Extranodal Natural Killer (NK)/T-cell Lymphoma Research Articles

Prognostic Impact of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio and Prognostic Score in Patients with Nasal Type, Extranodal Natural Killer/T Cell Lymphoma

Nasal type, extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a heterogeneous disorder with poor prognosis, requiring risk stratification in this population. We designed to investigate the prognostic significance of absolute lymphocyte count (ALC), absolute monocyte count (AMC), ALC/AMC ratio and ALC/AMC prognostic score (low risk, normal ALC and AMC; intermediate risk, low ALC or high AMC; high risk, low ALC and high AMC) and to determine whether ALC/AMC ratio or prognostic score is a better predictor of prognosis in ENKTL. A total of 264 patients with newly diagnosed ENKTL were retrospectively analyzed in present study. Receiver Operating Curve analysis showed that optimal cut-off values of ALC, AMC and ALC/AMC ratio were 1.0×109/L, 0.5×109/L and 2.85, respectively. In multivariate analysis all tested factors including ALC, AMC, ALC/AMC ratio and prognostic score were independent risk factors. After a median follow-up of 30 months (range 1-87), an estimated 3-year overall survival (OS) in the 264 patients was 75.4%. Patients with ALC/AMC ratio≥2.85 had a better OS and progression-free survival (PFS) than those with ALC/AMC ratio<2.85 at diagnosis (3-year OS rate: 83.4% versus 61.9%, P < 0.001; 3-year PFS rate: 76.5% versus 53.0%, P< 0.001). Significant difference has been noticed in the patients according to ALC/AMC prognostic score in 3-year OS (low risk vs. intermediate risk, 88.3% vs. 66.5%, p = 0.001; low risk vs. high risk, 88.3% vs. 0%, p < 0.001; intermediate risk vs. high risk, 66.5% vs. 0%, p = 0.001) and in 3-year PFS(low risk vs. intermediate risk, 80.7% vs. 58.3%, p = 0.002; low risk vs. high risk, 80.7% vs. 0%, p < 0.001; intermediate risk vs. high risk, 58.3% vs. 0%, p = 0.003) . The International Prognostic Index (IPI) and Korean Prognostic Index (KPI) were used for predicting these patients’ prognosis, the result showed that the discrimination was not power. When applying ALC/AMC ratio and prognostic score to the IPI and KPI model, the latter showed a better discrimination as compared to the former. DisclosuresNo relevant conflicts of interest to declare.

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

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

A new prognostic model for nasal-type, extranodal natural killer/T cell lymphoma.

e19042Background: Nasal type, extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a heterogeneous disorder with poor prognosis, and there are no optimal therapy and risk-based prognostic mode...

Nasal-type NK/T-cell lymphomas are more frequently T rather than NK lineage based on T-cell receptor gene, RNA, and protein studies: lineage does not predict clinical behavior

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type, comprises NK or cytotoxic T cells. We evaluated the clinical impact of cell type and the usefulness of T-cell receptor (TCR) gene transcripts in distinguishing cell lineage. One hundred and eight cases of ENKTL were analyzed for TCR gene rearrangements using the BIOMED-2 protocol and for TCR gene expression using immunohistochemistry for TCR-βF1 and TCR-cγM1, and RNA in situ hybridization for TCR gene transcripts. Prognostic factors were analyzed. Among the 108 cases, 44 were monoclonal for a TCR rearrangement (40%) while 64 (60%) were undefinable. The monoclonal cases expressed TCR-βF1 in 14 out of 40 cases (35%) and TCR-cγM1 in 1 out of 44 cases (2%). The 64 undetermined cases expressed TCR-βF1 in 15 cases (23%) and TCR-cγM1 in 1 (2%). Thirteen of 40 TCR-β constant gene transcript-positive cases (33%) expressed TCR-βF1 and one of nine TCR-γ constant gene transcript-positive cases (11%) expressed TCR-cγM1. TCR gene transcripts were not useful in the distinction of cell lineages. TCR gene transcripts were positive in ENKTLs as well as in normal B cells and aggressive NK-cell leukemia. Based on gene rearrangements and immunohistochemistry for TCR, there were 60 T-cell type cases (56%), 32 NK-cell type cases (30%), and 16 cases with an undetermined cell type (14%). TCR protein was expressed in 30/60 T-ENKTLs (50%) in a variable fraction of tumor cells. There were no significant differences in clinical findings or overall patient survival between T- or NK-cell types of ENKTL, although those with a T-cell type tended to show a better prognosis for those with localized nasal lymphomas. Univariate and multivariate analysis showed that a non-nasal ENKTL, age >60 years, high level of lactate dehydrogenase, bone marrow involvement, and the absence of radiotherapy were independent prognostic factors.

