Most adrenal gland tumors arise from acquired genetic changes in a single adrenal cell that cause it to grow or produce hormones unchecked, though the specific trigger for those changes is usually unknown. A smaller but significant fraction traces back to inherited gene mutations passed through families. What makes the picture complicated is that “adrenal tumor” is not one disease. The adrenal gland has two structurally distinct parts, the outer cortex and the inner medulla, and each gives rise to different tumor types driven by different molecular faults. The vast majority of these growths are benign and discovered by accident on imaging done for unrelated reasons, but understanding what causes them matters for anyone trying to assess their own risk or make sense of a diagnosis.
Two Glands in One and Why That Matters
Each adrenal gland is really two organs fused together. The cortex, which wraps around the outside, produces steroid hormones like cortisol and aldosterone. The medulla, nestled inside, produces adrenaline and noradrenaline. These two regions develop from entirely different embryonic tissues and behave like separate organs at the molecular level. The proteins they express, the signaling pathways they rely on, and the mutations that drive their tumors are largely distinct.
Cortical tumors include adenomas (benign, and by far the most common adrenal tumors overall), and adrenocortical carcinomas (rare and aggressive). Medullary tumors include pheochromocytomas, which overproduce adrenaline-type hormones. This division is not just academic: knowing which part of the gland a tumor comes from changes the conversation about its cause completely, because the genetic and molecular drivers are different for each type.
Inherited Gene Mutations Behind Adrenal Tumors
A meaningful minority of adrenal tumors, especially pheochromocytomas, are caused by mutations people are born with. Germline mutations in genes like RET, SDHB, SDHD, and VHL have been found in roughly 7.5 to 24% of patients with pheochromocytomas who had no family history suggesting a hereditary condition.1PubMed Central. Prevalence of Germline Mutations in Patients with Pheochromocytoma or Abdominal Paraganglioma and Sporadic Presentation: A Population-Based Study in Western Sweden That is a surprisingly high rate for tumors that appear sporadic, and it is one reason genetic testing is now recommended more broadly for pheochromocytoma patients.
Several well-known hereditary syndromes carry a risk of adrenal tumors:
- MEN2: Multiple endocrine neoplasia type 2, caused by mutations in the RET gene, leads to pheochromocytoma in roughly half of affected individuals, alongside medullary thyroid cancer in nearly all cases.2PubMed. MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives These pheochromocytomas can appear bilaterally, sometimes as the first sign of the syndrome before thyroid cancer is detected.3PubMed Central. Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case
- Li-Fraumeni syndrome: Caused by mutations in TP53, the gene encoding the p53 tumor-suppressor protein. In a study of unselected patients with adrenocortical carcinoma, about 7.5% carried a TP53 germline mutation, and most of these patients did not meet the classic clinical criteria for the syndrome.4PubMed Central. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma In Brazilian families carrying the specific TP53 R337H variant, adrenocortical carcinoma was the most common tumor at diagnosis, accounting for about 23% of cancers, and tended to be aggressive.5PubMed. Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumeni-like syndrome in Brazilian individuals with the TP53 p.R337H mutation
- Neurofibromatosis type 1: This condition, caused by mutations in the NF1 gene, occasionally produces pheochromocytomas alongside its better-known skin manifestations.6PubMed Central. Pheochromocytoma Associated With Neurofibromatosis Type 1: A Case Report7PubMed Central. Clinical Presentation and Outcomes of Phaeochromocytomas/Paragangliomas in Neurofibromatosis Type 1
- Von Hippel-Lindau disease: VHL gene mutations predispose to pheochromocytomas and paragangliomas alongside kidney tumors and other growths.
In children, inherited mutations play an even larger role. Between 50 and 80% of pediatric adrenocortical carcinomas involve genetic or epigenetic abnormalities, most commonly in TP53, and hereditary syndromes like Li-Fraumeni, Beckwith-Wiedemann, and MEN1 account for a substantial share of cases.8PubMed Central. Adrenocortical carcinoma: Pediatric aspects
Somatic Mutations That Drive Benign Adenomas
The most common adrenal tumors are benign cortical adenomas, and researchers have identified specific acquired mutations in many of them. These are somatic mutations, meaning they occur in the tumor cells themselves rather than being inherited, and they tend to be particular to the type of hormone the adenoma overproduces.
For aldosterone-producing adenomas, the ones behind a form of difficult-to-treat high blood pressure called primary aldosteronism, mutations in the KCNJ5 gene are the single most frequent genetic alteration.9PubMed. KCNJ5 mutations are the most frequent genetic alteration in primary aldosteronism KCNJ5 encodes a potassium channel, and mutations near its selectivity filter disrupt the channel’s normal function, allowing sodium to flood the cell and triggering excess aldosterone production.10PubMed Central. Primary aldosteronism diagnostics: KCNJ5 mutations and hybrid steroid synthesis in aldosterone-producing adenomas In a study of 85 aldosterone-producing adenomas, about half harbored a KCNJ5 mutation.11PubMed. Prevalence of KCNJ5 mutations in aldosterone-producing adenomas among Malaysian primary aldosteronism patients: Genotype-phenotype correlation Other genes in calcium and sodium channels, like CACNA1D and ATP1A1, account for additional cases.
