Search Results (53)

Programmed death-ligand 1 (PD-L1) on tumor cells, including Hodgkin and Reed–Sternberg (HRS) cells in classical Hodgkin’s lymphoma (cHL), suppresses immune responses in the tumor immune microenvironment (TME). We analyzed PD-L1 expression in macrophages and HRS cells of 98 cHL cases and correlated the findings with clinicopathological features, overall survival (OS), and progression-free survival (PFS). Epstein–Barr virus (EBV) was detected by in situ hybridization for EBV-encoded RNA. Ten high-power fields were evaluated to count the total number of macrophages and PD-L1+ macrophages, and to calculate PD-L1 histoscore (H-score) in HRS cells. EBV-positive cHL was found in 22.5% of patients. The median H-score was 80 (range 0–300). Bulky disease was associated with a lower number of PD-L1+ macrophages, and extranodal disease with a higher number (p = 0.05). EBV-positive cHL showed a higher PD-L1 H-score in HRS cells and a greater number of PD-L1⁺ macrophages (p = 0.005); both of these features, along with the proportion of PD-L1⁺ macrophages, were associated with shorter PFS and OS (p < 0.001). High PD-L1 expression in HRS and macrophages may be linked to worse clinical outcomes. Full article

The tumor necrosis factor (TNF) family, which includes 19 ligands and 29 receptors, influences cellular proliferation, differentiation, and apoptosis. The TNF family plays a crucial role in the pathogenesis of Hodgkin lymphoma (HL), particularly through its influence on the tumor microenvironment (TME). Hodgkin Reed–Sternberg (HRS) cells, the hallmark of classic HL (cHL), exhibit overexpression of TNF receptor family members such as CD30 and CD40. Given the critical roles of CD30 and CD40 in the survival and proliferation of HRS cells within the TME, targeting these TNF receptors represents a promising therapeutic strategy; therapies that target CD30 have already shown efficacy in clinical settings. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a crucial role in immune evasion by HRS cells, which express PD-L1 that interacts with PD-1 on T cells, leading to T cell exhaustion and a diminished immune response against the tumor. By blocking this interaction, checkpoint inhibitors such as nivolumab and pembrolizumab have demonstrated high response rates in patients with cHL, particularly in those who have not responded to conventional therapies. The integration of immune checkpoint inhibitors (ICIs) with standard chemotherapy regimens has improved outcomes for patients with advanced-stage cHL. By understanding how TNF signaling interacts with immune checkpoints, researchers can design more effective treatment regimens that simultaneously target multiple pathways. Combining TNF inhibitors with checkpoint blockade therapies may enhance the overall anti-tumor response by addressing both direct tumor signaling and the immune evasion mechanisms employed by tumor cells. Full article

The bi- or multinucleated Reed–Sternberg cell (RS) is the diagnostic cornerstone of Epstein–Barr Virus (EBV)-positive and EBV-negative classical Hodgkin lymphoma (cHL). cHL is a germinal center (GC)-derived B-cell disease. Hodgkin cells (H) are the mononuclear precursors of RS. An experimental model has to fulfill three conditions to qualify as common pathogenic denominator: (i) to be of GC-derived B-cell origin, (ii) to be EBV-negative to avoid EBV latency III expression and (iii) to support permanent EBV-encoded oncogenic latent membrane protein (LMP1) expression upon induction. These conditions are unified in the EBV-, diffuse large B-Cell lymphoma (DLBCL) cell line BJAB-tTA-LMP1. 3D reconstructive nanotechnology revealed spatial, quantitative and qualitative disturbance of telomere/shelterin interactions in mononuclear H-like cells, with further progression during transition to RS-like cells, including progressive complexity of the karyotype with every mitotic cycle, due to BBF (breakage/bridge/fusion) events. The findings of this model were confirmed in diagnostic patient samples and correlate with clinical outcomes. Moreover, in vitro, significant disturbance of the lamin AC/telomere interaction progressively occurred. In summary, our research over the past three decades identified cHL as the first lymphoid malignancy driven by a disturbed telomere/shelterin/lamin AC interaction, generating the diagnostic RS. Our findings may act as trailblazer for tailored therapies in refractory cHL. Full article

Background: Some cases of classic Hodgkin lymphoma (CHL) display similarities to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in terms of architecture, leading to potential challenges in diagnosis. However, these difficulties can be overcome by conducting a thorough set of immunohistochemical examinations. Objective: To examine cases of T-cell-rich CHL that closely resemble the diagnosis of NLPHL, specifically pattern D, which can pose challenges in accurately determining the diagnosis even after conducting a thorough immunophenotypic assessment. Materials and methods: Histopathology slides of three cases of T-cell-rich CHL were retrieved and thoroughly examined to assess their clinical, immunomorphologic, and molecular features. Results: We present three cases containing cells that resembled lymphocyte predominant and Hodgkin Reed–Sternberg cells, expressing some B-cell antigens and CHL markers but all were lacking Epstein–Barr virus-encoded small RNA. All three cases were found in a background rich in T-cells with focal remaining follicular dendritic cell meshwork in one case. Only one case had few eosinophils while the other two had no background of eosinophils and plasma cells. Two patients presented with stage IIA and B-symptoms presented in one of them. Two patients were treated with four and six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), respectively. One patient planned to be treated with four cycles of ABVD plus Rituximab therapy. Conclusions: Some cases of Reed–Sternberg cells can show expression of both B-cell and CHL markers. This overlapping characteristic, which has not been extensively discussed in the existing literature, presents a unique challenge for treatment. Further research into these neoplasms may reveal valuable diagnostic and therapeutic implications. Full article

