Surface CD3-negative monomorphic epitheliotropic intestinal T-cell lymphoma

Intestinal T/NK-cell lymphomas include enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), indolent T-cell lymphoproliferative disorders of the GI tract (ITCLPD), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and intestinal T-cell lymphoma NOS (ITCL-NOS). Here we describe a case of surface CD3-negative MEITL. A 63-year-old Japanese female had a tumor located in the conglomerated ileum, which formed multiple mass lesions. The resected tissue showed a diffuse infiltration of monomorphic medium-sized lymphocytes with epitheliotropism. Flowcytometry using a fresh specimen of the tumor revealed positivity for CD7, CD8, CD38, and CD56, but not surface CD3. On immunohistochemistry, the tumor showed positivity for cytoplasmic CD3, CD8, CD56, TIA-1, Granzyme B, and perforin. EBER with in situ hybridization was negative. Moreover, H3K36me3, which is negative in MEITL with SETD2-mutation, was positive. This is an important case of MEITL due to its oncogenesis.     

Frequent expression of CD30 in extranodal NK/T‐cell lymphoma: Potential therapeutic target for anti‐CD30 antibody‐based therapy

Extranodal NK/T‐cell lymphoma, nasal type (ENKTL) is a subtype of non‐Hodgkin lymphoma with a poor prognosis. Although first‐line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti‐CD30 antibody‐based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T‐cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut‐off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non‐nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30‐positive cases and CD30‐negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression‐free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti‐CD30 antibody‐based therapy may be an effective treatment.     

Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years.

BACKGROUND: Data on mature T-cell and natural killer (NK)-cell lymphomas diagnosed with the World Health Organization (WHO) classification scheme are scarce. They are regarded to be more common in Asian populations. METHODS: Consecutive T-cell and NK-cell lymphomas classified according to the WHO scheme within 10 years in a Chinese population were reviewed. RESULTS: There were 148 cases, constituting 16.6% (T-cell, n=90, 10.1%, NK-cell, n=58, 6.5%) of all non-Hodgkin lymphomas in this period. There was a male predominance (male:female = 2.5), young age at diagnosis (median age 50 years, range 8-86) and frequent extranodal presentation. Commonest T-cell lymphomas included anaplastic large cell lymphoma (ALCL, n=25, median age 35 years, nodal 60%, stage I/II 60%), peripheral T-cell lymphoma, unspecified (PTCL, n=24, median age 54 years, nodal 42%, stage I/II 42%), and angioimmunoblastic T-cell lymphoma (AILT, n=19, median age 67 years, nodal 95%, stage I/II 26%). Overall frequencies of T-cell lymphomas were comparable to Western patients. AILT, PTCL and ALCL were aggressive with a poor outcome. NK-cell lymphomas were predominantly extranodal (96%) and aggressive, with a frequency much higher than Western patients. CONCLUSIONS: The apparent high prevalence of T-cell and NK-cell lymphomas in the Chinese was due to more frequent NK-cell but not T-cell lymphomas.     

Hepatosinusoidal leukaemia/lymphoma consisting of epstein-barr virus-containing natural killer cell leukaemia/lymphoma and T-cell lymphoma; mimicking malignant histiocytosis

