Hodgkin Lymphoma Malignancies Research Articles

P029: Are Reed-Sternberg cells stuck in mitosis by short nucleoplasmic bridges as a consequence of centromeric instability?

Background: Multinucleated giant tumor cells are frequently observed in lymph nodes of untreated lymphoma patients. Malignant Hodgkin lymphoma (HL) cells i. e. small Hodgkin and large bi- or multinucleated Reed-Sternberg (HRS) cells are characterized by genomic instability and downregulation of numerous key regulators of e.g. cell cycle, spindle apparatus, cytokinesis and cell lineage differentiation. So far, the formation of HRS cells remains obscure. We have demonstrated previously that telomere instability is involved in the proliferation of small cells into large binucleated cells. Here, we have used a collection of HL cell lines to analyze the successive steps involved in the transformation of the mononucleated into the multinucleated RS-like cells. Materials and Methods: Seven HL cell lines and 30 HL lymph nodes were used. Cytokinesis-block micronucleus assay and telomere and centromere staining followed by the M-FISH technique were employed to analyze chromosomal instability. DNA repair pathways were investigated. Results: We demonstrate that telomere dysfunction in HL cell lines is associated with the formation of dicentric chromosomes with both centromeres in close proximity, but also with a high rate of formation of micronuclei. Two morphologically different types of nucleoplasmic bridges (NPBs) were observed: (1) Long NPBs related to telomere dysfunction and chromosome fusions, and (2) short NPBs related to centromere breakpoints with configurations of cells looking like “stuck” together as binucleated cells. Short NPBs and binucleated cells were seen in the cultures of all HL cell lines. However, each HL cell line was characterized by an individual signature of the proportion of long and short NPBs, which correlated with centrosome amplification and formation of stable binucleated cells. Similar mechanisms were identified in HL patient lymph nodes prior to treatment, thus underscoring the biological significance of our findings in cell cultures. Transcriptome analysis confirmed the variations in the DNA repair pathways regarding the rate of large cells among the different HL cell lines. Conclusion: The formation of dicentric chromosomes related to centromere instability, and short NPBs were associated with the emergence of binucleated cells through different mechanisms. Our findings open a novel route to understanding the transition from mononucleated cells to multinucleated cells in HL and in other B-cell lymphomas.

Assessment of oral mucositis degree due to cytostatic treatment in patients with malignant lymphomas

Abstract Introduction: Oral mucositis characterized by inflammation of the oral mucosa, ulcers, angular cheilitis, accompanied by pain in the maxillary facial area are symptoms of patients who have undergone cytostatic treatment, affecting over 75% of high-risk patients. Material and methods: From the total of 182 patients with hematological malignancies, we selected 59 patients, diagnosed with malignant lymphomas and treated at the Hematology Department of the Medical Clinic 1 in Tîrgu Mureș, between July 2013 and June 2016, analyzing the data in the data observation sheets. The study is a retrospective one. Results: In the group of patients studied, who were treated based on the aforementioned cytostatic plans, we found that the CVP + Rituximab plan frequently causes 1st and 2nd class stomatitis, with no patients with 3rd and 4th class stomatitis. The CHOP + Rituximab therapy plan in a total of 80 applications had complications of 1st and 2nd class stomatitis, much more frequent 1st class without stomatitis of 2nd and 4th degree. Grade III stomatitis occurs in two cases in the CHOP-Bleo belts. Introducing dental medicine in the context of medical multidisciplinarity in oncology hematology is a real necessity because the oral complications of chemotherapy treatments by their severity can lead to compromise of the treatment protocol by reducing the doses or even stopping the treatment Conclusions: Malignant hemopathies represent a significant percentage in dental disorders, and among them, the maximum severity belongs to the non-Hodgkin and Hodgkin malignant lymphomas. Stomatitis, also called gingivotoxic stomatitis caused by medication, is an acute oral complication, with erythema and edema of the entire oral cavity. The role of the dentist in the diagnosis, prevention and treatment of oral lesions, following the cytostatic therapy, is extremely important.

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1

CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. First, we confirmed high expression of CD123 in 2 of the 3 HL cell lines (KM-H2 and L-428), and its absence in NK cells. Cytotoxicity of haNK cells against CD123-positive HL cells was significantly higher in the presence of CSL362. This was also shown with IL-15-activated primary NK cells, although haNK cells showed a 10.87-fold lower estimated half-maximal stimulatory effective concentration (EC50). CSL362 facilitated a significant increase in the expression of CD107a, intracellular IFN-γ and TNF-α and enhanced expression of c-JUN, PLD-1, and ARF6 by NK cells. Inhibition of the ARF6–PLD-1 axis (NAV2729), but not of the MAPK pathway (U0126), completely abrogated CSL362-facilitated antibody-dependent cell-mediated cytotoxicity (ADCC) in haNK and activated primary NK cells. Our results support CD123 as an immunotherapeutic target for HL and the combination of NK cells and CSL362 as a treatment strategy for HL.

