bims-hodlyp Biomed News
on Hodgkin lymphoma: Pathology and Biology
Issue of 2023–10–15
twelve papers selected by
Old Bear
  1. Assessment of Effectiveness and Adverse Effect of New Combination Chemotherapy (irinotecan, cisplatin, and dexamethasone) in Relapse and Refractory Hodgkin Lymphoma.
  2. Molecular Characterization of Primary Mediastinal Large B-Cell Lymphomas.
  3. Improved survival of children and adolescents with classical Hodgkin lymphoma treated on a harmonised protocol in South Africa.
  4. The First Sign of Recurrent Angioimmunoblastic T-Cell Lymphoma: A Cutaneous Presentation.
  5. Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response.
  6. Epstein-Barr virus infection leading to multiorgan involvement in an immunocompetent man.
  7. Updates in pathobiological aspects of anaplastic large cell lymphoma.
  8. Classical Hodgkin Lymphoma on the Background of Castleman Disease: A Case Report.
  9. Revisiting the predictive role of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography on treatment outcome in early-stage favorable Hodgkin lymphoma.
  10. The Evolving Landscape of B Cells in Cancer Metastasis.
  11. FCRL1 immunoregulation in B cell development and malignancy.
  12. Could Immune Checkpoint Disorders and EBV Reactivation Be Connected in the Development of Hematological Malignancies in Immunodeficient Patients?
  1. Int J Hematol Oncol Stem Cell Res. 2023 Jul 01. 17(3): 194-199
    Assessment of Effectiveness and Adverse Effect of New Combination Chemotherapy (irinotecan, cisplatin, and dexamethasone) in Relapse and Refractory Hodgkin Lymphoma.
    Mahdi Tabarraee, Atefeh Rezaee, Sara Abolghasemi, Mojtaba Ghadiany, Maria Tavakoli Ardakani, Mahshid Mahdizadeh, Neda Hamidi, Katayoon Ghasemi.
      Background: Chemotherapy with Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen) cannot cure all patients with Hodgkin lymphoma. In this study, we evaluated the efficacy and adverse effect of a new regimen consist Irinotecan, Cisplatin, and Dexamethasone (ICD) in relapsed and refractory Hodgkin lymphoma as the second to fifth line of treatment. Materials and Methods: We performed a retrospective study in 26 relapsed or refractory patients with Hodgkin lymphoma receiving at least the first-line chemotherapy regimen (ABVD) and (ICD) as salvage therapy in Thaleghany Hospital from 2012 to 2018. This regimen consisted of Irinotecan 65mg/m2 D1, D8, Cisplatin 30mg/m2 D1, D8, and dexamethasone 40mg D1, 2, 8, and 9 was administered every 3 weeks for 6 cycles.  Treatment was discontinued in cases of disease progression or severe toxicity. Response to treatment was evaluated after two cycles. Patients with complete and partial remission were candidates for high-dose chemotherapy and autologous stem cell transplantation. Twenty-four patients were enrolled in the study. The mean age of 22 patients was 31.5 (19-67) years. Seven patients (29.1%) were in the first recurrence, and 17 (70.8%) were in the second or subsequent recurrence. Results: According to this study, three patients (12.5%) had complete response, 13 (45%) had partial response, four (16.6%) had stable disease, and four (16.6%) had progressive disease. Nine patients (37.5%) received high-dose chemotherapy and autologous stem cell support after ICD regimen. None of the cycles of chemotherapy were delayed due to treatment-related adverse event. Overall survival after six months in all patients was 91%, and mortality rate was 8.3% at the end of the study. Conclusion: The goal of salvage chemotherapy in relapsed or refractory Hodgkin Lymphoma is achieving CR or PR preparation patients for stabilization with BMT. Thus, we recommend ICD as one of the most effective protocols with overall response rate of 66% in this population.
    Keywords:  Cisplatin; Hodgkin lymphoma; Irinotecan; Refractory; Relapse; Salvage chemotherapy
    DOI:  https://doi.org/10.18502/ijhoscr.v17i3.13309
  2. Cancers (Basel). 2023 Oct 06. pii: 4866. [Epub ahead of print]15(19):
    Molecular Characterization of Primary Mediastinal Large B-Cell Lymphomas.
