Definition/General
Introduction:
Liver metastasis represents secondary malignant deposits from distant primary tumors
It accounts for 90-95% of hepatic malignancies
FNAC is highly effective for diagnosing metastatic disease
Common primaries include colorectal, lung, breast, and pancreatic carcinomas.
Origin:
Originates from distant primary malignancies via hematogenous spread
Liver receives dual blood supply (portal and systemic circulation)
This makes it a common site for metastases
Tumor cells lodge in hepatic sinusoids
They proliferate and form secondary deposits
Portal venous drainage from GI tract explains colorectal predominance.
Classification:
Classified by primary tumor origin
Most common: adenocarcinoma (colorectal, pancreatic, breast, lung)
Squamous cell carcinoma (lung, head/neck, cervix)
Neuroendocrine tumors (GI tract, pancreas)
Melanoma (skin, mucosal sites)
Renal cell carcinoma
Sarcomas (rare)
Pattern of spread: solitary vs multiple nodules.
Epidemiology:
More common than primary liver cancer (20:1 ratio)
Peak incidence in 5th-7th decades
Most common primaries: colorectal (40-50%)
Lung (20-30%)
Breast (10-15%)
Pancreas (5-10%)
Unknown primary (5-10%)
Indian population shows increasing incidence with lifestyle changes.
Clinical Features
Presentation:
Hepatomegaly (most common finding)
Abdominal pain (right upper quadrant)
Weight loss and fatigue
Jaundice (when bile ducts involved)
Ascites (extensive disease)
Palpable liver masses
Constitutional symptoms (fever, night sweats).
Symptoms:
Often asymptomatic in early stages
Abdominal fullness and discomfort
Nausea and vomiting
Loss of appetite
Back pain (when diaphragm involved)
Dyspnea (large hepatomegaly)
Symptoms from primary tumor site
Paraneoplastic syndromes (rare).
Risk Factors:
History of malignancy (most important factor)
Colorectal cancer (highest liver metastasis rate)
Advanced age (>50 years)
Multiple primary tumors
Synchronous presentation (liver metastases at primary diagnosis)
Poor differentiation of primary tumor
Vascular invasion in primary tumor.
Screening:
Tumor markers: CEA (colorectal), CA 19-9 (pancreatic), AFP (rare)
Imaging surveillance in cancer patients
CT/MRI with contrast (best detection)
PET-CT for unknown primary
Ultrasound for follow-up
Liquid biopsy (emerging technology).
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Gross Description
Appearance:
FNAC specimens show variable cellularity depending on tumor type
May be hemorrhagic or necrotic
Adenocarcinoma: mucoid to cellular aspirate
Squamous carcinoma: keratinous debris
Neuroendocrine: uniform cellular yield
Melanoma: pigmented material.
Characteristics:
Aspirate consistency varies by primary origin
Colorectal metastases: moderate to high cellularity
Pancreatic: often mucoid background
Breast: variable (depends on subtype)
Lung adenocarcinoma: cellular with mucin
Hepatocellular fragments may be admixed
Background inflammation variable.
Size Location:
Multiple nodules typical pattern
Size ranges from <1 cm to >10 cm
Bilobar distribution common
Peripheral predilection (sub-capsular)
Right lobe more commonly involved
Confluent masses in advanced disease
Solitary lesions (20% cases).
Multifocality:
Multiple hepatic nodules (80% cases)
Bilobar involvement frequent
Extrahepatic disease often present
Lymph node metastases (portal, celiac)
Peritoneal seeding (advanced cases)
Lung metastases (hematogenous spread)
Unknown primary in 10-15% cases.
Microscopic Description
Histological Features:
Cytomorphology reflects primary tumor characteristics
Adenocarcinoma: glandular architecture, mucin production
Squamous carcinoma: keratinization, intercellular bridges
Neuroendocrine: uniform cells, salt-and-pepper chromatin
Poorly differentiated: sheets of atypical cells
May see admixed hepatocytes.
Cellular Characteristics:
Cellular morphology matches primary site
Nuclear pleomorphism variable (grade-dependent)
Prominent nucleoli in high-grade tumors
Mitotic activity reflects grade
Cytoplasm varies: mucin-containing (GI), clear (renal), pigmented (melanoma)
Intracytoplasmic inclusions may be seen.
Architectural Patterns:
Adenocarcinoma pattern: glands, clusters, single cells
Squamous pattern: sheets, keratinization
Neuroendocrine: uniform cellular clusters
Sarcomatous: spindle cells (rare)
Mixed patterns in poorly differentiated tumors
Hepatocyte clusters may be intermixed.
Grading Criteria:
Grading based on primary tumor criteria
Well-differentiated: obvious morphologic pattern
Moderately differentiated: partial loss of differentiation
Poorly differentiated: minimal differentiation, marked pleomorphism
Undifferentiated: no recognizable pattern
Nuclear grade important for prognosis.
