Adrenal

Adrenal Gland

• Cortex → GFR
  • G: Aldosterone
  • F: Cortisol
  • R: Androgens
• Medulla → Catecholamines

Most abundant cortical product: Androgens

Daily output from the adrenal cortex

Class	Output
Mineralocorticoids	100–150 µg/day
Glucocorticoids	10–20 mg/day
Androgens	> 20 mg/day

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Initial Workup — Any Adrenal Case

• CBC
• Renal profile (K, Na)
• 24-hour urine free cortisol — also send urine creatinine to validate an adequate sample
• LD-DST or late-night salivary cortisol
• Serum metanephrines and 24-hour urinary metanephrines
• Plasma renin activity (PRA) + plasma aldosterone concentration (PAC) + ARR — if hypertensive or hypokalaemic
• Urinalysis
• PSA — in a male over 40
• CT adrenal protocol — the gold standard imaging

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Hypercortisolism / Cushing's Syndrome

Causes (3 groups)

Category	%	Notes
Exogenous	most common in Western world	iatrogenic steroid use
ACTH-dependent (endogenous)	85%	Cushing disease (pituitary, 80%), ectopic ACTH (bronchial carcinoid, SCLC), ectopic CRH (rare)
ACTH-independent (endogenous)	15%	adrenal pathology — adenoma, ACC, bilateral hyperplasia

Breakdown by individual cause

Cause	%
Exogenous steroids	The most common cause overall
Cushing's disease (pituitary adenoma)	70–80%
Ectopic ACTH	10% (atypical presentation)
Ectopic CRH	< 1%
Adrenal adenoma	10%
Adrenal carcinoma	8%
AIMAH — ACTH-independent macronodular adrenal hyperplasia	< 1%
PPNAD — primary pigmented nodular adrenocortical disease	< 1%

Sources of ectopic ACTH — 10% of Cushing's syndrome, and nearly always malignant

Source	%
Bronchial carcinoid	25%
Small cell lung carcinoma	11%
Medullary thyroid carcinoma	8%
Phaeochromocytoma	3%

Clinical Features

• Central obesity, moon facies, buffalo hump, facial plethora
• Striae, easy bruising, proximal muscle weakness, hirsutism
• HTN, dyslipidemia, insulin resistance
• Urological:
  • ED + low libido (hypogonadotropic hypogonadism — common in men)
  • Urolithiasis in up to 50% ( most common presentation )

By prevalence

Prevalence	Features
90–100%	Central obesity · rounded "moon" face · facial plethora · decreased libido
70–90%	Purple striae · menstrual disturbances · hirsutism · ED · hypertension
50–70%	Muscle weakness · buffalo hump · body bruising · glucose intolerance/diabetes · osteopenia/osteoporosis · emotional lability/depression
20–50%	Headache · backache · limb oedema · recurrent infections · hypokalaemic alkalosis · nephrolithiasis
0–20%	Acne · alopecia

• Cortisol is highest in the morning, with a nadir around 2300h — small changes in this rhythm are considered pathologic
• Ectopic ACTH does NOT present with the typical features — instead expect cachexia, hypertension, hypokalaemic alkalosis and skin pigmentation
• Children present with weight gain and growth retardation
• Virilisation in a female or feminisation in a male should raise the question of adrenal carcinoma

Diagnosis (Screening — 3 tests)

1. Low-dose dexamethasone suppression test (LD-DST)

• 1 mg dexamethasone at 11 PM–12 AM, then measure plasma cortisol at 8–9 AM
• Cushing's if cortisol remains elevated (> 140 nmol/L)
• Not affected by GFR

2. Late-night salivary cortisol

• Measured at 11 PM–12 AM
• Persistent elevation (> 145 ng/mL) may signal loss of diurnal variance
• Affected by smoking (stop 24h before), altered sleep patterns, depression, chronic illness

3. 24-hour urinary free cortisol

• Also order 24-hour urine creatinine to confirm the specimen is adequate
• Preferred in pregnancy — cut-off is 2–3× above normal, because of pregnancy hormonal changes
• Affected by GFR
• Not sensitive enough for subclinical Cushing's — not recommended in incidentalomas

4. Midnight plasma cortisol

• 24-hour UFC has been REPLACED by LD-DST or late-night salivary cortisol as the initial test for incidentalomas

