Extranodal Nasal-type Natural Killer Research Articles

Comparison of the clinical efficacies of two L‐asparaginase‐based chemotherapy regimens for newly diagnosed nasal‐type extranodal NK/T‐cell lymphoma

Nasal-type extranodal natural killer (NK)/T cell lymphoma (ENKTL) is a rare and aggressive type of lymphoma. The optimal chemotherapy regimen for ENKTL has not yet been established. In this study, we compared the LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) and GLIDE (gemcitabine, L-asparaginase, ifosfamide, dexamethasone, and etoposide) chemotherapy regimens for the treatment of ENKTL. A total of 267 patients with newly diagnosed ENKTL were included in this retrospective study. Propensity score matching (PSM) was used to adjust for confounders between the LVDP and GLIDE groups. Treatment responses, survival outcomes, and toxicities between the two groups were compared before and after PSM. At the end of therapy, the objective response rate (ORR) and complete response (CR) were 83.5% and 62.2%, respectively, for all patients. The ORR and CR were 85.5% and 62.2% for the LVDP group compared with 79.3% and 62.2% for the GLIDE group, respectively, and no differences between the two groups were found (ORR, p = 0.212; CR, p = 0.996). With a median 71 months follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 64.3% and 68.5%, respectively. The 5-year PFS and OS were 65.6% and 70.1% for the LVDP group compared with 61.6% and 64.6% for the GLIDE group, respectively (PFS, p = 0.478; OS, p = 0162). After PSM, no significant differences in short-term efficacy (ORR, p = 0.696; CR, p = 0.264) or long-term efficacy (PFS, p = 0.794; OS, p = 0.867) between the two groups were identified. However, treatment-related toxicities were milder in the LVDP group compared to the GLIDE group, even after adjusting for confounders via PSM. In conclusion, both LVDP and GLIDE regimens are effective for the treatment of ENKTL. However, the LVDP regimen is safer than the GLIDE regimen, with milder treatment-related toxicities. Therefore, the LVDP regimen could be a preferable option for patients with ENKTL.

Characteristics and prognosis of distant metastasis after primary treatment for early-stage extranodal nasal-type natural killer/T-cell lymphoma from the China Lymphoma Collaborative Group database.

This study aimed to investigate the characteristics and prognosis of distant metastasis (DM) after primary treatment for early-stage extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTCL). A total of 1619 patients from the China Lymphoma Collaborative Group database were retrospectively reviewed. The cumulative incidence of DM was assessed using Fine and Gray's competing risk analysis. The correlation between DM sites was evaluated using phi coefficients, while DM sites were classified using hierarchical clustering. Regression analysis was used to assess the linear correlation between DM-free survival (DMFS) and overall survival (OS). The 5-year cumulative DM rate was 26.2%, with the highest annual hazard rate being in the first year (14.9%). The most frequent DM sites were the skin and soft tissues (SSTs, 32.4%) and distant lymph nodes (LNs, 31.3%). DM sites were categorized into four subgroups of distinct prognosis - distant LN, SST, extracutaneous site, and lymphoma-associated hemophagocytic lymphohistiocytosis. SST or distant LN, solitary metastasis, and late-onset DM demonstrated a relatively favorable prognosis. Contemporary chemotherapy significantly decreased DM rates and improved DMFS. Decreased DM rates were further associated with increased OS probabilities. Our findings improve the understanding of the variable clinical behaviors of early-stage ENKTCL based on four distinct DM sites and thus provide guidance for future therapeutic decisions, metastatic surveillance, and translational trial design.

Analysis of latent T-cell epitopes in Epstein-Barr virus isolated from extranodal nasal-type natural killer/T-cell lymphoma in Taiwanese population

