Blastic Natural Killer Cell Research Articles

Challenge in diagnosis of CD56+ lymphoproliferative disorders: two cases of CD56+CD33+ lymphoma/leukemia.

Two cases of CD56+CD33+ leukemia/lymphoma are reported. The patient in case 1 presented with skin rash, diffuse lymphadenopathy, and hepatosplenomegaly. Blasts with monocytoid and lymphoid features were present in the peripheral blood. The tumor cells expressed HLA-DR, CD4, CD33, CD38, and CD56. Cytogenetic analysis revealed del(2)(p13),del(9)(q22),add(6)(q25),add(12)(p12),-13,-18, and -20. The clinicopathologic features were similar to those of blastic natural killer cell leukemia/lymphoma or type 2 dentritic cell leukemia. The patient in case 2 presented with generalized weakness and skin erythema not responding to antibiotics. Circulating blasts with monocytoid features were seen in the peripheral blood. The tumor cells expressed CD7, CD13, CD33, CD38, and CD56, and cytogenetic analysis revealed -5,add(7)(p22),-8, del(10)(p11.2),-12,der(13; 14)(p10;p10),+14,-16,-18,-19, and del(20)(q13.1). The clinicopathologic features were consistent with a myeloid/ natural killer cell precursor acute leukemia. Both disorders are aggressive hematopoietic malignancies that have similar clinical presentation and morphology but differ in immunophenotype and cytogenetic features.

Cutaneous T-Cell Lymphoma: Epidemiology, Etiology, and Classification

The term cutaneous T-cell lymphoma (CTCL) describes a heterogeneous group of neoplasms of skin-homing T-cells that vary considerably in clinical presentation, histologic appearance, immunophenotype, and prognosis. CTCL represent approximately 75–80% of all primary cutaneous lymphomas, whereas primary cutaneous B cell lymphomas account for approximately 20 – 25%. For many years mycosis fungoides and Sézary's syndrome were the only known types of CTCL. In the last decade, based on a combination of clinical, histological, and immunophenotypical criteria, new types of CTCL have been defined and new classifications for this group of primary cutaneous lymphomas have been formulated. In this overview, characteristic features of the different types of CTCL recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas and the World Health Organization (WHO) classification will be reviewed. Key conclusions from this brief overview are: (1) that the term CTCL does not refer to a single disease entity, but to a group of diseases with different clinical behaviors, therapeutic requirements, and prognoses; (2) that diagnosis and classification should always be based on a combination of clinical, histologic, and immunologic criteria; and (3) that the WHO and EORTC classification schemes are broadly equivalent for almost 90% of CTCL patients. Key research priorities are to develop effective therapies for peripheral T-cell lymphoma, extranodal NK (natural killer) T-cell lymphoma and so-called blastic NK cell lymphoma, and to determine molecular profiles for all forms of CTCL.

Non-B, non-T neoplasms with lymphoblast morphology: further clarification and classification.

We studied the morphologic, immunohistochemical, and clinical characteristics of 158 cases of lymphoblastic lymphoma. Based on immunophenotyping and cell lineage, cases were classified into B-cell type (CD20,CD19 or CD79a+, n = 53), T-cell type (surface CD3+, n = 84), and non-B, non-T type (B cell marker- and surface CD3-, n = 21). The latter group was further divided based on immunohistochemistry into: 1) CD7+ stem cell lymphoma (CD7+SCL) [CD4-, CD7+, CD33+/-, CD56-], 2) blastic natural killer cell lymphoma (B-NKL) [CD4-, CD7+/-, CD33-, CD56+, CD123-], 3) myeloid/NK precursor cell leukemia (M/NKL) [CD4-, CD7+, CD33+, CD56+], and 4) CD4+CD56+ hematodermic malignancy (CD4+CD56+) type [CD4+, CD7+/-, CD33-, CD56+, CD123+]. The CD7+SCL and M/NKL types frequently exhibited bone marrow invasion and mediastinal masses. All CD4+CD56+ types were associated with skin lesions. B-NKL type is included into Blastic NK lymphoma in new World Health Organization classification with CD4+CD56+ type. But the cases of B-NKL were more reminiscent of CD7+SCL or M/NKL type than the CD4+CD56+ type, both clinically and histologically. We propose that blastic NK lymphoma, a disease entity in the new WHO classification, should be divided into two types based on phenotypes and clinical features. The non-B, non-T lymphomas exhibited poorer prognoses, similar to that of B-cell lymphomas, than T-cell type tumors (P = 0.009). Among the 21 tumors, the prognosis of the four subtypes did not differ significantly; however, cases receiving aggressive chemotherapy and stem cell transplantation had a more favorable prognosis than those receiving only traditional chemotherapy and radiation therapy (P = 0.0089).

Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement.

Natural killer and natural killer-like T cell lymphomas represent a rare type of non-Hodgkin's lymphoma originally described to involve the upper aerodigestive tract. This malignancy has been increasingly observed in other extranodal sites, particularly in the skin. Patients with cutaneous natural killer cell lymphoma generally have a poor prognosis; however, the etiology and the underlying molecular pathogenesis remain unclear. This study aimed to investigate comprehensively genomic changes in blastic natural killer and extranodal natural killer-like T cell lymphoma with cutaneous involvement. Comparative genomic hybridization showed chromosome imbalances in six of eight cases studied (75%). The mean number of chromosome imbalances per sample was 2.18+/-1.63 with similar number of gains (1.18+/-1.17) and losses (1.00+/-1.34). The most frequent DNA copy number changes observed were losses of 9/9p (83%), followed by loss of 13q and gain of 7 (67%). Similar patterns of chromosome imbalances were observed in both blastic natural killer and cutaneous natural killer-like T cell lymphomas. Loss of the RB1 gene at 13q14.2 was detected in one blastic natural killer cell lymphoma with 13q loss using a gene dosage assay, and in one cutaneous natural killer-like T cell lymphoma without 13q loss using fluorescent in situ hybridization. Genomic microarray analysis identified oncogene copy number gains of PAK1 and JUNB in three of four cases studied, and gains of RAF1, CTSB, FGFR1, and BCR in two cases. Real-time polymerase chain reaction detected amplification of CTSB and RAF1 in four of five cases analyzed, JUNB and MYCN in three cases, and REL and YES1 in two cases, respectively. In conjunction with this study, an extensive literature search for the published G-banded karyotypes of four subsets of natural killer cell lymphomas was conducted, which showed a nonrandom pattern of multiple chromosome aberrations. These results reveal consistent genetic alterations in cutaneous natural killer cell lymphomas, and provide a basis for further investigation of molecular pathogenesis in this malignancy.

Variable manifestation in natural killer cell leukaemia.

Natural killer (NK) cell leukaemias are a relatively rare group of haematological disorders, now entitled in the T/NK lymphoproliferative disorders in the new WHO classification. Recent studies have clarified their biological and clinical manifestation gradually. However, some cases with NK malignancies still remain difficult to diagnose and differentiate into their subtypes in the absence of a distinct diagnostic hallmark, especially at initial presentation. We describe herein five patients with NK leukaemias with respect to the clinical, cytological, immunological and cytogenetic characteristics, varied among each case. Cytologically, two aggressive NK cell leukaemia/lymphoma (ANKL/L) cases were a morphologically hypogranular variant form. Clinically, one with ANKL/L was presented as haemophagocytic syndrome without leukaemic infiltration. Systemic chemotherapy resulted in complete remission in one ANKL/L and two blastic NK cell leukaemia/lymphoma (BNKL/L) patients; however, a good long-term outcome was achieved in only one CD4-positive BNKL/L patient with allogenic bone marrow transplantation. Cytogenetic analysis revealed that recurrent chromosomal aberration was rare; however, two had aberrations at 10p11 and 11q13. From these findings, we conclude that comprehensive individual studies should be carried out in these patients to obtain a correct diagnosis and to design an optimal therapeutic approach.

A Case of Blastic Natural Killer Cell Lymphoma with Rapidly Progressive Multi-Organ Involvement

