Clinical features, prognostic stratification, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma: a multi-institutional real-world study.

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs.

Risk stratification and prognostic value of multi-modal MRI-based radiomics for extranodal nasal-type NK/T-cell lymphoma.

BACKGROUND: Magnetic resonance imaging (MRI) performs well in the locoregional assessment of extranodal nasal-type NK/T-cell lymphoma (ENKTCL). It's important to assess the value of multi-modal MRI-based radiomics for estimating overall survival (OS) in patients with ENKTCL. METHODS: Patients with ENKTCL in a prospectively cohort were systemically reviewed and all the pretreatment MRI were acquisitioned. An unsupervised spectral clustering method was used to identify risk groups of patients and radiomic features. A nomogram-revised risk index (NRI) plus MRI radiomics signature (NRI-M) was developed, and compared with the NRI. RESULTS: The 2 distinct type I and II groups of the MRI radiomics signatures were identified. The 5-year OS rates between the type I and type II groups were 87.2% versus 67.3% (P = 0.002) in all patients, and 88.8% versus 69.2% (P = 0.003) in early-stage patients. The discrimination and calibration of the NRI-M for OS prediction demonstrated a better performance than that of either MRI radiomics or NRI, with a mean area under curve (AUC) of 0.748 and 0.717 for predicting the 5-year OS in all-stages and early-stage patients. CONCLUSIONS: The NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

The value of prognostic nutritional index in nasal-type, extranodal natural killer/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive disorder with heterogeneous clinical characteristics and poor prognosis. The combined value of baseline serum albumin level and absolute peripheral lymphocyte count showed prognostic information in a variety of malignancies, but its evidence is limited in ENKTL. The purpose of this study is to evaluate the impact of prognostic nutritional index (PNI) in ENKTL, and to provide some nutritionally and immunologically relevant information for better risk stratification. We conducted a retrospective study in 533 patients newly diagnosed with ENKTL. The PNI was calculated as albumin (g/L) + 5 × lymphocyte count (109/L). The optimal cutoff values for serum albumin and lymphocyte count were 40.6 g/L and 1.18 × 109/L, respectively, and 47.3 for PNI. After a median follow-up of 70 months, the 5-year overall survival (OS) and progression-free survival (PFS) were 56.2% and 49.5%, respectively. Patients in low PNI group had more unfavorable clinical features, and tended to have worse 5-year OS and PFS compared with those in high PNI group. According PNI-associated prognostic score, patients were classified into different risk groups. Significant difference has been found in 5-year OS and PFS in different risk groups. When PNI and PNI-associated prognostic score were superimposed on the International Prognostic Index (IPI), prognostic index of natural killer lymphoma (PINK), or nomogram-revised risk index (NRI) categories, the PNI and PNI-associated prognostic score provided additional prognostic information. Therefore, PNI and PNI-associated prognostic score could be independent prognostic factors for ENKTL and may be useful for risk stratification and clinical decision-making.

Pancreas Involvement of Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, Presenting as Acute Pancreatitis: A Case Report.

BACKGROUND: The main etiology of acute pancreatitis includes biliary origin and alcohol, although various other causes include drugs (i.e., L-asparaginase) or malignant tumors. Since accurate identification of etiologies is crucial for determining therapeutic planning, the assessment of cause should be performed as early as possible. CASE PRESENTATION: A 57-year-old Korean man was admitted for chemotherapy. The patient did not drink alcohol for religious reason. 26 days prior to admission, a 4 cm-sized testicular mass was observed in ultrasound and he received right radial orchiectomy. Extranodal natural killer/T-cell lymphoma, nasal type, was diagnosed. After confirming no additional abnormal findings, chemotherapy (using the regimens Dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) was begun. On Day 8 of chemotherapy, L-asparaginase was started and he complained of sudden onset epigastric pain after 2 days. Acute pancreatitis was diagnosed and, in order to determine if the acute pancreatitis occurred due to L-asparaginase or pancreas involvement of extranodal natural killer/T-cell lymphoma, endoscopic ultrasonography guided fine needle biopsy was performed and observed diffusely infiltrated tumor cells. Therefore, he was given a final diagnosis of acute pancreatitis due to pancreas involvement of extranodal natural killer/T-cell lymphoma, nasal type. DISCUSSION: Acute pancreatitis caused by pancreas involvement of extranodal natural killer/T-cell lymphoma, nasal type, is a very rare disease but can occur during chemotherapy. To identify the cause of acute pancreatitis, endoscopic ultrasonography guided fine needle biopsy can be considered.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