Extranodal nasal-type natural killer (NK)/T-cell lymphoma (NKTCL) is an aggressive lymphoma that is prevalent among East Asian and South American populations. Although Epstein-Barr virus (EBV) is commonly detected in NKTCL, there are limited studies that have analyzed the EBV genomic variations in NKTCL. In this study, 8 EBV latent genes were analyzed using targeted gene sequencing in 23 formalin-fixed paraffin-embedded tissues derived from 18 patients with NKTCL. Five cases with paired samples were comparatively analyzed. The consistency of EBV sequencing data between tissue samples was high (96.3%–98.7%), whereas that of variant calling among the tissue samples and plasma samples (74.3%–79.2%) was low. The highest densities of non-synonymous variants were detected in the EBNA3B gene. Among the 74 known T-cell epitopes, 363 non-synonymous variants were identified in 32 (43.2%) epitopes. Additionally, the AVFDRKSDAK (A1S/P and V2F/M/L) and YHLIVDTDSL (I4L and L10R/V/G/H) epitopes were associated with 5 patterns of amino acid changes in EBNA3B and EBNA-2, respectively. The frequency of variation in the human leukocyte antigen (HLA)-restricted epitopes with corresponding HLA types common among Taiwanese population was significantly low (P = 0.011), whereas that in anchor residues was significantly high (P = 0.012). In conclusion, this study demonstrated the genomic diversity of EBV in NKTCL and its correlation with the HLA-restricted epitope variations in Taiwanese population. The findings of this study provide useful insights for the development of novel therapeutic strategies for NKTCL.

Study of Radiotherapy on Extranodal Natural Killer (NK)/T-Cell Lymphoma of Stage IE

In this study, we will examine whether prophylactic cervical node irradiation (PCNI) is necessary for stage IE nasal type Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) and investigate the survival difference between patients with primary tumors originating from nasal cavity and the Waldeyer ring. From January 2009 to December 2015, 152 pathologically confirmed stage IE ENKTCL patients with nasal cavity and Waldeyer ring primary tumors were retrospectively analyzed. Those patients were divided into three groups according to their primary tumor locations: limited to the nasal cavity (NC group), originating from nasal cavity and invading the Waldeyer ring (NCWR group) and originating from the Waldeyer ring (WR group). All cases were treated with extended-field radiotherapy alone and no PCNI was performed. The overall survival (OS), progression-free survival (PFS) and distant recurrence free survival (DRFS) were obtained after long-term follow-up. Pearson’s chi-square test or Fisher’s exact test was used to analyze the distribution difference of clinical features among the three groups. Univariate and multivariate analyses were performed using the Kaplan-Meier method and the Cox proportional hazards regression. There were 140 cases with primary tumor originating from nasal cavity, including 122 cases in NC group and 18 cases in NCWR group. In addition, there are 12 cases in WR group. For NC group, NCWR group and WR group, the failure rates of cervical lymph nodes were 5.74%, 11.11% and 8.33%. The local recurrence rates were 6.56%, 11.11% and 8.33%. The distant metastasis rates were 11.48%, 22.22% and 41.67%, respectively. There was no significant difference in cervical lymph node failure rates and local recurrence rates among the three groups, but the distant metastasis rates were significantly different (P = 0.014).Survival analyses using Kaplan-Meier method and univariate COX model showed that the three groups had significantly different OS (P = 0.010), PFS (P = 0.019) and DRFS (P = 0.015). OS, PFS and DRFS in NC group was significantly better than those in WR group. However, there was no survival difference in OS, PFS and RFS between the NC group and NCWR group, as well as the NCWR group and WR group. Furthermore, multivariate COX survival analyses demonstrated that the primary site group and ECOG score were independent prognostic factors of OS. And the primary site group and B symptom were independent prognostic factors of PFS and DRFS. Stage IE ENKTCL patients with primary tumors originating from nasal cavity and the Waldeyer ring showed a similar low risk of cervical lymph node recurrence without PCNI, thus there is no need of PCNI for stage IE ENKTCL patients. The main cause of treatment failure was distant recurrence. Moreover, the OS, PFS and DRFS of the Waldeyer ring primary patients were inferior to the nasal cavity primary patients independent from other features, which indicated that they may need more systemic chemotherapy.

Efficacy and tolerance of GELOXD/P-GEMOXD in newly diagnosed nasal-type extranodal NK/T-cell lymphoma: A multicenter retrospective study.

