Adrenal Cortex Adenoma

Neoplastic MONDO:0003924 Pathograph 43 Show in embeddings browser adrenal cortex neoplasm benign neoplasm of adrenal gland

A benign, clonal neoplasm arising from the steroidogenic cells of the adrenal cortex. Most adrenal cortex adenomas are found incidentally on cross-sectional imaging performed for unrelated reasons — the "adrenal incidentaloma" — and the lesion itself is biologically indolent: it does not metastasize and its tumour-specific prognosis is excellent. Clinical significance is therefore determined almost entirely by autonomous hormone secretion, and this entry is organised on that functional axis. Cortisol-producing adenomas cause ACTH-independent Cushing syndrome and are driven predominantly by somatic activating mutations of PRKACA (and, less often, GNAS) that release the PKA catalytic subunit from regulatory-subunit restraint. Aldosterone-producing adenomas (APA, Conn adenoma) cause unilateral primary aldosteronism and are driven by mutually exclusive somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which converge on zona glomerulosa membrane depolarisation, calcium influx and CYP11B2 induction; CTNNB1 also occurs in a minority of APAs but is a transcriptional proliferation driver, not part of that ion-channel convergence. A large intermediate group shows mild autonomous cortisol secretion (MACS) without overt Cushing stigmata; MACS has been reclassified from a benign curiosity to a recognised cardiometabolic and skeletal risk state. Non-functioning adenomas, the largest single group, are molecularly heterogeneous with frequent Wnt/beta-catenin activation. Adrenal cortex adenoma must be distinguished from adrenocortical carcinoma, from bilateral macronodular adrenal hyperplasia (ARMC5) and from primary pigmented nodular adrenocortical disease (PRKAR1A / Carney complex); these are separate disease entities modelled elsewhere, not subtypes of this entry.

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Classifications

Harrison's Chapter

◆

Subtypes

Cortisol-Producing Adenoma (overt Cushing syndrome)

PRKACA hgnc:9380 GNAS hgnc:4392

A unilateral adenoma secreting cortisol autonomously and sufficiently to produce clinically overt ACTH-independent Cushing syndrome. Somatic PRKACA hotspot mutations are the dominant driver; GNAS activating mutations account for an additional subset. Cortisol autonomy suppresses pituitary ACTH and causes atrophy of the contralateral adrenal cortex, so unilateral adrenalectomy is followed by transient adrenal insufficiency requiring glucocorticoid cover.

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas"

Establishes the somatic-PRKACA cortisol-producing unilateral adenoma as a distinct entity.

Mild Autonomous Cortisol Secretion (MACS)

Biochemical cortisol autonomy — serum cortisol above 50 nmol/L (1.8 ug/dL) after a 1-mg overnight dexamethasone suppression test — in a patient without the clinical signs of overt Cushing syndrome. Formerly dismissed as "subclinical hypercortisolism", MACS is now recognised as a genuine cardiometabolic risk condition carrying excess hypertension, type 2 diabetes, osteoporosis, fracture and all-cause mortality relative to non-functioning adenomas. It is by far the largest functional group: roughly 45% of benign adrenal tumours in the ENSAT EURINE-ACT cohort fell into the MACS-1 or MACS-2 strata.

Show evidence (2 references)

PMID:37318239 SUPPORT Human Clinical

"Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality."

The ESE guideline defines MACS by the post-dexamethasone threshold and asserts the associated risk.

PMID:34978855 SUPPORT Human Clinical

"Of the 1305 participants, 49.7% had NFAT ... 34.6% had MACS-1 ... 10.7% had MACS-2"

Quantifies the relative sizes of the non-functioning and MACS strata.

Aldosterone-Producing Adenoma (APA, Conn adenoma)

KCNJ5 hgnc:6266 CACNA1D hgnc:1391 ATP1A1 hgnc:799 ATP2B3 hgnc:816 CTNNB1 hgnc:2514

A unilateral adenoma of zona glomerulosa lineage secreting aldosterone renin-independently, causing unilateral primary aldosteronism. Driven by mutually exclusive somatic mutations in KCNJ5 (most common), CACNA1D, ATP1A1, ATP2B3 and CTNNB1. Because CT cannot reliably identify the secreting side (non-functioning nodules become common with age), adrenal vein sampling is usually required before lateralising surgery.

Show evidence (1 reference)

PMID:21311022 SUPPORT Human Clinical

"We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."

Identifies KCNJ5 as a recurrent somatic driver defining this functional subtype.

Non-Functioning Adenoma (NFAT)

CTNNB1 hgnc:2514

An adenoma without demonstrable autonomous hormone secretion — normal metanephrines, a suppressed 1-mg dexamethasone test (below 50 nmol/L) and, where indicated, a normal aldosterone-to-renin ratio. This is the largest single group among incidentally detected adrenal masses. Molecularly heterogeneous; CTNNB1/Wnt-beta-catenin activation is the commonest recurrent alteration. A homogeneous lesion of 10 HU or less on unenhanced CT requires no further imaging follow-up and no surgery.

Show evidence (1 reference)

PMID:35731037 SUPPORT Human Clinical

"Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1."

Defines the dominant recurrent somatic alteration in the non-functioning subtype.

⚙

Pathophysiology

Clonal Adrenocortical Proliferation

A somatic driver mutation in a single adrenocortical cell produces a clonal, benign, well-circumscribed proliferation. Unlike adrenocortical carcinoma, this proliferation is self-limited: there is no destructive capsular or vascular invasion and no metastatic capacity. The driver that initiates the clone also determines the tumour's secretory phenotype, which is why the functional classification of adrenal adenomas maps onto distinct mutational classes rather than onto tumour size or histology.

adrenal cortical cell CL:0002097

adrenal cortex UBERON:0001235

Downstream

Adrenal Cortical Mass The clonal proliferation is itself the radiologically and pathologically detected adrenal mass.

Show evidence (1 reference)

PMID:35288842 SUPPORT Human Clinical

"recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease"

WHO 2022 affirms the clonal-neoplastic nature of benign adrenal cortical nodules.

PRKACA Catalytic Subunit Activation

Somatic hotspot mutations in PRKACA — the recurrent change is c.617A>C, designated p.Leu206Arg when the initiator methionine is counted and widely reported in the earlier literature as L205R under mature-protein numbering that omits it — lie in the P+1 loop at the interface between the PKA catalytic subunit and its regulatory subunit. The mutant catalytic subunit can no longer be held inactive by the regulatory subunit, so kinase activity becomes constitutive and cAMP-independent. Activating GNAS mutations produce the same functional endpoint one step upstream by locking Gs-alpha in its active state.

PRKACA hgnc:9380 GNAS hgnc:4392

cAMP-dependent protein kinase activity GO:0004691 ↑ INCREASED

Downstream

Constitutive cAMP-PKA Signalling Loss of regulatory-subunit inhibition renders PKA catalytic activity constitutive and independent of upstream cAMP.

Show evidence (3 references)

PMID:24571724 SUPPORT Human Clinical

"PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome"

Quantifies PRKACA somatic mutation frequency in overtly cortisol-producing adenomas.

PMID:24571724 SUPPORT In Vitro

"In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit"

Demonstrates the loss of regulatory-subunit restraint that is the molecular mechanism of the driver.

PMID:24700472 SUPPORT Human Clinical

"We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs."

Independent cohort confirming the PRKACA hotspot and its high frequency in cortisol-producing adenomas.

Constitutive cAMP-PKA Signalling

Unrestrained PKA catalytic activity phosphorylates CREB and other substrates, driving transcription of the steroidogenic program (STAR, CYP11A1, CYP11B1) in the absence of ACTH stimulation. The same signalling supports the modest proliferative advantage that allows the clone to form a macroscopic adenoma.

protein phosphorylation GO:0006468 ↑ INCREASED

Downstream

Clonal Adrenocortical Proliferation The same unrestrained PKA activity supports the proliferative advantage that lets the mutant clone grow into a macroscopic adenoma, so the cortisol arm feeds the shared proliferation trunk just as the aldosterone and Wnt arms do.

ACTH-Independent Cortisol Hypersecretion PKA-driven transcription of the steroidogenic machinery produces cortisol output that does not require ACTH.

Show evidence (1 reference)

PMID:24700472 SUPPORT In Vitro

"promoted PKA substrate phosphorylation and target gene expression"

Directly evidences increased PKA-dependent substrate phosphorylation and transcriptional output.

ACTH-Independent Cortisol Hypersecretion

Zona fasciculata-like tumour cells synthesise and release cortisol autonomously, uncoupled from the hypothalamic-pituitary axis. The magnitude of this autonomous output is the single variable that determines whether the patient presents with overt Cushing syndrome, with MACS, or with no cortisol-related phenotype at all — the same mechanism operating along a continuum of severity.

zona fasciculata cell CL:0002136

cortisol biosynthetic process GO:0034651 ↑ INCREASED

zona fasciculata UBERON:0002054

Downstream

Primary Hypercortisolism Autonomous adrenal cortisol output is, by definition, primary hypercortisolism.

HPA Axis Suppression and Contralateral Adrenal Atrophy Autonomous cortisol feeds back on the pituitary, suppressing ACTH and depriving the contralateral adrenal cortex of trophic support.

Chronic Glucocorticoid Excess When autonomous output is high, sustained supraphysiological glucocorticoid exposure of peripheral tissues follows.

Mild Autonomous Cortisol Secretion When autonomous output is low-grade, the patient has biochemical cortisol autonomy without the classical clinical stigmata — the MACS state.

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production."

States that adrenocortical tumours produce cortisol corticotropin-independently.

HPA Axis Suppression and Contralateral Adrenal Atrophy

Negative feedback from tumour-derived cortisol suppresses pituitary ACTH secretion; the non-tumorous ipsilateral and contralateral adrenal cortex atrophies. This is clinically silent while the adenoma is in place but becomes the dominant management problem immediately after adrenalectomy, when the remaining gland cannot mount a cortisol response — hence the requirement for perioperative and tapering glucocorticoid cover, with hypothalamic-pituitary-adrenal recovery often taking months.

Downstream

Adrenal Insufficiency After removal of the autonomous source, the suppressed contralateral gland is temporarily unable to sustain cortisol output.

Show evidence (1 reference)

PMID:37318239 PARTIAL Human Clinical

"Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess"

Indirect support only: the guideline mandates the endocrine work-up that detects cortisol autonomy, which is what predicts postoperative adrenal insufficiency. Marked PARTIAL because the abstract does not itself describe contralateral atrophy.

Chronic Glucocorticoid Excess

Sustained supraphysiological cortisol exposure produces the classical Cushing phenotype: central and abdominal fat redistribution, proteolytic muscle wasting with proximal weakness, dermal collagen loss with easy bruising, insulin resistance and type 2 diabetes, hypertension, and glucocorticoid-induced osteoporosis with fragility fracture.

Downstream

Abdominal Obesity Glucocorticoid-driven central fat redistribution.

Proximal Muscle Weakness Glucocorticoid-induced proteolysis of type II muscle fibres.

Bruising Susceptibility Glucocorticoid-induced dermal collagen loss and capillary fragility.

Hypertension Glucocorticoid excess raises blood pressure; hypertension prevalence and severity rise across the cortisol-autonomy strata.

Type II Diabetes Mellitus Glucocorticoid-induced insulin resistance and hepatic gluconeogenesis.

Hyperlipidemia Glucocorticoid-driven dyslipidaemia; prevalence rises across the cortisol-autonomy strata.

Osteoporosis Glucocorticoid-induced suppression of osteoblast function and bone loss.

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae"

Enumerates the catabolic consequences of severe glucocorticoid excess.

Mild Autonomous Cortisol Secretion

Low-grade cortisol autonomy sufficient to fail the 1-mg dexamethasone suppression test but insufficient to produce the classical Cushing habitus. The mechanistically important point — and the reason this node exists separately from Chronic Glucocorticoid Excess — is the reclassification of MACS. It was long treated as a biochemical curiosity of no consequence ("subclinical hypercortisolism"). Contemporary multicentre cohort data show that MACS is instead an independent cardiometabolic and skeletal risk state, carrying excess hypertension, insulin-requiring diabetes, vertebral fracture, and — critically — increased all-cause mortality relative to non-functioning adenomas, with the excess concentrated in women under 65. The 2023 ESE guideline formalised the term and mandated screening for cortisol-attributable comorbidity in every patient with MACS.

Downstream

Hypertension MACS-2 patients carry excess hypertension prevalence and need more antihypertensive agents than patients with non-functioning tumours.

Type II Diabetes Mellitus Diabetes in MACS-2 is more likely to require insulin, indicating greater metabolic severity than in non-functioning tumours.

Osteoporosis MACS is associated with lower lumbar-spine and femoral-neck bone mineral density and a higher prevalence of osteoporosis or osteopenia than non-functioning adenoma.

Vertebral Fracture The skeletal consequence of MACS is a roughly two-fold excess of vertebral fracture relative to non-functioning adrenal adenoma.

Show evidence (3 references)

PMID:35533704 SUPPORT Human Clinical

"Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years."

The mortality finding that drives the reclassification of MACS as a genuine risk state.

PMID:35533704 SUPPORT Human Clinical

"All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with..."

Quantifies the adjusted mortality hazard across both cortisol-autonomy strata.

PMID:34978855 SUPPORT Human Clinical

"A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes."

States the reclassification of MACS as a cardiometabolic risk condition explicitly.

Zona Glomerulosa Ion Channel and Pump Driver Mutation

Aldosterone-producing adenomas carry mutually exclusive somatic mutations in a small set of genes encoding ion channels and pumps of the zona glomerulosa plasma membrane: KCNJ5 (inwardly rectifying K+ channel; the commonest), CACNA1D (Cav1.3 L-type calcium channel), ATP1A1 (Na+/K+-ATPase alpha subunit) and ATP2B3 (plasma-membrane Ca2+-ATPase). CTNNB1 mutations occur in a minority. Different genes, one shared functional endpoint — the resting membrane potential of the glomerulosa cell can no longer be maintained.

zona glomerulosa cell CL:0002099

KCNJ5 hgnc:6266 CACNA1D hgnc:1391 ATP1A1 hgnc:799 ATP2B3 hgnc:816

zona glomerulosa UBERON:0002053

Downstream

Zona Glomerulosa Membrane Depolarisation Loss of K+ selectivity (KCNJ5), loss of Na+/K+-ATPase pump activity (ATP1A1) or loss of Ca2+ extrusion (ATP2B3) each depolarise the glomerulosa cell.

Show evidence (3 references)

PMID:23416519 SUPPORT Human Clinical

"In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3."

Quantifies the ATPase driver mutation frequencies in a large APA collection.

PMID:23913001 SUPPORT Human Clinical

"We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5."

Establishes CACNA1D as a driver in the KCNJ5-wild-type fraction of APAs, showing mutual exclusivity.

PMID:23913001 SUPPORT Human Clinical

"All CACNA1D mutations occurred in tumors without KCNJ5 or CTNN1B mutations."

Direct demonstration of mutual exclusivity between the APA driver classes. Note that the source spells beta-catenin "CTNN1B" in this sentence (a typographical error for CTNNB1, spelled correctly elsewhere in the same paper); the snippet is quoted verbatim.

Zona Glomerulosa Membrane Depolarisation

The glomerulosa cell resting potential, normally close to the K+ equilibrium potential, shifts toward depolarisation. This is the convergence point of the channel and pump drivers, and the reason a heterogeneous set of genes produces one clinical phenotype.

zona glomerulosa cell CL:0002099

membrane depolarization GO:0051899 ↑ INCREASED

Downstream

Calcium Influx and Calcium-Dependent Signalling Depolarisation opens voltage-gated calcium channels, raising cytosolic Ca2+. CACNA1D mutations reach the same endpoint by shifting channel activation to less depolarised potentials, bypassing the need for depolarisation.

Show evidence (1 reference)

PMID:21311022 SUPPORT In Vitro

"increased sodium (Na(+)) conductance and cell depolarization"

Direct evidence for the depolarised state in KCNJ5-mutant cells.

Calcium Influx and Calcium-Dependent Signalling

Increased cytosolic calcium is the final common pathway of aldosterone-producing adenoma formation. It is simultaneously the signal for aldosterone biosynthesis and for glomerulosa cell proliferation, which is why a single somatic channel mutation is sufficient to produce both constitutive hormone production and tumour growth.

zona glomerulosa cell CL:0002099

calcium ion import across plasma membrane GO:0098703 ↑ INCREASED

Downstream

CYP11B2 Induction and Autonomous Aldosterone Synthesis Calcium-dependent transcription induces aldosterone synthase (CYP11B2), committing the cell to renin-independent aldosterone output.

Clonal Adrenocortical Proliferation The same calcium signal drives glomerulosa cell proliferation, explaining why the hormone-producing lesion is also a growing adenoma.

Show evidence (2 references)

PMID:23913001 SUPPORT In Vitro

"These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa."

States that calcium influx is sufficient for both hormone production and proliferation.

PMID:23913001 SUPPORT In Vitro

"This suggests increased intracellular Ca2+ as a final common pathway to APA formation."

Explicitly names calcium as the convergent final common pathway.

CYP11B2 Induction and Autonomous Aldosterone Synthesis

Aldosterone synthase (CYP11B2) is upregulated in the tumour cells, which therefore synthesise aldosterone independently of angiotensin II and potassium. CYP11B2 immunohistochemistry is now the WHO-endorsed means of identifying which adrenal structures are actually the source of aldosterone excess — an important point, because a radiologically visible nodule is not necessarily the functional lesion.

zona glomerulosa cell CL:0002099

CYP11B2 hgnc:2592

aldosterone biosynthetic process GO:0032342 ↑ INCREASED

Downstream

Primary Hyperaldosteronism Renin-independent aldosterone output is, by definition, primary aldosteronism.

Renin-Independent Mineralocorticoid Excess Autonomous aldosterone drives renal sodium retention and potassium and hydrogen-ion loss, expanding volume and suppressing renin.

Show evidence (2 references)

PMID:35288842 SUPPORT Human Clinical

"the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production"

Establishes CYP11B2 as the marker of functional aldosterone production in adrenal tissue.

PMID:35288842 SUPPORT Human Clinical

"not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess"

Supports the caution that the imaged nodule may not be the aldosterone-producing lesion.

Renin-Independent Mineralocorticoid Excess

Excess aldosterone acting on the distal nephron produces sodium retention with volume expansion, kaliuresis and hydrogen-ion loss. The resulting biochemical signature is hypertension with a suppressed plasma renin and an elevated aldosterone-to-renin ratio, sometimes with hypokalaemia (and, when hypokalaemia is marked, a metabolic alkalosis that is not separately curated here for want of an adenoma-specific citable source). Normokalaemia does not exclude primary aldosteronism — an important reason the condition is under-recognised.