    Marie Donzel, Florian Pesce, Alexis Trecourt, Razika Groussel, Emmanuel Bachy, Hervé Ghesquières, Juliette Fontaine, Nazim Benzerdjeb, Claire Mauduit, Alexandra Traverse-Glehen.
      Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21-83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). "Hodgkin-like" cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: SOCS1 (30/33, 91%), TNFAIP3 (18/33, 54.5%), ITPKB (17/33, 51.5%), GNA13 (16/33, 48.5%), CD58 (12/33, 36.4%), B2M (12/33; 36.4%), STAT6 (11/33, 33.3%) as well as ARID1A (10/33, 30.3%), XPO1 (9/33, 27.3%), CIITA (8/33, 24%), and NFKBIE (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible.
    Keywords:  NGS; PMBL; molecular pathology; next generation sequencing; primary mediastinal large B-cell lymphoma
    DOI:  https://doi.org/10.3390/cancers15194866
  3. Pediatr Blood Cancer. 2023 Oct 09. e30712
    Improved survival of children and adolescents with classical Hodgkin lymphoma treated on a harmonised protocol in South Africa.
    Jennifer Geel, Anel van Zyl, Jan du Plessis, Marc Hendricks, Yasmin Goga, Amy Carr, Beverley Neethling, Artsiom Hramyka, Fareed Omar, Rema Mathew, Lizette Louw, Thanushree Naidoo, Thandeka Ngcana, Tanya Schickerling, Vutshilo Netshituni, Elelwani Madzhia, Liezl du Plessis, Tom Kelsey, Daynia E Ballot, Monika L Metzger.
       BACKGROUND: Historic South African 5-year overall survival (OS) rates for Hodgkin lymphoma (HL) from 2000 to 2010 were 46% and 84% for human immunodeficiency virus (HIV)-positive and HIV-negative children, respectively. We investigated whether a harmonised treatment protocol using risk stratification and response-adapted therapy could increase the OS of childhood and adolescent HL.
    METHODS: Seventeen units prospectively enrolled patients less than 18 years, newly diagnosed with classical HL onto a risk-stratified, response-adapted treatment protocol from July 2016 to December 2022. Low- and intermediate-risk patients received four and six courses of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), respectively. High-risk patients received two courses of ABVD, followed by four courses of cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDac). Those with a slow early response and bulky disease received consolidation radiotherapy. HIV-positive patients could receive granulocyte colony-stimulating factor and less intensive therapy if stratified as high risk, at the treating clinician's discretion. Kaplan-Meier survival analysis was performed to determine 2-year OS and Cox regression to elucidate prognostic factors.
    RESULTS: The cohort comprised 132 patients (19 HIV-positive, 113 HIV-negative), median age of 9.7 years, with a median follow-up of 2.2 years. Risk grouping comprised nine (7%) low risk, 36 (27%) intermediate risk and 87 (66%) high risk, with 71 (54%) rapid early responders and 45 (34%) slow early responders, and 16 (12%) undocumented. Two-year OS was 100% for low-risk, 93% for intermediate-risk, and 91% for high-risk patients. OS for HIV-negative (93%) and HIV-positive (89%) patients were similar (p = .53). Absolute lymphocyte count greater than 0.6 × 109 predicted survival (94% vs. 83%, p = .02).
    CONCLUSION: In the first South African harmonised HL treatment protocol, risk stratification correlated with prognosis. Two-year OS of HIV-positive and HIV-negative patients improved since 2010, partially ascribed to standardised treatment and increased supportive care. This improved survival strengthens the harmonisation movement and gives hope that South Africa will achieve the WHO Global Initiative for Childhood Cancer goals.
    Keywords:  GICC; Hodgkin lymphoma; South Africa; adolescent; child; harmonisation
    DOI:  https://doi.org/10.1002/pbc.30712
  4. Cureus. 2023 Sep;15(9): e44805
    The First Sign of Recurrent Angioimmunoblastic T-Cell Lymphoma: A Cutaneous Presentation.