Nasal-type extranodal natural killer NK/T-cell lymphoma (ENKTCL) is a distinct type of non-Hodgkin lymphoma with poor prognosis. This research aimed to evaluate the efficacy and safety of the GELOXD or P-GEMOXD regimens in patients with ENKTCL. Newly diagnosed ENKTCL patients treated with either theGELOXD or the P-GEMOXD regimen were identified from three cancer centers between January 2010 and December 2016. Kaplan-Meier and Cox regression analyses were used to calculate overall survival (OS) and progression-free survival (PFS) and to investigate prognostic factors. One hundred and eighty-four cases were identified from three cancer centers. After 1-5 treatment cycles of GELOXD or P-GEMOXD chemotherapy, 155 (84%) patients showed a complete response (CR). The 3-year OS (73.0% vs 38.2%, P=.001) and PFS (72.8% vs 32.4%, P=.000) rates were significantly higher in early-stage patients compared with advanced-stage patients. A multivariate analysis revealed that patient CR status was a significant independent factor in disease prognosis. Grade 3/4 leukopenia occurred in 43 (23.4%) patients. Major non-hematological toxicities included nausea (n=117, 63.6%) and vomiting (n=66, 35.9%). The GELOXD and P-GEMOXD chemotherapy regimens are well tolerated and provide favorable survival outcomes in patients with ENKTCL.

RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC.

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

A neutralized human LMP1-IgG inhibits ENKTL growth by suppressing the JAK3/STAT3 signaling pathway.

Latent membrane protein 1 (LMP1), which is associated with the development of different types of Epstein-Barr virus (EBV) related lymphoma, has been suggested to be an important oncoprotein. In this study, a human anti-LMP1 IgG antibody (LMP1-IgG) was constructed and characterized by ELISA, western blotting (WB), affinity and immunohistochemistry (IHC) analyses. CCK-8, MTT, apoptosis assays, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement-dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of LMP1-IgG on extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTL). Then, the influence of LMP1-IgG on the JAK/STAT signaling pathway was investigated. The results showed that the successfully constructed LMP1-IgG inhibited proliferation, induced apoptosis, and activated ADCC and CDC of ENKTL in a concentration- and time- dependent manner. Moreover, phosphorylation of JAK3 and STAT3 was inhibited by LMP1-IgG. Our data indicate that LMP1-IgG may provide a novel and promising therapeutic strategy for the treatment of LMP1-positive ENKTL.

Nasal-Type Extranodal Natural Killer/T-Cell Lymphoma Mimicking Recurrent Sinusitis: A Case Report and Review of the Literature

: Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare type of lymphoma that is endemic to East Asia. It typically demonstrates as a destructive mass involving the midline facial tissues that causes rhinosinusitis symptoms such as nasal obstruction, sinusitis, ulcer, and epistaxis. The diagnostic tendency of nasal-type ENKTL is to use computed tomography (CT), but this may present infiltrative patterns without a prominent mass, making it difficult to distinguish ENKTL from benign inflammatory diseases. Here, we report a 59-year-old male with a chief complaint of rhinosinusitis symptoms, mimicking chronic sinusitis and a CT scan showing a typical right sinusitis pattern. Functional endoscopic sinus surgery was performed and a positive culture was consistent with the diagnosis. However, histopathological and immunohistochemical evaluation established the diagnosis of nasal type ENKTL. Follow-up positron emission tomography-computed tomography (PET-CT) also corresponded with this diagnosis, and therefore, radiotherapy and chemotherapy were indicated.

L-asparaginase-based regimen as a first-line treatment for newly diagnosed nasal type extranodal natural killer cell/T-cell lymphoma.

The aim of the present study was to compare the efficacy of an L-asparaginase-based regimen and a CHOP regimen followed by radiotherapy as first-line treatments for newly diagnosed nasal type extranodal natural killer cell/T-cell lymphoma (ENKTL). A total of 69 patients received the CHOP regimen as the first-line treatment and 112 patients received the L-asparaginase-based regimen. All patients received radical radiotherapy following two cycles of chemotherapy. The overall response rates of the L-asparaginase-based and CHOP treatment groups were 90.18 and 72.46%, respectively (P=0.002). The one, two, and five-year overall survival (OS) rates and progression-free survival (PFS) rates of the L-asparaginase group were 96.0, 88.3, 65.1, 94.2, 79.8 and 50.0%, respectively. The one, two, and five-year OS and PFS rates of the CHOP group were 82.6, 61.9, 25.8, 63.8, 44.0 and 21.0%, respectively (P<0.001). Compared with CHOP treatment, L-asparaginase-based chemotherapy combined with radiotherapy was a safe and highly effective treatment for newly diagnosed ENKTL.