Wir berichten den Fall eines 72 Jahre alten Mannes mit einem blastischen NK-Zell-Lymphom mit initialem Befall der Haut und der axillären Lymphknoten. Die Behandlung erfolgte zunächst mit Cyclophosphamid, Doxorubicin, Vincristin und Prednison (CHOP). Es konnte lediglich ein partielles Ansprechen für 2 Monate erreicht werden. Das erste Rezidiv präsentierte sich mit einer Splenomegalie, einer leukämischen Generalisation und einem multifokalen Hautbefall. Unter der Behandlung mit Dexamethason und Cyclophosphamid trat eine spontane Milzruptur und ein Hämoperitoneum auf Nach einer Notfallsplenektomie kam es zur spontanen Rückbildung einer zuvor bestehenden Thrombozytopenie. In Anlehnung an ein Standard-Therapieprotokoll für die akute lymphatische Leukämie (ALL) wurde die Behandlung wieder aufgenommen (Standarddosis - Cytosinarabinosid, Cyclophosphamid und Steroide). Ein therapeutischer Effekt wurde nicht dokumentiert. Der Einsatz von Dexamethason, Carmustin, Etoposid, Doxorubicin und Melphalan (DexaBEAM) führte zu einer sechswöchigen Remission. Ein meningealer Rückfall wurde mit hochdosiertem Methotrexat behandelt. Es konnte eine Blasten-Clearance des zerebrospinalen Liquors und eine partielle Remission erreicht werden. Schließlich verstarb der Patient unter dem Bild profuser Blutungen aus dem oberen Aerodigestivtrakt neun Monate nach der Erstdiagnose. NK-Zell-Lymphome sind aggressive lymphoproliferative Erkrankungen mit besonderer Neigung zu einem extranodalen Befall an verschiedenen Stellen des Körpers. Bislang konnte keine Standardtherapie definiert werden. Aus diesem Grunde sollte frühzeitig während der Erkrankung der Einsatz auch experimenteller Therapieverfahren erwogen werden.

Blastic natural killer cell and extranodal natural killer cell-like T-cell lymphoma presenting in the skin: report of six cases from the UK.

Some lymphomas express natural killer (NK)-cell markers such as the neural cell adhesion molecule, which is recognized by the CD56 antibody. These lymphomas may present in the skin, but do not represent a homogeneous group. The new World Health Organization classification of lymphoma/leukaemia recognizes several types of NK/T-cell neoplasm, including blastic NK-cell lymphoma, which characteristically presents with cutaneous lesions. To describe the clinical, pathological and molecular features in six cases of CD56+ lymphoma with cutaneous presentation. The clinical, histopathological and immunophenotypic features of six patients were reviewed. In addition, in situ hybridization (ISH) to identify Epstein-Barr virus (EBV) mRNA, and polymerase chain reaction analysis to identify the presence of a clonal population of T cells or B cells were performed on lesional skin. All patients presented with widespread nodules and plaques, which in five cases were a characteristic purple colour. Four patients developed disseminated disease, three with neurological involvement. These four patients died between 14 and 46 months following diagnosis (median 30 months). In four of six cases the histopathological and immunohistological features were in keeping with a blastic NK-cell lymphoma. No clonal immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement was detected in the four cases consistent with an origin from NK cells. A further case fitted the criteria for an extranodal NK/T-cell lymphoma of nasal type and was also the only case to show evidence of EBV mRNA by ISH. A clonal T-cell population was identified in the final case. This patient also exhibited molecular evidence of a clonal B-cell population and a t(14;18) translocation confirmed by sequence analysis. Our data confirm that NK-cell lymphomas presenting in the skin are a heterogeneous group, and that in the U.K., blastic NK-cell lymphoma is more common than extranodal NK/T-cell lymphoma of nasal type. These lymphomas pursue an aggressive course, with rapid development of disseminated disease, and resistance to chemotherapy. Detailed immunophenotyping is needed to distinguish the different types. Our molecular data indicate that blastic NK-cell lymphoma cases lack clonal TCR/IgH gene rearrangements consistent with an NK-cell origin. Our ISH findings indicate that EBV plays a pathogenetic role only in extranodal NK/T-cell lymphoma of nasal type.

Leukemia and lymphoma of natural killer lineage cells.

Natural killer (NK) cells are lymphocytes with a large granular lymphocyte morphology, a CD3- CD56+ phenotype, a non-major histocompatibility complex-restricted cytotoxicity, and germline configuration T-cell receptor genes. NK cell lineage tumors originate from either precursor NK cells or mature NK cells. Tumors originating conceivably from precursor NK cells include myeloid/NK cell precursor acute leukemia, precursor NK cell acute lymphoblastic leukemia, and blastic NK cell lymphoma. However, because the developmental pathway of normal NK cells and the characteristics of these NK precursors are not fully understood, the definition and characterization of the tumors are only provisional. Tumors of mature NK cell origin include aggressive NK cell leukemia/lymphoma, nasal-type NK cell lymphoma, and chronic NK lymphocytosis, but the last disorder seems to be reactive in most cases. Because NK cell tumors are rare and difficult to manage, vigorous studies are required for their understanding and management.

