bims-hodlyp Biomed News
on Hodgkin lymphoma: Pathology and Biology
Issue of 2023–11–12
ten papers selected by
Old Bear
  1. Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program.
  2. The Comparison of Biomolecular Changes of Epstein-Barr Virus Infection in Nasopharyngeal Epithelial Cells Using Confocal Raman Microspectroscopy.
  3. Adult's Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: A case report.
  4. Plasma EBV DNA as a prognostic factor in EBV associated gastric cancer: a multicenter, prospective study (EBV PRESAGE study).
  5. Transcriptional reprogramming by mutated IRF4 in lymphoma.
  6. A Case of Minimal Change Nephrotic Syndrome Secondary to Methotrexate-associated Hodgkin Lymphoma.
  7. Concurrence of inflammatory bowel disease with multiple sclerosis or Hodgkin lymphoma.
  8. Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.
  9. Severe Insulin Resistance in a Patient Treated With Nivolumab and Brentuximab-Vedotin for Hodgkin Lymphoma.
  10. Measurable Residual Disease Monitoring in Lymphoma.
  1. Am J Pathol. 2023 Nov 03. pii: S0002-9440(23)00415-7. [Epub ahead of print]
    Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program.
    Jonathan Weiss, Kathryn Gibbons, Vida Ehyaee, Vanessa Perez-Silos, Alejandro Zevallos, Mark Maienschein-Cline, Eileen Brister, Maria Sverdlov, Eshana Shah, Jayalakshmi Balakrishna, Emily Symes, John K Frederiksen, Peter H Gann, Robert Post, Nicolas Lopez-Hisijos, John Reneau, Girish Venkataraman, Nathanael Bailey, Noah A Brown, Mina L Xu, Ryan A Wilcox, Kedar Inamdar, Carlos Murga-Zamalloa.
      Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing c-MYC and associated with worse clinical outcomes. We demonstrate frequent expression of PLK1 in the LP cells in NLPHL cases (100%; n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) show PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promotes cell proliferation and increased c-MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. In addition, the findings suggest that an active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.
    DOI:  https://doi.org/10.1016/j.ajpath.2023.10.008
  2. Clin Lab. 2023 Nov 01. 69(11):
    The Comparison of Biomolecular Changes of Epstein-Barr Virus Infection in Nasopharyngeal Epithelial Cells Using Confocal Raman Microspectroscopy.
    Baogui Cheng, Wei Wu, Dayang Chen, Feifan Guo, Xiaowen Dou, Yafei Xu, Xiuming Zhang, Dan Xiong.
       BACKGROUND: Due to its unique fingerprinting properties, Confocal Raman microscopy (CRM) can be used to examine the biomolecular changes of viruses invading and manipulating host cells. Recently, the biochemical changes due to the invasion and infection of B lymphocyte cells, nerve cells, and epithelial cells by Epstein-Barr virus (EBV) have been reported. However, biomolecular changes in nasopharyngeal epithelial cells that result from EBV infection are still poorly understood.
    METHODS: In continuation of our prior investigation of EBV infection in nasopharyngeal epithelial cells, we tried to expound on biomolecular changes in EBV-infected nasopharyngeal epithelial cells using Raman microspectroscopy. EBV has two life cycles, latent infection and lytic replication. We have established latent and lytic infection models at the cellular level. In order to understand the characteristics of the two patterns of EBV infection, we used Raman spectroscopy to identify the changes in biomolecules of EBV latent cells (CNE2, CNE2-EBV) and lytic cells (NPEC1-BMI1-CN, NPEC1-BMI1-EBV).
    RESULTS: During latent infection, levels of glycogen, protein, and lipid molecules in the cell increased while levels of nucleic acid and collagen molecules decreased. Molecular levels of glycogen, proteins, and nucleic acids are reduced during lytic infection. We found that molecular levels of nucleic acid decreased during two different periods of infection, whereas levels of other biomolecules showed the opposite trend. Glycogen, proteins, lipids, nucleic acids, and other molecules are associated with alterations in cellular biochemical homeostasis. These changes correspond to unique Raman spectra in infected and uninfected cells associated with specific biomolecules that have been proven. These molecules are mainly responsible for cellular processes such as cell proliferation and apoptosis. The Raman signatures of these biomolecular changes depend on the different phases of viral infection.
    CONCLUSIONS: Therefore, by using CRM, it is possible to discern details in the progression of EBV infection in nasopharyngeal epithelial cells at the molecular level.
    DOI:  https://doi.org/10.7754/Clin.Lab.2023.230225
  3. Clin Case Rep. 2023 Nov;11(11): e8117
    Adult's Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: A case report.
    Yi Sun, Han Yao, Xiaofeng Yu, Yunzhao Chen, Chen Chai.
      Adult's Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis is a rare and life-threatening condition characterized by atypical initial symptoms and rapid disease progression. To facilitate early diagnosis and prompt treatment, it is imperative to implement early multidisciplinary intervention and prioritize pathogen detection, as these measures significantly contribute to enhancing patient prognosis.
