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PA31.8-10 | Adrenal Gland Disorders — SDL Guide (Part 3)

Adrenocortical Neoplasms — Adenoma vs Carcinoma

Adrenal cortical neoplasms arise from any zone of the cortex. The central diagnostic challenge is distinguishing benign adenoma from malignant carcinoma.

Cortical Adenoma:
• Common (incidental finding — 'incidentaloma' in 1–5% of abdominal CTs).
• Usually small (<5 cm, <50 g), well-encapsulated, bright-yellow (lipid-rich), solitary.
• Most are non-functional. Functional adenomas produce cortisol (Cushing), aldosterone (Conn), or androgens.
• Histology: clear lipid-laden cells resembling zona fasciculata, with mild nuclear pleomorphism; no capsular/vascular invasion, low mitotic rate.

Adrenocortical Carcinoma (ACC):
• Rare but aggressive; bimodal peak (children <5 yr; adults 40–50 yr).
• Large tumours (>10 cm, >100 g) — weight >100 g is a useful threshold (though overlap exists with Weiss criteria).
• Cut section: haemorrhagic, necrotic, may invade adjacent organs.
• ~50% are functional — produce cortisol (±androgens → virilisation in women).
• Weiss criteria (histologic malignancy score, ≥3 of 9 = malignant):
- Nuclear grade 3 or 4 (Fuhrman)
- Mitotic rate >5/50 HPF
- Atypical mitoses
- Clear cells <25% of tumour cells
- Diffuse architecture >33%
- Necrosis present
- Venous invasion
- Sinusoidal invasion
- Capsular invasion
• Prognosis poor — 5-year survival ~35%.

Feature	Adenoma	Carcinoma
Size	<5 cm, <50 g	>10 cm, >100 g
Capsule	Intact, well-encapsulated	Invasion common
Mitoses	Rare, typical	>5/50 HPF, atypical
Necrosis	Absent	Present
Prognosis	Excellent	Poor (5-yr ~35%)

Adrenocortical Adenoma vs Carcinoma — Histology at Medium Power with Key Differentiating Features

Pheochromocytoma — Pathology and Rule of 10s

Pheochromocytoma is a catecholamine-secreting tumour arising from chromaffin cells of the adrenal medulla.

Pathogenesis: Tumour chromaffin cells secrete epinephrine and norepinephrine (and dopamine in extra-adrenal variants) → paroxysmal or sustained hypertension, headache, sweating, palpitations (the 'paroxysmal 4' — 5Ps: Pressure, Pain, Perspiration, Palpitations, Pallor).

Rule of 10s (must know for exams):
• ~10% are bilateral
• ~10% are extra-adrenal (paragangliomas; para-aortic, organ of Zuckerkandl)
• ~10% are familial (MEN2A, MEN2B, VHL, NF1, SDH mutations)
• ~10% are malignant (defined by metastasis, not histology alone)
• ~10% occur in children

MEN2 association: MEN2A = pheochromocytoma + medullary thyroid carcinoma (MTC) + hyperparathyroidism; MEN2B = pheo + MTC + mucosal neuromas + marfanoid habitus. Gene: RET proto-oncogene mutations.

Morphology:
• Gross: well-demarcated, tan-grey to haemorrhagic; average 5 cm, 100 g.
• Zellballen pattern (characteristic): nests of polygonal chromaffin cells separated by a delicate vascular network; 'zellballen' = German for 'cell balls'.
• Cells have abundant granular cytoplasm (catecholamine granules → brown with chromate fixative — 'chromaffin reaction').
• Cannot reliably distinguish benign from malignant histologically — malignancy defined only by metastasis.

Biochemical diagnosis: Elevated plasma metanephrines or 24-hour urinary VMA (vanillylmandelic acid) and fractionated metanephrines; urine catecholamines.

Histology of Pheochromocytoma — Zellballen Architecture (Medium & High Power)

Neuroblastoma — Paediatric Adrenal Medullary Tumour

Neuroblastoma is the commonest extracranial solid tumour of childhood, arising from primitive sympathoblasts (neural crest precursors of the adrenal medulla and sympathetic ganglia).

Epidemiology: Median age ~2 years; 90% present before age 5. Adrenal medulla is the primary site in ~40%; rest arise in paravertebral sympathetic ganglia (neck, chest, abdomen, pelvis).

Molecular biology (high-yield):
• N-myc (MYCN) amplification — most important adverse prognostic factor; >10 copies = poor prognosis.
• Deletion of chromosome 1p and 11q — additional poor prognostic markers.
• Trk-A (NTRK1) expression — favourable prognostic marker; tumours with TrkA undergo spontaneous differentiation (the basis of 'spontaneous regression' in Stage 4S).

Morphology:
• Small round blue cell tumour (along with Ewing sarcoma, Wilms tumour, rhabdomyosarcoma, PNET).
• Homer-Wright pseudorosettes (pathognomonic): tumour cells arranged in a circle around a central fibrillar core of neuropil (NOT around a vessel — this distinguishes them from true rosettes).
• Schwannian stroma absent (distinguishes from ganglioneuroblastoma/ganglioneuroma in the spectrum).

Clinical features: Abdominal mass; periorbital ecchymoses (Hutchinson sign — orbital metastasis); opsoclonus-myoclonus; bone pain from marrow metastasis; elevated urinary HVA (homovanillic acid) and VMA.

International Neuroblastoma Risk Classification (INRG): Very low, low, intermediate, high based on MYCN, stage, histology, age.

Neuroblastoma: Homer-Wright Pseudorosettes