Adrenocortical Adenoma: Comprehensive Disease-Characteristics Report

Executive summary

An adrenocortical adenoma (ACA) is a benign, usually well-circumscribed neoplasm derived from steroidogenic cells of the adrenal cortex. Most are discovered incidentally and are nonfunctioning, but clinically important subsets autonomously produce cortisol or aldosterone. The central clinical tasks are therefore to establish (1) whether the lesion is radiologically benign, (2) whether it produces hormones, and (3) whether surgery would improve outcomes.

The 2023 European Society of Endocrinology (ESE) framework substantially simplified imaging follow-up: a homogeneous lesion measuring ≤10 Hounsfield units (HU) on unenhanced CT requires no further imaging follow-up, irrespective of size. In patients without overt Cushing syndrome, post–1-mg dexamethasone cortisol >50 nmol/L (>1.8 μg/dL) is classified as mild autonomous cortisol secretion (MACS). Management of MACS is individualized according to age, general health, cortisol-related comorbidity, and patient preference. (park2023recentupdateson pages 5-6)

Table: This table condenses the key disease-knowledge elements for adrenocortical adenoma, including subtype-defining biology, current diagnostic thresholds, and management points. Ontology entries are explicitly marked as suggested when they were not source-validated in the gathered evidence.

1. Disease information

Definition and scope

ACA is a benign neoplastic proliferation of adrenal cortical cells. “Adrenal incidentaloma” is not synonymous with ACA: it is an imaging presentation—an unsuspected adrenal mass found during imaging for another reason—and includes adenoma, pheochromocytoma, myelolipoma, metastasis, adrenocortical carcinoma (ACC), cyst, hemorrhage, and other lesions. Approximately 75–80% of incidentally detected adrenal masses in major clinical series are benign/nonfunctioning adenomas, although the proportions vary with referral setting. (yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)

Functional classifications are:

• Nonfunctioning adrenocortical adenoma (NFA/NFAT).
• Cortisol-producing adenoma (CPA) causing overt ACTH-independent Cushing syndrome or MACS.
• Aldosterone-producing adenoma (APA; Conn adenoma) causing unilateral primary aldosteronism.
• Rare androgen-, estrogen-, or mixed steroid-producing adenomas. Marked sex-steroid excess should increase concern for ACC rather than routine ACA.

Identifiers and synonyms

• Preferred name: adrenocortical adenoma.
• Synonyms: adrenal cortical adenoma, adrenal cortex adenoma, cortical adrenal adenoma; functional forms include cortisol-producing adenoma and aldosterone-producing adenoma/Conn adenoma.
• ICD-10-CM: D35.0, benign neoplasm of adrenal gland; this code does not distinguish cortex from medulla or functional subtype.
• ICD-11: falls under benign neoplasms of endocrine glands/adrenal gland; the precise national-extension code should be validated against the implementation being used.
• MeSH: “Adrenocortical Adenoma”/the adrenal-cortex-neoplasm hierarchy should be mapped against the current MeSH release.
• MONDO, OMIM, and Orphanet: a stable disease-specific identifier was not established from the retrieved evidence and should not be inferred. ACA is usually sporadic and common enough that it is not conventionally treated as a single Mendelian or rare-disease entity. OMIM entries are more appropriate for predisposing syndromes such as Carney complex, MEN1, familial adenomatous polyposis, and familial hyperaldosteronism.
• Suggested NCIt concept: Adrenal Cortex Adenoma; validate the current NCIt code during ingestion.

This report synthesizes aggregated disease-level literature and guidelines, not individual EHR records. Some cited primary studies use patient-level clinical, imaging, pathology, or sequencing data.

2. Etiology

Causal factors

Most ACAs are sporadic clonal neoplasms. Their best-supported proximal causes are acquired, subtype-specific somatic alterations:

1. CPA: constitutive cAMP–protein kinase A signaling, especially activating PRKACA variants; GNAS and CTNNB1 alterations occur in additional subsets.
2. APA: mutually exclusive variants affecting potassium channels, calcium channels, or ATPases—principally KCNJ5, CACNA1D, ATP1A1, ATP2B3, and less often CACNA1H or CLCN2—produce membrane depolarization, calcium signaling, CYP11B2 induction, and aldosterone synthesis. (kim2024molecularandgenetics pages 9-11, leo2024molecularpathologyof pages 17-18)
3. Nonfunctioning ACA: molecularly heterogeneous; Wnt/β-catenin activation is found in a subset, but no single alteration defines all lesions.

