What are the recommendations for managing liver nodules?

Management of Liver Nodules

The management of liver nodules depends primarily on nodule size and patient risk factors, with nodules <1 cm requiring ultrasound follow-up every 3-4 months, nodules 1-2 cm requiring multiphasic CT or MRI with biopsy if imaging is inconclusive, and nodules >2 cm diagnosed as HCC based on typical arterial hypervascularity with washout on a single imaging technique. 1, 2

Size-Based Diagnostic Algorithm

Nodules <1 cm

• Perform repeat ultrasound at 3-4 month intervals during the first year 1, 2
• If the nodule shows growth or changing character, investigate according to the larger size category 1
• If stable for 12 months, return to regular six-month surveillance 3
• The Korean guidelines add stricter criteria: nodules <1 cm showing typical hallmarks on two imaging modalities plus elevated AFP and absence of hepatitis activity can be diagnosed as HCC 1

Nodules 1-2 cm

• Obtain multiphasic contrast-enhanced CT or MRI as first-line imaging 1, 2
• In centers of excellence with high-end radiological equipment, one positive imaging technique showing the HCC radiological hallmark (arterial hypervascularity with venous/late phase washout) is sufficient for diagnosis 1
• In sub-optimal settings, two coincidental imaging techniques are recommended to avoid false-positive diagnoses exceeding 10% 1
• If imaging is inconclusive or atypical, proceed to biopsy 1, 3, 2

Nodules >2 cm

• One imaging technique (4-phase CT or dynamic contrast-enhanced MRI) showing typical HCC hallmarks is sufficient for diagnosis 1, 2
• The HCC radiological hallmark consists of arterial hypervascularity with washout in the portal venous or delayed phases 1
• If typical features are absent, biopsy is indicated 1, 4

Advanced Imaging Considerations

Hepatobiliary Contrast Agents

• Multiphasic MRI with hepatocyte-specific contrast agents (gadoxetic acid/Gd-EOB-DTPA) can be used as first-line imaging 1
• For these agents, the radiological hallmarks include arterial hypervascularity with washout in the portal venous, delayed, OR hepatobiliary phases 1
• Apply these criteria only to lesions that do NOT show marked T2 hyperintensity or targetoid appearances on diffusion-weighted or contrast-enhanced images 1

Contrast-Enhanced Ultrasound (CEUS)

• Can be used as a second-line imaging study when first-line CT/MRI is inconclusive 1
• The hallmarks are arterial hypervascularity with late (≥60 seconds) and mild washout, or washout in the Kupffer phase 1
• Do NOT apply CEUS criteria to lesions showing rim or peripheral globular enhancement on arterial phase 1

Biopsy Indications and Technique

When to Biopsy

• Biopsy is mandatory when imaging findings are inconclusive or atypical 1, 3, 2
• Nodules showing arterial hypervascularity alone without washout require either additional imaging or biopsy 1, 4
• Always obtain pathological diagnosis for atypical nodules in non-cirrhotic livers 3, 2

Biopsy Technique and Limitations

• Core needle biopsy is preferred over fine needle aspiration for distinguishing early HCC from dysplastic nodules 3
• Sensitivity ranges from 70-90% depending on nodule location, size, and operator expertise 3
• The risk of needle-tract tumor seeding is approximately 2.7% overall, or 0.9% per year 1, 2
• Immunohistochemical markers (HSP70, GPC3, glutamine synthetase panel) improve diagnostic accuracy with 60% sensitivity and 100% specificity for early HCC 3

Management of Inconclusive Cases

"Probable" HCC Category

• For nodules with arterial hypervascularity but no washout, or nodules lacking arterial hypervascularity but showing ancillary features, assign "probable" HCC 1
• Ancillary features include: mild-to-moderate T2 hyperintensity, restricted diffusion, threshold growth, enhancing/non-enhancing capsule, mosaic architecture, nodule-in-nodule appearance, or fat/blood products 1
• For "probable" HCC, perform follow-up imaging within 3 months or proceed to biopsy 1

"Indeterminate" Nodules

• For nodules that cannot be classified as "definite" or "probable" HCC, perform follow-up imaging within 6 months or biopsy 1
• Use one of the first-line imaging modalities (multiphasic CT or MRI) for follow-up 1

After Inconclusive Biopsy

• Continue imaging surveillance every 3-4 months 3
• Consider repeat biopsy if the nodule shows growth or changes in enhancement pattern 1, 3
• A negative biopsy does NOT rule out HCC if the nodule increases in size during follow-up 1, 2

Critical Pitfalls to Avoid

False-Positive Diagnoses

• High-grade dysplastic nodules can mimic HCC on imaging, with false-positive rates exceeding 10% even with two imaging techniques in nodules 1-2 cm 1
• This is particularly problematic in sub-optimal settings without high-end equipment or expert radiologists 1
• Cholangiocarcinoma and other lesions may show similar enhancement patterns 1

Distinguishing Dysplastic from Neoplastic Nodules

• Dysplastic nodules are difficult to distinguish from early HCC even on biopsy, as stromal invasion is hard to recognize 1, 2
• At least one-third of dysplastic lesions develop malignant phenotype, requiring regular imaging follow-up 1
• High-grade dysplastic nodules warrant consideration for early intervention due to high transformation risk 2

Special Populations

• In patients with prior HCC, newly detected or growing nodules can be diagnosed as recurrent HCC regardless of size if they show radiological hallmarks or ancillary features with size increase 1
• For patients with multiple nodules, focus surveillance on those with higher-risk features 2

Benign Nodule Considerations

Regenerative and Dysplastic Nodules

• Regenerative nodules typically appear small, well-defined, multiple, and peripheral without typical HCC enhancement 2
• Dysplastic nodules may show some enhancement but not the classic HCC pattern 2
• Follow regenerative nodules with ultrasound every 3-4 months for the first year 2

Focal Nodular Hyperplasia (FNH)

• FNH shows strong hyperperfusion from a central artery creating a "spoke-wheel" appearance on CEUS with centrifugal filling and "light bulb" sign 5
• For atypical FNH or uncertain diagnosis, first follow-up at 6 months, then if stable for 12 months, return to normal surveillance 5
• Intervention is rarely required except for diagnostic uncertainty despite appropriate imaging/biopsy 5