B3, genes involved in sodium-potassium and calcium transport, have been found in a smaller fraction of APAs, together accounting for about 7 percent of cases.⁹ Surgical removal of the adenoma often cures or dramatically improves the hypertension, which is why screening for aldosterone excess matters when an adrenal nodule turns up.

Pheochromocytomas

Pheochromocytomas arise from the adrenal medulla, the inner part of the gland that produces adrenaline and related hormones. They are rarer than cortical adenomas but carry outsized importance because uncontrolled catecholamine surges can trigger dangerous spikes in blood pressure, rapid heart rate, sweating, and headaches. In rare cases, a “pheo crisis” during surgery or anesthesia can be life-threatening, which is why these tumors must be identified before any operation.

One of the most striking features of pheochromocytomas is how often they are hereditary. About 30 percent or more are thought to stem from inherited gene mutations across at least 10 well-characterized genes.¹⁰ That rate is among the highest of any tumor type in endocrinology. Genes in the SDH family (SDHA, SDHB, SDHC, SDHD), along with VHL, RET, NF1, and several others, are the usual suspects.¹¹ This hereditary link means that when a pheochromocytoma is diagnosed, genetic counseling and testing are routinely recommended, and first-degree relatives may need screening too.

Myelolipomas

Adrenal myelolipomas are benign tumors made up of mature fat and bone-marrow-like tissue. They look distinctive on imaging because of their high fat content and are generally easy to identify on CT. Most require no treatment unless they grow large enough to cause pain or pressure on nearby structures.

The cause of myelolipomas is not entirely settled, but there is a well-documented association with conditions that chronically elevate ACTH, the pituitary hormone that drives adrenal activity. Congenital adrenal hyperplasia (CAH) is the classic example. Patients with CAH who stop or reduce their steroid replacement therapy can experience persistently high ACTH levels, which appears to stimulate myelolipoma growth. Case reports describe massive bilateral myelolipomas developing in CAH patients after they discontinued their medications.¹² Cushing’s syndrome and Addison’s disease have also been reported alongside myelolipomas, reinforcing the idea that chronic hormonal stimulation plays a role.

Adrenal Cysts and Pseudocysts

Fluid-filled cysts in the adrenal gland are uncommon but worth mentioning because they sometimes show up as nodules on imaging and can be confused with solid masses. True adrenal cysts have an epithelial or endothelial lining, while pseudocysts do not. Most adrenal pseudocysts appear to result from prior hemorrhage within a normal adrenal gland. The blood collects, the clot organizes, and what is left behind is a fluid-filled sac.¹³ Pathological studies support this, showing evidence of vascular disruption and healing within the pseudocyst wall.¹⁴

Most adrenal cysts and pseudocysts are non-functional and cause no symptoms. Large ones, however, can produce abdominal discomfort and compress nearby organs. In rare instances, they rupture spontaneously, causing bleeding into the space behind the abdomen that requires emergency surgery.¹⁵

Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is the primary adrenal cancer that most people worry about when a nodule is found. It is genuinely rare, affecting roughly one to two people per million per year, but it tends to be aggressive and is often diagnosed late. ACC can produce excess hormones (cortisol, androgens, or aldosterone), which sometimes triggers symptoms that lead to discovery. In other cases, the tumor is non-functional and only found when it grows large enough to cause pain or is spotted incidentally.

Size is the strongest imaging predictor of malignancy. In a study of 457 adrenal cortical tumors, the average ACC measured 12 cm compared with 4.2 cm for benign tumors. At the commonly used threshold of 4 cm, sensitivity for catching cancer was 96 percent, but specificity was only 52 percent, meaning many benign nodules above 4 cm would be flagged. Raising the threshold to 6 cm improved specificity to 80 percent while still catching 90 percent of cancers.¹⁶ Most guidelines use 4 cm as a threshold for surgical consideration, though there is ongoing debate about whether this is too aggressive.¹⁷ In one series of hormonally inactive incidentalomas, no tumors under 4 cm were malignant, while the malignancy rate rose to about 3 percent for those between 4 and 6 cm and roughly 14 percent for those over 6 cm.¹⁸

Molecularly, ACC frequently involves disruption of the p53 and Wnt/β-catenin pathways, both of which are fundamental regulators of cell growth and division.¹⁹ TP53 mutations are particularly relevant because they also connect ACC to the inherited cancer syndrome Li-Fraumeni (discussed below). In a study of 30 ACC patients, those whose tumors carried TP53 mutations showed markedly abnormal p53 protein accumulation compared to mutation-negative patients.²⁰ Pathologists use the Weiss scoring system, which evaluates nine microscopic features, to distinguish ACC from benign tumors. A score of three or more out of nine points toward malignancy, and the system remains the gold standard despite being introduced decades ago.²¹

When Cancer Spreads to the Adrenal Glands

Not every malignant adrenal nodule starts in the adrenal gland. The adrenals are a common landing site for cancer that has spread from elsewhere, partly because of their rich blood supply. In patients with a known cancer history, an adrenal nodule is often a metastasis rather than a new primary tumor.

In a 30-year review from one teaching hospital, lung was the most common primary site for adrenal metastases, accounting for about 35 percent, followed by stomach, esophagus, and liver or bile duct cancers.²² A more recent institutional study found renal cell carcinoma as the leading primary source, followed by lung adenocarcinoma.²³ The difference likely reflects the patient populations at each hospital and advances in imaging that catch kidney cancers earlier. For patients being staged for any known malignancy, an adrenal nodule deserves careful evaluation rather than reassurance based on size alone.

