MRI of neck nodes in non-Hodgkin's lymphoma of the head and neck.
King A D,Lei K I,Ahuja A T
The British journal of radiology
The aim of this study is to describe the imaging features of neck nodes in non-Hodgkin's lymphoma (NHL). The MR scans of 61 patients undergoing staging of a primary extranodal NHL of the head and neck were reviewed retrospectively. Those MR images with nodal disease were assessed for (a) the pattern of nodal disease, (b) presence of nodal necrosis and (c) presence of extracapsular neoplastic spread (ENS) and nodal matting. The features of the nodal disease were analysed in relationship to the sites of the primary NHL (palatine tonsil (PT) n=23, nasal cavity (NC) n=24, nasopharynx (NP) n=6, other extralymphatic sites (OES) n=8), and histology (natural killer/T-cell (NK/T) n=26, diffuse large cell (DLC) n=24, other subtypes (OS) n=11). Nodal disease was present in 26 patients (43%) and occurred in NHL of the PT n=16 (70%), NP n=3 (50%), NC n=5 (21%) and OES n=2 (25%) and in DLC n=15 (63%), NK/T n=6 (23%) and OS n=5 (45%). Nodal disease was significantly more frequent in DLC than NK/T lymphomas (p=0.0053). Nodal disease spread in a contiguous fashion in 25 (96%) patients with nodes. Necrosis was present in 7 of 26 (27%) being present in DLC of the PT in 5, NK/T of the NP in one and NK/T of the NC in one. ENS and matting were present in 19 (73%) and 13 (50%) patients with nodes, respectively. ENS was found in DLC, NK/T, OS, NC, NP, PT, OES (11, 4, 4,1, 2, 14, 2, respectively) and matting was found in DLC, NK/T, OS, NC, NP, PT, OES (9, 3, 1, 0, 2, 10, 1, respectively). Nodal NHL spreads in a contiguous fashion and is most commonly associated with DLC lymphoma of the NP and PT in Waldeyer's ring. Extracapsular nodal spread is frequent and found in most histological subtypes especially those arising from Waldeyer's ring. Necrosis is more common than previously believed.
Central nervous system vasculitis from Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorder in children: A case report.
Lee Mi Seon,Hwang Su-Kyeung,Kim Yeong Eun,Suh Jin Kyung,Kim Hyery,Lee So Mi,Jeong Ji Yun,Kwon Soonhak,Lee Yun Jeong
Brain & development
BACKGROUND:Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders (EBV-T/NK-LPD) is a group of rare disorders resulting from EBV-infected T/NK-cells. It manifests as a broad spectrum of clinical symptoms according to immunologic status and viral load of an infected patient. Here, we report a boy who developed central nervous system (CNS) vasculitis and myelopathy as possible neurologic manifestations of EBV-T/NK-LPD. CASE REPORT:A 16-year-old boy came to our hospital with a necrotic skin lesion on his right shoulder. He suffered from local skin reactions with high fevers after mosquito bites since he was 10 years old. During the evaluation of his skin lesion, he suddenly developed left facial palsy. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) showed acute infarctions of the pons and middle cerebellar peduncle and irregularities of both anterior inferior cerebellar arteries. Serologic testing showed an elevation of total Ig E levels, anti-VCA IgG levels, and anti-EA IgG titers. EBV DNA copy numbers of the whole blood and cerebrospinal fluid (CSF) were elevated. Biopsy of the right shoulder skin showed extranodal NK/T-cell lymphoma. According to clinical features and laboratory findings, he was diagnosed with EBV-T/NK-LPD. He was treated with chemotherapy and hematopoietic stem cell transplantation but developed recurrent infarctions during treatment. CONCLUSION:This case showed the diagnostic challenge of neurologic manifestations of EBV-T/NK-LPD. EBV-T/NK-LPD-associated CNS vasculitis needs to be considered as a differential diagnosis of CNS vasculitis, when it is accompanied by the typical clinical spectrum of EBV-T/NK-LPD such as severe mosquito bite allergy, extranodal NK/T-cell lymphoma.
Fluorine-18 fluorodeoxyglucose positron emission tomography in mature T-cell and natural killer cell malignancies.
Khong Pek-Lan,Pang Clara B Y,Liang Raymond,Kwong Yok-Lam,Au Wing-Yan
Annals of hematology
Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) is useful in Hodgkin and B-cell lymphomas. Few data exist on T-cell and natural killer (NK)-cell lymphomas. Thirty consecutive T-cell and NK-cell lymphomas were investigated with PET-computerized tomography (CT). In 12 NK-cell lymphomas, all nasal/extranasal lesions were FDG-avid. In nasal/maxillary areas, FDG-avid tumours were consistently more localised than on CT, suggesting that soft tissue masses on CT were partly due to inflammation. These findings have important implications in radiotherapy planning. In two NK-cell lymphomas, PET did not detect morphologically occult marrow infiltration uncovered by in situ hybridisation for Epstein-Barr-virus-encoded small RNA. In angioimmunoblastic lymphoma (n = 7), peripheral T-cell lymphoma, unspecified (PTCL-U, n = 4) and anaplastic large cell lymphoma (ALCL, n = 3), involved nodal/extranodal sites shown on CT and/or biopsy were concordantly PET-positive. In one PTCL-U, PET detected FDG-avid marrow infiltrations not shown on biopsies. In contrast, cutaneous ALCL (n = 1) and mycosis fungoides (n = 2) showed minimal FDG uptake. In one case of T-cell large granular lymphocyte leukaemia, marrow, nodal and bowel infiltrations were not FDG-avid. PET maximum standardised uptake value did not correlate with clinicopathological features and prognosis. These observations defined the pre-treatment value of PET-CT in T-cell and NK-cell lymphomas. The post-treatment role requires further studies.
Non-Hodgkin's lymphoma of the nasopharynx: CT and MR imaging.
King A D,Lei K I K,Richards P S,Ahuja A T
OBJECTIVE:Nasopharyngeal (NP) non-Hodgkin's lymphoma (NHL) is an uncommon tumour. The aim of the study was to describe the appearances on CT and MR imaging, and identify the features which help to distinguish NPNHL from other NP tumours. MATERIALS AND METHODS:The CT (n=8) and MR (n=10) images of 14 patients with NPNHL were reviewed retrospectively. Patients with NPNHL were divided into primary NPNHL, where the primary tumour was in the NP (n=7) and secondary NPNHL where the primary tumour was at another extranodal site in the head and neck (n=7). All NPNHL were assessed for tumour size and distribution, appearance and local tumour invasion, in addition lymphadenopathy was assessed in primary NPNHL. RESULTS:The NPNHL ranged in size from 20-75 mm (mean of 55 mm for primary and 30 mm for secondary NHL) and were homogeneous on CT in eight (100%) and MR in seven (70%) and mildly heterogeneous on MR in three (30%) patients. NPNHL involved all walls of the NP in 10 (71%) (n=1). Primary NPNHL extended superficially in five (71%) to involve the nasal cavity (n=3) and oropharynx (n=2) and lymphadenopathy was present in five (71%) being bilateral and involving multiple nodal sites (n=4) with necrosis (n=2) and matting (n=3). CONCLUSION:NPNHL is a homogeneous tumour that tends to diffusely involve all walls of the nasopharynx and spread in an exophytic fashion to fill the airway, rather than infiltrating into the deep tissues. Deep tumour infiltration, when it occurs, is found in those patients with primary NHL and is usually limited in extent and of small volume. and extended in an exophytic fashion to fill the NP cavity in six (43%). Deep tumour invasion was present in two (14%) both patients with primary NHL, the extent and volume of this tumour invasion was small and involved the prevertebral muscles (n=2), parapharyngeal fat space (n=1) and skull base Primary NHL more commonly spreads superficially to involve the nasal cavity or oropharynx, lymphadenopathy is frequent and extensive. A large tumour that fills the nasopharynx, with no or minimal invasion into deep structures, and a propensity to extend down into the tonsil, rather than up into the skull base, may suggest the diagnosis of NHL over nasopharyngeal carcinoma.
Fox and Blimp in NK-cell lymphoma.
In this issue of Blood, Karube and colleagues have identified FOXO3 and PRDM1 (Blimp1) as tumor suppressor genes with a potentially critical role in the pathobiology of extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia.
Defective Epstein-Barr virus in chronic active infection and haematological malignancy.
Okuno Yusuke,Murata Takayuki,Sato Yoshitaka,Muramatsu Hideki,Ito Yoshinori,Watanabe Takahiro,Okuno Tatsuya,Murakami Norihiro,Yoshida Kenichi,Sawada Akihisa,Inoue Masami,Kawa Keisei,Seto Masao,Ohshima Koichi,Shiraishi Yuichi,Chiba Kenichi,Tanaka Hiroko,Miyano Satoru,Narita Yohei,Yoshida Masahiro,Goshima Fumi,Kawada Jun-Ichi,Nishida Tetsuya,Kiyoi Hitoshi,Kato Seiichi,Nakamura Shigeo,Morishima Satoko,Yoshikawa Tetsushi,Fujiwara Shigeyoshi,Shimizu Norio,Isobe Yasushi,Noguchi Masaaki,Kikuta Atsushi,Iwatsuki Keiji,Takahashi Yoshiyuki,Kojima Seiji,Ogawa Seishi,Kimura Hiroshi
Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF1, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.
Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases.
Laurini Javier A,Perry Anamarija M,Boilesen Eugene,Diebold Jacques,Maclennan Kenneth A,Müller-Hermelink H Konrad,Nathwani Bharat N,Armitage James O,Weisenburger Dennis D
The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.
How I treat NK/T-cell lymphomas.
Tse Eric,Kwong Yok-Lam
Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are surface CD3-, cytoplasmic CD3ε+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18-fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT.
Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma.
Kim W Y,Jeon Y K,Kim T M,Kim J E,Kim Y A,Lee S-H,Kim D-W,Heo D S,Kim C-W
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Extranodal natural killer/T-cell lymphoma (NKTCL) is a clinically heterogeneous disease with a poor prognosis, requiring risk-stratified management in affected patients. Recently, tumor microenvironment including regulatory T cells (Tregs) has been implicated as a prognostic marker in certain types of lymphoma. PATIENTS AND METHODS:We collected 64 NKTCL cases and numerically quantified the amount of tumor-infiltrating FOXP3-positive Tregs by automated slide scanning and image analysis program after immunohistochemical staining using anti-FOXP3 antibody. RESULTS:Patients were able to be classified into two end groups by their level of Tregs. Twenty-eight (44%) patients had Tregs <50/0.40 mm(2), while 36 (56%) had Tregs > or =50/0.40 mm(2) within the tumor. The decreased number of Tregs (<50/0.40 mm(2)) was more common in patients with poor performance status or in those presented in non-upper aerodigestive tract. However, the level of Tregs was not associated with other prognostic factors, including stage, lactate dehydrogenase level, International Prognostic Index, and NKTCL Prognostic Index. Importantly, patients with increased numbers of Tregs (> or =50/0.40 mm(2)) showed prolonged overall and progression-free survival (P = 0.0005 and P = 0.0079, respectively). The number of FOXP3-positive Tregs was an independent prognostic factor (P = 0.001) by multivariate analysis. CONCLUSION:Increased quantity of tumor-infiltrating Tregs predicted improved clinical outcome in NKTCL patients.
L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature.
Jaccard A,Petit B,Girault S,Suarez F,Gressin R,Zini J-M,Coiteux V,Larroche C,Devidas A,Thiéblemont C,Gaulard P,Marin B,Gachard N,Bordessoule D,Hermine O
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome. PATIENTS AND METHODS:We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV. RESULTS:All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed. CONCLUSION:These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.
Primary radiotherapy showed favorable outcome in treating extranodal nasal-type NK/T-cell lymphoma in children and adolescents.
Wang Zhao-Yang,Li Ye-Xiong,Wang Wei-Hu,Jin Jing,Wang Hua,Song Yong-Wen,Liu Qing-Feng,Wang Shu-Lian,Liu Yue-Ping,Qi Shu-Nan,Fang Hui,Liu Xin-Fan,Yu Zi-Hao
Extranodal nasal-type natural killer (NK)/T-cell lymphoma is rarely observed in children and adolescents. We aim to investigate the clinical features, prognosis, and treatment outcomes in these patients. Thirty-seven patients were reviewed. There were 19, 14, 2, and 2 patients with stage I, stage II, stage III, and stage IV diseases, respectively. Among the patients with stage I and II disease, 19 patients received initial radiotherapy with or without chemotherapy, and 14 patients received chemotherapy followed by radiotherapy. The 4 patients with stage III and IV disease received primary chemotherapy and radiation of the primary tumor. Children and adolescents with extranodal nasal-type NK/T-cell lymphoma usually presented with early-stage disease, high frequency of B symptoms, good performance, low-risk age-adjusted international prognostic index, and chemoresistance. The complete response rate after initial radiotherapy was 73.7%, which was significantly higher than the response rate after initial chemotherapy (16.7%; P = .002). The 5-year overall survival (OS) and progression-free survival (PFS) rates for all the patients were 77.0% and 68.5%, respectively. The corresponding OS and PFS rates for patients with stage I and II disease were 77.6% and 72.3%, respectively. Children and adolescents with early-stage extranodal nasal-type NK/T-cell lymphoma treated with primary radiotherapy had a favorable prognosis.
Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy.
Wang Zhao-Yang,Liu Qing-Feng,Wang Hua,Jin Jing,Wang Wei-Hu,Wang Shu-Lian,Song Yong-Wen,Liu Yue-Ping,Fang Hui,Ren Hua,Wu Run-Ye,Chen Bo,Zhang Xi-Mei,Lu Ning-Ning,Zhou Li-Qiang,Li Ye-Xiong
The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.
Aggressive natural killer (NK)-cell leukaemia and extranodal NK/T-cell lymphoma are two distinct diseases that differ in their clinical presentation and cytogenetic findings.
Yang Ching-Fen,Hsu Chih-Yi,Ho Donald M-T
AIMS:Aggressive natural killer (NK)-cell leukaemia (ANKCL) and extranodal NK/T-cell lymphoma (ENKTCL) with secondary bone marrow involvement are rare bone marrow NK/T-cell neoplasms and share similar features. This study aimed to distinguish these two entities. METHODS AND RESULTS:We studied bone marrow NK/T-cell neoplasms by classifying them into those with no extramedullary mass (group 1, eight cases) and those with extramedullary mass (group 2, 13 cases). The two groups showed similar clinical presentations and pathological features. Fever and cytopenia were the most common clinical presentations in both groups. The neoplastic cells varied from small and relatively monotonous cells to large pleomorphic cells. In six cases (two in group 1, and four in group 2), the neoplastic infiltrate was inconspicuous, consisting of ≤10% of marrow cells in the interstitium, which were hardly identified by haematoxylin and eosin staining alone. Nearly all patients rapidly died, regardless of the neoplastic infiltrate volume. All of the group 1 patients fulfilled the World Health Organisation 2017 diagnostic criteria of ANKCL, and their survival was significantly worse than that of the group 2 patients (P = 0.035). In addition, there was a significant association between being in group 1 and chromosome 7 abnormalities. Chromosome 6q deletion, which is commonly reported in ENKTCL, was seen in two of our group 2 patients, and was not observed in any of our group 1 patients. CONCLUSION:ANKCL with no extramedullary mass should be distinguished from ENKTCL with bone marrow involvement, as the former shows distinct outcomes and genetic features.
Diagnosis and management of extranodal NK/T cell lymphoma nasal type.
Tse Eric,Kwong Yok-Lam
Expert review of hematology
INTRODUCTION:Extranodal NK/T-cell lymphoma nasal type is a distinct clinicopathologic entity. The most common initial site of presentation is the nasopharyngeal area, but non-nasals sites including the skin and the gastrointestinal tract may be affected. AREAS COVERED:The diagnosis and management of NK/T-cell lymphoma is discussed, based on a literature search on PubMed. NK/T-cell lymphoma are typically positive for CD3 (cytoplasmic), CD56, cytotoxic markers (granzyme B, TIA1) and Epstein Barr virus (EBV). Plasma EBV DNA is an accurate surrogate biomarker for lymphoma load. For stage I/II nasal lymphoma, a combination of chemotherapy and radiotherapy yields the best results. Concomitant chemoradiotherapy and sequential chemotherapy and radiotherapy give similar response rates and survivals. For stage III/IV nasal lymphoma and non-nasal lymphomas, chemotherapy is the mainstay of treatment. Conventional anthracycline-based regimens are ineffective. Recommended chemotherapy protocols are based on the use of L-asparaginase combined with other effective drugs. Durable remission can be expected in at least 60% of patients irrespective of stage. Prognostically models based on clinicopathologic parameters and EBV DNA load are useful in stratification of patients for therapy. Expert commentary: Current treatment leads to long-term survival in a significant proportion of patients. For relapsed patients, novel strategies are needed.
Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression.
