CD4+/CD56+ hematodermic neoplasm: report of a rare variant with a T-cell receptor gene rearrangement

CD4+/CD56+ hematodermic neoplasm (HN), formerly known as a blastic natural killer (NK) cell lymphoma, is a rare subtype of a cutaneous dendritic cell neoplasm notable for highly aggressive behavior. The characteristic features are: expression of the T-helper/inducer cell marker CD4 and the NK-cell marker CD56 in the absence of other T cell or NK-cell specific markers. In particular, CD3 (surface or cytoplasmic) and CD2 are not expressed. Although T-cell receptor (TCR) genes are generally reported to be in a germline configuration, we present an unusual variant of a CD4+/CD56+ HN with a clonal rearrangement of TCR genes. This feature of a CD4+/CD56+ HN has been only rarely reported. Recognition of the presence of clonal TCR gene rearrangements in a small subset of CD4+/CD56+ HN is important to avoid misdiagnosis of this entity as an unusual variant of a cutaneous T-cell lymphoma.     

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.     

CD4-negative variant of CD4+/CD56+ hematodermic neoplasm: description of three cases

Background: CD4+/CD56+ hematodermic neoplasm (HN) (blastic natural killer (NK)‐cell lymphoma) is a rare entity characterized by dense, monomorphous infiltrates of medium‐sized cells with blastic appearance and a characteristic immunophenotype (positivity for CD4, CD56 and CD123). The combination of CD4 and CD56 positivity is thought to be so striking that it has been used to name this entity. Methods: Three cases of HN with ambiguous phenotypic profile were included in this study. In all cases, phenotypic, molecular and in situ hybridization studies were carried out. Results: All three cases showed an aberrant phenotype with negativity for CD4. Conclusions: CD4‐negative or CD56‐negative cases of HN have been rarely reported in the literature and represent a diagnostic problem. Our three cases confirm that CD4 is not always expressed in these neoplasms. The term ‘CD4+/CD56+ hematodermic neoplasm’ adopted in the World Health Organization–European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas may be misleading and should probably be revised in the light of all data published in the literature.     

Agranular CD4+ CD56+ hematodermic neoplasm: a new case report

BACKGROUND: "Agranular CD4+ CD56+ hematodermic neoplasm" are rare hematologic neoplasms which were recently shown to correspond to the plasmocytoid dendritic cells. CASE REPORT: A 83-year-old presented isolated skin lesions purple, infiltrating the dermis. The biopsy has shown a dense dermal infiltration with malignant cells CD4+ CD56+ CD43+. There were no bone marrow involvement and no circulating blood cells. A chemotherapy permitted a clinical remission after six courses. Unfortunately, skin and blood relapses appear four months later. After a short success of chemotherapy by DHAP, the patient died three month later. DISCUSSION: "Agranular CD4+ CD56+ hematodermic neoplasm" is a distinct entity from the cutaneous primary lymphomas. Recently plasmocytoid monocyte cells have been identified as the precursor of the malignant population with the high expression of CD123, IL3 receptor. It is a distinct clinicopathologic entity by its clinical presentation with skin tropism, bone marrow involvement with or without leukemic phase and poor prognosis independent of the kind of treatment and its particular phenotype CD4+ CD56+ CD43+. It would be interesting to use antibodies linked to CD123 in therapeutic because any treatment have efficacity in this disease.     

CD4+ CD56+ hematodermic neoplasm

We report a case of a 75-year-old man with a cutaneous CD4+CD56+ hematodermic neoplasm. CD4+CD56+ hematodermic neoplasms are rare and commonly present as cutaneous lesions. This is an important diagnosis in the differential diagnosis of cutaneous hematologic malignancies because of the extremely poor prognosis.     

CD4+ CD56+ hematodermic neoplasm and plasmacytoid dendritic cell tumor: case report and review of the literature

CD4+ CD56+ hematodermic neoplasm (HN) is a rare and aggressive neoplasm that has raised controversy regarding its etiology. CD4+ CD56+ HN is thought to be derived from plasmacytoid dendritic cells (pDCs) and most commonly stains with CD4, CD56, CD123, and T-cell leukemia/lymphoma 1 (TCL1). Skin manifestations usually are the presenting signs and vary in appearance. Lymph node involvement also is common at the time of presentation, and the natural course of the disease is a progression to leukemia. Treatment of CD4+CD56+ HN focuses on multiple chemotherapeutic regimens but none have been proven to successfully impact overall survival.     

