Born with Two Faces: Sequential development of Diffuse Large B-cell Lymphoma and Angioimmunoblastic T-cell Lymphoma with EBV positive and TET2 mutation

Born with Two Faces: Sequential development of Diffuse Large B-cell Lymphoma and Angioimmunoblastic T-cell Lymphoma with EBV positive and TET2 mutation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Born with Two Faces: Sequential development of Diffuse Large B-cell Lymphoma and Angioimmunoblastic T-cell Lymphoma with EBV positive and TET2 mutation Qing Li, Shishuo Dai, Weiping Liu, Yu Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3759312/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract There may be significant histopathological and pathogenetic overlap between Epstein–Barr virus (EBV) -positive diffuse large B cell lymphoma (DLBCL) and other lymphomas, including angioimmunoblastic T-cell lymphoma (AITL). Herein, we reported a rare case of an AITL developing two years after the initial diagnosis of EBV-positive DLBCL. Next-generation sequencing (NGS) is used to study genetic mutations in biopsy samples of DLBCL and subsequent AITL. NGS revealed that TET2 mutated in both DLBCL and AITL, while other differential mutations were also detected, reflecting their own characteristics. Since inherent EBV infection plays a role in both AITL and DLBCL, we evaluated the characteristics of lymphoma associated with EBV infection, including morphology and treatment, etc. We deduce that chronic EBV infection and epigenetic TET2 mutations may alter the immune profile or tumor microenvironment of lymphoma cells, resulting in patients presenting with different tumor types at different times. Patients with AITL secondary to DLBCL have a poor prognosis, and the combination of chidamide and chemotherapy is expected to provide new treatment options for these patients, mainly due to the multiplex antitumor mechanism of chidamide in lymphoma. Epstein–Barr virus TET2 mutation Next-generation sequencing diffuse large B cell lymphoma angioimmunoblastic T-cell lymphoma Figures Figure 1 Figure 2 Figure 3 Introduction The Epstein–Barr virus (EBV) has a powerful lymphocyte growth-transforming ability and is etiologically related to a series of lymphoproliferative disorders and malignant lymphomas [ 1 ]. Angioimmunoblastic T-cell lymphoma (AITL) is a mature T-cell lymphoma with poor clinical prognosis. Common mutant genes of AITL include RHO A, TET2 , DNMT3A , and IDH2 [ 2 ]. Case of diffuse large B-cell lymphoma (DLBCL) after initial diagnosis of AITL has been reported [ 3 ]. And case of developing AITL after the initial diagnosis of DLBCL has also been reported [ 4 ]. What sets this study apart from previous studies is that we are the first to attempt to perform deep sequencing of lymphoma tissue in both disease states to elucidate the potential link between DLBCL and AITL. Materials and Methods Next-generation sequencing (NGS) (Illumina sequencer, NovaSeq, 1500X) was used to study the possible mechanisms by which this patient developed AITL after DLBCL. Specifically, we detected one hundred fourteen hotspot genes associated with DLBCL in tonsil biopsy paraffin tissue when diagnosed with DLBCL and eighty-four genes related to intranodal and peripheral T-cell lymphoma in lymph node biopsy paraffin tissue when AITL was diagnosed. Results Case Report A 74-year-old man presents to Sichuan Provincial Cancer Hospital with progressive worsening of sore throat for more than four months without fever, night sweats, and weight loss. Before admission, the patient went to the community hospital for symptomatic treatment, but the pain was not relieved. He then underwent a tonsil biopsy and sent the biopsy specimen to the Department of Pathology, West China Hospital, Sichuan University. A plenty of diffuse large-sized proliferating atypical lymphocytes with necrosis can be seen under microscope (Fig. 1 A). Immunohistochemically, the atypical cells were positive for CD20 (Fig. 1 B), MUM-1(Fig. 1 C), Ki-67/MIB (80%) (Fig. 1 D), C-MYC (50%) (Fig. 1 E), and EBER1/2-ISH (Fig. 1 F). A positive rearrangement of the IgH gene was confirmed by Genescan analysis (Shanghai State Medical Laboratory Co.Ltd). The patient was in good health and have no family history of genetic history. The complete blood count, coagulation markers, liver and kidney function, electrolytes, electrocardiogram, and DNA copies of EBV were all within the normal range. Cardiac ultrasound showed mild regurgitation of the aortic valve and mitral valve, and ventricular diastolic function was reduced. Positron emission tomography/computed tomography (PET/CT) revealed abnormal metabolic activity in multiple sites, such as both lateral walls of the oropharynx, the left posterior wall of the nasopharynx, bilateral submandibular, bilateral cervical para-vascular and left posterior cervical triangle. The Deauville assessment was five. The patient was diagnosed with nongerminal central subtype stage II EBV-positive DLBCL. Then the patient received four cycles of R-CHOP regimen (rituximab, cyclophosphamide, vindesine, doxorubicin liposome and dexamethasone) and was assessed for efficacy using PET/CT, which revealed complete remission (Deauville assessment is two). The patient then received two cycles of R-CHOP and the efficacy was assessed using contrast-enhanced CT, indicating no new lesions. Since then, the patient has not been regularly followed up. After approximately two years, the patient sought medical help due to itching and swollen lymph nodes all over the body. Cervical lymph node biopsy shows that some areas of lymphoid tissue are distinguishable, see partial naked follicles. The interfollicular zone widens, in which small blood vessels are seen to proliferate, partially intertwined, and the endothelium is swollen (Fig. 2 A). Immunohistochemical analyses of tumor cells indicated positivity for CD3 (Fig. 2 B), CD4 (Fig. 2 C), CD10 (partially) (Fig. 2 D), CD21(Fig. 2 E), and EBER1/2-ISH (dispersedly) (Fig. 2 F). Ki67/MIB was expressed by 60% of lymphoma cells. Lymphoma cells were negative for CD20, CD8, CXCL13, CD15, PAX-5. Gene rearrangement found the clonal amplification peak of the TCR γ gene within the range of the target fragment; no IGH gene rearrangement was found. Sanger sequencing revealed that no mutations were detected in exon 2 (G17Val) of the RHOA gene and codon 172 of the IDH2 gene. Bone marrow tissue immunohistochemistry did not show exact lymphoma involvement. PET/CT revealed abnormally elevated glucose metabolism in cervical, thoracic, and abdominal lymph nodes. The DNA copies of EBV in serum were 1.25E + 4 copies/ml. Then, the patient was diagnosed with EBV-positive AITL. Given that the patient developed AITL after DLBCL, and the tumor accumulation was wide, new strategy of therapy should be considered. So, histone deacetylase (HDAC) inhibitor, chidamide, combined with COEP (cyclophosphamide, vindesine, etoposide, prednisone) was administered. The DNA copies of EBV in serum after treatment were 2.30E + 02 copies/ml. The patient ultimately died after six months diagnosed with AITL. The overall survival of this patient is thirty months. NGS To explore the possible mechanisms by which patients develop AITL following treatment with DLBCL, NGS was adopted. In the DLBCL hotspot gene profile, NGS detected that the patient had mutated genes, including EP300 , TET2 , KMT2D , and STAT6 . Furthermore, among the genes associated with intranodal and peripheral T-cell lymphoma, NGS also detected mutations in TET2 , and the mutation site was consistent with that detected in DLBCL. The TET2 mutation frequencies were 31.58% and 39.92% in DLBCL and AITL, respectively (Fig. 3). After the patient was diagnosed with AITL, a mutation at the same site (c.C4579T) of TET2 was also detected in the peripheral blood. The pathways and mutated genes involved in DLBCL and AITL are shown in Table 1 [ 2 , 5 ]. Table 1 Frequencies of gene mutations involved in different pathways in DLBCL and AITL Pathways Involved genes (frequency of mutations) DLBCL B cell development and