Cho Junhun,Kim Seok Jin,Park Woong-Yang,Kim Jinho,Woo Jeongmin,Kim Gahyun,Yoon Sang Eun,Ko Young Hyeh,Kim Won Seog
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Extranodal NK/T-cell lymphoma is an aggressive lymphoma that is strongly associated with Epstein-Barr virus infection. Although some extranodal NK/T-cell lymphoma patients have shown responses to immune checkpoint blockade, biomarkers for predicting extranodal NK/T-cell lymphoma patient response to immunotherapy have not yet been defined. To understand the tumor immune microenvironment, we analyzed the expression of 579 immune-related genes and characterized the immune cells using immunohistochemistries and in situ hybridization for EBER. Based on comprehensive analyses, we developed an immune subtyping model that classifies extranodal NK/T-cell lymphoma patients into four tumor immune microenvironment subgroups using three immunohistochemical markers (FoxP3, PD-L1, and CD68). The four tumor immune microenvironment subgroups were named immune tolerance, immune evasion-A, immune evasion-B, and immune silenced. The immune tolerance group was characterized by high-Treg counts and was frequently observed in early stage, and nasal extranodal NK/T-cell lymphoma. The immune evasion group showed high cytotoxic T-cell counts and high PD-L1 expression but low Treg counts. In the immune-silenced group, almost all immune responses were exhausted, most patients were at an advanced stage, and had the poorest disease prognosis among the tumor immune microenvironment subgroups. In some patients (n = 3), a shift in the tumor immune microenvironment subgroup classification was observed in sequential biopsies. The response rate to pembrolizumab, an anti-PD-1 antibody, was 100% (1/1) in the immune tolerance group, 60% (3/5) in the immune evasion group, and 0% (0/5) in the immune-silenced group. We classified extranodal NK/T-cell lymphoma into four tumor immune microenvironment subgroups using a new classification system. In conclusion, we propose that the tumor immune microenvironment of extranodal NK/T-cell lymphoma may change during disease progression and may serve as a useful biomarker for immunotherapy.
Epstein-Barr virus in T and natural killer (NK) cell non-Hodgkin's lymphomas.
Kanavaros P,Briere J,Emile J F,Gaulard P
Several studies using sensitive in situ hybridization techniques show that, in non-immunocompromised patients, Epstein-Barr virus (EBV) is more frequently detected in lymphomas expressing T cell markers than in B cell lymphomas. Among lymphomas expressing T cell markers, the presence of EBV is highly related to the site of origin of the tumor, being found in nearly all sinonasal lymphomas, in only a proportion of Waldeyer's ring, lung, gastrointestinal and nodal lymphomas, and undetectable in most primary cutaneous lymphomas. The role of EBV in their pathogenesis can be suggested in at least a proportion of extranodal lymphomas (nasal, lung, Waldeyer's ring, gastrointestinal) with T cell markers in which EBV genome is found in most if not all tumor cells (EBV-associated lymphomas) and the transforming LMP-1 protein is frequently expressed. Among these, sinonasal lymphomas constitute a distinct clinicopathologic entity which may present as lethal midline granuloma, are strongly associated with EBV and can be regarded in most cases as true NK cell lymphomas.
Sinonasal non-Hodgkin's lymphoma in patients infected with human immunodeficiency virus: report of three cases and review.
Pomilla P V,Morris A B,Jaworek A
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Non-Hodgkin's lymphoma (NHL) is a frequent complication of human immunodeficiency virus (HIV) infection, but involvement of the sinonasal region has only rarely been reported. We report three cases of AIDS-associated sinonasal NHL that occurred at our institution and review eight cases that were reported in the literature. The epidemiological and clinicopathologic features of these cases are described and compared with those of three other groups of patients: non-HIV-infected patients with sinonasal NHL, HIV-infected patients with NHL of any anatomic site, and HIV-infected patients with infectious sinusitis. Patients with AIDS-associated sinonasal NHL more frequently developed bony erosion and presented with signs and symptoms referable to adjacent structures, such as the orbit, than did HIV-infected patients with sinusitis, and patients with AIDS and NHL less frequently had typical sinus symptoms and diffuse sinus involvement than did patients with sinusitis. However, the clinical manifestations of these conditions overlap; thus a high index of suspicion for NHL is imperative for prompt diagnosis. These lymphomas typically are high-grade and disseminate early, and the prognosis is generally poor.
Expression of adult and fetal natural killer cell markers in sinonasal lymphomas.
Suzumiya J,Takeshita M,Kimura N,Kikuchi M,Uchida T,Hisano S,Eura Y,Kozuru M,Nomura Y,Tomita K
The majority of sinonasal non-Hodgkin's lymphomas (NHLs) are thought to originate from T-cell lineage. However, they often express natural killer (NK)-cell markers so that their origin still remains obscure. In this study, cell type of sinonasal NHLs were characterized by immunohistochemical and Southern blot analyses. We examined nine patients with sinonasal NHL. Six patients with tonsillar or pharyngeal non-B-cell lymphomas served as a control group. Immunohistochemical study showed that all nine cases of sinonasal NHL were CD56+CD2+, whereas controls were CD56-CD2+. According to the rearrangement of T-cell receptors (TCRs) and expression of CD3 markers, the sinonasal NHL cases were classified into three groups: TCR-CD56(Leu-19)+CD3(Leu4)- NHL (three patients), TCR-CD56+CD3+ NHL (five patients), and TCR+CD56+CD3+ NHL (one patient). In contrast, control patients' NHLs were TCR+CD56-CD3+. These results imply that eight cases of TCR-CD56+ sinonasal NHL are of NK-cell lineage. Among these eight cases, TCR-CD56+CD3+ cases (five of eight patients) were rather similar to the phenotype of fetal NK cells. From these results, the majority of sinonasal NHLs seem to originate from varying maturation stages of NK-cell lineage.
Different clinical characteristics and treatment strategies for patients with localized sinonasal diffuse large B cell lymphoma and extranodal NK/T cell lymphoma.
Huang Yu,Jia Bo,Jiang Shiyu,Zhou Shengyu,Yang Jianliang,Liu Peng,Gui Lin,He Xiaohui,Qin Yan,Sun Yan,Shi Yuankai
Journal of hematology & oncology
The difference in clinical features and treatment outcomes between localized sinonasal diffuse large B cell lymphoma (SN-DLBCL) and sinonasal extranodal NK/T cell lymphoma (SN-ENKTL) is unclear. Therefore, we analyzed a total of 47 patients with localized SN-DLBCL and 211 patients with localized SN-ENKTL. The age distribution for these two subtypes is very distinct and the B symptoms were more common in SN-ENKTL. However, both SN-DLBCL and SN-ENKTL patients could achieve high overall response rate (ORR) and favorable prognoses. The 3-year overall survival (OS) rates for patients with SN-DLBCL and SN-ENKTL were 79.7 and 83.6% (p = 0.707), and the 3-year progression-free survival (PFS) rates were 61.4 and 70.1% (p = 0.294), respectively. For SN-DLBCL patients, chemotherapy followed by involved-field radiotherapy (IFRT) resulted in higher OS (83.7 vs 62.5%) and PFS (63.9 vs 50.0%) compared with chemotherapy alone, but the difference was not significant. No significant difference was found in the OS or PFS between radiotherapy alone and radiotherapy combined with chemotherapy for all patients with SN-ENKTL. But in extensive stage I and stage II SN-ENKTL patients, radiotherapy combined with chemotherapy could significantly improve the PFS (73.8 vs 50.0%) compared with radiotherapy alone. These results indicate that remarkable clinical disparities exist between localized SN-DLBCL and SN-ENKTL. However, different treatment strategies for them can result in similarly favorable prognoses.
Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project.
Au Wing-yan,Weisenburger Dennis D,Intragumtornchai Tanin,Nakamura Shigeo,Kim Won-Seog,Sng Ivy,Vose Julie,Armitage James O,Liang Raymond,
Among 1153 new adult cases of peripheral/T-cell lymphoma from 1990-2002 at 22 centers in 13 countries, 136 cases (11.8%) of extranodal natural killer (NK)/T-cell lymphoma were identified (nasal 68%, extranasal 26%, aggressive/unclassifiable 6%). The disease frequency was higher in Asian than in Western countries and in Continental Asia than in Japan. There were no differences in age, sex, ethnicity, or immunophenotypic profile between the nasal and extranasal cases, but the latter had more adverse clinical features. The median overall survival (OS) was better in nasal compared with the extranasal cases in early- (2.96 vs 0.36 years, P < .001) and late-stage disease (0.8 vs 0.28 years, P = .031). The addition of radiotherapy for early-stage nasal cases yielded survival benefit (P = .045). Among nasal cases, both the International Prognostic Index (P = .006) and Korean NK/T-cell Prognostic Index (P < .001) were prognostic. In addition, Ki67 proliferation greater than 50%, transformed tumor cells greater than 40%, elevated C-reactive protein level (CRP), anemia (< 11 g/dL) and thrombocytopenia (< 150 x 10(9)/L) predicts poorer OS for nasal disease. No histologic or clinical feature was predictive in extranasal disease. We conclude that the clinical features and treatment response of extranasal NK/T-cell lymphoma are different from of those of nasal lymphoma. However, the underlying features responsible for these differences remain to be defined.
Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211.
Yamaguchi Motoko,Tobinai Kensei,Oguchi Masahiko,Ishizuka Naoki,Kobayashi Yukio,Isobe Yasushi,Ishizawa Kenichi,Maseki Nobuo,Itoh Kuniaki,Usui Noriko,Wasada Izumi,Kinoshita Tomohiro,Ohshima Koichi,Matsuno Yoshihiro,Terauchi Takashi,Nawano Shigeru,Ishikura Satoshi,Kagami Yoshikazu,Hotta Tomomitsu,Oshimi Kazuo
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:To explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy. PATIENTS AND METHODS:Treatments comprised concurrent radiotherapy (50 Gy) and 3 courses of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC). Patients with a newly diagnosed stage IE or contiguous IIE disease with cervical node involvement and a performance status (PS) of 0 to 2 were eligible for enrollment. The primary end point of the phase II portion was a 2-year overall survival in patients treated with the recommended dose. RESULTS:Of the 33 patients enrolled, 10 patients were enrolled in the phase I portion and a two thirds dose of DeVIC was established as the recommended dose. Twenty-seven patients (range, 21 to 68; median, 56 years) treated with the recommended dose showed the following clinical features: male:female, 17:10; stage IE, 18; stage IIE, 9; B symptoms present, 10; elevated serum lactate dehydrogenase, 5; and PS 2, 2. With a median follow-up of 32 months, the 2-year overall survival was 78% (95% CI, 57% to 89%). This compared favorably with the historical control of radiotherapy alone (45%). Of the 26 patients assessable for a response, 20 (77%) achieved a complete response, with one partial response. The overall response rate was 81%. The most common grade 3 nonhematologic toxicity was mucositis related to radiation (30%). No treatment-related deaths were observed. CONCLUSION:Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.
Clinical features and treatment outcome of nasal-type NK/T-cell lymphoma of Waldeyer ring.
Li Ye-Xiong,Fang Hui,Liu Qing-Feng,Lu Jiade,Qi Shu-Nan,Wang Hua,Jin Jing,Wang Wei-Hu,Liu Yue-Ping,Song Yong-Wen,Wang Shu-Lian,Liu Xin-Fan,Feng Xiao-Li,Yu Zi-Hao
The clinical characteristics and prognosis remain unclear for nasal-type NK/T-cell lymphoma of Waldeyer ring (WR-NKTL). The aim of this study is to determine the clinical features and outcome. Ninety-one patients with WR-NKTL were reviewed. According to the Ann Arbor system, 15, 56, 12, and 8 patients had stage I, II, III, and IV. Of patients with stage I and II, 54 received combined chemotherapy and radiotherapy (CMT), 13 received radiotherapy alone, and 4 patients received chemotherapy alone. All 20 patients with stage III/IV received primary chemotherapy. The disease is characterized by predominance in young males, good performance, a propensity for nodal involvement, frequent stage II through IV diseases, low frequency of elevated LDH, low-risk international prognostic index (IPI), high sensitivity to radiotherapy, and intermediate sensitivity to chemotherapy. The 5-year overall survival and progression-free survival for all patients were 65% and 51%, respectively. The age, B symptoms, stage, and IPI were important prognostic factors. CMT tended to improve the survival compared with radiotherapy alone for patients with stage I and II diseases. Both nodal involvement and distant extranodal dissemination were the primary failure patterns. WR-NKTL appears to have distinct clinical characteristics and favorable outcomes.
Absolute lymphocyte count is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type.
Huang J J,Jiang W Q,Lin T Y,Huang Y,Xu R H,Huang H Q,Li Z M
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a heterogeneous entity with poor survival, requiring risk stratification in affected patients. We proposed absolute lymphocyte count (ALC) as a new prognostic factor in ENKL. PATIENTS AND METHODS:we retrospectively analyzed 128 patients newly diagnosed with ENKL. Independent prognostic factors of survival were determined by Cox regression analysis. RESULTS:patients with low ALC (<1.0 × 10(9)/l) at diagnosis tended to have more adverse clinical features. Patients with high ALC (≥1.0 × 10(9)/l) at diagnosis had better overall survival (OS; P < 0.0001) and progression-free survival (PFS; P<0.0001), and achieved higher complete remission rates (P=0.001). Multivariate analysis with known prognostic factors showed that ALC, B symptoms and advanced stage were independent predictors for OS and PFS. Using the International Prognostic Index, Prognostic Index for Peripheral T-cell lymphoma unspecified, or Korean Prognostic Index for nasal NK/T-cell lymphoma, the majority of patients were in the low-risk category (with no or one adverse factor). ALC was helpful to differentiate the low-risk patients with different survival outcomes (P < 0.0001). CONCLUSIONS:our data suggest that ALC at diagnosis is a novel, powerful predictor of prognosis in ENKL. Immune status at diagnosis might have an important influence on survival in patients with ENKL.
Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.
Huang Yenlin,de Reyniès Aurélien,de Leval Laurence,Ghazi Bouchra,Martin-Garcia Nadine,Travert Marion,Bosq Jacques,Brière Josette,Petit Barbara,Thomas Emilie,Coppo Paul,Marafioti Teresa,Emile Jean-François,Delfau-Larue Marie-Hélène,Schmitt Christian,Gaulard Philippe
Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.
Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type.
Kim S J,Kim B S,Choi C W,Choi J,Kim I,Lee Y-H,Kim J S
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Localized extranodal natural killer (NK)/T-cell lymphoma, nasal type, commonly has a low or low-intermediate risk of the international prognostic index (IPI), so the IPI has shown inconsistency in predicting prognosis. Thus, we analyzed Ki-67 expression and proposed a new prognostic model including Ki-67 expression for stage I/II extranodal NK/T-cell lymphoma. PATIENTS AND METHODS:We studied Ki-67 expression and its relationship with prognosis in 50 patients with extranodal NK/T-cell lymphoma. RESULTS:The patients were dichotomized by the median value: low (<65%) versus high Ki-67 (> or =65%). High Ki-67 was associated with a worse overall survival (OS; P = 0.021) and disease-free survival (DFS; P = 0.044). In multivariate analysis, Ki-67 expression and primary site of involvement were found to be an independent prognostic factor for OS and DFS (P < 0.05). Based on these results, we proposed a new clinico-pathological prognostic model with Ki-67 expression and the primary site of involvement. It showed a high degree of correlation with worse OS and DFS (P < 0.001). CONCLUSIONS:Ki-67 expression is predictive of prognosis, and our prognostic model may become a useful tool for predicting prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type.
Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/T-cell lymphoma, nasal type.
Suzuki Ritsuro,Yamaguchi Motoko,Izutsu Koji,Yamamoto Go,Takada Kenzo,Harabuchi Yasuaki,Isobe Yasushi,Gomyo Hiroshi,Koike Tadashi,Okamoto Masataka,Hyo Rie,Suzumiya Junji,Nakamura Shigeo,Kawa Keisei,Oshimi Kazuo,
Epstein-Barr virus (EBV)-DNA was prospectively analyzed in plasma and mononuclear cells (MNCs) from peripheral blood in patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, to evaluate the clinical significance for diagnosis, monitoring the tumor burden, and prognostication. Thirty-three patients were enrolled, and 32 were evaluable. Pretreatment plasma and MNC EBV-DNA was detectable in 14 (range, 50-71 000 copies/mL) and 6 patients (range, 20-780 copies/μg DNA), respectively, and both were well correlated (r = 0.8741, P < .0001). Detectable plasma EBV-DNA was associated with higher clinical stage (P = .02), presence of B symptoms (P = .02), worse performance status (P = .02), and higher serum soluble IL-2 receptor level (P < .0001). Twenty-two patients attained complete response. Plasma EBV-DNA level was significantly higher in nonresponders than in responders (mean, 16,472 vs 2,645 copies/mL; P = .02). Multivariate analysis showed clinical stage (hazard ratio, 9.0; 95% confidence interval, 1.8%-45.0%) and pretreatment plasma EBV-DNA (hazard ratio, 10.6; 95% confidence interval, 1.3%-87.0%) were significant prognostic factors. Three-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (P = .0009). Plasma was a preferable sample for this purpose in NK/T-cell lymphoma, nasal type, and EBV-DNA level was a good indicator for response and overall survival.
When do we need central nervous system prophylaxis in patients with extranodal NK/T-cell lymphoma, nasal type?
Kim S J,Oh S Y,Hong J Y,Chang M H,Lee D H,Huh J,Ko Y H,Ahn Y C,Kim H-J,Suh C,Kim K,Kim W S
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:The incidence and risk factors of central nervous system (CNS) invasion is still unclear in extranodal natural killer (NK)/T-cell lymphoma, nasal type. PATIENTS AND METHODS:We analyzed 208 patients to study the clinical features and outcomes of CNS disease in extranodal NK/T-cell lymphoma. RESULTS:Twelve patients (5.76%, 12/208) experienced CNS disease during treatment or follow-up period (median 11.62 months, range 0.2-123.2 months). The clinical variables associated with CNS disease were Ann Arbor stage III/IV (15.87%, P <0.001), regional lymph node involvement (10.41%, P = 0.006), group III/IV of NK/T-cell lymphoma prognostic index (NKPI; 10.20%, P = 0.003), high/high-intermediate international prognostic index (9.30%, P = 0.072) and extra-upper aerodigestive primary sites (9.75%, P = 0.008). In multivariate analysis, NKPI retained the strongest statistical power to predict CNS disease (P = 0.007, relative risk 9.289, 95% confidence interval 1.828-47.212) in extranodal NK/T-cell lymphoma. CONCLUSIONS:Despite extranodal NK/T-cell lymphoma frequently involves paranasal sinus, a routine CNS evaluation and prophylaxis do not seem to be necessary in NKPI group I or II patients due to a very low incidence. Nevertheless, CNS prophylaxis should be considered in NKPI groups III and IV.
