Primary effusion lymphoma with biphenotypic and bigenotypic features of T-cell receptor and IGH genes in an HIV-negative patient with kidney transplant

Primary effusion lymphoma with biphenotypic and bigenotypic features of T-cell receptor and IGH genes in an HIV-negative patient with kidney transplant | 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 Case Report Primary effusion lymphoma with biphenotypic and bigenotypic features of T-cell receptor and IGH genes in an HIV-negative patient with kidney transplant Taesung Jeon, Young-Hyeh Ko, You-Na Sung, Hyunsung Kim, Ka-Won Kang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6062454/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Sep, 2025 Read the published version in Annals of Hematology → Version 1 posted 8 You are reading this latest preprint version Abstract Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma that primarily involves body cavities and is characterized by human herpes virus-8 (HHV-8) positivity and the presence of immunoblastic, plasmablastic or anaplastic cells. PEL typically lacks B-cell antigens, but involves immunoglobulin gene rearrangements, suggesting a B-cell origin. Here, we present a highly unusual case of PEL in which tumor cells expressed T-cell antigens but were also monoclonal for both T-cell receptor (TCR) and immunoglobulin heavy locus (IGH) gene rearrangements. An 81-year-old man with bilateral pleural effusions presented with atypical lymphoid cells. Immunohistochemistry revealed positivity for CD3, CD4, MUM-1, OCT2, BOB1, and HHV-8, but negativity for other T- and B-cell antigens. In situ hybridization identified Epstein-Barr virus and lambda light chain restriction. Gene rearrangement studies demonstrated monoclonal TRB (T-cell receptor beta locus) and TRG (T-cell receptor gamma locus) as well as IGH rearrangement. This unusual case of PEL with T-cell antigen expression and clonal rearrangement of both the TCR and IGH genes highlights the lineage complexity of this tumor. primary effusion lymphoma biphenotypic bigenotypic EBV-positive HIV-negative lineage infidelity Figures Figure 1 Figure 2 Figure 3 Highlights Primary effusion lymphoma typically lacks B-cell markers but involves immunoglobulin gene rearrangements, indicating a B-cell origin. This case highlights the unusual co-expression of T-cell antigens and clonal gene rearrangements for both T- and B-cell lineages in PEL. The findings underscore the complex lineage infidelity in PEL, making diagnosis challenging. Introduction Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma that primarily presents as a malignant effusion in the pleural, pericardial, or peritoneal cavities [ 1 ]. In some cases, it can manifest as a solid mass, and an extracavitary form of PEL has also been recognized [ 2 , 3 ]. While PEL predominantly occurs in patients with human immunodeficiency virus (HIV) and is less common in other immunosuppressed individuals, including solid organ transplant recipients and those with neoplastic diseases, autoimmune diseases, or cirrhosis [ 4 , 5 ]. PEL is defined by the presence of human herpes virus-8 (HHV-8), and co-infection with Epstein-Barr virus (EBV) is common, although some cases may be EBV-negative. The malignant cells typically harbor clonally rearranged and hypermutated immunoglobulin genes. however, they lack phenotypic evidence of B-cell differentiation and do not express typical B-cell markers such as CD19, CD20, and CD79a. Lymphomas are broadly classified into B-, T-, and NK-cell lineages based on their histomorphology, immunophenotype, immunoglobulin heavy locus (IGH), and T cell receptor (TCR) TCR gene rearrangements. CD20 and CD3 are markers commonly used to determine B- and T-cell lineages, respectively. However, owing to the malignant nature of neoplasms, deviations in antigen expression patterns often occur in certain lymphomas compared with their benign counterparts. The acquisition of specific antigens is referred to as aberrant expression, and cross-lineage expression is often observed in certain types of mature B-cell lymphomas/leukemias. Nevertheless, co-expression of CD3 in mature B-cell lymphoma is uncommon [ 6 ]. Molecular analysis of clonal rearrangements aids in determining the B- or T-cell lineages, complementing histomorphology and immunohistochemistry. In some studies, simultaneous rearrangement of both IGH and TCR has been observed in immature cell populations, and its occurrence has been reported in