Localising the Source

→ Confirm hypercortisolism → measure serum ACTH

• ACTH < 5 pg/mL → ACTH-independent → adrenal source → CT abdomen
  • Normal adrenals → exogenous steroids
• ACTH > 50 pg/mL → ACTH-dependent — Cushing's disease, ectopic ACTH or CRH syndrome → brain MRI (may be false negative); pituitary vs ectopic ( need further testing )

High-Dose Dexamethasone Test

• Inferior petrosal sinus sampling is the gold standard — compares petrosal sinus ACTH to peripheral ACTH. It is wise to do the brain MRI first, though it may be false negative
• High-dose 8 mg DST is of limited value and is not routinely used
  • >50% suppression → Pituitary adenoma
  • <50% suppression → Ectopic ACTH
• Raised ketosteroid and DHEA levels make ectopic ACTH LESS likely

Management

• ACTH-independent → ipsilateral adrenalectomy

• Cushing disease → trans-sphenoidal resection (preferred first-line)

  • Failed pituitary surgery → bilateral adrenalectomy + lifelong gluco-/mineralocorticoid replacement

• Ectopic ACTH → resect primary (only 10% resectable); unresectable → bilateral adrenalectomy

• Bridging meds (enzyme blockers): mitotane, metyrapone, ketoconazole, aminoglutethimide, etomidate, trilostane

• Cushing's disease → trans-sphenoidal resection: 60–80% cure rate, 25% relapse

• Bilateral adrenalectomy only after at least one failed attempt to treat the primary tumour — then lifelong mineralocorticoid and glucocorticoid replacement

• Exogenous steroids → gradual wean, to avoid steroid withdrawal syndrome

• AIMAH or PPNAD → bilateral adrenalectomy with lifelong replacement

Nelson's syndrome

• Progressive growth of the pituitary adenoma after bilateral adrenalectomy
• May cause optic chiasm compression, oculomotor deficiencies, and rarely raised ICP
• Occurs in 8–29% of patients
• Can be prevented by prophylactic pituitary radiotherapy — controversial

Cushing's syndrome in pregnancy

• Maternal and fetal morbidity are both reduced by treatment
• The adenoma can be removed surgically during pregnancy — wait until the second trimester
• Medical therapy: metyrapone

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Hyperaldosteronism

RAAS Recap

• Renin triggers: low perfusion, ↑ renal sympathetic activity, low Na at macula densa
• Angiotensin II = most potent stimulator of aldosterone
• Other stimulators: ↑ K⁺, ↓ Na⁺, ACTH (weak)
• Aldosterone → ↑ Na/H₂O reabsorption + ↑ K⁺ secretion in distal nephron

RAAS Pathway

Renin → Liver → Angiotensin I → Lung (ACE) → Angiotensin II → Adrenal → Aldosterone

Classification

	Renin	Aldosterone
Primary	suppressed	↑
Secondary	↑ (driver)	↑

• Secondary causes: renal artery stenosis, hypovolemia (CHF/cirrhosis), FMD, JG cell tumour

Causes of primary hyperaldosteronism, by frequency

Cause	%
Bilateral hyperplasia	60%
Adenoma	35%
Unilateral adrenal hyperplasia	2%
Carcinoma	< 1%
Ectopic aldosterone-producing tumour (e.g. ovarian)	< 1%
Familial hyperaldosteronism	< 1%

Juxtaglomerular cell tumour (reninoma, JGCT)

• Arises from the juxtaglomerular cells of the kidney
• The hallmark is overproduction of renin, so patients get symptoms of hyperaldosteronism — polydipsia, polyuria, myalgias, double vision, headaches
• On examination: hypertension, hypokalaemia and proteinuria

Finding	Points to
Suppressed renin	Primary hyperaldosteronism
Elevated renin	Secondary hyperaldosteronism, or a reninoma

• Addison's disease is the ONLY one of these with HYPERkalaemia. All the rest run hypokalaemic.

Primary Hyperaldosteronism

• Normokalemia in 50% (only 9–37% hypokalemic at diagnosis)
• No hypernatremia (Na reabsorption iso-osmotic with water)
• A low renin is more common in primary hyperaldosteronism than a low potassium

Findings are driven by increased total body sodium and a deficit in total body potassium.

