What is the appropriate management for an adult patient with elevated alpha-fetoprotein (AFP) and dehydroepiandrosterone (DHEA) levels, potentially indicating underlying malignancy or endocrine disorders?

Management of Elevated AFP and DHEA

When an adult patient presents with elevated AFP and DHEA together, immediately obtain testicular ultrasound in males, pelvic ultrasound in females, multiphasic contrast-enhanced CT or MRI of the abdomen and pelvis, and measure serum β-hCG and LDH to evaluate for germ cell tumors, adrenal malignancy, or hepatocellular carcinoma. 1, 2

Initial Diagnostic Workup

The combination of elevated AFP and DHEA is highly concerning and requires urgent evaluation for two primary malignancies:

Essential Laboratory Tests

• Measure serum β-hCG and LDH immediately alongside AFP, as germ cell tumors frequently produce multiple markers and β-hCG elevation occurs in 40% of advanced nonseminomatous germ cell tumors 1, 2
• Obtain liver function tests (ALT, AST, bilirubin, alkaline phosphatase) as hepatitis, cirrhosis, and hepatocellular carcinoma commonly elevate AFP 2
• Check hepatitis panel (HBsAg, hepatitis B surface antibody, HBcAb, HCV antibodies) since chronic viral hepatitis is a major risk factor for HCC 2

Critical Imaging Studies

• Testicular ultrasound with 7.5 MHz transducer is mandatory in males even if physical examination is normal, as occult testicular tumors can present with only marker elevation 1, 2
• Multiphasic contrast-enhanced CT or MRI of abdomen and pelvis to evaluate for adrenal masses, hepatic lesions, and retroperitoneal or mediastinal primary tumors 2, 1
• CT chest to identify mediastinal primary tumors and pulmonary metastases 1

Interpretation of Combined Elevation

AFP Pattern Recognition

• Cancer-associated AFP shows a consistent rising pattern, and serial measurements demonstrating progressive increases strongly suggest malignancy 1
• AFP >400 ng/mL is highly specific for malignancy but only occurs in 18% of HCC patients; 46% of HCC patients have normal AFP levels <20 ng/mL 2
• Pure seminoma never produces AFP, and significantly elevated AFP in a patient with "pure seminoma" histology indicates mixed germ cell tumor with nonseminomatous elements 2, 1

DHEA Significance

• Elevated DHEA suggests adrenal pathology, particularly androgen-secreting tumors which may present with virilization in women (hirsutism, deepening voice, amenorrhea) 2, 3
• High serum DHEAS occasionally provides great value in predicting adrenal malignancy, especially when combined with clinical virilization 4
• Adrenal tumors secreting more than one hormone raise suspicion for malignancy 2

Differential Diagnosis Priority

Primary Malignancies to Exclude

1. Nonseminomatous germ cell tumor - AFP elevation occurs in 10-20% of stage I and 40-60% of advanced disease 1
2. Adrenocortical carcinoma - suspected when tumor >4 cm, inhomogeneous, HU >20 on unenhanced CT, or secreting multiple hormones 5, 4
3. Hepatocellular carcinoma - elevated AFP with liver mass has high positive predictive value 2

Rare Considerations

• Sertoli-Leydig cell tumors of ovary can present with elevated AFP, ovarian mass, and androgen excess in young females 6
• Pure androgen-secreting adrenal tumors may be benign despite elevated DHEA and large size, though malignancy is difficult to confirm preoperatively 3

Imaging Characteristics Suggesting Malignancy

Adrenal Mass Features

• Malignancy strongly suspected if: tumor >4 cm, inhomogeneous, irregular margins, HU >20 on unenhanced CT, does not wash out on contrast-enhanced CT (enhancement washout <50% at 10-15 minutes) 5, 4
• Benign features: homogeneous lesions with HU ≤10 on unenhanced CT are benign regardless of size 5
• Tumors >6 cm have high risk of malignancy, while almost all lesions <3 cm are benign 4

Hepatic Mass Features

• Classic HCC enhancement pattern: arterial hyperenhancement with washout on portal venous or delayed phases on multiphasic CT or MRI 2
• If no mass detected with rising AFP, repeat imaging with different modality (CT if MRI done initially, or vice versa) 2

Management Algorithm

If Testicular or Retroperitoneal Mass Present

• Do not delay orchiectomy for marker results in males with testicular mass 1
• Measure pre-orchiectomy markers for interpreting post-orchiectomy levels and staging 1
• If rapidly increasing β-hCG with symptoms of disseminated disease, chemotherapy can be initiated immediately without waiting for biopsy diagnosis 2

If Adrenal Mass Present

• Discuss in multidisciplinary expert meeting for all lesions except homogeneous masses with HU ≤10 5
• Open adrenalectomy recommended when malignancy suspected (irregular morphology, lipid-poor, no washout, >3 cm, secreting multiple hormones) as these tumors are prone to rupture 2
• Imaging of chest, abdomen, and pelvis required to evaluate for metastases and local invasion before surgery 2

If Hepatic Mass Present

• Biopsy may be considered when lesion is suspicious for malignancy but multiphasic CT or MRI results do not meet imaging criteria for HCC 2
• Growing mass with negative biopsy does not rule out HCC; continual monitoring with multidisciplinary review including surgeons is recommended 2

If No Mass Identified

• Repeat AFP and DHEA in 2-4 weeks to determine if levels are stable, rising, or falling 1
• Refer to oncology if rising pattern observed 1
• Consider different imaging modality if suspicion remains high despite negative initial imaging 2

Common Pitfalls to Avoid

• Do not assume benign disease based on normal AFP alone - 46% of HCC patients and up to 30% of germ cell tumor patients have normal AFP levels 2, 1
• Do not rely on AFP cutoff values alone - imaging findings of classic enhancement are more definitive than AFP level alone 2
• Do not perform adrenal biopsy unless patient has known extra-adrenal malignancy and suspected adrenal metastasis as only evidence of disseminated disease 4
• Do not assume large adrenal tumors with high FDG uptake are malignant - benign pure androgen-secreting tumors can demonstrate extremely high FDG uptake (SUVmax >40) 3

Follow-Up if Malignancy Confirmed

• Measure AFP, β-hCG, LDH before each treatment cycle if germ cell tumor diagnosed 1
• Post-treatment surveillance: every 2-4 months in first year, every 3-4 months in second year, annually for at least 10 years 1
• Postoperative corticosteroid supplementation required after adrenalectomy until recovery of hypothalamus-pituitary-adrenal axis 2