Agranular CD4+CD56+ blastic natural killer leukemia/lymphoma

Blastic natural killer cell leukemia/lymphoma (blastic NKL/L) is characterized by blastic morphology and a distinctive immunophenotype combining blastic features and cytologically resembling acute myeloid or lymphoid leukemia. The clinical, pathologic, and cytogenetic features of blastic NKL/L have not yet been systematically identified. We report herein a case of blastic NKL/L with skin lesion, adenopathy, and systemic lymphoadenopathy. The identified tumor cells were positive for CD4 and CD56, and negative for T-cell, B-cell, and myeloid markers. T-cell receptor beta, gamma, delta, and immunoglobulin heavy chain genes in the bone marrow cells showed germ-line configurations. Southern blot analysis with a terminal probe did not reveal any Epstein-Barr virus infection. Although patients diagnosed as blastic NKL/L have generally shown chemotherapy resistance and poor prognosis, our patient was treated with a combined chemotherapy, which is also used for acute lymphoblastic leukemia, and has maintained complete remission (CR) for more than 13 months. In addition to clinical investigations, we thoroughly analyzed his karyotype by using a combination of G-banding and a new technique, spectral karyotyping. The karyotype was described as 45, XY, der(1)t(1;20)(p32;q11.2), der(6) (1pter-->1p32:: 6p21.1-->6q13:: 7q11.2-->7qter), der(7) t(7;20)(q11.2;q11.2), t(13;14)(q14;q32), der(13)t(6;13) (p21.1; q14), -20.     

An unusual case of CD4+ CD7+ CD56+ acute leukemia with overlapping features of type 2 dendritic cell (DC2) and myeloid/NK cell precursor acute leukemia

Type 2 dendritic cell (DC2) acute leukemia has been recently described. We report here an unusual case of a 17-yr-old adolescent with overlapping features of DC2 and myeloid/NK cell precursor acute leukemia as defined by Suzuki et al. The patient presented with lymphadenopathy and hepatosplenomegaly without extranodal manifestations in skin or elsewhere. The morphologic, cytochemical and immunophenotypic features were compatible with those described in DC2 acute leukemia, with co-expression of CD4, CD56 and CD123 antigens. The novel markers BDCA-4 and BDCA-2 considered specific for DC2s were co-expressed. However, bright CD7 positivity along with a dim expression of CD33 (57%) and CD117 (27%) were also noted. Additionally, there was bright expression of NG2 monoclonal antibody 7.1, a frequent finding in myeloid/NK cell precursor acute leukemia. The interpretation of the immunophenotypic profile leads to the hypothesis on the existence of borderline cases between DC2 and myeloid/NK cell precursor acute leukemia. Still, other hypotheses can not be overlooked, such as the possibility for a kind of variant monoblastic leukemia or of another rare entity of acute unclassified leukemia.     

CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia treated with idarubicin and cytosine arabinoside

We describe a 69-year-old Japanese male with acute leukemia with a CD7+ and CD56+ immunophenotype presenting with multiple lymphadenopathy. He was treated with idarubicin and cytosine arabinoside. Although the leukemia showed partial response, the patient did not achieve complete remission. He died of sepsis due to severe neutropenia after the third course of chemotherapy. His autopsy revealed blast infiltration in the lymph nodes, liver, spleen and vertebral bone marrow. Recently, CD7+ and CD56+ myeloid/natural killer precursor acute leukemia has been associated with a poor prognosis. Our case illustrates that myeloid/natural killer cell precursor acute leukemia shows some response to intensive chemotherapy for acute myeloid leukemia, but such therapy is insufficient to effect a cure. To overcome the resistance of this disease to chemotherapy, further studies should explore other treatment strategies.     

CD2+, CD3-, CD56/NCAM+ malignant lymphoma with TCRβ gene rearrangement: A case report

A case of CD56/NCAM+ malignant lymphoma is reported. Only a rare malignant lymphoma cell showed azurophilic granules in the cytoplasm of Giesma-stained preparations, while electron microscopic examination revealed occasional cytoplasmic granules with paracrystalline inclusions. The most common phenotype seen in NK lymphomas, CD2+, CD3-, CD56+, CD16-, CD57-, was present in the case. Cases with this phenotype have been interpreted to represent either true NK lymphoma or T-cell lymphoma with NK expression. Genotyping, where performed, has shown TCR germline configuration. Our case showed TCRβ rearrangement indicating that the above phenotype can be associated with a peripheral T-cell lymphoma.     

