Adrenal

Adrenal Gland

Cortex → GFR

• G: Aldosterone
  • Zona glomerulosa = outermost ~15% of the cortex → the only zone with aldosterone synthase (CYP11B2) → sole source of aldosterone
  • Stimulus: angiotensin II = most potent · ACTH only weak
    • → the zona glomerulosa is the only cortical zone that does not atrophy in pituitary failure
  • Acts on the distal renal tubules (distal nephron) → Na⁺ + Cl⁻ reabsorption, H⁺ + K⁺ secretion
• F: Cortisol
  • Zona fasciculata → 17α-, 21- and 11β-hydroxylase → cortisol, the main human glucocorticoid
  • Under tight ACTH control
• R: Androgens
  • Zona reticularis → androgens
  • Most abundant cortical product

Medulla → Catecholamines

• Only demonstrated nerves = sympathetic to the medulla → preganglionic T10–L1 fibers via the splanchnic nerves → catecholamine release from chromaffin cells
• No cortical or parasympathetic innervation has been demonstrated

Daily output from the adrenal cortex

Venous drainage — left side

• Left adrenal vein runs down from the hilum → joins the inferior phrenic vein → enters the top of the left renal vein
  • Bleeding at the medial margin during left laparoscopic adrenalectomy → most likely the inferior phrenic vein → identify and control it rather than tear it

Testicular adrenal rests

• In congenital adrenal hyperplasia (CAH), testicular adrenal rests can mimic testicular cancer → think of them in any CAH patient with a testicular mass to avoid an unnecessary orchiectomy

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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 hypokalemic
• 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)

Breakdown by individual cause

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

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

• 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, hypokalemic alkalosis and skin pigmentation
• Children present with weight gain and growth retardation
• Virilization in a female or feminization 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
  • Why not LD-DST: estrogen raises CBG → falsely elevates total cortisol, whereas UFC measures free cortisol — and it avoids fetal dexamethasone exposure
  • That raise applies in the second and third trimesters, above the standard laboratory threshold
• Affected by GFR
• Not sensitive enough for subclinical Cushing's — not recommended in incidentalomas

Localizing the Source

→ Confirm hypercortisolism → measure serum ACTH

• After a positive 24-h urinary cortisol → plasma ACTH, not low- or high-dose dexamethasone testing; abdominal CT only if ACTH is not elevated
• ACTH < 5 pg/mL → ACTH-independent → adrenal source → CT abdomen
  • High cortisol + low ACTH + no suppression on low- or high-dose DST → primary adrenal tumor — autonomous cortisol has already suppressed ACTH, so dexamethasone has nothing left to act on
  • Usually a unilateral adrenal neoplasm (rarely bilateral) → ipsilateral adrenalectomy
  • Normal adrenals → exogenous steroids
  • Normal adrenals → also consider PPNAD
• 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 )
• 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
  • Sampled after CRH stimulation (amplifies secretion from a corticotroph adenoma)
  • Central-to-peripheral ACTH gradient → pituitary (Cushing disease); no gradient → ectopic ACTH

High-Dose Dexamethasone Test

• 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 tumor — then lifelong mineralocorticoid and glucocorticoid replacement
• Exogenous steroids → gradual wean, to avoid steroid withdrawal syndrome
• AIMAH or PPNAD → bilateral adrenalectomy with lifelong replacement

Perioperative care — adrenalectomy for Cushing's

• Stress-dose steroids — the contralateral gland is suppressed → adrenal insufficiency once the source is removed
  • 100 mg IV hydrocortisone on the day of surgery → slow oral taper once tolerating oral intake
  • Adrenal recovery takes a median 11 months; 6.6% never fully recover
• Careful glycemic control — hypercortisolism causes glucose intolerance / diabetes
• Not α-blockers (→ pheochromocytoma) or K-sparing diuretics (→ Conn's)

