What is the diagnostic workup for a patient suspected of having primary hepatocellular carcinoma (HCC)?

Diagnostic Workup for Primary Hepatocellular Carcinoma

The diagnostic workup for suspected HCC requires a structured approach combining clinical assessment, laboratory testing, and imaging studies, with the diagnosis established either by tissue biopsy or by characteristic imaging findings in cirrhotic patients showing arterial hypervascularity with washout on dynamic CT/MRI. 1

Initial Clinical Assessment

History and Physical Examination

• Risk factors for chronic liver disease: intravenous drug use, alcohol intake, hepatitis B/C exposure 1
• Signs of chronic liver disease: jaundice, ascites, hepatic encephalopathy, splenomegaly 1
• Performance status and nutritional state to guide treatment decisions 1
• Constitutional symptoms: weight loss, anorexia, malaise, fever, upper abdominal pain (these typically indicate advanced disease) 2

Laboratory Evaluation

Essential Laboratory Tests

• Etiology of liver disease: hepatitis B surface antigen, hepatitis C antibody, iron studies, autoimmune markers 1, 3
• Liver function assessment: prothrombin time, serum albumin, bilirubin 1
• Platelet count (marker of portal hypertension) 1, 3
• Serum alpha-fetoprotein (AFP): 1, 3
  • AFP >200 ng/mL with typical imaging features allows diagnosis without biopsy 3
  • AFP >500 ng/mL in cirrhotic patients is diagnostic 1
  • However, 35-40% of HCC cases have normal AFP levels 4
  • AFP alone should never be used as the only diagnostic test 4

Optional Laboratory Tests

• Gamma-carboxyprothrombin (des-gamma-carboxy prothrombin) if AFP is normal in cirrhotic patients (exclude vitamin K deficiency first) 1

Imaging Studies

Primary Diagnostic Imaging

Dynamic contrast-enhanced imaging is the cornerstone of HCC diagnosis: 1

• Multiphasic CT or dynamic contrast-enhanced MRI (standard approach) 1, 3

  • Must demonstrate the typical vascular hallmark: arterial phase hypervascularity with washout in portal venous or delayed phases 1, 3
  • This pattern is diagnostic for HCC in cirrhotic patients without requiring biopsy 1

• Evaluation of tumor extent: number and size of nodules, vascular invasion, extrahepatic spread 1

Assessment of Distant Metastases

• Chest imaging: 1

  • Chest X-ray for initial screening 1
  • Chest CT if liver transplant is planned or if chest X-ray is abnormal 1
  • Consider chest CT in advanced disease 1

• Bone scan if clinically indicated (symptoms suggesting bone metastases) 1

Assessment of Portal Hypertension

Endoscopic Evaluation

• Upper endoscopy to evaluate for esophagogastric varices and hypertensive gastropathy (mandatory in cirrhotic patients) 1

Optional Assessment

• Transjugular measurement of hepatic-venous pressure gradient (optional, for precise portal pressure assessment) 1

Tissue Diagnosis

When Biopsy is Required

Biopsy is NOT indicated in three specific scenarios: 1

1. Patient not a candidate for any therapy due to serious comorbidity
2. Decompensated cirrhosis with patient on transplant waiting list
3. Patient is candidate for resection with acceptable surgical risk

When Biopsy is Indicated

• Non-cirrhotic patients with suspected HCC 1
• Atypical imaging findings that don't show characteristic vascular pattern 1
• Diagnostic uncertainty differentiating HCC from adenoma, cholangiocarcinoma, or metastatic lesion 1

Biopsy Technique

• Obtained by ultrasound or CT-guided biopsy, laparoscopy, or open surgery 1
• Should include surrounding non-tumoral parenchyma for comparison 1
• Fine-needle aspiration cytology is an option if core biopsy not possible 1

Histological Diagnosis

• Stromal invasion (tumor cell invasion into portal tracts or fibrous septa) defines HCC and distinguishes it from dysplastic lesions 1
• Immunohistochemical staining (keratin subtypes, reticulin staining, glypican-3) may help differentiate HCC from other lesions 1

Staging Assessment

Staging is critical for determining prognosis and optimal therapy: 1

• Barcelona Clinic Liver Cancer (BCLC) staging system should be used in patients with underlying cirrhosis 1
• Staging incorporates: tumor extent, liver function (Child-Pugh classification), portal pressure, and clinical performance status 1
• TNM classification is standard for patients undergoing surgical resection 1

Critical Pitfalls to Avoid

• Do not rely on AFP alone for diagnosis—up to 40% of HCC cases have normal AFP 4, 5
• Do not perform biopsy when typical imaging findings are present in cirrhotic patients, as this adds unnecessary risk 1
• Do not use CT/MRI for surveillance screening—these are diagnostic tools, not screening modalities 4
• Ensure imaging is performed with proper technique—multiphasic studies are essential; single-phase imaging is inadequate 1, 6