Primary CD56+ T/NK cell lymphoma of the colon

Primary T/natural killer (NK) cell lymphoma of the colon is extremely rare. Despite the advances in histological and immunophenotypic studies, the diagnosis of primary T/NK cell lymphoma of the colon can be delayed because the early symptoms and colonoscopic findings may be very similar to those of inflammatory bowel diseases such an Crohn's colitis, and most physicians have little available information on this group of neoplasms. Moreover, florid nonspecific inflammatory infiltrates would not allow characterization of the tumor cells in such an inflammatory background. Herein, we describe a patient who initially presented with features that were clinically and colonoscopically similar to Crohn's colitis. Three months later, he had cecal bleeding and perforation, and primary T/NK cell lymphoma of the colon was diagnosed through immunophenotypic and genotypic studies of surgical specimens. Received: March 5, 2001 / Accepted: August 24, 2001 Reprint requests to: D.K. Lee     

CD4+ and CD56+ acute monoblastic leukemia.

We report here a patient with acute monoblastic leukemia whose leukemia cells had CD4 (T4) and CD56 (NKH-1) antigens, in addition to CD36 (OKM5) antigen. The leukemia cells did not have NK or ADCC activities. They showed no rearrangements of immunoglobulin heavy (IgH) chain and T cell receptor (TCR)-beta chain genes, indicating that the leukemia cells were nonlymphoid. The presence of this case suggests that leukemia cells could be originated from monocytes with NK-associated antigen without IgH or TCR rearrangements.     

Chemotherapy-resistant CD7-positive stem cell lymphoma presenting with intra-abdominal mass

We report a case of CD7+ stem cell lymphoma. A 47-year-old man presented with general malaise and lumbago in April 1997. The patient exhibited swollen left cervical lymph-nodes and an intra-abdominal bulky mass. He was referred to us because lymph-node biopsy specimens indicated a diagnosis of diffuse type malignant lymphoma. An abdominal CT scan disclosed large retroperitoneal, para-aortic, and mesenteric root masses. Bone marrow involvement was shown by bone marrow biopsy specimens, though no circulating blasts were detected at presentation. The patient was treated with high-dose CHOP therapy without any benefit. Though ESHAP therapy was performed as salvage chemotherapy, the abdominal masses did not shrink at all. The patient died of tumor progression in November 1997. In the terminal stage, the lymphoma cells emerged in the peripheral blood and thus became available for analysis. The cells expressed CD5, 7, 34, 38, 71, but were negative for CD1, 2, 3, 4, 8, 10, 13, 14, 16, 19, 20, 21, 25, HLA-DR, and EMA. An immunoglobulin heavy chain gene rearrangement band was detected by Southern blot analysis. However, no T cell receptor lambda or beta chain gene rearrangement bands were detected.     

CD7+CD56+双阳性急性髓系白血病临床生物学特征

目的：探讨CD7^＋CD56^＋急性髓系白血病（AML）的临床生物学意义。方法：对25例初治CD7^＋CD56^＋AML患者进行细胞学形态、免疫表型、多药耐药P糖蛋白（PgP）检测，临床观察、并常规采用HAE方案诱导治疗，判定疗效，并随机选择66例CD7^-CD56^-AML患者进行对照。结果：CD7^＋CD56^＋AML阳性率4．08％（25／612）。CD7^＋CD56^＋AML在FAB分型中以M0、M1、M5、M7多见。与CD7^-CD56^-AML组比较CD7^＋CD56^＋AML具有高血红蛋白含量（89．29：75．62g／L，P〈0．05），高表达PgP（78．26％：34．85％，P〈0．01）和CD34表达（72．00％：45．45％，P〈0．05）等特征；此外，CD7^＋CD56^＋AML患者中枢神经系统浸润现象明显（36．00％：3．27％，P〈0．01），CD7CD56共表达与年龄、性别、白细胞计数、血小板计数、及外周血幼稚细胞数无关，也不影响完全缓解率和无病生存时间（均P〉0．05）。结论：CD7^＋CD56^＋AML具有独特的临床生物学特征，较少贫血，高表达PgP和CD34，常伴有中枢神经系统浸润。     

Coexistence of two distinct cell populations (CD56(+)TcRgammadelta(+) and CD56(+)TcRgammadelta(-)) in a case of aggressive CD56(+) lymphoma/leukemia

