Definition/General
Introduction:
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, representing 75-85% of primary liver cancers
It is the third leading cause of cancer-related death worldwide.
Origin:
Arises from hepatocytes through multistep carcinogenesis process
Most cases (80-90%) develop in the setting of chronic liver disease and cirrhosis
Dysplastic nodules are precursor lesions.
Classification:
WHO Classification includes conventional hepatocellular carcinoma and variants (fibrolamellar, scirrhous, clear cell, steatohepatitic)
Molecular classification emerging based on genomic profiling.
Epidemiology:
Higher incidence in Sub-Saharan Africa, East Asia due to hepatitis B
Male predominance (3-4:1)
Peak incidence 50-70 years
Rising incidence in Western countries due to hepatitis C.
Clinical Features
Presentation:
Abdominal pain and distension
Hepatomegaly
Weight loss
Jaundice (advanced cases)
Ascites
Variceal bleeding
Hepatic decompensation in cirrhotic patients.
Symptoms:
Right upper quadrant pain
Fatigue and weakness
Loss of appetite
Nausea and vomiting
Abdominal swelling
Early satiety
Bone pain (metastases).
Risk Factors:
Chronic hepatitis B infection (major risk factor in Asia/Africa)
Chronic hepatitis C infection (major risk factor in Western countries)
Cirrhosis (any cause)
Aflatoxin B1 exposure
Alcohol abuse.
Screening:
Alpha-fetoprotein (AFP) elevated in 60-70%
Ultrasound surveillance in high-risk patients
CT/MRI for diagnosis
PIVKA-II (des-gamma-carboxyprothrombin) useful adjunct.
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Gross Description
Appearance:
Three growth patterns: solitary large mass, multifocal nodules, diffuse infiltrative
Color varies from tan to green (bile)
Soft to firm consistency depending on differentiation.
Characteristics:
Well-demarcated nodules with pseudocapsule
Central necrosis and hemorrhage common
Bile staining may be present
Vascular invasion frequent.
Size Location:
Can involve any hepatic segment
Solitary masses typically >5 cm
Multifocal disease more common in cirrhotic livers
Portal vein invasion common.
Multifocality:
Multifocal in 50% of cases
Intrahepatic metastases vs multicentric origin difficult to distinguish
Satellite nodules within 2 cm of main tumor.
Microscopic Description
Histological Features:
Hepatocytes arranged in trabeculae, sheets, or pseudoglandular pattern
Nuclear pleomorphism
Increased nuclear-cytoplasmic ratio
Mitotic activity variable.
Cellular Characteristics:
Large polygonal cells resembling hepatocytes
Abundant eosinophilic cytoplasm
Enlarged hyperchromatic nuclei
Prominent nucleoli
Mallory-Denk bodies possible.
Architectural Patterns:
Trabecular (most common)
Pseudoglandular (acinar)
Solid/compact
Scirrhous (rare)
Mixed patterns frequent
Sinusoidal capillarization.
Grading Criteria:
Well differentiated (Grade I): Thin trabeculae, minimal atypia
Moderately differentiated (Grade II): Thick trabeculae, moderate atypia
Poorly differentiated (Grade III-IV): Solid growth, marked atypia.
Immunohistochemistry
Positive Markers:
Hep Par-1 positive (85-90%)
Arginase-1 positive (95%)
Glypican-3 positive (85%)
AFP positive (variable, 50-70%)
Albumin in situ hybridization positive.
Negative Markers:
CK7 negative (usually)
CK20 negative
CEA negative
MOC-31 negative
Ber-EP4 negative
TTF-1 negative.
Diagnostic Utility:
Hep Par-1 and Arginase-1 confirm hepatocytic differentiation
Glypican-3 useful for poorly differentiated tumors
Combined panel increases sensitivity.
Molecular Subtypes:
Proliferation class vs nonproliferation class
Wnt/β-catenin activated subgroup
TP53-mutated subgroup
Immune class with better prognosis.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (30%)
CTNNB1/β-catenin mutations (25%)
TERT promoter mutations (55%)
AXIN1 mutations (15%)
ARID1A mutations (15%).
Molecular Markers:
Chromosomal instability high
β-catenin nuclear accumulation in mutated cases
Hepatitis B integration sites may activate oncogenes.
Prognostic Significance:
Microvascular invasion most important histologic prognostic factor
Molecular subtyping may guide therapy
Early-stage disease has better prognosis.
Therapeutic Targets:
Sorafenib (multi-kinase inhibitor)
Lenvatinib (first-line)
Regorafenib (second-line)
Immunotherapy (nivolumab, pembrolizumab)
Ramucirumab (VEGFR2 inhibitor).
Differential Diagnosis
Similar Entities:
Metastatic adenocarcinoma
Cholangiocarcinoma
Combined hepatocellular-cholangiocarcinoma
Hepatoblastoma (children)
Dysplastic nodule
Hepatocellular adenoma.
Distinguishing Features:
HCC: Hep Par-1+, Arginase-1+, trabecular pattern
Metastatic adenocarcinoma: organ-specific markers, glandular architecture
Cholangiocarcinoma: CK7+, mucin+.
Diagnostic Challenges:
Well-differentiated HCC vs dysplastic nodule
Poorly differentiated HCC vs metastatic carcinoma
Recognition of fibrolamellar variant.
Rare Variants:
Fibrolamellar carcinoma (young patients, no cirrhosis)
Scirrhous HCC (extensive fibrosis)
Clear cell variant
Sarcomatoid HCC
Combined HCC-cholangiocarcinoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Liver resection specimen, [location], measuring [size] cm
Tumor Characteristics
[Single/Multiple] nodule(s), largest measuring [X] x [Y] x [Z] cm
Histologic Type
Hepatocellular carcinoma, [conventional/variant] type
Histologic Grade
[Well/Moderately/Poorly] differentiated (Grade [I/II/III])
Background Liver
Background liver shows [cirrhosis/fibrosis/normal], [etiology if known]
Vascular Invasion
Microvascular invasion: [Present/Absent], Macrovascular invasion: [Present/Absent]
Margins
Surgical margins: [negative/positive], closest margin [distance] cm
Satellite Nodules
Satellite nodules within 2 cm: [Present/Absent]
AFP Correlation
Serum AFP: [level] ng/mL (if available)
Immunohistochemistry
Hep Par-1: [positive/negative], Arginase-1: [positive/negative], Glypican-3: [positive/negative]
Staging
AJCC Stage: [I/II/III/IV], Barcelona Clinic Liver Cancer Stage: [0/A/B/C/D]
Final Diagnosis
Final diagnosis: Hepatocellular carcinoma, [grade], [staging information]