CD4-/CD56+/CD123+ Hematodermic Neoplasm Showing Early Liver Metastasis

Hematodermic neoplasm (HN) is a clinically aggressive neoplasm with a high incidence of cutaneous involvement and a risk of leukemic dissemination. In the recent WHO-EORTC classification, the term blastic natural killer cell lymphoma has been replaced with CD4+/CD56+ HN because of its derivation from a plasmacytoid dendritic cell precursor. Cases of HN that completely lack CD4 or CD56 expression, therefore represents a diagnostic problem. A 68-year-old Korean male was diagnosed with CD4-/CD56+ HN and treated with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) at initial treatment, and then switched to high dose methotrexate/cytarabine. His disease relapsed and resulted in death from bone and brain disease 6 months after complete clinical remission, despite diagnostic workups, including a radioisotope liver scan and ultrasound-guided fine needle aspiration biopsy. Further cytogenetic studies such as comparative genomic hybridization could elucidate the genetic mechanisms in the development and progression of lymphomas. We report an unusual case of ''CD4-/CD56+/CD123+ HN'' showing early liver metastasis.     

An Unusual Hematologic Malignancy Derived from Plasmacytoid Dendritic Cells

Recently reported cases of CD4+ CD56+ hematologic malignancies with a strong predilection for the skin correspond to the neoplastic counterpart of plasmacytoid dendritic cells. This rare, aggressive malignancy lacks pan‐myeloid and pan‐lymphoid markers and often presents with cutaneous lesions, splenomegaly, and involvement of lymph nodes and bone marrow. It has a poor prognosis, and many patients progress to acute myeloid leukemia. The proposed cellular origin is a CD56+ precursor cell related to plasmacytoid monocytes, which strongly expresses CD123 (IL‐3Ra). We describe a 70 year‐old man who presented with gray‐brown truncal nodules and plaques, lymphadenopathy, and splenomegaly. His bone marrow demonstrated malignant CD4+ CD56+ mononuclear cells. Histologic sections of skin lesions showed an atypical infiltrate extending into the deep reticular dermis. Immunohistochemical staining of these cells for CD4 was diffusely positive. Moreover, the infiltrate strongly expressed CD56 and CD123 but showed only patchy or negative staining for other T and B cell markers. The combination of the patient's clinical presentation and biopsy results best fits the diagnosis of this newly characterized, distinct clinicopathologic entity described in recent literature as agranular CD4+ CD56+ hematodermic neoplasm, plasmacytoid dendritic cell acute leukemia, and tumor‐forming accumulations of plasmacytoid monocytes associated with myeloid disorders.     

CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate

The CD4(+) CD56(+) hematodermic/plasmacytoid dendritic cell tumor is a rare, highly aggressive, systemic neoplasm for which effective therapies have not yet been established. These tumors express CD4, CD56, CD123, and T-cell leukemia/lymphoma (TCL)-1 and are clinically characterized by cutaneous involvement with spread to bone marrow and blood, and poor prognosis with current chemotherapy regimens. We describe a Caucasian woman who presented with plasmacytoid dendritic cell tumor, but an absence of systemic symptoms. Clinically, multiple cutaneous lesions were brown to violaceous firm nodules on the face, arms, and trunk. The patient underwent two courses of cyclophosphamide, Adriamycin, vincristine, and prednisone chemotherapy but relapsed quickly. The investigational agent, pralatrexate (30 mg/m(2)) was given weekly with vitamin B12 and folic acid and resulted in remarkable clinical response with regression of skin tumors. Our observation highlights pralatrexate as a promising therapeutic option for hematodermic/plasmacytoid dendritic cell lymphoma/leukemias.     

