EndocrinologyTier 2Disease (DEADMAN)

Adrenal gland disorders - adrenal incidentaloma

Description

Differential

Lesion	Share	Clue
Non-functioning adenoma	~70-80%	Homogeneous, <=10 HU, small
Mild autonomous cortisol secretion (MACS)	~5-15%	Commonest functional abnormality
Phaeochromocytoma	~5%	High attenuation, cystic/haemorrhagic, T2 bright
Aldosterone-producing adenoma	~1-5%	Hypertension +/- hypokalaemia
Adrenocortical carcinoma	~2-5%	Large, heterogeneous, irregular, high HU
Metastasis	~1-5% (higher with known cancer)	Bilateral, known primary
Myelolipoma	~5%	*Macroscopic fat - pathognomonic, no workup needed*
Other		Cyst, haemorrhage, ganglioneuroma, infection, lymphoma

Bilateral masses: metastases, congenital adrenal hyperplasia, bilateral macronodular hyperplasia, haemorrhage, infiltration (TB, lymphoma, amyloid), bilateral phaeochromocytoma

Found in ~3-5% of abdominal CTs, rising to ~10% over age 70
Prevalence rises with imaging use - most common "endocrine disease" a physician will encounter
Adrenocortical carcinoma incidence ~1-2/million/yr; risk of malignancy rises steeply with size

Most are clonal benign cortical adenomas with somatic mutations in the PKA pathway (PRKACA) for cortisol-secreting lesions, or KCNJ5, CACNA1D, ATP1A1, ATP2B3 for aldosterone-producing lesions
Mild autonomous cortisol secretion is ACTH-independent, mild, and continuous
- Suppressed ACTH and DHEAS; contralateral gland atrophies
- Not "subclinical" in effect - it is associated with hypertension, T2DM, obesity, osteoporosis (vertebral fracture) and excess cardiovascular mortality
Adrenocortical carcinoma - TP53 (Li-Fraumeni), IGF2 overexpression, beta-catenin/CTNNB1; often secretes cortisol and androgens
Syndromic: MEN1, Li-Fraumeni, Beckwith-Wiedemann, familial adenomatous polyposis, Carney complex, MEN2/VHL/NF1/SDHx (phaeochromocytoma)

1. Is it malignant? - imaging phenotype

Non-contrast CT attenuation is the single most useful measure
- *<=10 HU + homogeneous = lipid-rich adenoma. Benign. No further imaging follow-up, regardless of size*
- >10 HU -> dedicated adrenal protocol CT with washout
  - Absolute washout >60% (or relative >40%) at 10-15 min -> lipid-poor adenoma
  - Slow washout, >25 HU -> carcinoma, phaeochromocytoma or metastasis
Chemical-shift MRI - signal drop-out on out-of-phase imaging = intracellular lipid = adenoma
Macroscopic fat (negative HU) = myelolipoma - stop
Features of malignancy: size >4 cm, irregular margin, heterogeneity, necrosis/calcification, local invasion, growth >5 mm/yr, high HU
FDG-PET where the distinction remains unclear (especially with a known extra-adrenal primary)
*Never biopsy an adrenal mass until phaeochromocytoma has been excluded biochemically* - and biopsy only where the result changes management (suspected metastasis, lymphoma, infection)

2. Is it functioning? - test everyone

1 mg overnight dexamethasone suppression test in every patient
- Post-dexamethasone cortisol <=50 nmol/L -> autonomous secretion excluded
- >50 nmol/L without Cushingoid features -> mild autonomous cortisol secretion (MACS)
- >138 nmol/L -> overt autonomous secretion, more likely to have comorbidity
- False positives: oral oestrogen, CYP3A4 inducers, malabsorption, non-adherence, shift work. Confirm with ACTH (suppressed) and DHEAS (low)
- May be omitted in the frail with limited life expectancy
Plasma free metanephrines or 24h urinary fractionated metanephrines - unless the lesion is <=10 HU and homogeneous
Aldosterone:renin ratio - only if hypertensive or hypokalaemic
DHEAS and androgens (testosterone, 17-OHP, androstenedione) - only if virilisation or a suspicion of carcinoma
Oestradiol in men and postmenopausal women if feminisation

Surgery

Adrenalectomy if
- Overt hormone excess - Cushing syndrome, phaeochromocytoma, aldosteronoma (unilateral, after lateralisation on AVS)
- Suspected adrenocortical carcinoma - imaging phenotype, size >4 cm with worrying features, growth
- Open, en-bloc resection by a specialist centre if carcinoma is suspected - laparoscopy risks tumour spillage
Pre-operative alpha blockade for any phaeochromocytoma
Peri-operative and post-operative glucocorticoid cover after removing a cortisol-secreting lesion - the contralateral gland is suppressed and may take months to recover

Mild autonomous cortisol secretion - the judgement call

*Manage the comorbidity, not the number*
Assess for and actively treat: hypertension, T2DM, dyslipidaemia, obesity, osteoporosis (DEXA + vertebral imaging)
Consider adrenalectomy if the patient is younger and has cortisol-attributable comorbidity that is progressing or hard to control
Otherwise clinical follow-up for the development of these comorbidities - not repeated hormonal testing for its own sake

Non-functioning, benign imaging phenotype

*No further imaging and no repeated hormonal testing* if <=10 HU, homogeneous and non-functioning
Indeterminate imaging phenotype not resected -> repeat non-contrast CT/MRI at 6-12 months; discharge if unchanged
This is a major change from the older practice of serial annual imaging and annual biochemistry for everyone

Bilateral lesions

Test for CAH (17-OHP), adrenal insufficiency (Synacthen - infiltrative/haemorrhagic disease), and consider metastases

MACS -> hypertension, T2DM, obesity, dyslipidaemia, vertebral fracture, excess cardiovascular mortality
Adrenocortical carcinoma -> Li-Fraumeni (TP53), Beckwith-Wiedemann, MEN1, FAP, Lynch
Phaeochromocytoma -> MEN2, VHL, NF1, SDHx (germline testing in all)
Myelolipoma -> long-standing untreated congenital adrenal hyperplasia
Bilateral adrenal enlargement -> TB, histoplasmosis, lymphoma, metastases, amyloid, haemorrhage (APS, meningococcaemia, anticoagulation)

Most adenomas do not grow - <10% enlarge >1 cm over follow-up
Progression from non-functioning to functioning is uncommon (<5% at 5 years) - the basis for abandoning routine repeat biochemistry
MACS is usually stable, but the associated cardiometabolic and skeletal burden accumulates
Adrenocortical carcinoma has a poor prognosis - 5-year survival ~35-50% for localised disease, <15% metastatic; mitotane +/- EDP chemotherapy
A newly discovered mass in a patient with known malignancy is a metastasis in ~50-75% of cases
After removal of a cortisol-secreting adenoma: adrenal insufficiency for 6-18 months - taper slowly and give sick day rules

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