Adrenal Pathology
Pathology · Endocrine · lean revision notes
Adrenal Pathology
The adrenal gland is a two-organ-in-one structure: an outer cortex (mesodermal, steroid-producing) and an inner medulla (neural-crest, catecholamine-producing). Adrenal pathology is a perennial NEET PG favourite because each lesion couples a crisp biochemical syndrome with a signature morphology, named criteria and a classic cut-off. Master the cortical syndromes (Cushing, Conn, Addison) and the medullary tumours (phaeochromocytoma, neuroblastoma) and you cover the bulk of question stems.
Functional anatomy you must own first
The cortex has three zones, classically remembered as GFR → Salt, Sugar, Sex ("the deeper you go, the sweeter it gets"):
| Zone | Hormone | Regulation | Key enzyme |
|---|---|---|---|
| Glomerulosa (outer) | Aldosterone (mineralocorticoid – "salt") | Renin–angiotensin, K⁺ | Aldosterone synthase (CYP11B2) |
| Fasciculata (middle, widest) | Cortisol (glucocorticoid – "sugar") | ACTH | 17α-hydroxylase, 11β-hydroxylase |
| Reticularis (inner) | Androgens (DHEA – "sex") | ACTH | 17,20-lyase |
| Medulla | Adrenaline / noradrenaline | Sympathetic preganglionic | PNMT (cortisol-dependent) |
High-yield: PNMT (converts noradrenaline → adrenaline) needs high local cortisol delivered by the intra-adrenal portal system. This is why extra-adrenal phaeochromocytomas (paragangliomas) secrete predominantly noradrenaline — they lack this cortisol bath.
A useful mnemonic for the cortical zones and products: "The deeper you go, the sweeter it gets — Salt, Sugar, Sex."
1. Cushing Syndrome — hypercortisolism
Cushing syndrome = the clinical state of chronic glucocorticoid excess, regardless of cause. Cushing disease = the specific subset caused by an ACTH-secreting pituitary adenoma.
Etiological classification (most-tested table)
| Cause | ACTH level | Frequency | Adrenal morphology |
|---|---|---|---|
| Exogenous steroids (iatrogenic) | ↓ Low | Commonest overall | Bilateral atrophy |
| Pituitary adenoma (Cushing disease) | ↑ High | Commonest endogenous (~70%) | Bilateral hyperplasia |
| Adrenal adenoma | ↓ Low | ~10% | Solitary mass, atrophy of rest |
| Adrenal carcinoma | ↓ Low | Rare, severe | Large >100 g, necrosis |
| Ectopic ACTH (small-cell lung Ca, carcinoid) | ↑↑ Very high | ~10% | Bilateral hyperplasia |
High-yield: Overall the single commonest cause of Cushing syndrome is iatrogenic (exogenous corticosteroids). Among endogenous causes, pituitary (Cushing disease) leads. In a child, suspect adrenocortical neoplasm.
Pathophysiology & morphology
- ACTH-dependent causes (pituitary, ectopic) → bilateral diffuse/nodular cortical hyperplasia.
- ACTH-independent causes (adenoma, carcinoma, exogenous) → suppressed ACTH → atrophy of the contralateral cortex and the non-tumour cortex.
- Crooke hyaline change: accumulation of keratin filaments in pituitary corticotrophs due to high cortisol — a histological hallmark of hypercortisolism of any cause.
Clinical features
Central (truncal) obesity, moon facies, buffalo hump, supraclavicular fat pads, thin skin with purple/violaceous striae (>1 cm wide, abdomen), proximal myopathy, hypertension, hyperglycaemia/diabetes, osteoporosis, easy bruising, immunosuppression, psychiatric change, hirsutism. Hyperpigmentation only in ACTH-dependent (high POMC/MSH) causes.
Diagnostic flow — confirm THEN localise
Step 1 – Establish hypercortisolism (any 2 of 3): late-night salivary cortisol → 24-h urinary free cortisol → low-dose (1 mg overnight) dexamethasone suppression test (failure to suppress = positive).