Previously diagnosed cases of hepatosinusoidal T-cell lymphoma and malignant histiocytosis (MH) may include lymphoid neoplasms of natural killer (NK) cell lineage associated with Epstein-Barr virus (EBV). Such hepatosinusoidal neoplasms were found to demonstrate hepatomegaly but not lymphadenopathy, and all were diagnosed by a liver biopsy. Sixteen adult patients diagnosed with hepatosinusoidal leukaemia/lymphoma (six NK-cell leukaemia/lymphomas [NKLLs], five instances of MH, three T-cell malignant lymphomas [T-MLs], and two adult T-cell leukaemia/lymphomas [ATLLs] were examined for EBV by in situ hybridization, then were studied immunohistochemically and subjected to a DNA analysis. Among our five patients with MH, neoplastic cells showed T-cells, but no histiocytic markers, and they were considered to have either a T-cell or NK-cell lineage. All NKLLs, MHs and T-MLs, except for ATLLs accompanied by reactive hemophagocytic histiocytes, varied in number in each case. In situ hybridization revealed the presence of EBV in the nuclei of atypical cells in all of the six lymphoid neoplasms of NK-cell lineage. Each case of MH and each T-ML which represented EBV demonstrated no definite T-cell or histiocytic markers. Patients with ATLL did not reveal EBV. In all patients with hemophagocytosis, EBV was present in the nuclei of the neoplastic lymphocytes, but not in the hemophagocytic cells. Finally, the 16 cases were reclassified into eight cases with EBV -containing NKLLs, six T-MLs, and two ATLLs. In addition, no true histiocytic neoplasms were observed. The mechanism of hemophagocytosis may be therefore the production of lymphokines (macrophage-activating factors) by neoplastic lymphocytes. EBV-associated hepatosinusoidal leukaemia/lymphoma may thus contain a lymphoid neoplasm of NK-cell lineage, which made it difficult to be distinguished from the previously designated malignant histiocytosis.     

Treatment algorithms for mature T-cell and natural killer-cell neoplasms

Mature T-cell and natural killer (NK)-cell lymphomas are rare neoplasms, differing geographically in frequencies. T-cell lymphomas are more common in Asia than in western countries, and NK-cell lymphomas occur almost exclusively in Asia and South America. The rarity of these lymphomas means that treatment algorithms of T-cell and NK-cell lymphomas have not been well established. Angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, are the more commonly encountered T-cell lymphomas. Treatment with anthracycline-based regimens designed for aggressive B-cell lymphomas gives unsatisfactory results. Cutaneous T-cell lymphomas may remain indolent, but outcome is poor for advanced diseases. Novel therapies, including monoclonal antibodies, nucleoside analogs, histone deacetylase inhibitors and small molecules targeting cellular signaling pathways, are being explored alone or in combination with chemotherapy. High-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) is recommended for high-risk cases. NK-cell lymphomas exhibit the multidrug resistance phenotype due to P-glycoprotein expression, so that anthracycline-based regimens are ineffective. Non-multidrug resistance-dependent regimens and L-asparaginase-based protocols have been shown to be highly active. Autologous HSCT is not routinely performed. The role of allogeneic HSCT is being examined.     

CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature.

BACKGROUND: The aim of this study was to define prognostic parameters and guidelines for diagnosis and treatment for CD56+ hematological neoplasms with first presentation in the skin. PATIENTS AND METHODS: The study group included 153 cases (23 new and 130 from the literature). According to the World Health Organization classification, the group included 15 nasal and 38 nasal-type natural killer (NK)/T-cell lymphomas, 63 blastic NK-cell lymphomas, 14 cutaneous CD30+ lymphoproliferations, 10 cases of myeloid leukemia, six cases of subcutaneous panniculitis-like T-cell lymphoma (SCPLTCL) and seven peripheral T-cell lymphomas, unspecified. RESULTS: In general, these CD56+ hematological neoplasms had a poor prognosis, with only 27% of patients alive after a median follow-up of 12 months. The median survival was 13 months. Nasal and nasal-type NK/T-cell lymphomas and CD56+ SCPLTCL had the worst prognosis, with a median survival of 5, 6 and 5 months, respectively. Only nasal-type NK/T-cell lymphomas presenting with only skin lesions had a somewhat better prognosis (median survival 27 months). In blastic NK-cell lymphomas (median survival 14 months), age 相似文献   

鼻型结外NK/T细胞淋巴瘤治疗的研究进展

结外NK/T细胞淋巴瘤,鼻型(ENKTL)是一种侵袭性非霍奇金淋巴瘤.ENKTL目前尚无标准治疗方案,局限期患者可考虑单纯放疗或放化疗联合治疗,多药联合化疗为晚期患者主要治疗手段,以蒽环类药物为主的传统化疗方案对ENKTL的疗效欠佳.近年,一些新的治疗方案在ENKTL中显示出一定的疗效,文章就ENKTL治疗的进展进行综述.     

