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Hodgkin's Lymphoma

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2018) | Viewed by 46889

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Special Issue Editors

Prof. Dr. Hans Knecht

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Division of Hematology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, QC, Canada
Interests: 3D nuclear structure; telomere/shelterin dysfunction; Reed-Sternberg cell; Hodgkin’s lymphoma; EBV; LMP1 oncogene
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Prof. Dr. Camille Laurent

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Service d’anatomie et cytologie pathologique, Institut Universitaire du Cancer Toulouse- Oncopole, 1 av Irène Joliot-Curie, 31059 Toulouse, France
Interests: Tumoral microenvironment/Immune escape; Molecular pathology of B-cell lymphomas; Relapsing/refractory Hodgkin’s lymphoma

Special Issue Information

Dear Colleagues,

Hodgkin’s lymphoma is unique amongst germinal-center B-cell derived malignant lymphomas through its presentation. The mononuclear Hodgkin and diagnostic, at least bi-nuclear Reed-Sternberg cells, count generally for only 1–3% of the total nodal cellular components. Within the same case, the nuclear volume of distinct Hodgkin cells may vary >500% and Reed-Sternberg cells may be composed from 2 up to >10 nuclei. The clinical presentation may be rapid with/without impressive B-symptoms and localized or multiple lymphadenopathies, or slow with/without B-symptoms and localized or multiple lymphadenopathies. Hodgkin’s lymphoma is associated with Epstein-Barr-virus and expression of the LMP1 oncogene in about 40–50% of cases but with considerable variability according to socio-economic status and geographic localization. Apart the constitutive NF-κB activation, aberrant Notch-signalling, JAK/STAT activation, and inactivating SOCS1 mutations, an increasing pathogenic importance of non-malignant lymphoid subpopulations as well as telomere/shelterin interactions within the tumor cells are emerging. Chemotherapy, combined chemo-radiotherapy, autologous stem-cell transplant, and recently immunotherapy, increased the cure rate in Hodgkin’s lymphoma to >80%. However, despite this therapeutic success, about 15% of patients succumb to relapsing/refractory disease. Thus, deeper understanding of the pathogenic mechanisms is still a must and a challenge.

This Special Issue will address innovative research efforts to further characterize relapsing/refractory disease at the epidemiologic, diagnostic, molecular, and therapeutic level.

Prof. Dr. Hans Knecht
Prof. Dr. Camille Laurent
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (10 papers)

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Research

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17 pages, 3943 KiB

Open AccessArticle

Profiling Immune Escape in Hodgkin’s and Diffuse large B-Cell Lymphomas Using the Transcriptome and Immunostaining

by Sarah Péricart, Marie Tosolini, Pauline Gravelle, Cédric Rossi, Alexandra Traverse-Glehen, Nadia Amara, Camille Franchet, Elodie Martin, Christine Bezombes, Guy Laurent, Pierre Brousset, Jean-Jacques Fournié and Camille Laurent

Cancers 2018, 10(11), 415; https://doi.org/10.3390/cancers10110415 - 31 Oct 2018

Cited by 18 | Viewed by 4120

Abstract

Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin’s lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin’s lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3⁺ and CD4⁺ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8⁺ T-cells, but HL had less CD68⁺CD163⁺ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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28 pages, 13167 KiB

Open AccessArticle

Establishment and Characterization of a Reliable Xenograft Model of Hodgkin Lymphoma Suitable for the Study of Tumor Origin and the Design of New Therapies

by Radhia M’kacher, Monika Frenzel, Mustafa Al Jawhari, Steffen Junker, Corina Cuceu, Luc Morat, Anne-Laure Bauchet, Lev Stimmer, Aude Lenain, Nathalie Dechamps, William M. Hempel, Geraldine Pottier, Leonhard Heidingsfelder, Eric Laplagne, Claire Borie, Noufissa Oudrhiri, Dima Jouni, Annelise Bennaceur-Griscelli, Bruno Colicchio, Alain Dieterlen, Theodore Girinsky, Raphael Boisgard, Jean Bourhis, Jacques Bosq, Thomas Mehrling, Eric Jeandidier and Patrice Carde Show full author list Hide full author list