Genetic risk and predisposition

Routine ACA is not inherited. Germline testing becomes relevant with bilateral/multifocal disease, childhood or unusually young onset, syndromic features, or a strong family history. Relevant predisposition pathways include PRKAR1A in Carney complex/primary pigmented nodular adrenocortical disease, MEN1, APC in familial adenomatous polyposis, and familial-primary-aldosteronism genes. Germline PRKAR1A loss constitutively activates PKA; it accounts for more than 67% of Carney-complex index cases in the reviewed evidence, but this relates principally to nodular adrenal disease rather than ordinary unilateral ACA. (bonnetserrano2018geneticsoftumors pages 4-6)

Demographic and environmental risk

Detection rises strongly with age and imaging use. Older studies report an average incidentaloma prevalence near 2%, approximately 4% in middle age and up to 10% in elderly populations; contemporary imaging-study estimates are 1–5%. No consistent sex difference was identified in the older guideline synthesis, although genotype-specific differences occur—KCNJ5-mutant APA is enriched in younger women. (yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2, leo2024molecularpathologyof pages 17-18)

No toxin, infection, diet, smoking exposure, occupational exposure, or lifestyle factor has been established as a direct cause of ordinary ACA. Obesity, hypertension, and diabetes commonly coexist, but reverse causation is important because subtle cortisol secretion can itself produce these conditions.

Protective factors and gene–environment interactions

No validated genetic or environmental factor prevents ACA. General cardiovascular risk reduction may lessen morbidity from MACS or primary aldosteronism but is not proven to prevent tumor formation. A notable physiologic interaction is the occurrence of CTNNB1-mutant APA with GNAQ/GNA11 alterations around puberty, pregnancy, or menopause, suggesting that hormonal environments can expose or amplify a genetically primed aldosterone-producing phenotype. (kim2024molecularandgenetics pages 22-23, sousa2022colocalizationofwntβcatenin pages 18-23)

3. Phenotypes

Nonfunctioning lesions are usually asymptomatic and stable; symptoms arise predominantly from hormone excess or, rarely, mass effect.

Cortisol excess

• MACS: often lacks classic Cushing stigmata but is associated with hypertension, type 2 diabetes, dyslipidemia, obesity, cardiovascular risk, osteoporosis/osteopenia, and fractures. Severity is variable and usually chronic/insidious.
• Overt Cushing syndrome: proximal muscle weakness, easy bruising, facial plethora, wide violaceous striae, central adiposity, hypertension, diabetes, osteoporosis, infection susceptibility, and neuropsychiatric symptoms.
• Suggested HPO terms: Hypercortisolism (HP:0001578), Hypertension (HP:0000822), Type II diabetes mellitus (HP:0005978), Osteoporosis (HP:0000939), Proximal muscle weakness (HP:0003701), Easy bruising (HP:0000978), Abdominal obesity (HP:0012743), Depression (HP:0000716).

Aldosterone excess

APA produces sustained or episodically recognized hypertension, suppressed renin, elevated aldosterone-to-renin ratio, and sometimes hypokalemia, metabolic alkalosis, muscle weakness, cramps, polyuria, or arrhythmia. Normokalemia does not exclude primary aldosteronism. Cardiovascular and renal injury is disproportionate to blood-pressure elevation because aldosterone has direct tissue effects.

• Suggested HPO: Hyperaldosteronism (HP:0000848), Hypertension (HP:0000822), Hypokalemia (HP:0002900), Metabolic alkalosis (HP:0200114), Muscle weakness (HP:0001324), Cardiac arrhythmia (HP:0011675), Polyuria (HP:0000103).

Mass effects and mixed secretion

Large lesions can cause nonspecific flank or abdominal discomfort, although such symptoms are unusual in typical small ACA. Rare mixed steroid secretion can produce overlapping Cushing, mineralocorticoid, or sex-steroid phenotypes. Rapid virilization or feminization is a red flag for ACC.

Quality of life

Quality-of-life impairment is mainly endocrine-mediated: fatigue, weakness, mood symptoms, metabolic disease, fractures, polypharmacy, and cardiovascular morbidity. Disease-specific EQ-5D or SF-36 reference values were not established in the retrieved evidence. Surgical decisions in MACS should therefore consider patient-reported burden as well as biochemical status.