Step 2 – Measure plasma ACTH → branches the tree: ↓ ACTH → adrenal cause (CT abdomen) vs ↑/normal ACTH → high-dose dexamethasone + MRI pituitary.
Step 3 – High-dose dexamethasone suppression test:
| Source | Low-dose DST | High-dose DST | ACTH |
|---|---|---|---|
| Pituitary (Cushing disease) | No suppression | Suppresses (>50% ↓) | High |
| Ectopic ACTH | No suppression | No suppression | Very high |
| Adrenal tumour | No suppression | No suppression | Low |
High-yield: High-dose dexamethasone suppresses cortisol in pituitary Cushing disease but not in ectopic ACTH or adrenal tumours. Inferior petrosal sinus sampling is the gold standard to confirm a pituitary source when imaging is equivocal.
Investigation of choice: late-night salivary cortisol / overnight 1-mg DST for screening; CT for adrenal, MRI for pituitary localisation.
Management: treat the cause — trans-sphenoidal resection (Cushing disease), adrenalectomy (adenoma/carcinoma), tumour removal (ectopic), taper steroids (iatrogenic). Medical control: ketoconazole, metyrapone (block synthesis), metyrapone/mitotane for carcinoma, pasireotide, mifepristone (receptor block).
2. Conn Syndrome — primary hyperaldosteronism
Autonomous aldosterone excess independent of renin. Two main causes:
- Aldosterone-producing adenoma (Conn adenoma) — solitary, small (<2 cm), bright golden-yellow cut surface (lipid-laden), cells resemble fasciculata. Spironolactone bodies (eosinophilic laminated cytoplasmic inclusions) seen after spironolactone therapy.
- Bilateral idiopathic adrenal hyperplasia — actually the commonest cause now in many series.
Features & biochemistry
Classic triad → hypertension + hypokalaemia + metabolic alkalosis. Symptoms: muscle weakness, cramps, polyuria, paraesthesiae, often resistant hypertension. Note many patients are normokalaemic today.
High-yield: The screening test is the plasma aldosterone-to-renin ratio (ARR) — high aldosterone with SUPPRESSED renin. This separates primary (low renin) from secondary (high renin: renal artery stenosis, diuretics) hyperaldosteronism.
Diagnostic flow: ↑ARR screen → confirmatory salt/saline suppression test (aldosterone fails to suppress) → CT adrenals → adrenal venous sampling (AVS) to lateralise adenoma vs bilateral hyperplasia.
Management: unilateral adenoma → laparoscopic adrenalectomy; bilateral hyperplasia → mineralocorticoid receptor antagonist (spironolactone / eplerenone) — eplerenone preferred where gynaecomastia is a concern.
3. Phaeochromocytoma — the medullary classic
A catecholamine-secreting tumour of chromaffin cells of the adrenal medulla. Extra-adrenal counterparts = paragangliomas (organ of Zuckerkandl near aortic bifurcation being commonest extra-adrenal site).
The "Rule of 10s" — the single most asked fact
High-yield – Rule of 10s:
- 10% extra-adrenal (paraganglioma)
- 10% bilateral (more in familial)
- 10% malignant (malignancy defined by metastasis, not histology)
- 10% in children
- 10% familial / hereditary (older teaching; now ~25–40% are germline-linked)
- 10% calcify
- 10% NOT associated with hypertension
Familial associations: MEN 2A & 2B (RET), von Hippel-Lindau (VHL), NF-1, and SDHB/SDHD paraganglioma syndromes. SDHB mutations carry the highest malignant potential.
Clinical features
Episodic paroxysmal hypertension with the triad "PHE" → Palpitations + Headache + Episodic sweating (diaphoresis). Add pallor, anxiety, tremor, hyperglycaemia. Attacks may be precipitated by stress, surgery, or drugs.
High-yield mnemonic: Phaeochromocytoma "5 P's" → Pressure (BP), Pain (headache), Perspiration, Palpitation, Pallor.
Morphology
Tumour cells in nests ("Zellballen") surrounded by sustentacular cells; chromaffin reaction turns the tumour brown-black on dichromate fixation. Chromogranin A, synaptophysin positive; S-100 highlights sustentacular cells. Histology cannot reliably predict malignancy — only metastasis can.