From the raised sodium

• Hypertension, but NO OEDEMA — because of the renal escape phenomenon

From the low potassium

• Nocturia · paraesthesia/paralysis · urinary frequency · muscle weakness · polydipsia
• Frontal headache · cramps and tetany · visual disturbances · mild metabolic alkalosis

The mineralocorticoid "renal escape" phenomenon

• As sodium accumulates, the increased extracellular sodium is accompanied by water
• After a gain of about 1.5 kg of excess extracellular fluid, the kidneys stop reabsorbing sodium
• This maintains sodium balance — and is why patients with primary hyperaldosteronism do NOT have oedema

Screening Indications (9)

• Unexplained hypokalemia (spontaneous or diuretic-induced)
• HTN + hypokalemia
• Adrenal incidentaloma + HTN
• Resistant HTN (≥3 agents)
• Early-onset HTN (<20 yrs) or stroke (<50 yrs)
• Severe HTN (≥160/110)
• Considering secondary HTN (pheo, renovascular)
• End-organ damage disproportionate to HTN
• Family hx of primary aldosteronism

Diagnosis

Screening tests, in order

1. Serum electrolytes for hypokalaemia — most patients are normokalaemic, so this is not diagnostic
2. PRA or direct renin concentration (DRC) → Conn's if suppressed
3. PAC (8–10 AM) → Conn's if > 15 ng/dL
4. ARR (8–10 AM) → Conn's if > 30 — the test of choice

Before screening — which drugs to stop

Drug	Action
Mineralocorticoid receptor antagonists (spironolactone) and K-sparing diuretics (amiloride)	Stop 6 weeks before (some sources say at least 4)
Beta-blockers	Stop — they cause a false-positive rise in ARR, though aldosterone itself stays normal
CCBs and ACE inhibitors	No need to stop

Confirmatory tests

• The fludrocortisone suppression test has been replaced by oral sodium loading and IV saline infusion, because of the risk of hypertension and hypokalaemia

Oral sodium loading test

• High-sodium diet for 3 days, then a 24-hour urine for aldosterone, sodium and creatinine
• Diagnostic when 24-hour aldosterone > 12 µg/day

IV saline infusion test

• 2 L normal saline IV over 4 hours in the recumbent position, in the morning after an overnight fast
• Plasma aldosterone > 5 ng/dL is diagnostic; > 10 ng/dL suggests an aldosterone-producing adenoma

Captopril suppression test (25–50 mg)

• If the RAAS suppresses → normal

• PAC > 15 ng/dL → hyperaldosteronism

• Consider genetic testing if the patient is under 20, or has a family history of the same condition or of CVA

• Imaging: cross-sectional CT — adenoma = unilateral, <10 HU, non-enhancing

• Adrenal vein sampling (AVS) required for lateralisation

  • Exceptions (skip AVS):
    • <40 yrs with clear unilateral adenoma + normal contralateral
    • Suspected ACC

When to Do Adrenal Venous Sampling?

• Bilateral
• Micronodular < 1cm
• Normal adrenal imaging
• Unilateral Adrenal nodule >1 cm AND age more than 40 years

Preparation

• 1 hour of recumbency · correct hypokalaemia · stop antihypertensives · perform in the morning after an overnight fast

Procedure

• Femoral access; three samples — right adrenal vein, left adrenal vein, and infrarenal IVC — each for cortisol and aldosterone
• Lateralisation ratio = (A_dominant / C_dominant) ÷ (A_nondominant / C_nondominant)
• Aldosterone secretion is lateralised if the ratio is greater than 2:1 to 4:1
• Done properly, AVS has 95% sensitivity and 100% specificity
• If inconclusive, alternatives are nuclear scintigraphy, the postural stimulation test, or measurement of cortisol metabolites

Management

→ Surgically correctable (4): adenoma, unilateral hyperplasia, ectopic tumour, ACC

→ Not surgically correctable (4): bilateral hyperplasia, familial types I/II/III

• Surgical: laparoscopic adrenalectomy (small tumours)
  • Open if ACC suspected
• Medical: spironolactone or eplerenone (MRA) — start 1–2 wks pre-op, especially if on long-term ACEi

Bilateral adrenal hyperplasia — an MRA is the key to treatment

• Spironolactone is first line: 50–300 mg/day
• Side effects — painful gynecomastia, ED, decreased libido, menstrual irregularities, hyperkalaemia, hyponatraemia, dizziness, dry skin

Predictors of persistent hypertension needing medication after laparoscopic adrenalectomy