    Guy Charest, Michael McBride, Amanda K Thomas, Mitch Manway, David J DiCaudo.
      Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a nonspecific clinical presentation. Cutaneous manifestations of AITL are variable and include morbilliform eruptions, urticaria, papulonodules, and erythroderma. We present the case of a 74-year-old male with a medical history of AITL presenting with diffuse erythematous macules and papules coalescing into patches and plaques on the trunk and bilateral upper extremities. Histopathology demonstrated a mild perivascular lymphocytic infiltrate in the dermis. By immunohistochemistry, the lymphocytic infiltrate was strongly positive for programmed cell death protein 1 (PD-1) (CD279) as well as cluster of differentiation 3 (CD3), CD5, and (focally) B-cell lymphoma-6 (BCL-6). Many cells within the infiltrate were positive for Epstein-Barr virus (EBV) by in situ hybridization. Additionally, a bone marrow biopsy demonstrated an atypical lymphoid infiltrate with T-cell predominance, many EBV-positive cells, and clonal T-cell receptor (TCR) beta gene rearrangement. Based on these histopathological findings, a diagnosis of recurrent AITL with cutaneous involvement was made. This case is a rare example of skin findings presenting as a first sign of recurrent AITL.
    Keywords:  aitl; angioimmunoblastic t cell lymphoma; epstein- barr virus; peripheral t cell lymphoma; ptcl
    DOI:  https://doi.org/10.7759/cureus.44805
  5. mBio. 2023 Oct 13. e0178423
    Epstein-Barr virus infectious particles initiate B cell transformation and modulate cytokine response.
    Francesco Baccianti, Charlène Masson, Susanne Delecluse, Zhe Li, Remy Poirey, Henri-Jacques Delecluse.
      The Epstein-Barr virus (EBV) efficiently transforms primary B cells. Here, we show that this process starts immediately after cellular exposure to infectious viral particles. Virus binding to B cells led to the activation of intracytoplasmic tyrosine kinases and STAT3. Tegument proteins within the virion in turn activated the p38-MK2 pathway upon cell entry, independently of the viral DNA. Engagement of STAT3 and p38/MK2, two pro-inflammatory pathways, was essential for expression of the key EBV transforming gene EBNA2 but also facilitated IL-6 and TNFα release. However, these pathways simultaneously activated ZFP36L1, a stress response protein that targets transcripts with an AU-rich 3'UTR, to reduce IL-6 and TNFα transcription in infected cells. Expression of viral latent proteins after infection amplified the viral effects on p38 and MK2, but also on ZFP36L1, altogether resulting in a transitory and limited increase in IL-6 and TNFα transcription and release. Thus, EBV virions are not merely vehicles that allow injection of the viral DNA into the nucleus but manipulate cellular pathways to initiate transformation while limiting cytokine release. IMPORTANCE The Epstein-Barr virus efficiently infects and transforms B lymphocytes. During this process, infectious viral particles transport the viral genome to the nucleus of target cells. We show here that these complex viral structures serve additional crucial roles by activating transcription of the transforming genes encoded by the virus. We show that components of the infectious particle sequentially activate proinflammatory B lymphocyte signaling pathways that, in turn, activate viral gene expression but also cause cytokine release. However, virus infection activates expression of ZFP36L1, an RNA-binding stress protein that limits the length and the intensity of the cytokine response. Thus, the infectious particles can activate viral gene expression and initiate cellular transformation at the price of a limited immune response.
    Keywords:  Epstein-Barr virus; STAT3; ZFP36L1; p38-MK2
    DOI:  https://doi.org/10.1128/mbio.01784-23
  6. Clin Case Rep. 2023 Oct;11(10): e7993
    Epstein-Barr virus infection leading to multiorgan involvement in an immunocompetent man.
    Saina Paymannejad, Kiana Shirani, Mohammad Amin Najafi, Farzin Khorvash, Farid Shamlou.
