Definition/General
Introduction:
Cholangiocarcinoma is a malignant adenocarcinoma arising from the biliary tree epithelium
It represents 10-15% of primary liver malignancies
FNAC is a valuable diagnostic tool for liver masses
It demonstrates characteristic adenocarcinomatous cytology with biliary differentiation.
Origin:
Arises from intrahepatic or extrahepatic bile ducts
Specifically from cholangiocytes lining the biliary epithelium
The neoplastic transformation involves progressive genetic alterations
It results in loss of cellular differentiation
It demonstrates invasive growth pattern with desmoplastic stroma.
Classification:
Classified as intrahepatic or extrahepatic cholangiocarcinoma
Intrahepatic: peripheral or hilar (Klatskin tumor)
Extrahepatic: distal bile duct carcinoma
Morphologically: adenocarcinoma with various patterns
WHO classification: conventional adenocarcinoma
Variants include mucinous, signet ring, clear cell types.
Epidemiology:
Peak incidence in 6th-7th decades
Male predominance (M:F = 1.5:1)
Risk factors include PSC, hepatolithiasis
Clonorchis sinensis infection (endemic areas)
Chronic biliary inflammation
Indian population shows increasing incidence with industrial pollution
Thorotrast exposure (historical cases).
Clinical Features
Presentation:
Obstructive jaundice (most common in hilar/extrahepatic)
Abdominal pain (right upper quadrant)
Weight loss and fatigue
Cholangitis (fever, chills)
Hepatomegaly (intrahepatic tumors)
Palpable mass (large tumors)
Courvoisier sign (palpable gallbladder with painless jaundice).
Symptoms:
Progressive jaundice with dark urine and pale stools
Pruritus (bile salt deposition)
Abdominal distension
Nausea and vomiting
Fever (secondary cholangitis)
Back pain (retroperitoneal extension)
Constitutional symptoms (weight loss, fatigue).
Risk Factors:
Primary sclerosing cholangitis (PSC) (strongest risk factor)
Parasitic infections (Clonorchis sinensis, Opisthorchis)
Hepatolithiasis and choledochal cysts
Inflammatory bowel disease
Chronic hepatitis B/C
Cirrhosis
Chemical exposure (thorotrast, dioxin)
Lynch syndrome.
Screening:
High-risk patients: PSC with annual surveillance
CA 19-9 tumor marker (elevated in 70-80%)
CEA elevation (less specific)
Imaging: MRCP (magnetic resonance cholangiopancreatography)
CT with contrast enhancement
ERCP with brush cytology
PET-CT for staging.
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Gross Description
Appearance:
FNAC specimens show hemorrhagic to gray-white aspirate
Variable cellularity depending on tumor area sampled
May contain bile-stained material
Necrotic debris in poorly differentiated tumors
Mucoid material in mucinous variants
Scant to moderate cellular yield.
Characteristics:
Aspirate consistency varies from thin to thick mucoid
Color ranges from clear to bile-stained yellow-green
Blood contamination common due to vascular lesions
Cellular aggregates mixed with single cells
Background may show inflammatory cells
Calcifications rarely seen in aspirates.
Size Location:
Intrahepatic tumors: variable size (2-15 cm)
Peripheral location (segments II-VIII)
Hilar tumors: smaller size, strategic location
Extrahepatic: bile duct wall thickening
Multiple nodules in advanced disease
Satellite lesions in intrahepatic type.
Multifocality:
Multifocal disease common in intrahepatic type
Skip lesions along bile ducts
Lymphatic spread to portal lymph nodes
Peritoneal seeding in advanced cases
Direct extension to liver parenchyma
Vascular invasion (portal vein, hepatic artery).
Microscopic Description
Histological Features:
Malignant epithelial cells arranged in glands, tubules, and sheets
Cells show moderate to marked nuclear pleomorphism
Prominent nucleoli with coarse chromatin
Increased nuclear-cytoplasmic ratio
Mucin production (intracellular and extracellular)
Desmoplastic stromal reaction characteristic.
Cellular Characteristics:
Cells show columnar to cuboidal morphology
Moderate to abundant cytoplasm (pale to eosinophilic)
Nuclear enlargement with irregular contours
Prominent nucleoli (2-4 per nucleus)
Mitotic activity variable (grade-dependent)
Intracytoplasmic mucin vacuoles
Apical mucin caps in well-differentiated areas.
Architectural Patterns:
Adenocarcinoma pattern with glandular architecture
Tubular pattern (most common)
Cribriform pattern in some areas
Solid pattern in poorly differentiated areas
Papillary pattern (uncommon)
Mucinous pattern with abundant extracellular mucin
Single cell infiltration in advanced cases.
Grading Criteria:
Well-differentiated: obvious glandular pattern, minimal pleomorphism
Moderately differentiated: partial glandular loss, moderate pleomorphism
Poorly differentiated: solid sheets, marked pleomorphism
Nuclear grade based on size, shape, nucleoli
Mitotic count correlates with grade
Mucin production decreases with higher grade.
