title: The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma.
abstract: 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.
authors.affiliation: Division of Hematopathology, University of Pittsburgh School of Medicine, PA 15213-2582, USA.
authors.forename: Lorinda A
authors.initials: LA
authors.lastname: Soma
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Craig
authors.forename: Steven H
authors.initials: SH
authors.lastname: Swerdlow
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D011379:Prognosis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis; D000099218:Interferon Regulatory Factor-4
chemical_list: D051997:ADP-ribosyl Cyclase 1; D014408:Biomarkers, Tumor; D050835:Interferon Regulatory Factors; D008562:Membrane Glycoproteins; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099218:Interferon Regulatory Factor-4; C498154:CD38 protein, human