What is the diagnostic workup for a patient suspected of having an androgen-secreting solid tumor?

Diagnostic Workup for Suspected Androgen-Secreting Solid Tumor

When an androgen-secreting solid tumor is suspected based on rapid-onset virilization or severe hyperandrogenism, the workup must simultaneously localize the tumor and quantify hormonal hypersecretion through comprehensive biochemical testing and cross-sectional imaging of both the adrenal glands and ovaries. 1, 2

Clinical Assessment

Key Historical Features to Elicit

• Assess the rapidity and severity of symptom onset - androgen-secreting tumors characteristically cause rapidly progressive virilization over weeks to months, distinguishing them from chronic conditions like PCOS 2, 3
• Document specific virilizing symptoms: hirsutism, acne, frontal/male pattern balding, clitoral enlargement, voice deepening, increased muscle mass, and secondary amenorrhea in premenopausal women 2, 4
• In postmenopausal women, any signs of hyperandrogenism should raise immediate suspicion for an androgen-secreting tumor 2

Biochemical Evaluation

Essential Hormone Measurements

• Serum total testosterone - basal levels >7 nmol/L (>200 ng/dL) strongly suggest an androgen-secreting tumor rather than functional hyperandrogenism 3
• DHEA-S (dehydroepiandrosterone sulfate) - markedly elevated levels suggest adrenal origin, though some ovarian tumors can also produce DHEA-S 1, 5, 4
• Androstenedione - elevated in both adrenal and ovarian androgen-secreting tumors 1, 6, 5
• 17-hydroxyprogesterone - may be elevated in steroid cell tumors affecting early steroidogenic pathways 1, 5
• 24-hour urinary 17-ketosteroids - elevated in seven of nine patients with androgen-secreting adrenal tumors in one series 4

Critical Additional Endocrine Testing

• 1 mg overnight dexamethasone suppression test - mandatory to exclude autonomous cortisol co-secretion, as approximately 50% of androgen-secreting adrenal tumors may co-secrete cortisol 1, 6
• Plasma-free or urinary-fractionated metanephrines - essential to rule out pheochromocytoma before any intervention, as biopsy or surgery without alpha-blockade can precipitate fatal hypertensive crisis 7, 1, 8
• Aldosterone-to-renin ratio - if hypertension or hypokalemia present 1

Imaging Studies

First-Line Imaging

• Unenhanced CT of the abdomen and pelvis - identifies and characterizes both adrenal and ovarian masses; adrenal lesions <10 Hounsfield units suggest benign lipid-rich adenomas, while higher attenuation raises concern for malignancy 1, 8
• Pelvic ultrasound - evaluates ovarian masses, particularly useful as Sertoli-Leydig cell tumors (the most common androgen-secreting ovarian tumor) are typically unilateral 7, 2

Additional Imaging When Indicated

• Multiphase CT or chemical-shift MRI - for indeterminate adrenal lesions to assess washout characteristics and lipid content 1
• Chest CT - mandatory if adrenal mass >4 cm or if malignancy suspected, to evaluate for metastases 7, 1

Tumor Localization Strategy

Distinguishing Adrenal vs. Ovarian Origin

• DHEA-S levels >700 mcg/dL strongly favor adrenal origin, though this is not absolute 4, 3
• Ovarian tumors typically present with testosterone elevation disproportionate to DHEA-S 2, 3
• Most androgen-secreting ovarian tumors are sex cord-stromal tumors (Sertoli-Leydig cell tumors most common at 0.5% of ovarian neoplasms), typically unilateral and often benign 7, 2
• Androgen-secreting adrenal tumors are extraordinarily rare, with approximately 50% being malignant; benign tumors average 44g and 4.2 cm while malignant tumors average 232g and 9.8 cm 4

When Imaging is Equivocal

• Selective venous sampling (adrenal and ovarian veins) can lateralize hormone production when imaging fails to identify a clear source 3
• Consider functional testing with GnRH agonist to assess ovarian contribution 3

Critical Pitfalls to Avoid

• Never biopsy a suspected androgen-secreting adrenal mass before excluding pheochromocytoma - this can precipitate fatal hypertensive crisis 7, 1, 8
• Do not assume isolated androgen excess; always screen for co-secretion of cortisol, as this significantly impacts perioperative management 1, 6
• Adrenal masses >4 cm with androgen secretion have higher malignancy risk and warrant aggressive surgical approach rather than laparoscopic resection 1, 4
• In premenopausal women, do not delay workup assuming PCOS when virilization is rapid or severe 2, 3

Multidisciplinary Evaluation

All patients with suspected androgen-secreting tumors should be discussed in a multidisciplinary team meeting involving endocrinology, gynecology/urology, and radiology before definitive intervention 7, 1, particularly when:

• Imaging shows masses in both adrenal and ovarian locations
• Hormone levels are markedly elevated (testosterone >28 nmol/L has been reported) 5
• Tumor size suggests possible malignancy (>4 cm adrenal, any solid ovarian mass with virilization) 1, 4