Abstract
Simple SummaryNatural killer (NK)/T-cell lymphomas are aggressive extranodal Epstein–Barr virus (EBV)-positive malignancies. They can be divided into three subtypes: nasal (involving the nose and upper aerodigestive tract), non-nasal (involving skin, gastrointestinal tract, testis and other organs) and disseminated (involving multiple organs). Lymphoma cells are positive for CD3ε, CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asians. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial at diagnosis and follow-up. Stage I/II patients receive non-athracycline asparaginse-containing regimens, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients receive asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT). Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches include PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial.Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.
Highlights
Natural killer (NK) cells develop from a common lymphoid progenitor capable of differentiation to all lymphoid lineages [1]
Morphological evaluation can be supplemented by in situ hybridization for Epstein–Barr virus (EBV) encoded small RNA (EBER), which provides an accurate way of localizing lymphoma cells [8]
Whole blood should not be used, because of the variable presence of circulating memory B-cells that may be infected by EBV, which introduces unpredictable errors [46]
Summary
Natural killer (NK) cells develop from a common lymphoid progenitor capable of differentiation to all lymphoid lineages [1]. First reported more than seven decades ago, lethal midline granuloma was described as destructive midline facial malignancies that resulted inexorably in death [5] These lesions showed neoplastic lymphoid cells admixed with inflammatory cells and were morphologically referred to as polymorphic reticulosis. NK/T-cell lymphomas are almost exclusively extranodal in their distribution, with the nasal cavity, nasopharynx, oropharynx, the Waldeyer’s ring, and the upper aerodigestive tract most commonly involved (Figure 1A,B). They are referred to as nasal NK/T-cell lymphomas [9]. In about 10–20% of cases, other sites, including skin, testicles, gastrointestinal tract and salivary glands, are involved They are referred to as the non-nasal subtype (Figure 1C). Only few cases were described; it remains unclear if they were biologically or clinically similar to NK/T-cell lymphoma
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