Recurrence of nasal type NK/T cell lymphoma presenting as neurolymphomatosis on 18F-FDG PET/CT: A case report and literature review.
Pan Qingqing,Luo Yaping
INTRODUCTION:NK/T cell lymphomas seldom involve the peripheral nervous system. We report a case of recurrent nasal type NK/T cell lymphoma presenting as neurolymphomatosis and its manifestation on F-FDG PET/CT. PATIENT CONCERNS:A 55-year old man presented with a mass in the right nasal cavity was diagnosed with extranodal NK/T cell lymphoma, nasal type. F-FDG PET/CT showed intense FDG uptake within the mass. After radiotherapy the nasal tumor was completely relieved, but the patient experienced numbness and amyosthenia in the right upper extremity one week after completion of radiotherapy. DIAGNOSIS:PET/CT showed intense FDG uptake in the brachial plexus, axillary, suprascapular and median nerves, suggestive of recurrence of lymphoma presenting as neurolymphomatosis. INTERVENTIONS:After 1 cycle of chemotherapy, the follow-up PET/CT showed markedly reduced FDG uptake in the previous involved nerves, demonstrating a very good response of neurolymphomatosis to chemotherapy. OUTCOMES:The patient finally had a progression free survival of 8 months after completion of 4 cycles of chemotherapy and autologous stem cell transplantation. LESSONS:As neurolymphomatosis is a rare neurologic manifestation in recurrence of NK/T cell lymphoma, recognition of its presentation is important for prompt diagnosis and initiating treatment approach.
Clinical features and survival of extranodal natural killer/T cell lymphoma with and without hemophagocytic syndrome.
Jia Jing,Song Yuqin,Lin Ningjing,Liu Weiping,Ping Lingyan,Zheng Wen,Wang Xiaopei,Xie Yan,Tu Meifeng,Zhang Chen,Ying Zhitao,Deng Lijuan,Ding Ning,Zhu Jun
Annals of hematology
Extranodal natural killer (NK)/T cell lymphoma-associated hemophagocytic syndrome (HPS) (NK/T-LAHS) is a heterogeneous and life-threatening disease, which warrants investigation of its risk factors and clinical features. We retrospectively analyzed the clinical records of 202 patients with extranodal NK/T cell lymphoma and compared the characteristics and survival of extranodal NK/T cell lymphoma patients with and without HPS. The cumulative incidence of NK/T-LAHS was 11.4 % (23/202). In a multivariate logistic regression model, younger age (p = 0.012), bone marrow involvement (p = 0.012), and reduced serum albumin (p < 0.001) were independent risk factors for developing HPS in patients with extranodal NK/T cell lymphoma. The survival of extranodal NK/T cell lymphoma patients was aggravated when complicated with HPS, with an overall 2-year survival of 72.1 and 30.4 %, respectively (p < 0.001). Six patients with HPS onset at lymphoma diagnosis tended to have a poor performance status (p = 0.040), while the rate of elevated bilirubin was significantly higher in 17 patients with HPS onset at lymphoma relapse (p = 0.045). After HPS onset, treatment response was poor (response rate, 17.4 %) and survival was dismal with a median of 26 days. Univariate analysis showed that patients with lactate dehydrogenase >1000 U/L (p = 0.048) and disseminated intravascular coagulation (p = 0.004) had shorter survival time. Extranodal NK/T cell lymphoma was frequently complicated with HPS, and survival was discouraging in this circumstance. Intensive chemotherapy regimens including L-asparaginase or pegaspargase and allogeneic stem cell transplantation should be investigated.
ATP-binding cassette sub-family C member 4 (ABCC4) is overexpressed in human NK/T-cell lymphoma and regulates chemotherapy sensitivity: Potential as a functional therapeutic target.
Zhang Xudong,Zhao Lu,Li Xin,Wang Xinhua,Li Ling,Fu Xiaorui,Sun Zhenchang,Li Zhaoming,Nan Feifei,Chang Yu,Zhang Mingzhi
Nasal-type natural killer/T-cell (NK/T-cell) lymphomas are subtypes of non-Hodgkin's lymphoma (NHL), which are typically more clinically aggressive. There is, however relatively little understanding of nasal-type NK/T-cell lymphoma molecular pathogenesis. Thus, in this study we applied RNA sequencing to systematically screen for altered gene expression in human NK/T-cell lymphoma cell lines YTS and SNK-6 versus normal NK cells. We found that ATP-binding cassette sub-family C Member 4 (ABCC4) levels were significantly upregulated both in human NK/T-cell lymphoma YTS and SNK-6 cells, as compared with normal NK cells. These expression levels were further confirmed by real-time PCR. Protein levels of ABCC4 were also significantly higher in YTS and SNK-6 cells as compared with normal NK cells. Clinically relevant, ABCC4 expression levels were significantly higher in human NK/T-cell lymphoma tissues as compared with control nasal mucosa tissues, confirmed by immunohistochemical staining. In addition, we explored the biological function of such ABCC4 upregulation. Overexpression of ABCC4 by lentivirus transfection induced chemotherapy resistance to epirubicin (EPI) and cisplatin (DDP) in YTS cells. In contrast, knockdown of ABCC4 expression by shRNA contributed to chemotherapy sensitivity by both EPI and DDP. Furthermore, overexpression of ABCC4 inhibited, while downregulation of ABCC4 increased, YTS cell apoptosis following treatment by EPI or DDP. Therefore, the present study identified ABCC4 to be overexpressed in human NK/T-cell lymphoma cells, to regulate chemotherapy sensitivity to EPI and DDP, and possibly to be a functional therapeutic target. These findings may provide a basic rationale for new approaches in the effort to develop anti-tumor therapeutics for NK/T-cell lymphoma.
IL-13 Contributes to Drug Resistance of NK/T-Cell Lymphoma Cells by Regulating ABCC4.
Ni Mingli,Qin Beibei,Xie Ling,Zhang Xudong,Yang Jiezhi,Lv Hongqiong,Yang Mingyue,Zhang Mingzhi
BioMed research international
Background:Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL), represents a rare subtype of T-cell lymphomas with aggressive clinical behavior and is relatively resistant to chemotherapy. However, there is relatively poor understanding of molecular pathogenesis of multidrug resistance in ENKTL. Here, we aimed to explore the biological roles and potential mechanism of IL-13 and ABCC4 in multidrug resistance of NK/T-cell lymphoma. Methods:ELISA analysis was used to determine the level of serum IL-13 and immunohistochemical analysis was applied to detect the ABCC4 expression level in patients with human NK/T-cell lymphoma. Western blot assay was employed to measure the expression of ABCC4 in cells. Lenti-sh-ABCC4 viruses were constructed to knock down ABCC4 in YTS cells. CCK-8 assay and flow cytometric analysis were performed to detect the effects of IL-13 and ABCC4 on cell proliferation and apoptosis. CCK-8 assay was conducted to detect the effect of IL-13 and ABCC4 on cell sensitivity to adriamycin (ADM) in YTS cells. Results:Levels of serum IL-13 and ABCC4 expression were observed to be upregulated in patients with human NK/T-cell lymphoma. Moreover, ABCC4 protein expression was also increased in NK/T-cell lymphoma YTS cells compared to the normal NK cells. Interestingly, IL-13 promoted ABCC4 expression in YTS cells. IL-13 promoted proliferation and suppressed apoptosis of YTS cells and reversed the effects of ABCC4 knockdown on promotive proliferation and inhibitory apoptosis. In addition, IL-13 enhanced YTS cell chemotherapy resistance to ADM by promoting ABCC4 expression. Conclusion:Our findings concluded that IL-13 inhibited chemotherapy sensitivity of NK/T-cell lymphoma cells by regulating ABCC4, disrupting which may effectively improve the therapy protocols against resistant NK/T-cell lymphoma.
A prognostic model based on pretreatment platelet lymphocyte ratio for stage IE/IIE upper aerodigestive tract extranodal NK/T cell lymphoma, nasal type.
Wang Ke-feng,Chang Bo-yang,Chen Xiao-qin,Liu Pan-pan,Wuxiao Zhi-jun,Wang Zhi-hui,Li Su,Jiang Wen-qi,Xia Zhong-jun
Medical oncology (Northwood, London, England)
Patients with stage IE/IIE natural killer T (NK/T) cell lymphomas have discrepant survival outcome. This study aims to establish a prognostic model based on the pretreatment platelet lymphocyte ratio (PLR) specifically for localized extranodal NK/T cell lymphoma to guide the therapy. We retrospectively analyzed the data of 252 patients with early-stage upper aerodigestive tract NK/T cell lymphoma. The 5-year overall survival rate in 252 patients was 67.1%. Prognostic factors for survival were female (P = 0.025; relative risk, 0.51; 95% CI 0.28-0.92), older age (P = 0.000; relative risk, 3.34; 95% CI 1.94-5.75), stage II(P = 0.020; relative risk, 1.79; 95% CI 1.10-2.91), lactate dehydrogenase (LDH) level (P = 0.009; relative risk, 2.00; 95% CI 1.19-3.35), and PLR (P = 0.020; relative risk, 1.77; 95% CI 1.10-2.87). Based on these five parameters, we identified three different risk groups: group 1(106 cases, 43.4%), no or one adverse factor; group 2(85 cases, 34.8%), two factors; group 3(53 cases, 21.7%), three to five factors. Five-year overall survival was 83.3% for group 1, 62.2% for group 2, and 43.1% for group 3 (P = 0.000). Compared with International Prognostic Index and Korean Prognostic Index, the new model has a better prognostic discrimination for the patients of stage IE/IIE upper aerodigestive tract NK/T cell lymphoma. The PLR-based prognosis model is useful to stratify patients with localized extranodal NK/T cell lymphoma into different risk groups and guide the treatment modalities selection.
Epstein-Barr virus-associated T/natural killer-cell lymphomas in the elderly: the first consensus meeting in Kofu 2013.
Hamada Toshihisa,Nakamura Shigeo,Ko Young-Hyeh,Yoshino Tadashi,Ohshima Koichi,Matsuzawa Takamitsu,Miura Keiko,Takahashi Toshifumi,Nomura Hisashi,Hoshino Tomomi,Suzuki Daisuke,Shimada Shinji,Iwatsuki Keiji
The Journal of dermatology
From a clinicopathological conference on nine elderly patients with Epstein-Barr virus (EBV)-associated T/natural killer (NK)-cell lymphoma, we have addressed the patients' backgrounds, clinical manifestations, histopathological findings, cytogenesis, complications and prognoses. Among these elderly patients (>65 years old), seven patients had extranodal NK/T-cell lymphoma, nasal type (ENKL) with an NK-cell phenotype, and two patients had EBV(+) T-cell lymphomas or lymphoproliferative disorders (LPD) with cutaneous lesions mimicking pityriasis lichenoides et varioliformis acuta (PLEVA) or hydroa vacciniforme (HV). No patients had a previous episode of EBV-related symptoms such as infectious mononucleosis, chronic active EBV infection, HV or hypersensitivity to mosquito bites. Elderly patients with ENKL may show the centroblastoid variant. EBV(+) CD8(+) CD56(+/-) lymphocytes may be responsible for the development of PLEVA or HV-like cutaneous lesions in the elderly.
Extranodal natural killer/T-cell lymphoma, nasal type, involving the skin, misdiagnosed as nasosinusitis and a fungal infection: A case report and literature review.
Zheng Yan,Jia Jinjing,Li Wensheng,Wang Juan,Tian Qiong,Li Zhengxiao,Yang Jing,Dong Xinyu,Pan Ping,Xiao Shengxiang
The present study reports a case of extranodal natural killer (NK)/T-cell lymphoma, nasal type, involving the skin. The clinical manifestations, pathological characteristics, treatment and prognosis of the case were analyzed to improve the clinical diagnosis and treatment for this disease. The patient was a 56-year-old male, presenting with dark red nodules and plaques that had been visible on the nose for half a year. Based on the skin lesions and histopathological and immunohistochemical examination results, the patient was diagnosed with extranodal NK/T-cell lymphoma, nasal type. This disease has unique histopathological and immunohistochemical features and a high malignancy. The condition tends to be misdiagnosed and has a poor prognosis, but seldom involves the skin. In the present case, only radiotherapy was performed, with no relapse occurring within 6 months.
Shifting of erythroleukemia to myelodysplastic syndrome according to the revised WHO classification: Biologic and cytogenetic features of shifted erythroleukemia.
Ryu Sohee,Park Hee Sue,Kim Sung-Min,Im Kyongok,Kim Jung-Ah,Hwang Sang Mee,Yoon Sung-Soo,Lee Dong Soon
The 2016 revision of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues was published. According to 2016 WHO criteria, diagnostic criteria of acute erythroid leukemia was revised. We reassessed 34 de novo acute erythroid leukemia (AEL) diagnosed by 2008 WHO criteria, according to 2016 WHO criteria. A total of 623 patients (excluding M3) with acute myeloid leukemia including 34 patients with AEL were enrolled. Among 34 patients diagnosed with AEL, diagnosis was shifted to MDS-EB in 28 patients (28/34, 82.3%) and MDS-U in 2 patients (2/34, 5.9%), while remained as AEL in 4 patients (4/34, 11.8%) according to 2016 WHO criteria. Interphase FISH for cytogenetic changes of MDS (-5/del(5q), -7/del(7q), del(20q), +8) revealed cytogenetic aberrations in 50.0% (17/34) of AEL 2008 group. AEL 2008 group showed higher frequency of complex cytogenetic abnormalities and higher MDS related cytogenetic abnormalities than AML excluding AEL group. Transformation to another AML subtype was noted in 10% in AEL shifted to MDS. Majority (88.2%) of AEL by 2008 WHO criteria was reclassified to MDS by 2016 WHO criteria. Clinical characteristics of shifted AEL were similar to those of MDS rather than de novo AML.
Application of 2016 WHO classification in the diagnosis of paediatric high-grade -negative mature B-cell lymphoma with Burkitt-like morphological features.
Zhang Lei,Brown Laura E,Bowen Laurel M,McCarthy Laura C,Cooley Linda D,Repnikova Elena,Gener Melissa A,Garola Robert,August Keith J,Hays J Allyson,Zwick David L,Li Weijie
Journal of clinical pathology
AIMS:Historically, there has been no consensus on the diagnostic classification of high-grade B-cell lymphoma (HGBCL) with morphological features of Burkitt lymphoma (BL) but no gene rearrangement (-negative). The 2016 WHO classification of tumours of haematopoietic and lymphoid tissues has shed some light on this field with the modification of the grey-zone lymphoma with features intermediate between BL and diffuse large B-cell lymphoma, and the creation of several new entities. The aim of this study was to investigate how the revised WHO classification affects our practice in diagnosing these lymphomas in children. METHODS:We retrospectively reviewed cases of mature HGBCL diagnosed at our hospital between 2015 and 2018. RESULTS:Among 14 mature HGBCL cases with BL morphological features, 11 showed rearrangement consistent with BL and 3 were -negative. Two -negative cases showed regions of 11q gain and loss by microarray consistent with Burkitt-like lymphoma with 11q aberration (BLL-11q). The third -negative case showed diffuse and strong MUM1 expression, translocation involving 6p25 by chromosome analysis and rearrangement by fluorescence in situ hybridisation analysis consistent with large B-cell lymphoma with rearrangement (LBL-IRF4). All patients were treated according to applicable chemotherapeutic protocols and achieved remission. CONCLUSIONS:BLL-11q and LBL-IRF4, two newly defined entities, should be considered in paediatric -negative mature HGBCL cases. Accurate diagnosis needs careful histopathological examination and proper cytogenetic testing. Since they have unique cytogenetic features, specific treatments for them may emerge in the future. Therefore, accurate diagnosis based on the 2016 WHO classification is clinically significant.
The new World Health Organization classification of haematopoietic and lymphoid tumours: a dermatopathological perspective.
Slater D N
The British journal of dermatology
The World Health Organization (WHO) has published a new consensus classification of tumours of haematopoietic and lymphoid tissue, based on recognizable disease entities defined by clinical and scientific criteria. The WHO does not support the use of stand-alone organ-related classifications, such as for skin. The Royal College of Pathologists (London) has adopted the WHO classification in its minimum dataset for the histopathological reporting of lymphoma and this will be used in the National Health Service Skin Cancer Dataset. The purpose of this review is to highlight the principal primary and secondary cutaneous haematopoietic and lymphoid tumours that are defined in the WHO classification. The review also discusses selected problematical areas in the WHO classification relevant to the skin and contains suggestions to encourage a unified approach in the use of the WHO coded summary. These represent an attempt to facilitate future progress and research in the field of cutaneous lymphoma. They are perceived as possible building-blocks for wider discussion and not as alterations to the classification. The WHO classification has been compared with a road map that indicates directions for future clinical and scientific research.
The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion.
Barbui Tiziano,Thiele Jürgen,Gisslinger Heinz,Kvasnicka Hans Michael,Vannucchi Alessandro M,Guglielmelli Paola,Orazi Attilio,Tefferi Ayalew
Blood cancer journal
The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
Diagnostically relevant updates to the 2017 WHO classification of lymphoid neoplasms.
Choi Sarah M,O'Malley Dennis P
Annals of diagnostic pathology
The recent 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues contains a number of updates under the category of lymphoid neoplasms. These changes include introduction of new entities, amended classification or terminology, and addition of newly discovered diagnostic and molecular features. In this review, we perform a focused, concise summary of selected lymphoid neoplasms and discuss changes in their classification. Rather than a comprehensive overview, we place specific emphasis on important and diagnostically relevant aspects of each entity that are novel or different from the previous WHO iteration and bring the practicing pathologist quickly up to speed with the updated classification.