Nelson's syndrome

• Progressive growth of the pituitary adenoma after bilateral adrenalectomy
  • Loss of cortisol negative feedback → the ACTH-secreting adenoma grows → elevated ACTH
• May cause optic chiasm compression, oculomotor deficiencies, and rarely raised ICP
• Occurs in 8–29% of patients
• Classic picture: hyperpigmentation + visual disturbance (± headache) years after bilateral adrenalectomy for Cushing's disease
• Diagnosis → brain MRI + elevated ACTH
• Treatment → radiation, trans-sphenoidal surgery, or drugs — octreotide, temozolomide, pasireotide
• Can be prevented by prophylactic pituitary radiotherapy — controversial
• Mimic: excess cortisone replacement → Cushingoid features (striae, buffalo hump, central obesity) — not hyperpigmentation

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

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

Causes of primary hyperaldosteronism, by frequency

Juxtaglomerular cell tumor (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, hypokalemia and proteinuria

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

Primary Hyperaldosteronism

• Normokalemia in up to 90% (only 9–37% hypokalemic at diagnosis)
  • Hypokalemia is the classic textbook finding, but it is the minority presentation
• No hypernatremia (Na reabsorption iso-osmotic with water)
  • Volume expansion stays mild (~1.5 kg) (see renal escape below)
• A low renin is more common in primary hyperaldosteronism than a low potassium
  • Aldosterone secretion is renin-independent → renin suppressed → ↓ angiotensin II in most patients

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

From the raised sodium

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

From the low potassium

• Nocturia
• Paresthesia/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 edema

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

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Diagnosis

Screening tests, in order

1. Serum electrolytes for hypokalemia — most patients are normokalemic, 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

• ARR > 30 is only a positive screen — e.g. PAC 40 ng/dL ÷ PRA 0.25 ng/mL/h = ARR 160 → next is confirmatory testing (e.g. 24-hour urine aldosterone) before AVS or surgery

Before screening — which drugs to stop

• MRAs (spironolactone, eplerenone) are contraindicated during primary aldosteronism (PA) evaluation → switch to other antihypertensives for at least 6 weeks before testing
• Long-acting CCBs (e.g. amlodipine) have only a minimal effect on aldosterone/renin screening → the reason they can stay on

Confirmatory tests

• A raised aldosterone is only a screening result → confirm PA before lateralization — only 50–87% of positive screens are confirmed
• The fludrocortisone suppression test has been largely replaced by oral sodium loading and IV saline infusion, because of the risk of hypertension and hypokalemia — but it is still examined
  • Fludrocortisone 0.1 mg every 6 h + NaCl 2 g every 8 h × 4 days
  • Then upright PAC → failure to suppress below 6 ng/dL confirms PA

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

Lateralization

• Imaging: cross-sectional CT — adenoma = unilateral, <10 HU, non-enhancing
• Adrenal vein sampling (AVS) required for lateralization
  • Exceptions (skip AVS):
    • <40 yrs with clear unilateral adenoma + normal contralateral
    • Suspected ACC

When to Do Adrenal Venous Sampling?

• Bilateral
• Micronodular < 1cm
  • Confirmed PA with no unilateral nodule > 1 cm on CT (e.g. bilateral 5 mm nodules) → AVS next to determine lateralization
• Normal adrenal imaging
• Unilateral Adrenal nodule >1 cm AND age more than 40 years

Preparation

• 1 hour of recumbency
• Correct hypokalemia
• 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
• Lateralization ratio = (A_dominant / C_dominant) ÷ (A_nondominant / C_nondominant)
• Aldosterone secretion is lateralized 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 tumor, ACC

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

• Surgical: laparoscopic adrenalectomy (small tumors)
  • Open if ACC suspected
• Medical: spironolactone or eplerenone (MRA) — start 1–2 wks pre-op, especially if on long-term ACEi
• AVS lateralizes → consider unilateral adrenalectomy; no lateralization → treat medically with spironolactone
  • Bilateral adrenalectomy is NOT recommended without AVS localization

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, hyperkalemia, hyponatremia, 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 remodeling

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

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Pheochromocytoma

Background

• Chromaffin cell tumor of adrenal medulla
• Secretes dopamine, norepinephrine and epinephrine in varying ratios → norepinephrine is the most common (usually predominant) product
• Found in ~5% of adrenal incidentalomas → every adrenal mass needs metabolic evaluation (plasma free or 24-hr urinary fractionated metanephrines)
• ~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% pediatric