Cancers 2018, 10(11), 414; https://doi.org/10.3390/cancers10110414 - 31 Oct 2018

Cited by 5 | Viewed by 4487

Abstract

To identify the cells responsible for the initiation and maintenance of Hodgkin lymphoma (HL) cells, we have characterized a subpopulation of HL cells grown in vitro and in vivo with the aim of establishing a reliable and robust animal model for HL. To validate our model, we challenged the tumor cells in vivo by injecting the alkylating histone-deacetylase inhibitor, EDO-S101, a salvage regimen for HL patients, into xenografted mice. Methodology: Blood lymphocytes from 50 HL patients and seven HL cell lines were used. Immunohistochemistry, flow cytometry, and cytogenetics analyses were performed. The in vitro and in vivo effects of EDO-S101 were assessed. Results: We have successfully determined conditions for in vitro amplification and characterization of the HL L428-c subline, containing a higher proportion of CD30−/CD15− cells than the parental L428 cell line. This subline displayed excellent clonogenic potential and reliable reproducibility upon xenografting into immunodeficient NOD-SCID-gamma (−/−)(NSG) mice. Using cell sorting, we demonstrate that CD30−/CD15− subpopulations can gain the phenotype of the L428-c cell line in vitro. Moreover, the human cells recovered from the seventh week after injection of L428-c cells into NSG mice were small cells characterized by a high frequency of CD30−/CD15− cells. Cytogenetic analysis demonstrated that they were diploid and showed high telomere instability and telomerase activity. Accordingly, chromosomal instability emerged, as shown by the formation of dicentric chromosomes, ring chromosomes, and breakage/fusion/bridge cycles. Similarly, high telomerase activity and telomere instability were detected in circulating lymphocytes from HL patients. The beneficial effect of the histone-deacetylase inhibitor EDO-S101 as an anti-tumor drug validated our animal model. Conclusion: Our HL animal model requires only 10³ cells and is characterized by a high survival/toxicity ratio and high reproducibility. Moreover, the cells that engraft in mice are characterized by a high frequency of small CD30−/CD15− cells exhibiting high telomerase activity and telomere dysfunction. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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18 pages, 5663 KiB

Open AccessArticle

Distinct 3D Structural Patterns of Lamin A/C Expression in Hodgkin and Reed-Sternberg Cells

by Fabio Contu, Aline Rangel-Pozzo, Peter Trokajlo, Landon Wark, Ludger Klewes, Nathalie A. Johnson, Tina Petrogiannis-Haliotis, John G. Gartner, Yuval Garini, Roberta Vanni, Hans Knecht and Sabine Mai

Cancers 2018, 10(9), 286; https://doi.org/10.3390/cancers10090286 - 24 Aug 2018

Cited by 18 | Viewed by 3938

Abstract

Classical Hodgkin’s lymphoma (cHL) is a B-Cell lymphoma comprised of mononuclear Hodgkin cells (H) and bi- to multi-nucleated Reed-Sternberg (RS) cells. Previous studies revealed that H and RS cells express lamin A/C, a component of the lamina of the nuclear matrix. Since no information was available about the three-dimensional (3D) expression patterns of lamin A/C in H and RS cells, we analyzed the 3D spatial organization of lamin in such cells, using 3D fluorescent microscopy. H and RS cells from cHL derived cell lines stained positive for lamin A/C, in contrast to peripheral blood lymphocytes (PBLs), in which the lamin A/C protein was not detected or weak, although its presence could be transiently increased with lymphocyte activation by lipopolysaccharide (LPS). Most importantly, in H and RS cells, the regular homogeneous and spherically shaped lamin A/C pattern, identified in activated lymphocytes, was absent. Instead, in H and RS cells, lamin staining showed internal lamin A/C structures, subdividing the nuclei into two or more smaller compartments. Analysis of pre-treatment cHL patients’ samples replicated the lamin patterns identified in cHL cell lines. We conclude that the investigation of lamin A/C protein could be a useful tool for understanding nuclear remodeling in cHL. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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23 pages, 11044 KiB

Open AccessArticle

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability

by Corina Cuceu, Bruno Colicchio, Eric Jeandidier, Steffen Junker, François Plassa, Grace Shim, Justyna Mika, Monika Frenzel, Mustafa AL Jawhari, William M. Hempel, Sylwia Kabacik, Aude Lenain, Luc Morat, Theodore Girinsky, Alain Dieterlen, Joanna Polanska, Christophe Badie, Patrice Carde and Radhia M’Kacher

Cancers 2018, 10(7), 233; https://doi.org/10.3390/cancers10070233 - 13 Jul 2018

Cited by 14 | Viewed by 5052

Abstract

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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17 pages, 5986 KiB

Open AccessArticle

The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes

by Radhia M’kacher, Corina Cuceu, Mustafa Al Jawhari, Luc Morat, Monika Frenzel, Grace Shim, Aude Lenain, William M. Hempel, Steffen Junker, Theodore Girinsky, Bruno Colicchio, Alain Dieterlen, Leonhard Heidingsfelder, Claire Borie, Noufissa Oudrhiri, Annelise Bennaceur-Griscelli, Olivier Moralès, Sarah Renaud, Zoé Van de Wyngaert, Eric Jeandidier, Nadira Delhem and Patrice Carde Show full author list Hide full author list

Cancers 2018, 10(6), 169; https://doi.org/10.3390/cancers10060169 - 30 May 2018

Cited by 15 | Viewed by 5014

Abstract

Background: We analyzed telomere maintenance mechanisms (TMMs) in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA) was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT) was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30−/CD15− cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10⁻³), event-free survival (p < 10⁻⁴), and freedom from progression (p < 10⁻³) and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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Review