Diagnosis — investigation of choice
High-yield: Best screening test = plasma free metanephrines (highest sensitivity) or 24-h urinary fractionated metanephrines/catecholamines. Urinary VMA (vanillylmandelic acid) is the classic NEET PG answer for a catecholamine metabolite but is less sensitive. Localisation by CT/MRI, then MIBG (¹²³I-metaiodobenzylguanidine) scan for extra-adrenal/metastatic disease.
Management flow (sequence is examinable): α-blockade first (phenoxybenzamine / prazosin) → THEN β-blockade → volume repletion → surgical resection.
High-yield: NEVER start β-blocker before α-blocker — unopposed α-vasoconstriction precipitates a hypertensive crisis. Intra-op crisis is managed with phentolamine / sodium nitroprusside.
4. Neuroblastoma — the paediatric medullary tumour
The commonest extracranial solid tumour of childhood and commonest tumour of infancy; ~40% arise in the adrenal medulla, the rest along the sympathetic chain. A "small round blue cell tumour" of neural-crest origin; median age ~18 months.
Morphology & markers
- Homer-Wright pseudorosettes — tumour cells around a central tangle of neuropil (NO central lumen — distinguishes from true Flexner-Wintersteiner rosettes of retinoblastoma).
- Neuropil background, neuron-specific enolase (NSE)+, synaptophysin+, chromogranin+.
- N-myc (MYCN) amplification = poor prognosis and is the key molecular marker.
High-yield: N-myc amplification → aggressive disease/poor prognosis. Homer-Wright pseudorosettes are the histology buzzword. Elevated urinary VMA and HVA are diagnostic markers; raised NSE, LDH, ferritin indicate worse prognosis.
Clinical & staging pearls
Abdominal mass crossing the midline, may present with opsoclonus-myoclonus ("dancing eyes, dancing feet"), periorbital ecchymoses ("raccoon eyes") from orbital metastases, hypertension, and HVA/VMA elevation.
High-yield – Stage 4S (Special/Pepper): infant <1 yr with localised primary + metastases limited to skin, liver, bone marrow (NOT cortical bone) — paradoxically excellent prognosis with spontaneous regression. Neuroblastoma is famous for spontaneous regression and maturation into benign ganglioneuroma.
Other favourable factors: young age (<18 months), hyperdiploidy, TrkA expression. Unfavourable: older age, N-myc amplification, 1p deletion, diploidy.
5. Addison Disease — primary adrenocortical insufficiency
Destruction of >90% of the adrenal cortex → deficiency of cortisol and aldosterone.
Etiology
| Type | Causes |
|---|---|
| Primary (Addison) | Autoimmune adrenalitis (commonest in developed world), TB (commonest worldwide / in India), metastasis, amyloid, fungal (histoplasma), Waterhouse–Friderichsen (meningococcaemia → bilateral haemorrhage), adrenoleukodystrophy |
| Secondary | Pituitary failure (↓ACTH) — aldosterone preserved, no hyperpigmentation |
| Tertiary | Sudden withdrawal of chronic steroids — commonest cause of secondary insufficiency overall |
Autoimmune Addison may be part of APS-1 (APECED — AIRE gene: Addison + hypoparathyroidism + mucocutaneous candidiasis) or APS-2 (Schmidt syndrome: Addison + autoimmune thyroid + T1DM).
Clinical features
Fatigue, weight loss, anorexia, postural hypotension, salt craving, GI upset. Hyperpigmentation (skin creases, buccal mucosa, scars) from high ACTH/POMC → MSH — a primary-only sign. Biochemistry: hyponatraemia, hyperkalaemia, hypoglycaemia, metabolic acidosis, eosinophilia.
High-yield: Hyperpigmentation distinguishes primary Addison (↑ACTH) from secondary insufficiency (↓ACTH, pale). Aldosterone deficiency (and thus hyperkalaemia + salt craving) occurs only in primary disease.
Diagnosis: low morning cortisol → ACTH stimulation (Synacthen/cosyntropin) test = investigation of choice (no rise in primary). Plasma ACTH high in primary, low in secondary.