Over 50% will still need antihypertensives. Predictors:

• Age > 50 · male sex · high BMI

• Pre-operative ARR · more than 2 antihypertensive agents

• First-degree relative with hypertension

• Long duration of hypertension · renal insufficiency · degree of cardiac remodelling

• After adrenalectomy for an aldosterone-producing adenoma, watch for post-operative hypotension and hypoglycaemia

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Pheochromocytoma

Background

• Chromaffin cell tumour of adrenal medulla
• ~⅓ familial | 1–25% extra-adrenal (= paraganglioma)
• Extra-adrenal sites: Organ of Zuckerkandl (aortic bifurcation), sympathetic chain, perivesical
• Malignancy = clinical metastases only (no pathologic criteria)
• Rule of 10s (classic, imperfect): 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial, 10% paediatric

Hereditary Syndromes

Syndrome	Gene / Chromosome
MEN 2	RET, chromosome 10 (AD)
VHL (all types, type 2 more)	chromosome 3
NF1	chromosome 17
SDHB	chromosome 1
SDHD	chromosome 11 — maternal imprinting

• Familial pheos: nearly always bilateral, more often malignant
• Offer genetic testing for malignant, bilateral or familial disease

Clinical Features

• Classic triad: headache, episodic sweating, tachycardia
• Other: anxiety, palpitations, pallor, abdominal/chest pain, tremor, weight loss, flushing
• ~20% of patients are asymptomatic
• Paroxysmal hypertension — the classic presenting sign — occurs in only 30–50%

Manifestation	Frequency
Headache	60–90%
Sweating	55–75%
Palpitations	50–70%
Sustained hypertension	50–60%
Pallor	40–45%
Hyperglycaemia	40%
Nausea · weight loss · tiredness · psychological symptoms (anxiety, panic)	20–40%
Paroxysmal hypertension	30%
Flushing	10–20%
Orthostatic hypotension	10–50%

Labs

• Plasma free metanephrines — highest sensitivity (use if high index of suspicion)

  For screening ( high sensitivity )

• 24-hr urinary fractionated metanephrines + catecholamines

  For confirmatory ( high specificity )

• Hold before test:

  • Acetaminophen (5 days — cross-reactivity)
  • TCAs (1–2 weeks)
  • Phenoxybenzamine
  • Caffeine and nicotine also cause false-positive metanephrines

• Draw plasma free metanephrines with the patient SUPINE

• For 24-hour urinary fractionated metanephrines, verify normal renal function first

• Any abnormal result → refer to endocrinology for confirmatory testing. A completely normal result makes phaeochromocytoma extremely unlikely

• Urinary VMA has low sensitivity but high specificity — particularly useful in familial cases

• Clonidine suppression test — distinguishes pheo from essential HTN when catecholamines mildly ↑

  • Essential HTN → NE drops; pheo → no drop

Imaging

Modality	Finding
Unenhanced CT	>10 HU (mean ~35)
Contrast CT	Often >100 HU, washout <50%
MRI T2	High signal ("light bulb" sign — not specific or sensitive enough alone)
¹²³I-MIBG	NE analogue; high spec, low sens
¹⁸F-FDG PET	Gold standard for staging — superior to MIBG, especially for mets

• Functional imaging (MIBG/PET) can be omitted if solitary adrenal mass + biochemical pheo on cross-sectional imaging
• Do for tumours >5 cm to rule out mets pre-op
• MIBG is indicated when:
  1. There is a high index of suspicion but negative plasma or urine tests
  2. The patient has a syndrome associated with phaeochromocytoma — these are more likely to have extra-adrenal tumours

Pre-op Management (4 pillars)

• There is no role for observation in phaeochromocytoma — once diagnosed, management is surgical. Observation and biopsy are both inappropriate
• Blockade runs 7–14 days pre-op as an outpatient, then 1–2 days pre-op as an inpatient

1. Cardiology / anaesthesia / endocrinology consult + ECG + echo
2. IV volume repletion (most important; admit day before)
3. α-blockade THEN β-blockade
4. Monitored bed / ICU post-op