Downstream

Hypertension Volume expansion and vasoconstriction raise arterial pressure.

Hypokalemia Aldosterone-driven distal kaliuresis lowers serum potassium.

Aldosterone-Mediated Target Organ Damage Aldosterone exerts direct pro-fibrotic and pro-inflammatory effects on the heart, vasculature and kidney beyond the effect of the blood pressure it causes.

Show evidence (1 reference)

PMID:23913001 SUPPORT Human Clinical

"Aldosterone signaling defends intravascular volume by increasing intestinal and renal Na-Cl absorption and reabsorption, respectively."

Describes the renal sodium-retention mechanism underlying mineralocorticoid excess.

Aldosterone-Mediated Target Organ Damage

The clinically decisive feature of primary aldosteronism is that its cardiovascular and renal injury is disproportionate to the blood pressure. Compared with essential hypertensives, patients with primary aldosteronism have markedly higher odds of stroke, coronary disease, atrial fibrillation and heart failure. Combined with the fact that primary aldosteronism remains largely underdiagnosed and undertreated, this is the strongest argument for biochemical screening of hypertensive patients with an adrenal adenoma rather than treating blood pressure alone.

Downstream

Stroke Odds of stroke are roughly 2.6-fold those of essential hypertension.

Atrial Fibrillation Odds of atrial fibrillation are roughly 3.5-fold those of essential hypertension.

Coronary Artery Disease Odds of coronary artery disease are roughly 1.8-fold those of essential hypertension.

Heart Failure Odds of heart failure are roughly 2-fold those of essential hypertension.

Left Ventricular Hypertrophy Aldosterone-driven myocardial hypertrophy and fibrosis, part of the target organ damage measured in the meta-analysis.

Show evidence (3 references)

PMID:29129575 SUPPORT Human Clinical

"compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio ... 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)."

Quantifies the excess cardiovascular risk relative to essential hypertension.

PMID:29129575 SUPPORT Human Clinical

"These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups."

Confirms the excess risk applies specifically to the aldosterone-producing adenoma subgroup.

PMID:29629943 SUPPORT Human Clinical

"Disappointingly, primary aldosteronism remains a largely underdiagnosed and undertreated disorder."

Documents the underdiagnosis that makes the excess risk clinically consequential.

Wnt Beta-Catenin Pathway Activation

Activating CTNNB1 mutations stabilise beta-catenin, driving canonical Wnt transcription. This is the commonest recurrent alteration in non-functioning adrenocortical adenomas, and also occurs in a minority of aldosterone- and cortisol-producing lesions. It is a proliferation driver that does not itself impose a secretory phenotype, which is consistent with its enrichment in the non-functioning group.

CTNNB1 hgnc:2514

canonical Wnt signaling pathway GO:0060070 ↑ INCREASED

Downstream

Clonal Adrenocortical Proliferation Stabilised beta-catenin drives the clonal expansion that produces the adenoma, without conferring autonomous steroid secretion.

Show evidence (2 references)

PMID:35731037 SUPPORT Human Clinical

"Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1."

Quantifies CTNNB1 alteration frequency in non-functioning adrenocortical adenomas.

PMID:35731037 SUPPORT Human Clinical

"These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion."

Attributes benign adrenal tumorigenesis to Wnt/beta-catenin pathway involvement.

✶

Histopathology

Circumscribed Lipid-Rich Cortical Adenoma

Grossly circumscribed, often golden-yellow tumour composed of bland lipid-laden cortical cells, without destructive capsular or vascular invasion. Cortical origin is confirmed immunohistochemically with SF-1, inhibin-alpha, Melan-A and calretinin.

Show evidence (1 reference)

PMID:35288842 SUPPORT Human Clinical

"The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas."

Places adrenal cortical adenoma within the WHO 2022 spectrum of cortical proliferations.

Low Weiss Score

Adrenal cortical adenoma is distinguished from carcinoma by multiparameter histologic scoring. In Weiss's original series, none of the 24 tumours with two or fewer of the nine criteria metastasised or recurred, while almost all with four or more did. A Weiss score of 2 or less therefore supports adenoma. The 2022 WHO classification retains Weiss and modified Weiss alongside the reticulin algorithm, Lin-Weiss-Bisceglia and Helsinki systems.

Show evidence (2 references)

PMID:6703192 SUPPORT Human Clinical

"None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized."

The original derivation of the Weiss score threshold separating adenoma from carcinoma.

PMID:35288842 SUPPORT Human Clinical

"In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin-Weiss-Bisceglia system, and Helsinki scoring system)"

Confirms the continued role of Weiss scoring in the current WHO framework.

Low Proliferative Index

Adenomas show low mitotic activity and a low Ki67 labelling index. Most adult adrenal cortical carcinomas, by contrast, exceed 5 mitoses per 10 mm2 and 5% Ki67 — the proliferation-rate boundary is one of the most reproducible discriminators between the two entities.

Show evidence (1 reference)

PMID:35288842 SUPPORT Human Clinical

"Most adult adrenal cortical carcinomas show > 5 mitoses per 10 mm2 and > 5% Ki67."

Gives the proliferation thresholds above which carcinoma rather than adenoma is favoured.

CYP11B2 Immunoreactivity in Aldosterone-Producing Lesions

Aldosterone synthase (CYP11B2) immunohistochemistry identifies which cortical structures are actually producing aldosterone. The HISTALDO classification, endorsed by WHO 2022, uses this to distinguish a solitary CYP11B2-positive adenoma from multifocal or bilateral aldosterone-producing micronodules, which predicts the risk of persistent disease after unilateral adrenalectomy.

Show evidence (1 reference)

PMID:35288842 SUPPORT Human Clinical

"uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism"

Establishes CYP11B2 immunohistochemistry as the WHO-endorsed functional marker.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 1

Bruising Susceptibility Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"catabolic symptoms such as muscle weakness, skin fragility"

Skin fragility is the dermal substrate of easy bruising in cortisol excess.

Cardiovascular 6

Hypertension FREQUENT Hypertension HP:0000822

Frequency assigned FREQUENT from the counts quoted above (58.6-75.2% across the cortisol-autonomy strata of the NAPACA cohort). Hypertension is near-universal in the aldosterone-producing subtype specifically, since it is part of that subtype's case definition, so the subtype-level frequency is higher than this disease-level band; that subtype-specific figure was not separately curated.

Show evidence (1 reference)

PMID:35533704 SUPPORT Human Clinical

"hypertension occurred in 1186 ... of 2024 patients with non-functioning adenoma, 944 ... of 1275 with possible autonomous cortisol secretion, and 179 ... of 238 with autonomous cortisol secretion"

Gives the numerators and denominators for hypertension across the three cortisol strata (1186/2024 = 58.6%, 944/1275 = 74.0%, 179/238 = 75.2%), all of which fall in the FREQUENT (30-79%) band.

Coronary Artery Disease Coronary artery atherosclerosis HP:0001677

The meta-analysis endpoint is "coronary artery disease" as an event category; HP:0001677 (Coronary artery atherosclerosis) is the closest HPO term, which is slightly narrower than the reported endpoint.

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"coronary artery disease (1·77, 1·10-2·83)"

Quantifies the excess coronary artery disease risk in primary aldosteronism.

Heart Failure Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"and heart failure (2·05, 1·11-3·78)"

Quantifies the excess heart failure risk in primary aldosteronism.

Stroke Stroke HP:0001297

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"an increased risk of stroke (odds ratio ... 2·58, 95% CI 1·93-3·45)"

Quantifies the excess stroke risk in primary aldosteronism.

Atrial Fibrillation Atrial fibrillation HP:0005110

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"atrial fibrillation (3·52, 2·06-5·99)"

Quantifies the excess atrial fibrillation risk.

Left Ventricular Hypertrophy Left ventricular hypertrophy HP:0001712

Show evidence (1 reference)

PMID:29129575 SUPPORT Human Clinical

"primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."

Directly reports the 2.29-fold excess odds of left ventricular hypertrophy in primary aldosteronism.

Endocrine 2

Type II Diabetes Mellitus OCCASIONAL Type II diabetes mellitus HP:0005978

Show evidence (1 reference)

PMID:35533704 SUPPORT Human Clinical

"any diabetes occurred in 365 ... of 2002, 288 ... of 1250, and 62 ... of 232"

Gives the numerators and denominators for diabetes across the three cortisol strata (365/2002 = 18.2%, 288/1250 = 23.0%, 62/232 = 26.7%), all of which fall in the OCCASIONAL (5-29%) band.

Adrenal Insufficiency Adrenal insufficiency HP:0000846

Show evidence (1 reference)

PMID:37318239 PARTIAL Human Clinical

"All patients with MACS should be screened for potential cortisol-related comorbidities"

Indirect: the guideline's insistence on characterising cortisol autonomy is what identifies patients at risk of postoperative adrenal insufficiency. The abstract does not state the postoperative complication itself, hence PARTIAL.

Metabolism 2

Hypokalemia Hypokalemia HP:0002900

Frequency deliberately omitted. The cited source says only "often associated with hypokalemia" with no numerator or denominator, and contemporary reviews emphasise that primary aldosteronism is commonly normokalaemic. Assigning a FrequencyEnum band here would not be supported by quotable evidence.

Show evidence (1 reference)

PMID:23913001 SUPPORT Human Clinical

"Constitutive production of aldosterone (primary aldosteronism) results in hypertension, often associated with hypokalemia"

Links primary aldosteronism to hypokalaemia as a frequent but not obligate accompaniment.

Hyperlipidemia FREQUENT Hyperlipidemia HP:0003077

Show evidence (1 reference)

PMID:35533704 SUPPORT Human Clinical

"dyslipidaemia occurred in 724 ... of 1999 patients, 547 ... of 1250, and 123 ... of 237"

Numerators and denominators give 36.2%, 43.8% and 51.9% across the three cortisol strata, all within the FREQUENT (30-79%) band.

Musculoskeletal 3

Osteoporosis FREQUENT Osteoporosis HP:0000939

Show evidence (1 reference)

PMID:38703381 SUPPORT Human Clinical

"osteoporosis/osteopenia in MACS/SH were 43% ... and 50% (95% CI: 33%, 66%), respectively."

Pooled prevalence of the composite osteoporosis/osteopenia endpoint is 50% (95% CI 33-66%) in MACS. The FREQUENT (30-79%) band is assigned from this composite; osteoporosis alone would be lower, so the band is an upper-leaning estimate rather than a term-exact figure.

Vertebral Fracture FREQUENT Vertebral compression fracture HP:0002953

Bound to HP:0002953 (Vertebral compression fracture) because the claim and its evidence concern fracture *events*. An earlier draft used HP:0005625 (Osteoporosis of vertebrae), which asserts bone density rather than fracture and partly duplicated the separate Osteoporosis phenotype; that was corrected in review.

Show evidence (2 references)

PMID:38703381 SUPPORT Human Clinical

"vertebral fractures (OR 2.10; 95% CI: 1.28, 3.45; P = 0.0035)"

Quantifies the doubled odds of vertebral fracture in MACS versus non-functioning adenoma.

PMID:38703381 SUPPORT Human Clinical

"vertebral fractures, and osteoporosis/osteopenia in MACS/SH were 43% ... , 45% (95% CI: 22%, 68%)"

Pooled vertebral-fracture prevalence of 45% (95% CI 22-68%) in MACS supports the FREQUENT (30-79%) band.

Proximal Muscle Weakness Proximal muscle weakness HP:0003701

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"catabolic symptoms such as muscle weakness"

Names muscle weakness as a catabolic manifestation of severe Cushing syndrome.

Other 4

Adrenal Cortical Mass OBLIGATE Adrenocortical adenoma HP:0008256

Show evidence (1 reference)

PMID:37318239 SUPPORT Human Clinical

"Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease."

Defines the incidentally detected adrenal mass that constitutes the defining lesion.

Primary Hypercortisolism Primary hypercortisolism HP:0001579

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex."

Establishes adrenal tumours as a cause of ACTH-independent hypercortisolism.

Primary Hyperaldosteronism Primary hyperaldosteronism HP:0011736

Show evidence (1 reference)

PMID:23416519 SUPPORT Human Clinical

"Primary aldosteronism is the most prevalent form of secondary hypertension."

Establishes primary aldosteronism as the clinical phenotype of the aldosterone-producing adenoma.

Abdominal Obesity Abdominal obesity HP:0012743

Show evidence (1 reference)

PMID:34978855 PARTIAL Human Clinical

"Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS"

Supports the graded glucocorticoid exposure that produces central adiposity; the cohort abstract does not report adiposity as an endpoint, hence PARTIAL.

🧬

Genetic Associations

PRKACA (Recurrent activating hotspot mutations (c.617A>C; p.Leu206Arg counting the initiator methionine, equivalently L205R in the mature-protein numbering used in the earlier literature) in the P+1 loop of the PKA catalytic subunit. The mutant escapes inhibition by the PKA regulatory subunit, giving constitutive, cAMP-independent kinase activity.)

Gene: PRKACA hgnc:9380 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:24571724 SUPPORT Human Clinical

"Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase"

The discovery observation establishing PRKACA as the somatic driver.

PMID:24571724 SUPPORT Human Clinical

"these mutations were not detectable in 40 patients with subclinical hypercortisolism"

PRKACA mutation is absent in subclinical hypercortisolism (MACS), which is why this gene is scoped to the overt Cushing subtype rather than to cortisol autonomy generally — a direct constraint on the driver-to-subtype mapping.

GNAS (Activating mutations of the stimulatory G-protein alpha subunit lock Gs-alpha in its GTP-bound state, raising cAMP and activating PKA one step upstream of PRKACA.)

Gene: GNAS hgnc:4392 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:24571724 PARTIAL Human Clinical

"somatic mutations in the gene encoding the α subunit of the stimulatory G protein (GNAS1) cause adenomas or hyperplasias leading to Cushing's syndrome"

Establishes GNAS as a cAMP-pathway driver of cortisol-producing adrenal lesions. PARTIAL because the cited sentence continues "in patients with McCune-Albright syndrome or macronodular hyperplasia" — i.e. it evidences the pathway, not specifically the sporadic unilateral adenoma modelled here, and this study excluded somatic-GNAS cases from its own cohort.

KCNJ5 (Recurrent somatic mutations in and near the selectivity filter of the inwardly rectifying potassium channel Kir3.4 (p.Gly151Arg, p.Leu168Arg). Loss of K+ selectivity permits Na+ conductance and chronic depolarisation. The commonest APA driver.)

Gene: KCNJ5 hgnc:6266 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:21311022 SUPPORT In Vitro

"These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production."

Establishes the mechanism by which KCNJ5 mutation drives both proliferation and hormone excess. Tagged IN_VITRO because the mechanistic inference rests on the paper's electrophysiology, matching the tagging of the same sentence used on the Calcium Influx node.

CACNA1D (Gain-of-function mutations in the S6 pore-lining segments of the Cav1.3 L-type calcium channel (p.Gly403Arg, p.Ile770Met) shift channel activation to less depolarised potentials and impair inactivation, increasing calcium influx. Found in APAs that lack KCNJ5 mutations, demonstrating driver mutual exclusivity.)

Gene: CACNA1D hgnc:1391 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23913001 SUPPORT In Vitro

"Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation."

Electrophysiological demonstration of the gain-of-function mechanism.

ATP1A1 (Somatic hotspot mutations in the Na+/K+-ATPase alpha subunit cause loss of pump activity and strongly reduced potassium affinity, so the glomerulosa cell cannot maintain its hyperpolarised resting potential.)

Gene: ATP1A1 hgnc:799 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23416519 SUPPORT In Vitro

"Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium."

Functional demonstration of the loss-of-pump-activity mechanism.

ATP2B3 (Somatic hotspot mutations in the plasma-membrane calcium ATPase impair calcium extrusion, contributing to the raised cytosolic calcium that drives aldosterone synthesis and proliferation.)

Gene: ATP2B3 hgnc:816 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23416519 SUPPORT Human Clinical

"somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes"

Identifies ATP2B3 as a recurrent somatic driver encoding a calcium ATPase.

CTNNB1 (Activating mutations stabilising beta-catenin and driving canonical Wnt transcription. The commonest recurrent alteration in non-functioning adrenocortical adenomas; also present in a minority of aldosterone- and cortisol-producing lesions.)

Gene: CTNNB1 hgnc:2514 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35731037 SUPPORT Human Clinical

"These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion."

Attributes benign adrenal tumorigenesis to Wnt/beta-catenin activation.

💊

Medical Actions

Unilateral Adrenalectomy

Category: Therapeutic Action: Adrenalectomy NCIT:C15177

Definitive treatment for a unilateral aldosterone-producing adenoma and for an overt cortisol-producing adenoma; considered on an individualised basis in MACS when cortisol-attributable comorbidity is present. A minimally invasive approach is preferred for benign hormone-secreting lesions. It is not indicated for an asymptomatic, non-functioning unilateral mass with benign imaging features. Biochemical cure rates after adrenalectomy for unilateral primary aldosteronism are high (94% complete biochemical success in the PASO cohort), but complete clinical (blood-pressure) success is achieved in only about 37% — a distinction clinicians and curators should not conflate.

Mechanism Target:

INHIBITS CYP11B2 Induction and Autonomous Aldosterone Synthesis — Removal of the tumour eliminates the autonomous source of aldosterone.

INHIBITS ACTH-Independent Cortisol Hypersecretion — Removal of the tumour eliminates the autonomous source of cortisol.

Show evidence (3 references)

PMID:28576687 SUPPORT Human Clinical

"Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients."

Quantifies the divergence between biochemical cure and clinical (blood-pressure) cure after adrenalectomy.

PMID:37318239 SUPPORT Human Clinical

"In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach."

States the individualised indication for surgery in MACS.

PMID:37318239 SUPPORT Human Clinical

"Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies."

States the explicit contraindication to surgery in non-functioning benign lesions.

Mineralocorticoid Receptor Antagonist Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: spironolactone CHEBI:9241 eplerenone CHEBI:31547

Spironolactone or eplerenone block the mineralocorticoid receptor, addressing both the blood-pressure and the direct target-organ effects of aldosterone excess. Used when surgery is declined or not feasible, while awaiting lateralisation, or when disease proves bilateral. Requires monitoring for hyperkalaemia and declining renal function; spironolactone additionally causes gynaecomastia and menstrual disturbance through its antiandrogenic and progestogenic activity, which is the usual reason for switching to eplerenone.

Mechanism Target:

INHIBITS Renin-Independent Mineralocorticoid Excess — Receptor blockade prevents aldosterone from acting on the distal nephron and on cardiovascular tissue, even though tumour aldosterone output is unchanged.

Show evidence (2 references)

PMID:26934393 SUPPORT Human Clinical

"We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist."