4. Genetic and molecular information

Principal somatic drivers

PRKACA alterations are reported in approximately 35–66% of CPA in the 2024 synthesis. The same review reported GNAS enrichment in subclinical cortisol secretion and estimated that CTNNB1 contributes to roughly 23% of CPA, but exact frequencies vary substantially with phenotype definition and cohort selection. These figures should not be treated as universal population prevalences. (kim2024molecularandgenetics pages 9-11)

KCNJ5 is the most frequent APA driver, accounting for approximately 40% overall and showing enrichment in younger female patients. In CYP11B2-guided sequencing, known aldosterone-driver alterations can explain about 90% of APA; rare somatic CLCN2 variants were found in 2/115 tumors (1.74%). (leo2024molecularpathologyof pages 17-18)

Variant interpretation

These tumor variants are ordinarily somatic, not germline, and should be reported using a somatic-oncology framework rather than automatically labeled “pathogenic germline” under ACMG/AMP constitutional criteria. Population allele frequency is generally not meaningful for tumor-only variants; paired normal tissue is needed to establish origin. Routine ACA care does not require tumor sequencing because genotype rarely changes present standard treatment.

Modifiers, epigenetics, and chromosomal change

No clinically validated modifier gene is used to predict ACA severity. Pregnancy-associated DNA-methylation changes and additional candidate alterations have been reported, but they remain investigational. Broad copy-number instability, TP53 disruption, IGF2 overexpression, and extensive methylomic derangement favor ACC rather than ordinary ACA. (kim2024molecularandgenetics pages 22-23, kim2024molecularandgenetics pages 21-22)

5. Environmental information

There is no established infectious cause and no evidence for transmissibility. Radiation, pollutants, diet, smoking, and alcohol have not been proven causal for sporadic ACA. Exogenous glucocorticoids can mimic Cushing physiology and interfere with testing but do not constitute ACA. Licorice and medications affecting renin or aldosterone can confound primary-aldosteronism assessment. Prevention should consequently focus on avoiding diagnostic interference and controlling endocrine complications rather than avoiding a known carcinogen.

6. Mechanism and pathophysiology

CPA causal chain

Somatic PRKACA/GNAS activation → ACTH-independent cAMP/PKA activity → CREB-dependent transcription and induction of steroidogenic regulators/enzymes, including STAR and CYP11B1 → autonomous cortisol synthesis → suppression of pituitary ACTH and contralateral adrenal cortex → chronic glucocorticoid effects on liver, muscle, fat, bone, immune, cardiovascular, and nervous systems. PRKACA hotspot variants disrupt normal catalytic–regulatory PKA interaction and permit cAMP-independent signaling. (kim2024molecularandgenetics pages 9-11)

Suggested terms: GO:0019933 cAMP-mediated signaling; GO:0006468 protein phosphorylation; GO:0008202 steroid metabolic process; GO:0006694 steroid biosynthetic process; GO:0008210 estrogen metabolic process where applicable. Relevant cells are steroidogenic adrenal cortical cells, especially zona fasciculata-like cells; suggested CL: adrenal cortex cell and CL: steroid hormone-secreting cell mappings should be validated.

APA causal chain

Ion-channel/pump mutation → zona-glomerulosa-cell depolarization → opening of voltage-gated calcium channels and/or increased intracellular Ca²⁺ → calcium-dependent transcription → CYP11B2 expression and aldosterone production → renal sodium retention, potassium and hydrogen-ion loss, volume expansion and renin suppression → hypertension, hypokalemia, alkalosis, and aldosterone-mediated cardiovascular/renal remodeling. The same signaling supports proliferation and adenoma formation. (leo2024molecularpathologyof pages 17-18)

Suggested terms: GO:0006816 calcium ion transport; GO:0030007 cellular potassium-ion homeostasis; GO:0032342 aldosterone biosynthetic process; GO:0071372 cellular response to mineralocorticoid stimulus. Cell: zona glomerulosa steroidogenic cell.