Epstein–Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin

Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity. A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study. Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL.

Macrophage inflammatory protein 1 alpha (MIP-1α) may be associated with poor outcome in patients with extranodal NK/T-cell lymphoma.

The macrophage inflammatory protein 1α (MIP-1α) is anticipated to have a role in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) because the expression of MIP-1α is related to Epstein-Barr virus (EBV) latency in EBV-related non-Hodgkin lymphoma cells. Thus, we measured the serum level of MIP-1α in 69 patients with ENKTL using frozen serum samples that were archived at diagnosis. As serum level of MIP-1α was not detectable in 19 patients (range: 0-24.37 pg/mL), patients were dichotomized into positive (n = 50) and negative (n = 19) MIP-1α groups according to the presence of detectable level of MIP-1α in serum. MIP-1α-positive group showed a significantly poor overall survival (OS) in comparison with the MIP-1α-negative group (p = 0.004). In the subgroup analysis, the positivity of MIP-1α was significantly associated with OS in patients with stage IIIE/IV and a detectable level of EBV DNA (p = 0.002 and 0.032, respectively). Multivariate analysis also showed that the positivity of MIP-1α was independently associated with worse OS together with bone marrow involvement (p = 0.002). An in vitro study with patient-derived ENKTL tumour cells showed the expression of CCR1 and CCR5 on the surface of tumour cells (28% and 14%, respectively) , and the addition of MIP-1α to the culture media of tumour cells increased cell growth supporting the negative impact of MIP-1α on the prognosis of ENKTL patients. In conclusion, serum levels of MIP-1α could predict survival outcomes in patients with ENKTL. Therefore, MIP-1α should be considered for prognostication and a potential therapeutic target. Copyright © 2016 John Wiley & Sons, Ltd.

Comparative histopathologic analysis of cutaneous extranodal natural killer/T‐cell lymphomas according to their clinical morphology

Few studies have evaluated the histopathologic features of cutaneous extranodal natural killer (NK)/T-cell lymphoma (ENKTL), and the histopathologic spectrum of this disease according to its clinical morphology remains unclear. This study investigated the differences in pathologic findings of cutaneous ENKTL depending on clinical morphology. A total of 41 cases of cutaneous ENKTL were included. Skin lesions were classified according to clinical morphology as: (i) nodular lesions, (ii) cellulitis or abscess-like swellings and (iii) erythematous to purpuric patches. Histopathologic variables were compared between groups. Perivascular infiltration of tumor cells and vasculopathy in the dermis and subcutaneous layer were common microscopic findings irrespective of clinical morphology. Erythematous to purpuric patches were mainly composed of small-sized tumor cells, whereas medium- to large-tumor cells were predominant in lesions of other clinical morphologies. The density of tumor cell infiltration was significantly higher in cellulitis or abscess-like lesions or nodular lesions compared with erythematous to purpuric patches. A panniculitis-like pattern and angiocentricity were less common in patch lesions than in cellulitis-like swelling and nodular lesions. There is a histopathologic spectrum of cutaneous ENKTL that is dependent on the clinical morphology.