Guideline recommendation establishing mineralocorticoid receptor antagonism as the primary medical therapy when surgery is not the chosen route.

PMID:29129575 PARTIAL Human Clinical

"primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."

Quantifies the aldosterone-attributable end-organ burden that motivates receptor blockade. PARTIAL because this meta-analysis measures the untreated risk, not the treatment effect of mineralocorticoid receptor antagonists.

Perioperative and Postoperative Glucocorticoid Replacement

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: hydrocortisone CHEBI:17650

Patients with cortisol autonomy who undergo adrenalectomy have a suppressed hypothalamic-pituitary-adrenal axis and an atrophic contralateral cortex, and will develop adrenal insufficiency on removal of the tumour. Stress-dose hydrocortisone is given perioperatively and then tapered according to recovery of the axis, which may take months. Omitting this is a recognised cause of avoidable postoperative adrenal crisis.

Mechanism Target:

MODULATES HPA Axis Suppression and Contralateral Adrenal Atrophy — Exogenous glucocorticoid substitutes for the deficient endogenous output until the suppressed axis recovers.

Target Phenotypes: Adrenal insufficiency HP:0000846

Show evidence (1 reference)

PMID:37318239 PARTIAL Human Clinical

"The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference."

Supports the link between degree of hormone excess and surgical planning, of which glucocorticoid cover is part. PARTIAL because the abstract does not state the perioperative steroid recommendation explicitly.

Screening for and Treatment of Cortisol-Attributable Comorbidity in MACS

Category: Screening Action: Disease Screening NCIT:C15419

The practical consequence of the MACS reclassification: rather than reassuring the patient, every individual with MACS should be actively screened for hypertension, type 2 diabetes, dyslipidaemia and osteoporosis, and those conditions treated on their own terms. This is now a guideline recommendation and, for the large majority of MACS patients who do not undergo surgery, it is the entire intervention.

Show evidence (2 references)

PMID:37318239 SUPPORT Human Clinical

"All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated."

Direct guideline recommendation for comorbidity screening in MACS.

PMID:38703381 SUPPORT Human Clinical

"people with adrenal adenomas/incidentalomas and MACS/SH are at a 1.5- to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non-functional adrenal adenomas and should routinely be screened for bone disease"

Extends the screening recommendation to bone disease specifically.

Non-Operative Management of the Benign Non-Functioning Adenoma

Category: Monitoring Action: Diagnostic Imaging Testing NCIT:C16502

For a homogeneous adrenal mass measuring 10 HU or less on unenhanced CT with a normal endocrine work-up, the 2023 ESE guideline recommends no further imaging follow-up at all, irrespective of size, and no surgery. This is a deliberate de-escalation from earlier size-based surveillance protocols and spares a large number of patients repeated CT and its radiation burden.

Show evidence (2 references)

PMID:37318239 SUPPORT Human Clinical

"Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size."

Direct guideline basis for withholding imaging surveillance in benign lesions.

PMID:37583083 SUPPORT Human Clinical

"requires no further follow-up, irrespective of its size"

Confirms the removal of the size restriction from the follow-up rule.

Steroidogenesis Inhibitor Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: metyrapone CHEBI:44241

Metyrapone (an 11-beta-hydroxylase inhibitor) and related agents can lower cortisol in severe hypercortisolism when surgery must be delayed or is not possible. This is a bridging or salvage measure, not definitive therapy for a resectable benign adenoma.

Mechanism Target:

INHIBITS ACTH-Independent Cortisol Hypersecretion — Blockade of 11-beta-hydroxylase reduces cortisol synthesis by the tumour without removing it.

Show evidence (2 references)

PMID:35769081 SUPPORT Human Clinical

"Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase"

States the 11-beta-hydroxylase target that is the mechanism claimed for this treatment.

PMID:35769081 SUPPORT Human Clinical

"medical therapy is often required to control severe hypercortisolism"

Establishes the indication — medical cortisol lowering when surgery does not control hypercortisolism. The cohort included adrenal Cushing syndrome.

🔬

Biochemical Markers

1-mg Overnight Dexamethasone Suppression Test Cortisol

Reference Ranges

Cortisol [Moles/volume] in Serum or Plasma --post dose dexamethasone PO overnight –50.0 nmol/L (adults with an adrenal incidentaloma, no exogenous glucocorticoid or interfering medication)

Non-functioning adenoma (–50.0 nmol/L) Possible MACS (MACS-1) (50.0–138.0 nmol/L) → Increased circulating cortisol level Definitive MACS (MACS-2) (138.0– nmol/L) → Increased circulating cortisol level

Non-functioning adenoma: Cortisol suppressed. No cortisol autonomy; the adenoma is non-functioning with respect to glucocorticoid secretion.

Possible MACS (MACS-1): Partial non-suppression, classified as possible autonomous cortisol secretion in the NAPACA and EURINE-ACT stratifications. Already associated with excess cardiometabolic comorbidity and increased all-cause mortality.

Definitive MACS (MACS-2): Frank non-suppression above 138 nmol/L in the absence of typical clinical Cushing features. The same result accompanied by overt Cushing stigmata is classified as Cushing syndrome rather than MACS — the distinction at this threshold is clinical, not biochemical.

One-sided interval: suppression to below 50 nmol/L (1.8 ug/dL) is the normal / non-functioning result under the 2023 ESE guideline cutoff. Results are invalid in patients on drugs that induce or inhibit CYP3A4, or with abnormal cortisol-binding globulin. The LOINC code was verified against the NLM clinical-tables LOINC service; LOINC is not covered by the repository's OAK term validation.

Show evidence (1 reference)

PMID:37318239 SUPPORT Human Clinical

"a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L"

The ESE guideline states the 50 nmol/L cutoff for a suppressed (normal) result.

Show evidence (1 reference)

PMID:34978855 SUPPORT Human Clinical

"serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor ... ; 50 to 138 nmol/L, possible MACS ... ; >138 nmol/L and absence of typical clinical Cushing syndrome"

Source of the three interpretation bands and their exact numeric boundaries.

Aldosterone-to-Renin Ratio

Reference Ranges

Aldosterone/Renin [Ratio] in Plasma – {ratio} (hypertensive adults screened for primary aldosteronism)

No numeric cutoff is asserted here. The threshold for a positive aldosterone-to-renin ratio is assay- and unit-dependent: values differ by orders of magnitude depending on whether aldosterone is reported in ng/dL or pmol/L and whether renin is reported as activity or concentration, so a single interval would be misleading. The qualitative criterion — an elevated ratio with a suppressed renin — is what HP:6000318 (Elevated aldosterone:renin ratio) captures. The LOINC code was verified against the NLM clinical-tables LOINC service.

Show evidence (2 references)

PMID:26934393 SUPPORT Human Clinical

"we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"

Guideline basis for the aldosterone-to-renin ratio as the case-detection test, and for the requirement that it be measured under standardised conditions.

PMID:37318239 PARTIAL Human Clinical

"Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess"

Supports the requirement for endocrine screening for hormone excess; the abstract enumerates metanephrines and the dexamethasone test explicitly but not the aldosterone-to-renin ratio, hence PARTIAL.

Late-Night Salivary Cortisol

Reference Ranges

Cortisol [Mass/volume] in Saliva (oral fluid) – nmol/L (adults, specimen collected at 2300-2400 h)

No numeric interval asserted: late-night salivary cortisol cutoffs are strongly assay-dependent (immunoassay versus LC-MS/MS) and vary between laboratories, so a repository-wide interval would be misleading. Provenance is recorded here rather than as a citation because no quotable interval was found in a citable source during curation. The LOINC code was verified against the NLM clinical-tables LOINC service.

Show evidence (1 reference)

PMID:37318239 SUPPORT Human Clinical

"a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L"

Supports the point made in the notes: the guideline nominates the dexamethasone suppression test, not salivary cortisol, as the mandated first-line screen in adrenal incidentaloma.

Elevated Aldosterone with Suppressed Renin

Show evidence (2 references)

PMID:23416519 PARTIAL Human Clinical

"Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases."

Documents raised plasma aldosterone in genetically defined aldosterone-producing adenomas. PARTIAL because this sentence covers the aldosterone and potassium halves of the signature but says nothing about renin suppression; the item below carries the renin half.

PMID:23913001 SUPPORT Human Clinical

"All patients had hypertension with elevated aldosterone levels despite suppressed plasma renin activity (PRA)"

States the elevated-aldosterone-with-suppressed-renin pattern as the diagnostic criterion applied.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Adrenal Cortex Adenoma:

Adrenal Cortex Carcinoma Not Yet Curated MONDO:0006639

Overlapping Features The single most consequential distinction. Adrenocortical carcinoma is a malignant tumour of the same cortical lineage with an entirely different prognosis, and misclassifying one as the other is the main harm the adrenal incidentaloma work-up exists to prevent. Carcinoma is favoured by larger size, inhomogeneity and higher unenhanced attenuation on CT, by high proliferation rate and angioinvasion on histology, by IGF2 overexpression, and by TP53 and CTNNB1 alterations with broad copy-number instability. Rapid virilisation or feminisation, or mixed steroid excess, is a red flag for carcinoma rather than adenoma.

Distinguishing Features

Size greater than 4 cm with inhomogeneity or unenhanced CT attenuation above 20 HU
Weiss score of 4 or more (adenoma 2 or less); angioinvasion; more than 5 mitoses per 10 mm2 and more than 5% Ki67
IGF2 overexpression detectable by immunohistochemistry
Broad copy-number instability, TP53 disruption, extensive methylomic derangement
Rapid onset of virilisation, feminisation or mixed steroid excess

Show evidence (4 references)

PMID:6703192 SUPPORT Human Clinical

"None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized."

The Weiss threshold that operationalises the adenoma-versus-carcinoma distinction.

PMID:35288842 SUPPORT Human Clinical

"Most adult adrenal cortical carcinomas show > 5 mitoses per 10 mm2 and > 5% Ki67."

Gives the proliferation-rate thresholds distinguishing carcinoma from adenoma.

PMID:38108848 SUPPORT Human Clinical

"overexpression in adrenal cortical carcinoma can be identified by immunohistochemistry and may be useful in the differential diagnosis with adenoma"

States that IGF2 overexpression is a useful immunohistochemical discriminator between carcinoma and adenoma. The snippet begins mid-sentence because the cached full text renders "IGF2overexpression" without a separating space.

+ 1 more reference

Bilateral Macronodular Adrenal Hyperplasia Not Yet Curated MONDO:0009049

Overlapping Features A bilateral, multinodular adrenocortical disease causing ACTH-independent cortisol excess, caused in roughly half of cases by inactivating germline ARMC5 mutations with a somatic second hit in each nodule. It shares the cortisol phenotype with a cortisol-producing adenoma but is bilateral, macronodular, germline-driven and heritable — so it demands genetic counselling and family screening, and cannot be cured by unilateral adrenalectomy. It is a separate entity, not a bilateral variant of adrenal cortex adenoma.

Distinguishing Features

Bilateral macronodular adrenal enlargement rather than a solitary unilateral mass
Germline ARMC5 inactivating mutations in approximately 44% of cases
Heritable; warrants cascade genetic testing of relatives
Not curable by unilateral adrenalectomy

Show evidence (2 references)

PMID:24601692 SUPPORT Human Clinical

"Germline ARMC5 mutations were found in 15 of 34 patients (44.1%)."

Quantifies the germline ARMC5 contribution that distinguishes this entity mechanistically.

PMID:24601692 SUPPORT Human Clinical

"Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families."

Establishes the heritability and counselling implications absent from sporadic adrenal cortex adenoma.

Primary Pigmented Nodular Adrenocortical Disease MONDO:0015999

Overlapping Features Bilateral micronodular pigmented adrenocortical disease causing ACTH-independent Cushing syndrome, usually in children and young adults, caused by germline inactivating PRKAR1A mutations and frequently part of Carney complex. It converges on the same pathway as the cortisol-producing adenoma — loss of PKA regulatory-subunit restraint — but from the opposite direction (germline loss of the regulatory subunit rather than somatic gain in the catalytic subunit) and with a bilateral, germline, syndromic presentation. Curated separately in this knowledge base as Primary_Pigmented_Nodular_Adrenocortical_Disease.

Distinguishing Features

Bilateral pigmented micronodules rather than a solitary unilateral adenoma
Germline PRKAR1A inactivating mutations, often with Carney complex features (lentigines, myxomas, other endocrine tumours)
Typically presents in childhood or young adulthood
Paradoxical rise in urinary free cortisol on the Liddle dexamethasone test

Show evidence (1 reference)

PMID:24571724 SUPPORT Human Clinical

"have been identified in patients with Cushing’s syndrome due to primary pigmented nodular adrenocortical disease"

Establishes PRKAR1A as the driver of primary pigmented nodular adrenocortical disease, contrasting with the somatic PRKACA driver of unilateral cortisol-producing adenoma.

Pheochromocytoma Not Yet Curated MONDO:0008233

Overlapping Features A catecholamine-secreting tumour of the adrenal medulla, not the cortex. It is a mandatory exclusion in any adrenal incidentaloma work-up because unrecognised pheochromocytoma can precipitate a hypertensive crisis during biopsy, surgery or anaesthesia. Plasma or urinary metanephrines must be measured in every patient before any invasive procedure.

Distinguishing Features

Medullary (chromaffin) rather than cortical origin
Elevated plasma free or urinary fractionated metanephrines
High unenhanced CT attenuation (above 10 HU), often with marked contrast enhancement
Episodic headache, palpitations and sweating with paroxysmal hypertension
Biopsy or unprepared surgery can precipitate a hypertensive crisis

Show evidence (1 reference)

PMID:37318239 SUPPORT Human Clinical

"Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines"

Mandates metanephrine measurement to exclude pheochromocytoma in every adrenal incidentaloma.

Adrenal Metastasis Not Yet Curated MONDO:0024883

Overlapping Features Secondary deposit in the adrenal gland, most often from lung, breast, renal or gastrointestinal primaries or melanoma. In a patient with a known extra-adrenal malignancy this — not adenoma — is the leading explanation for a new adrenal mass, which is why the ESE guideline treats prior malignancy as a distinct management context. Metastases are typically inhomogeneous, lipid-poor with unenhanced attenuation above 10 HU, and are frequently bilateral.

Distinguishing Features

Known or suspected extra-adrenal primary malignancy
Lipid-poor, inhomogeneous, unenhanced attenuation above 10 HU
Frequently bilateral, unlike the typically unilateral adenoma
Hormonally silent, so a normal endocrine work-up does not exclude it

Show evidence (1 reference)

PMID:37318239 SUPPORT Human Clinical

"may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases"

The ESE guideline lists metastases among the incidentaloma diagnoses that must be separated from benign non-functioning adenoma.

Adrenal Myelolipoma Not Yet Curated MONDO:0006075

Overlapping Features A benign, hormonally inactive tumour composed of mature adipose tissue and haematopoietic elements. It is radiologically unmistakable because of its macroscopic fat, which gives strongly negative CT attenuation — well below the lipid-rich adenoma threshold. No endocrine work-up beyond the standard incidentaloma screen and no follow-up is needed for a typical lesion.

Distinguishing Features

Macroscopic fat with markedly negative CT attenuation, well below 0 HU
Composed of mature adipose tissue plus haematopoietic elements on histology
Hormonally inactive

Show evidence (1 reference)

PMID:37318239 PARTIAL Human Clinical

"Each adrenal mass requires dedicated adrenal imaging."

Supports the imaging-first triage in which myelolipoma is separated from adenoma by attenuation. PARTIAL because the abstract does not name myelolipoma explicitly.

{ }

Source YAML

click to show

name: Adrenal Cortex Adenoma
creation_date: "2026-08-01T06:20:00Z"
category: Neoplastic
disease_term:
  preferred_term: adrenal cortex adenoma
  term:
    id: MONDO:0003924
    label: adrenal cortex adenoma
synonyms:
- adrenocortical adenoma
- adrenal cortical adenoma
- adrenal adenoma
- benign adrenal gland adenoma
parents:
- adrenal cortex neoplasm
- benign neoplasm of adrenal gland
description: >
  A benign, clonal neoplasm arising from the steroidogenic cells of the adrenal
  cortex. Most adrenal cortex adenomas are found incidentally on cross-sectional
  imaging performed for unrelated reasons — the "adrenal incidentaloma" — and the
  lesion itself is biologically indolent: it does not metastasize and its
  tumour-specific prognosis is excellent. Clinical significance is therefore
  determined almost entirely by autonomous hormone secretion, and this entry is
  organised on that functional axis. Cortisol-producing adenomas cause
  ACTH-independent Cushing syndrome and are driven predominantly by somatic
  activating mutations of PRKACA (and, less often, GNAS) that release the PKA
  catalytic subunit from regulatory-subunit restraint. Aldosterone-producing
  adenomas (APA, Conn adenoma) cause unilateral primary aldosteronism and are
  driven by mutually exclusive somatic mutations in KCNJ5, CACNA1D, ATP1A1 and
  ATP2B3, which converge on zona glomerulosa membrane depolarisation, calcium
  influx and CYP11B2 induction; CTNNB1 also occurs in a minority of APAs but is
  a transcriptional proliferation driver, not part of that ion-channel
  convergence. A large intermediate group
  shows mild autonomous cortisol secretion (MACS) without overt Cushing stigmata;
  MACS has been reclassified from a benign curiosity to a recognised
  cardiometabolic and skeletal risk state. Non-functioning adenomas, the largest single group,
  are molecularly heterogeneous with frequent Wnt/beta-catenin activation.

  Adrenal cortex adenoma must be distinguished from adrenocortical carcinoma, from
  bilateral macronodular adrenal hyperplasia (ARMC5) and from primary pigmented
  nodular adrenocortical disease (PRKAR1A / Carney complex); these are separate
  disease entities modelled elsewhere, not subtypes of this entry.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM

has_subtypes:
- name: Cortisol-Producing
  display_name: Cortisol-Producing Adenoma (overt Cushing syndrome)
  description: >-
    A unilateral adenoma secreting cortisol autonomously and sufficiently to
    produce clinically overt ACTH-independent Cushing syndrome. Somatic PRKACA
    hotspot mutations are the dominant driver; GNAS activating mutations account
    for an additional subset. Cortisol autonomy suppresses pituitary ACTH and
    causes atrophy of the contralateral adrenal cortex, so unilateral
    adrenalectomy is followed by transient adrenal insufficiency requiring
    glucocorticoid cover.
  genes:
  - preferred_term: PRKACA
    term:
      id: hgnc:9380
      label: PRKACA
  - preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas"
    explanation: Establishes the somatic-PRKACA cortisol-producing unilateral adenoma as a distinct entity.