Efficacy and tolerance of pegaspargase-based chemotherapy in patients with nasal-type extranodal NK/T-cell lymphoma: a pilot study.

Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a highly invasive cancer with a poor prognosis. More effective and safer treatment regimens for ENKL are needed. Pegaspargase (PEG-Asp) has a similar mechanism of action to L-asparaginase (L-Asp), but presents lower antigenicity. The aim of the present research was to evaluate the safety profile and the latent efficacy of a PEG-Asp-based treatment regimen in patients with ENKL. Data collected from 20 patients with histologically confirmed ENKL, admitted to the Third Affiliated Hospital of Sun Yat-Sen University from January 2009 to August 2013, were included in the study. All patients received 2500 IU/m2/IM PEG-Asp on day 1 of every 21-day treatment cycle. Patients received combination chemotherapy with CHOP (n=5), EPOCH (n=7), GEMOX (n=7) or CHOP with bleomycin (n=1). After 2-5 treatment cycles (median, 4 cycles) of PEG-Asp-based chemotherapy, five patients (25%) showed a complete response (CR), and the overall response rate (ORR) was 60%. Grade 3/4 neutropenia occurred in fourteen patients (70%). Grade 3 alanine aminotransferase (ALT) elevation was observed in two. Grade 1-2 non-hematological toxicity consisted of activated partial thromboplastin time (APTT) elongation (n=9), hypofibrinogenemia (n=6), hypoproteinemia (n=17), hyperglycemia (n=3), and nausea (n=6). No allergic reactions were detected. No treatment related death was reported. Our results suggested that PEG-Asp-based chemotherapy presented an acceptable tolerance and a potential short-term outcome in patients with nasal-type ENKL.

Tumor testicular bilateral, tipo linfoma no Hodgkin de células T/NK extranasal

Lymphoma is a malignant neoplasia characterized by the proliferation of cells native to the lymphatic system. It makes up 1 % to 9 % of testicular neoplasia. Bilateral testicular tumor presentation was first described by Aberhouse in 1955. Extranodal nasal-type natural killer (NK) lymphoma is the most frequent variant of non-Hodgkin's tumors and presents with extensive vascular destruction and necrosis; the most common extranodal site is the upper respiratory system. It is characterized by poor outcome and systemic dissemination and does not respond well to current treatments.A 45-year-old man presented with bilateral increased testicular volume of 6-month progression, having received multiple treatments. Testicular ultrasound and abdominal computed tomography scan revealed increased testicular volume, retroperitoneal metastasis, and metastasis to the subcutaneous cell tissue. Tumor markers were negative. Right radical orchiectomy and biopsy of the left testis were performed. The definitive histopathologic diagnosis was extranasal- type NK/T-cell non-Hodgkin's lymphoma. The patient was referred to the Hematology Service and chemotherapy and hormone replacement treatment were begun.This tumor represents 1 % of all non-Hodgkin's lymphomas and 5 % of testicular masses. Mean presentation age is 50 years and there is a higher incidence in Asia and South America. Twenty percent of the cases affect areas outside of the nasal cavity. There is no staging classification for this disease. Five-year survival is 60 % and 17 % for disseminated disease. None of the current treatments (orchiectomy, chemotherapy and/or chemo-radiotherapy) are considered the criterion standard.

Clinical Disparity and Favorable Prognoses for Patients With Waldeyer Ring Extranodal Nasal-type NK/T-cell Lymphoma and Diffuse Large B-cell Lymphoma