The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms.
Vardiman James W
The World Health Organization (WHO) classification of myeloid and lymphoid neoplasms utilizes morphology, immunophenotype, genetics and clinical features to define disease entities of clinical significance. It is a consensus classification in which a number of experts have agreed on the classification and diagnostic criteria. In general, the classification stratifies neoplasms according to their lineage (myeloid, lymphoid, histiocytic/dendritic) and distinguishes neoplasms of precursor cells from those comprised of functionally mature cells. Lymphoid neoplasms are derived from cells that frequently have features that recapitulate stages of normal B-, T-, and NK-cell differentiation and function, so to some extent they can be classified according to the corresponding normal counterpart, although additional features, such as genotype, clinical features and even location of the tumor figure into the final classification listing as well. Five major subgroups of myeloid neoplasms are recognized based mainly on their degree of maturation and biologic properties: myeloproliferative neoplasms (MPNs) which are comprised primarily of mature cells with effective proliferation; myeloid (and lymphoid) neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB and FGFR1, defined largely by the finding of significant eosinophilia and specific genetic abnormalities; myelodysplastic/myeloproliferative neoplasms (MDS/MPN), comprised mainly of mature cells with both effective and ineffective proliferation of various lineages; myelodysplastic syndromes (MDS), in which immature and mature cells are found with abnormal, dysplastic and ineffective maturation, and acute myeloid leukemia (AML), comprised of precursor cells with impaired maturation. Genetic abnormalities play an important role as diagnostic criteria for further sub-classification of some myeloid neoplasms, particularly of AML. Although therapy-related MDS and AML (t-MDS/AML) often have genetic defects identical to those found in de novo AML and de novo MDS, they are classified separately from de novo AML and MDS in order to emphasize their unique clinical and biologic properties.
Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma.
Peng Rou-Jun,Han Bo-Wei,Cai Qing-Qing,Zuo Xiao-Yu,Xia Tao,Chen Jie-Rong,Feng Li-Na,Lim Jing Quan,Chen Shu-Wei,Zeng Mu-Sheng,Guo Yun-Miao,Li Bo,Xia Xiao-Jun,Xia Yi,Laurensia Yurike,Chia Burton Kuan Hui,Huang Hui-Qiang,Young Ken He,Lim Soon Thye,Ong Choon Kiat,Zeng Yi-Xin,Bei Jin-Xin
Extranodal natural killer T-cell lymphoma (nasal type; NKTCL) is an aggressive malignancy strongly associated with Epstein-Barr virus (EBV) infection. However, the role of EBV in NKTCL development is unclear, largely due to the lack of information about EBV genome and transcriptome in NKTCL. Here, using high-throughput sequencing, we obtained whole genome (n = 27) and transcriptome datasets (n = 18) of EBV derived from NKTCL tumor biopsies. We assembled 27 EBV genomes and detected an average of 1,152 single nucleotide variants and 44.8 indels (<50 bp) of EBV per sample. We also identified frequent focal EBV genome deletions and integrated EBV fragments in the host genome. Moreover, Phylogenetic analysis revealed that NKTCL-derived EBVs are closely clustered; transcriptome analysis revealed less activation of both latent and lytic genes and larger amount of T-cell epitope alterations in NKTCL, as compared with other EBV-associated cancers. Furthermore, we observed transcriptional defects of the BARTs miRNA by deletion, and the disruption of host NHEJ1 by integrated EBV fragment, implying novel pathogenic mechanisms of EBV. Taken together, we reported for the first time global mutational and transcriptional profiles of EBV in NKTCL clinical samples, revealing important somatic events of EBV and providing insights to better understanding of EBV's contribution in tumorigenesis.
JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma.
Bouchekioua A,Scourzic L,de Wever O,Zhang Y,Cervera P,Aline-Fardin A,Mercher T,Gaulard P,Nyga R,Jeziorowska D,Douay L,Vainchenker W,Louache F,Gespach C,Solary E,Coppo P
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.
The diagnosis and management of NK/T-cell lymphomas.
Tse Eric,Kwong Yok-Lam
Journal of hematology & oncology
Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignancy of putative NK-cell origin, with a minority deriving from the T-cell lineage. Pathologically, the malignancy occurs in two forms, extranodal NK/T-cell lymphoma, nasal type; and aggressive NK-cell leukaemia. Lymphoma occur most commonly (80%) in the nose and upper aerodigestive tract, less commonly (20%) in non-nasal areas (skin, gastrointestinal tract, testis, salivary gland), and rarely as disseminated disease with a leukemic phase. Genetic analysis showed mutations of genes involved in the JAK/STAT pathway, RNA assembly, epigenetic regulation, and tumor suppression. In initial clinical evaluation, positron emission tomography computed tomography, and quantification of plasma EBV DNA are mandatory as they are useful for response monitoring and prognostication. In stage I/II diseases, combined chemotherapy and radiotherapy (sequentially or concurrently) is the best approach. Conventional anthracycline-containing regimens are ineffective and should be replaced by non-anthracycline-containing regimens, preferably including L-asparaginase. Radiotherapy alone is associated with high systemic relapse rates and should be avoided. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are the standard. In relapsed/refractory cases, blockade of the programmed death protein 1 has recently shown promising results with high response rates. In the era of effective non-anthracycline-containing regimens, autologous haematopoietic stem cell transplantation (HSCT) has not been shown to be beneficial. However, allogeneic HSCT may be considered for high-risk or advanced-stage patients in remission or relapsed/refractory patients responding to salvage therapy. Prognostic models taking into account presentation, interim, and end-of-treatment parameters are useful in triaging patients to different treatment strategies.
RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC.
Selvarajan V,Osato M,Nah G S S,Yan J,Chung T-H,Voon D C-C,Ito Y,Ham M F,Salto-Tellez M,Shimizu N,Choo S-N,Fan S,Chng W-J,Ng S-B
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.
Prognostic nomogram for overall survival in previously untreated patients with extranodal NK/T-cell lymphoma, nasal-type: a multicenter study.
Yang Y,Zhang Y-J,Zhu Y,Cao J-Z,Yuan Z-Y,Xu L-M,Wu J-X,Wang W,Wu T,Lu B,Zhu S-Y,Qian L-T,Zhang F-Q,Hou X-R,Liu Q-F,Li Y-X
The aim of this study was to develop a widely accepted prognostic nomogram for extranodal NK/T-cell lymphoma, nasal-type (NKTCL). The clinical data from 1383 patients with NKTCL treated at 10 participating institutions between 2000 and 2011 were reviewed. A nomogram was developed that predicted overall survival (OS) based on the Cox proportional hazards model. To contrast the utility of the nomogram against the widely used Ann Arbor staging system, the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI), we used the concordance index (C-index) and a calibration curve to determine its predictive and discriminatory capacity. The 5-year OS rate was 60.3% for the entire group. The nomogram included five important variables based on a multivariate analysis of the primary cohort: stage; age; Eastern Cooperative Oncology Group performance status; lactate dehydrogenase; and primary tumor invasion. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.72 for both cohorts, which was superior to the predictive power (range, 0.56-0.64) of the Ann Arbor stage, IPI and KPI in the primary and validation cohorts. The proposed nomogram provides an individualized risk estimate of OS in patients with NKTCL.
Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma.
Ke Q-H,Zhou S-Q,Du W,Liang G,Lei Y,Luo F
Blood cancer journal
On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m(2) weekly, 3-5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4 and cisplatin 75 mg/m(2) i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n = 1) or because they had an infection (n = 3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3-year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL.
Treatment of localized extranodal NK/T cell lymphoma, nasal type: a systematic review.
Kim Seok Jin,Yoon Sang Eun,Kim Won Seog
Journal of hematology & oncology
Extranodal natural killer/T cell lymphoma (ENKTL), nasal type, presents predominantly as a localized disease involving the nasal cavity and adjacent sites, and the treatment of localized nasal ENKTL is a major issue. However, given its rarity, there is no standard therapy based on randomized controlled trials and therefore a lack of consensus on the treatment of localized nasal ENKTL. Currently recommended treatments are based mainly on the results of phase II studies and retrospective analyses. Because the previous outcomes of anthracycline-containing chemotherapy were poor, non-anthracycline-based chemotherapy regimens, including etoposide and L-asparaginase, have been used mainly for patients with localized nasal ENKTL. Radiotherapy also has been used as a main component of treatment because it can produce a rapid response. Accordingly, the combined approach of non-anthracycline-based chemotherapy with radiotherapy is currently recommended as a first-line treatment for localized nasal ENKTL. This review summarizes the different approaches for the use of non-anthracycline-based chemotherapy with radiotherapy including concurrent, sequential, and sandwich chemoradiotherapy, which have been proposed as a first-line treatment for newly diagnosed patients with localized nasal ENKTL.
SIE-SIES-GITMO guidelines for the management of adult peripheral T- and NK-cell lymphomas, excluding mature T-cell leukaemias.
Corradini P,Marchetti M,Barosi G,Billio A,Gallamini A,Pileri S,Pimpinelli N,Rossi G,Zinzani P L,Tura S
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. In this article, we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukaemias. DESIGN:By using the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) system, we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues. RESULTS:Six courses of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP) chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large-cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while l-asparaginase-containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong). CONCLUSION:In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.
A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis.
Kim Seok Jin,Yoon Dok Hyun,Jaccard Arnaud,Chng Wee Joo,Lim Soon Thye,Hong Huangming,Park Yong,Chang Kian Meng,Maeda Yoshinobu,Ishida Fumihiro,Shin Dong-Yeop,Kim Jin Seok,Jeong Seong Hyun,Yang Deok-Hwan,Jo Jae-Cheol,Lee Gyeong-Won,Choi Chul Won,Lee Won-Sik,Chen Tsai-Yun,Kim Kiyeun,Jung Sin-Ho,Murayama Tohru,Oki Yasuhiro,Advani Ranjana,d'Amore Francesco,Schmitz Norbert,Suh Cheolwon,Suzuki Ritsuro,Kwong Yok Lam,Lin Tong-Yu,Kim Won Seog
The Lancet. Oncology
BACKGROUND:The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS:We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS:We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION:PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING:Samsung Biomedical Research Institute.
Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.
Li Zheng,Xia Yi,Feng Li-Na,Chen Jie-Rong,Li Hong-Min,Cui Jing,Cai Qing-Qing,Sim Kar Seng,Nairismägi Maarja-Liisa,Laurensia Yurike,Meah Wee Yang,Liu Wen-Sheng,Guo Yun-Miao,Chen Li-Zhen,Feng Qi-Sheng,Pang Chi Pui,Chen Li Jia,Chew Soo Hong,Ebstein Richard P,Foo Jia Nee,Liu Jianjun,Ha Jeslin,Khoo Lay Poh,Chin Suk Teng,Zeng Yi-Xin,Aung Tin,Chowbay Balram,Diong Colin Phipps,Zhang Fen,Liu Yan-Hui,Tang Tiffany,Tao Miriam,Quek Richard,Mohamad Farid,Tan Soo Yong,Teh Bin Tean,Ng Siok Bian,Chng Wee Joo,Ong Choon Kiat,Okada Yukinori,Raychaudhuri Soumya,Lim Soon Thye,Tan Wen,Peng Rou-Jun,Khor Chiea Chuen,Bei Jin-Xin
The Lancet. Oncology
BACKGROUND:Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS:We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS:Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION:To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING:Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Racial Patterns of Peripheral T-Cell Lymphoma Incidence and Survival in the United States.
Adams Scott V,Newcomb Polly A,Shustov Andrei R
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:To compare incidence and survival of peripheral T-cell lymphoma (PTCL) subtypes among US racial/ethnic groups. METHODS:Patients with PTCL (age ≥ 15 years; 2000 to 2012) were identified in the Surveillance, Epidemiology, and End Results (SEER) registries. Race/ethnicity was categorized as non-Hispanic white, black, Asian/Pacific Islander, Hispanic white, or American Indian/Alaskan native. Age-standardized annual incidence rates and incidence rate ratios were estimated with 95% CIs, and case-case odds ratios were estimated by race/ethnicity using polytomous regression. Survival was estimated from SEER follow-up data with Cox regression. RESULTS:Thirteen thousand one hundred seven patients with PTCL were identified. Annual PTCL incidence was highest in blacks and lowest in Native Americans. Compared with non-Hispanic whites, blacks had a higher incidence of PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and adult T-cell leukemia/lymphoma (ATLL) and a lower incidence of angioimmunoblastic T-cell lymphoma (AITL); Asians/Pacific Islanders had a higher incidence of AITL, extranodal nasal-type natural killer/T-cell lymphoma and NK-cell leukemia (ENKCL), and ATLL and a lower incidence of anaplastic large-cell lymphoma; Hispanics had a higher incidence of AITL and ENKCL; and Native Americans had a lower incidence of PTCL-NOS (all P < .05). The ratio of ENKCL to PCTL-NOS among Native Americans, Asians/Pacific Islanders, and Hispanic whites was approximately three- to four-fold the same ratio among non-Hispanic whites. Survival varied significantly by race/ethnicity (P < .001), with blacks in particular experiencing shorter survival for most subtypes. CONCLUSION:Striking variation in incidence, proportions of PTCL subtypes, and survival was observed. Aspects of these PTCL subtype patterns, such as for ENKCL and ATLL, were similar to corresponding global populations. Despite the small population size and limited number of Native American patients, PTCL subtype frequencies in this group were distinct but most similar to Hispanic whites. Survival disparities were evident, especially for blacks compared with non-Hispanic whites.
Treatments and Outcomes of Patients With Extranodal Natural Killer/T-Cell Lymphoma Diagnosed Between 2000 and 2013: A Cooperative Study in Japan.
Yamaguchi Motoko,Suzuki Ritsuro,Oguchi Masahiko,Asano Naoko,Amaki Jun,Akiba Takeshi,Maeda Takeshi,Itasaka Satoshi,Kubota Nobuko,Saito Yoshihiro,Kobayashi Yukio,Itami Jun,Ueda Kyoko,Miyazaki Kana,Ii Noriko,Tomita Naoto,Sekiguchi Nodoka,Takizawa Jun,Saito Bungo,Murayama Tohru,Ando Toshihiko,Wada Hideho,Hyo Rie,Ejima Yasuo,Hasegawa Masatoshi,Katayama Naoyuki
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Purpose To elucidate the management and outcomes of patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKL), who were diagnosed between 2000 and 2013 in Japan. Patients and Methods Data from 358 patients with ENKL diagnosed between 2000 and 2013 from 31 institutes were retrospectively analyzed. Results Patients' median age was 58 years, and 257 (72%) had localized disease. The most common first-line treatment was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%) for localized ENKL and L-asparaginase-containing chemotherapy (30%) for advanced ENKL. With a median follow-up of 5.8 years, overall survival (OS) rates at 5 years for localized and advanced ENKL were 68% and 24%, respectively. The prognostic index of natural killer lymphoma was validated in our study, although only 4% of patients with localized ENKL were classified as high risk. With a median follow-up of 5.6 years, OS and progression-free survival at 5 years in the 150 patients who received RT-DeVIC in clinical practice were 72% (95% CI, 63% to 78%) and 61% (95% CI, 52% to 69%), respectively. Toxicities of RT-DeVIC were comparable to those in a previous trial. Multivariate analysis in patients with localized ENKL who received RT-DeVIC identified elevated soluble interleukin-2 receptor as an independent predictive factor for worse OS and progression-free survival (adjusted hazard ratios, 2.28 and 2.46; 95% CI, 1.24 to 4.23 and 1.42 to 4.28; P = .008 and .0014, respectively). Conclusion Favorable OS in response to new treatments was demonstrated in a large number of patients. Improved treatment approaches are needed for localized ENKL exhibiting elevated pretreatment soluble interleukin-2 receptor.
Nasal NK/T-cell lymphoma: RT, CT, or both.
Tse Eric,Kwong Yok-Lam
In this issue of Blood, Yang et al have proposed that for early-stage nasal type natural killer (NK)/T-cell lymphoma, combined radiotherapy (RT), and chemotherapy (CT) improve survival, but CT can be safely omitted in certain low-risk patients treated with RT.
Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study.
Yang Yong,Zhu Yuan,Cao Jian-Zhong,Zhang Yu-Jing,Xu Li-Ming,Yuan Zhi-Yong,Wu Jun-Xin,Wang Wei,Wu Tao,Lu Bing,Zhu Su-Yu,Qian Li-Ting,Zhang Fu-Quan,Hou Xiao-Rong,Li Ye-Xiong
The optimal combination and sequence of radiotherapy (RT) and chemotherapy (CT) for extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) are not well-defined. The aim of this study was to create a risk-adapted therapeutic strategy for early-stage NKTCL. A total of 1273 early-stage patients from 10 institutions were reviewed. Patients received CT alone (n = 170), RT alone (n = 253), RT followed by CT (n = 209), or CT followed by RT (n = 641). A comprehensive comparative study was performed using multivariable and propensity score-matched analyses. Early-stage NKTCL was classified as low risk or high risk based on 5 independent prognostic factors (stage, age, performance status, lactate dehydrogenase, primary tumor invasion). RT alone and RT with or without CT were more effective than CT alone (5-year overall survival [OS], 69.6% and 67.7% vs 33.9%, P < .001). For low-risk patients, RT alone achieved a favorable OS (88.8%); incorporation of induction or consolidation CT did not provide additional benefit (86.9% and 86.3%). For high-risk patients, RT followed by CT resulted in superior OS (72.2%) compared with induction CT and RT (58.3%, P = .004) or RT alone (59.6%, P = .017). After adjustment, similar significant differences in OS were still observed between treatment groups. New CT regimens provided limited benefit in early-stage NKTCL. Risk-adapted therapy involving RT alone for low-risk patients and RT consolidated by CT for high-risk patients is a viable, effective strategy for early-stage NKTCL.
Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.
Zhang Ya-Na,Song Jia,Wang Hai,Wang Heng,Zeng Ming,Zhai Guan-Ting,Ma Jin,Li Zhi-Yong,Liao Bo,Wang Bao-Feng,Zhen Zhen,Wang Nan,Cao Ping-Ping,Lin Peng,Ning Qin,Liu Zheng
The Journal of allergy and clinical immunology
BACKGROUND:Locally produced IgE contributes to the initiation and development of eosinophilic inflammation in eosinophilic nasal polyps independent of systemic atopy. However, whether CXCR5(+)CD4(+) T follicular helper (TFH) cells are involved in local IgE production at mucosal sites remains unexplored. OBJECTIVE:We sought to explore the presence, phenotype, and function of CXCR5(+)CD4(+) TFH cells in eosinophilic nasal polyp tissues compared with noneosinophilic nasal polyp and control normal nasal tissues. METHODS:TFH cell-surface phenotypes and subsets and B-cell subsets in nasal tissues and peripheral blood were studied by means of flow cytometry. Immunohistochemistry was used to detect the tissue location of TFH cells. Sorted nasal TFH cells and CXCR5(-) T cells were cultured with autologous naive B cells purified from blood. RESULTS:Nasal TFH cells expressed inducible costimulator, programmed cell death protein 1, and the transcription factor B-cell lymphoma 6 (Bcl-6) at an intermediate level when compared with bona fide TFH cells in tonsils and circulating TFH cells. Although counts of total TFH cells and IL-21(+), IFN-γ(+), and IL-17(+) TFH cells were increased in both eosinophilic and noneosinophilic nasal polyp tissues compared with those in normal nasal tissues, IL-4(+) TFH cell counts were only increased in eosinophilic polyp tissues. IL-4 and IL-21 were involved in polyp TFH cell-induced IgE production from naive B cells, and nasal IL-4(+) TFH cell counts correlated highly with local IgE levels in vivo. IL-4(+)Bcl-6(+)CD4(+) TFH cells were identified in ectopic lymphoid structures in eosinophilic nasal polyps. TFH cells also positively correlated with germinal center B cells and plasma cells in nasal tissues. CONCLUSION:Nasal IL-4(+) TFH cells might be involved in local IgE production in eosinophilic nasal polyps.
Risk stratification on the basis of Deauville score on PET-CT and the presence of Epstein-Barr virus DNA after completion of primary treatment for extranodal natural killer/T-cell lymphoma, nasal type: a multicentre, retrospective analysis.
Kim Seok Jin,Choi Joon Young,Hyun Seung Hyup,Ki Chang-Seok,Oh Dongryul,Ahn Yong Chan,Ko Young Hyeh,Choi Sunkyu,Jung Sin-Ho,Khong Pek-Lan,Tang Tiffany,Yan Xuexian,Lim Soon Thye,Kwong Yok-Lam,Kim Won Seog,
The Lancet. Haematology
BACKGROUND:Assessment of tumour viability after treatment is essential for prediction of treatment failure in patients with extranodal natural killer/T-cell lymphoma (ENKTL). We aimed to assess the use of the post-treatment Deauville score on PET-CT and Epstein-Barr virus DNA as a predictor of residual tumour, to establish the risk of treatment failure in patients with newly diagnosed ENKTL. METHODS:In a retrospective analysis of patient data we assessed the prognostic relevance of the Deauville score (five-point scale) on PET-CT and circulating Epstein-Barr virus DNA after completion of treatment in consecutive patients with ENKTL who met eligibility criteria (newly diagnosed and received non-anthracycline-based chemotherapy, concurrent chemoradiotherapy, or both together) diagnosed at the Samsung Medical Center in Seoul, South Korea. The primary aim was to assess the association between progression-free survival and risk stratification based on post-treatment Deauville score and Epstein-Barr virus DNA. With an independent cohort from two different hospitals (Hong Kong and Singapore), we validated the prognostic value of our risk model. FINDINGS:We included 102 patients diagnosed with ENKTL between Jan 6, 2005, and Nov 18, 2013, in the study cohort, and 38 patients diagnosed with ENKTL between Jan 7, 2009, and June 27, 2013, in the validation cohort. In the study cohort after a median follow-up of 47·2 months (IQR 30·0-65·5), 45 (44%) patients had treatment failure and 33 (32%) had died. Post-treatment Deauville score and Epstein-Barr virus DNA positivity were independently associated with progression-free and overall survival in the multivariable analysis (for post-treatment Deauville score of 3-4, progression-free survival hazard ratio [HR] 3·607, 95% CI 1·772-7·341, univariable p<0·0001; for post-treatment Epstein-Barr virus DNA positivity, progression-free survival HR 3·595, 95% CI 1·598-8·089, univariable p<0·0001). We stratified patients into three groups based on risk of treatment failure: a low-risk group (post-treatment Epstein-Barr virus negativity and post-treatment Deauville score of 1-2), a high-risk group (post-treatment Epstein-Barr virus negativity with a Deauville score 3-4, or post-treatment Epstein-Barr virus positivity with a Deauville score 1-2), and treatment failure (Deauville score of 5 or post-treatment Epstein-Barr positivity with a Deauville of score 3-4). This risk model showed a significant association with progression-free survival (for low risk vs high risk, HR 7·761, 95% CI 2·592-23·233, p<0·0001; for low risk vs failure, HR 18·546, 95% CI 5·997-57·353, p<0·0001). The validation cohort showed the same associations (for low risk vs high risk, HR 22·909, 95% CI 2·850-184·162, p=0·003; for low risk vs failure, HR 50·652, 95% CI 6·114-419·610, p<0·0001). INTERPRETATION:Post-treatment Deauville score on PET-CT scan and the presence of Epstein-Barr virus DNA can predict the risk of treatment failure in patients with ENKTL. Our results might be able to help guide clinical practice. FUNDING:Samsung Biomedical Research Institute.
Unfavorable prognosis of elderly patients with early-stage extranodal nasal-type NK/T-cell lymphoma.
Wang Z Y,Li Y X,Wang H,Wang W H,Jin J,Liu Y P,Song Y W,Wang S L,Liu X F,Yu Z H
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:Extranodal nasal-type NK (natural killer)/T-cell lymphoma in elderly patients is rare, and its prognosis is unclear. This study aims to investigate the clinical characteristics and prognosis of this lymphoma. PATIENTS AND METHODS:We analyzed 24 patients (age, >60 years old) with early-stage extranodal nasal-type NK/T-cell lymphoma. Among these patients, 23 received radiotherapy alone (n = 15) or radiotherapy and chemotherapy (n = 8) and 1 received chemotherapy alone. RESULTS:Elderly patients with early-stage extranodal nasal-type NK/T-cell lymphoma were characterized by male predominance, good performance, large proportion of localized disease, more comorbidities, low-risk international prognostic index, and unfavorable prognosis. The 5-year cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) rates for all patients were 54.3%, 42.0%, and 40.2%, respectively. The 5-year CSS, OS, and PFS rates were 43.5%, 36.6%, and 34.1% in patients who received radiotherapy alone, and 50%, 50%, and 50% in patients who received radiotherapy and chemotherapy, respectively (P = 0.852 for CSS, P = 0.801 for OS, and P = 0.694 for PFS). Four patients died of treatment-related mortality. CONCLUSION:Elderly patients with early-stage extranodal nasal-type NK/T-cell lymphoma exhibit poor prognosis and need special attention because of high treatment-related mortality.
Association of Improved Locoregional Control With Prolonged Survival in Early-Stage Extranodal Nasal-Type Natural Killer/T-Cell Lymphoma.
Yang Yong,Cao Jian-Zhong,Lan Sheng-Min,Wu Jun-Xin,Wu Tao,Zhu Su-Yu,Qian Li-Ting,Hou Xiao-Rong,Zhang Fu-Quan,Zhang Yu-Jing,Zhu Yuan,Xu Li-Ming,Yuan Zhi-Yong,Qi Shu-Nan,Li Ye-Xiong
Importance:The long-term survival benefit for radiotherapy (RT) in early-stage extranodal natural killer/T-cell lymphoma (NKTCL) is not known, and it is unclear whether improved locoregional control (LRC) translates into a survival benefit. Objective:To investigate the dose-dependent effect and potential survival benefits of RT on the basis of LRC improvements. Design, Setting, and Participants:Review of clinical data of patients with early-stage NKTCL at 10 institutions in China between 2000 and 2014. Radiotherapy dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between RT dose and events. Regression analysis was used to assess whether a linear correlation exists between LRC and progression-free survival (PFS) or overall survival (OS). Patients received chemotherapy (CT) alone, RT alone, or a combination. Chemotherapy alone was defined as 0 Gy. Main Outcomes and Measures:The association between LRC and OS or PFS. Results:A total of 1332 patients (923 [69%] male; median age, 43 years [range, 2-87 years]) were reviewed. For patients treated with RT, median dose was 50 Gy (range, 10-70 Gy); 996 (86%) received at least 50 Gy, and 164 (14%) received 10 to 49 Gy. The risk of locoregional recurrence, disease progression, and mortality decreased sharply until 50 to 52 Gy. For patients receiving RT, high-dose RT (≥50 Gy) was associated with significantly better 5-year LRC (85% vs 73%; P < .001), PFS (61% vs 50%; P = .004), and OS (70% vs 58%; P = .04) than low-dose RT (<50 Gy). Improved LRC with high-dose RT was independent of the RT/CT sequence or initial response to CT. Radiotherapy yielded a dose-dependent effect on LRC (range, 41%-87%), PFS (18%-63%), and OS (33%-71%). Dose-response regression analysis revealed a linear correlation between 5-year LRC and 5-year PFS (correlation coefficient, r = 0.994, P < .001; determination coefficient, R2 = 0.988) or 5-year OS (r = 0.985, P = .002; R2 = 0.97), which was externally validated using published data. Conclusions and Relevance:The optimal dose was 50 Gy for patients with early-stage disease. The improved LRC was associated with prolonged survival. These findings emphasize the importance of RT in optimizing first-line therapy, and provide evidence for making treatment decisions and designing clinical trials.
Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.
Chen Yun-Wen,Guo Tianhuan,Shen Lijun,Wong Kai-Yau,Tao Qian,Choi William W L,Au-Yeung Rex K H,Chan Yuen-Piu,Wong Michelle L Y,Tang Johnny C O,Liu Wei-Ping,Li Gan-Di,Shimizu Norio,Loong Florence,Tse Eric,Kwong Yok-Lam,Srivastava Gopesh
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive disease characterized by frequent deletions on 6q, and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylation at Tyr705 activates STAT3, inducing dimerization, nuclear translocation, and DNA binding. In this study, we investigated whether receptor-type tyrosine-protein phosphatase κ (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. PTPRK was highly expressed in normal NK cells but was underexpressed in 4 of 5 (80%) NKTCL cell lines and 15 of 27 (55.6%) primary tumors. Significantly, PTPRK protein expression was inversely correlated with nuclear phospho-STAT3(Tyr705) expression in NKTCL cell lines (P = .025) and tumors (P = .040). PTPRK restoration decreased nuclear phospho-STAT3(Tyr705) levels, whereas knockdown of PTPRK increased such levels in NKTCL cells. Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P = .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis.
Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type.
Yamaguchi Motoko,Suzuki Ritsuro,Oguchi Masahiko
Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and natural killer cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials. In patients with localized disease, radiotherapy is a core component of the recommended first-line therapy. Radiotherapy administered at 50 to 54 Gy, extended involved-site radiotherapy considering tumor invasiveness, and the use of intensity modulated radiation therapy or volumetric modulated arc therapy are associated with efficacy of radiotherapy. Although the use of concurrent chemoradiotherapy has been supported by the results of clinical trials, accumulating evidence supports the use of sequential chemoradiotherapy with non-anthracycline-containing regimens that include l-asparaginase and/or platinum anticancer agents. l-asparaginase-containing chemotherapy is a key component of first-line treatments for systemic ENKL. Hematopoietic stem cell transplantation is recommended as a front-line consolidation therapy for newly diagnosed advanced-stage ENKL. Newer agents including immune checkpoint inhibitors are being investigated for treating ENKL. In this modern ENKL treatment era, multidisciplinary efforts are needed to identify the best timing and sequencing of radiotherapy, l-asparaginase, platinum, newer agents, and hematopoietic stem cell transplantation.
Case of extranodal natural killer/T-cell lymphoma, nasal type, accompanied by Epstein-Barr virus-positive nasopharyngeal carcinoma.
Senda Naoyuki,Miyagaki Tomomitsu,Oka Tomonori,Itoigawa Aya,Kikuchi Kanako,Kobayashi Takashi,Nakamura Fumihiko,Kurokawa Mineo,Sugaya Makoto,Sato Shinichi
The Journal of dermatology
An unusual presentation of nasal type NK/T-cell lymphoma of the nose.
Meslemani Danny M,Jones Lamont
OBJECTIVES:Case report of a male with a rare nasal type NK/T cell lymphoma that presented as an aggressive nasal infection superimposed with squamous and basal cell carcinoma. A review of the diagnosis, management, and prognosis nasal type NK/T cell lymphoma will be presented. STUDY DESIGN:Case report and literature review. METHODS:Review of the literature for cases of nasal type NK/T cell lymphoma, with particular attention to its presentations. RESULTS:Differential diagnosis includes aggressive infection of the nasal skin, carcinoma, and lymphoma. CONCLUSION:No cases in the literature of NK/T cell lymphoma have been reported that presented with an aggressive infection with initial biopsies that revealed squamous cell and basal cell carcinoma, which led to surgical management and a definitive diagnosis of Nasal type NK/T cell lymphoma.
Nasal endoscopic evaluation and its impact on survival in patients with stage I/II extranodal natural killer/T-cell lymphoma, nasal type.
Cho Hyun-Jin,Jang Min-Seok,Hong Sang Duk,Kim Seok Jin,Ahn Yong Chan,Oh Dongryul,Ko Young Hyeh,Kim Hyo Yeol,Dhong Hun-Jong,Chung Seung-Kyu,Kim Won Seog
International forum of allergy & rhinology
BACKGROUND:Endoscopic findings of extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, are heterogeneous, but not fully understood. The objective of this study was to evaluate the role of nasal endoscopic examination and its implications for treatment of stage I/II ENKTL. METHODS:This retrospective study included 60 consecutive patients diagnosed with stage I/II ENKTL, nasal type, from 2000 to 2011. RESULTS:The endoscopic findings were classified into early (45%) and advanced (55%) lesions. Furthermore, the primary tumor extent assessed by endoscopy was significantly correlated with the radiologic imaging (p < 0.001). The results of univariate analysis showed that the patients with advanced lesions had worse overall survival (p = 0.004) and disease-free survival (p = 0.001) than those with early lesions. In multivariate analysis, advanced lesions on nasal endoscopy was an independent prognostic factor (p = 0.024; hazard ratio 5.29; 95% confidence interval, 1.25-22.39). CONCLUSION:We found that nasal endoscopic findings were important prognostic factors in stage I/II ENKTL, nasal type, suggesting that comprehensive endoscopic evaluation of primary tumor should be performed in this setting.
Rare case of low-grade extranodal NK/T-cell lymphoma, nasal type, arising in the setting of chronic rhinosinusitis and harboring a novel N-terminal KIT mutation.
Devins Kyle,Schuster Stephen J,Caponetti Gabriel C,Bogusz Agata M
BACKGROUND:Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr virus (EBV). ENKTCL-NT occurs worldwide and is more prevalent in Asian and the Native American populations of Mexico, Central and South America. It represents approximately 10% of all peripheral T-cell lymphomas worldwide. The aim of this report is to present a rare case of ENKTCL-NT with an unusually indolent clinical course and low-grade histopathologic features. CASE PRESENTATION:A 71-year-old Asian woman with a long-standing history of seasonal rhinosinusitis presented with persistent nasal congestion, cough, and fever unresponsive to antihistamines and antibiotics. Histopathological evaluation of a polypoid nasal mass revealed an atypical infiltrate with predominantly small lymphoid cells that were CD2+, surface CD3-, cytoplasmic CD3+, CD5(dim)+, CD7(dim)+, cytotoxic markers (granzyme B and perforin)+, EBER+ and CD56-. The Ki-67 proliferative index was very low (< 1%). T-cell receptor gamma gene rearrangement studies were positive for a monoclonal rearrangement, and sequencing studies identified a novel KIT mutation (p. K167 M, c. 500 A > T). A diagnosis of low-grade ENKTCL-NT was rendered. CONCLUSIONS:Our case of ENKTCL-NT is unusual due to (1) an indolent clinical course (2) low-grade histopathologic features including a low proliferative index (3) lack of CD56 expression and (4) a novel KIT mutation. This case raises awareness of the existence of a subset of cases of ENKTCL-NT that can potentially be misdiagnosed as a reactive process, particularly in patients with recurrent chronic rhinosinusitis.
[Clinico-pathologic forms of peripheral T-and NK-cell lymphomas].
