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Results for “Blastic Plasmacytoid Dendritic Cell Neoplasm”

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PubMed2026

Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.

Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.

Female↗
PubMed2006

Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms.

CD4+CD56+ hematodermic neoplasms are rare, aggressive hematopoietic malignancies usually presenting with cutaneous masses followed by a leukemic phase. The blastic morphology, CD56 expression and lack of definitive myeloid or T-cell markers initially resulted in assignment of this tumor to the NK-cell lineage. Accumulating evidence now suggests that these neoplasms represent malignant counterparts to the plasmacytoid dendritic cell. BDCA-2 is a cell surface protein whose expression is restricted to human plasmacytoid dendritic cells, in a differentiation stage-specific manner. In the current study, we assessed expression of BDCA-2 in CD4+CD56+ hematodermic neoplasms using a new antibody reagent we developed for use in fixed tissue sections. In 10 of 19 cases of CD4+CD56+ hematodermic neoplasm, BDCA-2 immunoreactivity was detected, whereas no expression was observed in NK-lineage tumors (0 of six). Interestingly, expression of terminal deoxynucleotidyl transferase, a marker of immaturity/blast stage, was significantly and negatively correlated with BDCA-2 in CD4+CD56+ hematodermic neoplasms whereas a positive correlation was observed between BDCA-2 and CD7. These findings demonstrate that BDCA-2 is expressed predominantly in the CD7+ subset of hematodermic neoplasms, and similar to non-neoplastic plasmacytoid dendritic cells, expression indicates a relatively more mature differentiation state. Clinical follow-up data confirm the aggressiveness of these tumors and suggests that BDCA-2 immunoreactivity, as identified here, may herald a significant reduction in survival.

Antigens, Neoplasm↗
PubMed2005

The new World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants.

Following consensus meetings of the two parent organizations, a new World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for primary cutaneous lymphomas has recently been published. This important development will now end the ongoing debate as to which of these was the preferred classification. The new classification will facilitate more uniformity in diagnosis, management and treatment of cutaneous lymphomas. In particular, it provides a useful distinction between indolent and more aggressive types of primary cutaneous lymphoma and provides practical advice on preferred management and treatment regimens. This will thereby prevent patients receiving high-grade treatment for low-grade biological disease. This review focuses on those diseases which have found new consensus agreement compared with the original WHO and EORTC classifications. In cutaneous T-cell lymphomas, these include folliculotropic mycosis fungoides, defining features of Sézary syndrome, primary cutaneous CD30+ lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis and borderline lesions) and subcutaneous panniculitis-like T-cell lymphoma. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are allocated provisional entry status and thereby afford better definitions for some cases of currently unspecified primary cutaneous peripheral T-cell lymphoma. In cutaneous B-cell lymphomas, diseases which have found new consensus agreement include primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular centre lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type and primary cutaneous diffuse large B-cell lymphoma, other. CD4+/CD56+ haematodermic neoplasm (early plasmacytoid dendritic cell leukaemia/lymphoma) now appears as a precursor haematological neoplasm and replaces the previous terminology of blastic NK-cell lymphoma. Other haematopoietic and lymphoid tumours involving the skin, as part of systemic disease, will appear in the forthcoming WHO publication Tumours of the Skin. The new classification raises interesting new problems and questions about primary cutaneous lymphoma and some of these are discussed in this article. It is, however, a splendid signpost indicating the direction in which research in cutaneous lymphoma needs to go. In the interim, we have an international consensus classification which is clinically meaningful.

Humans↗
PubMed2005

CD4+CD56+ lineage negative hematopoietic neoplasm: so called blastic NK cell lymphoma.

Blastic natural killer (NK) cell lymphoma is a rare neoplasm characterized by blastoid tumor cells expressing CD4 and CD56, with predominant skin involvement. Although this tumor has been regarded as a neoplasm related to NK cell, recent studies suggested that it is derived from plasmacytoid dendritic cells, but not from NK cell. Herein we report 4 cases of CD4+CD56+ lineage marker-blastic NK cell lymphomas with a review of literatures. The patients were 3 men and one woman. Three of them were young (17, 18, and 22 yr old). Three patients had skin lesions, at initial presentation in two patients and during the course of disease in other patient. Histologically, tumors consisted of monotonous medium to large blastoid cells showing no necrosis, angiocentric growth or epidermotrophism. All four tumors were CD4+ and CD56+. Three expressed CD68 antigen. Lineage specific markers for B- and T cell were negative. All tumors did not express myeloperoxidase. T-cell receptor gene rearrangement, EBV, CD13 and CD33 were negative. In one patient, tumor cells arranged in Homer-Wright type pseudorosette and expressed terminal deoxynucleotidyl transferase(TdT). Despite the standard lymphoma chemotherapy, the tumors, except one lost during follow-up, progressed and relapsed. The patients died 8-60 months after diagnosis.