Extranodal NK/T-cell lymphoma: diagnosis and treatment cues

Extranodal NK/T-cell lymphoma, nasal type (ENKL) is mostly endemic to East Asia. It predominantly occurs in the nasal or paranasal areas and less frequently in the skin. Most of the tumours show NK-cell, but rarely T-cell, phenotypes. The Epstein-Barr virus (EBV) genome can be usually detected in lymphoma cells. Geographic localization of ENKL matches the endemic distribution of EBV, suggesting that EBV plays an important role in lymphomagenesis. Originally, NK-cell and T-cell types were believed to present the same clinicopathologic characteristics, but recent data suggest more aggressive characteristics for the NK-cell phenotype. Although ENKL is sensitive to radiotherapy, it shows a poorer response to chemotherapeutic agents than other lymphomas due to expression of p-glycoprotein. Therefore, new therapeutic approaches must be considered. Several new clinical trials are now being conducted in East Asia.     

Clinicopathologic and genotypic study of extranodal nasal-type natural killer/T-cell lymphoma and natural killer precursor lymphoma among Koreans

BACKGROUND: This study aimed to define genotypic profile and to describe the clinicopathologic features of nasal-type natural killer (NK)/T-cell lymphoma of nasal and extranasal origin and NK precursor lymphoma. METHODS: NK/T-cell lymphomas from the upper aerodigestive tract (n = 45), skin (n = 2), gastrointestinal tract (n = 3), and soft tissue (n = 2) and NK precursor neoplasms (n = 3) were studied. Immunophenotype was analyzed by immunohistochemistry and flow cytometry. In situ hybridization with EBER 1/2 RNA probes was performed. T-Cell Receptor (TCR)-gamma gene rearrangement was analyzed by seminested polymerase chain reaction with heteroduplex analysis. Overall survival rate was correlated with clinicopathologic parameters and compared by Wilcoxon test. RESULTS: Clonal TCR-gamma gene rearrangement was detected in 3 of 31 upper aerodigestive and 1 of 2 skin tumors. When immunostained using paraffin embedded tissue, 6 upper aerodigestive lymphomas were negative for CD56 in which 4 cases lacked clonal TCR gene rearrangement. Epstein-Barr virus (EBV) mRNA was detected in 33 upper aerodigestive tumors including 26 of 29 nasal tumors (90%), and 7 of 10 extranasal tumors (70%). There was no histologic, immunophenotypic, or genotypic differences according to the lineage and EBV association in upper aerodigestive lymphomas. Among the patients with upper aerodigestive tumors, overall 1-year survival rate was 41%, and correlated well with the stage (P < 0.05) but not with the size of tumor cells, EBV status, and lineage (P > 0.05). Median survival rate of lymphomas from other sites excluding upper aerodigestive tract was not significantly different from that of upper aerodigestive lymphomas with same stage (P > 0.05). Unlike nasal-type NK/T-cell lymphomas, NK precursor lymphoma involved the bone marrow and lymph nodes at initial presentation or in the course of disease. Tumor cells were positive for TdT in all and myeloid markers in two. TCR gene rearrangement was germ line. CONCLUSIONS: Most upper aerodigestive nasal-type NK/T-cell lymphomas among Koreans are genotypically of NK derivation and few belong to T lineage. Presence or absence of EBV has no significant correlation with the histologic changes and the lineage of these lymphomas.     

Blastic natural killer (NK)-cell lymphoma: report of an unusual CD4 negative case and review of the CD4 negative neoplasms with blastic features in the literature

Blastic Natural Killer (NK)-cell lymphoma is a relatively new entity which has been recently included in the WHO classification. CD4 expression is observed in most cases of blastic NK-cell lymphomas and has been related with skin tropism. We report an unusual CD4 negative blastic NK-cell lymphoma with primary presentation in the skin, subsequent infiltration of the bone marrow and aggressive behavior. It is emphasized that extensive immunophenotyping and EBER RNA in situ hybridization are required in order to establish the diagnosis of blastic NK-cell lymphoma. We also present a review of the literature with respect to the CD4 negative NK-cell lymphomas with blastic morphological features.     

Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course.

PURPOSE: To describe and identify the clinical and pathologic features of prognostic significance for natural killer (NK) and NK-like T-cell (NK/T-cell) lymphoma presenting in the skin. PATIENTS AND METHODS: This study was a retrospective review of 30 patients with CD56+ lymphomas initially presenting with cutaneous lesions, with analysis of clinical and histopathologic parameters. RESULTS: The median survival for all patients was 15 months. Those with extracutaneous manifestations at presentation (11 patients) had a shorter median survival of 7.6 months as compared with those without extracutaneous involvement (17 patients), who had a more favorable median survival of 44.9 months (P =.0001). Age, gender, extent of cutaneous involvement, and initial response to therapy had no statistically significant effect on survival. Seven patients (24%) had detectable Epstein-Barr virus (EBV) within neoplastic cells. The patients with tumor cells that coexpress CD30 (seven patients) have not yet reached a median survival after 35 months of follow-up as compared with those with CD30- tumor cells (20 patients), who had a median survival of 9.6 months (P <.02). Routine histopathologic characteristics had no prognostic significance nor did the presence of CD3epsilon, EBV, or multidrug resistance. CONCLUSION: NK/T-cell lymphoma is an aggressive neoplasm; however, a subset with a more favorable outcome is identified in this study. The presence of extracutaneous disease at presentation is the most important clinical variable and portends a poor prognosis. The extent of initial skin involvement does not reliably predict outcome. Patients from the United States with NK/T-cell lymphoma presenting in the skin have a low incidence of demonstrable EBV in their tumor cells. Patients with coexpression of CD30 in CD56 lymphomas tend to have a more favorable outcome.     

CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified.

We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T-cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P < 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.     

FDG-PET in T-cell and NK-cell neoplasms.

BACKGROUND: A growing number of studies demonstrate the utility of (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. PATIENTS AND METHODS: We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T-cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). RESULTS: FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. CONCLUSION: T/NK-cell neoplasms incorporated in this study were generally FDG-avid except for cutaneous lesions and bone marrow involvement.     

Predicting treatment response of patients with extranodal natural killer/T-cell lymphoma based on levels of PD-L1 mRNA and soluble PD-L1

Appropriate biomarkers may help predict patient response to treatment for extranodal natural killer/T-cell lymphoma (ENKTL), a subtype of non-Hodgkin's lymphoma in China. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) have been investigated in various tumors. However, few studies have addressed expression of PD-1/PD-L1 in peripheral blood of ENKTL patients. To identify novel peripheral blood biomarkers for diagnosis and treatment of ENKTL, we retrospectively examined 89 healthy volunteers, 49 patients with ENKTL and 74 patients with diffuse large B-cell lymphoma treated at West China Hospital from September 2017 to September 2018. Both patient groups showed significantly higher expression of PD-1 and PD-L1 on CD4+ T cells, higher levels of PD-L1 mRNA in peripheral blood mononuclear cells (PBMCs) and higher levels of soluble PD-L1 in plasma than healthy volunteers (P < .05). In ENKTL patients, levels of PD-L1 mRNA and soluble PD-L1 were related to disease stage, level of lactate dehydrogenase, lymphocyte count, and copies of Epstein-Barr genome in blood. Levels of PD-L1 mRNA and soluble PD-L1 were similar between healthy volunteers and ENKTL patients who showed complete remission after treatment, and uni- and multivariate analyses identified soluble PD-L1 as a predictor of treatment response in ENKTL patients. Our results suggest that the levels of PD-L1 mRNA in PBMCs and soluble PD-L1 in plasma are useful for ENKTL staging and prediction of treatment response.     

造血干细胞移植在鼻型结外NK/T细胞淋巴瘤治疗中的地位

鼻型结外NK/T细胞淋巴瘤（ENKTL）是来源于NK细胞或T细胞的一种侵袭性淋巴瘤,预后较差.文章主要论述造血干细胞移植在该病治疗中的地位.     