differentiation MEF2B (7%–12%), IRF8 (8%–11%), BCL6 (6%–11%), PRDM1 (7%–12%), EBF1 (8%–11%) BCR and Toll-like receptor signaling MYD88 (18%–27%), CD79B (14%–15%), CARD11 (11%–15%), PRKCB (4%–5%), PTPN6 (4%–5%), LYN (3%–4%), GRB2 (2%–3%) and TLR2 (3%) NF-κB pathway TNFAIP3 (9%–18%), TBL1XR1 (7%–13%), KLHL6 (9%–10%), NFKBIE (3%–8%), ZC3H12A (3%–7%) and NFKBIA (5%) MAPK–ERK pathway BRAF (3%–6%) and KRAS (3%–4%) PI3K–AKT–mTOR PTEN (3%–4%) p53 and DNA damage TP53 (21%–24%), UBE2A (4%–8%) and ZNF423 (0.4%–2%) Cell cycle PIM1 (22%–29%), BTG1 (14%–16%) and CCND3 (5%–11%) Cell apoptosis BCL2 (10%–17%) and FAS (8%–10%) NOTCH pathway DTX1 (12%–15%), SPEN (9%–11%) and NOTCH2 (7%–8%) Cell migration GNA13 (8%–11%), RHOA (4%–5%) and CXCR4 (2%–3%) JAK–STAT STAT3 (6%–10%), STAT6 (4%–5%) and IL6 (2%) Epigenetic regulators KMT2D (25%–33%), HIST1H1E (13%–16%), CREBBP (17%–18%), HIST1H1C (10%–12%), TET2 (0%–12%), EZH2 (7%–9%) Immune escape HL AB (12%–22%), B2M (9%–17%), HL AA (8%–16%), CD70 (9%), CD58 (6%–11%), HL AC (4%–7%) AITL RAS superfamily RHOAG17V (50%–72%) Epigenetic regulators TET2 (47%–86%), DNMT3A (20%–48%), IDH2R172 (20%–45%) TCR signaling pathway PLCγ (14%), CD28 (9%–11%), FYN (3%–4%), VAV1 (5%) Structural alteration CTLA4-CD28fusion (58%), ICOS-CD28fusion (5%) Abbreviations: DLBCL, Diffuse large B cell lymphoma; AITL, Angioimmunoblastic T cell lymphoma. Table 2. Clinical manifestations, morphology, immunophenotype, genotype, treatment regimen and efficacy of EBV-associated lymphoma Clinical presentation Morphology Immunophenotype and genotype %EBV association Therapy Efficacy cHL A nodal disease with virtually all cases arising in peripheral lymph nodes (mediastinum). When the disease advances, it may infiltrate spleen, liver and other extranodal locations. Large neoplastic cells (CD30+ HRS) and a diverse group of reactive bystander cells (histiocytes, small lymphocytes, plasma cells, epithelioid histiocytes, epithelioid granulomas and eosinophils). CD30+(100%), CD15+(75%), PAX5(weak), CD20−/+. Expression of EBV markers (both EBER and EBV-LMP) is a useful finding in cHL cases, where EBV-LMP expression is characteristically seen in the HRS cells. 10-80 ABVD Nivolumab Pembrolizumab Tislelizumab Camrelizumab Nivolumab + BV EBV-CTL and LMP-2-CTL 5-year PFS/ OS: 71%/91%, CR %: 73% (primary). ORR: 66%-89%, CR: 59% (r/r). ORR: 69%, CR: 22.4% (r/r). ORR: 87.1%, CR: 62.9% (r/r). CR: 28%, ORR: 76% (r/r). CR: 67%, ORR:85%, OS: 98% (r/r, or high-risk). Tolerated and sustained clinical responses (relapsed). BL Bulky, rapidly growing masses, involving the bones of the jaw and other facial bones, as well as kidneys, gastrointestinal tract, ovaries, breast, and other extranodal sites. A diffuse infiltrate of monomorphic, medium-size B cells in a “starry sky” pattern, imparted by numerous benign macrophages, and by an extremely high proliferative index, with a Ki-67 approaching 100%. CD20+, CD10+, Bcl-6+, Bcl-2−, CD5−, TdT−, monotypic sIg+, Ki67 ~100%; t(8;14), t(2;8), or t(8;22) ( myc and IgH or IgL ); no bcl-2 or bcl-6 translocation. 100 (DA)R-EPOCH HyperCVAD +/-R EFS: 95%, OS: 100% (primary). 3-year EFS: 80%, 3-year OS: 89%. DLBCL Nodal involvement and high IPI scores, higher rates of extranodal involvement (gastrointestinal tract, skin, and BM being). Large, transformed cells/immunoblasts and HRS-like cells. Reactive background: small lymphocytes, plasma cells, histiocytes and epithelioid cells. Geographical necrosis and angioinvasion. PanB (CD19, CD20, CD22, CD79a, PAX5) +, MUM1+, CD10–, BCL6–, CD30+, CD15(–/+), EBNA2–/+(7-36%), LMP1+ (> 90%), PDL1/PDL2+/–, EBER+ (>80%, bcl-2 and bcl-6 abnormalities common, myc abnormal in a minority). 10 R-CHOP Polatuzumab vedotin+R-CHP Acalabrutinib+R-CHOP Sintilimab + R-CHOP Tislelizumab + zanubrutinib BV + chemotherapy BV + lenalidomide + rituximab ORR: 50-94%, CR: 25-67%, 5-year OS: 45%-54% (RWD). 2-year PFS 76.7%, 5-year OS: 45%-54% (primary). Clinical trial. Clinical trial. Clinical trial. Clinical trial (r/r). Clinical trial (r/r). AITL Lymphadenopathy, hepatosplenomegaly, systemic symptoms, and an aggressive course with a poor response to therapy. Complete structural effacement. Infiltrating cellular components include clear cells, blastic cells, arborizing vessels composed of HEVs, and inflammatory cells (small lymphocytes, eosinophils, macrophages, and plasma cells). CD3, CD4, and CD5 are positive in most cases. Tfh lymphomas be diagnosed by positive immunostaining for at least 2 (ideally 3) of the following 7 antigens: CD10, BCL6, PD1, CXCL13, CXCR5, ICOS, and SAP. 80-90 CHOP CHOP-like CHOEP 5-azacytidine+CHOP CHOP plus lenalidomide R-CHOP Geptanolimab Romidepsin Chidamide Bortezomib 3-year EFS: 50.0%, 5-year PFS: 23.0%(primary). CR: 35-39%, ORR: 70-79%, OS: 30-40% (primary or RWD). 3-year EFS: 67.5%, 5-year PFS: 40% (RWD). 1-year PFS: 61.1% (primary). 2-year PFS: 42% (primary). 2-year PFS: 40.0% (RWD). PR: 50%, SD: 50% (r/r). It can induce complete and lasting response (r/r). It has significant single drug activity and controllable toxicity (r/r) ORR: 67% (r/r). NKTCL Destructive ulcerative/necrotizing lesion, causing obstructive symptoms. Diffuse lymphoid infiltrate of small, medium sized or large cells, which show different degrees of atypia. Angiocentric and/or angioinvasive pattern. Zonal geographic necrosis. Majority of the cases: NK cells (CD56+, CD3ε, EBER+, cytotoxic molecules+, surface CD3-) CD56- subset: T cells (surface CD3+, CD3ε+, CD8+, cytotoxic molecules, TCRαβ or γδ, EBER+). 100 DDGP regimen SMILE regimen P-Gemox AspaMetDex regimen Daratumumab Sintilimab Avelumab LMP-CTL Bortezomib+ CHOP First-line treatment. ORR: 79%, CR: 45% (newly diagnosed stage IV, or r/r). ORR: 80%, CR: 51.4% (newly diagnosed advanced). ORR: 77.8% (newly diagnosed advanced stage or r/r). ORR: 25-35.7% (r/r). ORR: 68% (r/r). CR: 24%; ORR: 38% (r/r). OS: 100%; PFS:90% (primary). ORR: 61.5% (stage III or IV). CAEBV No known immunodeficiency. IM-like symptoms for at least 3 months. High viral load in peripheral blood (>102.5 copies/ml). Demonstration of EBER in affected tissues. Non-specific lymphoid infiltrate without atypia, mimicking a reactive disorder. Cytotoxic T, CD4+ or CD8+ or TCR γ+ (59%) or NK-cells (41%). Monoclonal, or oligoclonal or polyclonal TCR/EBV. EBER+ cells: % variable. 100 Steroids, etoposide, and cyclosporine or cytotoxic chemotherapy + HSCT OS: 87%. PTLD Nonspecific, systemic manifestations. Multiorgan failure and a fulminant clinical course that can fatal. Fever and lymphadenopathy, associated with widespread disease, B-symptoms and extranodal involvement (Waldeyer’s ring, liver, gastrointestinal tract, BM, and CNS). Preservation of underlying tissue architecture. PH shows plasma cells with scattered immunoblasts. IM-like lesions show predominantly immunoblasts, sometimes with RS like cells and/or plasmacytic differentiation. Plasma cells show polytypic light chain staining. Immunoblasts are CD20+, CD79a+, PAX-5+, CD30+, CD15-. Admixed T-immunoblasts present (CD3+, CD5+). EBER positivity in B-immunoblasts. >90 R-CHOP Rituximab EBV-CTL Bortezomib+Rituximab HDACIs First-line treatment. It is related to the elimination of PTLD related mortality. CR: 84.6%. ORR (4 months): 42.9%; CR:42.9%; PFS (6 months): 43%. Clinical trial. Abbreviations: cHL, classical Hodgkin’s lymphoma; HRS, Hodgkin and Reed–Sternberg cells; EBV, Epstein-Barr virus; EBER, Epstein-Barr virus encoded RNA's; EBV-LMP, EBV encodes latent membrane protein; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; PFS, Progression-free survival; OS, Overall survival; CR, Complete response; r/r, relapsed or refractory; ORR, Overall response rates; BL, Burkitt lymphoma; (DA)R-EPOCH, dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; EFS, Event-free survival; HyperCVAD +/-R, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone+/-rituximab; DLBCL (NOS), Diffuse large B-cell lymphoma (Non-specific); IPI, International Prognostic Index; BM, bone marrow; R-CHOP, Rituximab combination with cyclophosphamide, doxorubicin, vincristine and prednisolone; R-CHP, Rituximab