      Epstein-Barr virus (EBV) is a commonly asymptomatic widespread human herpes virus affecting over 90% of the population. It mostly originates complications like simple sore throat and infectious mononucleosis but severe manifestations are rare. Herein we report a 30-year-old immunocompetent man who presented with fever, sore throat, general weakness, and drowsiness. The diagnosis was formulated based on the positive RT-PCR test for EBV DNA and serological detection of IgM antibody against viral capsid antigen. The patient developed severe meningoencephalitis, myocarditis, and bowel perforation and passed away after 72 days of hospitalization.
    Keywords:  Epstein–Barr virus (EBV); bowel perforation; meningoencephalitis; multiorgan failure; myocarditis
    DOI:  https://doi.org/10.1002/ccr3.7993
  7. Front Oncol. 2023 ;13 1241532
    Updates in pathobiological aspects of anaplastic large cell lymphoma.
    Rui Wu, Megan S Lim.
      Anaplastic large cell lymphomas (ALCL) encompass several distinct subtypes of mature T-cell neoplasms that are unified by the expression of CD30 and anaplastic cytomorphology. Identification of the cytogenetic abnormality t(2;5)(p23;q35) led to the subclassification of ALCLs into ALK+ ALCL and ALK- ALCL. According to the most recent World Health Organization (WHO) Classification of Haematolymphoid Tumours as well as the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms, ALCLs encompass ALK+ ALCL, ALK- ALCL, and breast implant-associated ALCL (BI-ALCL). Approximately 80% of systemic ALCLs harbor rearrangement of ALK, with NPM1 being the most common partner gene, although many other fusion partner genes have been identified to date. ALK- ALCLs represent a heterogeneous group of lymphomas with distinct clinical, immunophenotypic, and genetic features. A subset harbor recurrent rearrangement of genes, including TYK2, DUSP22, and TP63, with a proportion for which genetic aberrations have yet to be characterized. Although primary cutaneous ALCL (pc-ALCL) is currently classified as a subtype of primary cutaneous T-cell lymphoma, due to the large anaplastic and pleomorphic morphology together with CD30 expression in the malignant cells, this review also discusses the pathobiological features of this disease entity. Genomic and proteomic studies have contributed significant knowledge elucidating novel signaling pathways that are implicated in ALCL pathogenesis and represent candidate targets of therapeutic interventions. This review aims to offer perspectives on recent insights regarding the pathobiological and genetic features of ALCL.
    Keywords:  ALCL; genetic abnormalities; lymphoma biology; pathogenesis; proteomics
    DOI:  https://doi.org/10.3389/fonc.2023.1241532
  8. Cureus. 2023 Sep;15(9): e44930
    Classical Hodgkin Lymphoma on the Background of Castleman Disease: A Case Report.
    Mohammad Ma'koseh, Akram Al-Ibraheem, Nidal Almasri, Eman Hamed, Kamal Alrabi.
      Castleman disease (CD) is a rare lymphoproliferative disorder that is associated with an increased risk for lymphoma. The association between CD and classical Hodgkin lymphoma (HL) is rare. The patient described here is a 44-year-old, HIV-seronegative male who presented with significant weight loss, fever, night sweats, and right axillary swelling. Imaging showed bulky infraclavicular, subpectoral, and axillary lymph nodes. A biopsy revealed classical HL on the background of a human herpesvirus-8 (HHV-8)-negative plasma cell variant of CD. The patient had a complete remission after six cycles of doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) that were followed by consolidative radiotherapy and continued to be disease-free for more than two years.
    Keywords:  bulky; castleman disease; chemotherapy; hodgkin lymphoma; unicentric
    DOI:  https://doi.org/10.7759/cureus.44930
  9. Hematol Oncol. 2023 Oct;41(4): 608-611
    Revisiting the predictive role of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography on treatment outcome in early-stage favorable Hodgkin lymphoma.
    Andrea Gallamini, Axel Sudria, Michał Kurlapski, Lauris Gastaud.