    Keywords:  Epstein–Barr virus; case report; early diagnosis; hemophagocytic lymphohistiocytosis; therapy
    DOI:  https://doi.org/10.1002/ccr3.8117
  4. Front Oncol. 2023 ;13 1276138
    Plasma EBV DNA as a prognostic factor in EBV associated gastric cancer: a multicenter, prospective study (EBV PRESAGE study).
    Andrea Alberti, Gertraud Stocker, Florian Lordick, Ulrich T Hacker, Benjamin Kobitzsch, Ivonne Haffner, Gian Luca Baiocchi, Manuel Zamparini, Guido A M Tiberio, Carla Baronchelli, Arnaldo Caruso, Paolo Bossi, Alfredo Berruti.
       Purpose: The Cancer Genome Atlas Research Network identified Epstein-Barr-Virus (EBV)-positive gastric cancer as a distinct molecular subtype. The prevalence is 8-9% and the histological examination shows pronounced lymphocytic infiltration, elevated levels of IFN-γ and consequently overexpression of PD-L1. The role of plasma EBV DNA load as a prognostic factor in patients with this cancer subtype is still to be defined.
    Methods and analysis: The present multicenter prospective observational study "EBV PRESAGE", involving German and Italian cancer centers, aims to evaluate the prognostic role of plasma EBV DNA in EBV-related gastric cancer (GC). The objective is to study the association between plasma EBV DNA load at different consecutive time points and the patient's prognosis. Every patient with a new diagnosis of gastric cancer (including gastroesophageal junction adenocarcinoma) will be screened for Epstein-Barr encoded small Region (EBER) on tissue biopsies using in situ hybridization (ISH). If EBER ISH is positive, blood analysis for plasma EBV DNA will be conducted. The plasma EBV quantitative analysis will be centralized, and extraction, detection, and quantification of EBV DNA in plasma samples will be performed using real-time PCR.
    Discussion: We hypothesized that plasma EBV DNA represents a non-invasive tool for monitoring EBV-related GC and might be valuable as a prognostic marker.
    Keywords:  disease-free survival; epstein barr virus DNA; gastric and gastroesophageal junction adenocarcinoma; prognostic factor; prospective multicenter study
    DOI:  https://doi.org/10.3389/fonc.2023.1276138
  5. Nat Commun. 2023 Nov 07. 14(1): 6947
    Transcriptional reprogramming by mutated IRF4 in lymphoma.
    Nikolai Schleussner, Pierre Cauchy, Vedran Franke, Maciej Giefing, Oriol Fornes, Naveen Vankadari, Salam A Assi, Mariantonia Costanza, Marc A Weniger, Altuna Akalin, Ioannis Anagnostopoulos, Thomas Bukur, Marco G Casarotto, Frederik Damm, Oliver Daumke, Benjamin Edginton-White, J Christof M Gebhardt, Michael Grau, Stephan Grunwald, Martin-Leo Hansmann, Sylvia Hartmann, Lionel Huber, Eva Kärgel, Simone Lusatis, Daniel Noerenberg, Nadine Obier, Ulrich Pannicke, Anja Fischer, Anja Reisser, Andreas Rosenwald, Klaus Schwarz, Srinivasan Sundararaj, Andre Weilemann, Wiebke Winkler, Wendan Xu, Georg Lenz, Klaus Rajewsky, Wyeth W Wasserman, Peter N Cockerill, Claus Scheidereit, Reiner Siebert, Ralf Küppers, Rudolf Grosschedl, Martin Janz, Constanze Bonifer, Stephan Mathas.
      Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
    DOI:  https://doi.org/10.1038/s41467-023-41954-8
  6. Intern Med. 2023 Nov 06.
    A Case of Minimal Change Nephrotic Syndrome Secondary to Methotrexate-associated Hodgkin Lymphoma.
    Misa Iimori, Kazuhiro Sonomura, Yuichi Ueyama, Yuki Oobayashi, Hiroya Adachi, Mayuka Nakayama.
      The patient was a 64-year-old man who had been receiving methotrexate (MTX) for rheumatoid arthritis for 8 years. Computed tomography (CT) obtained one month prior to admission revealed numerous enlarged lymph nodes. Lower leg edema appeared two weeks prior to admission. Severe proteinuria was confirmed, and the patient was admitted. A renal biopsy revealed minimal changes in glomeruli. CT on day 14 revealed shrinking lymph nodes, and the patient was diagnosed with Hodgkin lymphoma by a neck lymph node biopsy. This is the first report of secondary minimal change nephrotic syndrome caused by an MTX-associated lymphoproliferative disorder.
    Keywords:  Hodgkin lymphoma; T lymphocyte dysfunction; methotrexate; minimal change nephrotic syndrome; rheumatoid arthritis
    DOI:  https://doi.org/10.2169/internalmedicine.2572-23
  7. Eur J Gastroenterol Hepatol. 2023 Dec 01. 35(12): 1349-1353
    Concurrence of inflammatory bowel disease with multiple sclerosis or Hodgkin lymphoma.
    Amnon Sonnenberg, Hao T Duong, Daniel J McCarty, Hashem B El-Serag.
