Adrenocortical Carcinoma

Adrenocortical carcinoma is a rare malignancy of the adrenal cortex, with an incidence of 0.7 to 2 per million people a year. It has a bimodal age distribution, with a peak under 5 years (often with a germline TP53 mutation, especially in southern Brazil) and a second peak at 40 to 50 years, and women are affected 1.5 to 2 times more often than men.

Associations: Li-Fraumeni syndrome (TP53), Beckwith-Wiedemann syndrome, Lynch syndrome, multiple endocrine neoplasia type 1 and familial adenomatous polyposis. Molecular drivers include IGF2 overexpression, Wnt pathway activation (CTNNB1), TP53 and ZNRF3 alterations.

About 50 to 60% of tumors secrete hormones: cortisol (Cushing syndrome), androgens (virilization in women and children), estrogen (gynecomastia), and rarely aldosterone. Mixed secretion is typical. Diagnosis of malignancy uses a histologic score of at least 3 of 9 features (the Weiss system) and the Ki-67 index for prognosis.

Staging: stage I tumor 5 cm or smaller, stage II over 5 cm, stage III local invasion or nodes, stage IV distant metastasis. Five-year survival is 60 to 80% for stage I and II, 40 to 55% for stage III, and 10 to 15% for stage IV. Complications: rapidly progressive hormone excess with hypokalemia, diabetes, thromboembolism, infection and muscle weakness, tumor thrombus extending into the renal vein and inferior vena cava, and recurrence in about 50 to 80% after surgery.

• Abdominal or flank pain, a palpable mass, early satiety, back pain and weight loss
• Cortisol excess: rapid weight gain, central obesity, hypertension, proximal muscle weakness, bruising, hirsutism, diabetes, psychiatric disturbance and hypokalemia
• Androgen excess: hirsutism, acne, virilization, oligomenorrhea and deepening voice in women, precocious puberty in children
• Estrogen excess: gynecomastia and testicular atrophy in men
• Red flags: a mass over 4 cm, rapid growth, mixed hormone excess, liver symptoms, and venous obstruction

1. Adrenal protocol imaging: unenhanced CT with attenuation over 10 Hounsfield units, heterogeneous enhancement, delayed washout under 50% at 15 minutes, necrosis and calcification. Chemical shift MRI shows no signal loss. Fluorodeoxyglucose PET-CT adds staging information.
2. Hormonal evaluation of all suspected tumors:
   • Overnight dexamethasone 1 mg suppression test (serum cortisol over 50 nmol/L, or 1.8 microgram/dL, is abnormal), plus ACTH (suppressed), late-night salivary cortisol and 24-hour urinary free cortisol.
   • DHEA sulfate, testosterone, androstenedione, 17-hydroxyprogesterone and estradiol.
   • Plasma aldosterone and renin, and potassium.
   • Plasma free metanephrines to exclude pheochromocytoma before any procedure.
3. Biopsy is avoided before surgery for suspected carcinoma, because it risks seeding and rarely helps. It is used only when metastatic disease from another primary is suspected.
4. Staging: CT of the chest, abdomen and pelvis, and imaging of the inferior vena cava.
5. Genetic testing and counseling (TP53 and mismatch repair genes).

Differentials: adrenal adenoma, pheochromocytoma, metastasis (lung, breast, kidney, melanoma), adrenal lymphoma, myelolipoma and hemorrhage.

• Surgery: open adrenalectomy with en bloc resection of adjacent involved organs and regional lymph node dissection (the periadrenal, renal hilar and retrocaval or para-aortic nodes), avoiding capsule rupture. Laparoscopy is limited to small localized tumors in expert hands. Thrombus extending into the vena cava needs vascular surgery. Cefazolin 2 g IV before incision (3 g if over 120 kg), and enoxaparin 40 mg SC daily for 28 days after surgery.

• Perioperative glucocorticoid cover when cortisol is secreted (the contralateral gland is suppressed): hydrocortisone 100 mg IV at induction, then 50 mg IV every 6 to 8 hours. Then taper to 15 to 25 mg orally daily in 2 to 3 divided doses. Add fludrocortisone 0.05 to 0.2 mg orally daily when aldosterone deficiency follows. Test the axis before stopping.

• Adjuvant mitotane for high-risk disease (stage III, positive margin, Ki-67 over 10%): start 1.5 g orally daily, increasing every 1 to 2 weeks to 6 g daily in divided doses (maximum 8 to 10 g). Aim for a plasma level of 14 to 20 mg/L (measure every 4 to 6 weeks). Continue for at least 2 years. Adverse effects: nausea, diarrhea, ataxia and confusion, hepatotoxicity, hypercholesterolemia, hypothyroidism and gynecomastia.

  Mitotane causes adrenal insufficiency, so replace hydrocortisone at higher doses (30 to 50 mg daily) with fludrocortisone as needed. Pregnancy must be avoided during treatment and for at least 5 years afterward.

• Metastatic disease: mitotane with etoposide 100 mg/m2 IV on days 2 to 4, doxorubicin 40 mg/m2 IV on day 1 and cisplatin 40 mg/m2 IV on days 3 and 4, every 28 days for up to 6 cycles. Second line: streptozocin. Resection or ablation of oligometastases, and radiotherapy (50 to 60 Gy) to the tumor bed for positive margins and symptomatic metastases.

• Control of hormone excess: metyrapone 250 mg orally twice daily, increasing to a maximum of 6 g daily, or ketoconazole 200 mg orally twice daily, increasing to 400 mg three times daily (monitor liver tests every 2 weeks at first, avoid in liver disease). Spironolactone and antihypertensives for hypokalemia and hypertension.

Follow-up: CT of the chest, abdomen and pelvis every 3 months for 2 years, then every 6 months to year 5, with hormone tests. Counsel on genetic testing of relatives.