Wnt/β-catenin and microenvironment

CTNNB1 mutation stabilizes β-catenin, but molecular activation is more common than mutation alone. CTNNB1 variants occur in about 5% of APA while β-catenin activation is found in most aldosterone-producing structures. In a primary multiplex-imaging study, CYP11B2-positive regions showed activated β-catenin, high MC2R in some heterogeneous tumors, dense vasculature, and mast cells adjacent to aldosterone-producing cells. This supports a model in which lineage identity, ACTH responsiveness, vascular supply, and mast-cell paracrine signals cooperate with tumor genotype. (sousa2022colocalizationofwntβcatenin pages 18-23)

Omics and advanced technologies

Current applications include CYP11B2-guided sequencing, whole-exome sequencing, DNA methylation profiling, transcriptomics, steroid metabolomics, multiplex immunofluorescence, spatial proteomics, and machine-learning analysis of steroid profiles or CT. Steroid metabolomics by tandem mass spectrometry is promising for distinguishing benign from malignant adrenal disease but is not universally available. Spatial and single-cell methods are research tools rather than validated ACA diagnostics. (kim2024molecularandgenetics pages 22-23, park2023recentupdateson pages 5-6)

7. Anatomical structures affected

• Primary organ: adrenal gland—UBERON:0002369 (suggested mapping).
• Primary tissue: adrenal cortex, particularly zona fasciculata-like cells in CPA and zona glomerulosa-lineage cells in APA.
• Laterality: commonly unilateral; bilateral or multinodular disease suggests hyperplasia or hereditary/syndromic disease and requires a different framework.
• Secondary systems: cardiovascular and renal systems in aldosterone excess; metabolic, musculoskeletal, immune, psychiatric, reproductive, and cardiovascular systems in cortisol excess.
• Subcellular compartments: plasma membrane ion channels/pumps in APA; cytosolic/nuclear β-catenin; cytosolic PKA complex and nuclear CREB; mitochondrial and smooth-ER steroidogenic machinery.
• Suggested GO cellular components: plasma membrane (GO:0005886), voltage-gated calcium-channel complex (GO:0005891), nucleus (GO:0005634), mitochondrion (GO:0005739), smooth endoplasmic reticulum (GO:0005790).

8. Temporal development

ACA is generally an adult-onset, insidious, slowly evolving lesion, with prevalence increasing markedly with age. Pediatric ACA is uncommon and should prompt careful malignancy and germline-predisposition assessment. There is no AJCC staging system for benign ACA.

A homogeneous ≤10-HU lesion has a sufficiently benign natural history that the 2023 ESE approach recommends no repeat imaging. For indeterminate lesions under surveillance, growth >20% plus at least 5 mm in maximum diameter is considered significant and prompts reconsideration. Hormonal evolution can occur, but repeated endocrine testing is generally symptom/comorbidity driven after an initially normal evaluation rather than performed indefinitely in every patient. (park2023recentupdateson pages 5-6)

Functional disease generally persists until the source is removed or medically controlled. Post-adrenalectomy hypothalamic–pituitary–adrenal recovery can take months; this is a clinically important treatment-induced phase rather than tumor recurrence.

9. Inheritance and population

Imaging-study prevalence is approximately 1–5%, rising with age; historical estimates reach approximately 10% in older populations. A Japanese nationwide survey summarized in a 2024 review found 75% benign lesions and 25% functional lesions, including 10.5% cortisol-producing and 5.1% aldosterone-producing lesions; pheochromocytoma accounted for 8.5% but is medullary and not an ACA. (yoshida2024diagnosisandmanagement pages 1-3)

Incidence per 100,000 person-years is difficult to define because detection depends heavily on imaging. Ordinary unilateral ACA is sporadic, multifactorial, and not assigned Mendelian inheritance, penetrance, carrier frequency, anticipation, consanguinity, or founder-effect parameters. Such concepts apply only to the uncommon predisposing syndromes. KCNJ5-mutant APA has demographic enrichment in younger women, whereas mutation frequencies vary by ancestry; population-specific estimates should not be generalized without ancestry-matched cohorts. (leo2024molecularpathologyof pages 17-18, sousa2022colocalizationofwntβcatenin pages 23-25)

10. Diagnostics

Imaging

1. Unenhanced CT first: homogeneous, lipid-rich lesions measuring ≤10 HU are benign by current guideline criteria and need no further imaging follow-up, regardless of size.
2. Indeterminate lesions: 11–20 HU or heterogeneous appearance warrants dedicated adrenal imaging—contrast washout CT, chemical-shift MRI, or selected PET—preferably after multidisciplinary review.
3. Features concerning for malignancy include heterogeneity, irregular margins, necrosis/hemorrhage, local invasion, metastases, and significant interval growth. Size contributes to risk but should not be the only determinant. (park2023recentupdateson pages 5-6)

