Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features

Abstract

Nasal natural killer (NK)/T-cell lymphoma (NNKTL) is a clinical illness characterized by progressive unrelenting ulceration and necrosis of the nasal cavity and midline facial tissues. Histological features of the lymphoma include angiocentric and polymorphous lymphoreticular infiltrates, called polymorphic reticulosis. Surface antigens and the NK-cell marker, CD56, as well as pan-T antigen CD2, cytoplasmic CD3 (CD3epsilon), and CD45 are expressed in the lymphoma cells. The origin of the lymphoma is thought to be either NK-cell linkage without T-cell receptor (TCR) rearrangement or gammadeltaT-cell linkage with gammadeltaTCR rearrangement. Since the authors of this study first demonstrated the presence of Epstein Barr virus (EBV)-DNA and EBV oncogenic proteins in NNKTL, the lymphoma has been classified as one of the EBV-associated malignancies. The NNKTL cells produce interleukin (IL)-9, IL-10, and interferon-gamma-inducible protein-10 (IP-10), possibly due to EBV-oncogenic proteins in the lymphoma cells, and such cytokines take an important part in the cell proliferation and invasion, acting in an autocrine manner. Clinically, the serum EBV-DNA copy number is useful as a specific tumor marker and a predictive prognostic factor. Even in early clinical stages, the lymphoma shows poor prognosis caused by the rapid progression of the lesion into distinct organs. Our newly designed arterial infusion chemotherapy, from the superficial temporal artery, in combination with radiotherapy, has shown a favorable outcome in patients with NNKTL. In this article, the clinical, pathological, and virological characteristics of the lymphoma are reviewed, along with a report of our investigations.

Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

“…The mainstay of NKTL treatment is a combination of chemotherapy and radiotherapy. Patients treated with our regimen, known as MPVIC-P (methotrexate, peplomycin, etoposide, ifosfamide and carboplatin), achieved a high rate of complete remission [5]. Recent evidence suggests that platinum-containing chemotherapy has immune-modulating effects such as recruitment of effector CD8 T-cells and downregulation of Treg and MDSC [72].…”

“…Because latency type II EBV causes NKTL, which expresses the LMP-1, LMP-2 and EBNA-1 proteins but not the lytic cycle antigens, EBNA-2-6 or ZEBRA [5], identification of epitopes from LMP-1, LMP-2 or EBNA-1 is required to elicit anti-NKTL T-cell responses. We previously identified an LMP-1-derived CD4…”

“…However, because NKTL cells are thought to originate from NK cells or γδ T-cells [5], application of TLR ligands as adjuvants is not as straightforward as in solid tumors, because TLR signaling could stimulate NK cells [55]. However, TLR 2 triggering has been reported to induce EBV lytic protein, which is more highly immunogenic than latent protein, indicating that the TLR 2 ligand can play a role not only in stimulating immune cells but also in augmenting the immunogenicity of NKTL [56].…”

“…Several chemotherapy regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) and MPVIC-P (methotrexate, peplomycin, etoposide, ifosfamide, and carboplatin) have been used to treat NKTL patients and have shown favorable clinical responses [5,6]. However, chemotherapy causes severe adverse effects, including deaths from serious infections [6], and radiotherapy can cause radiation injury of the brain because of NKTL localization.…”

Soluble ICAM-1 secretion and its functional role as an autocrine growth factor in nasal NK/T cell lymphoma cells

“…According to the Ann Arbor classification system, ten and two patients were categorised as stage I and II, respectively. The patients underwent arterial infusion chemotherapy concomitant with radiotherapy, and are currently alive without relapse [26]. The patients signed informed consent forms for this study that were approved by the Institutional Review Board.…”