What is the diagnosis and management for a patient with a history of hepatocellular carcinoma (HCC) post-hepatectomy, presenting with characteristic microscopy and immunohistochemistry results?

Diagnosis: Recurrent Hepatocellular Carcinoma (HCC)

The histopathological features—trabecular and pseudoglandular architecture, polygonal cells with moderate cytoplasm, hyperchromatic nuclei with prominent nucleoli, Mallory-Denk bodies, and positive glypican-3 with negative CK7/CK20—confirm recurrent hepatocellular carcinoma in this post-hepatectomy patient. 1

Pathological Confirmation

The microscopic and immunohistochemical findings are diagnostic for HCC based on established criteria:

• Architectural features: Trabecular pattern (>2 cells broad), pseudoglandular arrangement, and sinusoidal lining are classic histological hallmarks of HCC 1
• Cytological features: Polygonal tumor cells with moderate cytoplasm, moderately pleomorphic hyperchromatic nuclei, and prominent eosinophilic nucleoli support HCC diagnosis 1
• Diagnostic inclusions: Mallory-Denk bodies and intranuclear pseudoinclusions are characteristic features of hepatocellular differentiation 1
• Immunohistochemistry: Glypican-3 positivity is part of the validated diagnostic panel (glypican-3, glutamine synthetase, HSP70) with 100% specificity for HCC when 2/3 markers are positive 1
• Exclusion of cholangiocarcinoma: Negative CK7 and CK20 effectively rule out intrahepatic cholangiocarcinoma and combined HCC-CC, which is critical since these require different therapeutic approaches 1

The absence of macrotrabecular pattern is favorable, as this subtype is associated with poor prognosis 1.

Staging and Risk Assessment

Comprehensive staging must be performed immediately to determine treatment eligibility and prognosis:

• Imaging for tumor extent: Multiphasic contrast-enhanced CT or MRI of the chest, abdomen, and pelvis to assess number/size of nodules, vascular invasion, and extrahepatic spread 1
• Liver function assessment: Child-Pugh score (bilirubin, albumin, ascites, prothrombin time, encephalopathy) and ALBI score to stratify prognosis within Child-Pugh A patients 1
• Portal hypertension evaluation: Endoscopy for esophagogastric varices and platelet count (<100 × 10⁹/L suggests clinically significant portal hypertension) 1
• Serum AFP level: Prognostic marker, though not diagnostic 1
• Performance status: ECOG score to determine treatment tolerance 1

Management Algorithm

For Resectable Recurrence (Child-Pugh A, No Portal Hypertension):

Surgical re-resection is the preferred curative option if technically feasible with adequate future liver remnant and no extrahepatic disease. 1

• Carefully selected Child-Pugh A patients without portal hypertension are candidates for repeat hepatectomy 1
• Liver transplantation may be considered if within Milan criteria (single lesion ≤5 cm or up to 3 lesions ≤3 cm each) with 5-year survival of 70-80% 2

For Unresectable Recurrence:

First-line systemic therapy with lenvatinib is indicated for unresectable HCC:

• Lenvatinib dosing: 12 mg orally once daily for patients ≥60 kg or 8 mg once daily for patients <60 kg, continued until disease progression or unacceptable toxicity 3
• Alternative first-line option: Atezolizumab plus bevacizumab (immune checkpoint inhibitor-based therapy) 4, 5

For Intermediate-Stage Disease (Preserved Liver Function):

Locoregional therapies are appropriate:

• Transarterial chemoembolization (TACE) for patients with Child-Pugh A/B liver function and no vascular invasion or extrahepatic spread 2, 5
• Radiofrequency ablation for small lesions (<3 cm) not amenable to surgery 6, 5

Critical Management Considerations

Multidisciplinary tumor board review is mandatory to integrate tumor burden, liver function, performance status, and available expertise into treatment decisions 1, 4, 5.

Key prognostic factors to document:

• Tumor differentiation grade (well/moderate/poor) has prognostic value in surgical series 1
• Vascular invasion status significantly impacts prognosis 1
• Time to recurrence after initial hepatectomy (early recurrence <1 year indicates aggressive biology) 7

Surveillance strategy post-treatment:

• Multiphasic CT or MRI every 3 months for the first year, then every 3-6 months 1, 4
• Serum AFP monitoring at each visit 4, 5

Common Pitfalls to Avoid

• Do not delay biopsy when imaging is atypical or inconclusive; the risk of needle track seeding is only 2.7% and does not affect overall survival 1
• Do not use liver transplantation if >50% cholangiocarcinoma component is present (though not applicable here given negative CK7/CK20), as this is associated with poor survival outcomes 7
• Do not initiate systemic therapy without confirming Child-Pugh status, as decompensated cirrhosis (Child-Pugh C) is a contraindication to most systemic agents 3
• Monitor for lenvatinib toxicities: hypertension, cardiac dysfunction, hepatotoxicity, proteinuria, and diarrhea require dose modifications or discontinuation 3