This study aimed to compare the clinical characteristics and prognosis of Waldeyer ring extranodal nasal-type natural killer (NK)/T-cell lymphoma (WR-NKTCL) and Waldeyer ring diffuse large B-cell lymphoma (WR-DLBCL). Consecutive diagnoses of 122 WR-DLBCL and 44 WR-NKTCL patients, receiving mainly primary radiotherapy in early-stage WR-NKTCL and primary chemotherapy in early-stage WR-DLBCL, were reviewed. WR-NKTCL occurred predominately in young males, as nasopharyngeal stage I disease with B-symptoms, extranodal dissemination, and involving adjacent structures. WR-DLBCL was mainly stage II tonsillar disease with regional lymph node involvement. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 74% and 67% in WR-DLBCL, respectively, and 68% (P=0.468) and 59% (P=0.303) in WR-NKTCL. In stages I and II disease, WR-DLBCL 5-year OS and PFS were 79% and 76% compared with 72% (P=0.273) and 62% (P=0.117) in WR-NKTCL. In stage I disease, WR-DLBCL 5-year OS and PFS were 81% and 81%, compared with 76% (P=0.394) and 63% (P=0.236) in WR-NKTCL. In addition, the prognostic factors and failure patterns in WR-DLBCL and WR-NKTCL differed substantially. These results indicate that remarkable clinical disparities exist between WR-DLBCL and WR-NKTCL; however, different treatment strategies for each can result in similarly favorable prognoses.

JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma

Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.

Flow cytometric immunophenotyping is of great value to diagnosis of natural killer cell neoplasms involving bone marrow and peripheral blood

Natural killer (NK) cell neoplasms are unusual disorders. In this study we compared results of flow cytometric immunophenotype (FCI) with cytomorphology, histopathology and clinical findings in a series of patients with NK cell neoplasms with peripheral blood and/or bone marrow involvement, and the FCI of neoplastic and normal NK cells were compared. Retrospective data and specimens (bone marrow aspiration or peripheral blood) from 71 cases of NK cell neoplasms were obtained. All patients have been demonstrated laboratory and clinical features consistent with NK cell neoplasms, and the subtypes were determined by integrated clinical estimation. Routine 4-color flow cytometry (FCM) using a NK/T cell related antibody panels was performed. NK cell neoplasms were divided into two major subtypes by FCI, namely malignant NK cell lymphoma, including extranodal nasal type NK cell lymphoma (ENKL, 11 cases) and aggressive NK cell lymphoma/leukemia (ANKL, 43 cases), and relative indolent chronic lymphoproliferative disorder of NK cell (CLPD-NK, 17 cases). The former exhibited stronger CD56-expressing, larger forward scatter (FSC) and more usually CD7- and CD16-missing. FCI of CLPD-NK was similar to normal NK cells, but CD56-expressing was abnormal, which was negative in five cases and partially or dimly expressed in eight cases. Cytomorphologic abnormal cells were found on bone marrow slides of 4 cases of ENKL and 30 cases of ANKL. Eight cases of ENKL were positive in bone marrow biopsies, and other three cases were negative. In 32 cases of ANKL which bone marrow biopsies were applied, 21 cases were positive in the first biopsies. Lymphocytosis was found only in six cases of CLPD-NK by cytomorphology, and biopsy pathology was not much useful for diagnosing CLPD-NK. These results suggest that FCM analysis of bone marrow and peripheral blood was superior to cytomorphology, bone marrow biopsy, and immunohistochemistry in sensitivity and early diagnosis for ANKL, stage III/IV ENKL and CLPD-NK. FCI could not only define abnormal NK cells but also determine the malignant classification. It is beneficial for clinical management and further study of NK cell neoplasms.

Extranodal nasal–type NK/T-cell lymphoma of the palate and paranasal sinuses

SummaryBackground:Extranodal nasal-type natural killer (NK)/T-cell lymphoma represents a rare entity, typically originating in the nasal cavity, palate or midfacial region. Signs and symptoms include non-specific rhinitis and/or sinusitis, nasal obstruction, epistaxis, facial swelling and development of deep necrotic ulceration in the midline of the palate, causing an oronasal defect. Differential diagnosis includes fungal infections, Wegener’s granulomatosis, tertiary syphilis, other non-Hodgkin’s lymphomas and malignant epithelial midline tumors.Case Report:We present a case of a 40-year-old man complaining of headache, facial pain, nasal congestion and fever. Examination revealed a large deep necrotic ulcer in the middle of the palate, presenting as an oronasal defect. Endoscopic rhinoscopy revealed crusts in the nasal cavities, moderate perforation of the nasal septum cartilage and contraction of the middle and inferior conchae. Computer tomography showed occupation of the maxillary sinuses, ethmoidal cells and sphenoidal sinus by a hyperdense soft tissue mass. Laboratory investigation revealed increased erythrocyte sedimentation rate. A wide excision of the lesion was performed. Histopathological and immunohistochemical evaluation established the diagnosis of extranodal nasal-type NK/T-cell lymphoma. The patient was treated with CHOP chemotherapy, involved-field radiotherapy and autologous bone marrow transplantation. A removable partial denture with obturator was fabricated and inserted to relieve problems caused by the oronasal defect.Conclusions:Extranodal nasal-type NK/T-cell lymphoma is a very aggressive, rapidly progressing malignant neoplasm with a poor prognosis, which can be improved by early diagnosis and combined treatment.