Adolescent↗
PubMed2007

Agranular CD4+/CD56+ hematodermic neoplasm: a distinct entity described in the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas.

Agranular CD4+/CD56+ hematodermic neoplasm is a distinct form of lymphoma with aggressive behavior and marked predilection for cutaneous involvement. Because of CD56 positivity, natural killer cells were initially suggested as the cell of origin in this tumor. In the recent World Health Organization-European Organization for Research and Treatment of Cancer classification, the term blastic natural killer cell lymphoma has been replaced with CD4+/CD56+ hematodermic neoplasm because of its derivation from a plasmacytoid dendritic cell precursor. Clinicopathologic features, immunohistochemical features, and differential diagnosis of this rare neoplasm with emphasis on the recent World Health Organization-European Organization for Research and Treatment of Cancer classification are discussed.

CD4 Antigens↗
PubMed2003

CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells.

BACKGROUND AND OBJECTIVES: The CD4+ CD56+ lin- immunophenotype characterizes rare malignancies, so far considered as arising from the transformation of NK progenitors, and therefore classified as blastic NK-cell leukemia/lymphoma by the WHO committee. Recently it was formally demonstrated that such malignancies do, in fact, develop from plasmacytoid dendritic cells (pDC), according to immunophenotypic and functional criteria. The clinico-biological features of this neoplasm were moreover recently summarized from a large series of 23 patients. INFORMATION SOURCES: The main symptoms at presentation were cutaneous lesions and bone marrow failure, due to invasion by blastic cells, all of which were EBV negative and agranular. Most patients were initially sensitive to chemotherapy regimens, but they rapidly relapsed and died within 3 years. Only 2 allotransplanted patients were long survivors. Recurrent chromosomal aberrations involving chromosomes 5q, 6q, 12p, 13q, 15q and 9 were described and it was characteristic that these were associated in the same cell. In the present review we compared these findings to those in the literature. STATE OF THE ART AND PERSPECTIVES: The concordant characteristics led us to confirm that this neoplasm actually represents a new entity, that we propose to rename early pDC leukemia/lymphoma. The diagnosis is primarily based on a characteristic immunophenotypic profile i.e. CD4+ CD56+ CD3- CD13- CD33- CD19-. Complementary analyses assessing the expression of more specific pDC-related markers showed the cells to be HLA-DR+, CD123high, CD116low, CD45RA+, BDCA-2+ or BDCA-4+. Such complementary investigations are necessary only in the case of an atypical phenotype, in order to confirm a pDC origin and exclude another hematologic disease. This presently regards the expression of CD33 or cytoplasmic CD3e (cyCD3e) and the negativity of CD56.

Adolescent↗
PubMed2004

TCL1 and CLA expression in agranular CD4/CD56 hematodermic neoplasms (blastic NK-cell lymphomas) and leukemia cutis.

Agranular CD4/CD56 hematodermic neoplasm (CD4/CD56 HN), also termed blastic natural killer cell lymphoma, is characterized by a peculiar immunophenotype and high skin tropism. The lineage of origin is not known, and a plasmacytoid dendritic cell derivation has been proposed. CD4/CD56 HN generally is diagnosed by using tumor skin biopsy, with the most important differential diagnosis being myelomonocytic leukemia cutis. We evaluated the expression of 2 plasmacytoid dendritic cell antigens, T-cell leukemia 1 (TCL1) and cutaneous lymphocyte-associated antigen (CLA), in 29 cases of CD4/CD56 HN and 18 cases of myelomonocytic leukemia cutis. TCL1 and CLA were expressed in 26 (90%) of 29 CD4/CD56 HN cases vs TCL1 expression in 3 (17%) and CLA expression in 14 (78%) of 18 leukemia cutis cases. Furthermore, CLA antiserum displays a peculiar small-dot staining pattern in CD4/CD56 HN. These results suggest that TCL1 and CLA are good markers for CD4/CD56 HN tumor cells and add support for a plasmacytoid dendritic cell origin. The high skin tropism of CD4/CD56 HN might be related to the skin-homing property of CLA.

Adult↗
PubMed2006

CD4+/CD56+ haematodermic neoplasm: a preculsor haematological neoplasm that frequently first presents in the skin.

CD4+/CD56+ hematodermic neoplasm, formerly known as blastic NK cell lymphoma, is an aggressive and rare preculsor hematologic neoplasm recently recognized by the WHO-EORTC classification consensus for cutaneous lymphomas. The neoplasm tends to affect elderly patients, who usually present with skin lesions but often have a disseminated disease, including bone marrow involvement. Although the lesions are composed of cells with a lymphoblast-like morphology and an NK-cell phenotype, exhibiting a CD4+, CD56+ positive immunophenotype, recent studies support a relationship to plasmacytoid dendritic cells. Because of the rarity of this disease, we describe two patients suffering a CD4+/CD56+ hematodermic neoplasm.