Hereditary Syndromes

• 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
  • The hallmark triad; perspiration is sudden and episodic → reflects paroxysmal catecholamine release (not continuous)
• Attacks provoked by: anesthetic induction, labor and delivery, tumor instrumentation or biopsy, strenuous physical activity, tyramine-rich foods (red wine, chocolate, cheese)
• 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%

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 )
• 2019 AUA → plasma free metanephrines are the recommended initial screening test
  • Intratumoral conversion of catecholamines → metanephrines is continuous → far more sensitive than catecholamines, whose rises are paroxysmal
  • High suspicion → plasma fractionated metanephrines; low suspicion → 24-hr urinary fractionated metanephrines + catecholamines (urine has slightly lower sensitivity)
• Hold before test:
  • Acetaminophen (5 days — cross-reactivity)
    • As with mesalamine and sulfasalazine → falsely ↑ metanephrines on LC with electrochemical detection → stop ≥5 days before testing
    • LC–tandem mass spectrometry is unaffected (interference is method-dependent)
  • TCAs (1–2 weeks)
    • e.g. amitriptyline → falsely ↑ metanephrines in plasma and 24-hr urine → stop the drug, repeat plasma metanephrines after 1–2 weeks
    • ACE inhibitors do not interfere
  • 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 pheochromocytoma 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

• MRI "light bulb" sign → best seen on fat suppression; reflects high water content + vascularity
  • Pheo is lipid-poor (unlike adenomas)
• Functional imaging (MIBG/PET) can be omitted if solitary adrenal mass + biochemical pheo on cross-sectional imaging
• Do for tumors >5 cm to rule out mets pre-op
• MIBG is indicated when:
  • There is a high index of suspicion but negative plasma or urine tests
  • The patient has a syndrome associated with pheochromocytoma — these are more likely to have extra-adrenal tumors
  • A pheochromocytoma cannot be localized, or metastases are suspected (taken up by chromaffin tissue wherever it lies)

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Pre-op Management (4 pillars)

• There is no role for observation in pheochromocytoma — 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 / anesthesia / 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
  • First-line preoperative blockade — non-competitive, so catecholamine surges cannot displace it
  • 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)
  • The receptor left unopposed is α₁ → β₁-blocker comes after adequate α-blockade, to treat phenoxybenzamine's reflex tachycardia
• 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

• Indication: BP still uncontrolled on maximal phenoxybenzamine
• Inhibits tyrosine hydroxylase → blocks tyrosine → L-DOPA, the rate-limiting step → ↓ catecholamine synthesis
• Added to phenoxybenzamine, not a replacement (receptor block + synthesis block act at different levels)
• 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
• Metyrapone and clonidine have no role in preoperative blockade or medical management (metyrapone ≠ metyrosine; clonidine is used only for the diagnostic suppression test)

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 tumor manipulation
  • Large left pheo → ligate the left adrenal vein first: the concern is catecholamine release, not bleeding
  • This also controls the inferior phrenic vein, which joins the left adrenal vein
• Thermal injury alone can trigger catecholamine release
• Notify anesthesia at adrenal vein ligation
• Hypotension after adrenal vein ligation = expected catecholamine-withdrawal response in an α-blocked patient (not a complication)
  • Saline bolus first → add vasopressors (e.g. phenylephrine) if needed (vasopressors are the pick when fluids aren't an option)
  • Continue the operation — do not abort
• Post-op: hypotension common (loss of tonic vasoconstriction)
  • → Aggressive fluids + phenylephrine
• Watch for hypoglycemia (rebound hyperinsulinemia 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
  • Still-raised plasma free metanephrines = residual, extra-adrenal or metastatic chromaffin tissue → next step is to localize it with MIBG scintigraphy
• 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)
• Small bilateral pheos → partial (cortical-sparing) adrenalectomy is best
  • Bilateral total adrenalectomy → lifelong glucocorticoid + mineralocorticoid replacement + Addisonian crisis risk
  • Bilateral disease → suspect a hereditary syndrome (MEN 2 or VHL)
  • Steroids may still be needed even after cortex-sparing surgery
  • Recurrence is significant → lifelong biochemical + radiographic follow-up
• VHL + pheo + small (1–2 cm) renal masses → α-blockade → partial adrenalectomy (observation and biopsy are inappropriate)
  • Add partial nephrectomy for larger renal masses (>3 cm)
  • Repeat surgeries on both kidneys and adrenals are likely → preserve maximal functioning tissue
• 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 + tumor resection in one operation (no vaginal delivery)

