Rare Natural Killer Cell Lymphoma Found During Surveillance Endoscopy

Introduction

Non-Hodgkin’s lymphoma is the sixth leading cause of cancer death in the USA and comprises 2–3% of primary neoplasms. Natural killer (NK)/T cell lymphomas are subtypes of non-Hodgkin’s lymphoma and are aggressive neoplastic disorders with frequent extranodal presentations. Clinically, most cases of aggressive NK cell lymphomas present in young males with massive hepatosplenic infiltration. The upper aerodigestive tract is the most common site of presentation.

Case Report

NK/T cell lymphomas are subtypes of non-Hodgkin’s lymphoma and are aggressive.

Case Discussion

Here we describe an unusual case of non-Hodgkin’s NK/ T cell lymphoma of colon and stomach found during surveillance upper endoscopy followed by a subsequent colonoscopy.     

鼻腔NK/T细胞淋巴瘤的临床特征和治疗现状

鼻NK／T细胞淋巴瘤属恶性淋巴瘤的一种少见的特殊类型，其诊断和治疗尚存在争议。本文综述了该病的流行病学、病因和发病机制、临床表现、分期、病理特征、诊断、治疗现状及预后，为提高认识、规范治疗提供线索。     

NK/T细胞淋巴瘤细胞凋亡和细胞增殖特征及意义

Objective:The aim was to study the features and clinical significance of cell apoptosis and proliferation of NK/T cell lymphoma.Methods:TdT-mediated dUTP nick end labeling and immunohistochemical Streptavidin-peroxidase method were used to study cell apoptosis and the expression of proliferation cell nuclear antigen in 25 NK/T cell lymphoma and 10 reactive lymphoid tissues.Results:Apoptotic index(AI) and proliferative index(PI) averaged(1.92%±0.86%) and(41.48%±5.10%) respectively in the 25 NK/T cell lymphom...     

早期鼻腔NK／T细胞淋巴瘤放疗模式的研究现状

 【摘要】　鼻腔NK／T细胞淋巴瘤属于结外非霍奇金淋巴瘤的一种少见特殊类型,目前研究已经确立了放疗在其治疗中的地位和作用,但对于具体的放疗模式,如适宜的放疗靶区、放疗剂量以及颈部预防照射等问题仍存在着较大的争议。多数研究表明扩大野放疗和较高的放疗剂量是取得较好放疗疗效的关键;局限期病例多不主张颈部预防照射,但对于病变范围广泛者仍有较大争论。     

Extranodal NK/T Cell Lymphoma,Nasal Type (ENKTL-NT): An Update on Epidemiology,Clinical Presentation,and Natural History in North American and European Cases

Purpose of Review

Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American (“Western”) cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience.

Recent Findings

We highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas.

Summary

Data on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL-NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome.

     

鼻NK／T细胞淋巴瘤相关噬血细胞综合征

 【摘要】　目的　探讨鼻NK／T细胞淋巴瘤并发噬血细胞综合征（HPS）的临床特征、治疗方法及预后。方法　对3例鼻NK／T细胞淋巴瘤并发HPS患者的临床资料进行回顾性分析。结果　3例鼻NK／T细胞淋巴瘤患者符合HPS诊断标准,初诊时具有多项淋巴瘤相关不良预后因素,1例以HPS为首发症状,2例发生HPS时处于疾病进展期,骨髓检查均发现淋巴瘤细胞浸润。并发HPS后患者病情进展迅速,最明显症状是发热、血象进行性下降、纤维蛋白原降低、血清铁蛋白升高及骨髓中出现噬血现象。给予以HLH-2004为基础的方案联合化疗后,HPS均有不同程度改善,但由于原发病无法控制,HPS很快复发,患者并发肝功能异常、凝血异常或弥散性血管内凝血,最终死亡。结论　鼻NK／T细胞淋巴瘤并发HPS时预后差,常发生在淋巴瘤进展期或终末阶段。以HLH-2004为基础的方案联合化疗有望逆转病情,延缓疾病进展,为原发病治疗创造机会。     

