IntroductionExtranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare and severe malignancy. It is more frequent in Asia and Central/South America than in Europe and North America. It is thought to arise from NK cells or, occasionally, from a subset of ␥␦ or ␣␤ cytotoxic T cells, and shows a tight association with Epstein-Barr virus (EBV). It is classically characterized by a cytoplasmic CD3 ⑀ phenotype, with no surface CD3 or T-cell receptor expression, no T-cell receptor gene rearrangements, an activated cytotoxic profile with perforin, granzyme B, and TIA-1 expression, and frequent CD56 expression. [1][2][3] Extranodal NK/T-cell lymphoma is usually diagnosed in adults, with a median age in the fifth decade. The nasal cavity or other parts of the upper aerodigestive tract are primarily involved, but some cases occur at extranasal sites. The term "nasal-type" is used in the World Health Organization classification to describe forms arising both in the nasal cavity and in extranasal sites. 3,4 Because disease incidence is rare even in prevalent areas, there has been no randomized controlled trial, and most treatment protocols are consensus-guided. 5 Localized NK/T-cell lymphomas often respond to radiotherapy 6,7 or to concurrent radiation and chemotherapy, 8 but relapse is common. Chemotherapy protocols used for lymphomas of other histologic subtypes are poorly effective, at least in part, because of frequent multidrug resistance gene expression by tumor cells. 9 Patients with disseminated or relapsing disease have a very poor outcome, 4,10,11 and there is no standard management for relapsed or refractory disease. We and others, in small retrospective studies, 12-16 have observed very good response and survival rates in patients treated with L-asparaginase, a drug with an original antitumoral mechanism not affected by MDR. NK cells lack asparagine synthase activity, and asparaginase has been shown to induce apoptosis of tumoral NK cells in vitro. 17 These findings provided the rationale for this open-label phase 2 study of an L-asparaginase-containing regimen for patients with relapsed and/or refractory extranodal NK/T-cell lymphoma. We chose to combine L-asparaginase with methotrexate, a drug insensitive to the multidrug resistance pathway, because of its well-known synergistic effect with asparaginase in acute lymphoblastic leukemia and its ability to prevent central nervous system involvement. Dexamethasone was added because T-cell lymphomas are usually sensitive to corticosteroids and dexamethasone For personal use only. on May 12, 2018. by guest www.bloodjournal.org From seems to be associated with a lower risk of thrombosis when given with L-asparaginase. 18 Methods PatientsThe patients were at least 18 years of age, with relapsed or refractory extranodal NK/T-cell lymphoma. Eligibility criteria included biopsyproven diagnosis of NK/T-cell lymphoma, nasal-type, irrespective of the anatomic site. Malignant cells in all cases had a CD3⑀ ϩ , CD20 Ϫ phenotype, a cytotoxic profile, and evidence of E...

on behalf of Groupe Français de Cytogéné tique Hé matologique (GFCH) CD4 ؉ , CD56 ؉ DC2 malignancies constitute a novel disease entity, which has recently been shown to arise from a transformed lymphoid-related plasmacytoid dendritic cell (DC2). Diagnosis is primarily based on a particular immunophenotype with tumor cells expressing CD4 and CD56 antigens in the absence of common lymphoid or myeloid lineage markers. Little is currently known about the cytogenetic features of this disease entity. In this setting, the Groupe Franç ais de Cytogéné tique Hé matologique (GFCH) initiated a cytogenetic study of 18 adults and 3 children with CD4 ؉ , CD56 ؉ DC2 acute leukemia using conventional and fluorescence in situ hybridization/24-color karyotyping. Clonal, mostly complex chromosome aberrations were found in 14 patients (66%). Six major recurrent chromosomal targets were defined. These were 5q, 12p, 13q, 6q, 15q, and 9, which were involved in 72% (5q), 64% (12p and 13q), 50% (6q), 43% (15q), and 28% (monosomy 9) of cases, respectively. Cytogenetic features can be summarized as follows: (1) gross genomic imbalances (mostly losses) predominate, (2) no single anomaly can be considered as specific, whereas their combination/accumulation is, and (3) both lymphoid and myeloid lineage-associated rearrangements are observed in unusual combinations in the same cell. This is suggestive of complex multistep tumorigenic mechanisms and is supportive of the hypothesis that CD4 ؉ , CD56 ؉ DC2 acute leukemia may arise from an undifferentiated nonmyeloid nonlymphoid progenitor cell. In conclusion, the present study documents for the first time the existence of a characteristic cytogenetic profile for this novel disease entity. (Blood. 2002;99:4154-4159)

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.