Virilising Adrenal Tumour

A virilising adrenal tumour is an androgen secreting adenoma or carcinoma of the adrenal cortex, causing rapid virilisation in women and children and precocious puberty in boys. Most are carcinomas in adults.

Adrenocortical carcinoma has an incidence of about 1 to 2 for each million people each year, with peaks in early childhood and in adults at 40 to 50 years. About half of the functioning carcinomas secrete androgens, often with cortisol.

Southern Brazil has a high childhood incidence from a TP53 variant (R337H), and Li-Fraumeni syndrome also predisposes. Adenomas that secrete only androgens are rare.

Pathophysiology.

Autonomous secretion of dehydroepiandrosterone sulphate, androstenedione and testosterone causes virilisation and suppresses LH and FSH. Cortisol co-secretion causes Cushing syndrome and suppresses ACTH.

Poorly differentiated tumours make steroid precursors inefficiently, so hormones are present but the patient may have mixed or non-specific features.

• Rapid virilisation in women: hirsutism, acne, voice deepening, clitoromegaly, balding and amenorrhoea. In girls and boys: early pubic hair, rapid growth, advanced bone age and, in boys, a prepubertal testis.
• Features of Cushing syndrome in many; abdominal mass, pain, weight loss.

Red flags.

• Rapid virilisation with a large adrenal mass.
• Mixed cortisol and androgen excess, weight loss or abdominal pain.

• Testosterone, androstenedione and dehydroepiandrosterone sulphate (the last markedly raised in adrenal sources), with LH and FSH suppressed. 17-hydroxyprogesterone to exclude congenital adrenal hyperplasia.
• Steroid profiling (including precursors) and cortisol tests: 1 mg overnight dexamethasone suppression (cortisol over 50 nmol/L, 1.8 micrograms/dL, unsuppressed) and ACTH. Plasma metanephrines.
• CT or MRI of the adrenals: large (over 4 cm), heterogeneous mass with high unenhanced density (over 20 Hounsfield units) and poor washout suggests carcinoma. Chest and abdominal CT for staging.
• Pelvic ultrasound and testicular examination. TP53 testing in children and in familial cases.

Differential diagnosis.

• Androgen secreting ovarian tumour (dehydroepiandrosterone sulphate normal).
• Non-classic congenital adrenal hyperplasia, Cushing syndrome and polycystic ovary syndrome.
• Exogenous androgens and ovarian hyperthecosis.

• Surgery: complete resection, open adrenalectomy with en bloc excision for suspected carcinoma, in an experienced adrenal centre. Cover with hydrocortisone 100 mg intravenously at induction then 200 mg over 24 hours if cortisol is co-secreted, then taper with replacement until recovery.
• Adjuvant mitotane for high risk disease (large, incompletely resected, high proliferation index): start about 1.5 to 2 g daily in divided doses and increase over weeks to reach a plasma level of 14 to 20 mg/L (maximum tolerated dose, often 4 to 6 g daily). Lifelong hydrocortisone replacement at higher doses (30 to 50 mg daily) while on mitotane, with fludrocortisone. Monitor liver tests, thyroid function and lipids.
• Metastatic disease: mitotane with etoposide, doxorubicin and cisplatin, or surgery and radiotherapy of metastases.
• Adenomas: laparoscopic adrenalectomy.
• Hirsutism persisting after cure: spironolactone 100 to 200 mg daily with contraception.

Special groups. Children: manage in a paediatric oncology and endocrine team, with TP53 testing and family surveillance. Pregnancy: virilisation of a female foetus is possible, and decisions need specialist input.

Monitoring. Imaging (CT chest, abdomen and pelvis) every 3 months for 2 years then every 3 to 6 months until 5 years, with androgen and cortisol levels as tumour markers.

Referral and escalation. Specialist adrenal multidisciplinary team for all cases; oncology for advanced disease.