For cortisol-producing adenomas, the ones that can cause Cushing’s syndrome, a different set of mutations takes center stage. Mutations in PRKACA, a gene encoding part of the protein kinase A signaling system, have been found in a large fraction of these adenomas. One study identified PRKACA mutations in 37% of adenomas from patients with overt Cushing’s syndrome.12PubMed Central. Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome Another identified the same hotspot mutation in roughly two-thirds of cortisol-producing adenomas.13PubMed. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome The mutation locks the enzyme in an “always on” state, driving the cell to keep pumping out cortisol regardless of the body’s normal regulatory signals.14PubMed. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome
What Goes Wrong in Adrenocortical Carcinoma
Adrenocortical carcinoma, the rare malignant cortical tumor, involves a different and more chaotic molecular landscape than benign adenomas. Two pathways stand out as frequently disrupted: the Wnt/β-catenin signaling pathway and the p53 tumor-suppressor pathway.
Abnormal activation of the Wnt pathway through mutations in the β-catenin gene (CTNNB1) has been documented in both benign and malignant adrenal tumors, but it is especially prominent in carcinomas. In one series of 39 adrenal tumors, abnormal β-catenin accumulation appeared in roughly 85% of carcinomas compared to about 38% of adenomas.15PubMed. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors When these mutations are present, they lead to uncontrolled activation of genes involved in cell growth.16PubMed Central. Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival
The combination of Wnt pathway activation with p53 loss appears to be particularly dangerous. Among the most aggressive adrenocortical carcinomas, roughly 88% harbor an alteration in at least one of these two pathways, and about 37% have both altered simultaneously. Patients whose tumors carry mutations in both pathways have lower survival rates than those with only one pathway affected.17Oncogene. Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice This cooperative effect helps explain why adrenocortical carcinoma, while rare, can be so aggressive when it does occur.
The Pseudohypoxia Pathway in Pheochromocytomas
Pheochromocytomas and the related tumors called paragangliomas have their own characteristic molecular story, centered on a phenomenon called pseudohypoxia. In normal cells, when oxygen levels drop, a set of proteins called hypoxia-inducible factors (HIFs) kick into action, switching on genes that help the cell survive low-oxygen conditions by promoting new blood vessel growth, altering energy metabolism, and suppressing normal cell death. In pheochromocytomas driven by mutations in VHL or SDH genes, these hypoxia pathways are activated even when oxygen is plentiful.18PubMed. Pheochromocytomas: the (pseudo)-hypoxia hypothesis
The cell essentially behaves as though it is suffocating when it is not, and the survival programs it activates in response, including increased blood vessel formation and resistance to programmed cell death, create conditions that favor tumor growth.19Frontiers in Endocrinology. The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma SDH-deficient tumors also appear to create an immunosuppressive environment around themselves, which may help them evade the immune system.20PubMed Central. Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype This pseudohypoxia framework has become central to how researchers classify and think about treating these tumors.
Incidentalomas and the Role of Aging
Many adrenal tumors are discovered by accident, earning the name “incidentalomas.” As cross-sectional imaging has become routine in medicine, adrenal masses show up on CT scans performed for completely unrelated complaints at a rate of roughly 0.5 to 2% of all abdominal scans, with some studies finding rates as high as 12% when a radiologist specifically re-examines images looking for adrenal abnormalities.21PubMed Central. An Adrenal Incidentaloma: How Often Is It Detected and What Are the Consequences? Autopsy studies put the prevalence at about 2.3%, and most of these turn out to be benign cortical adenomas.22European Journal of Endocrinology. Prevalence and natural history of adrenal incidentalomas
In a large series of over 1,000 incidentally found adrenal masses in patients without known cancer, 75% were adenomas, about 6% were myelolipomas (fatty tumors), and no malignant masses were found.23PubMed. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy Incidentalomas become more common with age, which raises the question of whether they are simply a normal consequence of decades of cell division and accumulated mutations in adrenal tissue. For many people, the discovery of an incidentaloma is more alarming than the tumor itself warrants, but the workup to rule out hormone overproduction or malignancy is still important.
Sex Differences in Adrenal Tumors
Adrenal tumors do not affect men and women equally. Most types, including adrenocortical carcinoma, cortisol-secreting adenomas, nonfunctioning adenomas, and pheochromocytomas, are more common in women, with female-to-male ratios ranging from about 1.1 to 1 up to nearly 4 to 1 depending on the tumor type.24PubMed Central. Asymmetric Adrenals: Sexual Dimorphism of Adrenal Tumors Aldosterone-producing adenomas are an exception, being slightly more common in men.
