Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies

Abstract

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.

Keywords: EBV; NK/T-cell lymphomas; PD1; asparaginase; haematopoietic stem cell transplantation; radiotherapy.

Figure 1

Different clinical forms of NK/T-cell lymphomas. (A) Nasal NK/T-cell lymphoma, eroding from the nasal cavity into the skin. (B) Nasal NK/T-cell lymphoma eroding into the orbit and cavernous sinus, resulting in third nerve palsy and complete ptosis. (C) Non-nasal NK/T-cell lymphoma of the skin. (D) Aggressive NK/T-cell leukaemia/lymphoma. Circulating lymphoma cells were cytologically large granular lymphocytes.

Figure 2

Molecular pathogenesis of NK/T-cell lymphomas. These molecular pathways are targetable therapeutically. Shown in the centre is a typical hard palate perforation due to erosion from an NK/T-cell lymphoma in the nasal cavity, giving the classical appearance of a “lethal midline granuloma”.