Skin manifestations in CD4+, CD56+ malignancies

CD4+ CD56+ hematologic neoplasms were recently individualized. We report three cases of CD4+ CD56+ malignancies with cutaneous lesions in three cases and also bone marrow involvement in two cases. Two patients relapsed 2 and 3 months after polychemotherapy. Two patients died within 3-10 months. A constant immunophenotype was observed with the co-expression of CD4 and CD56, the absence of B and T-cell markers. The salient fact of this report is the presence of T-cell clonal rearrangement. The clinical and pathological features closely resemble the specific cutaneous manifestations in acute leukemia with monocytic differentiation, especially the granulocytic sarcoma. Because of the positivity of the CD56, natural killer cell proliferations were discussed. Since 1994, 50 cases of CD4+, CD56+ cutaneous neoplasms have been reported with specific clinical, cytologic and immunohistochemical features. The diagnosis is more difficult when the cutaneous location is exclusive; on the contrary, the cytological features of the blood and medullar cells with cytoplasmic vacuoles and pseudopodia are characteristic of this hematologic neoplasm. The presence of CD123 antigen in most of the cases is an argument for a plasmacytoid dendritic cell proliferation and it is also a good marker for primary cutaneous lesions.     

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.     

Cutaneous monomorphous CD4- and CD56-positive large-cell lymphoma

BACKGROUND: Recently, CD56 (NCAM)-positive lymphomas, such as nasal and nasal-type angiocentric NK/T cell lymphoma, aggressive NK cell leukemia/lymphoma and blastic NK cell lymphoma, were described by several authors as a unique group of lymphoma. OBJECTIVE: In this study, we intend to clarify the clinicopathological features of cutaneous CD4+ and CD56+ lymphoma. METHODS: Four patients with cutaneous CD4+ and CD56+ lymphoma were studied. RESULTS: Age at the first examination ranged from 71 to 89 years (mean = 81.2 years). One patient was female and 3 were males. The organ mainly involved at presentation was the skin. Lymphadenopathy, splenomegaly, leukemic spread and central nervous system involvement were observed as the disease progressed. The mean survival time was 12.2 months. Epstein-Barr virus was not detected within the tumor cells. CONCLUSION: This peculiar lymphoma is different from nasal and nasal-type angiocentric NK/T cell lymphoma and aggressive NK cell leukemia/lymphoma. Similar cases have been reported as blastic NK cell lymphoma/leukemia.     

Cutaneous presentation preceding acute myeloid leukemia with CD4+/CD56+ expression misdiagnosed as a blastic plasmocytoid dendritic cell neoplasm: A case report

Acute myeloid leukemia (AML) may initially present as cutaneous lesions corresponding to blasts involving the skin as the first clinical manifestation prior to blood and bone marrow (BM) infiltration. Such presentation is known as myeloid leukemia cutis (LC). Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is an aggressive tumor derived from the precursors of plasmocytoid dendritic cells with cutaneous and BM involvement and leukemic dissemination. Myeloid LC and BPDCN may be difficult to distinguish as they share similar clinical and histopathological features, in particular AML with monocytic differentiation. Nevertheless, the correct diagnosis has to be made to determine adequate and effective therapy. Here, we report the case of a 61‐year‐old woman who presented with an AML with MLL rearrangement and CD4+/CD56+ expression presenting as LC and that was misdiagnosed as BPDCN. We emphasize that careful and exhaustive analyses should be performed to make the correct diagnosis.     

长期抗病毒治疗的艾滋病患者CD4^+/CD8^+比值影响因素分析

目的探讨艾滋病患者抗病毒治疗后影响CD4^+/CD8^+比值恢复的因素。方法回顾性分析455例患者的基线及随访资料,观察期60个月,对60个月时CD4^+ T细胞数大于350/μL的患者,用Logistic回归分析影响其CD4^+/CD8^+比值恢复的影响因素,同时分析基线CD4^+/CD8^+、CD4^+T细胞数的差异。结果治疗60个月,影响CD4^+ T细胞数大于350/μL的患者CD4^+/CD8^+比值恢复的独立危险因素为年龄、基线CD4^+ T细胞数小于100/μL、基线CD8^+ T细胞数。CD4^+ T细胞数大于350/μL组,与CD4^+ T细胞数小于350/μL组,基线CD4^+/CD8^+比值比较差异有统计学意义(P=0.00),基线CD4^+ T细胞数比较差异有统计学意义(P=0.00)。结论抗病毒治疗可改善CD4^+/CD8^+比值,治疗时间越早,长期治疗后免疫功能恢复情况越好。但高龄、低CD4^+ T细胞数、高CD8^+ T细胞数是长期治疗的HIV/AIDS患者免疫功能重建的影响因素。     

