Global quality assessment of liver allograft C4d staining during acute antibody mediated rejection in formalin-fixed paraffin-embedded tissue

Research output: Contribution to journalArticlepeer-review


  • Neil Dah
  • Bellamy Co
  • M. Smith
  • H. Haga
  • Y. Zen
  • M. Sebagh
  • K. Ruppert
  • J. Lunz
  • A. J. Demetris

Colleges, School and Institutes


Discussion of liver antibody mediated rejection during the 2011, 2013 and 2015 Banff liver sessions raised concerns over reliability of complement fragment 4d (C4d) staining, precipitating a global survey followed by a tissue microarray staining quality assessment study among centers on formalin-fixed, paraffin-embedded tissue. Tissue microarray sections containing tissue plugs of resected native and allograft (with acute antibody mediated rejection) liver, heart and kidney (n=33 total cores) were sent to 31 centers for C4d staining using local method (s) and pathologist scoring. Digital whole slide images (n=40) were then semi-quantitatively scored by 7 experts for background, distribution and intensity of portal vein and capillary, hepatic artery, sinusoidal, and central vein endothelia and portal and central stromal staining. Results showed that strong and diffuse portal vein and capillary C4d staining, as determined by both local and central pathologists, clearly distinguished allografts showing acute antibody mediated rejection from native livers and from those with evidence of weaker donor specific antibody. Downstream vascular endothelial cell C4d staining and assessment were more variable and difficult to identify. C4d staining in the majority of laboratories reliably detects acute liver allograft antibody mediated rejection in formalin-fixed, paraffin-embedded tissues. Assessment should focus on portal veins and capillaries, sinusoids and central veins present in peripheral core needle biopsies. C4d staining in one organ does not always translate to staining in another.


Original languageEnglish
JournalHuman Pathology
Early online date27 Dec 2017
Publication statusE-pub ahead of print - 27 Dec 2017


  • complementary fragment 4d , liver allograft , antibody mediated rejection , method , tissue microarray