原发鼻腔 NK - T 细胞淋巴瘤 61 例临床疗效分析简

目的：探讨鼻腔NK—T细胞淋巴瘤各种治疗方法及影响预后的因素。方法：回顾性分析本院收治的61例NK—T细胞淋巴瘤,男性39例,女性22例,年龄31—74岁,中位年龄48岁,单纯化疗20例,单纯放疗20例,放化疗联合治疗21例。放疗采用6MV—X线或8MV—X线直线加速器外照射,照射野包括双侧鼻腔、双侧前组筛窦、患侧上颌窦,如果超腔则肿瘤靶区同时包括超腔部分。放疗剂量45—55Gy,常规分割照射2Cy／次,5次／周。化疗采用CHOP（环磷酰胺、阿霉素、长春新碱、泼尼松）方案2—4周期,如果化疗尤效或疾病进展则更换其他方案。结果：单纯放疗的患者中15例达CR,CR率为75％,单纯化疗的患者中7例达CR,CR率为35％,放化联合治疗患者中17例达CR,CR率为81％。全组患者中PR14例,5例患者因严重不良反应退出治疗。3例患者治疗无效,其中2例为单纯化疗患者,后行挽救放疗,1例达到PR。结论：鼻腔NK—T细胞淋巴瘤放疗的疗效明显优于化疗。早期患者应接受放射治疗或以放疗为主的综合治疗,晚期患者以综合治疗为主。     

Natural killer cell lymphoma in the duodenum

We present a case of duodenal non-Hodgkin lymphoma in a 71-year-old woman. Immunohistochemistry characterized the lymphoma cells as CD2(+); surface CD3(-) but cytoplasmic CD3(+); CD7(+); and CD56(+) without a rearrangement of the T-cell receptor gene. Cells had a high N/C ratio and irregular nuclear outlines and lacked azurophilic granules and these features indicated that the lymphoma cells arose from natural killer (NK) cells. She was treated with intensive chemotherapy including pirarubicin, cyclophosphamide, vincristine, and prednisolone, but died three weeks after diagnosis. CD56(+) lymphomas originate from NK or cytotoxic T cells and are designated "extranodal NK/T-cell lymphoma, nasal type" in the WHO classification. Nasal NK cell lymphoma is most common in East Asians and CD56(+) lymphomas usually occur in the nasal area. Extranasal forms such as gastrointestinal lymphomas are very rare and usually carry a poor prognosis. Extranodal NK/T-cell lymphoma, nasal type, is characterized by a broad morphologic spectrum and have variable prognosis. These lymphomas constitute an heterogeneous group, and their subclassification has not yet been established.     

Lymphome NK/T de type nasal mimant un herpès cutané

Introduction

Extranodal T/NK Cell lymphoma nasal type is a clinico-pathological entity defined by necrotic process in nasal cavity with slow evolution. We report an unusual case with clinical presentation looking like cutaneous herpes.

Observation

Ms. A.L., 46 years old, consulted for vesiculobullous??s and crusting lesions of the left cheek and area under the right eyelid. Before the suspicion of herpetic etiology, she had received antiviral treatment without improvement. Evolution was marked by infiltration of lesions and facial??s edema, cheilitis, macroglossia, hepatomegaly and impaired general condition. Histological examination was for an atypical lymphoid infiltrate in the dermis with the characteristics of extranodal T/NK cell lymphoma nasal. After check-up, the patient was classified as stage IV. She was treated by chemotherapy, but she died of septic shock due to myelosuppression.

Conclusion

Our case is original in its initial presentation looking like cutaneous herpes; by it??s quick evolution in skin and worse prognosis. The absence of reached endonasal, initial lesions and general condition conserverd, made diagnosis difficult.     

Allogeneic haematopoietic stem cell transplantation as a salvage strategy for relapsed or refractory nasal NK/T-cell lymphoma

Nasal NK/T-cell lymphoma is rare and occurs most frequently in East Asia and Latin America. It is characterized by its aggressive nature and tends to become resistant to chemotherapy and radiotherapy. Autologous haematopoietic stem cell transplantation (auto-HSCT) is often associated with a high relapse rate for the active or disseminated disease. There are limited data about allogeneic haematopoietic stem cell transplantation (allo-HSCT) for relapsed or refractory nasal NK/T-cell lymphoma. In our study, two patients with nasal NK/T-cell lymphoma were successfully treated with allo-HSCT. The first patient was a 31-year-old woman who relapsed after auto-HSCT. Subsequently, HLA-matched allo-HSCT was considered as a salvage treatment. Modified BU/CY conditioning regimens included BU/CY/Vm26/Ara-C. Donor lymphocyte infusion was used to reduce the risk of relapse. After allo-HSCT, the tumor in her nasal cavity gradually disappeared. She has been in continuous complete remission (CR) for 3 years. The second patient was a 26-year-old woman diagnosed with stage IIIB advanced nasal NK/T-cell lymphoma who was resistant to combination radiochemotherapy. She underwent HLA-matched allo-HSCT as a salvage treatment. Modified BU/CY conditioning regimens included BU/CY/MeCCNu/Ara-C. She has been in continuous CR for five years. The stem cell source was peripheral blood for both patients, and there was no severe graft-versus-host disease in either patient. Our clinical experience suggests that allo-HSCT with a modified conditioning regimen is a promising treatment for patients with relapsed or refractory nasal NK/T-cell lymphoma.     