Growth Rate as a Diagnostic Clue

When imaging alone cannot determine whether a nodule is benign or malignant, growth rate on serial scans becomes a valuable tool. One study comparing proven adenomas to malignant adrenal nodules found that adenomas grew at an average of about 1 mm per year, while a growth threshold of 3 mm per year distinguished benign from malignant nodules with both sensitivity and specificity of 100 percent.²⁴ That is a remarkably clean cutoff in a field where few diagnostic tests are perfect, though it requires at least two scans separated by enough time to measure meaningful change. This is why doctors often recommend repeat imaging at 6 to 12 months for nodules that look indeterminate on their first scan.

Hereditary Syndromes That Cause Adrenal Tumors

Several inherited conditions raise the risk of developing adrenal tumors, and recognizing them matters because affected family members may need surveillance. The most important include:

• Li-Fraumeni syndrome: Caused by germline TP53 mutations, this condition carries a dramatically elevated risk of ACC, particularly in children and young adults. It also predisposes to breast cancer, brain tumors, and sarcomas.²⁵
• Multiple endocrine neoplasia type 2 (MEN2): An autosomal dominant syndrome caused by RET gene mutations, occurring in about 1 in 200,000 live births. It is characterized by medullary thyroid carcinoma, pheochromocytoma, and sometimes overactive parathyroid glands.²⁶
• SDHx-related syndromes: Mutations in the succinate dehydrogenase gene family (SDHA through SDHD) are a major cause of hereditary pheochromocytoma and paraganglioma. SDHB mutations in particular carry a higher risk of malignant tumors.
• Lynch and Beckwith-Wiedemann syndromes: More recently recognized as part of the adrenal tumor spectrum. Lynch syndrome, better known for colon cancer risk, has also been linked to ACC, as has Beckwith-Wiedemann syndrome in children.¹¹

Given the high hereditary rate of pheochromocytomas and the link between ACC and cancer predisposition syndromes, current expert recommendations emphasize germline genetic testing for patients diagnosed with either of these tumor types. The results shape not only the patient’s own surveillance plan but can trigger screening protocols for relatives.

Infections That Mimic Adrenal Nodules

In certain parts of the world, infections are a real and underappreciated cause of adrenal enlargement. Tuberculosis and histoplasmosis are the two most common culprits. Both can infect the adrenal glands, causing masses that range from mild enlargement to lesions nearly 10 cm across.²⁷ These infectious masses can look like tumors on imaging, sometimes leading to unnecessary surgery if the possibility of infection is not considered. Adrenal insufficiency is a frequent complication when enough gland tissue is destroyed. The clinical presentations of adrenal histoplasmosis and tuberculosis overlap considerably, but the treatments are different, making accurate diagnosis essential.

Adrenal Nodules in Children

The spectrum of adrenal masses in children looks very different from adults. While adults overwhelmingly have benign cortical adenomas, the most common adrenal tumor in children is neuroblastoma, a cancer of immature nerve cells. In one surgical series of 50 pediatric adrenal masses, neuroblastoma accounted for more than half, followed by ganglioneuroma and adrenal cortex tumors.²⁸ Pheochromocytomas, ganglioneuroblastomas, cysts, and hematomas made up the rest. Because the malignancy rate among childhood adrenal masses is high, the clinical approach is generally more aggressive than in adults, with a lower threshold for surgical removal and biopsy.

How Chronic Steroid Use Can Affect the Adrenal Glands

Long-term use of glucocorticoid medications, whether taken by mouth, inhaled, injected into joints, or applied to the skin, can suppress the body’s own adrenal function. The hypothalamic-pituitary-adrenal axis essentially goes dormant because the external steroids replace the need for the adrenals to produce cortisol. Even short courses of less than four weeks or low doses below the equivalent of 5 mg of prednisone per day can cause measurable suppression in some people.²⁹

This suppression does not typically create a visible nodule, but it does change the adrenal glands. Chronically suppressed glands atrophy and shrink, sometimes appearing thin or small on imaging. If steroid therapy is abruptly stopped, the rebound surge of ACTH from the pituitary can stimulate adrenal tissue in unpredictable ways. The clinical concern is adrenal insufficiency during the withdrawal period rather than nodule formation, but the broader point stands: exogenous hormones reshape the adrenal landscape, and this context matters when interpreting imaging findings in patients with a history of steroid use.

The Hormonal Workup After an Adrenal Nodule Is Found

Regardless of how benign a nodule looks on a scan, clinical guidelines call for biochemical testing to check whether it is producing excess hormones. The standard workup screens for cortisol excess (usually with an overnight dexamethasone suppression test), aldosterone and renin levels (to check for primary aldosteronism), and plasma or urinary catecholamines or metanephrines (to rule out pheochromocytoma).³⁰ If the patient has symptoms of androgen or estrogen excess, those hormones may be tested as well, since sex hormone production by an adrenal mass raises suspicion for ACC.

This biochemical screening is arguably more important than the imaging in many cases. A nodule that appears perfectly benign by size and density can still be churning out enough cortisol or aldosterone to quietly damage the cardiovascular system. Identifying and treating that hormonal excess prevents years of downstream harm that imaging alone would miss.