Aggressive NK cell lymphomas: insights into the spectrum of NK cell derived malignancies

The report in the current issue of Histopathology by Mori et al. provides new data that help to define the features of aggressive natural killer (NK) cell leukaemia. The authors describe four cases that presented clinically with systemic disease but, most importantly, without a leukaemic phase. The investigators classified their cases as aggressive NK-cell lymphoma, but noted the presence of widespread disease in all cases, similar to the systemic involvement by aggressive NK-cell leukaemia. Imamura originally described this disease as aggressive NK-cell leukaemia/lymphoma, in recognition of the variable presence of bone marrow and peripheral blood involvement. As the authors noted, the clinical presentation is comparable to that of HTLV1-associated adult T-cell leukaemia/lymphoma (ATLL), which may present with leukaemia, with lymphadenopathy, or involvement of other sites such as skin. In the recently proposed World Health Organization (WHO) classification of haematopoietic and lymphoid neoplasms, two principle neoplasias derived from mature NK-cells are recognized. The first is extranodal NK/T cell lymphoma, nasal type (extranodal NK/T lymphoma), which was included in the REAL classification as angiocentric lymphoma. The name angiocentric lymphoma was based on the extensive necrosis associated with frequent invasion and destruction of blood vessels. The second is aggressive NK-cell leukaemia (ANKL), which corresponds to the cases originally described in Japan as aggressive NK-cell leukaemia/lymphoma. The WHO committee chose the name aggressive NK-cell leukaemia to permit a clear distinction between ANKL which presents with widespread systemic disease, with or without peripheral blood involvement, and extranodal NK/T lymphoma. While the midline nasal area is the most common site of presentation, extranodal NK/T lymphoma may present in diverse extranodal sites. Imamura et al. in the original description of this entity coined the term aggressive NK-cell leukaemia/ lymphoma to stress certain peculiarities of the disease. Clinically, it is characterized by generalized lymphadenopathy, hepatosplenomegaly, the presence of atypical lymphocytes with large azurophilic cytoplasmic granules in the peripheral blood, and partial involvement of the bone marrow. An important feature of this disorder, which is unlike other leukaemias but similar to ATLL, is the patchy and sometimes minimal involvement of the bone marrow, even in the presence of peripheral blood disease. This finding suggests that the bone marrow is not the primary site of neoplastic transformation, in contrast to most leukaemias. Therefore, due to the clinical presentation with peripheral lymphadenopathy and hepatosplenomegaly on one side, and peripheral blood involvement on the other side, the term leukaemia/ lymphoma was preferred. The important point, regardless of the nomenclature, is to recognize ANKL as an aggressive entity that frequently manifests as leukaemia, but that might present with generalized lymphadenopathy with minimal or no involvement of the peripheral blood. ANKL shares many features with extranodal NK/T lymphoma, such as the presence of azurophilic granules in the cytoplasm of the neoplastic cells, identical immunophenotype (CD21, CD3±, CD561, CD16±/1, CD57±), and genotype (lack of T-cell receptor (TCR) gene rearrangements), and an increased incidence in Asian populations. There has been uncertainty as to whether ANKL, similar to extranodal NK/T lymphoma is an EBV-associated disorder. Unfortunately, in the initial reports of this entity, studies for EBV were not performed. The finding of Mori et al. that all four cases were EBV positive, is useful information and lends support to the concept that ANKL is an EBV-associated disorder. Despite similarities in phenotype and genotype, clinical and morphological features distinguish these