combination with cyclophosphamide, doxorubicin, and prednisolone; BV, brentuximab vedotin; AITL, Angioimmunoblastic T-cell lymphoma; HEVS, high endothelial venules; Tfh, Follicular helper T; CXCR5, C-X-C motif chemokine receptor 5; ICOS, CD28-related inducible T-cell costimulatory; SAP, signaling lymphocytic activation molecule-associated protein; RWD, real-world data; PR, Partial remission; NKTCL, nasal NK/T cell lymphoma; NK: Natural killer; DDGP, cisplatin, dexamethasone, gemcitabine and pegaspargase; SMILE, dexamethasone, methotrexate, ifosfamide, asparaginase, and etoposide; P-GEMOX, pegaspargase, gemcitabine, and oxaliplatin; AspaMetDex regimen: L-asparaginase with methotrexate and dexamethasone; LMP, latent membrane protein; CTL, cytotoxic T cells; CAEBV, chronic active Epstein Barr virus (Systemic form) Infection; IM, infectious mononucleosis; HSCT, Hematopoietic stem cell transplantation; PTLD, posttransplant lymphoproliferative diseases; CNS, central nervous system; PH, Plasmacytic hyperplasia; HDACi, Histone deacetylase inhibitors. Discussion One possible factor contributing to the development of secondary DLBCL to AITL in patients is persistent EBV infection. EBV infection in humans occurs in three distinct stages: lytic phase, latent phase, and reactivation. The virus achieves lifelong persistence in its human host by balancing its ability to evade the immune system via latent infection of B lymphocytes and its ability to replicate and shed from the oral mucosa [6]. The oncogenic effect of EBV on B cells occurs through the action of a number of viral microRNAs and the protein LMP-1 [7]. B cell clonality in EBV-positive DLBCL is common, the incidence of T cell cloning is also high in EBV-positive DLBCL patients (up to 24%), although these clones may be present in normal elderly patients and are thought to reflect the reduction in T cell diversity inherent in age-related immune senescence [8-9]. However, the presence or emergence of these clonal T cells may provide the possibility for EBV-positive DLBCL patients to develop T cell tumors. EBV-positive cells are detected in up to 85% to 95% of AITL biopsies, and the virus is predominantly located in large B-cell blasts [10-14]. In some cases, the neoplastic T cells can also become infected. The role of EBV in AITL remains uncertain, and several hypotheses coexist. Some authors believe that EBV reactivation is the result of immunodeficiency states produced by AITL, thereby favoring the expansion of T FH and B cells and playing a role in the development of the tumor microenvironment. Others claim that EBV itself drives the development of AITL by activating T FH cells [15]. The detection of EBV-positive cells early in the course of the disease, as well as the fact that EBV-positive B cell proliferation may occur during AITL progression, suggests that the virus may play a role in the development of AITL [11]. We then summarize the clinical manifestations, morphology, pathological features, and treatment regimens of some EBV-associated lymphomas In Table 2 [16-35]. Another possible factor contributing to the development of secondary DLBCL to AITL in patients is TET2 mutations. Nguyen, et al showed that TET2 mutations were found in programmed death 1 positive cells as well as CD20 + cells in 15/16 cases [36]. TET2 mutations of AITL clones are also present in patients' B cells in more than 50% of cases. Also, human precursor cells with TET2 mutations also frequently produce TET2 mutant B cells [37]. These findings suggest that clonal expansion following gene mutation is a multi-step multi-line acquisition. TET2 mutations may occur in both B cells and T cells, manifesting in different tumor types at different stages. Chidamide (CS055) is a novel oral HDAC inhibitors developed in China that selectively inhibits the activities of HDAC1, 2, 3, and 10, induce tumor cell growth arrest and apoptosis, and enhance cellular antitumor immunity. Chidamide was approved by Chinese Food and Drug Administration in 2014 for the treatment of peripheral T-cell lymphoma [38]. Currently, there is no efficient way to remove the EBV because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. Therefore, EBV-positive lymphoma generally responds worse to treatment than EBV-negative lymphoma. However, studies have shown that chidamide significantly switch EBV from the latent stage to the lytic stage in EBV-positive lymphomas [39-40]. Therefore, a combination of chidamide and chemotherapy may be an effective strategy for EBV-positive lymphomas. Cyclophosphamide, vindesine, etoposide, doxorubicin , bleomycin, and prednisone are commonly used to treat aggressive lymphoma [41-42]. A multicenter phase II clinical trial demonstrated that chidamide plus prednisone, etoposide, and thalidomide are effective, tolerable, and economical options for the treatment of untreated angioimmunoblastic T-cell lymphoma in Chinese populations [43]. Therefore, we chose the regimen of chidamide plus COEP for this patient. The regimen appeared to prolong the survival of the patient, who died six months after being diagnosed with AITL. Previous studies have reported that patients who develop AITL after EBV-negative or -positive DLBCL treatment die about two months after being diagnosed with AITL [4, 44]. Conclusion Here, we report a case of elderly EBV-positive DLBCL that developed into EBV-positive AITL two years later. We went on to discuss possible factors that may promote the development of AITL in patients following DLBCL, including EBV infection and TET2 mutation. When EBV-positive DLBCL patients with the TET2 mutation, it is necessary to beware of lymphoma recurrence and note that it may be completely different from the previous type. Accurate diagnosis of lymphoma type helps to provide patients with more appropriate treatment options. Our case suggests that chidamide plus COEP may be a treatment option for AITL after DLBCL and may prolong patient survival, but this requires a larger sample size to confirm. Declarations Author Contributions: Qing Li drew all the diagrams in the text and wrote the manuscript, Qing Li and Shishuo Dai collected the clinical data and did the follow up, Weiping Liu provided immunohistochemical pictures, and Yu Wu provided clinical cases and directed writing. Acknowledgments : The authors thank the Shanghai Righton Gene Biotechnology Co., Ltd. for providing the NGS, and the cooperation and contribution of the patient and her family. Funding: This work was supported by the National Natural Science Foundation of China (No. 82370171) and Science and Technology Department of Sichuan Province (No. 2022YFS0191). Institutional Review Board Statement: This study complied with the principles of the Declaration of Helsinki. Due to the retrospective nature of the study, local ethical committees were only notified. Informed Consent Statement: The consent was obtained from this patient for publication in print and electronically. Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants. 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Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol 2005; 23: 3383-9. DOI: 10.1200/JCO.2005.08.100. Sanz J and Andreu R. Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation. Curr Opin Oncol 2014; 26: 677-83. DOI: 10.1097/CCO.0000000000000119. Neparidze N and Lacy J. Malignancies associated with epstein-barr virus: pathobiology, clinical features, and evolving treatments. Clin Adv Hematol Oncol 2014; 12: 358-71. Chiba S and Sakata-Yanagimoto M. Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia 2020; 34: 2592-606. DOI: 10.1038/s41375-020-0990-y. Haverkos BM, Alpdogan O, Baiocchi R, Brammer JE, Feldman TA, Capra M, et al. Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study. Blood 2021; 138: 623-. DOI: 10.1182/blood-2021-152603. Lage L, Culler HF, Reichert CO, da Siqueira SAC and Pereira J. Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances. Front Oncol 2023; 13: 1177590. DOI: 10.3389/fonc.2023.1177590. Shi Y, Wu J, Wang Z, Zhang L, Wang Z, Zhang M, et al. Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002). J Hematol Oncol 2021; 14: 12. DOI: 10.1186/s13045-021-01033-1. Nguyen TB, Sakata-Yanagimoto M, Asabe Y, Matsubara D, Kano J, Yoshida K, et al. Identification of cell-type-specific mutations in nodal T-cell lymphomas. Blood cancer journal 2017; 7: e516. DOI: 10.1038/bcj.2016.122. Schwartz FH, Cai Q, Fellmann E, Hartmann S, Mayranpaa MI, Karjalainen-Lindsberg ML, et al. TET2 mutations in B cells of patients affected by angioimmunoblastic T-cell lymphoma. The Journal of pathology 2017; 242: 129-33. DOI: 10.1002/path.4898. Lu X, Ning Z, Li Z, Cao H and Wang X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res 2016; 5: 185-91. DOI: 10.5582/irdr.2016.01024. Yu H, Zhang H, Chu Z, Ruan Q, Chen X, Kong D, et al. Combination of betulinic acid and chidamide synergistically inhibits Epstein-Barr virus replication through over-generation of reactive oxygen species. Oncotarget 2017; 8: 61646-61. DOI: 10.18632/oncotarget.18661. Zhou J, Zhang C, Sui X, Cao S, Tang F, Sun S, et al. Histone deacetylase inhibitor chidamide induces growth inhibition and apoptosis in NK/T lymphoma cells through ATM-Chk2-p53-p21 signalling pathway. Invest New Drugs 2018; 36: 571-80. DOI: 10.1007/s10637-017-0552-y. Gkotzamanidou M and Papadimitriou CA. Peripheral T-cell lymphoma: the role of hematopoietic stem cell transplantation. Crit Rev Oncol Hematol 2014; 89: 248-61. DOI: 10.1016/j.critrevonc.2013.08.016. Gisselbrecht C, Lepage E, Molina T, Quesnel B, Fillet G, Lederlin P, et al. Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 2002; 20: 2472-9. DOI: 10.1200/JCO.2002.02.125. Wang Y, Zhang M, Song W, Cai Q, Zhang L, Sun X, et al. Chidamide plus prednisone, etoposide, and thalidomide for untreated angioimmunoblastic T-cell lymphoma in a Chinese population: A multicenter phase II trial. Am J Hematol 2022; 97: 623-9. DOI: 10.1002/ajh.26499. Wang C, Gong Y, Jiang Q, Liang X and Chen R. Epstein-Barr virus positive diffuse large B-cell lymphoma transformed into angioimmunoblastic T-cell lymphoma after treatment. Clin Case Rep 2021; 9: e04083. DOI: 10.1002/ccr3.4083. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3759312","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":261968552,"identity":"29fafae4-120e-44b4-a220-18cab8d3a590","order_by":0,"name":"Qing Li","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Li","suffix":""},{"id":261968553,"identity":"4b4415ef-f7f2-47ff-b259-58751bed992c","order_by":1,"name":"Shishuo Dai","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shishuo","middleName":"","lastName":"Dai","suffix":""},{"id":261968554,"identity":"d0bca752-ba43-4c36-bd96-fa9d26760ee1","order_by":2,"name":"Weiping Liu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weiping","middleName":"","lastName":"Liu","suffix":""},{"id":261968555,"identity":"c7565b7b-b6c5-4c33-8364-c18b55698b17","order_by":3,"name":"Yu Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApklEQVRIiWNgGAWjYNCCCgglQYKWMyRrYWwjRYvBjQQ2ad55dfIGB5gP3uZhsMsjUsu2w4YbDrAlW/MwJBcT1GIG0XIgweAAj5k0D8OBxAbitMypA2rh/0aKlgZmkC1sxGmxP/OA2XLOscOGMw+zGVvOMUgmrEWyPYHxxpuaOnm+480Pb7ypsCOshYGB/wskOphBhAFh9WC1H4hTNwpGwSgYBSMWAAB2NDT4iFoFIQAAAABJRU5ErkJggg==","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2023-12-15 14:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3759312/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3759312/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":48813960,"identity":"f738a11e-3621-4593-ad98-af13c57b4c32","added_by":"auto","created_at":"2023-12-26 15:37:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3170773,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining at diagnosis of DLBCL. (A)Tonsil biopsy (hematoxylin and eosin); (B) positive for CD20; (C) positive for MUM-1; (D) positive for Ki-67/MIB (+, 80%); (E) positive for C-MYC (+,50%); (F) positive for EBER2-ISH.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3759312/v1/198cd70ec43b15e85fd48d1c.png"},{"id":48813958,"identity":"42ffa42a-3739-4836-9f12-6991915ea576","added_by":"auto","created_at":"2023-12-26 15:37:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3025031,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining at diagnosis of AITL. (A) Lymph node (hematoxylin and eosin); (B) positive for CD3; (C) positive for CD4; (D) positive for CD10; (E) positive for CD21; (F) positive for EBER2-ISH.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3759312/v1/566c6515d7d4540627f0ca8c.png"},{"id":48813956,"identity":"612ef0a0-cc21-43df-ac09-7dd57aac1f66","added_by":"auto","created_at":"2023-12-26 15:37:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":890106,"visible":true,"origin":"","legend":"\u003cp\u003eMutational landscape of our reported case at the time of diagnosis of DLBCL and AITL. The color represents the type of mutation, the left ordinate represents the mutation gene and mutation site, and the right vertical coordinate represents the change of nucleotides and amino acids. The abscissa represents the frequency of mutations.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3759312/v1/4a63066b2844a9ad77062352.png"},{"id":48815799,"identity":"845458aa-3d5d-4dfb-9d32-f0ffc9ef90d3","added_by":"auto","created_at":"2023-12-26 16:09:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7126463,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3759312/v1/4a7e2283-0398-4831-a95a-aae15c0c4c23.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Born with Two Faces: Sequential development of Diffuse Large B-cell Lymphoma and Angioimmunoblastic T-cell Lymphoma with EBV positive and TET2 mutation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Epstein\u0026ndash;Barr virus (EBV) has a powerful lymphocyte growth-transforming ability and is etiologically related to a series of lymphoproliferative disorders and malignant lymphomas [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Angioimmunoblastic T-cell lymphoma (AITL) is a mature T-cell lymphoma with poor clinical prognosis. Common mutant genes of AITL include \u003cem\u003eRHO\u003c/em\u003eA, \u003cem\u003eTET2\u003c/em\u003e, \u003cem\u003eDNMT3A\u003c/em\u003e, and \u003cem\u003eIDH2\u003c/em\u003e [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Case of diffuse large B-cell lymphoma (DLBCL) after initial diagnosis of AITL has been reported [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. And case of developing AITL after the initial diagnosis of DLBCL has also been reported [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. What sets this study apart from previous studies is that we are the first to attempt to perform deep sequencing of lymphoma tissue in both disease states to elucidate the potential link between DLBCL and AITL.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eNext-generation sequencing (NGS) (Illumina sequencer, NovaSeq, 1500X) was used to study the possible mechanisms by which this patient developed AITL after DLBCL. Specifically, we detected one hundred fourteen hotspot genes associated with DLBCL in tonsil biopsy paraffin tissue when diagnosed with DLBCL and eighty-four genes related to intranodal and peripheral T-cell lymphoma in lymph node biopsy paraffin tissue when AITL was diagnosed.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCase Report\u003c/h2\u003e \u003cp\u003eA 74-year-old man presents to Sichuan Provincial Cancer Hospital with progressive worsening of sore throat for more than four months without fever, night sweats, and weight loss. Before admission, the patient went to the community hospital for symptomatic treatment, but the pain was not relieved. He then underwent a tonsil biopsy and sent the biopsy specimen to the Department of Pathology, West China Hospital, Sichuan University. A plenty of diffuse large-sized proliferating atypical lymphocytes with necrosis can be seen under microscope (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Immunohistochemically, the atypical cells were positive for CD20 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), MUM-1(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC), Ki-67/MIB (80%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD), C-MYC (50%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE), and EBER1/2-ISH (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). A positive rearrangement of the IgH gene was confirmed by Genescan analysis (Shanghai State Medical Laboratory Co.Ltd). The patient was in good health and have no family history of genetic history.