What is the recommended diagnostic workup, staging, and treatment algorithm for hepatocellular carcinoma?

Hepatocellular Carcinoma: Diagnostic Workup, Staging, and Treatment Algorithm

Diagnostic Workup

For nodules detected on surveillance ultrasound in cirrhotic patients, the diagnostic approach is size-dependent and relies on characteristic imaging features rather than routine biopsy. 1

Nodules <1 cm

• Monitor with ultrasound every 3-6 months 1
• If no growth over 2 years, return to routine 6-month surveillance 1
• If enlargement occurs, proceed to diagnostic algorithm based on new size 1

Nodules 1-2 cm

• Obtain two dynamic imaging studies (multiphasic CT, contrast-enhanced MRI, or contrast ultrasound) 1
• Diagnose as HCC without biopsy if both studies show typical vascular pattern: arterial hyperenhancement with washout in portal/venous phase 1
• Perform biopsy if imaging findings are atypical or discordant between techniques 1

Nodules >2 cm

• Biopsy is not required if one dynamic imaging technique shows typical HCC features (arterial hyperenhancement with washout) 1
• Biopsy is not required if AFP >200 ng/mL in the appropriate clinical context 1
• Biopsy is required if vascular profile is atypical or if the nodule occurs in non-cirrhotic liver 1

Key Imaging Modalities

• Dynamic contrast-enhanced MRI and multiphasic CT are the gold-standard techniques for non-invasive HCC diagnosis 1, 2
• MRI demonstrates superior sensitivity and specificity in nodular cirrhotic livers compared to CT 1, 2
• The diagnostic hallmark is arterial hypervascularity with washout in portal venous or delayed phases 1

Biopsy Considerations

• Small lesion biopsies require evaluation by expert hepatopathologists 1
• Negative biopsy does not exclude HCC; continue imaging surveillance every 3-6 months 1
• Tumor seeding risk ranges from 0-11% with median interval of 17 months 1
• Avoid biopsy in three scenarios: (1) patient unsuitable for any therapy due to comorbidity, (2) decompensated cirrhosis with patient already listed for transplant, (3) patient is resection candidate with acceptable surgical risk 1

Staging System

The Barcelona Clinic Liver Cancer (BCLC) staging system should be used as it integrates tumor burden, liver function (Child-Pugh score), portal hypertension, and performance status to guide treatment decisions. 1, 3, 4

BCLC Stage Definitions

BCLC 0 (Very Early Stage):

• Single tumor <2 cm 3
• Child-Pugh A 3
• Performance status 0 3
• Expected survival >36 months untreated; 5-year survival 50-75% with curative treatment 1, 3, 5

BCLC A (Early Stage):

• Single tumor ≤5 cm OR up to 3 nodules ≤3 cm (Milan criteria) 1, 3
• Child-Pugh A-B 1, 3
• Performance status 0 1, 3
• Expected survival >36 months untreated 1, 5

BCLC B (Intermediate Stage):

• Multinodular tumors 1, 3
• Child-Pugh A-B 1, 3
• Performance status 0 1, 3
• No vascular invasion or extrahepatic spread 1, 5
• Expected survival 16 months untreated 1, 5

BCLC C (Advanced Stage):

• Vascular invasion and/or extrahepatic spread 1, 3
• Child-Pugh A-B 1, 3
• Performance status 1-2 1, 3
• Expected survival 4-8 months untreated 1, 5

BCLC D (End-Stage):

• Any tumor burden 3
• Child-Pugh C (score ≥10) OR performance status 3-4 3, 5
• Expected survival <4 months (often <3 months with Child-Pugh C) 3, 5

Staging Workup

• Contrast-enhanced CT or MRI of abdomen to assess tumor number, size, vascular invasion, and extrahepatic spread 1, 5
• Chest CT to detect pulmonary metastases 1, 5
• Bone scan in advanced disease 1, 5
• Child-Pugh score calculation (bilirubin, albumin, ascites, prothrombin time, encephalopathy) 1, 5
• Assessment for clinically significant portal hypertension: esophageal varices on endoscopy, splenomegaly with platelets <100,000/μL, or hepatic venous pressure gradient >10 mmHg 1, 5
• ECOG performance status assessment 5
• MELD score for transplant candidates 1

Treatment Algorithm by BCLC Stage

BCLC 0 and A (Very Early and Early Stage): Curative Intent

Surgical Resection:

• Preferred for non-cirrhotic patients or highly selected cirrhotic patients 1, 4
• In cirrhosis, resection is safe (mortality <5%) only if: single lesion, Child-Pugh A, no clinically significant portal hypertension, and adequate future liver remnant 1, 4, 5
• Portal hypertension is an absolute contraindication to resection due to high risk of postoperative liver failure 5
• Minimum future liver remnant requirements: ≥20% for normal liver, ≥30% for chronic liver disease, ≥40% for cirrhotic liver 3
• Portal vein embolization may be used to induce hypertrophy when remnant is inadequate 3
• Caveat: Post-resection recurrence occurs in 50-70% within 5 years 3