The reasons behind these sex differences are not fully understood, but some clues have emerged. Cortisol-producing adenomas with PRKACA or GNAS mutations, which tend to produce a more severe hormonal syndrome, are seen more often in women.25European Journal of Endocrinology. Sexual dimorphism in benign adrenocortical tumours Among aldosterone-producing adenomas, women have a higher prevalence of KCNJ5 mutations and tend to have better outcomes after surgery. Single-cell analysis of aldosterone-producing adenomas has revealed that immune cells in the tumor environment differ between sexes, with female tumors showing stronger immune activation patterns.26PubMed Central. Exploring heterogeneity of tumor immune cells and adrenal cells in aldosterone-producing adenomas using single-cell RNA-seq and investigating differences by sex Whether sex hormones directly influence adrenal cell growth or alter the mutation landscape remains an open question.
Obesity, Insulin Resistance, and Metabolic Factors
There is growing evidence that metabolic health plays a role in adrenal tumor development, particularly for benign adenomas. A Mendelian randomization study, which uses genetic variants as natural experiments to test causal relationships, found that obesity and higher body fat are risk factors for benign adrenal tumors.27PubMed Central. Relationship of obesity, body fat, benign adrenal tumors and the mediating mechanism: a two-step mendelian randomization study
Clinically, patients with nonfunctioning adrenal incidentalomas tend to be obese with central fat accumulation and show features of metabolic syndrome, including insulin resistance, high blood pressure, abnormal cholesterol levels, and fatty liver disease.28PubMed. Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship? One early study proposed that adrenal incidentalomas might be a manifestation of metabolic syndrome, analogous to how insulin resistance drives ovarian cysts in polycystic ovary syndrome, given that insulin can stimulate adrenal cell growth in the laboratory.29PubMed. Adrenal incidentalomas: a manifestation of the metabolic syndrome?
The cause-and-effect relationship is not entirely settled. Some adrenal tumors produce low levels of cortisol that might themselves worsen metabolic health, creating a chicken-or-egg problem. But the Mendelian randomization data, which sidesteps this issue by looking at genetic predisposition to obesity rather than obesity itself, supports the idea that excess body fat genuinely contributes to adrenal tumor risk rather than just being a consequence of subclinical hormone excess.
Endocrine Disruptors and the Adrenal Gland
Environmental chemicals that interfere with the hormone system, collectively called endocrine disruptors, can affect the adrenal glands. Every step in the adrenal cortex’s hormone production process, from the initial receptor that responds to signals from the pituitary gland down to the specific enzymes that convert cholesterol into cortisol and aldosterone, is a potential target for chemical disruption.30PubMed Central. Endocrine disrupting chemicals and the adrenal gland These chemicals can either block or inappropriately activate these enzymes, and several studies have linked endocrine disruptor exposure to various cancers and reproductive dysfunction.
The evidence connecting specific environmental chemicals to adrenal tumor formation in humans is still relatively thin compared to the evidence for genetic causes. Most of the data comes from animal studies and cell-line experiments rather than human population studies. Still, the biological plausibility is strong: if a chemical chronically disrupts adrenal signaling, the gland may compensate by growing more tissue, and sustained growth pressure can increase the odds of a cell acquiring a tumor-driving mutation.
Epigenetics and MicroRNAs
Not all the molecular changes driving adrenal tumors involve mutations in the DNA sequence itself. Epigenetic alterations, which change how genes are read without altering the underlying code, also play a role. DNA methylation patterns differ between benign and malignant adrenal tumors, and methylation profiling has been proposed as a way to distinguish the two, which is particularly useful for borderline tumors where standard pathology is uncertain.31PubMed Central. Past, Present and Future of Epigenetics in Adrenocortical Carcinoma
Small RNA molecules called microRNAs, which regulate gene activity by silencing specific targets, also show distinct patterns across adrenal tumor types. Different microRNAs are expressed at markedly different levels in benign versus malignant cortical tumors and across different subtypes of pheochromocytomas.32PubMed Central. MicroRNAs in adrenal tumors: relevance for pathogenesis, diagnosis, and therapy Whether these changes are causes of tumor development or consequences of it is still being worked out, but they appear to affect pathways involved in cell growth and hormone production, making them more than passive bystanders.
Adrenal Tumors in Animals
Adrenal tumors are not unique to humans. In domestic ferrets, adrenal cortical tumors are strikingly common and appear to be increasing in prevalence. Researchers have linked this to early spaying and neutering, dietary factors, and genetics, suggesting that the chronic absence of sex hormones drives compensatory growth in the adrenal cortex that can eventually become tumorous.33PubMed Central. Endocrinopathy and Aging in Ferrets The ferret example is a useful reminder that adrenal tumors can be caused not just by specific genetic faults but by sustained hormonal imbalances that push adrenal cells to keep dividing year after year. This same principle, chronic stimulation leading to growth and eventually to autonomous tumor formation, is thought to play a role in some human adrenal tumors as well, though the specific hormonal context differs.