       BACKGROUND AND AIMS: Epidemiologic evidence suggests that Hodgkin lymphoma (HL) and multiple sclerosis (MS) share a common set of risk factors with Crohn's disease (CD) and ulcerative colitis (UC). It was hypothesized that such shared risk factors would lead to clustering of the 4 diagnoses in the same patients.
    METHODS: All patients with HL, MS, CD, or UC were identified in the veterans population from 2016-2020 and the Medicare population from 1986 to 1989. In a case-control study, the observed concurrences amongst these 4 diagnoses were compared with their expected frequencies in the overall veterans or Medicare population during the same time period by calculating odds ratios (OR) with their 95% confidence intervals (CI).
    RESULTS: The study included 6 million veterans and 35 million Medicare patients. In the veterans population, inflammatory bowel disease (IBD) was significantly associated with a concurrent diagnosis of HL (OR: 1.40, 95% CI: 1.15-1.71) and MS (1.34, 1.19-1.50). In the Medicare population, IBD was also significantly associated with HL (1.84, 1.07-3.17) and MS (2.31, 1.59-3.35). Similar trends were observed in CD or UC when analyzed separately in both datasets. In the veterans population, adjustment for the potentially confounding influence of ethnicity, sex, and age left all OR values largely unaffected and statistically significant.
    CONCLUSION: The concurrence of IBD with HL or MS could reflect on a common pathway in the etiology or pathogenesis of these 4 diseases.
    DOI:  https://doi.org/10.1097/MEG.0000000000002657
  8. Int J Food Sci Nutr. 2023 Nov 07. 1-10
    Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.
    Mingming Zhou, Junfen Xia, Xiaolin Chen, Tiantian Wu, Kedi Xu, Yuanlin Zou, Shaobo Zhang, Pengxia Guo, Haoqing Cheng, Saba Fida, Chunhua Song.
      Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.
    Keywords:  Hodgkin lymphoma; Mendelian randomisation; Non-Hodgkin lymphoma; causal effect; dietary vitamin
    DOI:  https://doi.org/10.1080/09637486.2023.2278420
  9. JCEM Case Rep. 2023 Nov;1(6): luad121
    Severe Insulin Resistance in a Patient Treated With Nivolumab and Brentuximab-Vedotin for Hodgkin Lymphoma.
    Elif Tama, Meghan Black, Muhamad Alhaj Moustafa, Maria D Hurtado.
      This is a case of a 26-year-old male patient, with relapsing Hodgkin lymphoma, treated with nivolumab and brentuximab-vedotin, who was admitted with hyperglycemia and severe insulin resistance requiring approximately 2000 units of intravenous insulin per day. He had no prior diagnosis of diabetes. He was eventually diagnosed with massive cytokine release and hemophagocytic lymphohistiocytosis that led to multi-organ failure and death. The mechanisms behind the hyperglycemia with severe insulin resistance remain unclear but are possibly related to hyperinflammation and immune dysregulation resulting from massive cytokine release. Nivolumab among other immunotherapeutic agents, brentuximab-vedotin, and lymphoid malignancies are rare but known risk factors for massive cytokine release and hemophagocytic lymphohistiocytosis.
    Keywords:  Hodgkin lymphoma; brentuximab-vedotin; cytokine release; hemophagocytic lymphohistiocytosis; hyperglycemia; immunotherapy; insulin resistance; nivolumab
    DOI:  https://doi.org/10.1210/jcemcr/luad121
  10. Curr Hematol Malig Rep. 2023 Nov 06.
    Measurable Residual Disease Monitoring in Lymphoma.
    Brian Cuzzo, Andrew Lipsky, Hua-Jay J Cherng.
       PURPOSE OF REVIEW: The utility of analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and disease in the bone marrow as an adjunctive tool in caring for hematologic cancer patients is expanding. This holds true for lymphoma where these biomarkers are being explored as a means of genotyping and quantifying disease. Regarding the latter, they can be used to monitor measurable residual disease (MRD) during and after treatment. This holds potential for aiding clinical decisions amidst treatment, detecting earlier relapse, and improving prognostication. Here, we review the evidence to support these applications in a variety of lymphoma subtypes.
    RECENT FINDINGS: Numerous clinical trials across a variety of lymphomas have demonstrated value in MRD monitoring. MRD monitoring is often prognostic for progression free survival (PFS) and even overall survival (OS) at several time points in a disease course, particularly when utilizing serial measurements. With regards to tailoring treatment, there are a growing number of trials examining MRD-adaptive treatment strategies to intensify or de-escalate treatment to individualize care. Lastly, MRD monitoring has been utilized successfully in detecting earlier relapse when compared to more standard methods of clinical surveillance such as radiographic assessment. Although not routinely implemented into clinical practice, MRD monitoring in lymphoma is helping shape the future landscape of this disease by aiding in prognostication, guiding therapy, and detecting earlier relapse. Steps to standardize and further examine this technology prospectively are being taken to bring MRD monitoring to the forefront of the field.
    Keywords:  Circulating tumor DNA; Lymphoma; Measurable residual disease; Next generation sequencing; Prognostic; Response adapted
    DOI:  https://doi.org/10.1007/s11899-023-00715-6
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