Prevalence of CD30 immunostaining in neoplastic mast cells: A retrospective immunohistochemical study.

Mastocytosis is a rare disease characterized by clonal neoplastic proliferation of mast cells (MCs). It ranges from skin lesions as cutaneous mastocytosis (CM) which may spontaneously regress to highly aggressive neoplasms with multiorgan involvement corresponding to some aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and/or mast cell sarcoma (MCS).There is increasing evidence of CD30 expression in neoplastic MCs of the bone marrow.

Impact of Expert Pathologic Review of Lymphoma Diagnosis: Study of Patients From the French Lymphopath Network.

Purpose To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care.

Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.

Background: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants.

Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children.

Haemophagocytic lymphohistiocytosis (HLH) has been rarely described in children treated for an anaplastic large-cell lymphoma (ALCL). We evaluated the incidence, the clinical and histological characteristics and the prognosis of HLH associated-ALCL. The medical, biological, cytological and histological data of patients treated for ALK-positive ALCL in the paediatric department of a single institution between 1975 and 2008 were analysed and assessed for HLH according to diagnosis criteria of the Histiocyte Society.

CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features.

Peripheral T-cell lymphoma, not otherwise specified is a heterogeneous group of aggressive neoplasms with indistinct borders. By gene expression profiling we previously reported unsupervised clusters of peripheral T-cell lymphomas, not otherwise specified correlating with CD30 expression. In this work we extended the analysis of peripheral T-cell lymphoma molecular profiles to prototypical CD30(+) peripheral T-cell lymphomas (anaplastic large cell lymphomas), and validated mRNA expression profiles at the protein level.

Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials.

Purpose: Systemic anaplastic large-cell lymphoma (ALCL) is a T-cell lymphoma, whose anaplastic lymphoma kinase (ALK) expression varies according to age. Long-term outcomes of chemotherapy-treated adults are not definitively established and should be evaluated.

Patients And Methods: Patients treated in three Groupe d'Étude des Lymphomes de l'Adulte prospective clinical trials with confirmed systemic ALCL after immunohistopathologic review and defined ALK expression status were analyzed.

Anaplastic lymphoma kinase as a therapeutic target.

Introduction: Anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, has been initially identified through its involvement in chromosomal translocations associated with anaplastic large cell lymphoma. However, recent evidence that aberrant ALK activity is also involved in an expanding number of tumor types, such as other lymphomas, inflammatory myofibroblastic tumor, neuroblastomas and some carcinomas, including non-small cell lung carcinomas, is boosting research progress in ALK-targeted therapies.

Areas Covered: The first aim of this review is to describe current understandings about the ALK tyrosine kinase and its implication in the oncogenesis of human cancers as a fusion protein or through mutations.

Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice.

A 4-weekly course of rituximab is safe and improves tumor control for patients with minimal residual disease persisting 3 months after autologous hematopoietic stem-cell transplantation: results of a prospective multicenter phase II study in patients with follicular lymphoma.

Background: This study explored the efficacy and safety of rituximab as treatment of clinical or molecular residual disease after autologous stem-cell transplantation (ASCT) in follicular lymphoma (FL).

Patients And Methods: Forty patients with CD20+ FL and clinically (group A, n = 14) or clono-specific PCR-detectable (group B, n = 25) residual disease persisting 3 months after ASCT received rituximab 375 mg/m² once weekly for 4 weeks.

Results: Response rate at day 50 was 36% [90% confidence interval (CI) 15-61] in group A (World Health Organization criteria) and 52% (90% CI 34-70) in group B (conversion PCR-undetectable status to undetectable status).

Technical note: Hapten synthesis, antibody production and development of an enzyme-linked immunosorbent assay for detection of the natural steroidal alkaloid Dendrogenin A.

We have recently discovered the existence of 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3β-ol, called Dendrogenin A (DDA), as the first endogenous steroidal alkaloid ever described in mammals. We found that the DDA content of tumors and cancer cell lines was low or absent compared with normal cells showing that a deregulation in DDA biosynthesis was associated with cancer and therefore suggesting that DDA could represent a metabolomic cancer biomarker. This prompted us to produce antibodies that selectively recognize DDA.

ALK+ALCLs induce cutaneous, HMGB-1-dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation.

Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK(+)ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase-positive (ALK(+)) lymphomas and human ALK(+)ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK(+) cells, and demonstrate extracellular HMGB-1-stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK(+) cells, which express the IL-8 receptors CXCR1 and CXCR2.

Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study.

Purpose: The prognostic value of pathologic characteristics of childhood ALK-positive anaplastic large-cell lymphomas (ALCL), such as histologic subtypes, immunophenotype, and presence of the t(2;5) translocation or its variants, was assessed.

Patients And Methods: All 375 patients with systemic ALK-positive ALCL included in an international trial launched by the European Intergroup for Childhood Non-Hodgkin's Lymphoma were reviewed by an international panel of pathologists based on conventional hematoxylin and eosin-stained and immunostained sections and classified according to the 2001 WHO classification.

Results: A small-cell (SC) or lymphohistiocytic (LH) component was observed in 114 (32%) of 361 patients, whereas ALCL of common type was diagnosed in 235 (65%) of 361 patients.

Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas.

The anaplastic lymphoma kinase (ALK), tyrosine kinase oncogene is implicated in a wide variety of cancers. In this study we used conditional onco-ALK (NPM-ALK and TPM3-ALK) mouse MEF cell lines (ALK+ fibroblasts) and transgenic models (ALK+ B-lymphoma) to investigate the involvement and regulation of angiogenesis in ALK tumor development. First, we observed that ALK expression leads to downregulation of miR-16 and increased Vascular Endothelial Growth Factor (VEGF) levels.

[Impact of the pathology in modern medicine].

In this review, the authors emphasize the pivotal role of the pathology in the setting of a revolution which progressively transforms medical sciences into basic sciences. Several key aspects of this specialty will be discussed together with the main perspectives in the fields of oncologic disorders.

MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression.

Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK(+)) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK(+) ALCL cell lines and biopsy specimens (n = 20) express a low level of miR-29a and that this down-modulation requires an active NPM-ALK kinase.

HuR-mediated control of C/EBPbeta mRNA stability and translation in ALK-positive anaplastic large cell lymphomas.

The CCAAT/enhancer-binding protein β (C/EBPβ) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK(+)). Although ALK-mediated C/EBPβ transcriptional activation has been reported, C/EBPβ mRNA possesses U- and AU-rich domains in its 3'-untranslated region (3'-UTR) that might be privileged targets for posttranscriptional control in ALK(+) ALCLs. The purpose of this study was to explore this possibility.

Immunoexpression of Survivin in non-neoplastic lymphoid tissues and malignant lymphomas using a new monoclonal antibody reactive on paraffin sections.

Survivin is a member of the inhibitor of apoptosis gene family, which is also implicated in mitosis regulation. Most reports in the literature impute poor prognosis to neoplasms with overexpression of this protein. The purpose of the present study is to validate and compare the immunohistochemical reactivity of malignant lymphomas and reactive lymphoid tissue using a new mouse monoclonal antibody to Survivin produced in our laboratory, 6-78.

[Molecular abnormalities in lymphomas].

Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas.

Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion.

Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.

Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia.

NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) and TPM3-ALK (nonmuscular tropomyosin 3-anaplastic lymphoma kinase) are oncogenic tyrosine kinases implicated in the pathogenesis of human ALK-positive lymphoma. We report here the development of novel conditional mouse models for ALK-induced lymphomagenesis, with the use of the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter. The expression of either oncogene resulted in the arrest of the differentiation of early B cells and lymphomagenesis.

Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases.

Background: Skin involvement is frequent in ALK-positive anaplastic large cell lymphomas. The role of an insect bite as a triggering event has been postulated but not well documented.

Design And Methods: We retrospectively investigated five cases of ALK-positive anaplastic large cell lymphoma who presented with skin lesions occurring after an insect bite.

Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma: a rare clinicopathologic entity with poor prognosis.

Purpose: Anaplastic lymphoma kinase (ALK) -positive diffuse large B-cell lymphoma (DLBCL) is a rare variant of DLBCL that has been described only in small case reports. To shed more light on the clinical and pathologic features and outcome of these tumors, we reviewed data from 38 patients.

Patients And Methods: We retrospectively analyzed 38 patients with ALK-positive DLBCL treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like regimens from different institutions to better define the presenting features, clinical course, and response to treatment.

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.

The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active.