Aged↗
PubMed2002

Clinical and biologic features of CD4(+)CD56(+) malignancies.

CD4(+)CD56(+) malignancies are rare hematologic neoplasms, which were recently shown to correspond to the so-called type 2 dendritic cell (DC2) or plasmacytoid dendritic cells. This study presents the biologic and clinical features of a series of 23 such cases, selected on the minimal immunophenotypic criteria defining the DC2 leukemic counterpart, that is, coexpression of CD4 and CD56 in the absence of B, T, and myeloid lineage markers. Clinical presentation typically corresponded to cutaneous nodules associated with lymphadenopathy or spleen enlargement or both. Cytopenia was frequent. Circulating malignant cells were often detected. Massive bone marrow infiltration was seen in 20 of 23 (87%) patients. Most tumor cells exhibited nuclei with a lacy chromatin, a blastic aspect, large cytoplasm-containing vacuoles or microvacuoles beside the plasma membrane, and cytoplasmic expansions resembling pseudopodia. Other immunophenotypic characteristics included both negative (CD16, CD57, CD116, and CD117) and positive (CD36, CD38, CD45 at low levels, CD45RA, CD68, CD123, and HLA DR) markers. The prognosis was rapidly fatal in the absence of chemotherapy. Complete remission was obtained in 18 of 23 (78%) patients after polychemotherapy. Most patients had a relapse in less than 2 years, mainly in the bone marrow, skin, or central nervous system. Considering these clinical and biologic features, the conclusion is made that CD4(+)CD56(+) malignancies constitute a genuine homogeneous entity. Furthermore, some therapeutic options were clearly identified. Finally, relationships between the pure cutaneous indolent form of the disease and acute leukemia as well as with the lymphoid/myeloid origin of the CD4(+)CD56(+) malignant cell are discussed.

Adolescent↗
PubMed2005

Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review.

Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published. In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed. The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.

Adult↗
PubMed2004

[Agranular CD4+ CD56+ CD123+ hematodermic neoplasm (blastic NK-cell lymphoma) revealed by cutaneous localization: 2 cases].

BACKGROUND: Agranular CD4+ CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) has been recently described. The skin is often the first organ involved. OBSERVATIONS: Two old men of respectively 70 and 77 years consulted for infiltrated cutaneous lesions. Preliminary histological examination of cutaneous biopsy taken in both patients showed a malignant proliferation suggesting a cutaneous lymphoma, and the patients were referred. Histological examination of new biopsies showed a very similar proliferation in the 2 cases of monotonous medium-sized mononuclear cells without expression of the common antigens CD3 and CD20 and the expression of CD4, CD56, and CD123. No rearrangement of the T-cell receptor gene or the immunoglobulin heavy chain gene were evidenced. No extracutaneous involvement was initially detected in the first patient. Thrombocytopenia associated with the abnormal presence of 15 p. 100 of circulating CD4+ CD56+ cells was initially found in the second patient. The first patient was treated with chemotherapy, with complete remission. A cutaneous relapse promptly occurred, followed by bone and cerebral localizations. The patient died one year after the diagnosis of the disease, in spite of intensification of the treatment. Treatment is still ongoing in the second patient. COMMENTS: The histological presentation of these two patients was very similar with an unusual phenotype of tumor cells expressing CD4, CD56, CD123, but not expressing CD3 and CD20. Some cases have been published under the "term of blastic NK lymphoma" which is the actual term for the disease in the WHO classification. However, the tumor cells derive from the dendritic plasmacytoid cells, also called type 2 dendritic cells, and perhaps from a common precursor to lymphocyte T and dendritic plasmacytoid cells. In spite of complete cutaneous response in the 2 cases presented, as in other reports, extra-cutaneous involvement occurs quickly. Overall survival is usually poor since nearly all the patients died in less than 3 years. This justifies attempting aggressive protocols, with bone marrow allograft in the younger patients.

Aged↗
PubMed2004

[Hematodermic CD4/CD56 neoplasm].