Le lymphome malin Hodgkinien au cours de la grossesse; quelle modalité thérapeutique: à propos d'un cas et une revue de la littérature

Bien que le lymphome malin Hodgkinien ou (maladie de Hodgkin) ne représente que 10% de tous les lymphomes, c'est l'un des sous-types de lymphomes les plus communs diagnostiqués pendant la grossesse, en grande partie à cause de l'incidence maximale de la maladie qui coïncide avec l'âge de reproduction. La prise en charge d'une patiente enceinte atteinte d'une maladie de Hodgkin nécessite une approche multidisciplinaire, ainsi qu'une communication efficace avec le patient et sa famille. L'objectif est d'optimiser les chances de guérison de la mère tout en permettant l'accouchement d'un enfant en bonne santé. Nous rapportant un cas rare d'une patiente enceinte diagnostiquée pour une maladie de Hodgkin à 17 semaines d'aménorrhée.

Association between SLC19A1 Gene Polymorphism and High Dose Methotrexate Toxicity in Childhood Acute Lymphoblastic Leukaemia and Non Hodgkin Malignant Lymphoma: Introducing a Haplotype based Approach.

BackgroundWe investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML).Patients and methodsEighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities.ResultsPatients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030).ConclusionsSLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results.

Molecular Analysis of IGH and Incomplete IGH D-J Clonality Gene Rearrangements in Hodgkin Lymphoma Malignancies.

We evaluated molecular clonality in immunoglobulin heavy chain (IGH) and incomplete IGH D-J genes for improvement of clinical diagnosis of Hodgkin's lymphoma (HL). We applied BIOMED-2 protocols in HL cases, which were previously approved by clonality detection in non-Hodgkin lymphoma (NHL) cases. We investigated 50 consecutive FFPE samples of classical HL (cHL) patients to assess IGH and IGH D-J clonal gene rearrangements by multiplex PCR protocols, which were provided by the European Biomedicine and Health (BIOMED-2) Concerted Action Project BMH4-CT98-3936. In the present study, there was a monoclonality of 86% (43/50) including a clonality of 74% (37/50) for IGH and a clonality of 42% (21/50) in IGHD-J. In addition, a lack of clonality was detected in 14% (7/50) of cases. Frequent gene rearrangements were detected in framework (FR) III (54%) and FRII (20%), whereas no clonality was seen in FRI. Furthermore, a monoclonality of 28% and 14% was detected in the DH(1-6)-JH and DH(see symbol)-JH gene rearrangements, respectively. The present study suggests that the complete IGH and incomplete IGH D-J clonality gene rearrangement assays using BIOMED-2 protocols could be considered a valuable method for detection of clonal gene rearrangements, especially in HL cases.

LOCALIZED FORM OF LYMPHOMATOID PAPULOSIS, EVALUATING ING IN T-CELL LYMPHOMA – Case Report

SUMMARY Lymphomatoid papulosis is presented by spontaneously regressing cutaneous infiltrates, that microscopically resemble a lymphomas and may evolve into Hodgkin or non- Hodgkin malignant lymphoma. We present a case of Lymphomatoid papulosis in a 64 years old male, who complains from reddish non painful papules, localized symmetrically on the back and lateral zone of the legs. The patient was treated for 10 weeks with low dose of methotrexat (15 mg per week) with good clinical result. One year after treatment interruption the same patient had a similar clinical changes and hystochemical signs for development of T-cell lymphoma.

Évaluation de la réponse thérapeutique en cancérologie : place de l’imagerie isotopique

In comparison with conventional imaging, nuclear medicine offers an original metabolic approach for the assessment of the therapeutic response. Gallium 67, thallium 201, technetium 99m-labeled sestamibi and diphosphonates can be performed for therapeutic response assessment in lymphoma, brain and breast tumours, sarcoma, or bone metastasis. PET-CT facilities are now easily available in France and are ready to provide a new and accurate tool in oncology, specially for therapeutic evaluation. The procedure consists in the injection of fluor-18-fluoro-déoxyglucose (18FDG), an analogue of glucose, followed by a PET then a CT acquisition for FDG uptake abnormalities location. Therapeutic response is assessed by a decrease of 18FDG tumoral uptake between two consecutive studies. Methodology and interpretation criteria have been recently defined in international guidelines. 18FDG-PET-CT seems to be a valuable tool for therapeutic response assessment of patients with Hodgkin or non Hodgkin malignant lymphoma. Promising preliminary results have been recently published for lung, gastro-intestinal and head and neck cancers. PET-CT could also be able to predict the therapeutic response after the first courses of chemotherapy, allowing an early treatment optimization. Finally, new PET agents pave the way for molecular imaging with promising results in gene therapy and targeted treatment in oncology.

