Chapter 105. Malignancies of Lymphoid Cells (Part 6)

Pathway of normal T cell differentiation and relationship to T cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell markers used to distinguish stages of development. T cell antigen receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes and peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T cell ALL; T-LL, T cell lymphoblastic lymphoma; T-CLL, T cell chronic lymphoid leukemia; CTCL, cutaneous T cell lymphoma; NHL, non-Hodgkins lymphoma.Although lymphoid malignancies often retain the cell-surface phenotype of lymphoid cells at particular stages of differentiation, this information is of little consequence....
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Chapter 105. Malignancies of Lymphoid Cells (Part 6) Chapter 105. Malignancies of Lymphoid Cells (Part 6)Figure 105-3 Pathway of normal T cell differentiation and relationship to T celllymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71are cell markers used to distinguish stages of development. T cell antigenreceptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodesand peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T cell ALL; T-LL,T cell lymphoblastic lymphoma; T-CLL, T cell chronic lymphoid leukemia;CTCL, cutaneous T cell lymphoma; NHL, non-Hodgkins lymphoma. Although lymphoid malignancies often retain the cell-surface phenotype oflymphoid cells at particular stages of differentiation, this information is of littleconsequence. The so-called stage of differentiation of a malignant lymphoma doesnot predict its natural history. For example, the clinically most aggressivelymphoid leukemia is Burkitts leukemia, which has the phenotype of a maturefollicle center IgM-bearing B cell. Leukemias bearing the immunologic cell-surface phenotype of more primitive cells (e.g., pre-B ALL, CD10+) are lessaggressive and more amenable to curative therapy than the more matureappearing Burkitts leukemia cells. Furthermore, the apparent stage ofdifferentiation of the malignant cell does not reflect the stage at which the geneticlesions that gave rise to the malignancy developed. For example, follicularlymphoma has the cell-surface phenotype of a follicle center cell, but itscharacteristic chromosomal translocation, the t(14;18), which involvesjuxtaposition of the antiapoptotic bcl-2 gene next to the immunoglobulin heavychain gene (see below), had to develop early in ontogeny as an error in the processof immunoglobulin gene rearrangement. Why the subsequent steps that led totransformation became manifest in a cell of follicle center differentiation is notclear. The major value of cell-surface phenotyping is to aid in the differentialdiagnosis of lymphoid tumors that appear similar by light microscopy. Forexample, benign follicular hyperplasia may resemble follicular lymphoma;however, the demonstration that all the cells bear the same immunoglobulin lightchain isotype strongly suggests the mass is a clonal proliferation rather than apolyclonal response to an exogenous stimulus. Malignancies of lymphoid cells are associated with recurring geneticabnormalities. While specific genetic abnormalities have not been identified for allsubtypes of lymphoid malignancies, it is presumed that they exist. Geneticabnormalities can be identified at a variety of levels including gross chromosomalchanges (i.e., translocations, additions, or deletions); rearrangement of specificgenes that may or may not be apparent from cytogenetic studies; andoverexpression, underexpression, or mutation of specific oncogenes. Alteredexpression or mutation of specific proteins is particularly important. Manylymphomas contain balanced chromosomal translocations involving the antigenreceptor genes; immunoglobulin genes on chromosomes 2, 14, and 22 in B cells;and T cell antigen receptor genes on chromosomes 7 and 14 in T cells. Therearrangement of chromosome segments to generate mature antigen receptorsmust create a site of vulnerability to aberrant recombination. B cells are even moresusceptible to acquiring mutations during their maturation in germinal centers; thegeneration of antibody of higher affinity requires the introduction of mutationsinto the variable region genes in the germinal centers. Other nonimmunoglobulingenes, e.g., bcl-6, may acquire mutations as well. In the case of diffuse large B cell lymphoma, the translocation t(14;18)occurs in ~30% of patients and leads to overexpression of the bcl-2 gene found onchromosome 18. Some other patients without the translocation also overexpressthe BCL-2 protein. This protein is involved in suppressing apoptosis—i.e., themechanism of cell death most often induced by cytotoxic chemotherapeuticagents. A higher relapse rate has been observed in patients whose tumorsoverexpress the BCL-2 protein, but not in those patients whose lymphoma cellsshow only the translocation. Thus, particular genetic mechanisms have clinicalramifications.