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe complete blood count, coagulation markers, liver and kidney function, electrolytes, electrocardiogram, and DNA copies of EBV were all within the normal range. Cardiac ultrasound showed mild regurgitation of the aortic valve and mitral valve, and ventricular diastolic function was reduced. Positron emission tomography/computed tomography (PET/CT) revealed abnormal metabolic activity in multiple sites, such as both lateral walls of the oropharynx, the left posterior wall of the nasopharynx, bilateral submandibular, bilateral cervical para-vascular and left posterior cervical triangle. The Deauville assessment was five. The patient was diagnosed with nongerminal central subtype stage II EBV-positive DLBCL. Then the patient received four cycles of R-CHOP regimen (rituximab, cyclophosphamide, vindesine, doxorubicin liposome and dexamethasone) and was assessed for efficacy using PET/CT, which revealed complete remission (Deauville assessment is two). The patient then received two cycles of R-CHOP and the efficacy was assessed using contrast-enhanced CT, indicating no new lesions. Since then, the patient has not been regularly followed up.\u003c/p\u003e \u003cp\u003eAfter approximately two years, the patient sought medical help due to itching and swollen lymph nodes all over the body. Cervical lymph node biopsy shows that some areas of lymphoid tissue are distinguishable, see partial naked follicles. The interfollicular zone widens, in which small blood vessels are seen to proliferate, partially intertwined, and the endothelium is swollen (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Immunohistochemical analyses of tumor cells indicated positivity for CD3 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), CD4 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), CD10 (partially) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD), CD21(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE), and EBER1/2-ISH (dispersedly) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). Ki67/MIB was expressed by 60% of lymphoma cells. Lymphoma cells were negative for CD20, CD8, CXCL13, CD15, PAX-5. Gene rearrangement found the clonal amplification peak of the \u003cem\u003eTCR\u003c/em\u003e γ gene within the range of the target fragment; no \u003cem\u003eIGH\u003c/em\u003e gene rearrangement was found. Sanger sequencing revealed that no mutations were detected in exon 2 (G17Val) of the \u003cem\u003eRHOA\u003c/em\u003e gene and codon 172 of the \u003cem\u003eIDH2\u003c/em\u003e gene. Bone marrow tissue immunohistochemistry did not show exact lymphoma involvement. PET/CT revealed abnormally elevated glucose metabolism in cervical, thoracic, and abdominal lymph nodes. The DNA copies of EBV in serum were 1.25E\u0026thinsp;+\u0026thinsp;4 copies/ml. Then, the patient was diagnosed with EBV-positive AITL. Given that the patient developed AITL after DLBCL, and the tumor accumulation was wide, new strategy of therapy should be considered. So, histone deacetylase (HDAC) inhibitor, chidamide, combined with COEP (cyclophosphamide, vindesine, etoposide, prednisone) was administered. The DNA copies of EBV in serum after treatment were 2.30E\u0026thinsp;+\u0026thinsp;02 copies/ml. The patient ultimately died after six months diagnosed with AITL. The overall survival of this patient is thirty months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eNGS\u003c/h2\u003e \u003cp\u003eTo explore the possible mechanisms by which patients develop AITL following treatment with DLBCL, NGS was adopted. In the DLBCL hotspot gene profile, NGS detected that the patient had mutated genes, including \u003cem\u003eEP300\u003c/em\u003e, \u003cem\u003eTET2\u003c/em\u003e, \u003cem\u003eKMT2D\u003c/em\u003e, and \u003cem\u003eSTAT6\u003c/em\u003e. Furthermore, among the genes associated with intranodal and peripheral T-cell lymphoma, NGS also detected mutations in \u003cem\u003eTET2\u003c/em\u003e, and the mutation site was consistent with that detected in DLBCL. The \u003cem\u003eTET2\u003c/em\u003e mutation frequencies were 31.58% and 39.92% in DLBCL and AITL, respectively (Fig.\u0026nbsp;3). After the patient was diagnosed with AITL, a mutation at the same site (c.C4579T) of \u003cem\u003eTET2\u003c/em\u003e was also detected in the peripheral blood. The pathways and mutated genes involved in DLBCL and AITL are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFrequencies of gene mutations involved in different pathways in DLBCL and AITL\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathways \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvolved genes (frequency of mutations)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDLBCL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eB cell development and differentiation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eMEF2B (7%\u0026ndash;12%), IRF8 (8%\u0026ndash;11%), BCL6 (6%\u0026ndash;11%), PRDM1 (7%\u0026ndash;12%), EBF1 (8%\u0026ndash;11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCR and Toll-like receptor signaling\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eMYD88 (18%\u0026ndash;27%), CD79B (14%\u0026ndash;15%), CARD11 (11%\u0026ndash;15%), PRKCB (4%\u0026ndash;5%), PTPN6 (4%\u0026ndash;5%), LYN (3%\u0026ndash;4%), GRB2 (2%\u0026ndash;3%) and TLR2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNF-\u0026kappa;B pathway\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eTNFAIP3 (9%\u0026ndash;18%), TBL1XR1 (7%\u0026ndash;13%), KLHL6 (9%\u0026ndash;10%), NFKBIE (3%\u0026ndash;8%), ZC3H12A (3%\u0026ndash;7%) and NFKBIA (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAPK\u0026ndash;ERK pathway\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eBRAF (3%\u0026ndash;6%) and KRAS (3%\u0026ndash;4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePI3K\u0026ndash;AKT\u0026ndash;mTOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003ePTEN (3%\u0026ndash;4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep53 and DNA damage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eTP53 (21%\u0026ndash;24%), UBE2A (4%\u0026ndash;8%) and ZNF423 (0.4%\u0026ndash;2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCell cycle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003ePIM1 (22%\u0026ndash;29%), BTG1 (14%\u0026ndash;16%) and CCND3 (5%\u0026ndash;11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCell apoptosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eBCL2 (10%\u0026ndash;17%) and FAS (8%\u0026ndash;10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNOTCH pathway\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eDTX1 (12%\u0026ndash;15%), SPEN (9%\u0026ndash;11%) and NOTCH2 (7%\u0026ndash;8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCell migration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eGNA13 (8%\u0026ndash;11%), RHOA (4%\u0026ndash;5%) and CXCR4 (2%\u0026ndash;3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJAK\u0026ndash;STAT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eSTAT3 (6%\u0026ndash;10%), STAT6 (4%\u0026ndash;5%) and IL6 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpigenetic regulators\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eKMT2D (25%\u0026ndash;33%), HIST1H1E (13%\u0026ndash;16%), CREBBP (17%\u0026ndash;18%), HIST1H1C (10%\u0026ndash;12%), TET2 (0%\u0026ndash;12%), EZH2 (7%\u0026ndash;9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmune escape\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eHL AB (12%\u0026ndash;22%), B2M (9%\u0026ndash;17%), HL AA (8%\u0026ndash;16%), CD70 (9%), CD58 (6%\u0026ndash;11%), HL AC (4%\u0026ndash;7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAITL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRAS superfamily\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eRHOAG17V (50%\u0026ndash;72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpigenetic regulators\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eTET2 (47%\u0026ndash;86%), DNMT3A (20%\u0026ndash;48%), IDH2R172 (20%\u0026ndash;45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTCR signaling pathway\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003ePLC\u0026gamma; (14%), CD28 (9%\u0026ndash;11%), FYN (3%\u0026ndash;4%), VAV1 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStructural alteration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.75757575757575%\" valign=\"top\"\u003e\n \u003cp\u003eCTLA4-CD28fusion (58%), ICOS-CD28fusion (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DLBCL, Diffuse large B cell lymphoma; AITL, Angioimmunoblastic T cell lymphoma.