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.     

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.     

Primary CD56 + nasal-type T/natural killer-cell subcutaneous panniculitic lymphoma: presentation as haemophagocytic syndrome

Natural killer (NK) cells are large granular lymphocytes that mediate cytotoxic reactions which are not restricted by the major histocompatibility complex. In recent years it has become apparent that a minor proportion of malignant lymphomas expresses an NK-cell phenotype defined by its reactivity with the CD56 antibody. Primary purely cutaneous CD56 + lymphomas have rarely been reported. They share a generally aggressive course and are highly associated with Epstein-Barr virus. We describe a patient with a primary cutaneous nasal-type T/NK-cell lymphoma that presented as a haemophagocytic syndrome and showed an aggressive clinical course.     

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.     

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.     

Cutaneous natural killer/T-cell lymphoma

Lymphomas are classified as either Hodgkin's or non-Hodgkin's. The 2 subtypes of non-Hodgkin's lymphoma that can present primarily in the skin are cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, both of which tend to be low-grade malignant neoplasms. Recently another distinct subtype of lymphoma was discovered, the natural killer (NK)/T-cell lymphoma, which can involve the skin in a primary or secondary fashion. The NK/T-cell subtype of lymphoma is characterized by the expression of the NK-cell antigen CD56. These CD56(+) lymphomas are further subdivided into nasal NK/T-cell lymphomas that commonly present as midfacial destructive disease and non-nasal NK/T-cell lymphomas that often arise in extranodal locations, including the skin. We report a case of aggressive NK-cell leukemia/lymphoma with numerous secondary cutaneous lesions and review the clinical and histopathologic spectrum of non-nasal CD56(+) lymphomas, with an emphasis on the dermatologic findings.     

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.     

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.     

Epstein-Barr virus-positive blastoid nasal T/natural killer-cell lymphoma in a caucasian

T/natural killer (NK)-cell lymphoma is a subtype of non-Hodgkin's lymphoma, with frequent cutaneous involvement; it follows an aggressive course. Most cases are reported in Asia, and typically present with nasopharyngeal involvement. There is a distinct variant known as blastoid T/NK-cell lymphoma, which affects elderly, non-Asian patients, with absence of nasal involvement. We report a middle-aged caucasian man who had blastoid T/NK-cell lymphoma with nasal involvement.     

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.     

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.     

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.     

Blastoid NK cell leukemia/lymphoma with cutaneous involvement

Malignant neoplasms from natural killer (NK) cells are characterized by their positivity for CD56 and absence of monoclonal TCR gene rearrangement. Recently, they have been classified into four main types (nasal and nasal-type NK cell lymphoma, aggressive NK cell leukemia/lymphoma, and blastoid NK cell leukemia/lymphoma), based on clinical features, racial predisposition, presence of azurophilic granules, immunophenotype and association with Epstein-Barr virus (EBV) infection. A 72-year-old Caucasian man presented with a malignant neoplasm comprised of blastoid cells without azurophilic granules in the Giemsa stain, with positivity for CD2, CD4, HLA-DR, CD45 and CD56, and negativity for CD3 (surface and cytoplasmic) and CD5. In situ hybridization for EBV and PCR analysis of rearrangement of the T cell receptor gene were negative. Based on these results, a diagnosis of blastoid NK cell lymphoma was made. In this case the first clinical manifestations were the cutaneous lesions, and, although the disease was already advanced at the diagnosis, the patient responded completely to the treatment and remains asymptomatic 14 months after diagnosis.     

Cutaneous CD8+ squamous T-cell bullous lymphoma

INTRODUCTION: Bullous forms of cutaneous T-cell lymphomas are rare. A new group of cutaneous T-cell lymphomas has recently been identified as a distinct clinicopathological and immunophenotype entity. These cutaneous T-cell lymphomas express a CD8+ phenotype, rarely expressed in other cutaneous T-cell lymphomas. CASE REPORT: We describe a cutaneous CD8+ squamous T-cell lymphoma with polymorphic clinical features, strongly epidermotropic lymphoid infiltrate and spongiosis, classical for this type of lymphoma. DISCUSSION: Bullous lesions in cutaneous T-cell lymphoma should evoke the possibility of a cutaneous CD8+ T-cell lymphoma, once other bullous diseases have been excluded. Spongiosis, rare in other types of T-cell lymphoma, and strongly epidermotropic pleomorphic lymphoid infiltrate are classical histological features. The association of polymorphic lesions, bullas and atypical CD8+ epidermotropic phenotype should evoke this diagnosis even at the early stage. Treatment is difficult and classical chemotherapy often fails. Prognosis is poor with a mean overall survival of 32 months.     