Liver Transplantation:

• Recommended for patients meeting Milan criteria (single ≤5 cm or up to 3 nodules ≤3 cm) with decompensated cirrhosis 1, 3, 5
• Provides 5-year survival of 65-78%, comparable to non-oncologic transplant indications 3
• Tumor recurrence <15% at 5 years when Milan criteria met 3
• Bridge therapy with RFA or TACE is recommended when waiting time exceeds 6 months to prevent tumor progression and dropout from transplant list 1, 3, 5
• RFA achieves superior complete necrosis rates (12-55%) compared to TACE (22-29%) for bridge therapy 3
• Consider transplantation even in Child-Pugh C if tumor meets Milan criteria, as it cures both tumor and cirrhosis 3, 5

Radiofrequency Ablation (RFA):

• Alternative to resection for single nodule <2 cm (BCLC 0) or early-stage patients unsuitable for resection 1, 4
• RFA provides superior local control compared to percutaneous ethanol injection (PEI), especially for tumors >2 cm 1, 3
• Maximum treatment parameters: ≤5 lesions and cumulative diameter ≤5 cm 1, 3

Adjuvant Therapy:

• Neo-adjuvant or adjuvant therapies are not routinely recommended after resection or ablation 1
• Antiviral therapy is essential for HBV/HCV-related HCC to reduce postoperative decompensation and prevent late recurrence 3, 5

BCLC B (Intermediate Stage): Locoregional Therapy

Transarterial Chemoembolization (TACE):

• Standard of care for multinodular HCC in patients with Child-Pugh A-B, performance status 0, no vascular invasion, and no extrahepatic spread 1, 4, 5
• Provides median survival of 16-22 months 3, 4, 5
• TACE with doxorubicin-eluting beads is preferred to minimize systemic chemotherapy side effects 1
• TACE is contraindicated in Child-Pugh C due to high risk of precipitating acute liver failure 5
• Combination of TACE with sorafenib cannot be recommended outside clinical trials 1

Alternative Approaches:

• Selected BCLC B patients with favorable characteristics may benefit from surgical resection rather than TACE, particularly in expert hepatobiliary centers 4
• Combination therapies (TACE plus RFA or TACE plus radiotherapy) may improve local control in selected cases 3

BCLC C (Advanced Stage): Systemic Therapy

First-Line Systemic Therapy:

• Atezolizumab plus bevacizumab is the current first-line standard for advanced HCC with Child-Pugh A-B and performance status 1-2 4, 6
• Sorafenib was the historical first-line therapy and remains an option 1
• Lenvatinib is an alternative first-line agent 5
• All systemic therapies are approved only for Child-Pugh A patients; Child-Pugh B/C patients were excluded from pivotal trials 5

Second-Line Options:

• Best supportive care is recommended after progression or intolerance to first-line therapy if no other systemic options are available 1

Special Considerations:

• BCLC C patients with limited portal vein invasion (PV1/PV2) may be considered for combined locoregional and systemic approaches 4

BCLC D (End-Stage): Best Supportive Care

Management Approach:

• Best supportive care is the only recommendation for Child-Pugh C (score ≥10) or performance status 3-4 3, 5
• Focus on symptom management: pain control, ascites management, variceal bleeding prevention, nutritional support 5
• Early palliative care involvement improves quality of life 5
• Exception: If tumor meets Milan criteria despite Child-Pugh C, liver transplantation should still be considered 3, 5
• Systemic therapy is poorly tolerated due to underlying cirrhosis, cytopenias, and unpredictable pharmacokinetics 5
• Expected survival <4 months without treatment; <3 months with Child-Pugh C 3, 5

Surveillance and Follow-Up

Post-Treatment Monitoring:

• After curative resection or ablation, perform AFP testing and hepatic imaging every 3-6 months for at least 2 years 3
• Patients on transplant waiting list require imaging every 3 months, AFP measurement, MELD scoring, and surveillance for progression beyond Milan criteria 3
• Monitor for macrovascular invasion or extrahepatic spread that would exclude transplant candidacy 3

Common Pitfalls and Caveats

• Up to one-third of patients do not fit standard BCLC recommendations due to advanced age, comorbidities, or strategic tumor location 3
• The BCLC system was developed and validated primarily in Western populations; Asian guidelines often adopt more aggressive surgical approaches for intermediate-stage disease 1, 3
• Child-Pugh score has limited discriminatory power in Child-Pugh A patients (80% of newly diagnosed HCC); consider ALBI grade for finer prognostic stratification 5
• Portal hypertension must be assessed independently of Child-Pugh score, as it is a critical contraindication to resection regardless of Child-Pugh class 5
• Non-invasive diagnostic criteria apply only to cirrhotic patients; non-cirrhotic patients require biopsy 1
• Fibrolamellar variant of HCC occurs in non-cirrhotic liver, does not elevate AFP, and has more favorable prognosis if resectable 1