Hematologic malignancies of cytotoxic cells: Introduction

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THIS ISSUE OF Seminars in Hematology is devoted to leukemias and lymphomas of killer cell origin. These hematologic malignancies can be derived from either cytotoxic T lymphocytes (CTL) or natural killer (NK) cells. These lymphoid malignancies are much less common than B cell lymphoproliferative disease. For example, it is estimated that approximately 10% of non-Hodgkin’s lymphomas fall into the category of either T-cell or NK cell disorders. The relative infrequency of such patients, varied terminology, recent recognition of most of these entities, and perhaps most importantly lack of an easily determined marker of clonality for the NK cell neoplasms has led to a considerable degree of confusion in this area of hematologic malignancies. Therefore one goal of the current issue is to summarize diagnostic criteria and clinicopathologic features of hematologic malignancies originating from CTL or NK cells.

Elaine Jaffe and colleagues review the current classification of CTL and NK cell lymphomas based on the World Health Organization (WHO) system. Jaffe et al emphasize that the WHO classification is based on a multiparameter approach. In particular, they highlight the important role of the clinical presentation in classification as these malignancies show great morphologic diversity. In addition to providing a good overview of many of the entities discussed in further detail in subsequent chapters, other lesions such as the enteropathy type of T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphomas are discussed in detail. Particularly valuable for discrimination of the differential diagnostic possibilities among this group of hematologic malignancies are the immunophenotypic properties. Jaffe’s group recently used granzyme M staining to distinguish NK lymphomas, γδ T-cell lymphomas, and enteropathy-associated T-cell lymphomas from other lymphomas arising from cytotoxic precursors.

The five chapters that follow focus on various aspects of large granular lymphocyte (LGL) leukemia. Clonal cytogenetic abnormalities and tissue invasion of marrow, spleen, and liver characterized the first description of LGL leukemia. Subsequently it was recognized that LGL leukemia could be derived from either T cells or NK cells, leading to the designations of T-LGL and NK-LGL leukemia, respectively. Lamy and Loughran provide an update on the clinical features of LGL leukemia. A fascinating aspect of LGL leukemia is the strong clinical association with autoimmune diseases such as rheumatoid arthritis. There may be a common pathogenesis and indeed LGL leukemia and Felty’s syndrome may be the same disease. There is also growing recognition that LGL leukemia may overlap clinically with disease states characterized by failure of hematopoiesis. The Mayo Clinic experience describing the association of LGL leukemia with either aplastic anemia or pure red cell aplasia is detailed by Go et al. Although not widely recognized, the most common identifiable cause of pure red cell aplasia is LGL leukemia. It is widely acknowledged that studies of hematologic malignancies have led to important insights into lymphoid and myeloid biology. Zambello and Semenzato and Loughran and Epling-Burnette focus on NK receptor utilization and molecular survival signals in leukemic LGL. The former provide a comprehensive overview of NK receptor biology and emphasize the skewed NK receptor repertoire expression on patients’ NK cells, while the latter summarize recent work implicating activated STAT and MAP kinase pathways in promoting leukemic LGL survival. Such studies offer potential means of identifying new molecular targets for therapeutic intervention.

The spectrum of NK cell neoplasms is reviewed more comprehensively by Cheung and colleagues. In addition to aggressive NK leukemias, the clinicopathologic features of the extranodal NK lymphomas are discussed. The latter group includes both nasal and extranasal presentations and almost always is of true NK cell derivation. This category of NK leukemia/lymphoma is strongly associated with Epstein-Barr virus (EBV) infection and has a predilection for Oriental, Mexican, and South American ethnic groups. Gaulard and colleagues review the salient characteristics of γδ T-cell lymphoma. The typical patient with this disorder is a young male presenting with prominent hepatosplenomegly, systemic systems, and often pancytopenia with subtle bone marrow involvement. Liver biopsy shows characteristic sinusoidal involvement of γδ T cells. Isochromosome 7 is the unique recurring cytogenetic hallmark of γδ T-cell lymphoma.

A common theme in the pathogenesis of many hematologic malignancies is a cytogenetic translocation resulting in constitutive gene activation. A good example of this process is found in systemic anaplastic large cell lymphomas, characterized by balanced translocations involving the ALK gene with various partner genes, most commonly nucleophosmin. Consequent phosphorylation of the ALK tyrosine kinase leads to growth stimulation. Kadin and Carpenter provide an extensive review of three downstream signaling pathways activated by NPM-ALK fusion: P13 kinase, STATs, and phospholipase Cγ. They also discuss primary cutaneous anaplastic large cell lymphoma and distinguish a clinically benign variant, lymphomatoid papulosis.

A new clinical entity characterized by CD4⁺ CD56⁺ malignant cells and frequent extranodal involvement typically involving the skin has been recognized in the past decade. The WHO classification uses the term “blastic NK lymphoma” to describe such cases. Béné and colleagues make a strong case for these malignancies originating from type 2 dendritic cells. Their review stems from a semi-retrospective study of 23 cases performed by Feuillard and colleagues with the French Groupe d’Etude Immunologique des Leucemies (GEIL).

I am sure readers of this issue will be fascinated by the diagnostic challenges provided by the killer cell malignancies as well as by the opportunities afforded to better understand the biology of cytotoxic cells. The clinicians among us are bound to be disappointed by the lack of evidence for effective treatment for many of these diseases. The NK leukemias, extranodal NK lymphomas, γδ T-cell lymphomas, and “blastic” NK lymphomas all have a very aggressive clinical course. One can only hope that better delineation of the pathogenesis of each of these individual entities will lead to improvements in care for these patients.