Concurrent Chemoradiation Therapy Followed by Consolidation Chemotherapy for Localized Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type

To evaluate the effectiveness of concurrent chemoradiation therapy (CCRT) with 40 Gy followed by consolidation chemotherapy for localized extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type. From August 2004 to August 2012, 62 patients with newly diagnosed stage IE to IIE ENKTL underwent CCRT followed by consolidation chemotherapy. The median RT dose was 40 Gy. Cisplatin, 30 mg/m(2), was administered weekly during the RT course. Responders to CCRT were encouraged to undergo consolidation chemotherapy. Three different consolidation chemotherapy regimens were used consecutively: VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone); VIDL (etoposide, ifosfamide, and dexamethasone followed by intramuscular injection of l-asparaginase); and MIDLE (methotrexate, etoposide, ifosfamide, mesna, and l-asparaginase). The median follow-up period was 49 months (range 8-112). After completion of CCRT, 56 patients (90.3%) had a complete response, 4 (6.4%) had a partial response, 1 (1.6%) had stable disease, and 1 patient (1.6%) had progressive disease (PD). Consolidation chemotherapy was recommended to 61 patients, after excluding the patient with PD, but was actually delivered to 58. Of these 58 patients, 56 (96.5%) had a complete response and 2 (3.5%) had PD. During the follow-up period, 17 patients (including 3 with PD) experienced progression. The median interval to progression was 11 months (range 1-61). Local failure developed in 6 patients, of whom, 2 had developed progression outside the RT field. For all patients, the 3-year overall survival, progression-free survival, and local control rates were 83.1%, 77.1%, and 92.4%, respectively. Grade ≥3 nonhematologic toxicity developed in only 3 patients (4.8%). Excellent clinical outcomes were achieved using CCRT with 40 Gy followed by consolidation chemotherapy. Additional investigation, however, is warranted to confirm our findings.

The serum CXCL13 level is associated with the Glasgow Prognostic Score in extranodal NK/T-cell lymphoma patients.

BackgroundThe Glasgow Prognostic Score (GPS) measures inflammation and proves its prognostic value in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL) which is commonly combined with inflammatory lesion. Given inflammatory chemokines play an important role in tumor progression, we hypothesized that chemokines might influence ENKTL aggressiveness through interaction with their receptors in the tumor tissue.MethodsWe measured the serum levels of C-X-C motif ligand 13 (CXCL13) in 69 patients with ENKTL who received non-anthracycline-based chemotherapy and/or concurrent chemoradiotherapy because CXCL13 is thought to have a pro-tumor effect through interaction with its receptor, the C-X-C chemokine receptor 5 (CXCR5). We analyzed the association of serum CXCL13 with the GPS, and their prognostic relevance. The levels of CXCL13 were measured using a multiplex chemokine assay on archived frozen serum samples.ResultsPatients were categorized into high and low CXCL13 groups if they had CXCL13 levels above or below the median value of 29.1 pg/mL, respectively. The high CXCL13 group and grouping by the GPS showed a significant association with poor progression-free survival. The elevated serum levels of CXCL13 were also significantly associated with a high score of the GPS. High CXCL13 levels and GPS were significantly associated with high tumor burden predicting poor prognosis including stages III/IV, extranasal presentation, bone marrow invasion, and presence of Epstein-Barr virus (EBV) DNA in blood. Furthermore, serum CXCL13 and GPS discriminated patients at risk of treatment failure among patients with low tumor burden (stage I/II) and non-detectable EBV DNA.ConclusionsSerum levels of CXCL13 were associated with the prognostic value of GPS. Grouping by the serum CXCL13 might predict survival outcomes in patients with ENKTL, suggesting that it is a potential therapeutic target.

Efficacy of gemcitabine combined with oxaliplatin, L-asparaginase and dexamethasone in patients with newly-diagnosed extranodal NK/T-cell lymphoma.

