Hematopathology / ANGIODESTRUCTION AND TISSUE NECROSIS OF SKIN-INVOLVING CD56+ NK/T-CELL LYMPHOMA Angiodestruction and Tissue Necrosis of Skin-Involving CD56+ NK/T-Cell Lymphoma Are Influenced by Expression of Cell Adhesion Molecules and Cytotoxic Granule and Apoptosis-Related Proteins

We compared the expression of cell adhesion molecules (CAMs), cytotoxic granule proteins, and apoptosis-related proteins by immunohistology and in situ terminal deoxynucleotidyl transferase–mediated digoxigenin–dUTP nick end labeling (TUNEL) of 10 cases of cutaneous CD56+ NK/T cell lymphoma with and 6 cases without angiodestruction. Lymphoma cells in cases with angiodestruction frequently expressed CAMs CD2, CD11a, and CD49d and their ligands CD58, CD54, and CD106 and were positive for CD122 and cytotoxic granule proteins TIA1, perforin, and granzyme B. Lymphoma cells in cases without angiodestruction mostly were negative for CD2, CD58, CD54, CD106, and TIA1 and weakly positive for perforin and granzyme B. In the TUNEL method, mean apoptotic indices (AI) for cases with angiodestruction showed a higher percentage than those without angiodestruction. CD95L, CD95, apoptosis-induced cysteine protease CPP32, apoptosis-promoting protein Bax, and proliferating marker (MIB1) frequently were positive in the lymphoma cells of cases with angiodestruction, but there was no expression of apoptosis-inhibitor protein Bcl2. In most cases without angiodestruction, lymphoma cells were positive for CD95L and Bax and negative for CD95, CPP32, and MIB1. CAMs and the 3 cytotoxic granule proteins and an apoptosis pathway might be important factors in the paracrine and autocrine mechanisms of tissue necrosis in cutaneous CD56+ NK/T cell lymphoma. CD56 (neural cell adhesion molecule [NCAM]) is a member of the immunoglobulin superfamily of homotypic cell adhesion molecules (CAMs).1 CD56+ lymphocytes consist mainly of natural killer (NK) and cytotoxic T cells (CTLs), which are activated by surface CAMs of CD2 (leukocyte function antigen [LFA2]), CD11a (LFA1 alpha), and very late antigen (VLA)4 and their ligands.2-5 NK cells are activated by interleukin (IL)-2, IL-12, and IL-15 and their IL-2 beta and gamma and IL-12 receptors. They increase an innate immune response and induce cytolysis by production and activation of interferon-gamma and cytotoxic granule proteins.6,7 T-cell–restricted intracellular antigen (TIA)1, perforin, and granzymes, which work mainly as a cytotoxic granule protein, are included in the cytoplasmic granules of NK cells and CTLs.8-10 As well as these proteins, it is known that stimulation through the CD95 (Fas)-CD95L (Fas ligand) pathway of NK cells induces activation of the IL-1 beta-converting enzyme and cysteine protease 3 (CPP32) of target cells and has an important role in target cell lysis and its nuclear fragmentation, so-called apoptosis.11-13 High expression of Bcl2-associated X protein (Bax) of NK cells and large granular lymphocytes (LGLs) is known to promote apoptosis, but Bcl2 protein inhibits this type of cell death and promotes cell survival by controlling the aforementioned proteinase cascade of the IL-1 beta-converting enzyme, CPP32, and their family.14 The tumor suppressor gene wild-type p53 also is involved in the DNA repair machinery of cells in cooperation with Bcl2, Bax, and other products.15 However, mutant p53 leads to loss of the apoptosis-inducing capacity of wild-type p53. Am J Clin Pathol 2000;113:201-211 201 © American Society of Clinical Pathologists Takeshita et al / ANGIODESTRUCTION AND TISSUE NECROSIS OF SKIN-INVOLVING CD56+ NK/T-CELL LYMPHOMA CD56+ NK/T-cell lymphoma is considered to be a tumor of NK cell and NK-like CTL lineages and frequently shows angiocentric and angiodestructive features and massive fibrinoid necrosis.16,17 Ng et al18 strongly suggested that the histologic apoptosis of CD2 (LFA2)negative and CD56+ lymphoma is influenced by expression of TIA1, perforin, and granzyme B of the lymphoma cells. It also has been suggested that systemic tissue damage of LGL leukemia and NK-cell lymphoma is influenced by the effect of CD95L (Fas ligand)–positive neoplastic cells.19 Lorenzen et al20 also demonstrated that expression of Bcl2 of nasal NK/T-cell lymphoma was not associated with apoptotic indices (AI) detected by the in situ terminal deoxynucleotidyl transferase (TdT)–mediated digoxigenin–deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) method and the ratio of MIB1-positive proliferating cells. Takeshita et al21 previously reported 16 cases of cutaneous CD56+ NK/CTL lymphoma with rare Epstein-Barr virus infection, and 10 cases showed angiodestructive features. In the present study, we examined and analyzed statistically which kinds of CAMs, cytotoxic granule– and apoptosisrelated proteins influenced the tissue necrosis and how this occurred by comparing cases of cutaneous CD56+ NK/Tcell lymphoma with and without angiodestruction and tissue necrosis. Materials and Methods