α-Blockade

• Phenoxybenzamine — irreversible non-selective α-blocker
  • Start 7–14 days pre-op
  • 10 mg BID → titrate by 10–20 mg q2–3 days → up to 1 mg/kg
  • Hold morning of surgery (prevents prolonged hypotension)
  • May cause reflex tachycardia → add β-blocker
• Doxazosin / prazosin / terazosin (selective α₁) — avoid need for β-blocker
• Phentolamine — short-acting α-blocker for acute crisis
• Metyrosine — if phenoxybenzamine fails (blocks tyrosine → L-dopa)

β-Blockade

• Never before α-blockade (unopposed α causes hypertensive crisis)
• Indications: SBP <100, tachycardia (true or reflex)
• Selective β₁ preferred: atenolol, metoprolol

Calcium Channel Blockers

• Alternative for normotensive patients with paroxysmal HTN
• 2 wks pre-op sufficient
• Amlodipine 10–20 mg daily · nicardipine 60–90 mg daily · nifedipine 30–90 mg daily · verapamil 180–540 mg daily

Catecholamine Synthesis Blockade — Metyrosine

• 250 mg PO bid or tid, increasing by 250–500 mg every 2–3 days
• Total 1.5–2 g/day is usually sufficient
• 500 mg PO on the night before surgery

Targets and Volume

• BP goal 120–130/80 mmHg seated
• Mild postural hypotension (SBP > 90) is ACCEPTABLE — it is a sign of appropriate blockade
• Intravascular volume restoration: IV fluids, with a 1–2 L bolus the night before surgery

In Children

• Phenoxybenzamine 0.2 mg/kg (max 10 mg) QID, increasing in 0.2 mg/kg increments

Intra-op + Post-op

• Ligate adrenal vein early + minimal tumour manipulation
• Thermal injury alone can trigger catecholamine release
• Notify anaesthesia at adrenal vein ligation
• Post-op: hypotension common (loss of tonic vasoconstriction)
• → Aggressive fluids + phenylephrine
• Watch for hypoglycaemia (rebound hyperinsulinaemia after α₂ withdrawal)
• ICU admit overnight

Follow-up

• Repeat metanephrines ~2 wks post-op
• Annual biochemical follow-up — lifelong
• 10-yr recurrence rate up to 16%
• Persistent HTN at 2–3 mo → recheck plasma metanephrines → MIBG if positive
• Obtain a post-operative CT to confirm complete gland removal

Special Scenarios

• Hereditary (MEN 2 / VHL) — low malignancy + high bilateral risk
  • → Partial cortical-sparing adrenalectomy (avoid lifelong replacement)
• Malignant pheo → surgical metastasectomy if resectable + α/β-blockade + metyrosine; palliative
  • Chemo if MIBG-negative or MIBG therapy failed
• Pregnancy (late term) → phenoxybenzamine until fetal maturity → C-section + tumour resection in one operation (no vaginal delivery)

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Adrenal Insufficiency

Classification

	Cause	Aldosterone	Skin
Primary (Addison's)	Autoimmune adrenalitis (Western world)	Deficient	Hyperpigmentation
Secondary	Pituitary/hypothalamic failure	Preserved (zona glomerulosa ACTH-independent)	Normal

Clinical

• Anorexia, abdominal pain, weakness, weight loss, fatigue
• Hypotension, salt craving
• Hyperpigmentation only in primary

Signs mapped to the missing hormone

Feature	Deficiency responsible
Fatigue, weakness, anorexia, weight loss	Glucocorticoid (± adrenal androgen)
Gastric pain, nausea, vomiting	Glucocorticoid + mineralocorticoid — more frequent in primary
Salt craving, dizziness, postural hypotension	Mineralocorticoid
Skin hyperpigmentation	Excess POMC-derived peptides — primary only
Alabaster-coloured pale skin	Deficiency of POMC-derived peptides — secondary only
Raised serum creatinine	Mineralocorticoid — primary only
Hyponatraemia	Mineralocorticoid + glucocorticoid (via SIADH)
Hyperkalaemia	Mineralocorticoid — primary only
Anaemia, lymphocytosis, eosinophilia	Glucocorticoid
Raised TSH	Glucocorticoid deficiency or autoimmune thyroid failure — primary only
Hypercalcaemia	Glucocorticoid — primary only
Hypoglycaemia	Glucocorticoid
Loss of axillary/pubic hair in women, absent adrenarche in children	Adrenal androgen
Dry, itchy skin; loss of libido (in women)	Adrenal androgen

Causes of acute adrenal crisis (4)

