ZAP-70 Linked to Worse Marrow Infiltration Pattern

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Hum Pathol. 2006 Sep;37(9):1153-61. Epub 2006 Jul 7.

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).

Schade U, Bock O, Vornhusen S, Jager A, Busche G, Lehmann U, Kreipe

H. Institute of Pathology, Medizinische Hochschule Hannover, Carl-

Neuberg-Strasse 1, 30625 Hannover, Germany.

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.

PMID: 16938520 [PubMed - in process]