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Adrenal Insufficiency

Classification

Clinical

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

Signs mapped to the missing hormone

Causes of acute adrenal crisis (4)

• Withdrawal of exogenous steroids
• Sepsis
• Bilateral adrenal hemorrhage
• Post-adrenalectomy state

Diagnosis

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

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 tumors, producing Cushing's syndrome
• Feminization of a male — testicular atrophy and gynecomastia — is highly suggestive of malignancy
• Mixed hormone secretion — e.g. hypercortisolism + androgen excess (hirsutism) — in a large adrenal mass → strongly suggests ACC rather than a single-hormone adenoma
• Li-Fraumeni = loss of TP53 · Beckwith-Wiedemann = raised IGF

Functional evaluation of an adrenal mass suspected to be ACC

Genetic Syndromes (6)

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

Risk of Malignancy by Size

• Contemporary incidentaloma series (exam answer): 0.1% <4 cm · 2.4% at 4–6 cm · 19.5% >6 cm

→ Resect masses >4–6 cm unless clearly benign

• The 4–6 cm band is the gray 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)

• Size > 5 cm
• Slow CT contrast washout
• Invasion of adjacent structures
• Heterogeneous, with necrosis and calcification
• Irregular borders
• High signal density on T2
• CT enhancement > 10 HU (mean 39 HU) — compared with adenoma (mean 8 HU)
• 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

• Classic ACC picture = these features combined in one large (e.g. 8 cm) enhancing mass > 10 HU — irregular borders, heterogeneous enhancement, calcification, necrosis with cystic degeneration → adrenocortical carcinoma

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 favor open surgery if the tumor is > 6 cm or locally invasive
• In metastatic ACC, cytoreductive adrenalectomy is considered if > 90% of the disease can be removed — it helps alleviate tumor-related side effects
• Multimodal: surgery + RT + chemo

Mitotane

• Mitotane = most common chemotherapeutic agent
• Inhibits P450scc, 11β-OHase, 18-OHase, 3β-HSD
• An oral agent used in the adjuvant and metastatic settings
  • A synthetic derivative of the insecticide DDT
  • Mitotane-based therapy is first-line in metastatic ACC
  • Adjuvant use remains controversial — retrospective data suggest benefit, but potential risks and uncertain benefit
• Steroid replacement is necessary during treatment
  • Why → mitotane is adrenolytic
  • Mitotane dose titrated to tolerability and serum levels
• Side effects — GI upset, lethargy, depression, rash, raised LFTs, hypothyroidism, dyslipidemia, feminization, thrombocytopenia
• As a single agent, response rate is up to 36%
  • Overall range 14–36%
• Mitotane + etoposide + doxorubicin + cisplatin — response rate 49%
  • i.e. mitotane + EDP (etoposide, doxorubicin, cisplatin)

Follow-up

• Cross-sectional imaging every 3 months for 2–3 years, then every 6 months until year 5
• In functional tumors, 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
  • → i.e. achieving negative surgical margins (R0 resection)
• Other OS predictors: size, nodal status, mets

Adrenal Metastases

• >50% of newly discovered adrenal lesions in patients with prior malignancy = metastatic
  • In a patient with a cancer history, ~50% of adrenal masses > 2 cm are metastases
• Malignant lesions usually show < 60% washout on CT · < 20% signal loss on out-of-phase MRI · adrenal-to-spleen ratio > 70%
  • Lipid-poor adenoma is the reverse: > 60% washout, > 20% signal loss, ASR < 70%
• Still need metabolic workup
• Adrenal insufficiency only with bilateral + bulky (>4 cm) disease

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Benign Adrenal Tumors

Adenoma

• Most common primary adrenal tumor — 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