Diagnosis of a multicentric extranodal nasal-type natural killer T-cell lymphoma made with an anterior chamber tap.

To report the case of an unusual multicentric Epstein-Barr virus (EBV)-associated extranodal nasal-type natural killer T-cell lymphoma masquerading as unilateral panuveitis, diagnosed with an anterior chamber tap. The clinical history and the morphological, immunohistochemical, and molecular features of a 51-year-old white man with left severe panuveitis were retrospectively evaluated. The patient initially presented with a 3-month history of recalcitrant sinusitis and new onset of unilateral loss of vision. Clinical examination revealed right peripheral facial nerve palsy, severe panuveitis of the left eye, and nasopharyngeal obstruction. Anterior chamber aspirates were examined. The combination of the presence of small- to intermediate-size lymphocyte proliferation, moderate elevation of the interleukin-10 level on cytokine profiling, and slightly positive polymerase chain reaction for EBV in the aqueous humor indicated an EBV-induced nasal-type natural killer T-cell lymphoma. Transnasal biopsy revealed the presence of numerous irregular lymphoma cells with positive staining for CD3, CD56, EBV-encoded RNA in situ hybridization, and negative staining for CD4, CD8, and CD1a. Lumbar puncture, cerebral magnetic resonance imaging, thoracoabdominal computed tomography, and upper digestive tract endoscopy revealed meningeal, renal, adrenal, and digestive involvement. Massive hemorrhage of the upper digestive tract caused rapid death. Extranodal nasal-type natural killer T-cell lymphoma is a very uncommon disease that may present acutely, sometimes as pseudouveitis. Simple investigations such as anterior chamber aspirates for cytological examination, reinforced by cytokine profiling and viral polymerase chain reaction looking for EBV, may provide a rapid diagnosis, necessary given the poor prognosis of the disease. To our knowledge, and after extensive review of the literature, we did not find another case report diagnosing this entity by anterior chamber paracentesis.

Extranodal nasal-type NK/T-cell lymphoma: Computed tomography findings of head and neck involvement

Extranodal nasal-type natural killer (NK)/T-cell lymphoma (NKTL) is a rare, but distinct clinical entity in Asian populations. However, it is not uncommon for NKTL to be belatedly or postoperatively diagnosed because radiologists are not familiar with its radiological features. To investigate the computed tomography (CT) findings in patients with extranodal nasal-type NKTL involving the head and neck. Twenty-nine patients (18 male, 11 female; mean age 51.5 years) with pathologically proven extranodal nasal-type NKTL were enrolled in this study. Two head-and-neck radiologists retrospectively evaluated the CT scans with special attention to the primary site, the extent of involvement, and patterns of the lesions (i.e., morphologic features, ulceration or necrosis, and bone destruction). The cases of nasal-type NKTL consisted of primary tumors arising from the sinonasal cavity in 13 patients (45%), the naso/oropharynx in three patients (10%), and simultaneous involvement in the nasal cavity and naso/oropharynx in 13 patients (45%). Fourteen patients (48%) showed tumor extension into adjacent structures. Of the 26 patients with involvement of the nasal cavity, 18 (69%) presented with an infiltrative pattern, seven (27%) with a polypoid pattern, and one (4%) with a combined pattern. Areas of necrosis within the tumor were observed in six patients (21%), bone destruction in five (17%), and regional lymphadenopathies in two (7%). Extranodal NKTL may be initially suggested by CT findings in the head and neck. Clinicians should consider these findings indicative of the possibility of NKTL, and should perform a histopathologic confirmation to establish a diagnosis.