\u003c/p\u003e\u003cp\u003eTable 2. Clinical manifestations, morphology, immunophenotype, genotype, treatment regimen and efficacy of EBV-associated lymphoma\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"104%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eClinical presentation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eMorphology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eImmunophenotype and genotype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e%EBV association\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eTherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eEfficacy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003ecHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eA nodal disease with virtually all cases arising in peripheral lymph nodes (mediastinum). When the disease advances, it may infiltrate spleen, liver and other extranodal locations.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eLarge neoplastic cells (CD30+ HRS) and a diverse group of reactive bystander cells (histiocytes, small lymphocytes, plasma cells, epithelioid histiocytes, epithelioid granulomas and eosinophils).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eCD30+(100%), CD15+(75%), PAX5(weak), CD20\u0026minus;/+. Expression of EBV markers (both EBER and EBV-LMP) is a useful finding in cHL cases, where EBV-LMP expression is characteristically seen in the HRS cells.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e10-80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eABVD\u003c/p\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003cp\u003eTislelizumab\u003c/p\u003e\n \u003cp\u003eCamrelizumab\u003c/p\u003e\n \u003cp\u003eNivolumab + BV\u003c/p\u003e\n \u003cp\u003eEBV-CTL and LMP-2-CTL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e5-year PFS/\u0026nbsp;OS: 71%/91%, CR %: 73% (primary).\u003c/p\u003e\n \u003cp\u003eORR: 66%-89%, CR: 59% (r/r).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eORR: 69%, CR: 22.4% (r/r).\u003c/p\u003e\n \u003cp\u003eORR: 87.1%, CR: 62.9% (r/r).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCR: 28%, ORR: 76% (r/r).\u003c/p\u003e\n \u003cp\u003eCR: 67%, ORR:85%, OS: 98% (r/r, or high-risk).\u003c/p\u003e\n \u003cp\u003eTolerated and sustained clinical responses (relapsed).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;BL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eBulky, rapidly growing masses, involving the bones of the jaw and other facial bones, as well as kidneys, gastrointestinal tract, ovaries, breast, and other extranodal sites.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eA diffuse infiltrate of monomorphic, medium-size B cells in a \u0026ldquo;starry sky\u0026rdquo; pattern, imparted by numerous benign macrophages, and by an extremely high proliferative index, with a Ki-67 approaching 100%.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eCD20+, CD10+, Bcl-6+, Bcl-2\u0026minus;, CD5\u0026minus;, TdT\u0026minus;, monotypic sIg+, Ki67 ~100%;\u0026nbsp;t(8;14), t(2;8), or t(8;22) (\u003cem\u003emyc\u0026nbsp;\u003c/em\u003eand \u003cem\u003eIgH\u0026nbsp;\u003c/em\u003eor \u003cem\u003eIgL\u003c/em\u003e); no \u003cem\u003ebcl-2\u0026nbsp;\u003c/em\u003eor \u003cem\u003ebcl-6\u0026nbsp;\u003c/em\u003etranslocation.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e(DA)R-EPOCH\u003c/p\u003e\n \u003cp\u003eHyperCVAD +/-R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eEFS: 95%, OS: 100% (primary).\u003c/p\u003e\n \u003cp\u003e3-year EFS: 80%, 3-year OS: 89%.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003eDLBCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eNodal involvement and high IPI scores, higher rates of extranodal involvement (gastrointestinal tract, skin, and BM being).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eLarge, transformed cells/immunoblasts and HRS-like cells.\u003c/p\u003e\n \u003cp\u003eReactive background: small lymphocytes, plasma cells, histiocytes and epithelioid cells. Geographical necrosis and angioinvasion.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003ePanB (CD19, CD20, CD22, CD79a, PAX5) +, MUM1+, CD10\u0026ndash;, BCL6\u0026ndash;, CD30+, CD15(\u0026ndash;/+), EBNA2\u0026ndash;/+(7-36%), LMP1+ (\u0026gt; 90%), PDL1/PDL2+/\u0026ndash;, EBER+ (\u0026gt;80%, \u003cem\u003ebcl-2\u0026nbsp;\u003c/em\u003eand \u003cem\u003ebcl-6\u0026nbsp;\u003c/em\u003eabnormalities common, \u003cem\u003emyc\u0026nbsp;\u003c/em\u003eabnormal in a minority).\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eR-CHOP\u003c/p\u003e\n \u003cp\u003ePolatuzumab vedotin+R-CHP\u003c/p\u003e\n \u003cp\u003eAcalabrutinib+R-CHOP\u003c/p\u003e\n \u003cp\u003eSintilimab + R-CHOP\u003c/p\u003e\n \u003cp\u003eTislelizumab + zanubrutinib\u003c/p\u003e\n \u003cp\u003eBV + chemotherapy\u003c/p\u003e\n \u003cp\u003eBV + lenalidomide + rituximab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eORR: 50-94%, CR: 25-67%, 5-year OS: 45%-54% (RWD).\u003c/p\u003e\n \u003cp\u003e2-year PFS 76.7%, 5-year OS: 45%-54% (primary).\u003c/p\u003e\n \u003cp\u003eClinical trial.\u003c/p\u003e\n \u003cp\u003eClinical trial.\u003c/p\u003e\n \u003cp\u003eClinical trial.\u003c/p\u003e\n \u003cp\u003eClinical trial (r/r).\u003c/p\u003e\n \u003cp\u003eClinical trial (r/r).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003eAITL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eLymphadenopathy, hepatosplenomegaly, systemic symptoms, and an aggressive course with a poor response to therapy.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eComplete structural effacement. Infiltrating cellular components include clear cells, blastic cells, arborizing vessels composed of HEVs, and inflammatory cells (small lymphocytes, eosinophils, macrophages, and plasma cells).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eCD3, CD4, and CD5 are positive in most cases. Tfh lymphomas be diagnosed by positive immunostaining for at least 2 (ideally 3) of the following 7 antigens: CD10, BCL6, PD1, CXCL13, CXCR5, ICOS, and SAP.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e80-90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eCHOP\u003c/p\u003e\n \u003cp\u003eCHOP-like\u003c/p\u003e\n \u003cp\u003eCHOEP\u003c/p\u003e\n \u003cp\u003e5-azacytidine+CHOP\u003c/p\u003e\n \u003cp\u003eCHOP plus lenalidomide\u003c/p\u003e\n \u003cp\u003eR-CHOP\u003c/p\u003e\n \u003cp\u003eGeptanolimab\u003c/p\u003e\n \u003cp\u003eRomidepsin\u003c/p\u003e\n \u003cp\u003eChidamide\u003c/p\u003e\n \u003cp\u003eBortezomib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e3-year\u0026nbsp;EFS: 50.0%, 5-year\u0026nbsp;PFS: 23.0%(primary).\u003c/p\u003e\n \u003cp\u003eCR: 35-39%, ORR: 70-79%, OS: 30-40% (primary or RWD).\u003c/p\u003e\n \u003cp\u003e3-year\u0026nbsp;EFS: 67.5%, 5-year\u0026nbsp;PFS: 40%\u0026nbsp;(RWD).\u003c/p\u003e\n \u003cp\u003e1-year PFS: 61.1% (primary).\u003c/p\u003e\n \u003cp\u003e2-year\u0026nbsp;PFS: 42%\u0026nbsp;(primary).