      In the present manuscript Gallamini et al. comment the results of three large, phase III, randomized clinical trials in early-stage favorable Hodgkin Lymphoma (HL), aimed at exploring the non-inferiority of ABVD chemotherapy alone compared to combined-modality treatment with ABVD and Involved Field/Node Radiotherapy (INRT). The authors also report the preliminary results of risk-stratification in the first 60 enrolled patients in the phase 2, prospective, international study RAFTING: RAdiotherapy Free Treatment IN Good-prognosis early-stage HL (National Trial Identifier 04866654). In this trial patients are stratified, before treatment onset, according to the risk of therapy failure in a single patient basis, taking into account non only the results of interim and End-of-Therapy PET, but also the value of new metrics extracted from the baseline PET/CT such as the Large Nodal Mass (LNM) and Total Metabolic Tumor Volume (TMTV). Treatment intensity, consisting in ABVD chemotherapy, INRT and Nivolumab maintenance, is modulated on the presence/absence of the above factors, in a personalized-medicine approach. The most frequently detected factors driving treatment intensity were LNM and TMTV, while the results of interim and end-of-treatment PET were also determinant, albeit in a lower percentage of cases.
    Keywords:  Large Nodal Mass; Total Metabolic Tumor Volume; baseline PET; end-of-therapy PET; interim PET
    DOI:  https://doi.org/10.1002/hon.3158
  10. Cancer Res. 2023 Oct 10.
    The Evolving Landscape of B Cells in Cancer Metastasis.
    Monika J Ramos, Asona J Lui, Daniel P Hollern.
      Metastasis is the leading cause of cancer mortality. Functional and clinical studies have documented diverse B cell and antibody responses in cancer metastasis. The presence of B cells in tumor microenvironments and metastatic sites has been associated with diverse effects that can promote or inhibit metastasis. Specifically, B cells can contribute to the spread of cancer cells by enhancing tumor cell motility, invasion, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling. Moreover, they can promote metastatic colonization by triggering pathogenic immunoglobulin responses and recruiting immune suppressive cells. Contrastingly, B cells can also exhibit anti-metastatic effects. For example, they aid in enhanced antigen presentation, which helps activate immune responses against cancer cells. Additionally, B cells play a crucial role in preventing the dissemination of metastatic cells from the primary tumor and secrete antibodies that can aid in tumor recognition. Here, we review the complex roles of B cells in metastasis, delineating the heterogeneity of B cell activity and subtypes by metastatic site, antibody class, antigen (if known), and molecular phenotype. These important attributes of B cells emphasize the need for a deeper understanding and characterization of B cell phenotypes to define their effects in metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0620
  11. Front Immunol. 2023 ;14 1251127
    FCRL1 immunoregulation in B cell development and malignancy.
    Murali K Mamidi, Jifeng Huang, Kazuhito Honjo, Ran Li, Edlue M Tabengwa, Indira Neeli, Nar'asha L Randall, Manasa V Ponnuchetty, Marko Radic, Chuen-Miin Leu, Randall S Davis.
      Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family (FCRL1-6) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders.
    Keywords:  B cell receptor; B cells; FCRL1; immunotherapy; lymphocyte development; malignancy; signaling
    DOI:  https://doi.org/10.3389/fimmu.2023.1251127
  12. Cancers (Basel). 2023 Sep 29. pii: 4786. [Epub ahead of print]15(19):
    Could Immune Checkpoint Disorders and EBV Reactivation Be Connected in the Development of Hematological Malignancies in Immunodeficient Patients?
    Paulina Mertowska, Sebastian Mertowski, Konrad Smolak, Gabriela Kita, Katarzyna Guz, Aleksandra Kita, Marcin Pasiarski, Jolanta Smok-Kalwat, Stanisław Góźdź, Ewelina Grywalska.
      Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein-Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.
    Keywords:  CD200; CD200R; CD86; CTLA-4; Epstein–Barr virus (EBV); PD-1; PD-L1; cancer risk; chronic lymphocytic leukemia (CLL); common variable immunodeficiency (CVID); immune checkpoints; immunodeficiency
    DOI:  https://doi.org/10.3390/cancers15194786
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