T-cell and NK/T-cell lymphomas in southern Taiwan: a study of 72 cases in a single institute

In an attempt to better understand the clinicopathologic features of T- and natural killer (NK)/T-cell lymphomas in Taiwan and the distribution and relative frequency of each subtype according to the new WHO classification, the pathology file of a medical center in southern Taiwan during 1989-2002 was retrospectively searched. The results of light microscopy, immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBER), and T-cell receptor (TCR)-gamma chain gene rearrangement were correlated with clinical findings. A total of 72 cases were identified. They were peripheral T-cell lymphoma, unspecified (PTLu; n = 23, 31.9%), NK/T-cell lymphoma (n = 14, 19.4%), anaplastic large cell lymphoma (n = 13, 18.0%), angioimmunoblastic T-cell lymphoma (AITL; n = 9, 12.5%), precursor T-lymphoblastic lymphoma (n = 8, 11.1%), enteropathy-type intestinal T-cell lymphoma (n = 2, 2.8%), adult T-cell leukemia/lymphoma (n = 2, 2.8%), and subcutaneous panniculitis-like T-cell lymphoma (n = 1, 1.4%). The male to female ratio was 1.5:1. Forty patients (55.6%) had extranodal presentation. Eleven cases including 9 of 14 (64.3%) NK/T-cell lymphomas expressed CD56. All 14 NK/T-cell lymphomas are EBER-positive. Seven of nine (77.8%) AITLs expressed CD10. The overall 5-year survival rate was 10.2%. In conclusion, we have characterized a large series of T- and NK/T-cell lymphomas in southern Taiwan, where there is male predominance and poor prognosis. CD56 is a specific but not very sensitive marker while EBER is most reliable for the diagnosis of NK/T-cell lymphoma. CD10 is a useful marker to differentiate AITL from PTLu.     

结外NK/T细胞淋巴瘤治疗进展

结外NK/T细胞淋巴瘤（ENKTL）是非霍奇金淋巴瘤中较为罕见的亚型,东亚地区比西方国家多见。主要发生在鼻腔或鼻窦区,皮肤受累少见。基于ENKTL的发病机理,几乎所有患者的淋巴瘤细胞中都存在EB病毒。EBV-DNA拷贝数与肿瘤负荷密切相关,并能预测ENKTL预后。由于P-糖蛋白的表达,使细胞产生耐药性,ENKTL预后较差。近年来,新的治疗方法的研究延长了ENKTL患者的生存期。对于局限期ENKTL放疗联合化疗已取得良好的疗效。对于晚期复发难治ENKTL以L-门冬酰胺酶为基础的化疗方案显著提高治疗有效率。有文献报道,造血干细胞移植在ENKTL的治疗中取得了重要地位,而靶向药物的出现为晚期ENKTL提供了新选择。本文综述了ENKTL的治疗进展。     

High numbers of tumor-associated macrophages correlate with poor prognosis in patients with mature T- and natural killer cell lymphomas

Various studies on lymphoma microenvironment have demonstrated the prognostic impact of tumor-associated macrophages (TAMs) in patients with B-cell lymphoma. Little is known about the correlation between TAMs and treatment outcome in mature T- and natural killer (NK) cell lymphomas. We analyzed the prognostic relevance of CD68+ TAMs by immunohistochemical analysis in 64 Chinese patients with mature T- and NK-cell lymphomas. Higher number of infiltrated TAMs was significantly related to B symptoms and extranodal involvement (p?<?0.05). The TAMs content did not differ significantly between pathological subtypes. Using the mean value of TAMs per high-power field (hpf) as the cutoff point (87/hpf), 36 cases (56.2?%) were categorized as low level of TAMs content and 28 cases (43.8%) as high level. Patients with high level of TAMs content had a worse 5-year overall survival compared to those with low level (28.1 vs. 44.3?%, p?=?0.039). In multivariate analysis, TAMs content remained an independent biological variable for survival distinct from the International Prognostic Index (Cox multivariate model, p?=?0.009). High TAMs content indicated an adverse overall outcome in mature T- and NK-cell lymphomas. Our results show that expression of stromal TAMs may become a useful marker for prognosis of mature T- and NK-cell lymphomas.