Hematodermic CD4/CD56 neoplasm is a recently described entity. This name has been initially proposed by the French Study Group on Cutaneous Lymphomas which established the primary anatomoclinical and pathogenic and cytogenic bases of the disease in 1999. This descriptive and provisional name allowed conceptualizing the entity by its main clinical and phenotypical characteristics. The first case in the literature goes back to 1994. Since that time, several other cases have been published. The expression of CD56 led most of the authors to propose an NK-cell lineage origin. In the last WHO classification of lymphomas, the entity was indexed under the name of "blastic NK-cell lymphoma". However, the authors underlined that there were currently no clues to the etiology of blastic NK-cell lymphoma and that the precise lineage of this disease was still unresolved. At the clinical level the main characteristics of the disease are the skin tropism and the occurrence of a leukemic phase at any time during the course of the disease. The median age is 59 but pediatric cases do exist. At the morphological level skin biopsy shows a monomorphous cell proliferation simulating a pleomorphic T cell cutaneous lymphoma. The diagnosis is based on phenotypic criteria which require frozen tissue. Currently, the main characteristics are the expression of CD4 and CD56 antigens while the main defined lineage specific markers are negative (B-cell, T-cell, NK-cell and myeloid-cell lineages). The origin of the tumor cells still remains uncertain but the plasmacytoid dendritic cell is presently a very serious candidate. The tumor cells share a great phenotypical homology and particularly the expression of the CD123 antigen. Functional homologies have also been demonstrated with tumor cells in vitro. Outcome of CD4/CD56 hematodermic neoplasms is very bad. The median time of survival is 14 months irrespective of the treatment given. Conventional chemotherapies used for the treatment of aggressive lymphomas or acute myeloid leukemias are quickly inefficient.

Adolescent↗
PubMed2006

[Blastic NK-cell lymphoma].

Blastic NK (< >) cell lymphoma is a rare type of lymphoma, recognized as an independent entity in the new World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas. Its clinical, morphological and immunophenotypical characteristics are relatively well defined. It frequently starts with extranodal involvement (primarily cutaneous), often presents with splenomegaly and pancytopenia, and initially responds well to chemotherapy, although the medium-term prognosis is usually poor. It was first considered to originate from immature NK lymphocytes, but now its origin is thought to be plasmacytoid dendritic cell precursors. We present the clinicopathological characteristics of a new case of this entity in a 78-year-old male patient.

Aged↗
PubMed2003

TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin.

Initially considered to be of natural killer (NK)-cell origin, CD4+ CD56+ blastic tumors (BTs) of skin have recently been proposed to be of dendritic cell lineage. We have previously described BTs with transformation to myelomonocytic leukemia. Here we report expression of the lymphoid proto-oncogene TCL1 in 10 (83%) of 12 BTs and in lymph node plasmacytoid dendritic cells (DC2s). TCL1 was also expressed in myelomonocytic blasts of 3 transformed BT cases but not in true NK-cell tumors (n = 18), de novo acute myelomonocytic leukemias (1 of 14, 7%), or mature T-cell malignancies (1 of 112, < 1%), with the exception of T-prolymphocytic leukemia (T-PLL). All BT cases were also positive for the DC2-associated marker CD123. These results further support derivation of BTs from DC2s, and demonstrate that TCL1 expression in this tumor is common to the immature blastoid, lymphoid-appearing, and subsequent myelomonocytic phases of this disease.

Bone Marrow↗
PubMed2002

NK cell lymphoma.

Natural killer (NK) cells are lymphocytes with large granular lymphocyte morphology, CD3-CD56+ phenotype, non-MHC-restricted cytotoxicity, and germ-line configuration T-cell receptor genes. Two types of lymphomas originating from NK cells have been described; blastic NK-cell lymphoma, and nasal-type NK-cell lymphoma. Because recent reports indicate that blastic NK-cell lymphoma originates from the precursors of plasmacytoid dendritic cells, I will focus mainly on nasal-type NK-cell lymphoma, and discuss its pathogenesis, diagnostic problems, treatment strategy, and outcome. Nasal-type NK-cell lymphoma develops mostly in the nasal cavity and rarely in other sites, such as the skin and intestinal tract. Epstein-Barr virus (EBV) is found in lymphoma cells of almost all the patients, and is considered to be the etiologic agent. Indeed, EBV easily infects NK cells in the absence of CD21 antigen, or EBV receptor, on the surface of NK cells. Further, various types of oncogenes and suppressor oncogenes are found to be involved in its pathogenesis. Based on the data obtained from paraffin-embedded specimens, it is difficult to determine whether the lymphoma cells are of T-cell or NK-cell lineage, because immunohistochemical staining of cytoplasmic CD3 is positive both in T and NK cells, and CD56 is positive in a part of T cells. The presence of CD5 antigen indicates T-cell lineage. When the disease is limited, radiation therapy is effective, but not satisfactory. A new trial to use simultaneously both radiation and chemotherapy has started in Japan. In advanced stages, a combination chemotherapy including L-asparaginase seems to be promising, and high-dose chemotherapy with autologous or allogeneic stem cell support is under investigation. A recent report described the expression of short-length P-glycoprotein (P-gp), but not full-length P-gp in NK cells, and this mini-P-gp is unable to extrude daunorubicin. These findings may change the treatment strategy. Finally, I will present the results on interim analysis of 166 cases of nasal-type NK-cell lymphoma collected in Japan between 1994 and 1998.

Combined Modality Therapy↗