[Induced pluripotent stem cell-derived rejuvenated cytotoxic T lymphocyte therapy for Epstein-Barr virus-associated lymphomas: application to clinical practice].

Epstein-Barr virus (EBV)-associated lymphomas are common in Asia and exhibit a poor prognosis. As EBV antigens LMP1 and LMP2 are often expressed in EBV-associated lymphomas, these lymphomas should be a good target for antigen-specific cytotoxic T lymphocyte (CTL) therapy. However, CTLs continuously exposed to viral or tumor antigens often become exhausted. Antigen-specific CTLs generated from induced pluripotent stem cells are functionally rejuvenated, showing a strong antitumor effect on EBV-associated lymphomas and persistence in vivo. For feasible "off-the-shelf" therapy, we generated allogeneic EBV-specific CTLs in the cell processing center and prepared them for actual use in clinical settings.

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

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

Primary cutaneous T-cell lymphomas other than mycosis fungoides and Sézary syndrome. Part II: Prognosis and management.

Primary cutaneous T-cell lymphomas (CTCLs) other than mycosis fungoides (MF) and Sézary syndrome (SS) encompass a heterogenous group of non-Hodgkin lymphomas with variable clinical courses, prognoses, and management approaches. Given the morphologic and histologic overlap among the CTCL subtypes and other T-cell lymphomas with cutaneous manifestations, thorough evaluation with clinicopathologic correlation and exclusion of systemic involvement are essential prior to initiating therapy. Staging and treatment recommendations vary, depending on the subtype, clinical behavior, and treatment response. Generally, for subtypes in which staging is recommended, Ann Arbor or tumor, node, metastasis staging specific to CTCL other than MF or SS are used. For many subtypes, there is no standard treatment to date. Available recommended treatments range widely, from no active or minimal intervention with skin-directed therapy to aggressive systemic therapies that include multi-agent chemotherapy with consideration for hematopoietic stem cell transplant. Emerging targeted therapies, such as brentuximab, a chimeric antibody targeting CD30, show promise in altering the disease course of non-MF/SS CTCLs.

Primary cutaneous T-cell lymphomas other than mycosis fungoides and Sézary syndrome. Part I: Clinical and histologic features and diagnosis.

Primary cutaneous T-cell lymphomas (CTCLs) are defined as lymphomas with a T-cell phenotype that present in the skin without evidence of systemic or extracutaneous disease at initial presentation. CTCLs other than mycosis fungoides and Sézary syndrome (SS) account for approximately one third of CTCLs and encompass a heterogenous group of non-Hodgkin lymphomas, ranging from indolent lymphoproliferative disorders to aggressive malignancies with a poor prognosis. The spectrum of CTCLs continues to broaden as new provisional entities are classified. Given the morphologic and histologic overlap among CTCLs and other diagnoses, a thorough clinical history, physical evaluation, and clinicopathologic correlation are essential in the work up and diagnosis of these rare entities. This article will summarize the epidemiologic, clinical, pathologic, and diagnostic features of CTCLs other than mycosis fungoides and SS.

[Outcome of radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type].

