1-10 Liver Cytology: M Pitman MD, J Misdraji MD, Marilyn Nutter CT

From MGH Learn Pathology



Indications for cytology examination for liver
Procuring the specimen (liver)
Test platforms/specimen processing and triage (liver)
Reporting and terminology (liver)


Basic cytomorphology


Regenerative, Dysplastic and Benign Neoplastic Hepatocellular Nodules – N12-12133 reactive, N12-4918 and N12-6339

  • Hepatocytes arranged in jagged irregular clusters, small clusters, short rows and singly (depending on regenerative, dysplastic or neoplastic nature)
  • No peripheral endothelium
  • Clusters rarely have transgressing endothelium (except for neoplastic aspirates)
  • Reactive hepatocytes show sibling polymorphism with normal nuclear-to-cytoplasmic ratio (1/3) and frequent binucleation
  • Sporadically placed large, atypical cells with mild pleomorphism of nuclear size but normal nuclear-to-cytoplasmic ratio (in dysplastic hepatocytes with large cell change)
  • Small uniformly monotonous hepatocytes with increased nuclear-to-cytoplasmic ratio and nuclear crowding (in dysplastic hepatocytes with small cell change)
  • Variably prominent nucleoli but no macroeosinophilic nucleoli
  • Cytoplasm is generally abundant (except in small cell change) and granular but may show fatty change, lipofuscin pigment, or iron deposition
  • Bile duct epithelium present (except in LCA)
  • Core biopsies provide specific diagnosis: Reticulin stain shows retention of 1 to 2 cells thick hepatic plate framework on cellblock; unpaired arterioles in parenchyma for LCA; bile duct proliferation and scar for FNH
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Reactive hepatocytes
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Benign liver (cirrhosis) with reticulin stain


Well-differentiated Hepatocellular Carcinoma – N13-6335 and N12-5663

  • Under low power microscopy, smear pattern shows trails of smooth-edged, arborizing clusters of thickened trabeculae with peripheral endothelium (pathognomonic)
  • Under low power, smear pattern shows many loosely cohesive sheets of hepatocytes with transgressing vessels (highly suspect finding)
  • Monotonous, uniform hepatocytic cell population with subtle malignant features
  • Pseudoacinar formation in cell clusters
  • Nuclear-to-cytoplasmic ratio higher than in normal hepatocytes (>1/3)
  • Macroeosinophilic nucleoli
  • Reduced number of binucleated cells
  • Background free of bile duct epithelial cells
  • Reticulin stain demonstrates a loss of the normal 1 to 2 cells thick hepatic plate architecture
  • Iron stain fails to stain tumor cells in cases of hemochromatosis
  • α-fetoprotein is helpful if positive but often is not
  • Novel markers, such as glypican-3, glutamine synthetase and heat shock protein 70, are helpful if two out of three show positivity
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WDHCC: reticulin staining showing thickened trabeculae (>3 cells)
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WDHCC with transgressing, arboring vessels


Moderately to Poorly Differentiated Hepatocellular Carcinoma –N12-6639, NC13-322 and N11-12944

  • Low power smear pattern generally resembles that seen in well-differentiated tumors; however, there is a dyshesive tendency in poorly differentiated tumors
  • Peripheral endothelium is virtually pathognomonic
  • Transgressing vessels are suggestive, but cannot distinguish hepatocellular from renal cell carcinoma
  • Presence of intracytoplasmic bile is pathognomonic
  • Polygonal cells with central nuclei and prominent nucleoli with visible, granular to clear cytoplasm in moderately differentiated tumors; scant to no cytoplasm with greater degree of pleomorphism and mitotic activity in poorly differentiated tumors
  • Immunophenotype: low-molecular-weight CK (Cam 5.2), polyclonal carcinoembryonic antigen and CD10 (canalicular), and HepPar-1 and TTF-1 positive; α-fetoprotein variable; high-molecular-weight CK (AE1) negative
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High grade hepatocellular carcinoma; note malignant cells making bile


Metastatic colonic Adenocarcinoma -- N12-85

  • Cigar-shaped, often palisaded nuclei
  • Variably prominent nucleoli, no macroeosinophilic nucleoli
  • Dirty necrosis in the background (key identification point)
  • Immunohistochemistry: CK20 positive, CK7 and CK19 negative, carcinoembryonic antigen positive
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