mature B-cell lymphomas [ 7 ]. However, simultaneous rearrangement in PEL is rare, with only two cases reported to date [ 8 , 9 ]. Here, we present the case of a patient with PEL who expressed both B- and T-cell-associated antigens and exhibited rearrangement of both the B- and T-cell receptor genes. Case Report An 81-year-old Asian man with a medical history of chronic kidney disease and kidney transplantation 20 years prior presented with underlying conditions including type 2 diabetes mellitus, retinopathy, hypertension, and tuberculous pleurisy. He reported symptoms associated with general weakness, edema, dyspnea on exercise, and recent melena. Their initial vital signs were within normal limits, but physical examination revealed pitting edema. Complete blood counts revealed bicytopenia with normocytic normochromic anemia (hemoglobin 5.3 g/dL), and thrombocytopenia (platelet count of 67 ×10 3 /µL). The white blood cell count and morphology were normal. The creatinine level was consistent with previous trends at 2.42 mg/dL, and the BNP (brain natriuretic peptide) level was elevated at 5081 pg/mL; however, echocardiography revealed no heart failure. Serum protein electrophoresis revealed a small dense band in the lambda antisera, suggesting lambda-type monoclonal gammopathy. HIV and hepatitis tests were negative. Chest computed tomography (CT) revealed bilateral pleural effusion with passive atelectasis without enlarged lymph nodes or mass-like lesions. Thoracentesis revealed an exudate containing 73.8% lymphoid cells. The pleural fluid tested negative for fungi, acid-fast bacilli, and bacteria using staining techniques and anaerobic culture. Cytological smears revealed numerous large atypical lymphoid cells with plasmablastic features, pleomorphic nuclei, vesicular appearance, prominent nucleoli, a high nuclear/cytoplasmic ratio, amphophilic cytoplasm, karyorrhectic debris, and mitotic figures (Fig. 1 A). Immunohistochemical staining revealed strong human herpesvirus-8 (HHV-8) positivity and positive in situ hybridization results for EBER (Figs. 1 I and 1 N). Based on the clinical findings, morphological features, and HHV-8 positivity, a diagnosis of PEL was made. The antibodies used in this study are listed in Table 1 . Immunohistochemical staining of cell blocks yielded positive findings for the T-cell markers CD2, CD3, and CD4, and the B-cell markers OCT2 (octamer-binding transcription factor 2), and BOB1 (B-cell-specific coactivator of octamer-binding transcription factors 1). In addition, the tumor cells expressed MUM-1. However, tests for other T-cell markers (CD5, CD7, and CD8) and B-cell markers (CD20 and CD79a) were negative. Vs38 and CD138 were not detected in this study. In-situ hybridization revealed lambda light-chain restriction. To clarify the biphenotypic features of the tumor cells, we performed double staining for the T-cell antigen CD3 and B-cell transcription factor OCT2 and confirmed dual staining of the two markers in the same tumor cells (Fig. 2 ). Polymerase chain reaction analysis revealed monoclonal peaks for T-cell receptor beta locus (TRB), T-cell receptor gamma locus (TRG) and IGH genes (Fig. 3 ). Table 1 List and details of the immunohistochemical antibody markers used in this study No. Antibody Clone Dilution Source 1 CD2 MRQ-11 RTU Roche 2 CD3 Polyclonal 1:300 Cell Marque 3 CD4 SP35 RTU Roche 4 CD5 SP19 RTU Roche 5 CD7 SP94 1:2 Roche 6 CD8 Sp57 RTU Roche 7 CD20 L26 100 Cell Marque 8 CD79a SP18 RTU Roche 9 Pax5 SP34 RTU Roche 10 BOB1 SP92 1:50 Cell Marque 11 OCT2 MRQ-2 1:100 Cell Marque 12 MUM-1 MUM1p RTU Dako 13 Vs38 NA 1:300 Dako 14 CD138 M15 1:300 Dako 15 Ki-67 MIB-1 1:80 Dako 16 HHV8 13B10 RTU Roche RTU, ready-to-use; NA, Not available The patient declined chemotherapy and opted for supportive care while continuing the cyclosporine therapy. Five months later, they presented with fever and dyspnea and died of pneumonia. Discussion Most PEL cases lack expression of common B-cell markers and instead frequently express markers of terminal B-cell differentiation (CD138, CD38, and MUM-1). This immunophenotypic profile is supported by transcriptomic studies that have revealed similarities between the gene expression profiles of PEL and plasma cells [ 10 ]. Although PEL is classified as a B-cell neoplasm, it often exhibits aberrant expression of T-cell markers, especially CD3. According to WHO 5th edition, aberrant expression of T-cell marker is observed in approximately 30% of PEL