Immunohistochemistry
Positive Markers:
Markers depend on suspected primary origin
Colorectal: CK20+, CDX2+, CK7-
Lung adenocarcinoma: TTF-1+, CK7+
Breast: GATA3+, mammaglobin+, ER/PR variable
Pancreatic: CK7+, CK20+/-, CA 19-9+
Neuroendocrine: synaptophysin+, chromogranin+.
Negative Markers:
Hepatocyte marker (negative, excludes HCC)
AFP (negative in most metastases)
Arginase-1 (negative, excludes HCC)
Site-specific negatives help narrow differential
Glypican-3 (negative, excludes HCC)
CD10 (positive in renal, negative in others).
Diagnostic Utility:
Essential for determining primary site
CK7/CK20 panel first-line approach
Tissue-specific markers confirm origin
Helps exclude primary liver malignancy
Prognostic markers (ER/PR in breast)
Predictive markers for targeted therapy
Immunocytochemistry on cell block preparation.
Molecular Subtypes:
Colorectal: KRAS/BRAF mutations, MSI status
Lung: EGFR mutations, ALK rearrangements
Breast: ER/PR/HER2 status
Melanoma: BRAF mutations
Neuroendocrine: Grade assessment (Ki-67)
Unknown primary: comprehensive molecular profiling.
Molecular/Genetic
Genetic Mutations:
Site-specific mutations reflect primary tumor
Colorectal: KRAS (40%), BRAF (10%), PIK3CA (15%)
Lung adenocarcinoma: EGFR (15% in non-smokers), KRAS (30%)
Breast: PIK3CA (35%), TP53 (30%)
Pancreatic: KRAS (90%), TP53 (70%)
Shared mutations: TP53 (common across types).
Molecular Markers:
Microsatellite instability (MSI) in colorectal
HER2 amplification in breast/gastric
PD-L1 expression (immunotherapy relevance)
TMB (tumor mutational burden) assessment
NTRK fusions (rare, pan-cancer)
Homologous recombination deficiency (HRD) in breast/ovarian.
Prognostic Significance:
Molecular subtype determines prognosis
MSI-high colorectal (better response to immunotherapy)
EGFR-mutated lung (targeted therapy benefit)
Triple-negative breast (aggressive course)
BRAF-mutated melanoma (targeted options available)
Grade and Ki-67 in neuroendocrine tumors.
Therapeutic Targets:
EGFR inhibitors (lung adenocarcinoma)
Anti-HER2 therapy (breast, gastric)
BRAF inhibitors (melanoma)
Immunotherapy (MSI-high, high TMB)
Anti-angiogenic therapy (various types)
CDK4/6 inhibitors (ER+ breast)
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Hepatocellular carcinoma (primary liver cancer)
Cholangiocarcinoma (intrahepatic bile duct carcinoma)
Combined HCC-cholangiocarcinoma (mixed primary tumor)
Hepatic adenoma with malignant change
Primary liver lymphoma (rare)
Hepatic sarcoma (very rare).
Distinguishing Features:
Metastasis: hepatocyte marker negative, site-specific IHC positive
HCC: hepatocyte positive, AFP elevation, trabecular pattern
Cholangiocarcinoma: CK7+/CK19+, mucin production
Clinical history crucial: known primary malignancy
Imaging pattern: multiple nodules favor metastases.
Diagnostic Challenges:
Distinguishing from well-differentiated HCC
Unknown primary metastases (10-15% cases)
Poorly differentiated tumors (loss of site-specific features)
Adenocarcinoma with biliary differentiation
Neuroendocrine metastases vs primary
Synchronous liver masses with extrahepatic primary.
Rare Variants:
Sarcomatoid metastases (renal, lung primaries)
Small cell carcinoma metastases (lung, extrapulmonary sites)
Adenoid cystic carcinoma (salivary gland)
Mucinous adenocarcinoma (appendiceal, ovarian)
Clear cell metastases (renal, gynecologic)
Signet ring cell metastases (gastric, breast).
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.
Clinical Information
Patient with history of [primary malignancy], imaging shows [liver lesion pattern]
Specimen Adequacy
Adequate for evaluation with [cellularity description]
Cytomorphological Features
Shows [cellular pattern] consistent with [tumor type] morphology
Comparison with Primary
Morphology [consistent/similar/different] with known [primary tumor site]
Immunocytochemistry
[Site-specific markers]: [positive/negative]
Hepatocyte marker: [negative]
[Additional markers as indicated]: [results]
Differential Diagnosis
Differential includes [primary liver malignancy, other metastases]
Final Cytological Diagnosis
Metastatic [tumor type], consistent with [primary site] origin
Recommendations
Recommend [staging studies, molecular testing, treatment planning]