Addisonian (adrenal) crisis: hypotension/shock, hypoglycaemia, hyponatraemia — precipitated by stress/infection. Treatment = immediate IV hydrocortisone + IV normal saline + dextrose; do not delay for tests.
Maintenance: hydrocortisone (glucocorticoid) + fludrocortisone (mineralocorticoid); stress-dosing during illness/surgery.
Key differentials & distinguishing pearls
| Confusion | Discriminator |
|---|---|
| Adrenal adenoma vs carcinoma | Adenoma small (<5 cm, <50 g), well-circumscribed; carcinoma large (>100 g), necrosis, vascular invasion, often functional, poor prognosis |
| Pituitary vs ectopic ACTH Cushing | High-dose dexamethasone suppresses pituitary, not ectopic |
| Conn (primary) vs secondary hyperaldosteronism | Renin suppressed in primary, high in secondary |
| Phaeochromocytoma vs neuroblastoma | Phaeo = adults, Zellballen, metanephrines; Neuroblastoma = infants, Homer-Wright rosettes, N-myc, HVA/VMA |
| Neuroblastoma vs ganglioneuroma | Ganglioneuroma = fully mature ganglion cells, benign; neuroblastoma = immature small round blue cells |
| Primary vs secondary adrenal insufficiency | Hyperpigmentation + hyperkalaemia in primary only |
Adrenal incidentaloma flow: found on imaging → assess (1) functional status (cortisol, metanephrines, ARR) and (2) malignant potential (size >4 cm, irregular, low lipid/high HU on CT) → resect if functional or suspicious.
Recently asked / exam angle
- Rule of 10s for phaeochromocytoma — repeatedly asked; remember 10% extra-adrenal, bilateral, malignant, paediatric, familial, calcify, normotensive.
- Organ of Zuckerkandl = commonest site of extra-adrenal paraganglioma (near aortic bifurcation/IMA origin).
- α-blocker before β-blocker in phaeochromocytoma — single best step question.
- N-myc amplification = worst prognostic marker in neuroblastoma; Homer-Wright pseudorosettes image-based identification.
- Stage 4S neuroblastoma spontaneously regresses — counter-intuitive prognosis question.
- High-dose dexamethasone suppression differentiates pituitary vs ectopic Cushing.
- VMA = catecholamine metabolite asked for both phaeochromocytoma and neuroblastoma; plasma free metanephrines = most sensitive modern test.
- Crooke hyaline change & spironolactone bodies as histology one-liners.
- Waterhouse–Friderichsen syndrome — bilateral adrenal haemorrhage in meningococcaemia.
- APS-1 (AIRE) vs APS-2 (Schmidt) associations of autoimmune Addison.
- TB is the commonest cause of Addison disease in India; autoimmune in the West.
Rapid revision
- Commonest Cushing overall = iatrogenic steroids; commonest endogenous = pituitary (Cushing disease).
- High-dose dexamethasone suppresses pituitary Cushing, not ectopic/adrenal.
- Crooke hyaline change in corticotrophs = marker of hypercortisolism of any cause.
- Conn syndrome → HTN + hypokalaemia + alkalosis; screen with aldosterone:renin ratio (renin SUPPRESSED).
- Conn adenoma = golden-yellow; spironolactone bodies after Rx.
- Phaeochromocytoma = Rule of 10s; malignancy defined by metastasis, not histology.
- Zellballen + chromaffin + chromogranin; plasma free metanephrines most sensitive, VMA classic.
- α-blocker (phenoxybenzamine) BEFORE β-blocker — always.
- Neuroblastoma = commonest extracranial solid tumour of childhood; Homer-Wright pseudorosettes; N-myc amplification = poor prognosis.
- Stage 4S neuroblastoma → spontaneous regression, excellent prognosis.
- Addison: TB worldwide/India, autoimmune in West; hyperpigmentation + hyperkalaemia = primary only.
- ACTH stimulation test = investigation of choice for adrenal insufficiency; crisis Rx = IV hydrocortisone + saline + dextrose.