Gain of CD26 expression on the malignant T‐cells in relapsed erythrodermic leukemic mycosis fungoides

Loss of CD26 surface expression on the circulating malignant T‐cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T‐cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T‐cells with high CD26 expression. Polymerase chain reaction studies and high‐throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T‐cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.     

Lack of suppressive CD4+CD25+FOXP3+ T cells in advanced stages of primary cutaneous T-cell lymphoma

Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapable of suppressing autologous CD4+CD25- T-cell proliferation, whereas suppressive function was intact in the other six patients. Suppressive activity of Tregs inversely correlated with the peripheral blood tumor burden. T-plastin gene expression, used as a Sezary cell marker, confirmed that Sezary cells were heterogeneous for CD25 expression. Mixed lymphocyte reactions demonstrated that CD4+CD25- T cells from patients who lacked functional Tregs were susceptible to suppression by Tregs from healthy controls, and had not become suppressive themselves. Furthermore, we found reduced expression of Foxp3 in the CD4+CD25+ Tregs of these patients relative to the other six CTCL patients and controls. Our findings thus indicate a dysfunction of peripheral Tregs in certain CTCL patients, which correlates with tumor burden.     

Haematodermic CD4+CD56+ neoplasm: complete remission after methotrexate–asparaginase treatment

Haematodermic neoplasm is a recently recognized condition, characterized by tumour cells expressing CD4, CD56 and CD123. This phenotype is strongly suggestive of a plasmacytoid dendritic cell origin. This haematopoietic malignancy is a distinct clinicopathological condition with frequent skin involvement, an evolution toward leukaemia and a rapidly aggressive course. We report the case of a 64-year-old woman who presented with a haematodermic CD4+CD56+CD123+ neoplasm affecting the left cheek; the initial staging was otherwise negative. Despite this early stage of the disease, aggressive treatment including methotrexate–asparaginase and local radiotherapy was proposed as first-line therapy. Complete clinical remission was rapidly reached and the patient was still alive after > 30 months of follow-up. To date there is no consensus on the first-line treatment for such patients but intensive treatment is probably needed immediately even in cases of localized disease. The response obtained with CHOP (cyclophosphamide, doxyrubicin, vincristine, prednisone) or CHOP-like chemotherapy regimens is disappointing. Other regimens, such as those used in acute leukaemia, may improve the outcome of these patients.     

Cutaneous T-cell lymphoma lesional epidermal cells activate autologous CD4+ T lymphocytes: involvement of both CD1+OKM5+ and CD1+OKM5- antigen-presenting cells

Cutaneous T-cell lymphoma is characterized by infiltration of the skin by activated CD4+ T lymphocytes. The mechanism by which these T lymphocytes achieve and maintain their activated state is unknown. Antigen-specific activation of T lymphocytes is dependent upon antigen-presenting cells which express HLA-DR class II major histocompatibility complex molecules, such as epidermal Langerhans cells. In addition to CD1+DR+ Langerhans cells, cutaneous T-cell lymphoma lesional epidermis contains major histocompatibility complex class II positive non-Langerhans cell populations, including CD1+OKM5+ bone-marrow-derived cells and DR+ keratinocytes. We asked whether any of these epidermal cell populations demonstrate capacity to activate T lymphocytes. Various numbers of epidermal cells from uninvolved and involved cutaneous T-cell lymphoma plaques were therefore used to stimulate autologous CD4+ and CD8+ T lymphocytes in the absence of exogenous antigen. Involved epidermal cells potently induced proliferation of CD4+ T lymphocytes (S.I. +/- SEM = 466 +/- 45). In contrast, uninvolved epidermal cells only induced background levels of proliferation (S.I. +/- SEM = 2 +/- 0.5, N = 8, p less than 0.01). Neither involved nor uninvolved epidermal cells were able directly to activate CD8+ lymphocytes. The capability of involved epidermal cells to activate CD4+ T lymphocytes was dependent upon CD1+DR+ leukocytes and not DR+ keratinocytes, because depletion of either HLA-DR+, CD1+ or HLe1+ epidermal cells totally abrogated the T-lymphocyte proliferation. Interestingly, on a cell per cell basis CD1+DR+ cells obtained from involved skin, demonstrated relative to CD1+DR+ cells from uninvolved skin, enhanced capacity to activate CD4+ T lymphocytes. Furthermore, CD1+OKM5+ cells from involved epidermis stimulated autologous CD4+ T lymphocytes. This indicates that a unique hitherto undescribed CD1+OKM5+ epidermal antigen-presenting cell population may participate in T-lymphocyte activation. These findings provide support for the concept that the epidermal cells in cutaneous T-cell lymphoma patients, particularly the antigen-presenting cells, may contribute significantly to the activation of CD4+ malignant and/or non-malignant inflammatory T lymphocytes within the skin.     

