NK/T-cell lymphoma is a rare and specific type of malignant lymphoma. The names used in the past were: necrotizing (lethal) midline sarcoidosis, pleomorphic reticulocytosis, midline malignant reticulocytosis, and angiocentric lymphoma. Most of the cases are NK cell tumors, but a few cases do not express NK cell markers but cytotoxic T cell markers, so they are called NK/T cell lymphoma. 1 Epidemiology There are obvious regional and gender differences in the development of this disease. The disease has a high prevalence in Asia and South America, with a significantly higher incidence in the yellow population and a rare incidence in the white population, indicating a racial susceptibility to the disease. The exact incidence is unknown. In Korea, the incidence of NK/T-cell lymphoma per 100,000 people in ear, nose and throat clinics was 40 in 1977-1989 and 20 in 1990-1996 [1]. Primary nasal or nasopharyngeal lymphoma was reported to account for 3% ~10. 7% of malignant lymphomas in the Oriental population in Asia, 7. 1% ~10% in Beijing [2-3], 8. 3% in Guangzhou [4], and 3% ~10. 7% in Hong Kong, China [5-6]. South America is about 2. 6% ~8% [6], while North America, Europe and other western countries are only 0. 17% ~1. 5% [6-7]. In terms of gender, there are significantly more men than women, with a male to female ratio of 2:1, and the median age of onset is 44 years [2]. 2 Etiology and pathogenesis The etiology of NK/T-cell lymphoma is unknown. The association of nasal NK/T-cell lymphoma with EBV, which is positive for EBV in tumor cells regardless of the patient’s ethnicity, suggests a pathogenic role of EBV in the disease. In contrast, in Chinese patients, all types of lymphomas occurring in the nasopharyngeal region are more closely associated with EBV infection. p53 mutations are rare in NHL, but the rate of p53 mutations in nasal NK/T-cell lymphoma is relatively high. p53 mutations are geographically related, with 24% in Mexican patients [9] and up to 47. 6% in China and Japan [10], with missense mutations in the former and silent mutations in the latter. The former is a missense mutation, while the latter is a silent mutation. This suggests that the p53 mutation rate and mutation mode are influenced by geography, environment or ethnicity. The mutation rate of the Fas (Apo-1/CD95) gene in nasal NK/T-cell lymphoma is also high, reported to be up to 50%, showing shift mutations, missense mutations and silent mutations [11]. These mutations may be associated with EBV, but the mechanism of EBV-induced mutations is still unclear. Clinical manifestations are characterized by a predilection for the midline of the face with destructive features. Early on, the disease mainly occurs in the nasal cavity, especially in the mucosa of the turbinates and nasal septum, but also in the lateral wall of the nasal cavity and the nasopharynx and oropharynx. 3. 1 Local symptoms Commonly, there are nasal congestion, blood in the nose, enlarged cervical lymph nodes, bad odor, facial swelling, eye symptoms, oral ulcers or masses, cranial nerve palsy, hoarseness, nasal mucosa erosion, necrosis, nasal septum perforation and oral hard palate bone destruction and perforation, and even nasal bone collapse. In Hong Kong, China [5], the symptoms of lymphoma originating from the nose include nasal congestion, runny nose, enlarged cervical lymph nodes, nasal swelling, ocular symptoms, oral ulcers or masses, skin nodules, cranial nerve palsy, and hoarseness, with incidences of 72%, 31%, 17%, 10%, 5%, 4%, 2%, 2%, and 1%, respectively. 3. 2 Local invasion Nasal lesions can spread from one side of the nasal cavity to the other side, paranasal sinuses, hard palate, nasopharynx, and other adjacent tissues. li et al [2] reported 175 cases of NHL in the primary nasal cavity in Beijing, and the tissues that spread from the primary nasal cavity to the nearby area in the following order: maxillary sinus 74 cases (42% ), septal sinus 63 cases (36% ), nasopharynx 43 cases (25% ), nasal skin 22 cases (13% ), hard palate 18 cases (10% ), orbit 14 cases (8% ), oropharynx 12 cases (7% ), soft palate 11 cases (6% ), skull base, frontal sinus and pterygoid sinus 3 cases (2% ), 2 cases (1% ) and 2 cases (1% ), respectively. 