\u003c/p\u003e\n \u003cp\u003e2-year\u0026nbsp;PFS: 40.0%\u0026nbsp;(RWD).\u003c/p\u003e\n \u003cp\u003ePR: 50%, SD: 50% (r/r).\u003c/p\u003e\n \u003cp\u003eIt can induce complete and lasting response (r/r).\u003c/p\u003e\n \u003cp\u003eIt has significant single drug activity and controllable toxicity (r/r)\u003c/p\u003e\n \u003cp\u003eORR: 67% (r/r).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003eNKTCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eDestructive ulcerative/necrotizing\u003c/p\u003e\n \u003cp\u003elesion, causing obstructive symptoms.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eDiffuse lymphoid infiltrate of small, medium sized or large cells, which show different degrees of atypia. Angiocentric and/or angioinvasive pattern. Zonal geographic necrosis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eMajority of the cases: NK cells (CD56+, CD3\u0026epsilon;,\u003c/p\u003e\n \u003cp\u003eEBER+, cytotoxic molecules+, surface CD3-)\u003c/p\u003e\n \u003cp\u003eCD56- subset: T cells (surface CD3+, CD3\u0026epsilon;+,\u003c/p\u003e\n \u003cp\u003eCD8+, cytotoxic molecules, TCR\u0026alpha;\u0026beta; or \u0026gamma;\u0026delta;, EBER+).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eDDGP regimen\u003c/p\u003e\n \u003cp\u003eSMILE regimen\u003c/p\u003e\n \u003cp\u003eP-Gemox\u003c/p\u003e\n \u003cp\u003eAspaMetDex regimen\u003c/p\u003e\n \u003cp\u003eDaratumumab\u003c/p\u003e\n \u003cp\u003eSintilimab\u003c/p\u003e\n \u003cp\u003eAvelumab\u003c/p\u003e\n \u003cp\u003eLMP-CTL\u003c/p\u003e\n \u003cp\u003eBortezomib+ CHOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eFirst-line treatment.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eORR: 79%, CR: 45% (newly diagnosed stage IV, or r/r).\u003c/p\u003e\n \u003cp\u003eORR: 80%, CR: 51.4% (newly diagnosed advanced).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eORR: 77.8% (newly diagnosed advanced stage or r/r).\u003c/p\u003e\n \u003cp\u003eORR: 25-35.7% (r/r).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eORR: 68% (r/r).\u003c/p\u003e\n \u003cp\u003eCR: 24%; ORR: 38% (r/r).\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOS: 100%; PFS:90% (primary).\u003c/p\u003e\n \u003cp\u003eORR: 61.5% (stage III or IV).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003eCAEBV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eNo known immunodeficiency. IM-like symptoms for at least 3 months. High viral load in peripheral blood (\u0026gt;102.5 copies/ml). Demonstration of EBER in affected tissues.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003eNon-specific lymphoid infiltrate without atypia, mimicking a reactive disorder.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003eCytotoxic T, CD4+ or CD8+ or TCR \u0026gamma;+ (59%) or NK-cells (41%). Monoclonal, or oligoclonal or polyclonal TCR/EBV. EBER+ cells: % variable.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eSteroids, etoposide, and cyclosporine or cytotoxic\u003c/p\u003e\n \u003cp\u003echemotherapy + HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eOS: 87%.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.123711340206185%\" valign=\"top\"\u003e\n \u003cp\u003ePTLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eNonspecific, systemic manifestations. Multiorgan failure and a fulminant clinical course that can fatal. Fever and lymphadenopathy, associated with widespread disease, B-symptoms and extranodal involvement (Waldeyer\u0026rsquo;s ring, liver, gastrointestinal tract, BM, and CNS).\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.587628865979383%\" valign=\"top\"\u003e\n \u003cp\u003ePreservation of underlying tissue architecture. PH\u003c/p\u003e\n \u003cp\u003eshows plasma cells with scattered immunoblasts. IM-like\u003c/p\u003e\n \u003cp\u003elesions show predominantly immunoblasts, sometimes with RS like cells and/or plasmacytic differentiation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003ePlasma cells show polytypic light chain staining. Immunoblasts are CD20+, CD79a+, PAX-5+, CD30+, CD15-. Admixed T-immunoblasts present (CD3+, CD5+). EBER positivity in B-immunoblasts.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.154639175257732%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eR-CHOP\u003c/p\u003e\n \u003cp\u003eRituximab\u003c/p\u003e\n \u003cp\u003eEBV-CTL\u003c/p\u003e\n \u003cp\u003eBortezomib+Rituximab\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHDACIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eFirst-line treatment.\u003c/p\u003e\n \u003cp\u003eIt is related to the elimination of PTLD related mortality.\u003c/p\u003e\n \u003cp\u003eCR: 84.6%.\u003c/p\u003e\n \u003cp\u003eORR (4 months): 42.9%; CR:42.9%; PFS (6 months): 43%.\u003c/p\u003e\n \u003cp\u003eClinical trial.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: cHL, classical Hodgkin\u0026rsquo;s lymphoma; HRS, Hodgkin and Reed\u0026ndash;Sternberg cells; EBV, Epstein-Barr virus; EBER, Epstein-Barr virus encoded RNA\u0026apos;s; EBV-LMP, EBV encodes latent membrane protein; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; PFS, Progression-free survival; OS, Overall survival; CR, Complete response; r/r, relapsed or refractory; ORR, Overall response rates; BL, Burkitt lymphoma; (DA)R-EPOCH, dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; EFS, Event-free survival; HyperCVAD +/-R, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone+/-rituximab; DLBCL (NOS), Diffuse large B-cell lymphoma (Non-specific); IPI, International Prognostic Index; BM, bone marrow; R-CHOP, Rituximab combination with cyclophosphamide, doxorubicin, vincristine and prednisolone; R-CHP, Rituximab combination with cyclophosphamide, doxorubicin, and prednisolone; BV, brentuximab vedotin; AITL, Angioimmunoblastic T-cell lymphoma; HEVS, high endothelial venules; Tfh, Follicular helper T; CXCR5, C-X-C motif chemokine receptor 5; ICOS, CD28-related inducible T-cell costimulatory; SAP, signaling lymphocytic activation molecule-associated protein; RWD, real-world data; PR, Partial remission; NKTCL, nasal NK/T cell lymphoma; NK: Natural killer; DDGP, cisplatin, dexamethasone, gemcitabine and pegaspargase; SMILE, dexamethasone, methotrexate, ifosfamide, asparaginase, and etoposide; P-GEMOX, pegaspargase, gemcitabine, and oxaliplatin; AspaMetDex regimen: L-asparaginase with methotrexate and dexamethasone; LMP, latent membrane protein; CTL, cytotoxic T cells; CAEBV, chronic active Epstein Barr virus (Systemic form) Infection; IM, infectious mononucleosis; HSCT, Hematopoietic stem cell transplantation; PTLD, posttransplant lymphoproliferative diseases; CNS, central nervous system; PH, Plasmacytic hyperplasia; HDACi, Histone deacetylase inhibitors.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOne possible factor contributing to the development of secondary DLBCL to AITL in patients is persistent EBV infection. EBV infection in humans occurs in three distinct stages: lytic phase, latent phase, and reactivation. The virus achieves lifelong persistence in its human host by balancing its ability to evade the immune system via latent infection of B lymphocytes and its ability to replicate and shed from the oral mucosa [6]. The oncogenic effect of EBV on B cells occurs through the action of a number of viral microRNAs and the protein LMP-1 [7]. B cell clonality in EBV-positive DLBCL is common, the incidence of T cell cloning is also high in EBV-positive DLBCL patients (up to 24%), although these clones may be present in normal elderly patients and are thought to reflect the reduction in T cell diversity inherent in age-related immune senescence [8-9]. However, the presence or emergence of these clonal T cells may provide the possibility for EBV-positive DLBCL patients to develop T cell tumors. EBV-positive cells are detected in up to 85% to 95% of AITL biopsies, and the virus is predominantly located in large B-cell blasts [10-14]. In some cases, the neoplastic T cells can also become infected. The role of EBV in AITL remains uncertain, and several hypotheses coexist. Some authors believe that EBV reactivation is the result of immunodeficiency states produced by AITL, thereby favoring the expansion of T\u003csub\u003eFH\u003c/sub\u003e and B cells and playing a role in the development of the tumor microenvironment. Others claim that EBV itself drives the development of AITL by activating T\u003csub\u003eFH\u003c/sub\u003e cells [15]. The detection of EBV-positive cells early in the course of the disease, as well as the fact that EBV-positive B cell proliferation may occur during AITL progression, suggests that the virus may play a role in the development of AITL [11]. We then summarize the clinical manifestations, morphology, pathological features, and treatment regimens of some EBV-associated lymphomas In Table 2 [16-35].