Foss H D,Coupland S E,Stein H
Malignant lymphomas, originating from peripheral T or NK cells, are rare tumours in Europe and account for less than 10% of all malignant lymphomas. In this review, the salient features of the more frequently occurring entities derived from T or NK cells will be presented. Nasal NK/T cell lymphoma is mainly found in the nose and paranasal sinuses and often, but not always, display an angiocentric growth pattern leading to coagulation necrosis. The tumor cells consistently express CD56, CD2 and the EBER molecules encoded by the Epstein-Barr virus. Clonal T cell receptor gene rearrangements are often absent indicating, in the majority of cases, a derivation of these tumors from NK cells. Enteropathy-type intestinal T-cell lymphomas often arise in patients with celiac disease and have a dismal prognosis. The tumour cells express T cell antigens, CD103 and cytotoxic molecules, but are negative for CD4. Approximately 20% of the cases display CD56 mostly in combination with CD8. Recently, an early purely intraepithelial form of this tumour was identified. Histologically these cases resemble celiac disease, however the intraepithelial lymphocytes often exhibit an abnormal immunophenotype with absent CD8 and T-cell-receptor protein expression, and, they are clonal by molecular analysis. Clinically, the patients suffer from refractory sprue or ulcerative jejunitis. The prognosis is bad with the patients often dying from malnutrition or an invasive tumour-forming T-cell lymphoma. Angioimmunoblastic T-cell lymphoma is defined by characteristic morphological findings (atypical lymphoid cells in part with pale cytoplasm, arborizing high endothelial venules and large FDC-meshworks) as well as clinical features (systemic symptoms, signs of a dys-regulated immune response). Peripheral T-cell lymphomas, that do not fit into a distinct entity, are classified in the REAL and the new WHO classifications as peripheral T-cell lymphomas unspecified. These display a broad morphological spectrum (including the T-cell lymphomas of different cell sizes, Lennert's lymphoma and T-zone lymphoma of the Kiel-classification) and in general are clinically aggressive.
Lymphoid lesions of the head and neck: a model of lymphocyte homing and lymphomagenesis.
Jaffe Elaine S
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Lymphoid lesions of the head and neck mainly affect the nasopharynx, nasal and paranasal sinuses, and salivary glands. These three compartments each are affected by a different spectrum of lymphoid malignancies and can serve as model for mechanisms of lymphomagenesis. The type of lymphoma seen reflects the underlying biology and function of the particular site involved. The nasopharynx and Waldeyer's ring are functionally similar to the mucosal associated lymphoid tissue (MALT) of the gastrointestinal tract and are most commonly affected by B-cell lymphomas, with mantle cell lymphoma being a relatively frequent subtype. The most prevalent lymphoid lesion of the salivary gland is lymphoepithelial sialadenitis, associated with Sjögren's syndrome. Lymphoepithelial sialadenitis is a condition in which MALT is acquired in a site not normally containing lymphoid tissue. Patients with Sjögren's syndrome are at increased risk to develop B-cell lymphomas, most commonly MALT lymphomas. The nasal and paranasal sinuses are the prototypical site for the development of extranodal natural killer (NK) /T-cell lymphoma, nasal type. This condition must be distinguished from other conditions causing the clinical picture of lethal midline granuloma, including Wegener's granulomatosis and infectious disorders. Lymphomatoid granulomatosis is common in the lung but is rarely seen in the midline facial structures.
The aggressive peripheral T-cell lymphomas: 2012 update on diagnosis, risk stratification, and management.
Armitage James O
American journal of hematology
BACKGROUND:T-cell lymphomas make up approximately 10-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. DIAGNOSIS:The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnose aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72-97% for the aggressive PTCLs. RISK STRATIFICATION:Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography (PET) scans appear to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large-cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. RISK ADAPTED THERAPY:Anaplastic large-cell lymphoma is the only subgroup to have a good response to a cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ∼20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-not otherwise specified (NOS) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy.
The aggressive peripheral T-cell lymphomas: 2013.
Armitage James O
American journal of hematology
BACKGROUND:T-cell lymphomas make up approximately 10-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. DIAGNOSIS:The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72-97% for the aggressive PTCLs. RISK STRATIFICATION:Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, PET scans appear to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large cell lymphoma-particularly young patients with the anaplastic lymphoma kinase positive subtype. RISK ADAPTED THERAPY:Anaplastic large cell lymphoma is the only subgroup to have a good response to a CHOP-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ~20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-NOS (not otherwise specified) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy.
Clinical analysis of extranodal non-Hodgkin's lymphoma in the sinonasal tract.
Woo J-S,Kim J M,Lee S H,Chae S W,Hwang S J,Lee H-M
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery
We investigated the clinical analysis of non-Hodgkin's lymphoma (NHL) of the sinonasal tract, including the survival rate and treatment outcome. Fifty patients who had previously received a diagnosis of extranodal NHL of the sinonasal cavity from May 1992 to April 2001 were included. We reviewed the patients' clinical characteristics and the survival rates, retrospectively. Of 50 patients, 49 were classified as having extranodal NK/T cell lymphoma and only one patient as having diffuse large B cell (DLBC) lymphoma according to the new WHO classification. Even though higher mortality rates were observed in patients receiving chemotherapy alone than in those receiving chemotherapy and radiation therapy in the advanced stage, the combination treatment of chemotherapy and radiation therapy failed to demonstrate a significantly higher survival rate.
Nasal NK/T cell lymphoma presenting as transverse myelopathy.
Sadahira Y,Wada H,Nakamura E,Terayama K,Sugihara T,Yamada O,Mikami Y,Shirabe T
Virchows Archiv : an international journal of pathology
A case of nasal NK/T cell lymphoma with central nervous system (CNS) involvement is reported. A 56-year-old man presented with eyelid edema and transverse myelopathy. Cerebrospinal fluid examination revealed atypical lymphoid cells with azurophilic granules, which were positive for CD2, CD8, and CD56, and negative for CD3 and CD5 by flow cytometry. Because a tumor mass was found involving the ethmoid and maxillary sinuses, CNS involvement was considered to have resulted from local invasion by the nasal lymphoma. In spite of intensive chemotherapy including intrathecal infusion, the patient died 6 months after the initial diagnosis. Autopsy revealed that lymphoma cells were positive for cytotoxic molecules, granzyme B and TIA-1, and EB virus-encoded RNA-1 (EBER-1), and they showed no rearrangement of TCR-beta, -gamma, or -delta genes, suggesting an NK-cell origin of the lymphoma cells. They showed an angiocentric and angiodestructive pattern in the subarachnoid space, focally extending to the cerebral cortex and cranial and spinal nerve roots. Marked demyelination was found in the lateral and posterior funiculi of the spinal cord. Thus, the pathogenesis of this spinal demyelination might be attributed to ischemia secondary to angiocentric and angiodestructive infiltration by lymphoma cells.
Hodgkin and non-Hodgkin lymphoma of the head and neck: clinical, pathologic, and imaging evaluation.
Weber Alfred L,Rahemtullah Aliyah,Ferry Judith A
Neuroimaging clinics of North America
Lymphomas are subdivided into HL and NHL and are more specifically classified into subtypes of HL or NHL according to the WHO classification. HLs involve the lymph nodes predominantly and only approximately 5% arise in extranodal sites, whereas 30% of NHLs present in extranodal sites. Imaging studies, including CT and MR imaging, cannot distinguish [figure: see text] HL from NHL, and cannot differentiate their various subtypes, necessitating a pathologic diagnosis. Clinical parameters, however, can be helpful in differentiating the two broad categories of lymphomas, and subtypes of lymphomas have predilections for different sites within the head and neck. HL is most commonly located in the lymph nodes of the neck and mediastinum. Marginal-zone lymphoma has an affinity for the ocular adnexa, salivary glands, larynx, and the thyroid gland. Diffuse large B-cell lymphoma is commonly encountered in the paranasal sinuses, mandible, maxilla, and Waldeyer ring. Burkitt lymphoma occurs more frequently in children and young adults and frequently affects the maxilla and mandible, with a greater distribution of involvement at a lower frequency. On imaging studies, the lymph nodes of HL and NHL are homogeneous and variable in size, with an average diameter from 2 to 10 cm. They may enhance slightly to moderately, display necrosis before and after treatment, and display calcification post-treatment. NHL in extranodal sites in the head and neck (nasopharynx, Waldeyer ring, oral cavity, and larynx) manifests frequently as a submucosal mass accompanied [figure: see text] by polypoid, bulky masses with a smooth mucosal surface. Clinically aggressive lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, and NK-/T-cell lymphomas are characterized by destruction of the maxilla, mandible, and bones around the paranasal sinuses, which is indistinguishable from bony destruction in other malignant tumors, such as SCC. Contrast CT is indicated for evaluation of cervical lymph nodes; the chest, including the mediastinum; the pelvic cavity; paranasal sinuses; and orbits. CT is also useful for detection of bone destruction involving the base of the skull, paranasal sinuses, and the mandible or maxilla. MR imaging is preferred for the assessment of extension of lymphomas to different fascial spaces (parapharyngeal, masticator, infratemporal fossa, tongue, and nasopharynx) and for intracranial extension. Lymphomas are isodense to muscle on CT and circumscribed with distinct margins that occasionally display extranodal extension with less-well-defined margins and areas of necrosis within the tumor matrix. Lymphomas appear low in signal intensity on T1-weighted images and low to high in signal intensity on T2-weighted images, with variable, but usually low, enhancement following introduction of Gadolinium-DTPA (Gd-DTPA) contrast material.
Extranodal NK/T-cell lymphoma mimicking cellulitis.
Jia Hongchen,Sun Tsieh
Leukemia & lymphoma
NK/T-cell lymphoma is difficult to diagnose because there is no characteristic cytology to help the diagnosis in tissue sections, particularly when there is polymorphic cellular infiltration in the early stage of the disease. However, the nasal type of extranodal NK/T-cell lymphoma has a characteristic histologic pattern, which is angiocentric, angioinvasive and angiodestructive. Therefore, many cases of this tumor may show extensive necrosis that mimics infectious process. Furthermore, because the immunosuppressive status of these patients, they may, in fact, have superimposed infections. We are reporting a case that presented as cellulitis and only after careful examination with immunohistochemistry that a correct diagnosis of extranodal NK/T-cell lymphoma, nasal type, was established. Since this lymphoma is incurable and immunophenotyping is instrumental for the diagnosis and prediction of the prognosis, a high index of suspicion for this tumor is needed when an angiocentric lesion is found in the midline of the head and neck region, and a thorough immunohistological study should always be conducted in these cases.
Lymphoma of the ocular adnexa: A study of 353 cases.
Ferry Judith A,Fung Claire Y,Zukerberg Lawrence,Lucarelli Mark J,Hasserjian Robert P,Preffer Frederic I,Harris Nancy L
The American journal of surgical pathology
We studied the cases of 353 patients with lymphoma involving the ocular adnexa diagnosed at the Massachusetts General Hospital between 1974 and 2005. The patients included 153 males and 200 females, aged 7 to 95 years, with a mean age of 64 years. In 277 cases, there was no known history of lymphoma. Seventy-six patients had a history of lymphoma, with the ocular adnexa being involved at relapse or with progression of the previously diagnosed lymphoma. The patients had marginal zone lymphoma (182 cases), follicular lymphoma (80 cases), mantle cell lymphoma (18 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (13 cases), lymphoplasmacytic lymphoma (4 cases), splenic marginal zone lymphoma (2 cases), low-grade B cell, not subclassified (19 cases), precursor B lymphoblastic lymphoma (3 cases), diffuse large B-cell lymphoma (26 cases), and 1 case each of high-grade B-cell lymphoma, not subclassified, peripheral T-cell lymphoma, unspecified type, extranodal NK/T-cell lymphoma, nasal type, and Hodgkin lymphoma, nodular sclerosis type. Almost all marginal zone lymphoma patients (168 of 182, 92%) had primary ocular adnexal lymphoma. Fourteen marginal zone lymphoma patients (8%) had a prior history of lymphoma, usually arising in another extranodal site. Twenty-five of 80 (31%) follicular lymphoma patients had a prior history of lymphoma, usually arising in lymph nodes. Patients with mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma almost always had a prior history of lymphoma or were known to have widespread disease at the time of diagnosis of ocular adnexal lymphoma. A subset of the diffuse large B-cell lymphomas were associated with large destructive masses involving adjacent structures such as paranasal sinuses, raising the possibility that they may have arisen from one of the adjacent structures and involved the ocular adnexa by direct extension. The relatively high proportion of low-grade lymphoma, not subclassified, highlights the difficulty that may arise in distinguishing different types of low-grade lymphoma, particularly when biopsies are small and artifactually distorted. Ocular adnexal lymphoma is primarily a disease of older adults, with a slight female preponderance. Most lymphomas are low-grade B-cell lymphomas, with marginal zone lymphoma being by far the most common type. Marginal zone lymphoma typically involves the ocular adnexa primarily, whereas other types of low-grade B-cell lymphoma often involve the ocular adnexa secondarily. High-grade B-cell lymphomas only occasionally involve the ocular adnexa, and T-cell lymphoma, NK-cell lymphoma, and Hodgkin lymphoma are only rarely encountered in this site.
A case of NK/T-cell lymphoma complicated by a squamous cell carcinoma of hard palate during combination chemotherapy and radiation therapy.
Lee Hang Lak,Ahn Myung Ju,Choi Jung Hye,Jun Woon Hyun,Lee Young Yuel,Kim In Soon,Choi Il Young,Jang Se Jin,Park Yong Wook
The Korean journal of internal medicine
NK/T-cell lymphoma, which often shows an angiocentric growth pattern, is a distinct clinicopathologic entity highly associated with Epstein-Barr virus. The disease is characterized by a destruction of the upper respiratory tract, particularly the nasal cavity, palate and paranasal sinuses. Interestingly, NK/T-cell lymphoma is closely linked to a variety of complications, such as hemophagocytic syndrome, second primary cancer, sepsis and bleeding. Here we report a case of a 50-year-old man diagnosed initially as NK/T-cell lymphoma of the oropharynx and who developed a second primary carcinoma of the hard palate during combination chemotherapy and radiation therapy.
Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital.
Cuadra-Garcia I,Proulx G M,Wu C L,Wang C C,Pilch B Z,Harris N L,Ferry J A
The American journal of surgical pathology
Few large series compare lymphomas of the nasal cavity with those of the paranasal sinuses. We studied the cases of 58 patients, 34 males and 24 females, aged 7 to 92 years (mean, 57 years), who had lymphoma involving the nasal cavity or paranasal sinuses. Thirty-three patients had diffuse large B-cell lymphoma (DLBCL). Twenty-three were male and 10 were female, with an age range of 7 to 91 years (mean, 63 years); two were HIV-positive. Only 2 of 11 cases tested (one in an HIV-positive patient and one of lymphomatoid granulomatosis type) were Epstein-Barr virus (EBV)-positive. Thirty (91%) involved paranasal sinuses, 10 with nasal involvement, whereas three cases had nasal, but not sinus, involvement. At last follow-up, 16 (67%) were free of disease 7 to 169 months later (mean, 65 months), and 8 (33%) had died of disease 2 to 166 months later (mean, 45 months). Seventeen patients had nasal-type natural killer (NK)/T-cell lymphoma. There were 10 women and 7 men, aged 27 to 78 years (mean, 48 years). Thirteen of 14 were EBV-positive. Sixteen patients had nasal involvement, eight with sinus involvement. Eleven (73%) of 15 were alive and well 6 to 321 months later (mean, 139 months), three (20%) died of lymphoma 1, 11, and 12 months later, and one (7%) is alive with disease. There was one case each of marginal zone B-cell lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, peripheral T-cell lymphoma of unspecified type, and adult T-cell lymphoma/leukemia. In an additional three cases, the lymphomas were composed predominantly of large cells, but no immunophenotyping could be performed for subclassification. In 19 cases (17 DLBCLs, 1 Burkitt-like lymphoma, and 1 lymphoma of uncertain lineage), presenting symptoms included complaints related to the eyes. In 16 cases (13 DLBCLs, 1 Burkitt-like lymphoma, 1 nasal NK/T-cell lymphoma, and 1 lymphoma of uncertain lineage), the orbit was invaded by lymphoma. In our series, the most common lymphoma to arise in the sinonasal area is DLBCL, followed by nasal NK/T-cell lymphoma. Comparison of these two types of lymphoma showed that lymphomas involving sinuses without nasal involvement were predominantly DLBCLs (20 of 21), whereas nasal cavity lymphomas without sinus involvement were usually NK/T-cell type (8 of 11) (p = 0.000125). Compared with patients with DLBCL, patients with nasal NK/T-cell lymphoma were overall younger, with a lower male-to-female ratio. Lymphomas of B-cell lineage were more likely to be associated with symptoms related to the eyes (p < 0.0005) and to have extension to the orbit (p < 0.01) than were lymphomas of T- or NK-cell lineage. In contrast to results of Asian studies in which nasal NK/T-cell lymphoma has a very poor prognosis, our nasal NK/T-cell lymphomas had an outcome similar to that of DLBCL.
Extranodal natural killer/T-cell lymphoma, nasal type: the significance of radiotherapeutic parameters.
Isobe Koichi,Uno Takashi,Tamaru Jun-ichi,Kawakami Hiroyuki,Ueno Naoyuki,Wakita Hisashi,Okada Jun-ichi,Itami Jun,Ito Hisao
BACKGROUND:The objective of this study was to investigate the correlation between local recurrence and radiotherapeutic parameters, including dose and RT radiotherapy (RT) field. METHODS:The current study included 35 patients who were diagnosed with immunohistochemically confirmed nasal natural killer (NK)/T-cell lymphoma between 1976 and 2004. There were 21 males and 14 females, and they ranged in age from 18 years to 76 years (median, 51 yrs). The primary tumor originated in the nasal cavity in 28 patients, and 32 patients had Stage I disease. Seventeen patients received treatment solely with RT, and the remaining 18 patients received a combination of chemotherapy and RT. The median tumor dose was 50 grays (Gy) (range, 22-60 Gy). Twenty-seven patients received RT to include all macroscopic lesions, all paranasal sinuses, the palate, and the nasopharynx. Eight patients received RT to all macroscopic lesions with generous margins. RESULTS:A complete remission (CR) or a CR/unconfirmed was achieved in 28 patients (80%). The 5-year overall survival (OAS) rate, disease-free survival (DFS) rate, and local control probability (LCP) were 47.3%, 42.9%, and 65.2%, respectively. Patients who received RT only to macroscopic lesions fared less well in terms of LCP (LCP 5 years, 71.9% vs. 41.7%; P=0.007). The difference in RT field also affected both the OAS rate and the DFS rate. Patients who received RT doses>or=50 Gy tended to achieve favorable local control. CONCLUSIONS:In the management of nasal NK/T-cell lymphoma, the RT field affected treatment outcomes. RT doses>or=50 Gy resulted in favorable local control.
Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis.
Kim Gwi Eon,Koom Woong Sub,Yang Woo-Ick,Lee Sang-Wook,Keum Ki Chang,Lee Chang Geol,Suh Chang Ok,Hahn Jee Sook,Roh Jae Kyung,Kim Joo Hang
Head & neck
BACKGROUND:The purpose of this study was to investigate the clinical relevance of subtypes categorized by immunophenotypic analysis in primary sinonasal lymphomas. METHODS:Eighty patients with localized non-Hodgkin's lymphoma involving the nasal cavity and/or paranasal sinuses were divided into three subtypes on the basis of their immunohistochemical findings: (A) B-cell lymphoma (n = 19), (B) T-cell lymphoma (n = 27), and (C) natural killer (NK)/T-cell lymphoma (n = 34). The clinicopathologic profiles, immunophenotypic data, patterns of treatment failure, and survival data among the three patient groups were retrospectively compared. RESULTS:The nasal cavity was the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease was common in B-cell lymphoma. Systemic B symptoms were frequently observed in NK/T-cell lymphoma. Almost all patients with NK/T-cell lymphoma showed a strong association with the Epstein-Barr virus by in situ hybridization studies. Sixty-five patients (81%) patients achieved complete remission after initial treatment, but 36 (55%) of these subsequently experienced treatment failure. Although there were no significant differences in locoregional failure rates among the patients of the three groups, distant failure was far more common in B-cell or NK/T-cell lymphoma than in T-cell lymphoma (p =.005). Most B-cell lymphoma cases showed a predilection for sites of systemic failure in the nodal and extranodal sites below the diaphragm, such as the paraaortic lymph nodes or the gastrointestinal (GI) tract, whereas patients with NK/T-cell lymphoma showed an increased risk of systemic dissemination to the skin, testes, or GI tract, including the development of hemophagocytic syndrome. The 5-year actuarial and disease-free survival rates for all patients were 57% and 51%, respectively. Of the three subtypes of primary sinonasal lymphomas, T-cell lymphoma seemed to carry the most favorable prognosis and NK/T-cell lymphoma the worst. (The 5-year actuarial survival rate was 57% for B-cell lymphoma, 80% for T-cell lymphoma, 37% for NK/T-cell lymphoma; p =.02, log-rank.) By univariate and multivariate analyses, immunophenotype was identified as the most important prognostic factor. CONCLUSIONS:Our data indicate that the three subtypes of primary sinonasal lymphomas classified by immunohistochemical studies exhibit different clinical profiles, different patterns of failure, and different treatment outcomes. Given these observations, it is concluded that the recognition of these distinct subsets, diagnosed on the basis of immunophenotypic study, is very important and clinically relevant in predicting their potential behavior and prognosis.
Orbital Nasal-Type Extranodal Natural Killer/T-Cell Lymphoma: An Ongoing Diagnostic Challenge Further Confounded by Small-Cell Predominance.
Wolkow Natalie,Jakobiec Frederick A,Habib Larissa A,Freitag Suzanne K
Ophthalmic plastic and reconstructive surgery
PURPOSE:To highlight the histopathologic diagnostic challenges of small-cell predominant extranodal nasal-type natural killer/T-cell lymphoma (ENTNKT) of the orbit. METHODS:Retrospective chart review and histopathologic study with immunohistochemistry and in situ hybridization of 3 cases. RESULTS:Three cases of ENTNKT presented to the Mass Eye and Ear emergency room as orbital cellulitis over 1 year. The first case was unusual in that there was a predominance of small cells, giving the ENTNKT the histopathologic appearance of a nonmalignant inflammatory process. This challenging case is juxtaposed alongside 2 other cases, which exhibited the more typical lymphomatous microscopic appearance. DISCUSSION:ENTNKT can extend into the orbit from the adjacent sinuses or rarely arise primarily in the orbit. A diagnosis is typically made with a biopsy. Occasionally, however, the histopathologic diagnosis can be elusive when a predominance of small lymphomatous cells that are virtually indistinguishable from non-neoplastic inflammatory cells is present. Demonstration of CD56 positivity by immunostaining and in situ hybridization for Epstein-Barr virus are essential in confirming the diagnosis. CONCLUSIONS:ENTNKT should be considered both in the clinical and histopathologic differential diagnoses of orbital infections and idiopathic inflammations (pseudotumor).
Extranodal NK/T-cell lymphoma presenting as a pituitary mass. Case report and review of the literature.
Liu James K,Sayama Christina,Chin Steven S,Couldwell William T
Journal of neurosurgery
Primary pituitary lymphomas (PPLs) are rare tumors of the central nervous system, and most are of B-cell origin. Extranodal NK/T-cell lymphomas are uncommon neoplasms that are highly aggressive and show a strong association with Epstein-Barr virus. They most commonly affect the nasal cavity and paranasal sinuses; manifestation as a primary pituitary tumor has never been described. The authors report a case of NK/T-cell lymphoma of the pituitary gland and review 17 cases of PPL from the literature. All patients had been evaluated at presentation for clinical, neuroimaging, and histopathological findings. Patients who had systemic lymphoma with secondary involvement of the pituitary gland were excluded. The mean patient age was 55.5 years (range 26-86 years); the male/female ratio was 13:5. The most common presentation was pituitary insufficiency (72%), followed by headache (56%), diplopia (39%), visual loss (28%), and fever (22%). Thirteen patients (72%) exhibited anterior hypopituitarism and seven (39%) had diabetes insipidus at presentation. Magnetic resonance imaging demonstrated enhancing parasellar masses with diffuse enlargement of the pituitary gland (94%), suprasellar extension (44%), cavernous sinus extension (39%), and stalk thickening (22%). Thirteen patients (72%) had B-cell lymphoma, four (22%) had T-cell lymphoma, and one (6%) had NK/T-cell lymphoma. Primary pituitary lymphomas are rare entities with a range of clinical presentations and neuroimaging findings that are unique from those of patients who present with pituitary adenomas. The pathological entity of NK/T-cell lymphoma is distinct, and its course is very aggressive with a poor prognosis.
Third cranial nerve palsy caused by intracranial extension of a sino-orbital natural killer T-cell lymphoma.
Chen Celia S,Miller Neil R,Lane Andrew,Eberhart Charles
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Natural killer/T-cell lymphomas (NKTLs) are rare destructive lesions that usually involve the nasal cavity or paranasal sinuses. Orbital and intracranial involvement is rare. A 53-year-old man with systemic lupus erythematosus who was receiving chronic low-dose prednisone treatment developed proptosis of the right eye. Biopsy of a sino-orbital lesion suggested nonspecific inflammation. Clinical and imaging manifestations resolved with a higher dose of prednisone, but when the prednisone dose was tapered, the patient developed a complete right third cranial nerve palsy. Imaging showed return of the original lesion, now with intracranial extension and enhancement of the right third cranial nerve. Repeat biopsy showed features consistent with NKTL. Biopsy of this lesion in its early stage may misleadingly suggest a primary inflammatory disorder because of a paucity of neoplastic cells, a large number of inflammatory cells recruited by the innate natural killer (NK) cell immune response, and extensive necrosis caused by angiodestructive tumor cells.
Differentiation between sinonasal natural killer/T-cell lymphomas and diffuse large B-cell lymphomas by RESOLVE DWI combined with conventional MRI.
He Mengge,Tang Zuohua,Qiang Jinwei,Xiao Zebin,Zhang Zhongshuai
Magnetic resonance imaging
OBJECTIVE:To explore the feasibility of using RESOLVE DWI combined with conventional magnetic resonance imaging (MRI) to discriminate between sinonasal NKTLs and DLBCLs and to investigate the correlation between ADC value and Ki-67 expression in the two subtypes of NHLs. MATERIALS AND METHODS:Sixty patients with NKTLs and twenty-six patients with DLBCLs in the sinonasal region who were confirmed by histopathology underwent high-resolution DWI and conventional MRI. The apparent diffusion coefficients (ADCs) and conventional MRI features associated with NKTLs and DLBCLs were compared using multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was performed, and the area under the curve (AUC) values for conventional MRI and MRI in combination with DWI were compared to determine the diagnostic performances of the approaches in the differentiation of NKTLs and DLBCLs. Spearman's rank correlations were used to analyze the correlation between ADC value with the higher AUC and Ki-67 expression. RESULTS:For conventional MRI, localization in the nasal cavity and poor or moderate enhancement indicated an NKTL, whereas localization in the paranasal sinus and intense enhancement indicated a DLBCL, with sensitivity, specificity and area under the curve(AUC)value of 88.5%, 85.0% and 0.883, respectively. A combination with a cut-off ADC value of 0.646 × 10 mm/s yielded sensitivity, specificity and AUC values of 100.0%, 80.0% and 0.951, respectively. A significant difference between the AUCs for conventional MRI and MRI in combination with DWI (p = 0.02) was identified. Ki-67 expression of NKTLs was significantly lower than that of DLBCLs (p < 0.001). Besides, there was an inversely poor correlation between them in the overall sample (r = -0.395, p < 0.001). However, the ADC value was not significantly correlated with Ki-67 LI in neither NKTLs nor DLBCLs (both p > 0.05). CONCLUSIONS:Location and enhancement degree were the most valuable conventional MRI features for differentiating between NKTLs and DLBCLs. A combination of DWI and MRI could significantly improve the differential performance. ADC values may be used to noninvasively evaluate the proliferation level of sinonasal NHLs.
An extranodal NK/T cell lymphoma, nasal type, with specific immunophenotypic and genotypic features.
Katsaounis Panagiotis,Alexopoulou Alexandra,Dourakis Spyros P,Smyrnidis Alexandros,Marinos Leonidas,Filiotou Anna,Archimandritis Athanasios J
International journal of hematology
Extranodal NK/T cell lymphoma, 'nasal type,' is a rare clinicopathological entity in Europe. The main clinical features are nasal congestion, sore throat, dysphagia and epistaxis, due to a destructive mass involving the midline facial tissues. Pathologically, lymphoma cells exhibit angioinvasion, angiodestruction and coagulative necrosis. We report the case of a patient who presented with fever, dyspnea, nasal congestion, headache, distention of right nasal turbinates and exophytic lower leg ulcerating lesions. A CT scan of visceral scull demonstrated a filling mass of right frontal, ethmoidal and maxillary sinuses with erosion of the wall of right maxillary sinus and ventral portion of the diaphragm. A biopsy was performed in the skin lesion and showed an angioinvasive NK/T cell lymphoma CD56 negative with clonal rearrangement of the T-cell-receptor gamma gene. Up to our knowledge, this is a rare immunophenotype for NK/T-cell, 'nasal type,' lymphomas. However, the lymphoma may be classified as extranodal NK/T cell lymphoma, 'nasal type,' due to typical clinical presentation, radiologic findings and pathological characteristics of polymorphism, angioinvasion, angiodestruction and coagulative necrosis.
Quantitative proteomics of CSF reveals potential predicted biomarkers for extranodal NK-/T-cell lymphoma of nasal-type with ethmoidal sinus metastasis.
Gong Yanqiu,Pu Wenchen,Jin Hongyu,Yang Pei,Zeng Hao,Wang Yuqi,Pang Fuwen,Ma Xuelei
AIM:Extranodal natural killer cell/T-cell lymphoma of nasal-type (NKTCL) is an aggressive human lymphoma, but its predicted biomarkers after chemotherapy are less known. The aim of this study is to find some potential predicted biomarkers in cerebrospinal fluid (CSF) of NKTCL patients with ethmoidal sinus metastasis (NESM). MATERIALS AND METHODS:The CSF samples were obtained from NKTCL patients with NESM before and after chemotherapy from Cancer Center of West China Hospital. Comparative proteomic profiling using label-free method was performed to characterize the fold change of proteins in NESM patients. KEY FINDING:In this study, 102 proteins with <1% false discovery rate in CSF of NKTCL with NESM patients were quantified. Furthermore, significantly reduced IGFBP2, SERP1NC1, AMBP and GPX3, as well as dramatically increased CPE levels were observed in the CSF of NKTCL patients after cytarabine chemotherapy. SIGNIFICANCE:IGFBP2, SERP1NC1, AMBP, GPX3 and CPE together or alone have a potential to be predicted indicators of NKTCL with NESM in response to chemotherapy.
Primary extranodal nasal-type natural killer/T-cell lymphoma of the brain: a case report.
Kaluza Vesna,Rao Dinesh S,Said Jonathan W,de Vos Sven
Natural killer (NK)/T-cell lymphomas represent a rare type of lymphoma derived from either activated NK cells or, rarely, cytotoxic T cells. These lesions are most commonly extranodal and tend to present as destructive lesions within the midline facial structures. Other than the nasal cavity and paranasal sinuses, several other extranodal sites of involvement have been reported, including the pharynx, gastrointestinal tract, and testis. Although secondary involvement of the central nervous system has been reported, a convincing case of primary brain NK/T-cell lymphoma has not been previously reported. Here, we report a case of primary brain lymphoma of NK/T-cell type with a characteristic phenotype expressing CD3epsilon, CD56, granzyme B, Epstein-Barr virus-encoded small nuclear RNAs, with germline T-cell receptor gene configuration, and showing an unusual intravascular component. The patient underwent extensive imaging studies, revealing only the brain lesion. The lymphoma failed to respond to therapy and the patient eventually died after transfer to a hospice facility. This unusual case highlights an unusual presentation of a rare disease entity and highlights the need for a better understanding of the biology and treatment of T-cell lymphomas.
Natural Killer T-Cell Lymphoma of the Orbit: An Evidence-Based Approach.
Jiménez-Pérez Juan C,Yoon Michael K
Seminars in ophthalmology
Natural killer T-cell lymphoma (NKTCL) is a rare and aggressive condition with a high mortality rate. It is most commonly seen in the nasal sinuses, generally affecting the orbit by direct extension. Primary orbital NKTCL is even more rare, with only a few published cases with occasional secondary nasal involvement. This malignancy can present as a "masquerade syndrome," delaying proper diagnosis and treatment. Biopsy is required for diagnosis, which shows specific histopathological characteristics. Radiation and chemotherapy are the mainstay of treatment. Newer chemotherapies show improved prognosis.
Nasal NK/T-cell lymphoma: computed tomography and magnetic resonance imaging findings.
Ou Chang-Hsien,Chen Clayton Chi-Chang,Ling Jin-Ching,Chai Jyh-Wen,Wu Chen-Hao,Chen Wen-Hsien,Hung Hao-Chun,Tain-Lee ,Ho Tzu-Lung
Journal of the Chinese Medical Association : JCMA
BACKGROUND:Primary nasal natural killer (NK)/T-cell lymphoma is the most common cellular subtype seen in nasal lymphomas. It is rare in the Western population but occurs more frequently in Asia, South America, and Mexico. The purpose of this study was to describe the computed tomography (CT) and magnetic resonance (MR) imaging findings of primary nasal NK/T-cell lymphoma. METHODS:During the period between January 1990 and June 2006, the CT (n=24) and MR (n=6) images of 24 patients with biopsy-proved nasal NK/T-cell lymphoma were reviewed retrospectively. Both CT and MR images were evaluated for site and extent of disease and for pattern of involvement of adjacent areas. RESULTS:The most common symptoms at presentation were nasal obstruction, nasal discharge, and epistaxis. There was involvement of the unilateral nasal cavity in 16, bilateral nasal cavity including nasal septum in 5 and nasal choana in 3. Sites of extension outside the nasal cavity included tumor extension into paranasal sinuses (n=15), nasopharynx (n=5), nasal labial fold (n=3), oropharynx (n=2), infratemporal fossa (n=2), other subcutaneous soft tissue of the face (n=2) and anterior cranial fossa base (n=1). Bony destruction was demonstrated in 18 cases, involving the sinus bony wall (n=15), nasal turbinate (n=10), lamina papyracea (n=6), orbital floor (n=3), and hard palate (n=2). Regional lymphadenopathy was also detected in 3 patients with nasal NK/T-cell lymphoma. CONCLUSION:The CT and MR appearances of nasal NK/T-cell lymphoma are nonspecific, and the diagnosis requires histologic confirmation. However, the differential diagnosis of nasal NK/T-cell lymphoma should be included if the images present soft tissue of the nasal cavity with bony erosion or destruction; involvement of the orbital cavity, nasopharynx and infratemporal fossa; and subcutaneous or nasolabial fold soft tissue infiltration, especially in Asian populations.
A comparative population-based analysis of sinonasal diffuse large B-cell and extranodal NK/T-cell lymphomas.