Thymic regulatory lymphocytes (Tregs) are rare in the normal periphery where they mediate immune tolerance but accumulate in the tumor immune microenvironment (TIM), reducing the antitumor response. Subtypes of classical Hodgkin lymphoma (CHL) are characterized by a minority of malignant Hodgkin and Reed–Sternberg cells (HRS) and an abundant TIM that plays a key role in modulating the disease. CHL is related to the Epstein–Barr virus (EBV), whose oncogenes influence the growth of HRS. We analyzed the number of T lymphocytes expressing the regulatory marker FOXP3 in CHL with regard to EBV status. The tumor tissue of 182 patients was stained by double immunohistochemistry for FOXP3, CD4, and CD8, and the number of different phenotypes was analyzed microscopically. EBV status was determined by EBER in situ hybridization. EBV-positive CHL was confirmed in 28% of patients and was associated with mixed cellularity (MC) (p < 0.001), older age (p < 0.001), and unfavorable outcomes (p = 0.038). The number of CD8+ T lymphocytes differed according to the EBV status of MC and nodular sclerosis (NS), and was the lowest in EBV-negative NS (p = 0.001). Likewise, the numbers for FOXP3 and FOXP3/CD4 were different, and were the lowest in EBV-negative MC (p = 0.035 and p = 0.041, respectively). Values above a median of FOXP3 and CD4 are associated with longer progression-free survival (p = 0.039 and p < 0.001, respectively). EBV impacts the composition of T cell phenotypes in TIM, among which the amount of CD4 and FOXP3 is prognostically valuable. Full article

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin–Reed–Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation. Full article

Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma in which tumour cells, the so-called Hodgkin Reed–Sternberg (HRS) cells, are admixed with non-malignant cell types that are a functional part of the disease. Immune cells, fibroblasts, specialised mesenchymal cells, and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. HRS cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils, and mast cells. A cross-talk occurs between HRS cells and immune cells of the TME. This cross-talk is mediated either by a large network of cytokines and chemokines expressed by HRS cells or molecules produced by different cell types of the TME, i.e., CD30/CD30L, CD40/CD40L, OX40L/OX40, Il- 3/Il-3R, CCR5/CCL5, CD74 macrophage migration inhibitory factor/macrophages, and PD-L1/PD-1. The over-expression of CD30 and CD40, members of the TNF receptor family, is a hallmark of HRS cells. This review highlights the current development of newer therapeutic strategies as a means of immune checkpoint blockade and suggests that further research should explore innovative molecules aimed at targeting components of HL that are involved in cancer cell growth and/or immune escape. Hopefully, this will influence sensitivity or resistance to checkpoint inhibitor therapy in an individual patient. Full article

Classical Hodgkin lymphoma (cHL) is a hematological malignancy of B-cell origin. The tumor cells in cHL are referred to as Hodgkin and Reed–Sternberg (HRS) cells. This review provides an overview of the currently known miRNA–target gene interactions. In addition, we pinpointed other potential regulatory roles of microRNAs (miRNAs) by focusing on genes related to processes relevant for cHL pathogenesis, i.e., loss of B-cell phenotypes, immune evasion, and growth support. A cHL-specific miRNA signature was generated based on the available profiling studies. The interactions relevant for cHL were extracted by comprehensively reviewing the existing studies on validated miRNA–target gene interactions. The miRNAs with potential critical roles included miR-155-5p, miR-148a-3p, miR-181a-5p, miR-200, miR-23a-3p, miR-125a/b, miR-130a-3p, miR-138, and miR-143-3p, which target, amongst others, PU.1, ETS1, HLA-I, PD-L1, and NF-κB component genes. Overall, we provide a comprehensive perspective on the relevant miRNA–target gene interactions which can also serve as a foundation for future functional studies into the specific roles of the selected miRNAs in cHL pathogenesis. Full article