1. Withdrawal of exogenous steroids
2. Sepsis
3. Bilateral adrenal haemorrhage
4. Post-adrenalectomy state

Diagnosis

• Morning serum cortisol + ACTH (+ aldosterone/renin if primary suspected)
• Confirm: ACTH stimulation (cortrosyn) test
• Diagnostic triad — hyponatraemia, hyperkalaemia and azotaemia

Management

• Replace cortisol + mineralocorticoid (if primary)
  • Cortisol → hydrocortisone or cortisone acetate
  • Mineralocorticoid → fludrocortisone
• Post-op adrenal crisis:
  • At risk: prior contralateral nephrectomy + current contralateral renal/adrenal surgery
  • → Check old op notes + imaging for adrenal tissue
  • Treatment: 2 mg dexamethasone or 100 mg hydrocortisone

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Adrenal Cortical Carcinoma (ACC)

Background

• Avg 10–12 cm at presentation
• Most are functional — most common hormone secreted = cortisol, in 50–80% of functional tumours, producing Cushing's syndrome
• Feminisation of a male — testicular atrophy and gynecomastia — is highly suggestive of malignancy
• Li-Fraumeni = loss of TP53 · Beckwith-Wiedemann = raised IGF

Functional evaluation of an adrenal mass suspected to be ACC

Suspected hypersecretion	Tests
Glucocorticoid excess	LD-DST (or late-night salivary / 24-hour urine cortisol) · ACTH
Sexual steroids and precursors	DHEA-S · testosterone · 17-OH-progesterone · androstenedione · 17-OH-pregnenolone · 11-deoxycorticosterone · progesterone · estradiol (in men and postmenopausal women)
Catecholamine excess	Serum or urinary metanephrines
Mineralocorticoid excess	ARR — only in patients with hypertension or hypokalaemia

Genetic Syndromes (6)

• Li-Fraumeni
• Beckwith-Wiedemann
• Lynch
• Carney complex
• MEN-1
• McCune-Albright

Risk of Malignancy by Size

Size	Malignancy risk
<4 cm	5%
>4 cm	10%
>6 cm	25%

→ Resect masses >4–6 cm unless clearly benign

• The 4–6 cm band is the grey zone, with a malignancy rate of about 6%. Masses < 4 cm and non-functional can be safely observed; masses > 6 cm are malignant until proven otherwise. Most experts use 4 cm as the cut-off warranting resection, and any metabolically active adenoma should be resected

Imaging (CT — 5 features)

1. Size > 5 cm
2. Slow CT contrast washout
3. Invasion of adjacent structures
4. Heterogeneous, with necrosis and calcification
5. Irregular borders
6. High signal density on T2
7. CT enhancement > 10 HU (mean 39 HU) — compared with adenoma (mean 8 HU)
8. Heterogeneous with NO signal drop-out on "out-of-phase" T1 MRI

• Plain CT is the first-line imaging for an adrenal mass; CT adrenal protocol is the gold standard

MRI

• T1: isointense to liver/spleen
• T2: intermediate–high signal
• Marked gadolinium uptake

Biopsy

• Not recommended pre-op (seeding risk)
• Cannot reliably distinguish adenoma vs carcinoma histologically
• → Useful only for suspected metastasis to adrenal from known primary

Pathology — Modified Weiss (5)

• Necrosis
• Abnormal mitoses
• Cytoplasm (clear cells ≤25%)
• Capsular invasion
• Mitotic rate >5/50 HPF

→ Score = 2×(mitotic rate) + 2×(clear cells) + abnormal mitoses + necrosis + capsular invasion → ≥3 = malignant

Management

• Surgical resection = mainstay (open, no-touch technique)
• Recent guidelines favour open surgery if the tumour is > 6 cm or locally invasive
• In metastatic ACC, cytoreductive adrenalectomy is considered if > 90% of the disease can be removed — it helps alleviate tumour-related side effects
• Mitotane = most common chemotherapeutic agent
  • Inhibits P450scc, 11β-OHase, 18-OHase, 3β-HSD
  • An oral agent used in the adjuvant and metastatic settings
  • Steroid replacement is necessary during treatment
  • Side effects — GI upset, lethargy, depression, rash, raised LFTs, hypothyroidism, dyslipidaemia, feminisation, thrombocytopenia
  • As a single agent, response rate is up to 36%
  • Mitotane + etoposide + doxorubicin + cisplatin — response rate 49%
• Multimodal: surgery + RT + chemo