Hormonal evaluation

• Cortisol: 1-mg overnight dexamethasone-suppression test. Post-DST cortisol >50 nmol/L (>1.8 μg/dL) in a patient without overt Cushing signs supports MACS; confirm ACTH independence and consider confounders. The 2024 review reported sensitivity 98.6% and specificity 90.6% at this threshold. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3)
• Primary aldosteronism: plasma aldosterone-to-renin ratio in patients with hypertension or unexplained hypokalemia, followed by confirmatory testing and subtype evaluation where required. Reported screening performance was 97% sensitivity and 80% specificity. (yoshida2024diagnosisandmanagement pages 1-3)
• Pheochromocytoma exclusion: plasma-free or urinary fractionated metanephrines when imaging is not unequivocally typical of benign adenoma or symptoms warrant testing. Reported plasma-free-metanephrine performance was 95.7% sensitivity and 97.3% specificity. (yoshida2024diagnosisandmanagement pages 1-3)
• Sex steroids/steroid precursors: test if virilization, feminization, or suspected ACC is present.

Localization and pathology

In confirmed primary aldosteronism, CT alone cannot reliably identify the secreting side because nonfunctioning nodules become common with age. Adrenal-vein sampling is usually required before surgery unless a narrowly defined young patient has a compelling unilateral phenotype.

ACA is typically circumscribed and yellow owing to intracellular lipid. Histology shows bland cortical cells, low mitotic activity, absence of atypical mitoses, and no destructive capsular or vascular invasion. Immunohistochemical support for cortical origin includes SF-1, inhibin-α, Melan-A, and calretinin; CYP11B2 identifies aldosterone-producing tissue. The Weiss system and related algorithms distinguish adenoma from ACC but require expert endocrine pathology and are not screening tests.

Differential diagnosis

ACC, pheochromocytoma, metastasis, myelolipoma, adrenal cyst/hemorrhage, ganglioneuroma, oncocytic adrenocortical neoplasm, adrenal hyperplasia, and renal or retroperitoneal masses must be considered. Percutaneous biopsy does not determine cortical adenoma versus ACC reliably and should never precede biochemical exclusion of pheochromocytoma.

Genetic and omics testing

WES, WGS, chromosomal microarray, FISH, karyotyping, mitochondrial testing, and repeat-expansion testing are not routine. A focused germline panel is appropriate only when the presentation suggests a syndrome; potential genes include PRKAR1A, MEN1, APC, and familial-hyperaldosteronism genes selected according to phenotype. Tumor sequencing and steroid metabolomics remain specialist/research applications.

Screening

No population-wide screening is recommended. Targeted biochemical screening for primary aldosteronism is appropriate in guideline-defined hypertensive groups. Cascade testing applies only after a pathogenic germline predisposition is identified.

11. Outcome and prognosis

A completely characterized benign ACA has an excellent tumor-specific prognosis: it does not metastasize, and disease-specific mortality or five-year cancer survival statistics are not meaningful. Published poor-survival statistics for ACC must not be applied to ACA.

Morbidity is instead driven by hormone exposure. MACS can contribute to diabetes, hypertension, cardiovascular disease, and skeletal fragility; APA increases cardiovascular and renal risk beyond that expected from blood pressure alone. Correct diagnosis is important because inadequate perioperative management can lead to cardiovascular events or adrenal insufficiency. (yoshida2024diagnosisandmanagement pages 1-3)

After unilateral adrenalectomy, biochemical cortisol or aldosterone excess is often corrected, although hypertension, diabetes, or osteoporosis may not fully reverse because of disease duration, age, and coexisting essential disease. Persistent hypertension after APA surgery does not necessarily mean persistent aldosterone excess. Key prognostic factors include duration/severity of hormonal excess, age, renal function, cardiometabolic comorbidity, contralateral adrenal suppression, and accurate unilateral localization.

