In a male with elevated serum human chorionic gonadotropin (hCG) and high‑normal follicle‑stimulating hormone (FSH) and luteinizing hormone (LH), does this indicate a testicular or other malignancy and what evaluation is recommended?

Elevated hCG in Males: Cancer Evaluation

An elevated serum hCG in a male patient is highly concerning for a germ cell tumor (GCT) and warrants immediate comprehensive evaluation including testicular ultrasound, serum AFP and LDH measurement, and CT imaging of the chest, abdomen, and pelvis to identify testicular, retroperitoneal, or mediastinal malignancy. 1

Immediate Diagnostic Workup Required

When a male presents with elevated serum hCG, the following must be obtained urgently:

• Testicular ultrasound (using 7.5 MHz transducer) even if physical examination is normal, as occult testicular tumors can present with only marker elevation 1, 2
• Serum AFP and LDH measured concurrently, as GCTs frequently produce multiple markers (hCG elevation occurs in 40% of advanced nonseminomatous GCTs, AFP in 40-60%) 1, 2
• CT chest, abdomen, and pelvis to identify retroperitoneal or mediastinal primary tumors, which occur in young men with midline masses 1, 2

Critical Interpretation of hCG Levels with High-Normal FSH/LH

The combination of elevated hCG with high-normal FSH and LH creates a diagnostic challenge that requires careful interpretation:

True Tumor-Derived hCG

• When beta-hCG exceeds 100 U/L, it causes subtotal inhibition of FSH secretion 3
• If FSH/LH remain high-normal or elevated despite elevated hCG, this suggests the hCG may NOT be tumor-derived 3
• For adequate interpretation of elevated beta-hCG, FSH values from the same serum sample are necessary to determine if the hCG is tumor-derived 3

False-Positive hCG Considerations

Several non-malignant causes must be excluded before initiating cancer treatment:

• Heterophilic antibodies are the most common cause of false-positive serum hCG, particularly in patients exposed to animal antigens 4, 5
• Key diagnostic clue: obtain urine hCG immediately - heterophilic antibodies in blood rarely appear in urine, so a positive serum with negative urine hCG indicates false-positive 4
• Hypogonadism (from prior orchiectomy or other causes) increases pituitary LH production, which can cross-react with some hCG assays 4, 6
• Marijuana use has been associated with elevated hCG levels 1, 4
• Cross-reaction with LH occurs when beta-hCG values exceed 100 U/L, making true LH levels unassessable 3

Diagnostic Algorithm for Elevated hCG in Males

1. Confirm the elevation is real:

   • Obtain urine beta-hCG immediately 4
   • If serum positive but urine negative, suspect heterophilic antibodies 4
   • Measure beta-hCG using a different commercial assay to identify assay-specific interference 4

2. Assess FSH/LH relationship:

   • If beta-hCG >100 U/L with suppressed FSH, this strongly suggests tumor-derived hCG 3
   • If beta-hCG elevated with high-normal or elevated FSH (>50 U/L), the hCG may be pituitary-derived or cross-reactive with LH, not tumor-derived 3

3. Complete malignancy workup:

   • Testicular ultrasound 1, 2
   • Serum AFP and LDH 1
   • CT chest/abdomen/pelvis 1, 2

4. Serial measurements:

   • Cancer-associated hCG shows consistent rising pattern 2
   • Stable, modestly elevated hCG without serial increase and no tumor evidence suggests false-positive 6

Tumor Marker Patterns in GCTs

Understanding which tumors produce which markers is essential:

• Pure seminoma: 15-20% have elevated hCG in advanced disease, but AFP is NEVER elevated 1, 2
• Nonseminomatous GCT: 40% have elevated hCG in advanced disease, 40-60% have elevated AFP 1, 2
• At least one marker (hCG, AFP, or LDH) is elevated in 91% of patients with advanced nonseminomatous GCT 7

Common Pitfalls to Avoid

• Never initiate chemotherapy based solely on elevated serum hCG without confirming with urine testing and imaging 4
• A discordant hCG result should be suspected when hCG is only modestly elevated, shows no serial increase, and no other tumor evidence exists 6
• False-positive hCG has led to inappropriate chemotherapy in male cancer patients, including second- and third-line regimens 5
• If substantially elevated AFP or hCG is present with testicular, retroperitoneal, or anterior mediastinal mass and urgent treatment is needed, this may be considered sufficient for GCT diagnosis without waiting for histology 1

Management Based on Findings

If imaging reveals a testicular or extragonadal mass:

• Do not delay orchiectomy for marker results 2
• Measure pre-orchiectomy markers for interpreting post-orchiectomy levels and staging 1
• Post-orchiectomy markers should be measured to determine if levels normalize (hCG half-life 1.5-3 days, AFP 5-7 days) 1

If no mass is identified:

• Repeat hCG in 2-4 weeks to determine if levels are stable, rising, or falling 2
• Consider referral to oncology if rising pattern observed 2
• Investigate other causes: check liver function tests, assess for hypogonadism, obtain urine hCG 4, 2