1 2 3 4 2 5 6 7 8 9 10 13 +  +  + − − +  1 14 15 16 Fig. 1 HE. Polymorphous pattern of proliferation in the nasal cavity. Large cells show positive immunoreactivity with CD3ε, TIA-1, and CD56. ABC method, ×400  Association with Epstein–Barr virus (EBV) 17 2 1 18 23 + 24 22 25 26 27 28 29 Fig. 2 In situ hybridization with EBER-1 probe reveals positive signals in the nucleus of proliferating cell  Table 1 EBV in nasal NK/T-cell lymphoma Source Country EBV positive rate (%) EBV subtype  Expression of latent 18 a France 7/7 (100) NA 7/7 LMP+ 20 China 21/21 (100) NA 5/21 LMP-1+ 21 Japan 11/12 (92) 10/11 typeA 8/12 LMP-1+ 22 Korea 15/16 (94) 15/15 typeA 7/15 LMP-1+ 24 Indonesia 18/20 (90) NA NA EBV LMP NA a 1 30 31 32 33 34 31 35 36 37 Genetical changes Lymphoma arises from clonal expansion of lymphoid cells that are transformed by the accumulation of genetic lesions affecting oncogenes and tumor suppressor genes. In general, amount of samples from NKTCL lesions available for genetical analyses is small, and samples usually contain massive necrotic areas. Therefore information for genetical changes in NKTCL has been relatively limited until present. Alterations of tumor suppressor genes and oncogenes 38 42 43 44 45 46 2 43 47 Table 2 p53 mutations in nasal NK/T-cell lymphoma  Number of cases  Exons examined Frequency of mutations (%) Predominance of transition mutation Asia 41 58 4–8 62% yes 41 42 4–8 31% yes  China 38 42 5–8 48% yes 40 20 4–8 40% yes 42 27 4–8 63% yes 43 21 5–8 24% no 43 48 15 38 49 8 14 50 41 39 41 41 40 42 FAS 51 FAS 52 FAS 53 54 FAS FAS 3 4 54 FAS Fig. 3 FAS The shaded rectangles  Fig. 4 The mouse WR19L cell line expressing recombinant human FAS protein with (T1102C, A978G, 1095 ins A) or without (wild type) mutations were incubated with various concentrations of anti-FAS antibody at 37.0°C for 16 h. Clones expressing FAS receptor with any mutations (A978G, 1095 ins A, T1102C) were resistant to apoptosis induced by the anti-FAS antibody  Others 55 Epidemiological features 56 58 56 57 5 59 60 3 61 63 61 64 65 66 67 Table 3 Frequency of lethal midline granuloma in Japan, Korea (Seoul), and China (Shanghai) Disease Number of patients (frequency per 100,000 ENT patients) Japan other than Okinawa (1965–1986) Okinawa (1973–1991) Seoul (1979–1989) Shanghai (1979–1990) Wegener’s granulomatosis 64(4) 1(3) 0(0) 1(4) Polymorphic reticulosis 114(8) 9(27.4) 56(40.8) 73(9.8) Malignant lymphoma 82(6) 11(33.5) 15(10.9) 54(7.2) Others 42(3) 1(3) 6(4.4) 0(0) Total 302(21) 22(69.9) 77(56) 128(17) 68 Life-style and environmental factors 69 70 71 72 4 73 74 t t 75 Table 4 Risk of nasal NK/T-cell lymphoma in relation to cultivation of crops and pesticide use  a  N  N 95% CI Lower Upper Cultivation of crops  At present 2.81 27 36 1.49 5.29  More than 5 years 5.08 24 19 2.47 10.43 Pesticides       Users 4.01 23 23 1.99 8.09 Type of pesticide  Herbicide 3.17 13 16 1.36 7.38  Insecticide 3.45 20 21 1.67 7.13  Fungicide 6.05 10 6 1.98 18.46 Precautions   Gloves used 3.30 10 11 1.28 8.54   Gloves not used  4.76 13 12 1.93 11.72   Mask used 5.44 14 10 2.20 13.47   Mask not used  2.82 9 13 1.08 7.37   Glasses used 1.18 1 3 0.11 12.13   Glasses not used 4.52 22 20 2.17 9.42   Sprinkling downward attended 2.20 9 16 0.88 5.53   Sprinkling downward not attended 8.45 14 7 3.01 23.70 CI a Conclusions Clinical course of patients with NKTCL is usually highly aggressive. Therefore clarification of risk factors for disease development is especially important to establish a strategy for disease prevention. Because EBV infection and pesticides could be risk factors for NKTCL, investigation on effects of pesticides for EBV activation is needed. Employment of the similar kind of the epidemiological study is desirable in other areas than East Asia. Patients with NKTCL cluster in Asia and Latin American countries, therefore some genetical factors might be involved in the disease development. Further studies including HLA antigen typing of patients is important to further clarify the mechanism for disease development.