- name: MACS
  display_name: Mild Autonomous Cortisol Secretion (MACS)
  description: >-
    Biochemical cortisol autonomy — serum cortisol above 50 nmol/L (1.8 ug/dL)
    after a 1-mg overnight dexamethasone suppression test — in a patient without
    the clinical signs of overt Cushing syndrome. Formerly dismissed as
    "subclinical hypercortisolism", MACS is now recognised as a genuine
    cardiometabolic risk condition carrying excess hypertension, type 2 diabetes,
    osteoporosis, fracture and all-cause mortality relative to non-functioning
    adenomas. It is by far the largest functional group: roughly 45% of benign
    adrenal tumours in the ENSAT EURINE-ACT cohort fell into the MACS-1 or MACS-2
    strata.
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality."
    explanation: The ESE guideline defines MACS by the post-dexamethasone threshold and asserts the associated risk.
  - reference: PMID:34978855
    reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 1305 participants, 49.7% had NFAT ... 34.6% had MACS-1 ... 10.7% had MACS-2"
    explanation: Quantifies the relative sizes of the non-functioning and MACS strata.

- name: Aldosterone-Producing
  display_name: Aldosterone-Producing Adenoma (APA, Conn adenoma)
  description: >-
    A unilateral adenoma of zona glomerulosa lineage secreting aldosterone
    renin-independently, causing unilateral primary aldosteronism. Driven by
    mutually exclusive somatic mutations in KCNJ5 (most common), CACNA1D, ATP1A1,
    ATP2B3 and CTNNB1. Because CT cannot reliably identify the secreting side (non-functioning nodules become
    common with age), adrenal vein sampling is usually required before
    lateralising surgery.
  genes:
  - preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  - preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  - preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  - preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  evidence:
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied."
    explanation: Identifies KCNJ5 as a recurrent somatic driver defining this functional subtype.

- name: Non-Functioning
  display_name: Non-Functioning Adenoma (NFAT)
  description: >-
    An adenoma without demonstrable autonomous hormone secretion — normal
    metanephrines, a suppressed 1-mg dexamethasone test (below 50 nmol/L) and,
    where indicated, a normal aldosterone-to-renin ratio. This is the largest
    single group among incidentally detected adrenal masses. Molecularly
    heterogeneous; CTNNB1/Wnt-beta-catenin activation is the commonest recurrent
    alteration. A homogeneous lesion of 10 HU or less on unenhanced CT requires no
    further imaging follow-up and no surgery.
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  evidence:
  - reference: PMID:35731037
    reference_title: Mutational landscape of non-functional adrenocortical adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1."
    explanation: Defines the dominant recurrent somatic alteration in the non-functioning subtype.

prevalence:
- population: Adults older than 50 years
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3000.0
  notes: >-
    Stated as "at least 3%" of persons older than 50 years. Detection is strongly
    imaging-dependent, so reported prevalence rises with the intensity of
    cross-sectional imaging in the source population.
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age."
    explanation: Direct statement of adrenal adenoma point prevalence in the over-50 population.

- subtype: MACS
  population: Patients with a benign adrenal tumour referred to endocrine centres (ENSAT EURINE-ACT)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 45300.0
  notes: >-
    45.3% of 1305 prospectively recruited patients with benign adrenal tumours met
    criteria for MACS (34.6% MACS-1 plus 10.7% MACS-2). This is a proportion
    within the adrenal-tumour population, not a general-population rate, and it is
    subject to referral bias toward secondary and tertiary endocrine centres.
  evidence:
  - reference: PMID:34978855
    reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "34.6% had MACS-1 ... 10.7% had MACS-2"
    explanation: Gives the MACS-1 and MACS-2 fractions summing to the quoted MACS proportion.

pathophysiology:
- name: Clonal Adrenocortical Proliferation
  biological_scale: CELLULAR
  role: trigger
  description: >-
    A somatic driver mutation in a single adrenocortical cell produces a clonal,
    benign, well-circumscribed proliferation. Unlike adrenocortical carcinoma,
    this proliferation is self-limited: there is no destructive capsular or
    vascular invasion and no metastatic capacity. The driver that initiates the
    clone also determines the tumour's secretory phenotype, which is why the
    functional classification of adrenal adenomas maps onto distinct mutational
    classes rather than onto tumour size or histology.
  cell_types:
  - preferred_term: adrenal cortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  evidence:
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease"
    explanation: WHO 2022 affirms the clonal-neoplastic nature of benign adrenal cortical nodules.
  downstream:
  - target: Adrenal Cortical Mass
    causal_link_type: DIRECT
    description: >-
      The clonal proliferation is itself the radiologically and pathologically
      detected adrenal mass.
    evidence:
    - reference: PMID:37318239
      reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas"
      explanation: Links the detected adrenal mass to an underlying adrenocortical adenoma.

- name: PRKACA Catalytic Subunit Activation
  biological_scale: MOLECULAR
  role: driver
  description: >-
    Somatic hotspot mutations in PRKACA — the recurrent change is c.617A>C,
    designated p.Leu206Arg when the initiator methionine is counted and widely
    reported in the earlier literature as L205R under mature-protein numbering
    that omits it — lie in the P+1 loop at the interface between the PKA
    catalytic subunit and its regulatory subunit. The mutant catalytic subunit can no longer be held inactive by the
    regulatory subunit, so kinase activity becomes constitutive and
    cAMP-independent. Activating GNAS mutations produce the same functional
    endpoint one step upstream by locking Gs-alpha in its active state.
  genes:
  - preferred_term: PRKACA
    term:
      id: hgnc:9380
      label: PRKACA
  - preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  molecular_functions:
  - preferred_term: cAMP-dependent protein kinase activity
    modifier: INCREASED
    term:
      id: GO:0004691
      label: cAMP-dependent protein kinase activity
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome"
    explanation: Quantifies PRKACA somatic mutation frequency in overtly cortisol-producing adenomas.
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit"
    explanation: Demonstrates the loss of regulatory-subunit restraint that is the molecular mechanism of the driver.
  - reference: PMID:24700472
    reference_title: "Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs."
    explanation: Independent cohort confirming the PRKACA hotspot and its high frequency in cortisol-producing adenomas.
  downstream:
  - target: Constitutive cAMP-PKA Signalling
    causal_link_type: DIRECT
    description: >-
      Loss of regulatory-subunit inhibition renders PKA catalytic activity
      constitutive and independent of upstream cAMP.
    evidence:
    - reference: PMID:24700472
      reference_title: "Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression"
      explanation: Functional demonstration that the hotspot mutation increases PKA substrate phosphorylation.

- name: Constitutive cAMP-PKA Signalling
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    Unrestrained PKA catalytic activity phosphorylates CREB and other substrates,
    driving transcription of the steroidogenic program (STAR, CYP11A1, CYP11B1)
    in the absence of ACTH stimulation. The same signalling supports the modest
    proliferative advantage that allows the clone to form a macroscopic adenoma.
  biological_processes:
  - preferred_term: protein phosphorylation
    modifier: INCREASED
    term:
      id: GO:0006468
      label: protein phosphorylation
  evidence:
  - reference: PMID:24700472
    reference_title: "Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "promoted PKA substrate phosphorylation and target gene expression"
    explanation: Directly evidences increased PKA-dependent substrate phosphorylation and transcriptional output.
  downstream:
  - target: Clonal Adrenocortical Proliferation
    causal_link_type: DIRECT
    description: >-
      The same unrestrained PKA activity supports the proliferative advantage that
      lets the mutant clone grow into a macroscopic adenoma, so the cortisol arm
      feeds the shared proliferation trunk just as the aldosterone and Wnt arms do.
    evidence:
    - reference: PMID:24700472
      reference_title: "Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "promoted PKA substrate phosphorylation and target gene expression"
      explanation: >-
        Evidences the increased PKA transcriptional output that underlies the
        proliferative advantage. PARTIAL because the cited sentence demonstrates
        signalling output rather than measuring proliferation directly.
  - target: ACTH-Independent Cortisol Hypersecretion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - CREB phosphorylation and CRE-dependent transcription
    - Induction of STAR and steroidogenic cytochrome P450 enzymes (CYP11A1, CYP11B1)
    description: >-
      PKA-driven transcription of the steroidogenic machinery produces cortisol
      output that does not require ACTH.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex."
      explanation: Establishes that the cortisol excess in these adenomas is corticotropin-independent.

- name: ACTH-Independent Cortisol Hypersecretion
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Zona fasciculata-like tumour cells synthesise and release cortisol
    autonomously, uncoupled from the hypothalamic-pituitary axis. The magnitude of
    this autonomous output is the single variable that determines whether the
    patient presents with overt Cushing syndrome, with MACS, or with no
    cortisol-related phenotype at all — the same mechanism operating along a
    continuum of severity.
  cell_types:
  - preferred_term: zona fasciculata cell
    term:
      id: CL:0002136
      label: type II cell of adrenal cortex
  biological_processes:
  - preferred_term: cortisol biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0034651
      label: cortisol biosynthetic process
  locations:
  - preferred_term: zona fasciculata
    term:
      id: UBERON:0002054
      label: zona fasciculata of adrenal gland
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production."
    explanation: States that adrenocortical tumours produce cortisol corticotropin-independently.
  downstream:
  - target: Primary Hypercortisolism
    causal_link_type: DIRECT
    description: Autonomous adrenal cortisol output is, by definition, primary hypercortisolism.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Endogenous hypercortisolism, referred to as Cushing’s syndrome, is associated with substantial morbidity and mortality."
      explanation: Links autonomous cortisol production to endogenous hypercortisolism and its morbidity.
  - target: HPA Axis Suppression and Contralateral Adrenal Atrophy
    causal_link_type: DIRECT
    description: >-
      Autonomous cortisol feeds back on the pituitary, suppressing ACTH and
      depriving the contralateral adrenal cortex of trophic support.
    evidence:
    - reference: PMID:37318239
      reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L"
      explanation: >-
        Indirect support: the diagnostic test itself is a feedback-suppression
        test, whose failure demonstrates that tumour cortisol output is not under
        hypothalamic-pituitary control. The guideline does not state contralateral
        atrophy explicitly, hence PARTIAL.
  - target: Chronic Glucocorticoid Excess
    causal_link_type: DIRECT
    description: >-
      When autonomous output is high, sustained supraphysiological glucocorticoid
      exposure of peripheral tissues follows.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When Cushing’s syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae."
      explanation: Connects sustained cortisol excess to the catabolic multi-system phenotype.
  - target: Mild Autonomous Cortisol Secretion
    causal_link_type: DIRECT
    description: >-
      When autonomous output is low-grade, the patient has biochemical cortisol
      autonomy without the classical clinical stigmata — the MACS state.
    evidence:
    - reference: PMID:37318239
      reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality"
      explanation: Defines the low-grade autonomy state that the ESE guideline names MACS.

- name: HPA Axis Suppression and Contralateral Adrenal Atrophy
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Negative feedback from tumour-derived cortisol suppresses pituitary ACTH
    secretion; the non-tumorous ipsilateral and contralateral adrenal cortex
    atrophies. This is clinically silent while the adenoma is in place but becomes
    the dominant management problem immediately after adrenalectomy, when the
    remaining gland cannot mount a cortisol response — hence the requirement for
    perioperative and tapering glucocorticoid cover, with
    hypothalamic-pituitary-adrenal recovery often taking months.
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess"
    explanation: >-
      Indirect support only: the guideline mandates the endocrine work-up that
      detects cortisol autonomy, which is what predicts postoperative adrenal
      insufficiency. Marked PARTIAL because the abstract does not itself describe
      contralateral atrophy.
  downstream:
  - target: Adrenal Insufficiency
    causal_link_type: DIRECT
    description: >-
      After removal of the autonomous source, the suppressed contralateral gland
      is temporarily unable to sustain cortisol output.
    evidence:
    - reference: PMID:37318239
      reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess"
      explanation: >-
        Indirect: the guideline ties surgical planning to the degree of hormone
        excess, which is what determines postoperative adrenal insufficiency risk.
        No abstract sentence states the complication directly, hence PARTIAL.

- name: Chronic Glucocorticoid Excess
  biological_scale: ORGANISM
  role: effector
  description: >-
    Sustained supraphysiological cortisol exposure produces the classical Cushing
    phenotype: central and abdominal fat redistribution, proteolytic muscle wasting
    with proximal weakness, dermal collagen loss with easy bruising, insulin
    resistance and type 2 diabetes, hypertension, and glucocorticoid-induced
    osteoporosis with fragility fracture.
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae"
    explanation: Enumerates the catabolic consequences of severe glucocorticoid excess.
  downstream:
  - target: Abdominal Obesity
    causal_link_type: DIRECT
    description: Glucocorticoid-driven central fat redistribution.
    evidence:
    - reference: PMID:34978855
      reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS"
      explanation: >-
        Supports the graded glucocorticoid-exposure axis on which central adiposity
        sits; the abstract does not report adiposity itself, hence PARTIAL.
  - target: Proximal Muscle Weakness
    causal_link_type: DIRECT
    description: Glucocorticoid-induced proteolysis of type II muscle fibres.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "catabolic symptoms such as muscle weakness"
      explanation: Names muscle weakness as a direct catabolic consequence of severe cortisol excess.
  - target: Bruising Susceptibility
    causal_link_type: DIRECT
    description: Glucocorticoid-induced dermal collagen loss and capillary fragility.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "catabolic symptoms such as muscle weakness, skin fragility"
      explanation: Skin fragility is the substrate for the easy bruising seen in cortisol excess.
  - target: Hypertension
    causal_link_type: DIRECT
    description: >-
      Glucocorticoid excess raises blood pressure; hypertension prevalence and
      severity rise across the cortisol-autonomy strata.
    evidence:
    - reference: PMID:34978855
      reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT"
      explanation: Directly relates cortisol autonomy strata to hypertension burden.
  - target: Type II Diabetes Mellitus
    causal_link_type: DIRECT
    description: Glucocorticoid-induced insulin resistance and hepatic gluconeogenesis.
    evidence:
    - reference: PMID:34978855
      reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Type 2 diabetes was more prevalent in CS than NFAT"
      explanation: Directly relates overt cortisol excess to diabetes prevalence versus non-functioning tumours.
  - target: Hyperlipidemia
    causal_link_type: DIRECT
    description: >-
      Glucocorticoid-driven dyslipidaemia; prevalence rises across the
      cortisol-autonomy strata.
    evidence:
    - reference: PMID:35533704
      reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dyslipidaemia occurred in 724 ... of 1999 patients, 547 ... of 1250, and 123 ... of 237"
      explanation: Gives dyslipidaemia prevalence rising across the three cortisol strata.
  - target: Osteoporosis
    causal_link_type: DIRECT
    description: Glucocorticoid-induced suppression of osteoblast function and bone loss.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "catabolic symptoms such as muscle weakness, skin fragility, osteoporosis"
      explanation: Names osteoporosis as a direct catabolic consequence of cortisol excess.

- name: Mild Autonomous Cortisol Secretion
  biological_scale: ORGANISM
  role: effector
  description: >-
    Low-grade cortisol autonomy sufficient to fail the 1-mg dexamethasone
    suppression test but insufficient to produce the classical Cushing habitus.
    The mechanistically important point — and the reason this node exists
    separately from Chronic Glucocorticoid Excess — is the reclassification of
    MACS. It was long treated as a biochemical curiosity of no consequence
    ("subclinical hypercortisolism"). Contemporary multicentre cohort data show
    that MACS is instead an independent cardiometabolic and skeletal risk state,
    carrying excess hypertension, insulin-requiring diabetes, vertebral fracture,
    and — critically — increased all-cause mortality relative to non-functioning
    adenomas, with the excess concentrated in women under 65. The 2023 ESE
    guideline formalised the term and mandated screening for cortisol-attributable
    comorbidity in every patient with MACS.
  evidence:
  - reference: PMID:35533704
    reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years."
    explanation: The mortality finding that drives the reclassification of MACS as a genuine risk state.
  - reference: PMID:35533704
    reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma."
    explanation: Quantifies the adjusted mortality hazard across both cortisol-autonomy strata.
  - reference: PMID:34978855
    reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes."
    explanation: States the reclassification of MACS as a cardiometabolic risk condition explicitly.
  downstream:
  - target: Hypertension
    causal_link_type: DIRECT
    description: >-
      MACS-2 patients carry excess hypertension prevalence and need more
      antihypertensive agents than patients with non-functioning tumours.
    evidence:
    - reference: PMID:34978855
      reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "aPRs for use of ≥3 antihypertensives: MACS-2, 1.31"
      explanation: Quantifies excess antihypertensive requirement attributable to MACS-2.
  - target: Type II Diabetes Mellitus
    causal_link_type: DIRECT
    description: >-
      Diabetes in MACS-2 is more likely to require insulin, indicating greater
      metabolic severity than in non-functioning tumours.
    evidence:
    - reference: PMID:34978855
      reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "more likely to require insulin therapy for MACS-2"
      explanation: Quantifies insulin-requiring diabetes attributable to MACS-2.
  - target: Osteoporosis
    causal_link_type: DIRECT
    description: >-
      MACS is associated with lower lumbar-spine and femoral-neck bone mineral
      density and a higher prevalence of osteoporosis or osteopenia than
      non-functioning adenoma.
    evidence:
    - reference: PMID:38703381
      reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subjects with MACS/SH had significantly lower bone mineral density (BMD) at lumbar spine"
      explanation: Meta-analytic evidence of reduced BMD attributable to MACS.
  - target: Vertebral Fracture
    causal_link_type: DIRECT
    description: >-
      The skeletal consequence of MACS is a roughly two-fold excess of vertebral
      fracture relative to non-functioning adrenal adenoma.
    evidence:
    - reference: PMID:38703381
      reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "vertebral fractures (OR 2.10; 95% CI: 1.28, 3.45; P = 0.0035)"
      explanation: Quantifies the doubled odds of vertebral fracture in MACS versus non-functioning adenoma.