GATA3 is a transcription factor involved in T-cell maturation and has been previously shown to be aberrantly overexpressed in malignant Hodgkin and Reed–Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). However, the immunophenotypes of the cell types expressing GATA3 have not been precisely characterized so far in cHL tissues. In this single-center retrospective cohort study we analyzed the expression patterns of GATA3 alone and in combination with B, T, NK or macrophage-associated markers in 73 cases with newly diagnosed cHL and investigated for a possible correlation with clinical and laboratory parameters. Immunohistochemistry (single and double) was performed using GATA3 alone and in combination with CD20, CD3, CD56, CD68, CD30 or CD15. Clinical and laboratory parameters were collected and correlated with the expression of GATA 3. GATA3 nuclear expression was found in HRS cells in 39/73 (54%) cases of cHL. The Nodular Sclerosis (NS) subtype showed the highest positivity rate (35/56, 63%), followed by mixed cellularity (MC; 4/14, 29%) and lymphocyte rich (LR; 0/3). Double immunostainings showed that GATA3 was expressed by CD30+ or CD15+ HRS cells and a few CD3+ T-cells, whereas GATA3 expression was not detected in CD20, CD56 or CD68+ cells. GATA3-negative cHL was significantly associated with unfavorable prognostic factors such as older age at diagnosis and increased levels of serum β2-microglobulin. The heterogenous expression patterns of GATA3 in HRS cells that were observed in a substantial proportion of cHL, mainly in the NS subtype, further support the biological heterogeneity of cHL. Full article

Hodgkin’s lymphoma (HL) is a monoclonal lymphoid neoplasm that is mainly characterized by multinucleated Reed–Sternberg cells on a background of non-neoplastic inflammatory cells. The incidence rate of Hodgkin’s lymphoma is 2.5 new cases per 100,000 people per year (1). Paraneoplastic syndromes are conditions that are related to malignancy; however, they are not a result of tumor invasion or compression of malignant tissues. These paraneoplastic syndromes can occur virtually at any point in the disease course, and paraneoplastic syndromes in HL and their various forms are not well studied. In this review article, we will be discussing paraneoplastic syndromes in general and then delve into specific syndromes seen in HL, followed by a brief discourse regarding their early recognition and timely management. Full article

Classical Hodgkin lymphoma (cHL) accounts for 0.4% of all new cancer cases globally. Despite high cure rates with standard treatment, approximately 15% of patients still experience relapsed or refractory (RR) disease, and many of these eventually die from lymphoma-related causes. Exciting new targeted agents such as anti-PD-1 agents and brentuximab vedotin have changed the therapeutic paradigm beyond chemotherapy and radiotherapy alone. Advances in understanding of the molecular biology are providing insights in the context of novel therapies. The signature histology of cHL requires the presence of scant malignant Hodgkin Reed–Sternberg cells (HRSCs) surrounded by a complex immune-rich tumour microenvironment (TME). The TME cellular composition strongly influences outcomes, yet knowledge of the precise characteristics of TME cells and their interactions with HRSCs is evolving. Novel high-throughput technologies and single-cell sequencing allow deeper analyses of the TME and mechanisms elicited by HRSCs to propagate growth and avoid immune response. In this review, we explore the evolution of knowledge on the prognostic role of immune cells within the TME and provide an up-to-date overview of emerging prognostic data on cHL from new technologies that are starting to unwind the complexity of the cHL TME and provide translational insights into how to improve therapy in the clinic. Full article

CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed–Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30’s roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment. Full article

Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed–Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T cells (CD4 helper, CD8 cytotoxic and regulatory) and tumor-associated macrophages (TAMs), but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through the production of various cytokines and/or the aberrant expression of immune checkpoint molecules in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis, as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency. Full article

Genome-wide association studies (GWAS) have revealed approximately 100 genomic signals associated with Hodgkin lymphoma (HL); however, their target genes and underlying mechanisms causing HL susceptibility remain unclear. In this study, transcriptome-wide analysis of expression quantitative trait loci (eQTL) was conducted to identify target genes associated with HL GWAS signals. A mixed model, which explains polygenic regulatory effects by the genomic covariance among individuals, was implemented to discover expression genes (eGenes) using genotype data from 462 European/African individuals. Overall, 80 eGenes were identified to be associated with 20 HL GWAS signals. Enrichment analysis identified apoptosis, immune responses, and cytoskeletal processes as functions of these eGenes. The eGene of rs27524 encodes ERAP1 that can cleave peptides attached to human leukocyte antigen in immune responses; its minor allele may help Reed–Sternberg cells to escape the immune response. The eGene of rs7745098 encodes ALDH8A1 that can oxidize the precursor of acetyl-CoA for the production of ATP; its minor allele may increase oxidization activity to evade apoptosis of pre-apoptotic germinal center B cells. Thus, these minor alleles may be genetic risk factors for HL susceptibility. Experimental studies on genetic risk factors are needed to elucidate the underlying mechanisms of HL susceptibility and improve the accuracy of precision oncology. Full article

Although classical Hodgkin lymphoma (CHL) is typically curable, 15–25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed–Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory cells. The interplay of H/RS cells with other immune cells in the microenvironment may provide novel strategies for targeted immunotherapies. In this paper we analyzed the microenvironment content in CHL patients with responsive disease (RESP) and patients with relapsed/refractory disease to treatment (REL). Our results indicate the increase of CD68⁺ and CD163⁺ macrophages, the increase of PDL-1⁺ cells and of CD34⁺ microvessels in REL patients respective to RESP patients. In contrast we also found the decrease of CD3⁺ and of CD8⁺ lymphocytes in REL patients respective to RESP patients. Finally, in REL patients our results show the positive correlation between CD68⁺ macrophages and PDL-1⁺ cells as well as a negative correlation between CD163⁺ and CD3⁺. Full article