adrenal carcinoma

**Epidemiology:** Rare (~1-2 per million/year). Bimodal age distribution: <5 years and 40-50 years. Slight female predominance in adults. Pediatric cases are strongly linked to Li-Fraumeni syndrome (TP53 mutation) and Beckwith-Wiedemann syndrome (IGF-2 overexpression, 11p15). In southern Brazil, a germline TP53 R337H mutation causes a high pediatric incidence. Other associations: MEN1, Lynch syndrome, familial adenomatous polyposis (Wnt/β-catenin pathway activation).

**Pathophysiology:** Malignant transformation of cortical cells (zona fasciculata/reticularis/glomerulosa). Common molecular changes include TP53 inactivation, IGF-2 overexpression, and β-catenin (CTNNB1) activation. Tumors are usually large, heterogeneous, with necrosis and hemorrhage, and often invade the adrenal vein/IVC.

**Clinical presentation:** - About 50-60% are functional (hormone-secreting): - Cortisol excess (Cushing syndrome): most common. Presents with central obesity, striae, hypertension, hyperglycemia, and proximal muscle weakness. ACTH is suppressed, so the contralateral adrenal atrophies. - Androgen excess: virilization in women (hirsutism, deep voice, amenorrhea) and precocious puberty in children. Elevated DHEA-S is a clue to malignancy. - Mixed cortisol + androgen secretion is highly suggestive of ACC. - Estrogen excess (gynecomastia in men) is rare. - Aldosterone excess (Conn syndrome) is rare. - Nonfunctional: abdominal pain, early satiety, flank mass, weight loss, fever.

**Diagnosis:** - Hormonal workup of every adrenal mass: dexamethasone suppression test, plasma/urine metanephrines (rule out pheochromocytoma before biopsy or surgery), DHEA-S, sex steroids, and aldosterone/renin if hypertensive or hypokalemic. - Imaging: CT/MRI shows a large (>4-6 cm), irregular, heterogeneous mass with necrosis and calcifications. Unenhanced CT >10-20 Hounsfield units and slow contrast washout suggest malignancy (benign adenomas are lipid-rich with <10 HU). Staging with chest/abdomen/pelvis CT; PET can help. - Avoid percutaneous biopsy unless metastatic disease is already established, because of the risk of tumor seeding and the need to exclude pheochromocytoma first. - Histology: Weiss criteria (≥3 of 9 suggests malignancy), including high nuclear grade, mitoses >5/50 HPF, atypical mitoses, clear cells <25%, diffuse architecture, necrosis, and venous, sinusoidal, or capsular invasion. Ki-67 index gives prognostic information.

**Treatment:** - Stage I-III: complete en bloc surgical resection (R0) is the only curative therapy. Open adrenalectomy is preferred for suspected ACC. - Adjuvant mitotane (an adrenolytic derivative of DDT) for high-risk disease. Mitotane causes adrenal insufficiency, so patients need glucocorticoid replacement. Other adverse effects: GI upset, neurotoxicity, and hepatotoxicity. - Metastatic disease: mitotane ± chemotherapy (etoposide, doxorubicin, cisplatin = EDP). Use ketoconazole or metyrapone to control hormone excess (steroidogenesis inhibitors). - Post-op: the contralateral adrenal is suppressed in cortisol-secreting tumors, so give perioperative steroid coverage to prevent adrenal crisis.

**Prognosis:** Poor overall. 5-year survival is ~60-80% for stage I-II, but under 15% for stage IV. Common metastatic sites: lung, liver, bone, and lymph nodes.

**High-yield board points and differentials:** - Adrenal incidentaloma: size >4 cm, irregular borders, and high HU raise concern for malignancy. Most incidentalomas are benign nonfunctional adenomas. - Adenoma vs carcinoma: carcinomas are typically >6 cm, heavier (>100 g), and invasive. Adenomas are small, well-circumscribed, and lipid-rich. - Pheochromocytoma (chromaffin cells, medulla; episodic hypertension, elevated metanephrines, "rule of 10s") is different from ACC. Neuroblastoma (children, N-myc) is an adrenal medullary tumor. - Adrenal metastases (lung, breast, melanoma, renal) are more common than primary ACC in the adrenal gland. - Pediatric clue: a child with an adrenal mass and virilization should raise suspicion for ACC and Li-Fraumeni (TP53).