- name: Zona Glomerulosa Ion Channel and Pump Driver Mutation
  biological_scale: MOLECULAR
  role: driver
  description: >-
    Aldosterone-producing adenomas carry mutually exclusive somatic mutations in a
    small set of genes encoding ion channels and pumps of the zona glomerulosa
    plasma membrane: KCNJ5 (inwardly rectifying K+ channel; the commonest),
    CACNA1D (Cav1.3 L-type calcium channel), ATP1A1
    (Na+/K+-ATPase alpha subunit) and ATP2B3 (plasma-membrane Ca2+-ATPase).
    CTNNB1 mutations occur in a minority. Different genes, one shared functional
    endpoint — the resting membrane potential of the glomerulosa cell can no longer
    be maintained.
  genes:
  - preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  - preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  - preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  - preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  cell_types:
  - preferred_term: zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: zona glomerulosa
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3."
    explanation: Quantifies the ATPase driver mutation frequencies in a large APA collection.
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5."
    explanation: Establishes CACNA1D as a driver in the KCNJ5-wild-type fraction of APAs, showing mutual exclusivity.
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All CACNA1D mutations occurred in tumors without KCNJ5 or CTNN1B mutations."
    explanation: >-
      Direct demonstration of mutual exclusivity between the APA driver classes.
      Note that the source spells beta-catenin "CTNN1B" in this sentence (a
      typographical error for CTNNB1, spelled correctly elsewhere in the same
      paper); the snippet is quoted verbatim.

  downstream:
  - target: Zona Glomerulosa Membrane Depolarisation
    causal_link_type: DIRECT
    description: >-
      Loss of K+ selectivity (KCNJ5), loss of Na+/K+-ATPase pump activity (ATP1A1)
      or loss of Ca2+ extrusion (ATP2B3) each depolarise the glomerulosa cell.
    evidence:
    - reference: PMID:21311022
      reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Both produce increased sodium (Na(+)) conductance and cell depolarization"
      explanation: Functional demonstration that KCNJ5 mutations depolarise the cell.
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations."
      explanation: Shows the ATPase drivers converge on the same depolarisation endpoint.

- name: Zona Glomerulosa Membrane Depolarisation
  biological_scale: CELLULAR
  role: mediator
  description: >-
    The glomerulosa cell resting potential, normally close to the K+ equilibrium
    potential, shifts toward depolarisation. This is the convergence point of the
    channel and pump drivers, and the reason a heterogeneous set of genes produces
    one clinical phenotype.
  biological_processes:
  - preferred_term: membrane depolarization
    modifier: INCREASED
    term:
      id: GO:0051899
      label: membrane depolarization
  cell_types:
  - preferred_term: zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  evidence:
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "increased sodium (Na(+)) conductance and cell depolarization"
    explanation: Direct evidence for the depolarised state in KCNJ5-mutant cells.
  downstream:
  - target: Calcium Influx and Calcium-Dependent Signalling
    causal_link_type: DIRECT
    description: >-
      Depolarisation opens voltage-gated calcium channels, raising cytosolic Ca2+.
      CACNA1D mutations reach the same endpoint by shifting channel activation to
      less depolarised potentials, bypassing the need for depolarisation.
    evidence:
    - reference: PMID:21311022
      reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation"
      explanation: States that depolarisation drives Ca2+ entry, the proximate aldosterone signal.

- name: Calcium Influx and Calcium-Dependent Signalling
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Increased cytosolic calcium is the final common pathway of
    aldosterone-producing adenoma formation. It is simultaneously the signal for
    aldosterone biosynthesis and for glomerulosa cell proliferation, which is why a
    single somatic channel mutation is sufficient to produce both constitutive
    hormone production and tumour growth.
  biological_processes:
  - preferred_term: calcium ion import across plasma membrane
    modifier: INCREASED
    term:
      id: GO:0098703
      label: calcium ion import across plasma membrane
  cell_types:
  - preferred_term: zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa."
    explanation: States that calcium influx is sufficient for both hormone production and proliferation.
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This suggests increased intracellular Ca2+ as a final common pathway to APA formation."
    explanation: Explicitly names calcium as the convergent final common pathway.
  downstream:
  - target: CYP11B2 Induction and Autonomous Aldosterone Synthesis
    causal_link_type: DIRECT
    description: >-
      Calcium-dependent transcription induces aldosterone synthase (CYP11B2),
      committing the cell to renin-independent aldosterone output.
    evidence:
    - reference: PMID:23913001
      reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production"
      explanation: Directly links calcium influx to aldosterone production.
  - target: Clonal Adrenocortical Proliferation
    causal_link_type: DIRECT
    description: >-
      The same calcium signal drives glomerulosa cell proliferation, explaining
      why the hormone-producing lesion is also a growing adenoma.
    evidence:
    - reference: PMID:21311022
      reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production"
      explanation: Links the driver mechanism to constitutive proliferation as well as hormone output.

- name: CYP11B2 Induction and Autonomous Aldosterone Synthesis
  biological_scale: CELLULAR
  role: effector
  description: >-
    Aldosterone synthase (CYP11B2) is upregulated in the tumour cells, which
    therefore synthesise aldosterone independently of angiotensin II and
    potassium. CYP11B2 immunohistochemistry is now the WHO-endorsed means of
    identifying which adrenal structures are actually the source of aldosterone
    excess — an important point, because a radiologically visible nodule is not
    necessarily the functional lesion.
  genes:
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  biological_processes:
  - preferred_term: aldosterone biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032342
      label: aldosterone biosynthetic process
  cell_types:
  - preferred_term: zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  evidence:
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production"
    explanation: Establishes CYP11B2 as the marker of functional aldosterone production in adrenal tissue.
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess"
    explanation: Supports the caution that the imaged nodule may not be the aldosterone-producing lesion.
  downstream:
  - target: Primary Hyperaldosteronism
    causal_link_type: DIRECT
    description: >-
      Renin-independent aldosterone output is, by definition, primary
      aldosteronism.
    evidence:
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion"
      explanation: Links the somatic driver to autonomous (renin-independent) aldosterone secretion.
  - target: Renin-Independent Mineralocorticoid Excess
    causal_link_type: DIRECT
    description: >-
      Autonomous aldosterone drives renal sodium retention and potassium and
      hydrogen-ion loss, expanding volume and suppressing renin.
    evidence:
    - reference: PMID:23913001
      reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Constitutive production of aldosterone (primary aldosteronism) results in hypertension, often associated with hypokalemia"
      explanation: Links autonomous aldosterone to the mineralocorticoid-excess clinical state.

- name: Renin-Independent Mineralocorticoid Excess
  biological_scale: ORGANISM
  role: effector
  description: >-
    Excess aldosterone acting on the distal nephron produces sodium retention with
    volume expansion, kaliuresis and hydrogen-ion loss. The resulting biochemical
    signature is hypertension with a suppressed plasma renin and an elevated
    aldosterone-to-renin ratio, sometimes with hypokalaemia (and, when
    hypokalaemia is marked, a metabolic alkalosis that is not separately curated
    here for want of an adenoma-specific citable source). Normokalaemia does not
    exclude primary aldosteronism — an important
    reason the condition is under-recognised.
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone signaling defends intravascular volume by increasing intestinal and renal Na-Cl absorption and reabsorption, respectively."
    explanation: Describes the renal sodium-retention mechanism underlying mineralocorticoid excess.
  downstream:
  - target: Hypertension
    causal_link_type: DIRECT
    description: Volume expansion and vasoconstriction raise arterial pressure.
    evidence:
    - reference: PMID:23913001
      reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Constitutive production of aldosterone (primary aldosteronism) results in hypertension"
      explanation: Directly links autonomous aldosterone to hypertension.
  - target: Hypokalemia
    causal_link_type: DIRECT
    description: Aldosterone-driven distal kaliuresis lowers serum potassium.
    evidence:
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases."
      explanation: Correlates the driver mutations with lower serum potassium in patients.
  - target: Aldosterone-Mediated Target Organ Damage
    causal_link_type: DIRECT
    description: >-
      Aldosterone exerts direct pro-fibrotic and pro-inflammatory effects on the
      heart, vasculature and kidney beyond the effect of the blood pressure it
      causes.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke"
      explanation: Establishes excess vascular risk in primary aldosteronism over hypertensive controls.

- name: Aldosterone-Mediated Target Organ Damage
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinically decisive feature of primary aldosteronism is that its
    cardiovascular and renal injury is disproportionate to the blood pressure.
    Compared with essential hypertensives, patients with primary aldosteronism
    have markedly higher odds of stroke, coronary disease, atrial fibrillation and
    heart failure. Combined with the fact that primary aldosteronism remains
    largely underdiagnosed and undertreated, this is the strongest argument for
    biochemical screening of hypertensive patients with an adrenal adenoma rather
    than treating blood pressure alone.
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio ... 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78)."
    explanation: Quantifies the excess cardiovascular risk relative to essential hypertension.
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups."
    explanation: Confirms the excess risk applies specifically to the aldosterone-producing adenoma subgroup.
  - reference: PMID:29629943
    reference_title: Primary aldosteronism in the primary care setting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disappointingly, primary aldosteronism remains a largely underdiagnosed and undertreated disorder."
    explanation: Documents the underdiagnosis that makes the excess risk clinically consequential.
  downstream:
  - target: Stroke
    causal_link_type: DIRECT
    description: Odds of stroke are roughly 2.6-fold those of essential hypertension.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an increased risk of stroke (odds ratio ... 2·58, 95% CI 1·93-3·45)"
      explanation: Quantifies the stroke excess.
  - target: Atrial Fibrillation
    causal_link_type: DIRECT
    description: Odds of atrial fibrillation are roughly 3.5-fold those of essential hypertension.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atrial fibrillation (3·52, 2·06-5·99)"
      explanation: Quantifies the excess atrial fibrillation risk.
  - target: Coronary Artery Disease
    causal_link_type: DIRECT
    description: Odds of coronary artery disease are roughly 1.8-fold those of essential hypertension.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "coronary artery disease (1·77, 1·10-2·83)"
      explanation: Quantifies the excess coronary artery disease risk.
  - target: Heart Failure
    causal_link_type: DIRECT
    description: Odds of heart failure are roughly 2-fold those of essential hypertension.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "and heart failure (2·05, 1·11-3·78)"
      explanation: Quantifies the excess heart failure risk.
  - target: Left Ventricular Hypertrophy
    causal_link_type: DIRECT
    description: >-
      Aldosterone-driven myocardial hypertrophy and fibrosis, part of the target
      organ damage measured in the meta-analysis.
    evidence:
    - reference: PMID:29129575
      reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "left ventricular hypertrophy (2·29, 1·65-3·17)."
      explanation: Quantifies the excess left ventricular hypertrophy risk in primary aldosteronism.

- name: Wnt Beta-Catenin Pathway Activation
  biological_scale: MOLECULAR
  role: driver
  description: >-
    Activating CTNNB1 mutations stabilise beta-catenin, driving canonical Wnt
    transcription. This is the commonest recurrent alteration in non-functioning
    adrenocortical adenomas, and also occurs in a minority of aldosterone- and
    cortisol-producing lesions. It is a proliferation driver that does not itself
    impose a secretory phenotype, which is consistent with its enrichment in the
    non-functioning group.
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  evidence:
  - reference: PMID:35731037
    reference_title: Mutational landscape of non-functional adrenocortical adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1."
    explanation: Quantifies CTNNB1 alteration frequency in non-functioning adrenocortical adenomas.
  - reference: PMID:35731037
    reference_title: Mutational landscape of non-functional adrenocortical adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion."
    explanation: Attributes benign adrenal tumorigenesis to Wnt/beta-catenin pathway involvement.
  downstream:
  - target: Clonal Adrenocortical Proliferation
    causal_link_type: DIRECT
    description: >-
      Stabilised beta-catenin drives the clonal expansion that produces the
      adenoma, without conferring autonomous steroid secretion.
    evidence:
    - reference: PMID:35731037
      reference_title: Mutational landscape of non-functional adrenocortical adenomas.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis"
      explanation: Links the pathway directly to benign adrenal tumour formation.

phenotypes:
- category: Neoplastic
  name: Adrenal Cortical Mass
  description: >-
    A discrete adrenal cortical lesion, typically unilateral, homogeneous and
    lipid-rich. Most are detected incidentally on imaging performed for unrelated
    indications.
  phenotype_term:
    preferred_term: Adrenocortical adenoma
    term:
      id: HP:0008256
      label: Adrenocortical adenoma
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease."
    explanation: Defines the incidentally detected adrenal mass that constitutes the defining lesion.

- category: Endocrine
  name: Primary Hypercortisolism
  subtype: Cortisol-Producing
  description: >-
    ACTH-independent cortisol excess of adrenal origin, demonstrated by failure of
    cortisol to suppress after 1 mg of dexamethasone in the presence of a
    suppressed plasma ACTH.
  phenotype_term:
    preferred_term: Primary hypercortisolism
    term:
      id: HP:0001579
      label: Primary hypercortisolism
  diagnostic: true
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex."
    explanation: Establishes adrenal tumours as a cause of ACTH-independent hypercortisolism.

- category: Endocrine
  name: Primary Hyperaldosteronism
  subtype: Aldosterone-Producing
  description: >-
    Renin-independent aldosterone excess of adrenal origin, demonstrated by an
    elevated aldosterone-to-renin ratio with confirmatory testing.
  phenotype_term:
    preferred_term: Primary hyperaldosteronism
    term:
      id: HP:0011736
      label: Primary hyperaldosteronism
  diagnostic: true
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary aldosteronism is the most prevalent form of secondary hypertension."
    explanation: Establishes primary aldosteronism as the clinical phenotype of the aldosterone-producing adenoma.

- category: Cardiovascular
  name: Hypertension
  description: >-
    Elevated arterial blood pressure. It arises through two mechanistically
    distinct routes in this disease — mineralocorticoid excess in
    aldosterone-producing adenoma, and glucocorticoid excess in cortisol-producing
    adenoma and MACS.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  frequency: FREQUENT
  evidence:
  - reference: PMID:35533704
    reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertension occurred in 1186 ... of 2024 patients with non-functioning adenoma, 944 ... of 1275 with possible autonomous cortisol secretion, and 179 ... of 238 with autonomous cortisol secretion"
    explanation: >-
      Gives the numerators and denominators for hypertension across the three
      cortisol strata (1186/2024 = 58.6%, 944/1275 = 74.0%, 179/238 = 75.2%), all
      of which fall in the FREQUENT (30-79%) band.
  notes: >-
    Frequency assigned FREQUENT from the counts quoted above (58.6-75.2% across
    the cortisol-autonomy strata of the NAPACA cohort). Hypertension is
    near-universal in the aldosterone-producing subtype specifically, since it is
    part of that subtype's case definition, so the subtype-level frequency is
    higher than this disease-level band; that subtype-specific figure was not
    separately curated.

- category: Endocrine
  name: Hypokalemia
  subtype: Aldosterone-Producing
  description: >-
    Low serum potassium from aldosterone-driven distal kaliuresis. Present in only
    a minority of patients with primary aldosteronism — normokalaemia does not
    exclude the diagnosis.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Constitutive production of aldosterone (primary aldosteronism) results in hypertension, often associated with hypokalemia"
    explanation: Links primary aldosteronism to hypokalaemia as a frequent but not obligate accompaniment.
  notes: >-
    Frequency deliberately omitted. The cited source says only "often associated
    with hypokalemia" with no numerator or denominator, and contemporary reviews
    emphasise that primary aldosteronism is commonly normokalaemic. Assigning a
    FrequencyEnum band here would not be supported by quotable evidence.

- category: Metabolic
  name: Type II Diabetes Mellitus
  description: >-
    Insulin resistance and overt type 2 diabetes attributable to glucocorticoid
    excess. In MACS-2 the diabetes is more likely to require insulin than in
    non-functioning adenomas.
  phenotype_term:
    preferred_term: Type II diabetes mellitus
    term:
      id: HP:0005978
      label: Type II diabetes mellitus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35533704
    reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "any diabetes occurred in 365 ... of 2002, 288 ... of 1250, and 62 ... of 232"
    explanation: >-
      Gives the numerators and denominators for diabetes across the three cortisol
      strata (365/2002 = 18.2%, 288/1250 = 23.0%, 62/232 = 26.7%), all of which
      fall in the OCCASIONAL (5-29%) band.

- category: Metabolic
  name: Hyperlipidemia
  description: >-
    Dyslipidaemia attributable to glucocorticoid excess. Prevalence rises from
    36.2% in non-functioning adenoma to 51.9% with overt cortisol autonomy, a
    gradient comparable to that seen for hypertension.
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:35533704
    reference_title: "Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dyslipidaemia occurred in 724 ... of 1999 patients, 547 ... of 1250, and 123 ... of 237"
    explanation: >-
      Numerators and denominators give 36.2%, 43.8% and 51.9% across the three
      cortisol strata, all within the FREQUENT (30-79%) band.

- category: Cardiovascular
  name: Coronary Artery Disease
  subtype: Aldosterone-Producing
  description: >-
    Coronary artery disease at roughly 1.8-fold the odds seen in essential
    hypertension, part of the aldosterone-attributable target organ damage.
  phenotype_term:
    preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coronary artery disease (1·77, 1·10-2·83)"
    explanation: Quantifies the excess coronary artery disease risk in primary aldosteronism.
  notes: >-
    The meta-analysis endpoint is "coronary artery disease" as an event category;
    HP:0001677 (Coronary artery atherosclerosis) is the closest HPO term, which is
    slightly narrower than the reported endpoint.

- category: Cardiovascular
  name: Heart Failure
  subtype: Aldosterone-Producing
  description: >-
    Heart failure at roughly 2-fold the odds seen in essential hypertension,
    reflecting aldosterone-driven myocardial fibrosis and remodelling.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and heart failure (2·05, 1·11-3·78)"
    explanation: Quantifies the excess heart failure risk in primary aldosteronism.

- category: Musculoskeletal
  name: Osteoporosis
  description: >-
    Reduced bone mineral density from glucocorticoid suppression of osteoblast
    function, significantly more common in MACS than in non-functioning adenomas.
    Note that the pooled 50% figure below is for the composite
    "osteoporosis/osteopenia", so it overstates osteoporosis as strictly defined.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:38703381
    reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "osteoporosis/osteopenia in MACS/SH were 43% ... and 50% (95% CI: 33%, 66%), respectively."
    explanation: >-
      Pooled prevalence of the composite osteoporosis/osteopenia endpoint is 50%
      (95% CI 33-66%) in MACS. The FREQUENT (30-79%) band is assigned from this
      composite; osteoporosis alone would be lower, so the band is an upper-leaning
      estimate rather than a term-exact figure.

- category: Musculoskeletal
  name: Vertebral Fracture
  subtype: MACS
  description: >-
    Fragility fracture of the vertebral body. Roughly twice as likely in adrenal
    adenoma with MACS as in non-functioning adenoma — one of the key observations
    that reclassified MACS from benign to consequential.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
  frequency: FREQUENT
  evidence:
  - reference: PMID:38703381
    reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vertebral fractures (OR 2.10; 95% CI: 1.28, 3.45; P = 0.0035)"
    explanation: Quantifies the doubled odds of vertebral fracture in MACS versus non-functioning adenoma.
  - reference: PMID:38703381
    reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vertebral fractures, and osteoporosis/osteopenia in MACS/SH were 43% ... , 45% (95% CI: 22%, 68%)"
    explanation: >-
      Pooled vertebral-fracture prevalence of 45% (95% CI 22-68%) in MACS supports
      the FREQUENT (30-79%) band.
  notes: >-
    Bound to HP:0002953 (Vertebral compression fracture) because the claim and its
    evidence concern fracture *events*. An earlier draft used HP:0005625
    (Osteoporosis of vertebrae), which asserts bone density rather than fracture
    and partly duplicated the separate Osteoporosis phenotype; that was corrected
    in review.