Objective: To evaluate the prognosis and determine the failure patterns after radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL). Methods: A total of 557 patients from 2000-2015 with low-risk early-stage ENKTCL who received radiotherapy (RT) with or without chemotherapy (CT) from China Lymphoma Collaborative Group were retrospectively reviewed. Among them, 427 patients received combined modality therapy, whereas 130 patients received RT alone. Survivals were calculated by Kaplan-Meier method and compared with Log-rank test. Overall survival (OS) was compared with age and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Cox stepwise regression model was used for multivariate analysis. Results: The 5-year OS and progression-free survival (PFS) were 87.2% and 77.2%. The SMR was 3.59 (P<0.001) at 1 year after treatment, whereas it was 1.50 at 4 years after treatment, without significant difference between ENKTCL group and country-matched general population (P=0.146). Compared with RT alone, CMT did not result in significantly superior 5-year OS (87.0% vs 87.4%, P=0.961) or PFS (76.1% vs 80.7%, P=0.129). Local failure (11.5%, 64/557) and distant failure (10.8%, 60/557) were the main failure modes, while regional failure was rare (2.9%, 16/557). The 5-year locoregional control rate (LRC) was 87.2% for the whole group, with 89.5% for ≥50 Gy versus 73.7% for <50 Gy (P<0.001). Radiotherapy dose was an independent factor affecting LRC(P<0.05). Conclusions: Radiotherapy achieves a favorable prognosis in patients with low-risk early-stage ENKTCL. The incidence of either locoregional or distant failure is low. Radiation dose still is an important prognostic factor for LRC.

Efficient recruitment of c-FLIPL to the death-inducing signaling complex leads to Fas resistance in natural killer-cell lymphoma.

Activation-induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL-derived NK cell lines NK-YS and Hank1, and primary lymphoma cells expressed procaspase-8/FADD-like interleukin-1ß-converting enzyme (FLICE) modulator and cellular FLICE-inhibitory protein (c-FLIP), along with Fas and FasL. Compared with Fas-sensitive Jurkat cells, NK-YS and Hank1 showed resistance to Fas-mediated apoptosis in spite of the same expression levels of c-FLIP and the death-inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c-FLIP (c-FLIPL ) was coimmunoprecipitated with Fas predominantly in both ENKL-derived NK cell lines after Fas ligation. Indeed, c-FLIPL was more sufficiently recruited to the DISC in both ENKL-derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c-FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK-YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c-FLIPL , which prevents their Fas-mediated apoptosis. Our results show that c-FLIPL could be a promising therapeutic target against ENKL.

A proposal for a prognostic index for non-nasal type natural killer/T cell lymphoma after asparaginase-based treatment.

In the era of asparaginase-based therapy for extranodal natural killer/T cell lymphoma (ENKTL), the clinical outcomes of ENKTL have notably improved. However, as a rare subtype of ENKTL, the therapeutic effect and prognostic factors of non-nasal type ENKTL remain unclear. Thus, we performed this study to analyze the clinical characteristics and to establish a prognostic model specifically for the non-nasal disease. We performed a retrospective study of consecutive patients newly diagnosed with non-nasal type ENKTL and mainly received asparaginase-based therapy at Sun Yat-sen University Cancer Center (SYSUCC) between January 2011 and December 2019, to analyze the prognostic factors and to propose a prognostic model. We validated the prognostic model in an independent cohort. In total, 98 non-nasal type ENKTL patients were included in the training cohort. Multivariate analyses showed that prognostic factors for OS were elevated LDH levels, involvement of bone marrow and serum total protein (TP) < 60 g/L. We developed a new prognostic model named the non-nasal type ENKTL prognostic index (NPI) by grouping the prognostic factors: group 1, no risk factors; group 2, one risk factor; and group 3, two or three risk factors, which were associated with 3-year OS rates of 84.1% (95% CI, 70.9-97.2), 46.8% (27.7-65.8), and 14.9% (0-32.9), respectively (P < 0.001). These results were validated and confirmed in an independent cohort. The new model is efficient in distinguishing non-nasal-type ENKTL patients with various outcomes in the contemporary era of asparaginase-based therapy.