12. Treatment

Nonfunctioning benign ACA

No tumor-directed drug is indicated. A homogeneous ≤10-HU lesion receives reassurance and clinical care for unrelated comorbidities, without serial imaging under the 2023 ESE framework. Indeterminate lesions may undergo one-time additional imaging or interval surveillance. Suggested NCIt interventions: Active Surveillance; Computed Tomography; Magnetic Resonance Imaging. (park2023recentupdateson pages 5-6)

Functional ACA

• Adrenalectomy: definitive treatment for unilateral APA and overt cortisol-producing adenoma; considered individually for MACS when relevant comorbidities are present. Minimally invasive adrenalectomy is preferred for benign hormone-secreting lesions and selected suspicious masses ≤6 cm without invasion. High-volume surgery—defined in the reviewed ESE summary as at least 12 adrenalectomies annually—is favored. Suggested NCIt: Adrenalectomy; Laparoscopic Adrenalectomy. (park2023recentupdateson pages 5-6)
• Perioperative cortisol care: patients with cortisol autonomy require stress-dose glucocorticoids followed by tapering based on hypothalamic–pituitary–adrenal recovery. Suggested NCIt: Glucocorticoid Replacement Therapy.
• APA medical therapy: mineralocorticoid-receptor antagonists—spironolactone or eplerenone—are used when surgery is not chosen, while awaiting localization/surgery, or for bilateral disease. Suggested NCIt: Spironolactone Therapy; Eplerenone Therapy. Hyperkalemia, renal dysfunction, gynecomastia, menstrual disturbance, and hypotension require monitoring.
• Cortisol-lowering drugs: metyrapone, osilodrostat, ketoconazole/levoketoconazole, or mifepristone can control selected severe hypercortisolism but are not routine definitive therapy for a resectable benign adenoma.

There is no approved gene, cell, RNA, immune, or genotype-guided therapy for ACA. Pharmacogenomic selection is not standard.

Current research applications

ClinicalTrials.gov searches identified observational work on adrenal-disease cohorts (NCT03474237), steroid-panel diagnosis (NCT04948970), detection of MACS (NCT06344143), spatial proteomics of APA (NCT05927961), and bone effects of MACS (NCT04343560). Early imaging studies include [18F]CETO (NCT05361083). These are diagnostic or mechanistic studies, not evidence of an approved molecular ACA treatment.

13. Prevention

There is no proven primary prevention, vaccine, prophylactic drug, or population screening program for ACA. Secondary prevention consists of correct biochemical characterization of incidentally detected lesions and targeted primary-aldosteronism screening in high-risk hypertension. Tertiary prevention includes treatment of cortisol or aldosterone excess, blood-pressure and diabetes control, potassium normalization, cardiovascular-risk management, bone-density assessment, and perioperative prevention of adrenal crisis. Genetic counseling is reserved for young, bilateral, familial, or syndromic cases.

14. Other species and natural disease

Naturally occurring adrenocortical tumors occur in dogs and cats and may produce cortisol, aldosterone, progesterone, sex steroids, or combinations. A documented 14-year-old spayed female cat with a right adrenocortical tumor had hyperaldosteronism, hyperprogesteronism, evidence of cortisol excess, hypertension, and hypokalemia; unilateral adrenalectomy resolved the endocrine abnormalities. This supports conserved steroidogenic biology but represents case-level rather than population evidence.

Suggested taxonomy: Homo sapiens—NCBI Taxon 9606; Mus musculus—10090; Rattus norvegicus—10116; Canis lupus familiaris—9615; Felis catus—9685. Breed-specific VBO associations and robust veterinary incidence estimates were not established. These tumors are noninfectious and have no zoonotic potential.

15. Model organisms and experimental systems

Mouse models

Genetically engineered mice with adrenal β-catenin activation develop cortical hyperplasia and, depending on model duration and cooperating events, macroscopic tumors. These models demonstrate causality for Wnt signaling but often fail to reproduce the full spectrum, latency, hormone phenotype, and benign-to-malignant evolution of human disease. PKA-pathway models interrogate PRKAR1A/PRKACA signaling and cortisol-producing disease. Conditional, cortex-specific systems are preferable because ubiquitous activation may be embryonic-lethal or cause nonadrenal phenotypes.

Cellular systems

Human NCI-H295R and mouse Y1 adrenocortical cells are widely used to study steroidogenesis and Wnt/PKA signaling, but they are carcinoma-derived or transformed and therefore imperfect ACA models. In vitro Wnt/TCF inhibition reduces steroidogenesis and proliferation and increases apoptosis in adrenocortical tumor cells, demonstrating pathway dependence but not clinical efficacy in benign ACA.