- category: Musculoskeletal
  name: Proximal Muscle Weakness
  subtype: Cortisol-Producing
  description: Catabolic myopathy of glucocorticoid excess, affecting proximal limb girdles.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "catabolic symptoms such as muscle weakness"
    explanation: Names muscle weakness as a catabolic manifestation of severe Cushing syndrome.

- category: Dermatologic
  name: Bruising Susceptibility
  subtype: Cortisol-Producing
  description: Easy bruising from glucocorticoid-induced dermal collagen loss and capillary fragility.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "catabolic symptoms such as muscle weakness, skin fragility"
    explanation: Skin fragility is the dermal substrate of easy bruising in cortisol excess.

- category: Metabolic
  name: Abdominal Obesity
  subtype: Cortisol-Producing
  description: Central fat redistribution characteristic of glucocorticoid excess.
  phenotype_term:
    preferred_term: Abdominal obesity
    term:
      id: HP:0012743
      label: Abdominal obesity
  evidence:
  - reference: PMID:34978855
    reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS"
    explanation: >-
      Supports the graded glucocorticoid exposure that produces central adiposity;
      the cohort abstract does not report adiposity as an endpoint, hence PARTIAL.

- category: Cardiovascular
  name: Stroke
  subtype: Aldosterone-Producing
  description: >-
    Cerebrovascular event. Odds are approximately 2.6-fold those of essential
    hypertensives, illustrating target organ damage out of proportion to blood
    pressure.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an increased risk of stroke (odds ratio ... 2·58, 95% CI 1·93-3·45)"
    explanation: Quantifies the excess stroke risk in primary aldosteronism.

- category: Cardiovascular
  name: Atrial Fibrillation
  subtype: Aldosterone-Producing
  description: >-
    Aldosterone-driven atrial remodelling and fibrosis. Odds are approximately
    3.5-fold those of essential hypertensives — the largest of the excess
    cardiovascular risks in primary aldosteronism.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrial fibrillation (3·52, 2·06-5·99)"
    explanation: Quantifies the excess atrial fibrillation risk.

- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  subtype: Aldosterone-Producing
  description: Aldosterone-driven myocardial hypertrophy and interstitial fibrosis.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."
    explanation: Directly reports the 2.29-fold excess odds of left ventricular hypertrophy in primary aldosteronism.

- category: Endocrine
  name: Adrenal Insufficiency
  subtype: Cortisol-Producing
  description: >-
    Postoperative glucocorticoid deficiency after removal of a cortisol-producing
    adenoma, caused by chronic ACTH suppression and atrophy of the remaining
    adrenal cortex. Requires stress-dose then tapering glucocorticoid replacement;
    hypothalamic-pituitary-adrenal recovery may take months.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  context: Postoperative, following unilateral adrenalectomy for cortisol autonomy.
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with MACS should be screened for potential cortisol-related comorbidities"
    explanation: >-
      Indirect: the guideline's insistence on characterising cortisol autonomy is
      what identifies patients at risk of postoperative adrenal insufficiency. The
      abstract does not state the postoperative complication itself, hence PARTIAL.

biochemical:
- name: 1-mg Overnight Dexamethasone Suppression Test Cortisol
  biomarker_term:
    preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  notes: >-
    The pivotal test for cortisol autonomy in adrenal adenoma. Dexamethasone 1 mg
    is given at 2300 h and serum cortisol measured at 0800-0900 h the next
    morning. In a normal hypothalamic-pituitary-adrenal axis, cortisol suppresses
    below 50 nmol/L. Failure to suppress indicates that adrenal cortisol output is
    not under pituitary control.
  reference_ranges:
  - loinc_term:
      id: LOINC:97765-2
      label: Cortisol [Moles/volume] in Serum or Plasma --post dose dexamethasone PO overnight
    upper_bound: 50.0
    unit: nmol/L
    population: adults with an adrenal incidentaloma, no exogenous glucocorticoid or interfering medication
    notes: >-
      One-sided interval: suppression to below 50 nmol/L (1.8 ug/dL) is the normal
      / non-functioning result under the 2023 ESE guideline cutoff. Results are
      invalid in patients on drugs that induce or inhibit CYP3A4, or with abnormal
      cortisol-binding globulin. The LOINC code was verified against the NLM
      clinical-tables LOINC service; LOINC is not covered by the repository's OAK
      term validation.
    evidence:
    - reference: PMID:37318239
      reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L"
      explanation: The ESE guideline states the 50 nmol/L cutoff for a suppressed (normal) result.
    interpretation_bands:
    - name: Non-functioning adenoma
      upper_bound: 50.0
      unit: nmol/L
      abnormal_flag: NORMAL
      interpretation: >-
        Cortisol suppressed. No cortisol autonomy; the adenoma is non-functioning
        with respect to glucocorticoid secretion.
    - name: Possible MACS (MACS-1)
      lower_bound: 50.0
      upper_bound: 138.0
      unit: nmol/L
      abnormal_flag: HIGH
      phenotype_term:
        preferred_term: Increased circulating cortisol level
        term:
          id: HP:0003118
          label: Increased circulating cortisol level
      interpretation: >-
        Partial non-suppression, classified as possible autonomous cortisol
        secretion in the NAPACA and EURINE-ACT stratifications. Already associated
        with excess cardiometabolic comorbidity and increased all-cause mortality.
    - name: Definitive MACS (MACS-2)
      lower_bound: 138.0
      unit: nmol/L
      abnormal_flag: HIGH
      phenotype_term:
        preferred_term: Increased circulating cortisol level
        term:
          id: HP:0003118
          label: Increased circulating cortisol level
      interpretation: >-
        Frank non-suppression above 138 nmol/L in the absence of typical clinical
        Cushing features. The same result accompanied by overt Cushing stigmata is
        classified as Cushing syndrome rather than MACS — the distinction at this
        threshold is clinical, not biochemical.
  evidence:
  - reference: PMID:34978855
    reference_title: "Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor ... ; 50 to 138 nmol/L, possible MACS ... ; >138 nmol/L and absence of typical clinical Cushing syndrome"
    explanation: Source of the three interpretation bands and their exact numeric boundaries.

- name: Aldosterone-to-Renin Ratio
  biomarker_term:
    preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  notes: >-
    The screening test for primary aldosteronism: plasma aldosterone concentration
    divided by plasma renin activity or concentration. An elevated ratio indicates
    aldosterone production that is not being driven by renin. It should be
    measured with the patient off interfering agents (mineralocorticoid receptor
    antagonists in particular) and with potassium repleted, and a positive result
    requires confirmatory testing before subtype work-up.
  reference_ranges:
  - loinc_term:
      id: LOINC:30894-0
      label: Aldosterone/Renin [Ratio] in Plasma
    unit: '{ratio}'
    population: hypertensive adults screened for primary aldosteronism
    notes: >-
      No numeric cutoff is asserted here. The threshold for a positive
      aldosterone-to-renin ratio is assay- and unit-dependent: values differ by
      orders of magnitude depending on whether aldosterone is reported in ng/dL or
      pmol/L and whether renin is reported as activity or concentration, so a
      single interval would be misleading. The qualitative criterion — an elevated
      ratio with a suppressed renin — is what HP:6000318 (Elevated
      aldosterone:renin ratio) captures. The LOINC code was verified against the
      NLM clinical-tables LOINC service.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions"
    explanation: >-
      Guideline basis for the aldosterone-to-renin ratio as the case-detection test,
      and for the requirement that it be measured under standardised conditions.
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess"
    explanation: >-
      Supports the requirement for endocrine screening for hormone excess; the
      abstract enumerates metanephrines and the dexamethasone test explicitly but
      not the aldosterone-to-renin ratio, hence PARTIAL.

- name: Late-Night Salivary Cortisol
  biomarker_term:
    preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  notes: >-
    Measures loss of the normal nocturnal nadir of cortisol secretion. Useful as a
    second-line confirmatory test for overt Cushing syndrome, but insensitive in
    MACS, where the circadian nadir is often preserved — which is precisely why
    the dexamethasone suppression test, not salivary cortisol, is the recommended
    first-line screen in adrenal incidentaloma.
  reference_ranges:
  - loinc_term:
      id: LOINC:2142-8
      label: Cortisol [Mass/volume] in Saliva (oral fluid)
    unit: nmol/L
    population: adults, specimen collected at 2300-2400 h
    notes: >-
      No numeric interval asserted: late-night salivary cortisol cutoffs are
      strongly assay-dependent (immunoassay versus LC-MS/MS) and vary between
      laboratories, so a repository-wide interval would be misleading. Provenance
      is recorded here rather than as a citation because no quotable interval was
      found in a citable source during curation. The LOINC code was verified
      against the NLM clinical-tables LOINC service.
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L"
    explanation: >-
      Supports the point made in the notes: the guideline nominates the
      dexamethasone suppression test, not salivary cortisol, as the mandated
      first-line screen in adrenal incidentaloma.

- name: Elevated Aldosterone with Suppressed Renin
  biomarker_term:
    preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  notes: >-
    The paired biochemical signature of an aldosterone-producing adenoma: raised
    plasma aldosterone in the face of a renin that has been suppressed by
    aldosterone-driven volume expansion. Either measurement alone is
    uninterpretable; it is the discordance that establishes autonomy.
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases."
    explanation: >-
      Documents raised plasma aldosterone in genetically defined
      aldosterone-producing adenomas. PARTIAL because this sentence covers the
      aldosterone and potassium halves of the signature but says nothing about
      renin suppression; the item below carries the renin half.
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had hypertension with elevated aldosterone levels despite suppressed plasma renin activity (PRA)"
    explanation: States the elevated-aldosterone-with-suppressed-renin pattern as the diagnostic criterion applied.

imaging_findings:
- name: Homogeneous Lipid-Rich Adrenal Mass with Low Unenhanced CT Attenuation
  modality: CT
  description: >-
    The single most useful imaging discriminator. Adrenal cortical adenomas are
    rich in intracytoplasmic lipid, which lowers their unenhanced CT attenuation.
    Under the 2023 ESE guideline a homogeneous lesion measuring 10 Hounsfield
    units or less on unenhanced CT is benign and requires no further imaging
    follow-up irrespective of size — a substantive change from earlier size-based
    surveillance.
  imaging_finding_term:
    preferred_term: Adrenocortical adenoma
    term:
      id: HP:0008256
      label: Adrenocortical adenoma
  located_in:
    preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  diagnostic: true
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size."
    explanation: Direct guideline statement of the diagnostic imaging criterion and its size independence.
  - reference: PMID:37583083
    reference_title: Recent Updates on the Management of Adrenal Incidentalomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size"
    explanation: Independent restatement of the same criterion in the guideline review.

- name: Indeterminate Large or High-Attenuation Adrenal Mass
  modality: CT
  description: >-
    A lesion that is inhomogeneous or has unenhanced attenuation above 20 HU, and
    is larger than 4 cm, carries sufficient malignancy risk that surgery is the
    usual management. This is the imaging boundary between adrenal cortex adenoma
    and adrenocortical carcinoma.
  located_in:
    preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice"
    explanation: Defines the imaging threshold that shifts management from surveillance to resection.
  notes: >-
    This finding argues *against* adrenal cortex adenoma and toward carcinoma; it is
    recorded here because it is the decision boundary of the incidentaloma work-up,
    not because it is diagnostic of adenoma.

histopathology:
- name: Circumscribed Lipid-Rich Cortical Adenoma
  description: >-
    Grossly circumscribed, often golden-yellow tumour composed of bland
    lipid-laden cortical cells, without destructive capsular or vascular invasion.
    Cortical origin is confirmed immunohistochemically with SF-1, inhibin-alpha,
    Melan-A and calretinin.
  diagnostic: true
  evidence:
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas."
    explanation: Places adrenal cortical adenoma within the WHO 2022 spectrum of cortical proliferations.

- name: Low Weiss Score
  description: >-
    Adrenal cortical adenoma is distinguished from carcinoma by multiparameter
    histologic scoring. In Weiss's original series, none of the 24 tumours with
    two or fewer of the nine criteria metastasised or recurred, while almost all
    with four or more did. A Weiss score of 2 or less therefore supports adenoma.
    The 2022 WHO classification retains Weiss and modified Weiss alongside the
    reticulin algorithm, Lin-Weiss-Bisceglia and Helsinki systems.
  diagnostic: true
  evidence:
  - reference: PMID:6703192
    reference_title: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized."
    explanation: The original derivation of the Weiss score threshold separating adenoma from carcinoma.
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin-Weiss-Bisceglia system, and Helsinki scoring system)"
    explanation: Confirms the continued role of Weiss scoring in the current WHO framework.

- name: Low Proliferative Index
  description: >-
    Adenomas show low mitotic activity and a low Ki67 labelling index. Most adult
    adrenal cortical carcinomas, by contrast, exceed 5 mitoses per 10 mm2 and 5%
    Ki67 — the proliferation-rate boundary is one of the most reproducible
    discriminators between the two entities.
  diagnostic: true
  evidence:
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most adult adrenal cortical carcinomas show > 5 mitoses per 10 mm2 and > 5% Ki67."
    explanation: Gives the proliferation thresholds above which carcinoma rather than adenoma is favoured.

- name: CYP11B2 Immunoreactivity in Aldosterone-Producing Lesions
  subtype: Aldosterone-Producing
  description: >-
    Aldosterone synthase (CYP11B2) immunohistochemistry identifies which cortical
    structures are actually producing aldosterone. The HISTALDO classification,
    endorsed by WHO 2022, uses this to distinguish a solitary CYP11B2-positive
    adenoma from multifocal or bilateral aldosterone-producing micronodules, which
    predicts the risk of persistent disease after unilateral adrenalectomy.
  diagnostic: true
  evidence:
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism"
    explanation: Establishes CYP11B2 immunohistochemistry as the WHO-endorsed functional marker.

genetic:
- name: PRKACA
  gene_term:
    preferred_term: PRKACA
    term:
      id: hgnc:9380
      label: PRKACA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Cortisol-Producing
  association: >-
    Recurrent activating hotspot mutations (c.617A>C; p.Leu206Arg counting the
    initiator methionine, equivalently L205R in the mature-protein numbering used
    in the earlier literature) in the P+1 loop of the PKA catalytic subunit. The mutant escapes inhibition by the PKA regulatory subunit, giving
    constitutive, cAMP-independent kinase activity.
  case_fractions:
  - population: Patients with unilateral adenoma and overt Cushing syndrome (European cohort)
    case_fraction_percent: 37.0
    cohort_size: 59
    notes: Somatic PRKACA mutations in 22 of 59 unilateral adenomas with overt Cushing syndrome.
    evidence:
    - reference: PMID:24571724
      reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome"
      explanation: Direct numerator and denominator for the PRKACA case fraction in this cohort.
  - population: Cortisol-producing adrenocortical adenomas (Chinese cohort)
    case_fraction_percent: 65.5
    cohort_size: 87
    notes: >-
      Markedly higher than the European estimate. Cohort composition and the
      threshold used to define "cortisol-producing" differ between the two
      studies, so the two figures should not be averaged.
    evidence:
    - reference: PMID:24700472
      reference_title: "Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs"
      explanation: Direct case fraction in the validation cohort of 87 adenomas.
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase"
    explanation: The discovery observation establishing PRKACA as the somatic driver.
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were not detectable in 40 patients with subclinical hypercortisolism"
    explanation: >-
      PRKACA mutation is absent in subclinical hypercortisolism (MACS), which is why
      this gene is scoped to the overt Cushing subtype rather than to cortisol
      autonomy generally — a direct constraint on the driver-to-subtype mapping.
  notes: >-
    Germline copy-number gain of the PRKACA locus causes bilateral
    cortisol-producing adrenal hyperplasia, not unilateral adenoma. That is a
    distinct disease entity and is out of scope for this entry.

- name: GNAS
  gene_term:
    preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Cortisol-Producing
  association: >-
    Activating mutations of the stimulatory G-protein alpha subunit lock Gs-alpha
    in its GTP-bound state, raising cAMP and activating PKA one step upstream of
    PRKACA.
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "somatic mutations in the gene encoding the α subunit of the stimulatory G protein (GNAS1) cause adenomas or hyperplasias leading to Cushing's syndrome"
    explanation: >-
      Establishes GNAS as a cAMP-pathway driver of cortisol-producing adrenal
      lesions. PARTIAL because the cited sentence continues "in patients with
      McCune-Albright syndrome or macronodular hyperplasia" — i.e. it evidences the
      pathway, not specifically the sporadic unilateral adenoma modelled here, and
      this study excluded somatic-GNAS cases from its own cohort.

- name: KCNJ5
  gene_term:
    preferred_term: KCNJ5
    term:
      id: hgnc:6266
      label: KCNJ5
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Aldosterone-Producing
  association: >-
    Recurrent somatic mutations in and near the selectivity filter of the inwardly
    rectifying potassium channel Kir3.4 (p.Gly151Arg, p.Leu168Arg). Loss of K+
    selectivity permits Na+ conductance and chronic depolarisation. The commonest
    APA driver.
  case_fractions:
  - population: Aldosterone-producing adenomas (discovery cohort)
    case_fraction_percent: 36.4
    cohort_size: 22
    notes: 8 of 22 APAs in the original discovery series.
    evidence:
    - reference: PMID:21311022
      reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied"
      explanation: Direct numerator and denominator for the discovery-cohort case fraction.
  evidence:
  - reference: PMID:21311022
    reference_title: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production."
    explanation: >-
      Establishes the mechanism by which KCNJ5 mutation drives both proliferation
      and hormone excess. Tagged IN_VITRO because the mechanistic inference rests on
      the paper's electrophysiology, matching the tagging of the same sentence used
      on the Calcium Influx node.
  notes: >-
    Germline variants at the same KCNJ5 residues cause familial hyperaldosteronism
    type III with massive bilateral adrenal hyperplasia — a separate entity,
    curated under Familial_Hyperaldosteronism, not as a subtype here. The germline
    substitutions are not always identical to the somatic G151R/L168R changes.