BACKGROUND AND OBJECTIVE: Large granular lymphocytes derive from two major lineages: one expressing the CD3 surface antigen (T-lymphocytes), and the other lacking this marker (NK-cells). Although developmental overlaps between natural killer cells and T-cells have been described, malignancies derived from these two cell types are considered as distinct lymphoid disorders. DESIGN AND METHODS: We report the case of a 30-year old man affected by a lymphoma/leukemia syndrome presenting with hepatosplenic lymphoma which rapidly transformed into aggressive NK-leukemia. Extensive flow cytometry studies and molecular analysis were repeated during the course of the disease, and showed an unexpected changing pattern. RESULTS: At diagnosis, flow cytometry analysis showed the co-existence of two cell populations, one CD56(+), CD3(+), TcRgd(+), and the other CD56(+), CD3(-) and TcRgd(-). Molecular analysis showed that the TcR genes had the same clonally rearranged pattern involving b, g and d genes in both populations. At disease relapse and during the terminal refractory phase, only CD3(-) cells were present. INTERPRETATION AND CONCLUSIONS: This is an unusual case of CD56(+) aggressive lymphoma/leukemia characterized by the clonal expansion of two phenotypically different cell populations, variably balanced during the course of the disease. The presence of the same TcR genomic rearrangement suggests the origin from a common progenitor able to differentiate along both T- and NK-pathways.     

Prognostic significance of CD7+CD56+ phenotype and chromosome 5 abnormalities for acute myeloid leukemia M0

Myeloid/natural killer (NK) cell precursor acute leukemia is an entity of acute leukemia characterized by poor prognosis and a CD7+CD56+ myeloid antigen+ phenotype without light-microscopic myeloperoxidase reactivity. This disease shares several clinical characteristics with acute myeloid leukemia (AML) M0. To clarify the relationship between these 2 leukemias, we analyzed 105 cases of AML M0. Among them, 17 were CD7+ and CD56+, 77 were negative for either antigen, and 11 could not be determined. CD7+CD56+ AML M0 showed onset at significantly lower patient age (median 46 versus 63 years, P = .004). The disease localization and the hematological manifestations were significantly different: CD7+CD56+ AML showed more frequent extramedullary involvement, fewer circulating leukemic blasts, less anemia, and less thrombocytopenia than did AML M0. The cytogenetic aberrations were also unique, because no 5q abnormalities were found in CD7+CD56+ M0. The prognosis of CD7+CD56+ M0 was poor in patients younger than 46 years (P = .03). Multivariate analysis showed that the CD7+CD56+ phenotype was a significant prognostic factor for AML M0, as well as age, circulating blast percentage, and chromosome 5 abnormalities These findings suggest that AML M0 consists of heterogeneous subgroups to be managed separately, and CD7+CD56+ M0 constitutes a distinct subtype of AML M0.     

HC56基因转染对淋巴瘤或白血病细胞株活力的作用

目的：探讨外源HC56基因产物对B淋巴瘤细胞株Raji和髓系白血病细胞株K562细胞活力的作用。方法：应用脂质体介导的基因转染方法，将外源基因HC56分别导入Raji和K562细胞，用苔盼兰拒染试验，观察外源基因的瞬时表达对细胞活力的作用。结果：Raji和K562细胞转染HC56基因后，与转染PBK／CMV空载体的实验对照组比较，细胞的活力明显受到抑制(P＜0.05)。结论：外源HC56基因产物可明显抑制淋巴瘤或白血病细胞株的活力。     

The CD3- 16+ 56+ NK cell count independently predicts autologous blood stem cell mobilization

Better predictive factors for autologous blood stem cell mobilization (BSCM) are needed. The purpose of this study was to determine if an independent association exists between lymphocyte or NK cell counts and BSCM. Data were analyzed on 141 consecutive patients aged 19-69 years (median 45) who received combined chemotherapy plus G-CSF for BSCM, and who had measurements of immune cells prior to BSCM. Of the 141 patients, 41% had breast cancer, 14% Hodgkin's disease, 34% non-Hodgkin's lymphoma, and 11% other diagnoses. BSCM involved dose-intensive cyclophosphamide, etoposide, cisplatin (DICEP) plus G-CSF 300 microg (<70 kg) or 480 microg (>70 kg) for 45% of patients, while the remaining 55% received other chemotherapy plus similar doses of G-CSF. Only a single apheresis was performed for 94% of patients. The following factors were analyzed for predictors of BSCM: age, gender, prior chemotherapy, prior radiotherapy, diagnosis, disease status, marrow involvement, mobilization regimen, Hb, WBC, platelet count, B cell, T cell, and NK cell counts. The peripheral blood CD34+ counts on the first day of apheresis (PBCD34) were 6-1783 x 10(6)/l (median 150). The PBCD34 count correlated strongly with the number of CD34+ cells collected/l blood apheresed and with the number of CD34+ cells collected/kg. By multivariate analysis using continuous variables, relapsed status (P = 0.0003), not using DICEP mobilization (P = 0.0001), female gender (P = 0.0057), low platelet count (P = 0.051), and low CD3- 16+ 56+ count (P = 0.0158) were associated with low PBCD34 counts. Using categorical variables, the only factors that independently predicted a PBCD34 count <150 x 10(6)/l were: >1 prior chemotherapy regimen (odds ratio = 5.12, P = 0.0003), not using DICEP mobilization (odds ratio = 4.94, P = 0.0001), and CD3- 16+ 56+ count <125 x 10(6)/l (odds ratio= 2.58, P = 0.0157). In conclusion, the CD3- 16+ 56+ count may be a useful additional predictor of BSCM and warrants further study.     