Dubal Pariket M,Dutta Rahul,Vazquez Alejandro,Patel Tapan D,Baredes Soly,Eloy Jean Anderson
OBJECTIVE/HYPOTHESIS:Diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are aggressive tumors. ENTKL is very rare in the United States and often affects the nasal cavity and paranasal sinuses; DLBCL, although more common, rarely occurs in these locations. Our study aims to compare incidence and survival of these lymphomas in the sinonasal cavity. STUDY DESIGN:Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. METHODS:The SEER database was searched for patients diagnosed with sinonasal ENKTL and DLBCL between 1973 and 2011. Data analyzed included patient demographics, incidence, treatment modality, and survival. RESULTS:Three hundred and twenty-eight sinonasal ENKTL (SN-ENKTL) cases and 1,054 sinonasal DLBCL (SN-DLBCL) cases were identified. The mean ages at diagnosis for SN-ENKTL and SN-DLBCL were 51.7 and 67.8 years, respectively (P = 0.0001). Overall 1-, 5-, and 10-year disease-specific survival (DSS) rates for SN-DLBCL were 85.5%, 63.5%, and 44.0%, compared to 66.4%, 30.9%, and 9.2% for SN-ENKTL, respectively (P < 0.0001). For patients matched for stage, age, and treatment modality, the 1-, 5-, and 10-year DSS for the SN-DLBCL group was 94.4%, 72.8%, and 46.8%, respectively, whereas the respective survival rates for the SN-ENKTL group were 77.6%, 38.4%, and 13.9%, respectively (P < 0.0001 at each time interval). CONCLUSIONS:To our knowledge, this study represents the only population-based comparison between SN-DLBCL and SN-ENKTL. SN-DLBCL has a better prognosis regardless of gender, stage, treatment modality, and age. LEVEL OF EVIDENCE:2b.
Lymphoma of the nasal cavity and paranasal sinuses: treatment and outcome of early-stage disease.
Proulx Gary M,Caudra-Garcia Ivone,Ferry Judith,Harris Nancy,Greco William R,Kaya Unsal,Chan Annie,Wang C C
American journal of clinical oncology
The records of 23 patients diagnosed and treated at the Massachusetts General Hospital for extranodal non-Hodgkin's lymphoma of the paranasal sinus and nasal cavity were reviewed. The majority of patients were Ann Arbor stage I and approximately evenly divided in T1 or T2 (n = 10) and T3 or T4 (n = 13). Eight patients had nasal-type NK/T cell and 15 patients had diffuse large B-cell lymphoma (DLBCL). The patients with nasal-type NK/T cell lymphoma predominately involved the nasal cavity (5/8), whereas the DLBCL more often had the paranasal sinuses as the primary site (12/15). All patients received radiation as part of their treatment. Only three patients received chemotherapy as part of their initial treatment for three cycles using a cyclophosphamide, doxorubicin, vincristine, and prednisone-based regimen. By coincidence, the estimated overall survival (OS) and disease-free survival rates for both 5 and 10 years were all the same for all analyses. The OS for the entire group at 10 years was 78%. Significant prognostic factors were Ann Arbor stage IEA versus IIEA ( p = 0.0001) and T stage with (T1 or T2) versus (T3 or T4) (p = 0.0243). Combining Ann Arbor stage and T stage created a highly significant prognostic variable (IEA & [T1 or T2], IEA & [T3 or T4], IIEA & [T1 or T2], IIEA & [T3 or T4]) at p = 0.0001, regardless of site or histology. Patients with local-regional disease appear to be well controlled with radiation alone, but distant failure remains a problem. A combined-modality approach with local-regional radiation and systemic chemotherapy is recommended for these patients.
An unusual presentation of NK/T-cell lymphoma, nasal-type in the United States.
Kidwai Sarah M,Parasher Arjun K,Lin Fred Y
American journal of otolaryngology
INTRODUCTION:NK/T-cell lymphoma (NKCL), nasal-type is rare in the United States, representing only 1.5% of non-Hodgkin lymphomas. Classically, patients initially present with nasal obstruction (70%), caused by invasion of the localized lesion into the sinuses and nasal cavities. Initial presentation with persistent sore throat and odynophagia due to oropharyngeal tumor extension is rare, and thus, is often overlooked as viral or bacterial pharyngitis. By studying a case of NKTCL nasal type, we emphasize the need to apply high clinical suspicion for NKTCL, nasal type for early diagnosis and improved survival. METHODS:A case report of a rare presentation of NKTCL, nasal-type is discussed. A literature review is provided to define clinical signs crucial for early diagnosis, appropriate work-up, and expedient treatment of this aggressive, rapidly progressive malignancy. RESULTS:In the present case, a 25year-old healthy male presented with a 2-week history of sore throat and odynophagia. On exam, the patient had an ulcerative lesion of the soft palate, an enlarged uvula, and tonsillar exudate with tender submandibular lymphadenopathy. After the patient failed to respond to antibiotic therapy for presumptive pharyngitis, a biopsy of the oropharyngeal tissue was completed, which identified necrotizing sialometaplasia. High clinical suspicion led to repeat deep-tissue biopsy, where a final diagnosis of NKTCL, nasal type was made. The patient then began definitive treatment with chemotherapy and radiation. CONCLUSIONS:High clinical suspicion is key to early diagnosis and improved survival of NKTCL, nasal-type. Otolaryngologists who encounter prolonged, complicated cases of pharyngitis or necrotizing sialometaplasia should consider a diagnosis of NKTCL, nasal-type, in order to prevent rapid disease progression.
Extranodal natural killer/T-cell lymphoma nasal type with central nervous system involvement mimicked tuberculous meningitis: A case report.
Yang Yina,Li Zhouling,Zhiyang Chen,Liang Hui
RATIONALE:Neurologic deficits are rare in patients with extranodal natural killer/T-cell lymphoma (NKTL), nasal type. We present a case that was initially suspected as tuberculous meningitis, but later diagnosed as central nervous system metastasis of NKTL, nasal type, which has never been published previously. PATIENT CONCERNS:A 55-year-old Chinese man presented with persistent headache and fever. The initial head computed tomography and magnetic resonance imaging (MRI) scan was normal. Low glucose, elevated protein, and pleocytosis of cerebral spinal fluid led to a diagnosis of tuberculous meningitis. The patient did not respond to anti-tuberculosis treatment, and his symptoms aggravated. MRI showed abnormal lesions in the right hemisphere and a lesion in the maxillary sinus region. DIAGNOSIS:Endoscopic biopsy of the maxillary lesion showed features consistent with NKTL. Positron emission tomography revealed a hypermetabolic mass involving the right maxillary sinus and brain. INTERVENTIONS:The patient received chemotherapy. OUTCOMES:The patient died 30 days after chemotherapy. LESSONS:Lymphoma of the nasal cavity and paranasal sinuses is extremely rare and may be easily misdiagnosed. Nasal NKTL metastasis should be considered when a patient presents with symptoms of leptomeningeal involvement.
Nasal-type extranodal T-cell/NK lymphoma in association with hemophagocytic syndrome.
Guedes Juliana Chaves Ruiz,Cunha Karen de Almeida Pinto Fernandes da,Machado Jorge Ricardo da Silva,Pinto Luciana Wernersbach
Anais brasileiros de dermatologia
Extranodal NK/T-cell lymphoma nasal type is a rare disease that mainly affects the nasal cavity and paranasal sinuses of males in the fifth decade of life. It has aggressive and locally destructive behaviour, and can be complicated by the hemophagocytic syndrome, conferring high lethality to the disease. This article describes a case of NK/T-cell lymphoma nasal type in a previously healthy patient, exemplifying its rapid and fulminant course.
Extranodal natural killer/T-cell lymphoma nasal type: detection by computed tomography features.
Hsu Yin-Ping,Chang Po-Hung,Lee Ta-Jen,Hung Liang-Yueh,Huang Chi-Che
OBJECTIVES/HYPOTHESIS:Nasal natural killer/T-cell lymphoma (NKTL) often has an infiltrative pattern in computed tomography that makes them difficult to distinguish from benign inflammatory diseases. This study aimed to design a method of measuring the thickness of the nasal floor and nasal septum, determine the critical value of mucosal thickness that may implicate these NKTL cases from benign inflammatory disease, and finally make a complete flowchart to detect NKTL with minimal mistake. STUDY DESIGN:Thirty-two patients with nasal NKTL and 173 patients with severe chronic rhinosinusitis with or without polyposis were enrolled. The patients' data were collected retrospectively. METHODS:All patients underwent standard computed tomography of the paranasal sinuses. The coronal section near the vertical part of the ground lamina was chosen for measurement, and the thickest points along the nasal floor and septum were measured. RESULTS:Patients with NKTL had thicker nasal floors and/or septa than those with chronic rhinosinusitis, recurrent sinusitis, or pansinusitis (P < .001). If the cutoff points of the nasal floor and nasal septum thickness were set at 2.0 mm and 2.5 mm, respectively, the probability of being thicker than the corresponding points in the CRS group was <2%, and the possibility of other diagnoses should be considered. CONCLUSIONS:Nasal floor mucosal thickness >2.0 mm or nasal septum mucosal thickness >2.5 mm may be indicators serving as one of several important hints for implicit NKTL. Finally, we established a diagnostic flowchart to include all of these important hints. LEVEL OF EVIDENCE:4.
Natural killer T-cell lymphoma originating from the orbit.
Dai Wei,Zhong Ming,Shen Wei,Zou Ke,Bai Chen-Guang
Chinese medical journal
Natural killer T-cell lymphoma (NKTL) is a malignant neoplasm which usually involves the nasal cavity or paranasal sinuses, while an orbit origin is extremely rare. Here we report the clinical, radiological and histopathologic features of a patient with NKTL originating from the orbit. We analyzed the clinical and radiologic records in the whole course of the disease. We also reviewed the morphology and immunohistochemistry of the neoplasm biopsy, including the presence of CD56, CD3 and cytotoxic molecules. This case demonstrated that nasal-type NKTL with a poor prognosis can originate from the orbit.
Clinical and otorhinolaryngological aspects of extranodal NK/T cell lymphoma, nasal type.
Miyake Marcel Menon,Oliveira Mariana Vendramini Castrignano de,Miyake Michelle Menon,Garcia Julio Oliva de Almeida,Granato Lidio
Brazilian journal of otorhinolaryngology
INTRODUCTION:Extranodal NK/T-Cell lymphoma, nasal type (NKTLN) is a disease that mainly affects the nasal cavity and the paranasal sinuses. Early nasal symptoms are nonspecific, simulating sinus infection. With disease progression, necrosis of the nasal mucosa increases, hindering histological diagnosis. Thus, multiple biopsies may be necessary until definitive diagnosis. Most studies on NKTLN address the hematological and immunological aspects of the disease. OBJECTIVES:To present data from a Brazilian quaternary hospital, with emphasis on the clinical aspects of the disease, and to correlate the findings with the most recent literature data. METHODS:Case study of seven patient files. RESULTS:Patients were evaluated on their medical history, number of biopsies necessary, association with Epstein-Barr virus, treatment, and outcome. All patients had nonspecific nasal complaints and underwent at least three cycles of antibiotic therapy. The earlier a biopsy was performed, the fewer biopsies were required to diagnose the disease and start treatment. However, this fact did not translate into better prognosis. CONCLUSION:The otolaryngologist plays a fundamental role in the prognosis of NKTLN and can shorten time between symptom onset and treatment of the patient.
Extranodal NK/T-cell lymphoma, nasal type: report of 15 cases.
Tababi S,Kharrat S,Sellami M,Mamy J,Zainine R,Beltaief N,Sahtout S,Besbes G
European annals of otorhinolaryngology, head and neck diseases
OBJECTIVES:To define the epidemiological and clinical features and complementary investigation findings of extranodal NK/T-cell lymphoma, nasal type and to discuss the diagnostic difficulties and the various treatment options. PATIENTS AND METHODS:This retrospective study was based on 15 patients with extranodal NK/T-cell lymphoma, nasal type, managed between 1990 and 2009. RESULTS:This series comprised 13 men and two women (sex ratio=6.5) with a mean age of 52 years (range: 35-81 years). The mean time to first consultation was 6 months. The most common symptoms were nasal obstruction (87%) and purulent nasal discharge (73%), followed by epistaxis (60%). Physical examination demonstrated the presence of a tumour of the nasal cavity in 11 patients. The diagnosis was confirmed by histological examination of a biopsy completed by immunohistochemistry. CT scan of the facial bones was performed in all patients of this series. The site of extranodal NK/T-cell lymphoma was essentially nasal (12 cases). Orbital extension was observed in four cases, associated with intracranial extension in two cases and osteolysis was observed in 11 patients. Lymphomas were classified as stage IE in 74% of cases and stage IIE in 26% of cases. Only one patient was lost to follow-up during treatment. Three patients died before any treatment. Treatment therefore concerned 12 patients. Stage IE lymphomas were treated by radiotherapy and/or chemotherapy. All stage IIE lymphomas were treated by chemotherapy alone. Stage IE patients had a better prognosis. CONCLUSION:Extranodal NK/T-cell lymphoma, nasal type, is an aggressive form of non-Hodgkin's lymphoma comprising specific clinicopathological characteristics. The addition of chemotherapy for advanced stages does not appear to improve survival compared radiotherapy alone, which remains the treatment of choice especially for localized stages.
Patterns of Primary Tumor Invasion and Regional Lymph Node Spread Based on Magnetic Resonance Imaging in Early-Stage Nasal NK/T-cell Lymphoma: Implications for Clinical Target Volume Definition and Prognostic Significance.
Wu Run-Ye,Liu Kang,Wang Wei-Hu,Jin Jing,Song Yong-Wen,Wang Shu-Lian,Liu Yue-Ping,Ren Hua,Fang Hui,Liu Qing-Feng,Yang Yong,Chen Bo,Qi Shu-Nan,Lu Ning-Ning,Tang Yu,Tang Yuan,Li Ning,Ouyang Han,Li Ye-Xiong
International journal of radiation oncology, biology, physics
PURPOSE:This study aimed to determine the pathways of primary tumor invasion (PTI) and regional lymph node (LN) spread based on magnetic resonance imaging (MRI) in early-stage nasal NK/T-cell lymphoma (NKTCL), to improve clinical target volume (CTV) delineation and evaluate the prognostic value of locoregional extension patterns. METHODS AND MATERIALS:A total of 105 patients with newly diagnosed early-stage nasal NKTCL who underwent pretreatment MRI were retrospectively reviewed. All patients received radiation therapy with or without chemotherapy. RESULTS:The incidences of PTI and regional LN involvement were 64.7% and 25.7%, respectively. Based on the incidence of PTI, involved sites surrounding the nasal cavity were classified into 3 risk subgroups: high-risk (>20%), intermediate-risk (5%-20%), and low-risk (<5%). The most frequently involved site was the nasopharynx (35.2%), followed by the maxillary (21.9%) and ethmoid (21.9%) sinuses. Local disease and regional LN spread followed an orderly pattern without LN skipping. The retropharyngeal nodes (RPNs) were most frequently involved (19.0%), followed by level II (11.4%). The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates for all patients were 72.8%, 65.2%, and 90.0%, respectively. The presence of PTI and regional LN involvement based on MRI significantly and negatively affected PFS and OS. CONCLUSIONS:Early-stage nasal NKTCL presents with a high incidence of PTI but a relatively low incidence of regional LN spread. Locoregional spread followed an orderly pattern, and PTI and regional LN spread are powerful prognostic factors for poorer survival outcomes. CTV reduction may be feasible for selected patients.
Extranodal natural killer/T-cell lymphoma, nasal type: clinical and computed tomography findings in the head and neck region.
Hung Liang-Yueh,Chang Po-Hung,Lee Ta-Jen,Hsu Yin-Ping,Chen Yi-Wei,Fu Chia-Hsiang,Huang Chi-Che
OBJECTIVES/HYPOTHESIS:In patients with nasal natural killer/T-cell lymphoma (NKTL), it is commonly without an obvious mass found in the nasal cavity by clinical or computed tomography (CT) findings. As a result, it takes longer to make a definite diagnosis when compared with other nasal malignancy. This study was designed to investigate clinical and CT findings of nasal NKTL. STUDY DESIGN:Forty-three patients with nasal NKTL were enrolled. The patients' data were collected retrospectively. METHODS:All patients underwent contrast-enhanced CT scans and endoscopic examinations. Symptoms were noted and recorded in detail. RESULTS:Patients with lymphoma limited to their nasal cavity or paranasal sinus (N/PN) presented symptoms similar to chronic rhinosinusitis, such as nasal obstruction and purulent nasal discharge. Patients with lymphoma of the nasopharynx or oropharynx (NPx/OPx) tended to present more frequently with epistaxis or blood-tinged sputum. On CT, NKTL was usually nonenhanced (79.1%), homogenous (100%), unilateral (61.9%), infiltrative (67.4%), and without central necrosis. Only 30.2% of the patients presented with a prominent mass. One disease-specific sign, different from patients with chronic rhinosinusitis, was that the mucosa of the nasal cavity was thickened without involvement of the mucosa of the paranasal sinus (40.6%). CONCLUSIONS:The thickening of the mucosa of the nasal cavity without similar involvement of the paranasal sinuses is easily overlooked in patients with NKTL. In addition, the imaging findings of thickened mucosa of the nasal floor and/or nasal septum near the inferior meatus, a prominent mass, and bony destruction should raise suspicion of this diagnosis.
Extranodal natural killer/T-cell lymphoma, nasal type: 'midline lethal granuloma.' A case report.
Tlholoe Martha M,Kotu Monica,Khammissa Razia A G,Bida Meschack,Lemmer Johan,Feller Liviu
Head & face medicine
Extranodal natural killer/T cell lymphoma, nasal type, is a non-Hodgkin lymphoma, most commonly affecting the nasal cavity, paranasal sinuses and nasopharynx. Clinically it is characterised by destruction of facial tissues, commencing in the midline. In most cases it arises from malignant transformation of natural killer cells (NK); sometimes from malignant transformation of cytotoxic T cells.Extranodal NK/T cell lymphoma, nasal type, is rare, but even more rare in black persons. The purpose of this article is to report a severe case of extranodal NK/T cell lymphoma, nasal type, in an elderly black male.