- name: CACNA1D
  gene_term:
    preferred_term: CACNA1D
    term:
      id: hgnc:1391
      label: CACNA1D
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Aldosterone-Producing
  association: >-
    Gain-of-function mutations in the S6 pore-lining segments of the Cav1.3 L-type
    calcium channel (p.Gly403Arg, p.Ile770Met) shift channel activation to less
    depolarised potentials and impair inactivation, increasing calcium influx.
    Found in APAs that lack KCNJ5 mutations, demonstrating driver mutual
    exclusivity.
  case_fractions:
  - population: Aldosterone-producing adenomas (combined exome and Sanger cohort)
    case_fraction_percent: 7.8
    cohort_size: 64
    notes: 5 of 64 APAs overall; 5 of 41 (12.2%) among those without KCNJ5 or CTNNB1 mutations.
    evidence:
    - reference: PMID:23913001
      reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Collectively, CACNA1D mutations were identified in 5 of 64 APAs (7.8%), including 5/41 without KCNJ5 or CTNNB1 mutations (12.2%)."
      explanation: Direct case fractions, both overall and in the KCNJ5-wild-type subset.
  evidence:
  - reference: PMID:23913001
    reference_title: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation."
    explanation: Electrophysiological demonstration of the gain-of-function mechanism.
  notes: >-
    De novo germline mutations at the same CACNA1D residues cause a distinct
    Mendelian syndrome of primary aldosteronism with seizures and neuromuscular
    abnormalities. That is a separate entity and is not curated here; only the
    somatic tumour driver is in scope.

- name: ATP1A1
  gene_term:
    preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Aldosterone-Producing
  association: >-
    Somatic hotspot mutations in the Na+/K+-ATPase alpha subunit cause loss of
    pump activity and strongly reduced potassium affinity, so the glomerulosa cell
    cannot maintain its hyperpolarised resting potential.
  case_fractions:
  - population: Aldosterone-producing adenomas (multicentre collection)
    case_fraction_percent: 5.2
    cohort_size: 308
    evidence:
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1"
      explanation: Direct case fraction in a large APA collection.
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium."
    explanation: Functional demonstration of the loss-of-pump-activity mechanism.

- name: ATP2B3
  gene_term:
    preferred_term: ATP2B3
    term:
      id: hgnc:816
      label: ATP2B3
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Aldosterone-Producing
  association: >-
    Somatic hotspot mutations in the plasma-membrane calcium ATPase impair calcium
    extrusion, contributing to the raised cytosolic calcium that drives aldosterone
    synthesis and proliferation.
  case_fractions:
  - population: Aldosterone-producing adenomas (multicentre collection)
    case_fraction_percent: 1.6
    cohort_size: 308
    evidence:
    - reference: PMID:23416519
      reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3"
      explanation: Direct case fraction for ATP2B3 in a large APA collection.
  evidence:
  - reference: PMID:23416519
    reference_title: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes"
    explanation: Identifies ATP2B3 as a recurrent somatic driver encoding a calcium ATPase.

- name: CTNNB1
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Non-Functioning
  association: >-
    Activating mutations stabilising beta-catenin and driving canonical Wnt
    transcription. The commonest recurrent alteration in non-functioning
    adrenocortical adenomas; also present in a minority of aldosterone- and
    cortisol-producing lesions.
  case_fractions:
  - population: Non-functioning adrenocortical adenomas (pan-genomic series)
    case_fraction_percent: 36.67
    cohort_size: 60
    evidence:
    - reference: PMID:35731037
      reference_title: Mutational landscape of non-functional adrenocortical adenomas.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1."
      explanation: Direct case fraction for CTNNB1 in non-functioning adenomas.
  evidence:
  - reference: PMID:35731037
    reference_title: Mutational landscape of non-functional adrenocortical adenomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion."
    explanation: Attributes benign adrenal tumorigenesis to Wnt/beta-catenin activation.

treatments:
- name: Unilateral Adrenalectomy
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Definitive treatment for a unilateral aldosterone-producing adenoma and for an
    overt cortisol-producing adenoma; considered on an individualised basis in
    MACS when cortisol-attributable comorbidity is present. A minimally invasive
    approach is preferred for benign hormone-secreting lesions. It is not
    indicated for an asymptomatic, non-functioning unilateral mass with benign
    imaging features. Biochemical cure rates after adrenalectomy for unilateral
    primary aldosteronism are high (94% complete biochemical success in the PASO
    cohort), but complete clinical (blood-pressure) success is achieved in only
    about 37% — a distinction clinicians and curators should not conflate.
  treatment_term:
    preferred_term: Adrenalectomy
    term:
      id: NCIT:C15177
      label: Adrenalectomy
  target_mechanisms:
  - target: CYP11B2 Induction and Autonomous Aldosterone Synthesis
    treatment_effect: INHIBITS
    description: Removal of the tumour eliminates the autonomous source of aldosterone.
  - target: ACTH-Independent Cortisol Hypersecretion
    treatment_effect: INHIBITS
    description: Removal of the tumour eliminates the autonomous source of cortisol.
  evidence:
  - reference: PMID:28576687
    reference_title: "Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients."
    explanation: Quantifies the divergence between biochemical cure and clinical (blood-pressure) cure after adrenalectomy.
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach."
    explanation: States the individualised indication for surgery in MACS.
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies."
    explanation: States the explicit contraindication to surgery in non-functioning benign lesions.

- name: Mineralocorticoid Receptor Antagonist Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Spironolactone or eplerenone block the mineralocorticoid receptor, addressing
    both the blood-pressure and the direct target-organ effects of aldosterone
    excess. Used when surgery is declined or not feasible, while awaiting
    lateralisation, or when disease proves bilateral. Requires monitoring for
    hyperkalaemia and declining renal function; spironolactone additionally causes
    gynaecomastia and menstrual disturbance through its antiandrogenic and
    progestogenic activity, which is the usual reason for switching to eplerenone.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
    - preferred_term: eplerenone
      term:
        id: CHEBI:31547
        label: eplerenone
  target_mechanisms:
  - target: Renin-Independent Mineralocorticoid Excess
    treatment_effect: INHIBITS
    description: >-
      Receptor blockade prevents aldosterone from acting on the distal nephron and
      on cardiovascular tissue, even though tumour aldosterone output is unchanged.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist."
    explanation: >-
      Guideline recommendation establishing mineralocorticoid receptor antagonism
      as the primary medical therapy when surgery is not the chosen route.
  - reference: PMID:29129575
    reference_title: "Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17)."
    explanation: >-
      Quantifies the aldosterone-attributable end-organ burden that motivates
      receptor blockade. PARTIAL because this meta-analysis measures the untreated
      risk, not the treatment effect of mineralocorticoid receptor antagonists.

- name: Perioperative and Postoperative Glucocorticoid Replacement
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Patients with cortisol autonomy who undergo adrenalectomy have a suppressed
    hypothalamic-pituitary-adrenal axis and an atrophic contralateral cortex, and
    will develop adrenal insufficiency on removal of the tumour. Stress-dose
    hydrocortisone is given perioperatively and then tapered according to recovery
    of the axis, which may take months. Omitting this is a recognised cause of
    avoidable postoperative adrenal crisis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
  target_phenotypes:
  - preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  target_mechanisms:
  - target: HPA Axis Suppression and Contralateral Adrenal Atrophy
    treatment_effect: MODULATES
    description: >-
      Exogenous glucocorticoid substitutes for the deficient endogenous output
      until the suppressed axis recovers.
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference."
    explanation: >-
      Supports the link between degree of hormone excess and surgical planning, of
      which glucocorticoid cover is part. PARTIAL because the abstract does not
      state the perioperative steroid recommendation explicitly.

- name: Screening for and Treatment of Cortisol-Attributable Comorbidity in MACS
  action_category: SCREENING
  description: >-
    The practical consequence of the MACS reclassification: rather than reassuring
    the patient, every individual with MACS should be actively screened for
    hypertension, type 2 diabetes, dyslipidaemia and osteoporosis, and those
    conditions treated on their own terms. This is now a guideline recommendation
    and, for the large majority of MACS patients who do not undergo surgery, it is
    the entire intervention.
  treatment_term:
    preferred_term: Disease Screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated."
    explanation: Direct guideline recommendation for comorbidity screening in MACS.
  - reference: PMID:38703381
    reference_title: "Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical hypercortisolism: a systematic review, meta-analysis and meta-regression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "people with adrenal adenomas/incidentalomas and MACS/SH are at a 1.5- to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non-functional adrenal adenomas and should routinely be screened for bone disease"
    explanation: Extends the screening recommendation to bone disease specifically.

- name: Non-Operative Management of the Benign Non-Functioning Adenoma
  action_category: MONITORING
  description: >-
    For a homogeneous adrenal mass measuring 10 HU or less on unenhanced CT with a
    normal endocrine work-up, the 2023 ESE guideline recommends no further imaging
    follow-up at all, irrespective of size, and no surgery. This is a deliberate
    de-escalation from earlier size-based surveillance protocols and spares a large
    number of patients repeated CT and its radiation burden.
  treatment_term:
    preferred_term: Diagnostic Imaging Testing
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size."
    explanation: Direct guideline basis for withholding imaging surveillance in benign lesions.
  - reference: PMID:37583083
    reference_title: Recent Updates on the Management of Adrenal Incidentalomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "requires no further follow-up, irrespective of its size"
    explanation: Confirms the removal of the size restriction from the follow-up rule.

- name: Steroidogenesis Inhibitor Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Metyrapone (an 11-beta-hydroxylase inhibitor) and related agents can lower
    cortisol in severe hypercortisolism when surgery must be delayed or is not
    possible. This is a bridging or salvage measure, not definitive therapy for a
    resectable benign adenoma.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metyrapone
      term:
        id: CHEBI:44241
        label: metyrapone
  target_mechanisms:
  - target: ACTH-Independent Cortisol Hypersecretion
    treatment_effect: INHIBITS
    description: >-
      Blockade of 11-beta-hydroxylase reduces cortisol synthesis by the tumour
      without removing it.
  evidence:
  - reference: PMID:35769081
    reference_title: "Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing's Syndrome: Results From a Single Center Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase"
    explanation: States the 11-beta-hydroxylase target that is the mechanism claimed for this treatment.
  - reference: PMID:35769081
    reference_title: "Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing's Syndrome: Results From a Single Center Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "medical therapy is often required to control severe hypercortisolism"
    explanation: >-
      Establishes the indication — medical cortisol lowering when surgery does not
      control hypercortisolism. The cohort included adrenal Cushing syndrome.

differential_diagnoses:
- name: Adrenal Cortex Carcinoma
  disease_term:
    preferred_term: adrenal cortex carcinoma
    term:
      id: MONDO:0006639
      label: adrenal cortex carcinoma
  description: >-
    The single most consequential distinction. Adrenocortical carcinoma is a
    malignant tumour of the same cortical lineage with an entirely different
    prognosis, and misclassifying one as the other is the main harm the adrenal
    incidentaloma work-up exists to prevent. Carcinoma is favoured by larger size,
    inhomogeneity and higher unenhanced attenuation on CT, by high proliferation
    rate and angioinvasion on histology, by IGF2 overexpression, and by TP53 and
    CTNNB1 alterations with broad copy-number instability. Rapid virilisation or
    feminisation, or mixed steroid excess, is a red flag for carcinoma rather than
    adenoma.
  distinguishing_features:
  - Size greater than 4 cm with inhomogeneity or unenhanced CT attenuation above 20 HU
  - Weiss score of 4 or more (adenoma 2 or less); angioinvasion; more than 5 mitoses per 10 mm2 and more than 5% Ki67
  - IGF2 overexpression detectable by immunohistochemistry
  - Broad copy-number instability, TP53 disruption, extensive methylomic derangement
  - Rapid onset of virilisation, feminisation or mixed steroid excess
  evidence:
  - reference: PMID:6703192
    reference_title: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized."
    explanation: The Weiss threshold that operationalises the adenoma-versus-carcinoma distinction.
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most adult adrenal cortical carcinomas show > 5 mitoses per 10 mm2 and > 5% Ki67."
    explanation: Gives the proliferation-rate thresholds distinguishing carcinoma from adenoma.
  - reference: PMID:38108848
    reference_title: "Molecular pathology of endocrine gland tumors: genetic alterations and clinicopathologic relevance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overexpression in adrenal cortical carcinoma can be identified by immunohistochemistry and may be useful in the differential diagnosis with adenoma"
    explanation: >-
      States that IGF2 overexpression is a useful immunohistochemical discriminator
      between carcinoma and adenoma. The snippet begins mid-sentence because the
      cached full text renders "IGF2overexpression" without a separating space.
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice"
    explanation: Gives the imaging criteria that raise suspicion of carcinoma.
  notes: >-
    Adrenal cortex carcinoma is a distinct disease entity, not a subtype or a
    progression stage of adrenal cortex adenoma. There is no established
    adenoma-to-carcinoma sequence in the adrenal cortex analogous to the colorectal
    adenoma-carcinoma sequence.

- name: Bilateral Macronodular Adrenal Hyperplasia
  disease_term:
    preferred_term: Cushing syndrome due to macronodular adrenal hyperplasia
    term:
      id: MONDO:0009049
      label: Cushing syndrome due to macronodular adrenal hyperplasia
  description: >-
    A bilateral, multinodular adrenocortical disease causing ACTH-independent
    cortisol excess, caused in roughly half of cases by inactivating germline
    ARMC5 mutations with a somatic second hit in each nodule. It shares the
    cortisol phenotype with a cortisol-producing adenoma but is bilateral,
    macronodular, germline-driven and heritable — so it demands genetic counselling
    and family screening, and cannot be cured by unilateral adrenalectomy. It is a
    separate entity, not a bilateral variant of adrenal cortex adenoma.
  distinguishing_features:
  - Bilateral macronodular adrenal enlargement rather than a solitary unilateral mass
  - Germline ARMC5 inactivating mutations in approximately 44% of cases
  - Heritable; warrants cascade genetic testing of relatives
  - Not curable by unilateral adrenalectomy
  evidence:
  - reference: PMID:24601692
    reference_title: "Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline ARMC5 mutations were found in 15 of 34 patients (44.1%)."
    explanation: Quantifies the germline ARMC5 contribution that distinguishes this entity mechanistically.
  - reference: PMID:24601692
    reference_title: "Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families."
    explanation: Establishes the heritability and counselling implications absent from sporadic adrenal cortex adenoma.

- name: Primary Pigmented Nodular Adrenocortical Disease
  disease_term:
    preferred_term: primary pigmented nodular adrenocortical disease
    term:
      id: MONDO:0015999
      label: primary pigmented nodular adrenocortical disease
  description: >-
    Bilateral micronodular pigmented adrenocortical disease causing
    ACTH-independent Cushing syndrome, usually in children and young adults,
    caused by germline inactivating PRKAR1A mutations and frequently part of
    Carney complex. It converges on the same pathway as the cortisol-producing
    adenoma — loss of PKA regulatory-subunit restraint — but from the opposite
    direction (germline loss of the regulatory subunit rather than somatic gain in
    the catalytic subunit) and with a bilateral, germline, syndromic presentation.
    Curated separately in this knowledge base as
    Primary_Pigmented_Nodular_Adrenocortical_Disease.
  distinguishing_features:
  - Bilateral pigmented micronodules rather than a solitary unilateral adenoma
  - Germline PRKAR1A inactivating mutations, often with Carney complex features (lentigines, myxomas, other endocrine tumours)
  - Typically presents in childhood or young adulthood
  - Paradoxical rise in urinary free cortisol on the Liddle dexamethasone test
  evidence:
  - reference: PMID:24571724
    reference_title: "Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "have been identified in patients with Cushing’s syndrome due to primary pigmented nodular adrenocortical disease"
    explanation: >-
      Establishes PRKAR1A as the driver of primary pigmented nodular adrenocortical
      disease, contrasting with the somatic PRKACA driver of unilateral
      cortisol-producing adenoma.

- name: Pheochromocytoma
  disease_term:
    preferred_term: pheochromocytoma
    term:
      id: MONDO:0008233
      label: pheochromocytoma
  description: >-
    A catecholamine-secreting tumour of the adrenal medulla, not the cortex. It is
    a mandatory exclusion in any adrenal incidentaloma work-up because
    unrecognised pheochromocytoma can precipitate a hypertensive crisis during
    biopsy, surgery or anaesthesia. Plasma or urinary metanephrines must be
    measured in every patient before any invasive procedure.
  distinguishing_features:
  - Medullary (chromaffin) rather than cortical origin
  - Elevated plasma free or urinary fractionated metanephrines
  - High unenhanced CT attenuation (above 10 HU), often with marked contrast enhancement
  - Episodic headache, palpitations and sweating with paroxysmal hypertension
  - Biopsy or unprepared surgery can precipitate a hypertensive crisis
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines"
    explanation: Mandates metanephrine measurement to exclude pheochromocytoma in every adrenal incidentaloma.

- name: Adrenal Metastasis
  disease_term:
    preferred_term: metastatic neoplasm
    term:
      id: MONDO:0024883
      label: metastatic neoplasm
  description: >-
    Secondary deposit in the adrenal gland, most often from lung, breast, renal or
    gastrointestinal primaries or melanoma. In a patient with a known extra-adrenal
    malignancy this — not adenoma — is the leading explanation for a new adrenal
    mass, which is why the ESE guideline treats prior malignancy as a distinct
    management context. Metastases are typically inhomogeneous, lipid-poor with
    unenhanced attenuation above 10 HU, and are frequently bilateral.
  distinguishing_features:
  - Known or suspected extra-adrenal primary malignancy
  - Lipid-poor, inhomogeneous, unenhanced attenuation above 10 HU
  - Frequently bilateral, unlike the typically unilateral adenoma
  - Hormonally silent, so a normal endocrine work-up does not exclude it
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases"
    explanation: >-
      The ESE guideline lists metastases among the incidentaloma diagnoses that must
      be separated from benign non-functioning adenoma.