Extranodal nasal‐type natural killer/T‐cell lymphoma masquerading as recalcitrant sinusitis

Extranodal nasal-type natural killer (NK)/T-cell lymphoma is a very uncommon disease process often mimicking refractory sinusitis. The diagnosis may be discovered after an extensive exclusion process. Careful immunohistochemical evaluation is crucial to differentiate NK/T-cell lymphoma from other malignancies. We describe a 46-year-old white man presenting with a 4-month history of refractory sinusitis and new onset visual field loss in his right eye, right facial tingling, and pain. Examination revealed right periorbital edema and scleritis, and necrotic appearing turbinates with purulence and fibrinous debris. CT/MRI delineated extensive paranasal sinus involvement. Immunohistopathology demonstrated extranodal nasal-type NK/T-cell lymphoma. Additional radiography revealed widespread involvement. Severe recalcitrant sinusitis with orbital involvement may be the initial presentation of NK/T-cell lymphoma. Ulcerative or necrotic lesions in the midline of the head and neck should raise concern for this disease. In addition to radiographic and laboratory testing, large biopsies should be taken for immunohistochemical analysis to achieve diagnosis and guide further management.

Immunohistochemical Characterization of Nasal-Type Extranodal NK/T-Cell Lymphoma Using a Tissue Microarray

Nasal-type extranodal natural killer (NK)/T-cell lymphoma is an uncommon malignancy. By using a tissue microarray, we characterized 84 cases of extranodal NK/T-cell lymphoma with regard to expression of 18 immunohistochemical markers and the presence of Epstein-Barr virus (EBV) RNA. In our series, CD2 was positive in 69 (93%) of 74 cases, CD3 in 68 (84%) of 81, CD5 in 22 (27%) of 81, CD20 in 0 (0%) of 82, CD29 in 75 (91%) of 82, CD30 in 29 (35%) of 84, CD43 in 81 (96%) of 84, CD54 in 58 (72%) of 81, CD56 in 46 (58%) of 79, CD62L in 23 (28%) of 83, CD183 in 66 (80%) of 83, BCL2 in 33 (39%) of 84, cutaneous lymphocyte antigen in 21 (25%) of 84, granzyme B in 70 (83%) of 84, Ki-67 in 59 (71%) of 83, linker for activation of T cells in 60 (71%) of 84, perforin in 66 (86%) of 77, TIA1 in 76 (90%) of 84, and EBV in 73 (87%) of 84. Hierarchical cluster analysis separated primary cutaneous cases from cases manifesting in other sites based on lower expression of the cell adhesion molecule CD54.

Skp2/p27 expression profile is correlated with Epstein–Barr virus status in extranodal nasal-type natural killer cell lymphoma

Extranodal nasal-type natural killer cell lymphoma (ENKL) is a high-grade malignancy and is associated with Epstein-Barr virus (EBV) latent infection. Little is known about its molecular abnormalities. Here, we studied the expression of Skp2 and p27 proteins in 48 cases of ENKL, and we evaluated their correlations with EBV status and clinical outcomes. EBV infection was observed in 90% of the cases. In all, 71% of the ENKLs were positive to Skp2 and 73% were negative to p27. A significant negative correlation was observed between the expression of Skp2 and p27 proteins (P = 0.022). Fifty-eight percent of the cases were Skp2+/p27- phenotype and correlated with EBV status (P = 0.047). The overall survival was influenced by the expression of Skp2, p27, and Skp2/p27. Patients with Skp2+, p27-, and Skp2+/p27- phenotypes had worse overall survival (P < 0.01, P = 0.016, and P < 0.01, respectively). Multivariance analysis showed the Skp2/p27 expression profile was an independent prognostic factor for overall survival (RR = 3.09, P < 0.01, 95% CI: 1.27-7.51). In conclusion, the Skp2/p27 expression profile is a helpful prognostic factor for ENKL. Latent EBV infection may increase the expression levels of Skp2, and consequently, p27 protein degradation is accelerated. EBV may be a good target for treatment of EBV-associated ENKL.