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12 pages, 219 KiB

Open AccessReview

Novel Therapies and Approaches to Relapsed/Refractory HL Beyond Chemotherapy

by Alain Antoine Mina, Chetan Vakkalagadda and Barbara Pro

Cancers 2019, 11(3), 421; https://doi.org/10.3390/cancers11030421 - 25 Mar 2019

Cited by 7 | Viewed by 3081

Abstract

Although Hodgkin lymphoma (HL) is highly curable with first-line therapy, relapses occur in approximately 10–20% of patients with early stage disease and 30–40% of patients with advanced stage disease. The standard approach for relapsed or refractory disease is salvage therapy, followed by consolidation with high dose therapy and autologous stem cell transplant (ASCT). Patients who achieve a complete response to salvage therapy prior to ASCT have better outcomes, thus recent studies have focused on incorporating newer agents in this setting. Major challenges in the management of relapsed patients remain how to choose and sequence the many salvage therapies that are currently available and how to best incorporate novel agents in the current treatment paradigms. In this article, we will summarize the most recent advances in the management of patients with recurrent HL and will mainly focus on the role of new agents approved and under investigation. Aside from brentuximab vedotin and checkpoint inhibitors, other novel agents and therapies are showing promising early results. However, at least with some of the newest targeted strategies, it is important to recognize that we are facing new challenges in terms of toxicities, which require very close monitoring and education of both the patient and treating physician. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

15 pages, 980 KiB

Open AccessReview

The Role of Immune Checkpoint Inhibitors in Classical Hodgkin Lymphoma

by Nicholas Meti, Khashayar Esfahani and Nathalie A. Johnson

Cancers 2018, 10(6), 204; https://doi.org/10.3390/cancers10060204 - 15 Jun 2018

Cited by 27 | Viewed by 7168

Abstract

Hodgkin Lymphoma (HL) is a unique disease entity both in its pathology and the young patient population that it primarily affects. Although cure rates are high, survivorship can be linked with significant long-term morbidity associated with both chemotherapy and radiotherapy. The most significant recent advances have been with the use of the anti-CD30-drug conjugated antibody brentuximab vedotin (BV) and inhibitors of program death 1 (PD-1). HL is genetically wired to up-regulate program death ligand 1 (PD-L1) in >95% of cases, creating a state of so-called “T cell exhaustion”, which can be reversed with immune checkpoint-inhibitor blockade. The overall and complete response rates to PD-1 inhibitors in patients with relapsed or refractory HL are 70% and 20%, respectively, with a long median duration of response of ~16 months. In fact, PD-1 inhibitors can benefit a wide spectrum of relapsed HL patients, including some who have “progressive disease” by strict response criteria. We review the biology of HL, with a focus on the immune micro-environment and mechanisms of immune evasion. We also provide the rationale supporting the use of PD-1 inhibitors in HL and highlight some of the challenges of monitoring disease response in patients treated with this immunotherapy. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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11 pages, 509 KiB

Open AccessReview

[¹⁸F]FDG-PET/CT in Hodgkin Lymphoma: Current Usefulness and Perspectives

by Salim Kanoun, Cedric Rossi and Olivier Casasnovas

Cancers 2018, 10(5), 145; https://doi.org/10.3390/cancers10050145 - 18 May 2018

Cited by 17 | Viewed by 5015

Abstract

Functional imaging using 18-fluorodeoxyglycose ([¹⁸F]FDG) positron emission tomography combined with computed tomography (PET/CT) has become a major imaging modality in Hodgkin lymphoma. This imaging modality allows for a significant improvement in staging, increased sensitivity, which involves differentiating residual tumors from fibrosis during assessment, and highly impacts treatment decisions into new PET-driven strategies. This review presents the main scientific data concerning the current applications of [¹⁸F]FDG-PET/CT in Hodgkin lymphoma at baseline, interim, and the end of treatment evaluation along with the main PET-driven trials for therapeutic decisions. The emergence of total metabolic tumor volume as a new functional prognostic factor will also be discussed. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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19 pages, 39803 KiB

Open AccessFeature PaperReview

Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives

by Corina Cuceu, William M. Hempel, Laure Sabatier, Jacques Bosq, Patrice Carde and Radhia M’kacher

Cancers 2018, 10(4), 91; https://doi.org/10.3390/cancers10040091 - 26 Mar 2018

Cited by 27 | Viewed by 5026

Abstract

The study of Hodgkin lymphoma (HL), with its unique microenvironment and long-term follow-up, has provided exceptional insights into several areas of tumor biology. Findings in HL have not only improved our understanding of human carcinogenesis, but have also pioneered its translation into the clinics. HL is a successful paradigm of modern treatment strategies. Nonetheless, approximately 15–20% of patients with advanced stage HL still die following relapse or progressive disease and a similar proportion of patients are over-treated, leading to treatment-related late sequelae, including solid tumors and organ dysfunction. The malignant cells in HL are characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations, complex chromosomal rearrangements, and aneuploidy. Here, we review the chromosomal instability mechanisms in HL, starting with the cellular origin of neoplastic cells and the mechanisms supporting HL pathogenesis, focusing particularly on the role of the microenvironment, including the influence of viruses and macrophages on the induction of chromosomal instability in HL. We discuss the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management. Full article

(This article belongs to the Special Issue Hodgkin's Lymphoma)

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