3. 3 Systemic dissemination Nasal NK/T-cell lymphoma can also undergo systemic dissemination in some patients with systemic dissemination who may present with hemophagocytic syndrome (HPS) or leukemia with extensive bone marrow infiltration. cheung et al [6] reported that systemic dissemination occurred in 17 of 51 cases of nasal NK/T-cell lymphoma, and the sites of involvement were In 1997, Kwong et al [12] reported that four patients with 24 cases of nasal NK/T-cell lymphoma had diffuse bone marrow involvement and hemophagocytic syndrome in four patients with progressive nasal NK/T-cell lymphoma. Takahashi et al [13] reported a median survival of only 1 to 2 months after the development of hemophagocytic syndrome. 3. 4 B symptoms NK/T-cell lymphoma can present with B symptoms of fever, wasting, and night sweats in both limited and disseminated types. 33% of patients with B symptoms were reported in China [2] and 10% in the United States [7]. We investigated 61 cases of NK/T-cell lymphoma from 1997 to 2004, and those with B symptoms accounted for 50. 8%. 4 Staging According to Ann Arbor staging, nasal NK/T-cell lymphoma was classified into IE, IIE, IIIE, and IVE stages. Some experts suggest that the IE stage should be further divided into IE limited group (lesions confined to the nasal cavity), and IE supercavity group (lesions extending beyond the nasal cavity) according to the extent of lesions, in order to fully estimate the prognosis [2]. 5 Pathological histological features and immunohistochemical manifestations 5. 1 Morphological features Nasal NK/T-cell lymphoma is characterized by tumor cells infiltrating the mucosal layer, often destroying the intrinsic glands, infiltrating and destroying the vascular wall, and focal necrosis of the tissue. The tumor cells are a mixture of small, medium and large cells, and may be mixed with many inflammatory cells, such as small lymphocytes, histiocytes, neutrophils, eosinophils and/or plasma cells. Capillary hyperplasia, tumor cells may infiltrate the perivascular and vascular wall with necrosis. 5. 2 Cell phenotype The NK cell phenotype of NK/T cell lymphoma is CD2, CD56, CD3ε positive and membrane CD3 and CD5 negative [13]. The T cell phenotype of NK/T cell lymphoma is CD45RO, CD43, CD3ε positive [14]. 5. 3 Expression of cytotoxic granule-associated proteins The vast majority of patients were positive for cytotoxic granule-associated proteins TIA-1, granzyme B and perforin [8]. The expression of killer cell immunoglobulin-like receptor profiles (KIPs) without rearrangement of the TCR-γ gene is diagnostic of nasal NK/T-cell lymphoma [15].T-cell intracel-lular antigen (TIA) is a cytoplasmic RNA-attached protein with a gene located on human chromosome 2 p13.TIA is a cytotoxic-granule associated pro- TIA is a cytotoxic-granule associated pro- tein that is thought to be expressed in up to 100% of nasal NK/T-cell lymphoma tissues [7], and thus the detection of TIA-1 has some value in the diagnosis of this type of lymphoma. 6 Diagnosis Patients with the above-mentioned typical clinical manifestations of masses or necrotic ulcers in the nasal cavity and tissues near the nasal cavity were diagnosed as NK/T-cell lymphoma by biopsy of the lesion tissue and immunohistochemical staining, if the tumor cells were positive for membrane CD3-, cytoplasmic CD3ε+, CD56+ and cytotoxic T-cell molecules (TIA, perforin and granzyme) and positive for EBV. However, because NK/T-cell lymphoma is characterized by angiocentric and vascular destructive growth, the tissue is often necrotic, making it difficult to obtain tumor tissue for biopsy and easy to miss the diagnosis. Therefore, repeated biopsies should be performed in suspected cases. 