Organoids, spheroids, xenografts, and spatial models

Three-dimensional cultures and organoid-like systems improve tissue architecture and microenvironment modeling, while multiplex imaging and spatial proteomics can resolve CYP11B2-positive regions, vasculature, mast cells, and intratumoral heterogeneity. Most mature repositories and xenograft resources concern ACC rather than ACA. Patient-derived benign adenoma organoids, faithful APA models, and models integrating genotype with long-term endocrine phenotype remain major unmet needs.

Recent developments and authoritative interpretation

The major 2023–2024 advances are: (1) removal of the historical size restriction for homogeneous ≤10-HU lesions; (2) adoption of a single >1.8-μg/dL post-DST threshold for MACS; (3) greater emphasis on comorbidity-based shared decisions rather than cortisol strata alone; (4) multidisciplinary, high-volume adrenal surgery; and (5) increasing use of steroid metabolomics, CYP11B2-guided sequencing, spatial proteomics, and machine learning. (park2023recentupdateson pages 5-6, kim2024molecularandgenetics pages 22-23)

The clearest guideline statement is: “a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size.” The same 2023 review states that post-DST cortisol above 50 nmol/L (>1.8 μg/dL) should be regarded as MACS in patients without overt Cushing syndrome. (park2023recentupdateson pages 5-6)

Expert interpretation is that ACA should no longer be treated as a single biologic entity. Cortisol-producing, aldosterone-producing, and nonfunctioning adenomas have distinct initiating pathways, and an imaging diagnosis must remain separate from endocrine phenotype. Molecular profiling is rapidly clarifying pathogenesis, but—outside suspected hereditary disease—it has not yet displaced imaging, biochemical testing, adrenal-vein sampling, expert pathology, and individualized surgical judgment.

Key sources and dates

1. Park SS, Kim JH. Recent Updates on the Management of Adrenal Incidentalomas. Endocrinology and Metabolism. Published August 2023. DOI/URL: https://doi.org/10.3803/enm.2023.1779. (park2023recentupdateson pages 5-6)
2. Yoshida Y, et al. Diagnosis and management of adrenal incidentaloma: use of clinical judgment and evidence in dialog with the patient. Surgery Today. Published December 2024. DOI/URL: https://doi.org/10.1007/s00595-023-02781-y. (yoshida2024diagnosisandmanagement pages 1-3)
3. Kim S, Chaudhary PK, Kim S. Molecular and Genetics Perspectives on Primary Adrenocortical Hyperfunction Disorders. International Journal of Molecular Sciences. Published October 2024. DOI/URL: https://doi.org/10.3390/ijms252111341. (kim2024molecularandgenetics pages 22-23, kim2024molecularandgenetics pages 9-11)
4. De Leo A, et al. Molecular pathology of endocrine gland tumors: genetic alterations and clinicopathologic relevance. Virchows Archiv. Published in volume 484 (2024); DOI registered December 2023. URL: https://doi.org/10.1007/s00428-023-03713-4. (leo2024molecularpathologyof pages 17-18)
5. De Sousa K, et al. Colocalization of Wnt/β-Catenin and ACTH Signaling Pathways and Paracrine Regulation in Aldosterone-producing Adenoma. Journal of Clinical Endocrinology & Metabolism. 2022. DOI/URL: https://doi.org/10.1210/clinem/dgab707. (sousa2022colocalizationofwntβcatenin pages 18-23)
6. Bonnet-Serrano F, Bertherat J. Genetics of tumors of the adrenal cortex. Endocrine-Related Cancer. Published March 2018. DOI/URL: https://doi.org/10.1530/ERC-17-0361. (bonnetserrano2018geneticsoftumors pages 4-6)
7. Lee JM, et al. Clinical Guidelines for the Management of Adrenal Incidentaloma. Endocrinology and Metabolism. Published June 2017. DOI/URL: https://doi.org/10.3803/enm.2017.32.2.200. (lee2017clinicalguidelinesfor pages 1-2)

PMIDs were not present in the retrieved source metadata and are therefore not invented here; DOI URLs provide stable primary identifiers. Ontology mappings marked “suggested” should be validated against the current releases of MONDO, HPO, GO, CL, UBERON, NCIt, LOINC, and MeSH before production ingestion.

References

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