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.     

A systematic review of the accuracy and utility of peritoneal cytology in patients with gastric cancer

Background  

Although malignant diseases are known to be associated with immune suppression, the detailed mechanisms involved are still unknown. NKG2D is an activating cell surface receptor expressed by natural killer (NK) cells and CD8+ T cells, and the engagement of NKG2D is extremely important for NK cell activation. Although decreased NKG2D expression on NK cells is closely related to immune evasion by some cancers, the immunopathological importance of this phenomenon in gastric cancer patients remains unclear.     

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer

Purpose

Administration of 5 million alloreactive natural killer (NK) cells after low-dose chemo-irradiation cured mice of 4T1 breast cancer, supposedly dose dependent. We now explored the efficacy of bone marrow as alternative in vivo source of NK cells for anti-breast cancer treatment, as methods for in vitro clinical scale NK cell expansion are still in developmental phases.

Methods

Progression-free survival (PFS) after treatment with different doses of spleen-derived alloreactive NK cells to 4T1-bearing Balb/c mice was measured to determine a dose–response relation. The potential of bone marrow as source of alloreactive NK cells was explored using MHC-mismatched mice as recipients of 4T1. Chemo-irradiation consisted of 2× 2 Gy total body irradiation and 200 mg/kg cyclophosphamide. Antibody-mediated in vivo NK cell depletion was applied to demonstrate the NK cell’s role.

Results

Administration of 2.5 instead of 5 million alloreactive NK cells significantly reduced PFS, evidencing dose responsiveness. Compared to MHC-matched receivers of subcutaneous 4T1, fewer MHC-mismatched mice developed tumors, which was due to NK cell alloreactivity because in vivo NK cell depletion facilitated tumor growth. Application of low-dose chemo-irradiation increased plasma levels of NK cell-activating cytokines, NK cell activity and enhanced NK cell-dependent elimination of subcutaneous tumors. Intravenously injected 4T1 was eliminated by alloreactive NK cells in MHC-mismatched recipients without the need for chemo-irradiation.

Conclusions

Bone marrow is a suitable source of sufficient alloreactive NK cells for the cure of 4T1 breast cancer. These results prompt clinical exploration of bone marrow transplantation from NK-alloreactive MHC-mismatched donors in patients with metastasized breast cancer.

     

鼻型NK/T细胞淋巴瘤26例临床病理分析

目的：研究鼻型NK/T细胞淋巴瘤（ENKL）的免疫表型、病理特点、临床特点。方法：回顾性分析26例ENKL的临床表现、病理组织学特点,采用免疫组化SP法检测LCA、CD3、UCHL1、CD20、CD79a、CD56、TIA-1、Granzyme B、perforin,原位杂交方法检测EBER在ENKL中的表达情况。结果：NK/T细胞淋巴瘤发生在鼻腔占80.77%（21/26）,伴坏死、溃疡、鼻出血者100%（26/26）,肿瘤细胞嗜血管现象占46.15%（12/26）,伴＂鳞状细胞癌样反应＂占20.08%（6/26）。CD3、CD56、TIA-1、Granzyme B、perforin及EBER阳性表达率达100%。结论：临床及病理形态复杂多样性是NK/T细胞淋巴瘤的特点。病理诊断中须注意与炎症或高分化鳞状细胞癌鉴别。ENKL根据典型的临床表现、病理形态学改变、免疫表型特点及EBER原位杂交阳性能准确诊断。     