There is currently no standard first-line regimen for patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). In this study, we investigated the efficacy and toxicity of gemcitabine (GEM) combined with oxaliplatin (L-OHP), L-asparaginase (L-ASP) and dexamethasone (DXM) (GOLD regimen) as a systemic treatment scheme for newly-diagnosed ENKTCL cases. A total of 55 patients were recruited at the Henan Province Cancer Hospital and the Cancer Center of Sun Yat-sen University between May, 2008 and August, 2012. The GOLD regimen included a 14-day treatment cycle with GEM (1,000 mg/m2) on day 1, L-OHP (100 mg/m2) on day 1, L-ASP (10,000 U/m2) on days 1-5 and DXM (20 mg b.i.d.) on days 1-4. The response rate, survival rate and treatment toxicity were analyzed. The overall response rate was 91% (48/55) with a complete response in 62% (34/55) and a partial response in 29% (15/55) of the patients. For all patients, the 1-, 2- and 3-year progression-free survival (PFS) rate was 86, 64 and 57% and the overall survival (OS) 91, 80 and 74%, respectively. The 1-year PFS in patients with stage I/II vs. those with III/IV disease was 87 vs. 66% (P<0.001) and the 1-year OS was 98 vs. 75%, respectively (P<0.001). No chemotherapy-related mortality or severe complications were recorded. In conclusion, the GOLD regimen was found to be highly effective and safe for the treatment of patients with newly-diagnosed ENKTCL.

Clinical Analysis Of 120 Cases Of Natural Killer/T Cell Lymphoma, Nasal Type By Single Hospital In The North-Western China

ObjectivesTo improve the understanding of extranodal natural killer(NK)/ T cell lymphoma (ENKTCL) with poor prognosis and provide experiential references for individual therapy via a retrospective analysis of the clinical and pathological features. Methods120 NKTCL cases from April 2007 to Oct 2012 in single center of Northwestern China were retrospectively analyzed on their pathologic diagnosis and clinical manifestations. Pathological examinations were mainly depended on morphology, immunohistochemisty for immunophenotype and In situ hybridizationc for epstein - barr virus (EBV) small encoded RNA£¨EBER£©. Polymerase chain reaction (PCR) for the amount of EBV DNA in whole-blood and T-cell receptor (TCR) gene rearrangement were performed. Chemotherapy and or radiotherapy were the main treatments. Complete remission(CR), 2 year(2y) overall survival (OS) and progressive free survival (PFS) according to clinical characteristics were analyzed. ResultsThe median age of 120 NKTCL cases was 43.19+13.7 years old. 98 primary nasal ENKTCL cases accounted for 81.4%, whose 2y OS and PFS were 88.6% and 69.1% respectively. 22 non-nasal ENKTCL accounted for 18.3%£€whose 2y OS and PFS were 58.8% and 45.5% respectively, which was statistically significant comparing with primary nasal ENKTCL cases. It was found that patients with primary intestinal or Ki67 greater than 80% were dead in first year. Patients with primary liver and intestinal had higher Ki67 than patients with primary nasal. Rate of 2y OS of 43 patients with Ki67 from 60% to 80% was 60% and PFS was 36% as compared to 86.3% of rate of OS and 57.5% for PFS of 30 patients with Ki67 from 30% to 50% and 100% of rate of OS and 78% for PFS of 7 patients with Ki67 less than 30%. Basing on analysis showed that from the cell of origin, it was found that primary site was nasal and 2y OS 100%¡¢PFS 75%£€in 8 cases with CD56+,CD3+ and T-cell receptor (TCR) gene rearrangement, which was statistically significant comparing with CD56- nasal ENKTCL cases. EBER was positive in every case. Among the 13 EBV –DNA samples detected, there were 5 samples with more than 6.1X107 copies/ml with OS 60%. 2y OS and PFS of Patients with normal ferritin ¦Â-microglobulin were longer than that of higher ferritin and ¦Â-microglobuli( P). 2y OS and PFS of 10 cases with I stage who had only radiotherapy was 100% respectively. 47 cases with II-IV stage received only chemotherapy. Their 2y OS and PFS was 100% and 90% respectively for patients with II stage better than that of III and IV stage. 63 cases with treatment of chemotherapy and radiotherapy. Among them, 2y OS and PFS of local nasal and invasion nasal were different. International prognostic index, IPI was good for prognosis for OSºÍPFS. Conclusion£ºIt was implied that Ki67, CD56, EBER, EBV-DNA and primary site was related with the prognosis of NKTCL. It needs further and more clinical observation and verification to judge if they could be additional markers for prognostication and clinical stratification to be incorporated in clinical individual management algorithms. The chemotherapies containing asparaginase or polyehylene glycol asparaginase are more effective. Autologous stem cell transplantation could make patients long live and pretransplant CR status was a major prognostic factors. Disclosures:No relevant conflicts of interest to declare.

