title: Bone marrow infiltration pattern in B-cell chronic lymphocytic leukemia is related to immunoglobulin heavy-chain variable region mutation status and expression of 70-kd zeta-associated protein (ZAP-70).
abstract: B-cell chronic lymphocytic leukemia (B-CLL) consists of at least 2 subtypes with either somatically mutated or unmutated immunoglobulin heavy-chain variable region (IgVH) genes. A prognostic significance of the infiltration pattern in bone marrow trephine biopsy has been described before. The combined pattern analysis and detection of 70-kd zeta-associated protein (ZAP-70) expression in formalin-fixed, paraffin-embedded bone marrow trephines has not been investigated so far. To evaluate the relationship between ZAP-70 expression, mutation status, and the infiltration pattern in B-CLL, we analyzed bone marrow trephine biopsies from B-CLL patients (n = 35). The expression of ZAP-70 was related to the infiltration type: in all samples with diffuse infiltration pattern, the leukemic cells showed ZAP-70 staining, whereas leukemic cells in a nodular infiltration pattern were negative. By contrast, the mixed-pattern type showed a variable ZAP-70 expression. Besides definitely negative or positive ZAP-70 expression, a few samples showed a faint ZAP-70 staining, and the classification into the positive or negative group was difficult. In addition, the infiltration type was related to the mutation status in a subset of samples: mutation of the IgVH gene was restricted to the nondiffuse infiltration pattern and was not found in cases with diffuse infiltration of bone marrow. The expression of ZAP-70, detected by an immunohistochemical assay and also by real-time quantitative reverse transcriptase-polymerase chain reaction assigned 83% of the chronic lymphocytic leukemia cases to the suspected immunoglobulin mutation subtype. In 2 patients with ZAP-70 expression, a mutated IgVH status was found. These cases exhibited a mixed pattern of infiltration. We conclude that the pure nodular type of marrow infiltration in B-CLL is associated with IgH hypermutation and ZAP-70 negativity, whereas the predominantly diffuse type of infiltration reveals unmutated IgH genes with ZAP-70 overexpression. The mixed type of infiltration is displayed by mutated as well as unmutated cases with a varying pattern of ZAP-70 expression.
authors.affiliation: Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Schade
authors.forename: Oliver
authors.initials: O
authors.lastname: Bock
authors.forename: Sylke
authors.initials: S
authors.lastname: Vornhusen
authors.forename: Anna
authors.initials: A
authors.lastname: Jäger
authors.forename: Guntram
authors.initials: G
authors.lastname: Büsche
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D005260:Female; 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*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; 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