ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor

• Published in: Leukemia Vol. 21; no. 1; pp. 102 - 109
• Main Authors: ZANOTTI, R, AMBROSETTI, A, GUIDA, G, CALIGARIS-CAPPIO, F, MENESTRINA, F, PIZZOLO, G, CHILOSI, M, LESTANI, M, GHIA, P, PATTARO, C, REMO, A, ZANETTI, F, STELLA, S, PERBELLINI, O, PRATO, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-01-2007; Nature Publishing Group
• Subjects: ADP-ribosyl Cyclase 1 - biosynthesis; Adult; Aged; Biological and medical sciences; Biomarkers, Tumor; Biopsy; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Bone marrow examination; Care and treatment; Chronic lymphocytic leukemia; Dehydrogenases; Disease; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Genes; Genes, Immunoglobulin; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Immunoglobulins; Immunohistochemistry; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemia, Lymphocytic, Chronic, B-Cell - physiopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Male; Medical prognosis; Medical sciences; Middle Aged; Morphology; Predictive Value of Tests; Prognosis; Protein tyrosine kinase; Proteins; Retrospective Studies; Survival Analysis; Up-Regulation; ZAP-70 Protein-Tyrosine Kinase - biosynthesis; Italy; Human; Immunohistochemistry; Prognosis; Hematology; bone marrow biopsy; Early phase; Malignant hemopathy; prognostic factors; ZAP-70 expression; Anatomic pathology; Chronic lymphocytic leukemia; chronic lymphocytic leukaemia; Biopsy; Bone marrow
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404458

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.