Ｂｌａｓｔｉｃ ＮＫ Ｃｅｌｌ Ｌｙｍｐｈｏｍａ 鼻腔内浸潤を伴ったＢｌａｓｔｉｃ ＮＫ ｃｅｌｌ ｌｙｍｐｈｏｍａの１例

Blastic natural killer (NK) cell lymphoma is a neoplasm of NK origin with aggressive behavior. Blastic morphology, an NK cell immunophenotype, and a lack of association with Epstein-Barr virus are the clues for the diagnosis. We report the case of a 67-year-old man who has maintained complete remission for 3 months after CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chernotherapy. However, he died 10 rnonths after his first visit. In addition to blastic NK cell lyrnphoma, he had a nasopharynx tumor and cutaneous tumors when he visited our clinic. [Skin Cancer (Japan) 2003; 18: 66-69]

CD56(+) TdT(+) blastic natural killer cell tumor of the skin: a primitive systemic malignancy related to myelomonocytic leukemia.

An unusual cutaneous tumor that has blastic morphology and coexpresses CD56 and terminal deoxynucleotidyl transferase (TdT) has been recently recognized and termed blastic natural killer cell lymphoma. The authors identified seven cases of such CD56(+)TdT(+) blastic tumors presenting in skin at their institution. The authors correlated clinical course with histomorphology and immunophenotype. All 7 patients (6 men, 1 woman, 52-85 years) presented with rapidly growing, frequently multiple cutaneous nodules. All patients had low level bone marrow involvement at diagnosis and frequently had lymph node involvement. Tumor cells were of intermediate size with irregular nuclear contours, fine chromatin, and indistinct small nucleoli. The expression of TdT varied between 5% and over 90% of the neoplastic cell population. Tumor cells were negative for surface CD3, CD5, and CD20 in all cases, but some patients showed expression of CD2 (three out of five), cytoplasmic CD3 (two out of seven), CD4 (six out of seven), and CD16 (three out of seven). Molecular studies showed absence of T-cell receptor gene rearrangements in all cases. All seven patients had rapid progression of disease, and six patients have died of their disease or complications. Three patients developed progressively increasing numbers of bone marrow blasts that had a myeloid immunophenotype and were negative for TdT and CD56. Two patients met criteria for acute myeloid leukemia at 11 and 22 months after presentation, respectively. CD56(+) TdT(+) blastic tumor presenting in skin is a systemic malignancy likely of primitive/undifferentiated hematopoietic origin. Patients might subsequently develop tumors of myeloid or myelomonocytic phenotype, indistinguishable from acute myelogenous leukemia.

Comprehensive cytogenetic study by spectral karyotyping on blastic natural killer cell leukemia/lymphoma

Comprehensive cytogenetic study by spectral karyotyping on blastic natural killer cell leukemia/lymphoma

Pediatric Acute Blastic Natural Killer Cell Leukemia

The goal of this report is to describe a rare case of pediatric blastic natural killer (NK) cell leukemia and to compare pediatric blastic NK cell leukemia/lymphoma to other reported cases of pediatric NK cell leukemia. The patient, a 9-year-old girl, presented with acute leukemia with a phenotype similar to adult blastic NK cell leukemia/lymphoma. The blasts were agranular and expressed CD7, 45, 56, and HLA-DR, but not CD3, 11c, 13, 33, or TdT. She had a complete response to ALL-directed chemotherapy, but had multiple relapses involving the cerebrospinal fluid, nasal sinus, lymph node and skin. In addition to the reported case, a review of the literature identified 9 previously reported cases of NK cell leukemia in patients 18 years of age or less. Cases were subdivided into blastic, acute/aggressive, and myeloid precursor NK cell leukemia based upon CD13/33 expression and morphologic characteristics. Compared to pediatric acute/aggressive NK cell leukemia, children with blastic NK cell leukemia showed greater variation in age and race. Prognosis was poor for all groups. Pediatric blastic NK cell leukemia is a distinct clinicopathologic entity which differs from other types of pediatric NK cell leukemia.