Use of an expanded immunohistochemical panel to distinguish cutaneous Hodgkin lymphoma from histopathologic imitators

In lymph nodes, classical Hodgkin lymphoma can typically be distinguished from non-Hodgkin lymphoma (NHL) by the presence of Hodgkin and Reed-Sternberg cells that co-express CD30 and CD15. However, anaplastic large cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL) can show identical features, and some cases of classical Hodgkin lymphoma lack CD15 expression, rendering them difficult to differentiate from CD30-positive NHL. The differential diagnosis of cutaneous Hodgkin lymphoma similarly includes ALCL and DLBCL, and, additionally, tumors of mycosis fungoides. Recent studies have shown that classical Hodgkin lymphoma is of B-cell origin in virtually all cases, and shows at least focal weak expression of the B-cell marker PAX5 and often focal weak expression and no expression of the B-cell markers Oct-2 and BOB.1, respectively. All three of these markers are almost invariably absent in T-cell lymphomas and are strongly expressed in B-cell lymphomas. We report a 40-year-old man with classical Hodgkin lymphoma who developed cutaneous nodules. A biopsy from one revealed Hodgkin/Reed-Sternberg cells with a similar immunophenotype to the diagnostic lymph node biopsy, namely CD30+/CD15+, diffusely but weakly PAX5+, focally weakly Oct-2+ and lacking BOB.1 expression, thereby confirming a diagnosis of cutaneous Hodgkin lymphoma. To our knowledge, this is the first report of the expression pattern of the combination of PAX5, Oct-2 and BOB.1 in the context of cutaneous involvement by Hodgkin lymphoma.     

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.     

Primary cutaneous B-cell lymphoma: a clinical, histological, phenotypic and genotypic study of 21 cases

The clinical, histological, phenotypic and genotypic features of 21 primary cutaneous B-cell lymphomas (CBCLs) have been investigated. The patients were 13 men and eight women aged 34-91 years (median 67) at diagnosis. Eighteen patients had localized disease, and three had multiple skin lesions at diagnosis. Twelve patients developed cutaneous or extracutaneous recurrences, and five died from malignant lymphoma 7-84 months (median 36) after diagnosis. Histological examination showed features of marginal zone/mucosa-associated lymphoid tissue (MALT)-type lymphoma in 12 cases. Three of these had transformed to diffuse large B-cell lymphoma (DLBCL) in relapse biopsies. The remaining cases were seven primary DLBCLs and two cases tentatively classified as follicle centre cell (FCC) lymphoma. The neoplastic B cells showed similar phenotypes and genotypes in most cases (CD20+, CD79+, CD5-, CD10-, cyclin D1-, bcl-2+, bcl-x-, bax-, t(14;18)-negative). p53 protein was expressed in five cases, and four harboured mis-sense or loss-of-function mutations in the p53 gene. Deletion or promoter region hypermethylation of the p16INK4a gene was detected in two patients with DLBCL. The level of retinoblastoma protein expression and the proliferative fraction were significantly higher in DLBCL (> 50%) than in MALT- or FCC-type lymphomas (< 10%). Features associated with an unfavourable prognosis were the presence of multiple skin lesions at diagnosis, transformation from MALT-type lymphoma to DLBCL, and possibly p16INK4a aberrations. It is concluded that most CBCLs are dissimilar from FCC lymphomas and seem to be more closely related to marginal zone/MALT-type lymphomas. It is also suggested that there are fundamental differences between DLBCL and other histological categories of CBCL, indicating that cutaneous DLBCL is a separate entity with an increased growth potential and genetic features similar to DLBCL originating in other anatomical sites.     

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.     

Cytotoxic γ/δ subcutaneous panniculitis-like T-cell lymphoma: report of a case with pulmonary involvement unresponsive to therapy

Peripheral subcutaneous panniculitis-like T-cell lymphoma (PSPTCL) is a rare form of cutaneous lymphoma recently proposed as a distinct clinicopathological entity. It usually presents with multiple indurated subcutaneous plaques or tumours, most commonly located on the extremities and trunk and clinically mimicking lobular panniculitis. Associated constitutional symptoms due to haemophagocytic syndrome may advance or, more often, complicate the clinical course in about 40-70% of cases. Finding of TIA-1+ and perforin + cytolytic granules in atypical pleomorphic lymphocytes suggests PSPTCL origin from granular cells of T-cell or natural killer cell phenotype. Cells have a CD3+ CD4+ CD8- or CD3+ CD4- CD8+ T-cell phenotype. Moreover, these lymphomas can express natural killer cell associated antigens, such as CD56, especially in gamma/delta variants. PSPTCL following an indolent clinical course with recurrent self-healing lesions have been described. The prognosis of most PSPTCL is poor even when treated with aggressive chemotherapy. This paper reports a case of PCTCL in a young woman with T-cytotoxic differentiation, with rapid progression unresponsive to several treatments.