Cutaneous CD4+/CD56+ hematodermic neoplasm

CD4+/CD56+ hematodermic neoplasm, formerly known as blastic NK cell lymphoma, is a rare and aggressive neoplasm with a high incidence of cutaneous involvement, risk of leukemic dissemination and poor prognosis. 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 NKcell specific markers. Because of the rarity of this disease, we describe a 48 year old woman suffering from CD4+/CD56+ hematodermic neoplasm on her cheek without leukemic infiltration.     

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.     

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.     

A case of primary cutaneous CD56+, TdT+, CD4+, blastic NK-cell lymphoma in a 19-year-old woman.

The classification of blastic or blastoid natural killer (NK)-cell lymphoma is controversial. Reports of primary cutaneous blastic CD56+ NK-cell lymphoma are rare, which necessitates further clinicopathologic definition of this type of lymphoma. Most CD56+ lymphomas display angiocentric histologic features, especially in Asian patients, and these are mostly associated with the presence of Epstein-Barr virus (EBV) genome and with an aggressive clinical course. We report on a young woman with a primary cutaneous blastic NK lymphoma which showed no angiocentric features but showed an unusual immunophenotype; CD56+, TdT+, CD4+, EBV-, and germline configuration of T-cell receptor gene. This unusual lymphoblastic lymphoma seems to have an immature or progenitor NK cell lineage.     

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.     

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

BACKGROUND: 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. OBJECTIVES: To describe the clinical, pathological and molecular features in six cases of CD56+ lymphoma with cutaneous presentation. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

CD56 expression in a case of primary cutaneous CD30+ anaplastic large cell lymphoma

We describe clinicopathological features of an unusual case of CD30+/CD56+ T-cell lymphoma in a 58-year-old Korean man who presented with disseminated nodules, papules and hyperpigmented patches. Coexpression of CD30 and CD56 in T-cell lymphoma is very rare. Our patient did not respond to an intensive chemotherapy regimen, in contrast to the previously reported cases of primary cutaneous CD30+ anaplastic large cell lymphoma. Coexpression of CD56 might therefore identify a subset of CD30+ lymphomas with more aggressive features.     

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.     

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.     

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.     

Primary cutaneous CD56 positive lymphoma: a diagnostic conundrum in an unusual case of lymphoma

We present an unusual case of a CD56-positive T-cell lymphoma exhibiting immunophenotypic characteristics of both γδ T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal-type. The patient presented with a 2-month history of rapidly progressive, pruritic and cutaneous nodules on his arms. A biopsy showed a dense pan-dermal infiltrate of markedly atypical CD3-positive lymphocytes, compatible with tumor stage cutaneous T-cell lymphoma. Retrospective review of a preceding biopsy and flow cytometric analysis, performed at an outside institution, showed strong expression of surface CD3, CD7, CD43 and γδ T-cell receptor (TCR), findings consistent with a diagnosis of cutaneous γδ T-cell lymphoma. In light of these data, we performed additional studies that showed diffuse positive staining of the atypical lymphocytes for CD56, CD4 and CD43 as well as Epstein-Barr virus-encoded small nonpolyadenylated RNA (EBER). Interestingly, this case displays characteristic features of γδ T-cell lymphoma, with strong surface expression of CD3 and γδ-TCR, as well as characteristics of natural killer (NK)/T-cell lymphoma, including expression of CD4 and EBER positivity, that represent two separate categories in the current classification of cutaneous lymphomas. Taken together, these findings underscore the difficulty of rendering an unambiguous classification of the presented neoplasm given the close ontogenetic relationship between NK and cytotoxic T-cells and highlight the need for continued reevaluation of the current classification system.     

TCR gene-rearranged,extranodal NK/T-cell lymphoma,nasal type,presenting as gyrate patches

In the CD56+ cutaneous nasal-type NK/T-cell lymphoma strongly associated with latent EBV infection, subcutaneous or dermal nodules are the most common skin findings, but great morphologic heterogeneity has been noted including papules, infiltrated plaques, and ulcerated tumors, and TCR genes are mostly germline. We describe a case of nasal and nasal-type NK/T-cell lymphoma featuring multiple erythematous polycyclic patches on the trunk, which is similar to patch stage mycosis fungoides or other cutaneous T cell lymphoma. Immunohistochemical study of a skin biopsy specimen revealed CD2+, CD3epsilon+, CD56+, and CD45RO+ expression in the neoplastic cells. In situ hybridization using an anti-sense Epstein Barr virus early regions probe showed a positive reaction. However, clonal TCR beta gene rearrangement was found.     