Abnormal pretreatment coagulation factor levels correlate with poor prognosis in patients with early-stage extranodal nasal-type natural/killer T cell lymphoma.

Coagulative dysfunction is frequently observed among patients with extranodal nasal-type natural killer/T cell lymphoma (NKTCL) in our clinical practice. However, the true prognostic value of coagulation factors in patients with NKTCL has not been evaluated systemically. Data for patients with stage I/II NKTCL who were treated in the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2008 to January 2019 were collected retrospectively. The patients enrolled in this study were initially diagnosed as having early-stage disease. The patients' baseline characteristics and pretreatment laboratory tests for coagulation function, including fibrinogen (FIB) and D-dimer (D-D), were reviewed and analyzed. The influence of coagulative factors on the responses and prognosis of patients with early-stage NKTCL was evaluated. Among 394 patients assessed, 154 were included in this study. Abnormal coagulation function was found in nearly half of the patients (48.1%). Univariate analysis showed that reduced complete remission (CR) was associated with elevated D-D (P = 0.001) and elevated FIB levels (P = 0.006). The D-D level was demonstrated as associated with unfavorable progression-free survival (PFS) (P = 0.003) and overall survival (OS) (P = 0.002). Multivariate analysis indicated that an elevated D-D level was an independent factor for poor clinical response (P = 0.019), PFS (P = 0.046), and OS (P = 0.024). Elevated pretreatment levels of coagulation factors, especially D-D and plasma FIB, are unfavorable predictors for clinical response, OS, and PFS in early-stage NKTCL.

Extranodal NK/T-cell lymphoma, nasal type, with extranasal presentation - a case report and a review of the literature.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL), nasal type is a very rare and aggressive non-Hodgkin lymphoma. Most commonly it occurs in the upper aerodigestive tract. But, it can also manifest at locations such as the skin, soft tissue, gastrointestinal tract (GI), lungs, testis, etc. These locations are designated as extranasal ENKTCL. The patients with the latter have often more adverse clinical features and poorer survival rate compared with nasal sites. We present a case of an 83-year-old patient with a primary ENKTCL, nasal type, with extranasal presentation in the right upper eyelid. MATERIAL AND METHODS: Materials for the literature review was obtained by a comprehensive search on PubMed, which yielded 82 eligible cases with extranasal ENKTCL. RESULTS: Sixty-eight cases (83 %) were localized as primary ENKTCL in the lungs (17), central nervous system (CNS) (14), testis (11), GI-tract (7), skin (6), orbit and intraocular tissue (4), pancreas (2), adrenal gland (2), breast (1), etc. 14 cases (17 %) presented as extended or disseminated diseases involving exclusively organs outside the upper aerodigestive tract. There was no systematic pattern of organ involvement in the extended/disseminated ENKTCL. 63 % of the patient with localized extranasal ENKTCL and about 50% of patients with extended/disseminated disease were reported to have died of the disease. Treatment strategies varied with no preferred option. Among the used treatment options were chemotherapy, radiotherapy, surgery, stem cell transplantation alone or in different combinations. CONCLUSION: ENKTCL is a highly aggressive disease which may present in extranasal areas. Although the tumors respond to both chemotherapy and radiotherapy, durable complete remissions are very rare.

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.

[The Application Value of True Whole-body PET/CT Scanning Protocol in Patients of Extranodal NK/T Cell Lymphoma].