Primary CD56+ NK/T-cell lymphoma of the rectum accompanied with refractory ulcerative colitis

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.     

Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation

Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7-34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops.     

CD5 positive B cell leukemic lymphoma associated with BCL6 rearrangement

A 59-year-old man was admitted in December 1995 because of general fatigue without lymphadenopathy. Increased abnormal lymphocytes (70%) were observed in peripheral blood. Bone marrow aspiration was a dry tap. Biopsy specimens revealed hypercellularity with infiltration of abnormal lymphocytes. Surface marker analysis of tumor cells was positive for CD5, CD19, CD20, HLA -DR, kappa, and sIgM and negative for CD10. Cytogenetic analysis disclosed a complex abnormal karyotype including t(3;22) and rearrangement of the BCL6 gene. The patient was given a diagnosis of CD5 positive B-cell lymphoma, but died in January 1997 despite repeated chemotherapy. This case was unique because BCL6 rearrangement has been reported in various types of B-cell lymphoma but rarely associated with leukemic types without lymphadenopathy.     

CD5和B细胞淋巴瘤/白血病蛋白-2对老年弥漫大B细胞淋巴瘤患者预后的影响

目的探讨CD5和B细胞淋巴瘤/白血病蛋白-2(Bcl-2)对老年弥漫大B细胞淋巴瘤(DLBCL)患者预后的影响。方法回顾性分析2007年1月至2013年12月空军军医大学西京医院血液内科被诊断为DLBCL、年龄60岁的患者35例,对入选患者进行2年随访。收集入选患者临床病理资料及治疗预后信息,免疫组织化学检测CD5、Bcl-2表达,并分别根据CD5、Bcl-2是否为阳性表达(以肿瘤细胞染色阳性30%)、中枢神经累及与否以及肿瘤临床分期对患者进行分组,并比较各组患者间生存情况。采用SPSS 22.0统计软件对数进行分析。组间比较采用Fisher精确检验法。应用Kaplan-Meier法绘制生存曲线,Log-Rank法进行曲线间单因素分析;多因素分析采用Cox回归模型。结果研究最终有3例失访,失访率8.6%。入选患者CD5阳性率为21.9%(7/32),Bcl-2阳性率为46.9%(15/32),CD5及Bcl-2共阳性15.6%(5/32)。21.9%(7/32)患者出现中枢累及。10例患者为肿瘤临床Ⅲ期,22例为临床Ⅳ期。患者中位总生存期(OS)为24个月,中位无进展生存期(PFS)为18个月。1年生存率为96.9%(31/32),2年生存率为71.9%(23/32)。单因素分析显示,与CD5-和Bcl-2~-患者比较,CD5~+和Bcl-2~+患者OS和PFS均较低(P0.05);临床Ⅲ期及Ⅳ期患者PFS(P=0.055)及OS(P=0.076)比较差异均无统计学意义;与无中枢累及患者相比,中枢累及患者OS和PFS较低(均为P=0.004)。另外,CD5~+患者中枢累及率显著大于CD5-患者(57.1%vs 12.0%;P=0.026),Bcl-2~+患者中枢累及率显著大于Bcl-2~-患者(40.0%vs 5.9%;P=0.033),差异均有统计学意义。多因素Cox分析显示,CD5阳性为影响DLBCL患者OS的独立危险因素(OR=11.205,95%CI1.717~73.112;P=0.012)。结论 CD5阳性表达可作为影响老年DLBCL患者预后不良的独立危险因素,对预后判断和未来治疗策略的选择具有重要的临床价值。     

The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations

Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56(+)CD16(+)KIR(+) NK cells and a reciprocal increase in CD56(+)CD16(-)KIR(-) cells. These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca(2+) oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-gamma-producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56(+)KIR(-) NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.