Serum C-Reactive Protein (CRP) as a Simple and Independent Prognostic Factor in Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type

BackgroundC-reactive protein (CRP) is a biomarker of the inflammatory response, and it shows significant prognostic value for several types of solid tumors. The prognostic significance of CRP for lymphoma has not been fully examined. We evaluated the prognostic role of baseline serum CRP levels in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL).MethodsWe retrospectively analyzed 185 patients with newly diagnosed ENKTL. The prognostic value of the serum CRP level was evaluated for the low-CRP group (CRP≤10 mg/L) versus the high-CRP group (CRP>10 mg/L). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were evaluated and compared with the newly developed prognostic model.ResultsPatients in the high-CRP group tended to display increased adverse clinical characteristics, lower rates of complete remission (P<0.001), inferior progression-free survival (PFS, P = 0.001), and inferior overall survival (OS, P<0.001). Multivariate analysis demonstrated that elevated serum CRP levels, age >60 years, hypoalbuminemia, and elevated lactate dehydrogenase levels were independent adverse predictors of OS. Based on these four independent predictors, we constructed a new prognostic model that identified 4 groups with varying OS: group 1, no adverse factors; group 2, 1 factor; group 3, 2 factors; and group 4, 3 or 4 factors (P<0.001). The novel prognostic model was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the low- and intermediate-low-risk groups, the intermediate-low- and high-intermediate-risk groups, and the high-intermediate- and high-risk groups.ConclusionsOur results suggest that pretreatment serum CRP levels represent an independent predictor of clinical outcome for patients with ENKTL. The prognostic value of the new prognostic model is superior to both IPI and KPI.

Cutaneous EBV‐positive γδ T‐cell lymphoma vs. extranodal NK/T‐cell lymphoma: a case report and literature review

Primary cutaneous γδ T-cell lymphoma and extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type are two distinct lymphoma entities in the World Health Organization (WHO) classification. We report the case of an aggressive cutaneous lymphoma of γδ T-cell origin showing overlapping features of both lymphomas. A 78-year-old female presented with confluent erythematous plaques with ulcerations over her right thigh. Microscopically, section of the skin showed a diffuse dermal and subcutaneous lymphocytic infiltration with tumor necrosis and angioinvasion. The medium- to large-sized tumor cells expressed CD3, CD8, cytotoxic molecules and T-cell receptor (TCR)-γ but not CD4, CD20, CD30, CD56 or βF1. In situ hybridization for Epstein-Barr virus-encoded mRNA (EBER) was diffusely positive. Polymerase chain reaction-based clonality assay showed a clonal TCR-γ chain gene rearrangement. The features compatible with γδ T-cell lymphoma include dermal and subcutaneous involvements, cytotoxic phenotype, expression of TCR-γ, as well as an aggressive course. On the other hand, the diffuse EBER positivity, angioinvasion, tumor necrosis and cytotoxic phenotype may also fit in the diagnosis of an ENKTL of T-cell lineage. We review the literature on EBER-positive γδ T-cell lymphoma and discuss the diagnostic dilemma using the current WHO classification system.

Stage IE/IIE Extranodal NK/T-cell Lymphoma Arising From the Nasal Cavity: Investigation of Computed Tomography Findings and Its Prognostic Values

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare and aggressive tumor. Although most patients present as localized disease in the nasal cavity, because of its rarity, their radiologic findings are not familiar with clinicians. We, therefore, retrospectively investigated the computed tomography (CT) findings in patients with stage IE/IIE ENKTL arising from the nasal cavity and evaluated whether imaging findings revealed by CT could provide prognostic values.