title: ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.
abstract: Zeta-associated protein-70 (ZAP-70), mostly assessed by flow-cytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and beta2-microglobulin serum levels and lymphocyte doubling time <12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (P<0.0001) and overall survival (median 106 months vs not reached) (P=0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Zanotti
authors.forename: A
authors.initials: A
authors.lastname: Ambrosetti
authors.forename: M
authors.initials: M
authors.lastname: Lestani
authors.forename: P
authors.initials: P
authors.lastname: Ghia
authors.forename: C
authors.initials: C
authors.lastname: Pattaro
authors.forename: A
authors.initials: A
authors.lastname: Remo
authors.forename: F
authors.initials: F
authors.lastname: Zanetti
authors.forename: S
authors.initials: S
authors.lastname: Stella
authors.forename: O
authors.initials: O
authors.lastname: Perbellini
authors.forename: G
authors.initials: G
authors.lastname: Prato
authors.forename: G
authors.initials: G
authors.lastname: Guida
authors.forename: F
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: F
authors.initials: F
authors.lastname: Menestrina
authors.forename: G
authors.initials: G
authors.lastname: Pizzolo
authors.forename: M
authors.initials: M
authors.lastname: Chilosi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001706:Biopsy; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051746:ZAP-70 Protein-Tyrosine Kinase; D051997:ADP-ribosyl Cyclase 1