Definition/General
Introduction:
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy
Accounts for 85-90% of primary liver cancers
Major cause of cancer death worldwide
Strong association with chronic liver disease
FNAC shows characteristic hepatocellular differentiation.
Origin:
Arises from hepatocytes (liver parenchymal cells)
Develops in setting of chronic liver disease and cirrhosis
Multistep carcinogenesis from dysplastic nodules
Results from chronic inflammation and regeneration
Viral hepatitis major etiological factor.
Classification:
WHO classification based on differentiation grade
Well-differentiated (Grade 1)
Moderately differentiated (Grade 2)
Poorly differentiated (Grade 3)
Undifferentiated (Grade 4)
Variants: fibrolamellar, scirrhous, clear cell.
Epidemiology:
Major global health problem with 782,000 deaths annually
Male predominance (M:F = 3:1)
Peak incidence 5th-6th decades
High incidence in Asia-Pacific region
India: 20,000+ new cases annually.
Clinical Features
Presentation:
Right upper quadrant pain (most common)
Hepatomegaly and abdominal mass
Ascites and jaundice
Weight loss and cachexia
Underlying cirrhosis signs
Portal hypertension complications.
Symptoms:
Abdominal pain (60-90%)
Abdominal distension
Weight loss (50-80%)
Early satiety
Jaundice (20-40%)
Peripheral edema
Bone pain (metastases)
Paraneoplastic syndromes.
Risk Factors:
Hepatitis B virus (most important globally)
Hepatitis C virus (major in developed countries)
Alcohol-related cirrhosis
NAFLD/NASH
Aflatoxin exposure
Hemochromatosis
Alpha-1-antitrypsin deficiency.
Screening:
Alpha-fetoprotein (AFP) and ultrasound every 6 months
High-risk patients (cirrhosis, chronic hepatitis)
CT/MRI for further characterization
EUS-FNAC for tissue diagnosis when imaging non-diagnostic.
Master Hepatocellular Carcinoma FNAC Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Variable appearance depending on background liver
Single large mass (50%) or multiple nodules
Tan-yellow to green coloration
Areas of hemorrhage and necrosis
May show central scarring.
Characteristics:
Soft to firm consistency
Variegated cut surface
Hemorrhage and necrosis common
Bile production may be evident (green discoloration)
Central stellate scar in fibrolamellar variant.
Size Location:
Size ranges from small nodules to massive tumors
Multifocal disease common (70%)
Right lobe more commonly involved
May involve both lobes
Portal/hepatic vein invasion frequent.
Multifocality:
Multifocal disease in 70% of cases
Satellite nodules around main tumor
May represent intrahepatic metastases
Multinodular type common in cirrhotic livers.
Microscopic Description
Histological Features:
Malignant cells with hepatocellular differentiation
Trabecular, pseudoacinar, solid patterns
Increased nuclear-cytoplasmic ratio
Prominent nucleoli
Bile production
Sinusoidal invasion
Loss of reticulin framework.
Cellular Characteristics:
Large polygonal cells resembling hepatocytes
Abundant eosinophilic cytoplasm
Round to oval nuclei with coarse chromatin
Prominent nucleoli
Intracytoplasmic bile (pathognomonic)
Mallory-Denk bodies occasional.
Architectural Patterns:
Trabecular pattern (most common)
Pseudoacinar pattern with bile in center
Solid pattern (poorly differentiated)
Compact pattern
Scirrhous pattern (rare)
Macrotrabecular pattern.
Grading Criteria:
Edmondson-Steiner grading: Grade I (well-differentiated, resembles hepatocytes)
Grade II (moderate differentiation)
Grade III (poor differentiation)
Grade IV (undifferentiated)
Nuclear grade and architectural pattern.
Immunohistochemistry
Positive Markers:
Hepatocyte Paraffin 1 (HepPar1) - highly specific
Arginase-1 - highly sensitive and specific
Glypican-3 - useful in poorly differentiated cases
Alpha-fetoprotein - variable (30-60%)
Albumin in-situ hybridization
CD10 canalicular pattern.
Negative Markers:
CK7, CK19 typically negative (bile duct markers)
CEA negative (polyclonal)
TTF-1 negative
CDX2 negative
Chromogranin A negative
MOC-31 negative.
Diagnostic Utility:
HepPar1 and Arginase-1 diagnostic combination
Glypican-3 distinguishes from adenoma
CD10 canalicular staining supportive
Helps distinguish from cholangiocarcinoma and metastases
Combined panel essential.
Molecular Subtypes:
Proliferation class (S1-S3 based on gene expression)
Non-proliferation class
CTNNB1-mutated subclass
Immune class
Recently defined by molecular profiling for targeted therapy.
Molecular/Genetic
Genetic Mutations:
TERT promoter mutations (54% of HCC)
CTNNB1 mutations (27%)
TP53 mutations (21%)
AXIN1 mutations (8%)
RB1 alterations
ARID1A mutations
MYC amplification.
Molecular Markers:
Alpha-fetoprotein (AFP) elevated in 60-70%
AFP-L3 (lectin-reactive AFP)
Des-gamma-carboxy prothrombin (DCP/PIVKA-II)
Glypican-3 overexpression
Genomic instability common.
Prognostic Significance:
CTNNB1 mutations associated with better prognosis
TP53 mutations indicate aggressive behavior
Satellite lesions worsen prognosis
Vascular invasion major prognostic factor
Molecular classification guides treatment.
Therapeutic Targets:
Sorafenib (multi-kinase inhibitor)
Lenvatinib (first-line therapy)
Regorafenib (second-line)
Pembrolizumab (immunotherapy)
Cabozantinib
Ramucirumab (anti-VEGFR2).
Differential Diagnosis
Similar Entities:
Cholangiocarcinoma (intrahepatic)
Metastatic carcinoma to liver
Hepatocellular adenoma
Combined hepatocellular-cholangiocarcinoma
Angiomyolipoma
High-grade dysplastic nodule.
Distinguishing Features:
HCC: HepPar1, Arginase-1 positive
HCC: Trabecular pattern, bile production
Cholangiocarcinoma: CK7, CK19 positive
Metastases: Organ-specific markers
Adenoma: Glypican-3 negative.
Diagnostic Challenges:
Poorly differentiated HCC vs metastases
Well-differentiated HCC vs adenoma
Combined tumors with mixed features
Fibrolamellar variant vs focal nodular hyperplasia
Sampling adequacy in FNAC.
Rare Variants:
Fibrolamellar carcinoma (young patients, no cirrhosis)
Scirrhous HCC (abundant fibrosis)
Clear cell variant
Pleomorphic giant cell
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
FNAC from liver mass, [location], [number] passes
Clinical Information
AFP: [level] ng/ml, Background: [cirrhosis/normal]
Adequacy
Specimen is adequate for diagnosis
Cellular Findings
Highly cellular smears showing [malignant hepatocytes]
Cell Morphology
Large polygonal cells with [cytoplasmic] and [nuclear] features
Hepatocellular Features
Shows hepatocellular differentiation with [bile/trabecular pattern]
Background
Background liver shows [cirrhosis/normal hepatocytes]
Immunocytochemistry
HepPar1: [result], Arginase-1: [result], CK7: [result]
Final Diagnosis
FNAC liver: Hepatocellular carcinoma, [grade]