7 Treatment 7.1 Radiotherapy In the treatment of limited stage NK/T-cell lymphoma, radiotherapy alone accounts for a large proportion of the treatment. The treatment is usually performed with conventional dose fractionation (1.8-2.0 Gy), with a total dose of 45-50.4 Gy. 3 fields are usually irradiated, and selective neck prophylaxis is limited to the primary tumor in the nasopharynx, Wechsler’s ring and hypopharynx. Since local recurrence still occurs in half of the patients treated with radiotherapy alone, some authors hope to increase the local control rate by increasing the dose or by concurrent chemotherapy. First, Shikama et al [16] found that a dose greater than 50 Gy significantly increased the local control rate. Second, Cheung et al [17] conducted an exploratory study of concurrent radiotherapy in combination with cisplatin. In this Hong Kong, China study, a total of 79 patients with immunologically confirmed stage I and II nasal NK/T-cell lymphoma were treated, 69 of whom received radiotherapy alone or consolidation radiotherapy after induction chemotherapy, with complete tumor remission rates and 5-year overall survival rates of 68. 4% and 37. 9%, respectively. In contrast to the Korean study mentioned above, although most patients received chemotherapy, systemic dissemination occurred in 75.6%, while only 31.1% had an uncontrolled local rate. The analysis found that among the 25 patients who received >50 Gy irradiation and/or concurrent radiotherapy, only 3 (12% ) experienced local 673 Chinese Journal of Cancer, Vol. 16, No. 8, 2006 treatment failure. In addition, since more than one-third of the patients had local tumor invasion of the paranasal sinuses, the authors emphasize the importance of pre-treatment imaging diagnosis and precise fielding. With the advancement of multidisciplinary treatment of lymphoma, clinical studies in recent years have increased the use of combined radiotherapy (induction or consolidation) for the treatment of limited-stage NK/T-cell lymphoma. Unfortunately, most of the studies have failed to demonstrate the superiority of adding chemotherapy, while the advantage of first-line radiotherapy has been demonstrated in some studies. 7. 2 Chemotherapy The choice of regimen can be CHOP, DICE, EP, NP, ProMACE/cytaBOM, etc. Most of them still report that CHOP is the first choice, and some report that the addition of nitrosoureas can improve the efficacy, and a salvage regimen based on levomenadione can be used in refractory cases. Complete remission rates of 50% have been reported in refractory patients who did not respond to 2 courses of CHO regimens treated with the levomenadinase-based salvage regimen ADV (L-ASP 5 000-6 000 u/m2iv days 1-7, dexamethasone 10 mg/d, days 1-7, VCR 1 mg/m2iv day 1), which was significantly better than the CR 0% treated with non-ADV regimens (P<0. 05) [3]. The response to the combination chemotherapy regimen with doxorubicin (Adriamycin)-based regimens was extremely low in uniformly disseminated NK/T cells. A CMED regimen of cyclophosphamide (CTX) 2 g/m2, methotrexate (MTX) 200 mg/m2, etoposide (VP16) 600 mg/m2, and dexamethasone 80 mg/m2, administered intravenously every 2 weeks, has been reported in Mexico. Thirty-two cases were treated and 21 of them achieved CR with 69. 1 months of follow-up without recurrence [18]. Autologous stem cell transplantation has only been reported as a case study. 8 Prognosis NK/T-cell lymphoma is a highly malignant lymphoma, mostly occurring in the nose and surrounding tissues, and is mostly aggressive and highly progressive, with a poor outcome with conventional treatment. Its prognosis may be related to the extent and stage of the lesion: the more extensive the lesion and the more advanced the clinical stage, the worse the prognosis. The poor prognostic factors of nasal NK/T-cell lymphoma in our survey from 1997 to 2004 include poor general condition, late clinical stage, ineffective first treatment, and high Ki-67 expression. Age older than 60 years, presence of B symptoms, elevated LDH, β-2 microglobulin, and tumor resistance have also been considered as poor prognostic factors [3-4]