Skewed expression of activation, differentiation and homing-related antigens in circulating cells from patients with cutaneous T cell lymphoma associated with CD7- T helper lymphocytes expansion.

Mycosis fungoides and Sézary syndrome represent the most frequent forms of cutaneous T cell lymphoma. Both are characterized by skin infiltrating and/or circulating malignant cells displaying a CD4+CD7- phenotype in the majority of cases. Because an expansion of CD4+CD7- cells may also be found in inflammatory dermatoses or in the aging process, we evaluated, by flow cytometry, the relationship between CD7 expression and the distribution of differentiation/activation or homing antigens on peripheral blood lymphocytes from 36 cutaneous T cell lymphoma patients and from healthy donors. CD4+CD7- cells were increased in all patients with cutaneous T cell lymphoma. As a consequence, the CD7+/- ratio was reduced in stage I-II mycosis fungoides (3.96 vs 6.55 in healthy donors), and inverted in stage III-IV MF and Sézary syndrome (0.28 and 0.12 respectively). In the late stage of disease, the CD7+/- inverted ratio was strictly related to the expression of CD15s, CD60, and CD45R0, and the lack of expression of CD26 and CD49d. Interestingly, in leukemic patients, this phenotype was also associated with peculiar morphologic (large size) or phenotypical (CD3dim expression) characteristics. Furthermore, a progressive reduction of circulating CD8+ cells was also seen throughout all stages of disease. The presence of these populations in cutaneous T cell lymphoma at late phases of disease and Sézary syndrome suggests that all of these molecules may play an important part in the activation pathway and skin homing of circulating T cells in lymphoproliferative disorders. Therefore, this may constitute a distinctive feature in cutaneous T cell lymphoma patients with more aggressive characteristics.     

Lacking CD56 expression in a relapsing cutaneous blastic plasmacytoid dendritic cell neoplasm after allogeneic bone marrow transplantation: FISH analysis revealed loss of 11q

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare entity characterized by a CD4+/CD56+/CD123+ immunophenotype and a fatal clinical course. The average survival of 12–14 months may be prolonged by allogeneic bone marrow transplantation (BMT). Objectives We report about a male patient who suffered from BPDCN with a typical histology and co‐expression of CD4/CD123 and a CD56 expression by 80% of the tumour cells. The cutaneous tumour relapse after chemotherapy and allogeneic BMT was completely negative for CD56. Methods We performed interphase fluorescence in situ hybridization (FISH) analysis of tumour tissue, asserved before and after BMT, using specific probes for chromosome 11, which encompass the CD56 gene region. Results The tumour cells revealed a partial loss of 11q as well as a monosomy of chromosome 11. Conclusion This case demonstrates for the first time that loss of CD56 expression can also occur as a secondary event after chemotherapy and BMT. In our case, DNA loss of 11q23 could be responsible for the negativity of 20% of tumour cells as observed before chemotherapy. However, the complete loss of CD56 expression in the relapsed tumour cannot be explained by the loss of 11q23 alone. Additional factors such as chemotherapy‐induced mutations might also have contributed.