鼻型NK/T细胞淋巴瘤26例临床病理分析

目的:研究鼻型NK/T细胞淋巴瘤(ENKL)的免疫表型、病理特点、临床特点。方法:回顾性分析26例ENKL的临床表现、病理组织学特点,采用免疫组化SP法检测LCA、CD3、UCHL1、CD20、CD79a、CD56、TIA-1、Granzyme B、perforin,原位杂交方法检测EBER在ENKL中的表达情况。结果:NK/T细胞淋巴瘤发生在鼻腔占80.77%(21/26),伴坏死、溃疡、鼻出血者100%(26/26),肿瘤细胞嗜血管现象占46.15%(12/26),伴"鳞状细胞癌样反应"占20.08%(6/26)。CD3、CD56、TIA-1、Granzyme B、perforin及EBER阳性表达率达100%。结论:临床及病理形态复杂多样性是NK/T细胞淋巴瘤的特点。病理诊断中须注意与炎症或高分化鳞状细胞癌鉴别。ENKL根据典型的临床表现、病理形态学改变、免疫表型特点及EBER原位杂交阳性能准确诊断。     

Cytologic evaluation of lymphadenopathy associated with mycosis fungoides and Sezary syndrome

BACKGROUND.

The most common presenting site of extracutaneous disease in mycosis fungoides and Sezary syndrome is the peripheral lymph node. Although fine‐needle aspiration biopsy has been shown to be a valuable diagnostic technique in evaluating lymphadenopathy, its utility in patients with cutaneous T‐cell lymphoma has not been extensively studied. With fine‐needle aspiration biopsy, material can be collected for ancillary diagnostic studies and for morphologic evaluation.

METHODS.

The authors report a series of 11 fine‐needle aspiration biopsy specimens from 10 mycosis fungoides and Sezary syndrome patients. Flow cytometric immunophenotyping and T‐cell receptor gamma chain polymerase chain reaction were performed on fine‐needle aspiration biopsy material and correlated with cytologic findings.

RESULTS.

Seven of 10 patients had lymph node involvement by cutaneous T‐cell lymphoma, with 3 cases exhibiting large‐cell transformation and 4 cases exhibiting a small‐cell pattern. Flow cytometric immunophenotyping identified an abnormal T‐cell population in 6 cases. A clonal T‐cell rearrangement by T‐cell receptor gamma chain polymerase chain reaction (TCR‐γ PCR) was identified in 1case in which insufficient events were present for evaluation by flow cytometry and in 1 case in which flow cytometry was not diagnostic of T‐cell lymphoma. Two cases showed involvement by classic Hodgkin lymphoma diagnosed by immunohistochemistry on cell block material.

CONCLUSIONS.

Fine‐needle aspiration biopsy in conjunction with immunophenotyping and T‐cell receptor gamma chain polymerase chain reaction is significantly useful in evaluation of lymphadenopathy in patients with mycosis fungoides and Sezary syndrome, especially for triaging lymph nodes that would otherwise not be sampled or for evaluating multiple lymph nodes. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Pathogenesis of Enteropathy-Associated T Cell Lymphoma

Purpose of Review

To provide an update on the pathogenesis of enteropathy-associated T cell lymphoma (EATL) and its relationship with refractory celiac disease (RCD), in light of current knowledge of immune, genetic, and environmental factors that promote neoplastic transformation of intraepithelial lymphocytes (IELs).

Recent Findings

EATL frequently evolves from RCD type II (RCD II) but can occur “de novo” in individuals with celiac disease. Recurrent activating mutations in members of the JAK/STAT pathway have been recently described in EATL and RCD II, which suggests deregulation of cytokine signaling to be an early event in lymphomagenesis. Intraepithelial T cells are presumed to be the cell of origin of EATL (and RCD II). Recent in vitro molecular and phenotypic analyses and in vivo murine studies, however, suggest an origin of RCD II from innate IELs (NK/T cell precursors), which could also be the cell of origin of RCD II-derived EATL.

Summary

The immune microenvironment of the small intestinal mucosa in celiac disease fosters the development of EATL, often in a multistep pathway.

     

Natural Killer/T-cell Neoplasms: Analysis of Incidence,Patient Characteristics,and Survival Outcomes in the United States

Background

Limited data are available regarding the incidence, survival patterns, and long-term outcomes of natural killer (NK)/T-cell neoplasms in the United States.

A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome

BackgroundThe prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome.Patients and methodsThis study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other.ResultsMedian follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients.ConclusionAllogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.