Sekundärneoplasien nach erfolgreicher Primärtherapie des malignen Hodgkin-Lymphoms

Malignant Hodgkin's lymphoma (HL) has become a curable disease through the increasing intensity of the treatment strategies applied. These regimens are aggressive, including radiotherapy and chemotherapy leading to the possibility of secondary malignancies. The German Hodgkin Lymphoma Study Group considered three cohorts including 5,411 patients with all stages of HL. In 127 patients a secondary solid tumor was diagnosed (cumulative risk 2%, median follow-up 72 months), with bronchial carcinomas (23.6%) and colorectal adenocarcinomas (20.5%) being the most frequent neoplasms. Secondary acute myeloid leukemia was found in 36 patients, another ten developed myeloid dysplasia (cumulative risk 1%, median follow-up 55 months). A total of 52 patients revealed a non-Hodgkin's lymphoma (NHL; cumulative risk 0.9%, median follow-up 46 months). The overall incidence of secondary malignancies was 3.9% in patients who had been treated successfully for their HL with radio- and/or chemotherapy.A secondary NHL can be particularly difficult to be distinguished from the preceding HL. Therefore, in case of a suspected relapse, a complete histopathological work-up must be performed.

Malignant lymphoma of mucosa associated lymphoid tissue: a new etiology of amyloidosis

Non Hodgkin Malignant lymphomas (NHML) of mucosa associated lymphoid tissue (MALT) are known to have multiple involvement of the digestive tract. We report one case, presenting with an infiltrative process of the jejuno-ileum, associating lymphoplasmacytoid proliferating cells and amyloidosis. The plasmacytoid cells expressed Alpha and scarce Mu heavy chains, and lambda light chain. Lympho-epithelial lesions were more obvious at the second site of involvement, in the gastric mucosa. The amyloid substance was negative with the Amyloid A component antibody and gave a background noise with Alpha, Mu and lambda chains. No similar report of amyloidosis associated with MALT NHML has been found in the literature.

Primary non Hodgkin's malignant lymphoma of the vagina: Report of 3 cases with review of the literature

Twenty cases of primary non-Hodgkin's malignant lymphoma (ML) of the vagina were studied: the 17 cases reported in the literature, and 3 further cases observed at the Hotel-Dieu Hospital in Paris over the last 10 years. The mean age of the women was 49 years. The most frequent complaint was vaginal bleeding, only a few patients presented an ulcerated mass. No evidence of ML was seen on any of the cervico-vaginal cytologic smears. Diagnosis was made on the vaginal biopsy. According to the Kiel classification, 8 of these ML were of low malignancy and 12 of high malignancy. Apart from one of our cases, which was an angiocentric pleomorpbic T ML with predominance of medium-sized cells, they were all B ML. According to the Ann Arbor staging system for extra-nodal ML, 12 of these ML were stage IE, 2 were stage IIE and 2 others stage IVE. Eight patients died, 6 of ML less than 17 months after diagnosis, 2 much later of diseases unrelated to ML. The mean follow-up period of patients who survived, free of disease, was 75 months. The surgical treatment has to be limited, associated with polycbemotberapy and completed by local radiotherapy.

Qui se cache derrière la maladie de Castleman multicentrique ? À propos de 11 observations

We report 11 cases of multicentric Castleman's disease. Four patients presented with isolated lymphadenopathy, 3 patients had lymphadenopathy and associated dysimmune disease (2 POEMS' syndrom, 1 mediterranean Kaposi sarcoma), and 4 patients developed non Hodgkin malignant lymphoma.

Non Epidermotropic Cutaneous Lymphoma Ending in Leukemia: A Case of Adult T Cell Lymphoma (ATL) in France?

A case of uncommon non Hodgkin malignant lymphoma with initial skin involvement is reported. The pathological pattern does not come under standard classifications. An aspect of non epidermotropic diffuse pleomorphic lymphoma is observed. In an immunological cell membrane study, the T-cell lineage of the malignant proliferation exhibited a very unusual pattern including the presence of the E rosette receptor and the expression of HLA-DR monomorphic determinant. This type of T cell malignant lymphoma can probably be included in the group of adult T cell leukemia/lymphoma (ATL) which is endemic in South Western Japan and occasionally observed in Western countries. The emergence of such cases in these countries raises important epidemiological questions.

Immunoelectronmicroscopic Profile of Intracytoplasmic Immunoglobulins in B Non Hodgkin's Malignant Lymphomas: Comparison with the Normal Pattern of B Lymphoid Cells

An immunoelectronmicroscopic method using Fab fragment of anti human IgG (H + L) has been employed to study the localization of cytoplasmic immunoglobulins in the tumoral cells of 12 B non Hodgkin's malignant lymphomas (B-M.L.). A comparison with normal homologous B lymphoid cells was performed on 10 non tumoral reactive lymph nodes. Immunostaining was observed in PNC, RER and Golgi complex. The criterions of differentiation were discussed in the different B-M.L.. Because of a granular hyaloplasmic immunostaining in normal and tumoral centroblasts and immunoblasts, monospecific antibodies against gamma, mu, alpha heavy chains were used to rule out a non specific uptake. Presence of mu heavy chain was discussed as an argument for immunoglobulin free ribosomal synthesis.