Follow-up

• Cross-sectional imaging every 3 months for 2–3 years, then every 6 months until year 5
• In functional tumours, follow the hormones — they can rise with recurrence or metastasis before anything appears radiologically

Prognosis

• Recurrence 60–80% despite resection
• Margin status = most important predictor of overall survival
• Other OS predictors: size, nodal status, mets

Adrenal Metastases

• >50% of newly discovered adrenal lesions in patients with prior malignancy = metastatic
• Still need metabolic workup
• Adrenal insufficiency only with bilateral + bulky (>4 cm) disease

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Benign Adrenal Tumours

Adenoma

• Most common primary adrenal tumour — it arises from the cortex; < 10 HU
• 93% metabolically silent
• Goal of workup → differentiate non-functional benign adenoma from functional or malignant lesion
• Non-functional + <4 cm → surveillance
• Functional → adrenalectomy

Myelolipoma

• Benign, metabolically silent, contains fat + bone marrow
• CT: −30 to −140 HU
• Usually asymptomatic, but some present with flank pain
• Resect only if symptomatic

Adrenal Cysts

• > 30 HU
• 4 types: pseudocyst, endothelial, epithelial, parasitic

Type	%
Endothelial (lymphangiomatous or angiomatous)	45%
Pseudocysts (e.g. post-haemorrhagic)	39%
Epithelial (true)	9%
Parasitic (echinococcal)	7%

• 7% of cysts associated with malignancy (all pseudocysts) — observe with caution
• If asymptomatic → observe. If > 5 cm, thick-walled, heterogeneous or symptomatic → adrenalectomy
• Routine endocrine workup mandatory despite usually benign

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Incidental Adrenal Mass

Definition

• Adrenal lesion >1 cm on imaging done for non-adrenal reasons

Workup

Labs (3):

• LD-DST or 24-hr urine cortisol → rule out hypercortisolism
• 24-hr urinary metanephrines/catecholamines → rule out pheo
• ARR → if hypertensive, rule out hyperaldosteronism

Imaging (1):

• Unenhanced CT first
  • <10 HU → adenoma (sens ~70%, spec 98%)
  • ≥10 HU → adrenal protocol CT with washout

Adrenal Washout CT (3 phases)

• Non-contrast → enhanced (1 min) → delayed (15 min)
• Absolute washout >60% = adenoma
  • (Enhanced − delayed) / (Enhanced − unenhanced) × 100
• Relative washout >40% = adenoma
  • (Enhanced − delayed) / Enhanced × 100
• If less than 60 or 40 need further evaluation

Pheo / Malignant Features on Imaging (5)

• Size >3 cm
• Heterogeneous texture
• ↑ vascularity
• Attenuation >10 HU unenhanced
• ↓ contrast washout at 10–15 min

MRI

• Chemical-shift useful for adenomas
• CT washout > chemical-shift MRI (gold standard)

Indications for Adrenalectomy:

• Size ≥4 cm (except myelolipoma)
  • >6 cm = malignant until proven otherwise
• Growth >1 cm on follow-up
• Any imaging suspicious for malignancy regardless of size
• Adrenal hyperfunction (functional adenoma, pheo, aldosteronoma, ACC)
• Symptomatic / large cyst or myelolipoma
• Isolated adrenal metastasis (multidisciplinary)
• During RCC surgery if:
  • Adrenal abnormal / obscured by large renal tumour
  • Vein thrombus to adrenal vein level

Adrenal Mass Algorithm (Traffic-Light System)

A. Imaging Feature

• Lipid-rich → Green
• Lipid-poor → Purple

B. Size

• <4 cm → Green
• ≥4 cm → Purple

C. Metabolic Work-up

• Silent → Green
• Subclinical → Purple
• Functional → Red

Management Rules

• All Green → No follow-up
• One Purple → Follow-up
• Two Purple OR One Red → Surgical resection

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Partial Adrenalectomy

• Total adrenalectomy = gold standard for functioning/malignant tumours
• Indications for partial (3):
  • Bilateral adrenal tumours
  • Solitary adrenal gland
  • Familial syndromes (VHL, MEN 2A, familial pheo)
• Amount of tissue needed to preserve function — unknown
• Bilateral adrenalectomy → lifelong replacement + ↓ QOL + Addisonian crisis risk

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