What is metastatic hepatocellular carcinoma (HCC) or metastatic disease?

Definition of Metastatic Hepatocellular Carcinoma and Metastatic Disease

Metastatic hepatocellular carcinoma (HCC) refers to HCC that has spread beyond the liver to distant organs, representing advanced disease with poor prognosis and limited treatment options.

Metastatic Disease: General Definition

Metastatic disease is characterized by the spread of cancer cells from the primary tumor site to distant organs through blood vessels, lymphatic system, or direct invasion. This represents advanced cancer with the following key features:

• Cancer cells have detached from the primary tumor
• Invaded surrounding tissues
• Entered circulation (blood or lymphatic)
• Established growth at distant sites

Metastatic HCC: Specific Characteristics

Diagnostic Criteria

Metastatic HCC is defined by:

• Presence of HCC in the liver (primary tumor)
• Evidence of tumor spread to distant organs 1
• Common metastatic sites include:
  • Lungs (most common)
  • Lymph nodes
  • Adrenal glands
  • Bones
  • Brain (less common) 2, 3

Staging and Classification

The Barcelona Clinic Liver Cancer (BCLC) staging system classifies metastatic HCC as:

• Stage C (advanced): HCC with vascular invasion or extrahepatic spread but preserved liver function 1
• Stage D (terminal): End-stage disease with heavily impaired liver function or poor performance status 1

Imaging Characteristics

Metastatic HCC is identified through:

• Dynamic CT or MRI showing:
  • Arterial phase enhancement
  • Portal venous phase washout
  • Late phase hypoattenuation 4
• Chest CT and bone scans to detect distant metastases 1

Clinical Implications of Metastatic Disease

Prognosis

• Metastatic HCC has a poor prognosis with 5-year survival rates as low as 2.5% for advanced metastatic disease 5
• Median survival for untreated metastatic HCC is approximately 7.9 months 6

Treatment Approaches

For metastatic HCC (BCLC stage C):

1. Systemic therapy is the standard treatment:

   • Sorafenib is the first-line treatment for patients with well-preserved liver function 1, 6
   • Median survival with sorafenib is approximately 10.7 months versus 7.9 months with placebo 6

2. Palliative treatments:

   • External beam radiotherapy for bone metastases to control pain 1
   • Symptomatic treatment for end-stage disease 1

3. Clinical trials should be considered when available 1

Pathophysiological Mechanisms

Metastatic progression in HCC involves:

• Epithelial-mesenchymal transition allowing tumor cells to detach 7
• Tumor-stromal interactions and changes in the microenvironment 7
• Cancer stem cells contributing to metastatic potential 7
• Circulating tumor cells entering bloodstream 7
• Immune system evasion 7

Key Distinctions in Management

• Early HCC (BCLC 0-A): Potentially curative treatments (resection, transplantation, ablation)
• Intermediate HCC (BCLC B): Transarterial chemoembolization (TACE)
• Advanced/Metastatic HCC (BCLC C): Systemic therapy with sorafenib or clinical trials
• Terminal HCC (BCLC D): Symptomatic treatment only 1

Common Pitfalls in Diagnosis and Management

1. Diagnostic challenges:

   • Small metastatic lesions (<1 cm) have low detection sensitivity (10-43%) 4
   • Infiltrative HCC has poorly defined borders making detection difficult 4

2. Treatment considerations:

   • Avoid systemic chemotherapy, tamoxifen, immunotherapy, anti-androgens, or somatostatin analogs as they are not recommended for metastatic HCC 1
   • Consider both tumor factors and underlying liver function when planning treatment 8

Understanding metastatic HCC is crucial for appropriate staging, treatment selection, and prognostication in patients with this aggressive malignancy.