- name: Adrenal Myelolipoma
  disease_term:
    preferred_term: adrenal gland myelolipoma
    term:
      id: MONDO:0006075
      label: adrenal gland myelolipoma
  description: >-
    A benign, hormonally inactive tumour composed of mature adipose tissue and
    haematopoietic elements. It is radiologically unmistakable because of its
    macroscopic fat, which gives strongly negative CT attenuation — well below the
    lipid-rich adenoma threshold. No endocrine work-up beyond the standard
    incidentaloma screen and no follow-up is needed for a typical lesion.
  distinguishing_features:
  - Macroscopic fat with markedly negative CT attenuation, well below 0 HU
  - Composed of mature adipose tissue plus haematopoietic elements on histology
  - Hormonally inactive
  evidence:
  - reference: PMID:37318239
    reference_title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Each adrenal mass requires dedicated adrenal imaging."
    explanation: >-
      Supports the imaging-first triage in which myelolipoma is separated from
      adenoma by attenuation. PARTIAL because the abstract does not name
      myelolipoma explicitly.

diagnosis:
- name: Adrenal Vein Sampling
  description: >-
    Bilateral adrenal venous sampling is the reference standard for deciding
    whether confirmed primary aldosteronism is unilateral (an aldosterone-producing
    adenoma, curable by adrenalectomy) or bilateral (hyperplasia, treated
    medically). It is required because CT cannot reliably identify the secreting
    side: non-functioning adrenal nodules become common with age, so a visible
    nodule may not be the source of the aldosterone, and conversely an
    aldosterone-producing lesion may be too small to see. Getting this wrong means
    either removing the wrong gland or denying a curable patient surgery.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy."
    explanation: Guideline basis for adrenal vein sampling as the lateralisation standard before adrenalectomy.
  - reference: PMID:35288842
    reference_title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess"
    explanation: States the reason imaging alone cannot lateralise primary aldosteronism.
  notes: >-
    No structured `diagnosis_term` is bound: NCIT has no adrenal-venous-sampling
    concept that is both specific and reachable from the procedure roots used by
    this schema, so a term is omitted rather than approximated.

- name: Adrenal CT for Subtype Testing
  description: >-
    Unenhanced adrenal CT is the initial subtype study in confirmed primary
    aldosteronism, used both to look for a lateralising lesion and to exclude
    adrenocortical carcinoma before any surgical plan.
  evidence:
  - reference: PMID:26934393
    reference_title: "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma."
    explanation: Guideline basis for adrenal CT as the initial subtype and malignancy-exclusion study.

references:
- reference: PMID:37318239
  title: "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors."
- reference: PMID:35288842
  title: Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.

notes: >-
  Scope and boundaries. This entry covers the benign adrenal cortical neoplasm
  only. Three adjacent entities were deliberately excluded and modelled as
  differential diagnoses rather than subtypes, because each has a distinct driver,
  laterality and inheritance: adrenal cortex carcinoma (MONDO:0006639), bilateral
  macronodular adrenal hyperplasia (ARMC5; MONDO:0009049), and primary pigmented
  nodular adrenocortical disease (PRKAR1A / Carney complex; MONDO:0015999), the
  last of which is already curated in this knowledge base as
  Primary_Pigmented_Nodular_Adrenocortical_Disease.

  Relationship to existing entries. The downstream clinical syndromes caused by
  functional adenomas are curated separately and are not duplicated here:
  Cushings_Syndrome covers the full hypercortisolism syndrome across all
  aetiologies (pituitary, ectopic and adrenal), and Familial_Hyperaldosteronism
  and Familial_Hyperaldosteronism_Type_I cover the germline forms of aldosterone
  excess. This entry models the adenoma itself and the mechanistic chain from its
  somatic driver to the hormone excess; the syndrome entries model the systemic
  consequences of that hormone excess in full.

  On the functional axis. Subtypes are defined by autonomous secretion rather than
  by histology or size because that is what determines management, and because the
  somatic driver classes map cleanly onto the secretory phenotypes. MACS is
  modelled as a subtype in its own right rather than as mild Cushing syndrome,
  reflecting its 2023 ESE-formalised status and the mortality and fracture data
  that reclassified it.

  Curation gaps for a future pass. (1) No numeric interval is asserted for the
  aldosterone-to-renin ratio or for late-night salivary cortisol; both are strongly
  assay- and unit-dependent and no citable quotable interval was found. (2) Rare
  androgen-, estrogen- and mixed-steroid-secreting adenomas are noted in the
  literature but are not modelled as subtypes, because marked sex-steroid excess
  should raise suspicion of carcinoma rather than adenoma. (3) Bilateral adrenal
  hyperplasia (idiopathic hyperaldosteronism) is the differential that adrenal vein
  sampling exists to resolve and is discussed in the Adrenal Vein Sampling
  diagnosis entry, but is not curated as a structured differential_diagnoses item
  because MONDO has no distinct term for it separate from primary aldosteronism
  itself. (4) Metabolic alkalosis, a recognised accompaniment of marked
  hypokalaemic mineralocorticoid excess, was removed during review: the only
  cached source for it was a germline PASNA case with no adrenal adenoma, and no
  adenoma-specific citable statement was found. (5) No `conforms_to` link is
  declared to `osteoporosis_bone_resorption`; glucocorticoid-induced osteoporosis
  is a plausible conformer but the module's node-level expectations were not
  checked against this entry. (6) `clinical_trials:` is absent; the six NCTs
  surfaced by deep research are all observational or diagnostic rather than
  interventional.

📚

References & Deep Research

References

PMID:37318239

European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors.

No top-level findings curated for this source.

PMID:35288842

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors.

No top-level findings curated for this source.

Deep Research

Falcon ▸

Adrenocortical Adenoma: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 33 citations 2026-08-01T06:46:45.348968

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)

domain	core finding	quantitative data/clinical threshold	suggested ontology terms
Disease identity	Adrenocortical adenoma (ACA) is a benign neoplasm of the adrenal cortex; in practice, many ACAs are detected as adrenal incidentalomas on imaging done for unrelated reasons. Distinguish disease-level entity (ACA) from imaging presentation (adrenal incidentaloma). (kim2024molecularandgenetics pages 4-7, yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)	Adrenal incidentaloma prevalence in imaging studies: 1–5%; older guideline summary: average 2% overall, rising to 4% in middle age and 10% in elderly. (yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)	MONDO: adrenocortical adenoma [suggested, ID not source-validated]; MeSH: Adrenocortical Adenoma [suggested]; UBERON: adrenal gland [suggested: UBERON:0002369]; NCIT: Adrenal Cortex Adenoma [suggested]
Functional subtypes	Functional ACAs include cortisol-producing adenoma (CPA; overt Cushing syndrome or mild autonomous cortisol secretion/MACS), aldosterone-producing adenoma (APA), and more rarely mixed steroid-secreting tumors; many lesions are nonfunctioning. (kim2024molecularandgenetics pages 4-7, yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)	Japanese survey proportions among incidentalomas: 75% benign, 25% functional; 10.5% cortisol-producing, 5.1% aldosterone-producing, 8.5% pheochromocytoma. Older guideline summary: ~80% nonfunctional benign adenomas; ~12% cortisol-secreting, 2.5% aldosterone-secreting, 7% pheochromocytoma, 8% carcinoma. (yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)	HPO: Hypercortisolism [suggested: HP:0001578]; Hyperaldosteronism [suggested: HP:0000848]; Hypertension [suggested: HP:0000822]; Hypokalemia [suggested: HP:0002900]
Cortisol genetics	CPA/MACS are strongly linked to cAMP/PKA pathway activation. PRKACA hotspot mutations are major drivers of cortisol-producing adenomas; GNAS is enriched in subclinical/MACS phenotypes; CTNNB1 also contributes in a subset. (kim2024molecularandgenetics pages 21-22, kim2024molecularandgenetics pages 9-11)	PRKACA mutations reported in 35–66% of CPA cases; GNAS mutations reported as most frequent in subclinical Cushing’s (~70% in the cited review summary); CTNNB1 accounts for ~23% of total CPA in the cited review summary. (kim2024molecularandgenetics pages 9-11)	HGNC/genes [all suggested]: PRKACA, GNAS, CTNNB1; GO: cAMP-dependent protein kinase activity [suggested]; GO: Wnt signaling pathway [suggested]; CL: adrenal cortex cell [suggested]
Aldosterone genetics	APA is driven by mutually exclusive somatic mutations in ion channel/pump genes causing membrane depolarization, calcium influx/signaling, aldosterone excess, and tumor growth in zona glomerulosa-lineage cells. Recurrently implicated genes include KCNJ5, CACNA1D, ATP1A1, ATP2B3, CACNA1H, and CLCN2; CTNNB1 activation occurs in a minority but β-catenin activation is broader. (kim2024molecularandgenetics pages 22-23, sousa2022colocalizationofwntβcatenin pages 18-23, leo2024molecularpathologyof pages 17-18)	KCNJ5 mutations account for ~40% of APAs and are especially associated with younger female patients; CTNNB1 mutations occur in ~5% of APAs, while β-catenin activation is present in the majority. Somatic CLCN2 variants were identified in 2/115 APAs (1.74%) in cited primary data referenced by the review set. (sousa2022colocalizationofwntβcatenin pages 18-23, leo2024molecularpathologyof pages 17-18)	HGNC/genes [all suggested]: KCNJ5, CACNA1D, ATP1A1, ATP2B3, CACNA1H, CLCN2, CTNNB1; GO: calcium ion transport [suggested]; GO: aldosterone biosynthetic process [suggested]; CL: zona glomerulosa cell [suggested]
Imaging	A homogeneous adrenal mass with low attenuation on non-contrast CT is strongly suggestive of benign adenoma. Indeterminate lesions require additional imaging rather than size-only management. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3)	Benign criterion: homogeneous mass with ≤10 Hounsfield units (HU) on unenhanced CT, with no further follow-up required regardless of size per 2023 ESE update summary. Indeterminate: 11–20 HU; growth concerning on follow-up if >20% and at least ≥5 mm increase in maximum diameter. (park2023recentupdateson pages 5-6)	RadLex/non-ontology note: unenhanced adrenal CT [suggested]; UBERON: adrenal gland [suggested: UBERON:0002369]; NCIT: Computed Tomography of Abdomen [suggested]
Hormonal tests	Standard hormonal work-up aims to detect cortisol autonomy, primary aldosteronism, and pheochromocytoma when clinically indicated. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3, lee2017clinicalguidelinesfor pages 1-2)	1-mg overnight dexamethasone suppression: post-DST cortisol >50 nmol/L (>1.8 μg/dL) supports MACS; screening performance in one review summary: sensitivity 98.6%, specificity 90.6%. Plasma aldosterone-to-renin ratio: sensitivity 97%, specificity 80% for primary aldosteronism. Fractionated plasma-free metanephrines: sensitivity 95.7%, specificity 97.3% for pheochromocytoma. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3)	LOINC-related tests [all suggested]: serum cortisol after dexamethasone; aldosterone/renin ratio; plasma free metanephrines; HPO: Elevated serum cortisol [suggested], Elevated aldosterone level [suggested]
Treatment	Management depends on function and malignancy risk. Benign hormone-secreting tumors are typically treated with adrenalectomy; benign-appearing nonfunctioning lesions may be observed. Multidisciplinary review and experienced/high-volume surgeons are recommended. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3)	Minimally invasive adrenalectomy preferred for benign hormone-secreting tumors and suspicious masses ≤6 cm without invasion; recommended surgeon volume ≥12 adrenalectomies/year; perioperative glucocorticoid coverage advised for MACS patients undergoing surgery. (park2023recentupdateson pages 5-6)	NCIT [all suggested]: Adrenalectomy, Laparoscopic Adrenalectomy, Glucocorticoid Replacement Therapy, Active Surveillance
Prognosis	ACA prognosis is generally favorable because lesions are benign, but morbidity depends on hormonal excess and cardiovascular/metabolic complications rather than local tumor behavior. Functional disease requires correct diagnosis and perioperative management to avoid adrenal insufficiency or cardiovascular events. (yoshida2024diagnosisandmanagement pages 1-3)	No disease-specific ACA survival statistic was established in gathered evidence; prognostic concern is driven by cortisol or aldosterone excess comorbidities and by radiologic suspicion for non-adenoma pathology. (park2023recentupdateson pages 5-6, yoshida2024diagnosisandmanagement pages 1-3)	HPO: Cardiovascular abnormality [suggested], Adrenal insufficiency [suggested: HP:0000846]; NCIT: Cardiovascular Complication [suggested]

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:

CPA: constitutive cAMP–protein kinase A signaling, especially activating PRKACA variants; GNAS and CTNNB1 alterations occur in additional subsets.
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)
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

Subtype	Gene/pathway	Functional consequence
CPA	PRKACA, usually activating hotspot changes around p.Leu206	Impaired regulatory-subunit binding; constitutive catalytic PKA activity and CREB signaling
CPA/MACS	GNAS	Activating Gαs signaling, increased cAMP and PKA activity
CPA/NFA/APA subset	CTNNB1	Stabilized β-catenin and canonical Wnt transcription
APA	KCNJ5	Loss of potassium-channel selectivity, sodium entry, depolarization, calcium influx
APA	CACNA1D/CACNA1H	Increased voltage-gated calcium entry
APA	ATP1A1/ATP2B3	Abnormal ion gradients/depolarization and calcium signaling
APA	CLCN2	Altered chloride conductance and depolarization

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

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.
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.
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

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)
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)
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)
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)
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)
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)
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

(park2023recentupdateson pages 5-6): Seung Shin Park and Jung Hee Kim. Recent updates on the management of adrenal incidentalomas. Endocrinology and Metabolism, 38:373-380, Aug 2023. URL: https://doi.org/10.3803/enm.2023.1779, doi:10.3803/enm.2023.1779. This article has 43 citations and is from a peer-reviewed journal.
(kim2024molecularandgenetics pages 4-7): Sanggu Kim, Preeti Kumari Chaudhary, and Soochong Kim. Molecular and genetics perspectives on primary adrenocortical hyperfunction disorders. International Journal of Molecular Sciences, 25:11341, Oct 2024. URL: https://doi.org/10.3390/ijms252111341, doi:10.3390/ijms252111341. This article has 6 citations.
(yoshida2024diagnosisandmanagement pages 1-3): Yusaku Yoshida, Kiyomi Horiuchi, Michio Otsuki, and Takahiro Okamoto. Diagnosis and management of adrenal incidentaloma: use of clinical judgment and evidence in dialog with the patient. Surgery Today, 54:1417-1427, Dec 2024. URL: https://doi.org/10.1007/s00595-023-02781-y, doi:10.1007/s00595-023-02781-y. This article has 13 citations and is from a peer-reviewed journal.
(lee2017clinicalguidelinesfor pages 1-2): Jung-Min Lee, Mee Kyoung Kim, Seung-Hyun Ko, Jung-Min Koh, Bo-Yeon Kim, Sang Wan Kim, Soo-Kyung Kim, Hae Jin Kim, Ohk-Hyun Ryu, Juri Park, Jung Soo Lim, Seong Yeon Kim, Young Kee Shong, and Soon Jib Yoo. Clinical guidelines for the management of adrenal incidentaloma. Endocrinology and Metabolism, 32:200-218, Jun 2017. URL: https://doi.org/10.3803/enm.2017.32.2.200, doi:10.3803/enm.2017.32.2.200. This article has 189 citations and is from a peer-reviewed journal.
(kim2024molecularandgenetics pages 21-22): Sanggu Kim, Preeti Kumari Chaudhary, and Soochong Kim. Molecular and genetics perspectives on primary adrenocortical hyperfunction disorders. International Journal of Molecular Sciences, 25:11341, Oct 2024. URL: https://doi.org/10.3390/ijms252111341, doi:10.3390/ijms252111341. This article has 6 citations.
(kim2024molecularandgenetics pages 9-11): Sanggu Kim, Preeti Kumari Chaudhary, and Soochong Kim. Molecular and genetics perspectives on primary adrenocortical hyperfunction disorders. International Journal of Molecular Sciences, 25:11341, Oct 2024. URL: https://doi.org/10.3390/ijms252111341, doi:10.3390/ijms252111341. This article has 6 citations.
(kim2024molecularandgenetics pages 22-23): Sanggu Kim, Preeti Kumari Chaudhary, and Soochong Kim. Molecular and genetics perspectives on primary adrenocortical hyperfunction disorders. International Journal of Molecular Sciences, 25:11341, Oct 2024. URL: https://doi.org/10.3390/ijms252111341, doi:10.3390/ijms252111341. This article has 6 citations.
(sousa2022colocalizationofwntβcatenin pages 18-23): Kelly De Sousa, Alaa B Abdellatif, Isabelle Giscos-Douriez, Tchao Meatchi, Laurence Amar, Fabio L Fernandes-Rosa, Sheerazed Boulkroun, and Maria-Christina Zennaro. Colocalization of wnt/β-catenin and acth signaling pathways and paracrine regulation in aldosterone-producing adenoma. The Journal of Clinical Endocrinology & Metabolism, 107:419-434, Sep 2022. URL: https://doi.org/10.1210/clinem/dgab707, doi:10.1210/clinem/dgab707. This article has 19 citations.
(leo2024molecularpathologyof pages 17-18): Antonio De Leo, Martina Ruscelli, Thais Maloberti, Sara Coluccelli, Andrea Repaci, Dario de Biase, and Giovanni Tallini. Molecular pathology of endocrine gland tumors: genetic alterations and clinicopathologic relevance. Virchows Archiv, 484:289-319, Dec 2024. URL: https://doi.org/10.1007/s00428-023-03713-4, doi:10.1007/s00428-023-03713-4. This article has 8 citations and is from a peer-reviewed journal.
(bonnetserrano2018geneticsoftumors pages 4-6): Fidéline Bonnet-Serrano and Jérôme Bertherat. Genetics of tumors of the adrenal cortex. Endocrine-Related Cancer, 25:R131-R152, Mar 2018. URL: https://doi.org/10.1530/erc-17-0361, doi:10.1530/erc-17-0361. This article has 81 citations and is from a domain leading peer-reviewed journal.
(sousa2022colocalizationofwntβcatenin pages 23-25): Kelly De Sousa, Alaa B Abdellatif, Isabelle Giscos-Douriez, Tchao Meatchi, Laurence Amar, Fabio L Fernandes-Rosa, Sheerazed Boulkroun, and Maria-Christina Zennaro. Colocalization of wnt/β-catenin and acth signaling pathways and paracrine regulation in aldosterone-producing adenoma. The Journal of Clinical Endocrinology & Metabolism, 107:419-434, Sep 2022. URL: https://doi.org/10.1210/clinem/dgab707, doi:10.1210/clinem/dgab707. This article has 19 citations.

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References & Deep Research

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Adrenocortical Adenoma: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and scope

Identifiers and synonyms

2. Etiology

Causal factors

Genetic risk and predisposition

Demographic and environmental risk

Protective factors and gene–environment interactions

3. Phenotypes

Cortisol excess

Aldosterone excess

Mass effects and mixed secretion

Quality of life

4. Genetic and molecular information

Principal somatic drivers

Variant interpretation

Modifiers, epigenetics, and chromosomal change

5. Environmental information

6. Mechanism and pathophysiology

CPA causal chain

APA causal chain

Wnt/β-catenin and microenvironment

Omics and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Imaging

Hormonal evaluation

Localization and pathology

Differential diagnosis

Genetic and omics testing

Screening

11. Outcome and prognosis

12. Treatment

Nonfunctioning benign ACA

Functional ACA

Current research applications

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse models

Cellular systems

Organoids, spheroids, xenografts, and spatial models

Recent developments and authoritative interpretation

Key sources and dates

Artifacts