OBJECTIVE: To assess the staging, restaging, and treatment strategy determination of extranodal NK/T cell lymphoma (ENKT) by PET/CT real body (true whole-body, TWB) imaging, which is superior to PET/CT limitation of the whole body (limited whole-body, LWB, from skull vertex to upper thighs) by adding 'distal lower extremity' images. METHODS: TWB 18F-FDG PET/CT studies performed for staging and follow-up of ENKTL patients between January 2012 and September 2017 were retrospectively reviewed. Patients in staging group received TWB PET/CT evaluation for staging at the first diagnosis. In follow-up group, patients received follow-up evalution with TWB PET/CT and progressive disease (PD) in the LWB range with or without clinical diagnosis or suspicion before follow-up examination, and then divided into four subgroups: staging (+) PD (－), staging (+) PD (+), staging (－) PD (－), staging (－) PD (+). Then the percentage of unexpected ENKTL lesions found at the distal extremity (outside the LWB range) (P1), and the percentage of changes in the staging, restaging/outcome evaluation (P2) in each group were recorded. RESULTS: Among the 225 patients in the staging group, 200 (88.9%) had tumors confined to LWB, while P1 was 11.1% (25 cases) and P2 was 0.4% (1 case). In the follow-up group, the P1 in staging (+) PD (－)( n=85), staging (+) PD (+)( n=4), staging (－) PD (－)( n=43), staging (－) PD (+) goups ( n=15) were 1.2%, 75.0%, 0%, 26.7%, and P2 were 1.2%, 0%, 0%, 13.3%, respectively. In the follow-up group, regardless of whether the TWB PET/CT examination was performed at the initial diagnosis stage, P1 in PD (－) group and PD (+) group was 0.8 vs. 36.8% ( P<0.000 1), and P2 was 0.8% vs. 10.5% ( P<0.000 1). CONCLUSION: It is not recommended that the TWB PET/CT imaging from the top of the head to the bottom of the foot use for the first diagnosis of ENKTL patients. And for follow-up patients with no clinical evidence of tumor progression or with evidence of tumor progression but whose lesions were limited to LWB at the initial diagnosis of TWB PET/CT staging, LWB PET/CT from the top of the head to the middle of the thigh is recommended for routine follow-up. For ENKTL patients, TWB PET/CT was not performed at the initial stage of diagnosis to detect the condition of lower limbs. If the evidence of tumor progression in the LWB range appeared before the follow-up examination, TWB PET/CT was recommended for the follow-up evaluation to evaluate the systemic tumor involvement.

Extranasal extranodal NK/T cell lymphoma: A post-transplantation lymphoproliferative disease.

Extranodal NK/T cell lymphoma (ENKTL) is a rare form of non-Hodgkin lymphoma. It mostly occurs in the upper respiratory tract. Cutaneous involvement can be seen among the extranasal ENKTLs. After solid organ and haematopoietic stem cell transplantation, post-transplantation lymphoproliferative disease because of immunosuppressive therapy is usually B cell-derived; T and NK/T cell-derived disease is rarely seen. A 43-year-old female patient who had renal transplantation 14 years ago presented with cutaneous ulceration and subcutaneous nodules located in the abdomen. The patient was diagnosed with ENKTL, nasal type. Although it is rare, ENKTL nasal type is a lymphoproliferative disease that should be considered in the differential diagnosis of ulcerated cutaneous tumoural lesions.

[Extra-nodal NK/T-cell lymphoma, nasal-type, revealed by cutaneous and ocular involvement]. / Atteintes cutanée et oculaire révélatrices d'un lymphome T/NK extra-nodal de type nasal.

