The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma

Hum Pathol. 2006 Feb;37(2):152-9. doi: 10.1016/j.humpath.2005.09.029. Epub 2006 Jan 10.


Prognostication in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) based, in part, on ZAP-70 and CD38 expression, and to a lesser extent, on MUM1/IRF4 expression, is currently of great interest. The more aggressive type of CLL/SLL is reportedly characterized by neoplastic cells that are more responsive to B-cell signaling with proliferation centers (PCs), a potentially important site of neoplastic cell stimulation. To study the relationship of these markers to each other and to the pattern of PCs, immunohistochemical stains for ZAP-70 and MUM1/IRF4 were performed and the PC patterns assessed (where possible) in 29 tissue biopsies with CLL/SLL. CD38 expression was assessed in 18 cases using flow cytometry. Ten evaluable cases had a typical PC pattern and 16 an atypical pattern with larger or more confluent PCs and/or more numerous paraimmunoblasts/transformed cells. ZAP-70 was positive in 14 of 28 cases, including 3 with atypical PCs and enhanced PC staining. All 29 cases showed MUM1/IRF4 expression in PCs. Seven cases, none with atypical PC, also showed uniform positivity throughout, 14 showed weaker staining of surrounding lymphocytes, and 8 had PC staining only. CD38 was positive in 14 of 18 cases. The only significant association identified was between uniform MUM1/IRF4 positivity and typical PCs (P = .004). These findings highlight the complex interrelationship of prognostic markers in CLL/SLL and demonstrate potentially important microenvironmental variations in their expression. They support the hypothesis that PCs are a site for B-cell receptor signaling, which helps explain reported site-dependent antigenic variation in CLL/SLL, and suggest that PC morphology may correlate with other biological features.

MeSH terms

  • ADP-ribosyl Cyclase 1 / biosynthesis
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Cell Proliferation
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Interferon Regulatory Factors / biosynthesis
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Male
  • Membrane Glycoproteins / biosynthesis
  • Prognosis
  • ZAP-70 Protein-Tyrosine Kinase / biosynthesis


  • Biomarkers, Tumor
  • Interferon Regulatory Factors
  • Membrane Glycoproteins
  • interferon regulatory factor-4
  • ZAP-70 Protein-Tyrosine Kinase
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1