• 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

• Every adrenal mass → screen for cortisol + catecholamine excess, even a lipid-rich 7 HU lesion
• Metabolic workup comes first, even for a 7 cm mass already bound for adrenalectomy
  • Silent pheo → adrenergic blockade before resection
  • Cortisol-secreting lesion → perioperative glucocorticoid cover
• Young patient + multifocal enhancing renal tumors + adrenal mass → suspect a genetic syndrome (e.g. VHL)
  • Adrenal metabolic workup (plasma free metanephrines for pheo) before any biopsy or surgery

Labs (3):

• LD-DST or 24-hr urine cortisol → rule out hypercortisolism
  • Alternative: late-night salivary cortisol
• 24-hr urinary metanephrines/catecholamines → rule out pheo
  • Alternative: plasma free metanephrines
• ARR → if hypertensive, rule out hyperaldosteronism
  • Measured as plasma aldosterone concentration (PAC) + plasma renin activity (PRA)

Imaging (1):

• Unenhanced CT first
  • <10 HU → adenoma (sens ~70%, spec 98%)
    • 98% of lesions ≤10 HU are adenomas
  • ≥10 HU → adrenal protocol CT with washout
  • Metabolically normal mass seen on ultrasound → next = unenhanced CT (US is poor at characterizing adrenal lesions)

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
  • Used when unenhanced attenuation is unavailable
• If less than 60 or 40 need further evaluation
• Any lesion >10 HU → this dedicated 3-phase washout CT, not other contrast studies
  • Single-phase contrast CT → suboptimal (post-contrast attenuation overlaps)
  • Gadolinium MRI → suboptimal (lacks iodine-CT washout kinetics)
  • Chemical-shift MRI → kept for inconclusive or contraindicated CT
• ~30% of adenomas are lipid-poor (>10 HU unenhanced) → confirmed as adenoma by the 60% / 40% washout cut-offs on the 15-min delayed phase
  • Lipid-poor adenomas wash out as fast as lipid-rich ones; pheo, ACC and metastases retain contrast

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
  • Lipid-poor adenoma: >20% signal loss on out-of-phase imaging + adrenal-to-spleen ratio (ASR) <70%
  • Malignant: <20% signal loss, ASR >70%
• CT washout > chemical-shift MRI (gold standard)
• >10 HU nodule + >60% CT washout + adenoma-range chemical-shift signal loss (above) → lipid-poor adenoma, even in a cancer patient
  • ~50% of >2 cm adrenal masses in cancer patients are metastases

Indications for Adrenalectomy:

• Size ≥4 cm (except myelolipoma)
  • >6 cm = malignant until proven otherwise
  • Younger patients → more caution, even <4 cm (older, comorbid patients >4 cm may be better observed)
• Growth >1 cm on follow-up
  • Resect even with a repeatedly negative metabolic workup → many ACCs are non-secreting
• Any imaging suspicious for malignancy regardless of size
  • Radiological resection criteria: >10 HU unenhanced; washout <50% with delayed attenuation >35 HU
  • Resection criterion, not a replacement for the 60%/40% adenoma washout cut-offs
  • Size and imaging are independent indications → a non-functioning 7 cm enhancing mass is still resected
• 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 tumor
  • Vein thrombus to adrenal vein level

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Adrenal Mass Algorithm (Traffic-Light System)

A. Imaging Feature

• Lipid-rich → Green
• Lipid-poor → Orange

B. Size

• <4 cm → Green
• ≥4 cm → Orange

C. Metabolic Work-up

• Silent → Green
• Subclinical → Orange
• Functional → Red

Management Rules

• All Green → No follow-up
  • Recent European guidelines: no follow-up for metabolically inactive <4 cm lesions with benign imaging features
• One Orange → Follow-up
  • e.g. non-functioning adenoma <4 cm (25 HU, 70% absolute washout) → repeat CT at 6, 12 and 24 months
    • Classic answer still repeat CT at 6 months (despite the European no-follow-up position above)
  • No biopsy → cannot reliably distinguish adenoma from carcinoma
• Two Orange OR One Red → Surgical resection

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Partial Adrenalectomy

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

Intra-op Pitfalls

• Pale 3 cm upper-pole kidney area after left adrenal mobilization → devascularization
  • Cause: injured accessory renal artery or upper-pole branch of the main renal artery
  • Observe → no long-term harm from a small ischemic area
  • IV fluids, mannitol or heparin won't restore arterial inflow; partial nephrectomy not indicated