Immunohistochemistry
Positive Markers:
CK7 (90-95% positive)
CK19 (80-90% positive)
CA 19-9 (70-80% positive)
CEA (60-70% positive)
EMA (epithelial membrane antigen)
MUC1 (membrane mucin)
CDX2 (variable, 20-30%)
S100P (biliary marker).
Negative Markers:
CK20 (usually negative, helps differentiate from colorectal)
TTF-1 (negative, excludes lung primary)
Hepatocyte (negative, excludes hepatocellular carcinoma)
AFP (alpha-fetoprotein negative)
PSA (excludes prostate)
CDX2 (mostly negative, unlike intestinal adenocarcinoma).
Diagnostic Utility:
Essential for confirming adenocarcinoma nature
CK7+/CK20- pattern supports biliary origin
Helps distinguish from hepatocellular carcinoma
Important for excluding metastatic adenocarcinoma
Mucin stains (PAS, mucicarmine) highlight mucin production
S100P emerging as biliary-specific marker.
Molecular Subtypes:
KRAS mutations (40-50% cases)
TP53 mutations (30-40% cases)
SMAD4 loss (20-30% cases)
IDH1/2 mutations (10-20% in intrahepatic)
FGFR2 fusions (10-15% intrahepatic type)
BAP1 loss (associated with poor prognosis).
Molecular/Genetic
Genetic Mutations:
KRAS mutations (most common, 40-50%)
TP53 mutations (30-40% cases)
CDKN2A/p16 inactivation (30% cases)
SMAD4 mutations (20-30%)
IDH1/2 mutations (intrahepatic type, 10-20%)
ARID1A mutations (chromatin remodeling)
PIK3CA mutations (5-10%).
Molecular Markers:
FGFR2 fusions (targetable alterations)
HER2 amplification (5-10% cases)
EGFR overexpression (variable)
BRAF mutations (rare, <5%)
Microsatellite instability (rare, <5%)
PD-L1 expression (immunotherapy relevance)
VEGF overexpression (angiogenesis).
Prognostic Significance:
IDH1/2 mutations associated with better prognosis
KRAS mutations linked to poor outcome
TP53 mutations indicate aggressive behavior
FGFR2 fusions predict response to targeted therapy
BAP1 loss correlates with poor survival
Molecular profiling guides targeted therapy selection.
Therapeutic Targets:
FGFR2 inhibitors (pemigatinib for fusion-positive cases)
IDH1 inhibitors (ivosidenib for mutant cases)
Immunotherapy (pembrolizumab for MSI-high/TMB-high)
HER2-targeted therapy (trastuzumab, pertuzumab)
EGFR inhibitors (selected cases)
Anti-angiogenic therapy (bevacizumab).
Differential Diagnosis
Similar Entities:
Hepatocellular carcinoma (HCC with adenoid pattern)
Metastatic adenocarcinoma (pancreatic, colorectal, lung, breast origin)
Combined HCC-cholangiocarcinoma (mixed tumor)
Hepatic adenoma with malignant transformation
Benign biliary stricture with reactive atypia
Inflammatory pseudotumor.
Distinguishing Features:
Cholangiocarcinoma: CK7+/CK19+, mucin production, glandular architecture
HCC: Hepatocyte positive, AFP elevation, trabecular pattern
Metastatic pancreatic: similar morphology, requires clinical correlation
Colorectal metastases: CK20+/CDX2+
Lung adenocarcinoma: TTF-1 positive
Reactive biliary epithelium: preserved polarity, minimal atypia.
Diagnostic Challenges:
Distinguishing from well-differentiated hepatocellular carcinoma
Separating from metastatic pancreatic adenocarcinoma
Reactive biliary epithelium vs low-grade cholangiocarcinoma
Combined HCC-cholangiocarcinoma recognition
Scant cellular yield in some FNACs
Morphological overlap with metastatic adenocarcinomas.
Rare Variants:
Mucinous cholangiocarcinoma (abundant extracellular mucin)
Signet ring variant (intracellular mucin)
Clear cell variant (glycogen-rich cytoplasm)
Adenosquamous carcinoma (mixed epithelial elements)
Sarcomatoid variant (spindle cell component)
Small cell variant (neuroendocrine features).
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 [clinical presentation], imaging shows [liver lesion characteristics]
Specimen Adequacy
Adequate for evaluation with [cellularity description]
Cytomorphological Features
Shows [cellular arrangement] with [nuclear features] and [cytoplasmic characteristics]
Background
Background shows [blood, debris, inflammatory cells, mucin]
Special Studies
ICC: [CK7, CK19, other markers]: [results]
Mucin stains: [PAS, mucicarmine]: [results]
[other studies]: [results]
Differential Diagnosis
Differential includes [HCC, metastatic adenocarcinoma, reactive changes]
Final Cytological Diagnosis
Malignant: Adenocarcinoma, consistent with cholangiocarcinoma
Recommendations
Recommend [histopathological confirmation, staging, molecular studies]