Lymphomatoid papulosis with a natural killer-cell phenotype

Lymphomatoid papulosis (LyP) is defined as a recurrent self-healing papulonodular eruption with the histological features of a (CD30+) cutaneous T-cell lymphoma. The atypical cells usually have a CD3+/-, CD4+/-, CD8-, CD30+, CD56- T-cell phenotype. We report an unusual case of LyP, in which the atypical cells expressed a CD3-, CD4-, CD8-, CD30+, CD56+ phenotype. Detailed phenotypic and genotypic analysis confirmed that these cells had a natural killer (NK)-cell phenotype. Lymphomas with an NK-cell phenotype usually have a poor prognosis. However, the waxing and waning of papular lesions for more than 20 years and the excellent response to low-dose oral methotrexate in this patient suggest similar clinical behaviour to LyP cases with a T-cell phenotype.     

A Case of Aggressive NK/T-cell Lymphoma/Leukemia with Cutaneous Involvement in Adolescence

NK/T-cell lymphoma (NKTCL) is characterized by the expression of the NK-cell antigen CD56. Non-nasal NK/T-cell lymphomas are subdivided into primary cutaneous and 4 subtypes of secondary cutaneous lymphomas; nasal type, aggressive, blastic (blastoid), and other specific NK-like cell lymphoma. Aggressive NK/T-cell lymphoma/leukemia is a rare leukemic variant of nasal type NKTCL. We herein report a rare case of aggressive NK/T-cell lymphoma/leukemia with cutaneous involvement in adolescence.     

Cutaneous presentation of steroid responsive blastoid natural killer cell lymphoma

CD56+ lymphomas derived from natural killer (NK) cell lineage are rarely encountered in Western populations and their clinical and pathological features have not been fully defined. The majority of reported cases are lymphomas of the nasal cavity, which are most commonly seen in Asia. A subtype of CD56+ lymphoma has recently been described (blastoid NK-cell lymphoma) which characteristically presents in older patients with cutaneous infiltrates and disease at other nodal and extranodal sites. We describe a case that correlates well with the clinicopathological features of blastoid NK-cell lymphoma. An unusual feature in our patient was that the cutaneous features of the lymphoma showed complete resolution shortly following commencement of oral steroid therapy.     

Solitary primary cutaneous CD30+ large cell lymphoma of natural killer cell phenotype bearing the t(2;5)(p23;q35) translocation and presenting in a child

Primary cutaneous CD30+ large cell lymphoma is an unusual tumor most commonly seen in adults. Most of these lymphomas are of T-cell origin and carry a good prognosis. We present the case of a 4-year-old girl with stage IEA CD30+ large cell lymphoma with a CD56+ natural killer cell phenotype and the t(2;5)(p23;q35) translocation. After excision, the patient has been free of disease for 44 months. Primary cutaneous CD30+ large cell lymphoma is uncommon in children. To our knowledge, primary cutaneous CD30+ natural killer type lymphoma has not been reported previously. The indolent behavior of this tumor indicates its similarity to other primary cutaneous CD30+ large cell lymphomas and its difference from other CD56+ lymphomas involving the skin, which often exhibit an aggressive clinical course. Cases such as this one illustrate why the use of a single, or even a few, immunohistochemical stains can be misleading in regard to lymphoma classification and prognostication.     

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.     

Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T‐cell lymphomas: a clinicopathologic study of three cases

Primary cutaneous T‐cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical‐stained sections were examined in all the cases. Molecular analysis for rearrangement of the T‐cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T‐cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8? phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.     

Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma

Cutaneous peripheral T-cell lymphoma unspecified is a rare neoplasm that is infrequently associated with Epstein-Barr virus (EBV) infection. In contrast, extranodal natural killer (NK)/T-cell lymphoma, although also rare, is known to be strongly associated with EBV and occurs most commonly in the nasal region. We report the case of a 55-year-old male who presented with fever and an indurated cutaneous plaque with ulceration. This cutaneous neoplasm showed diffuse dermal lymphomatous infiltration and tumor necrosis, with neoplastic cells expressing CD2, cytoplasmic CD3 (CD3ε), CD8, CD16, CD30, T-cell intracellular antigen-1, and granzyme B but not CD56, BF1, or T-cell receptor (TCR) δ1. Furthermore, the tumor cells were noted to be diffusely positive for EBV by in situ hybridization. A monoclonal TCR gene rearrangement was demonstrated. The disease showed an aggressive clinical course, and the patient died within 3 weeks of diagnosis without complete staging or chemotherapy. According to the 2005 World Health Organization/European Organization for Research and Treatment of Cancer scheme for cutaneous lymphoma and the 2008 WHO classification for lymphoid neoplasms, our case would have been classified as a nasal type extranodal NK/T-cell lymphoma with T-cell lineage. However, the expressions of CD8 and CD16, in addition to a monoclonal TCR gene rearrangement, are unusual findings in NK/T-cell lymphoma, and we believe such a phenotype/genotype should be more appropriately classified as an EBV-positive peripheral T-cell lymphoma, unspecified with a cytotoxic phenotype. Detailed clinicopathologic and molecular studies of similar cases may shed light on the prognostic impact of NK vs. T-cell lineage on extranodal NK/T-cell lymphomas.