Blastic Natural Killer Cell Leukemia/Lymphoma Presenting as Overt Leukemia

Blastic natural killer (NK)-cell leukemia/lymphoma is a neoplasm of NK origin with aggressive behavior. The disease affects mainly elderly people and often presents with skin lesions and overt leukemia. Blastic morphology, an NK-cell immunophenotype, and lack of association with Epstein-Barr virus are the clues for the diagnosis. We report herein, the case of a patient with a blastic NK-cell leukemia/lymphoma with overt leukemia at diagnosis, who achieved a complete response after CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy. However, the patient relapsed a few months later and died due to disease progression. Cases of blastic NK-cell leukemia/ lymphoma previously reported are briefly reviewed.

Commentary on “Blastic Natural Killer Cell Leukemia/Lymphoma Presenting as Overt Leukemia”

B-cell and T-cell malignancies can be definitively diagnosed by demonstrating clonal rearrangements of their antigen-receptor genes. In contrast, natural killer (NK) cells do not have antigen-receptor genes, making unequivocal assignment of tumors to NK-cell lineage more problematic. Normal NK cells are classically defined functionally as a subset of receptornull lymphocytes that have cytotoxic activity in the absence of prior stimulation. CD56 and CD16 are expressed at variable levels by most normal NK cells and are two of the more commonly used diagnostic markers. However, CD16 is expressed on subsets of myeloid and T cells as well as some myeloid leukemias and T-cell tumors. CD56 expression is a feature of a subset of B-cell and T-cell lymphomas, monocytic leukemias, and approximately 10% of poorly differentiated myeloid leukemias. 1,2 Despite their lack of sensitivity and specificity, CD56 and CD16 remain the most commonly used diagnostic markers for NK-cell tumors. Although more specific markers of NK cells are now available, they are not yet in routine diagnostic use. 3 Recently, immunostaining for cytotoxic granule proteins (eg, TIA-1, perforin, and granzyme B) has become common. The diagnostic value of these markers is unclear given that many types of T-cell tumors (anaplastic large-cell lymphoma and mycosis fungoides) and some B-cell tumors show cytoplasmic immunoreactivity with these antibodies. In everyday practice, NK-cell lineage is commonly assigned to all lymphoid-appearing tumors that show expression of CD2 and/or cytoplasmic CD3 in the absence of T-cell–specific findings, such as surface expression of CD3 or clonal Tcell–receptor gene rearrangements. Using these criteria, a range of NK-cell tumors have been described that exhibit a wide spectrum in their clinical presentation and behavior. These tumors of proposed NKcell origin are summarized in Table 1. Traditionally, these tumors have been divided into lymphomas (ie, those presenting primarily in tissue sites such as the sinonasal area, skin, and gastrointestinal tract) and leukemias. However, many NK-cell lymphomas show a propensity for leukemic involvement and widespread extranodal dissemination leading to the designation of NK-cell lymphoma/leukemia.

Molecular analysis of tumor suppressor genes, Rb, p53, p16INK4A, p15INK4B and p14ARF in natural killer cell neoplasms.

Natural killer (NK) cell neoplasms, which are derived from mature or precursor NK cells, are rare diseases and are observed predominantly in Asian countries. We analyzed the status of the Rb, p53, p15INK4B, p16INK4A and p14ARF genes in these diseases by Southern blot, polymerase chain reaction–single strand conformational polymorphism (PCR–SSCP) and western blot analysis. We used 31 NK cell neoplasms, including four cell lines derived from NK cell neoplasms, 3 myeloid/ NK cell precursor acute leukemias, 4 blastic NK cell lymphoma/leukemias, 4 aggressive NK cell leukemia/lymphomas, 4 nasal NK cell lymphomas, and 12 chronic NK lymphocytosis. We found gene amplification of the p53 gene in one nasal NK cell lymphoma, and point mutations of the p53 gene in one blastic NK cell lymphoma/leukemia and one chronic NK lymphocytosis. In addition, homozygous deletions ofpl5,p16 andp14 genes in 5 out of 31 samples were detected; 3 were from nasal NK cell lymphoma and 2 from blastic NK cell lymphoma/leukemia. Also hemizygous deletion of the Kb gene in one blastic NK cell lymphoma was detected. Rb proteins were highly expressed in one cell line as well as two myeloid/NK cell precursor acute leukemias. In other cell lines, complete loss and an aberrant migration pattern of Rb protein expression were observed. Comparative genomic hybridization suggested that the homozygous deletions of the p15, p16 and p14 were subtle chromosomal deletions and could not be identified by standard karyotyping in some cases. Although the number of cases we analyzed was not large, alterations identified in the Rb, p53, p16, p15 and p14 genes are of significance and might be associated with tumorigenesis in NK cell neoplasms