\u003c/p\u003e\n\u003cp\u003eAnother possible factor contributing to the development of secondary DLBCL to AITL in patients is \u003cem\u003eTET2\u0026nbsp;\u003c/em\u003emutations. Nguyen, et al showed that \u003cem\u003eTET2\u003c/em\u003e mutations were found in programmed death 1 positive cells as well as CD20\u003csup\u003e+\u003c/sup\u003ecells in 15/16 cases [36]. \u003cem\u003eTET2\u003c/em\u003e mutations of AITL clones are also present in patients\u0026apos; B cells in more than 50% of cases. Also, human precursor cells with \u003cem\u003eTET2\u003c/em\u003e mutations also frequently produce \u003cem\u003eTET2\u003c/em\u003e mutant B cells [37]. These findings suggest that clonal expansion following gene mutation is a multi-step multi-line acquisition. \u003cem\u003eTET2\u003c/em\u003e mutations may occur in both B cells and T cells, manifesting in different tumor types at different stages.\u003c/p\u003e\n\u003cp\u003eChidamide (CS055) is a novel oral HDAC inhibitors developed in China that selectively inhibits the activities of HDAC1, 2, 3, and 10, induce tumor cell growth arrest and apoptosis, and enhance cellular antitumor immunity. Chidamide was approved by Chinese Food and Drug Administration in 2014 for the treatment of peripheral T-cell lymphoma [38]. Currently, there is no efficient way to remove the EBV because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. Therefore, EBV-positive lymphoma generally responds worse to treatment than EBV-negative lymphoma. However, studies have shown that chidamide significantly switch EBV from the latent stage to the lytic stage in EBV-positive lymphomas [39-40]. Therefore, a combination of chidamide and chemotherapy may be an effective strategy for EBV-positive lymphomas. Cyclophosphamide, vindesine, etoposide, doxorubicin , bleomycin, and prednisone are commonly used to treat aggressive lymphoma [41-42]. A multicenter phase II clinical trial demonstrated that chidamide plus prednisone, etoposide, and thalidomide are effective, tolerable, and economical options for the treatment of untreated angioimmunoblastic T-cell lymphoma in Chinese populations [43]. Therefore, we chose the regimen of chidamide plus COEP for this patient. The regimen appeared to prolong the survival of the patient, who died six months after being diagnosed with AITL. Previous studies have reported that patients who develop AITL after EBV-negative or -positive DLBCL treatment die about two months after being diagnosed with AITL [4, 44].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHere, we report a case of elderly EBV-positive DLBCL that developed into EBV-positive AITL two years later. We went on to discuss possible factors that may promote the development of AITL in patients following DLBCL, including EBV infection and \u003cem\u003eTET2\u0026nbsp;\u003c/em\u003emutation. When EBV-positive DLBCL patients with the \u003cem\u003eTET2\u003c/em\u003e mutation, it is necessary to beware of lymphoma recurrence and note that it may be completely different from the previous type. Accurate diagnosis of lymphoma type helps to provide patients with more appropriate treatment options. Our case suggests that chidamide plus COEP may be a treatment option for AITL after DLBCL and may prolong patient survival, but this requires a larger sample size to confirm.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAuthor Contributions:\u0026nbsp;Qing Li drew all the diagrams in the text and wrote the manuscript, Qing Li and\u0026nbsp;Shishuo Dai\u0026nbsp;collected the clinical data and did the follow up, Weiping Liu provided immunohistochemical pictures, and\u0026nbsp;Yu Wu\u0026nbsp;provided clinical cases and directed writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThe authors thank the Shanghai Righton Gene Biotechnology Co., Ltd. for providing the NGS, and the cooperation and contribution of the patient and her family.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the\u0026nbsp;National Natural Science Foundation of China\u0026nbsp;(No.\u0026nbsp;82370171) and Science and Technology Department of Sichuan Province (No.\u0026nbsp;2022YFS0191).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eThis study complied with the principles of the Declaration of Helsinki. Due to the retrospective nature of the study, local ethical committees were only notified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eThe consent was obtained from this patient for publication in print and electronically.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe data presented in this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare that they have no relevant conflicts of interest regarding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYoung LS, Yap LF and Murray PG. Epstein-Barr virus: more than 50 years old and still providing surprises. 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DOI: 10.1002/ccr3.4083.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Epstein–Barr virus, TET2 mutation, Next-generation sequencing, diffuse large B cell lymphoma, angioimmunoblastic T-cell lymphoma","lastPublishedDoi":"10.21203/rs.3.rs-3759312/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3759312/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThere may be significant histopathological and pathogenetic overlap between Epstein\u0026ndash;Barr virus (EBV) -positive diffuse large B cell lymphoma (DLBCL) and other lymphomas, including angioimmunoblastic T-cell lymphoma (AITL). Herein, we reported a rare case of an AITL developing two years after the initial diagnosis of EBV-positive DLBCL. Next-generation sequencing (NGS) is used to study genetic mutations in biopsy samples of DLBCL and subsequent AITL. NGS revealed that \u003cem\u003eTET2\u003c/em\u003e mutated in both DLBCL and AITL, while other differential mutations were also detected, reflecting their own characteristics. Since inherent EBV infection plays a role in both AITL and DLBCL, we evaluated the characteristics of lymphoma associated with EBV infection, including morphology and treatment, etc. We deduce that chronic EBV infection and epigenetic \u003cem\u003eTET2\u003c/em\u003e mutations may alter the immune profile or tumor microenvironment of lymphoma cells, resulting in patients presenting with different tumor types at different times. Patients with AITL secondary to DLBCL have a poor prognosis, and the combination of chidamide and chemotherapy is expected to provide new treatment options for these patients, mainly due to the multiplex antitumor mechanism of chidamide in lymphoma.\u003c/p\u003e","manuscriptTitle":"Born with Two Faces: Sequential development of Diffuse Large B-cell Lymphoma and Angioimmunoblastic T-cell Lymphoma with EBV positive and TET2 mutation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-26 15:37:30","doi":"10.21203/rs.3.rs-3759312/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5bcc54c-1638-4348-bb37-00561dbc79a0","owner":[],"postedDate":"December 26th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-26T15:37:32+00:00","versionOfRecord":[],"versionCreatedAt":"2023-12-26 15:37:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3759312","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3759312","identity":"rs-3759312","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}