BACKGROUND: Extra-nodal NK/T-cell lymphoma (ENKTL) is a form of highly malignant non-Hodgkin's lymphoma. There are two types: nasal forms primarily affecting the oropharyngeal sphere and so-called nasal-type extra-nasal forms in which primary skin involvement is the most common feature enabling diagnosis. Herein, we report a case of systemic nasal-type ENKTL (ENKTL-NT) that was diagnosed based on skin involvement associated with ocular involvement. PATIENTS AND METHODS: A 67-year-old female patient, without immunodepression, was admitted to the dermatology department for a worsening inflammatory scaly patch of skin on her right calf. Secondarily, further lesions appeared on her body as well as a generalized macropapular rash and sores. These were associated with fever spikes, as well as ophthalmoplegia and edema, preventing her from opening her right eyelid. Tests for infectious, autoimmune and inflammatory disorders were negative. A cerebro-orbital scan revealed infiltration and contrast enhancement of the right periocular fat without any mass effect or cerebral extension. A positron emission tomography (PET) scan revealed multiple hypermetabolic skin lesions. Histological analyses indicated dermal-hypodermal lymphomatous tumor proliferation, and immunohistochemical analyses revealed lymphocytes expressing NK-cell markers (strong CD56+ expression), cytotoxic markers (granzyme B and TIA-1), and the presence of Epstein Barr virus (EBV) in the tumor cells. The patient was diagnosed with systemic ENKTL-NT. Her condition deteriorated rapidly, with the onset of refractory macrophage activation syndrome leading to death due to multiple organ failure. DISCUSSION: Skin involvement in ENKTL is non-specific and uncommon, which can delay diagnosis. Treatment is based on polychemotherapy comprising L-asparaginase and possibly consolidation therapy with autologous or allogeneic hematopoietic stem cell transplantation. The prognosis of ENKTL-NT is poor due the more aggressive nature of the disease compared with the nasal forms, with frequent visceral involvement and macrophage activation syndrome. Skin involvement seems to be a poor prognostic factor. Although ocular involvement is documented, its association with skin involvement is rare and mainly secondary to nasal forms of ENKTL. This case of an extra-nasal form of ENKTL-NT with systemic involvement illustrates the difficulty of diagnosis and the poor prognosis of this type of lymphoma.

[Bortezomib Inhibits Extranodal Natural Killer/T Cell Lymphoma, Nasal Type by Targeting NF-κB Signaling Pathway].

OBJECTIVE: To investigate the anti-tumor effect of bortezomib on extranodal natural killer/T cell lymphoma, nasal type (ENKTL). METHODS: SNK-6 cells were treated with different mass concentrations of bortezomib (0, 1, 2, 4, 5, 6 ng/mL) for 24, 48, 72 h, and different concentrations of nuclear factor-kappa B (NF-κB) signaling pathway inhibitor BAY11-7082 (0, 1, 2, 2.5, 5, 10, 20 µmol/L) for 24 h respectively, then the cell viability was measured by CCK8 kit and the half inhibitory concentration (IC 50) was calculated. SNK-6 cells were treated with 30µmol/L Z-VAD-FMK (Pan-caspase inhibitor)+3ng/mL bortezomib, and 5, 10 µmol/L BAY11-7082+3 ng/mL bortezomib for 24 h respectively, then the cell viability was measured by CCK8 kit. After treatment of SNK-6 cells with different mass concentrations of bortezomib for 24 h, apoptosis was detected by AnnexinⅤ/PI flow cytometry; the expression of apoptosis-related protein Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl-2 and NF-κB signaling pathway key proteins P65 and P100/P52 were detected by Western blot. RESULTS: Bortezomib inhibited the proliferation of SNK-6 cells in a dose-dependent manner ( P<0.05), and IC 50( (2.87±0.06) ng/mL) at 24 h was lower than that at 48 h and 72 h ( P<0.05). BAY11-7082 also inhibited the proliferation of SNK-6 cells with an IC 50= (9.73±0.36) µmol/L at 24 h. The combination treatment indicated that Z-VAD-FMK could attenuate the inhibitory effect of bortezomib on the proliferation of SNK-6 cells ( P<0.05), while BAY11-7082 could enhance the inhibitory effect of bortezomib on the proliferation of SNK-6 cells ( P<0.05). After treatment of SNK-6 cells with bortezomib for 24 h, apoptosis-related protein Caspase-3 cleavage, PARP activation, and Bcl-2 cleavage; NF-κB signaling pathway-related protein P65 phosphorylation level decreased, and P52 decreased. CONCLUSION: Bortezomib inhibits ENKTL cells proliferation by inhibiting NF-κB signaling pathway and induces apoptosis of ENKTL cells via mitochondria-mediated caspase pathway.

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

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