cases [ 3 , 8 , 11 , 12 ]. Aberrant expression of lineage markers has been documented in various hematolymphoid neoplasms, particularly in immature neoplasms, including precursor cell leukemia [ 13 ]. However, such aberrant expression has also been observed in mature B- and T-cell neoplasms. In classic Hodgkin lymphoma, expression of T-cell associated antigens has been reported [ 14 ], and several case reports and small series have described T-cell marker expression in mature B-cell neoplasm [ 6 , 15 – 19 ]. Conversely, aberrant expression of B-cell markers in T-cell lymphomas has also been observed. To date, 48 cases of CD20-positive PTCL-NOS have been reported [ 20 ], and CD20 expression has been identified in 24% (14/60) of cases of type II enteropathy associated T-cell lymphoma [ 21 ]. CD20-positive NK/T-cell lymphomas have also been documented, including 10.3% (4/39) of testicular extranodal NK/T-cell lymphoma [ 22 , 23 ]. Among B-cell neoplasms, those associated with EBV, such as plasmablastic lymphoma, PEL, and diffuse large B-cell lymphoma associated with chronic inflammation, frequently exhibit biphenotypic features, especially downregulation of B-cell antigens [ 15 ]. EBV promotes phenotypic infidelity by disrupting host gene expression control mechanisms, including those related to T-cell antigens. This disruption can activate genes that are normally silenced or repressed and that are related to T-cell differentiation. Viral proteins interfere with the expression of specific genes in the host cells [ 24 ], thereby disrupting normal gene regulation. Additionally, neoplastic transformation at the progenitor cell level, upregulation of genetic repression during neoplastic transformation, and neoplastic proliferation of a subset of B-cell clones expressing T-cell antigens have been proposed to explain the phenotypic infidelity observed in EBV-positive malignant lymphoma [ 6 ]. Previous studies have described CD3 staining patterns in large B-cell lymphomas with aberrant CD3 expression. In a series of 21 cases of B-cell lymphoma with aberrant CD3 expression, all cases with plasma cell differentiation exhibited a cytoplasmic staining pattern’ and 10 out of 13 expressed CD3 as the sole aberrant T-cell antigen [ 15 ], similar to the present case. Although previously reported cases of aberrant CD3 expression were polyclonal for TCR rearrangements, the present case involved a monoclonal TCR rearrangement, which makes our case unique. In a gene rearrangement study using total tumor samples, dual genotypes were observed in 13% of B-cell lymphomas and 11% of T-cell lymphomas [ 7 ]. In mature B-cell lymphomas with aberrant CD3 expression, dual TCR and IGH rearrangements were observed in 4 of 24 (16.7%) cases [ 6 , 7 , 15 , 17 , 25 ]. The high number of double genotypes was mostly attributed to background non-neoplastic cells. For example, in nodal T-follicular helper cell lymphoma, the angioimmunoblastic type, formerly known as angioimmunoblastic T-cell lymphoma, in addition to the TCR monoclonal peak originating from tumor T cells, non-neoplastic B cells expanded by EBV infection exhibit oligo-or monoclonal peaks [ 26 ]. Therefore, determining whether these cases are truly bigenotypic is difficult. Only a few studies to date have demonstrated simultaneous rearrangements of the TCR and IGH genes in the same cell using single-cell PCR. In our case, we confirmed the co-expression of the B-cell transcription factor OCT2 and the T-cell antigen CD3 within the same tumor cells using double-staining techniques, providing morphological evidence of a biphenotypic population. In addition, PCR analysis demonstrated monoclonal rearrangements of both the TCR and IGH genes, supporting the bigenotypic nature of the tumor. However, a key limitation of this case is that we were unable to confirm whether the B-cell and T-cell clonalities originated from the same individual tumor cell. Further studies employing cell sorting method and single-cell analysis will be necessary in future cases to overcome this limitation. Conclusion In summary, aberrant expression of CD3 and monoclonal rearrangement of the TCR gene in PEL are rare but can occur. This phenotypic and genotypic infidelity makes the diagnosis difficult and warrants caution when interpreting laboratory data at the time of diagnosis. While EBV is one of the well-known contributors to such lineage infidelity, additional genetic and epigenetic mechanisms likely play a role and remain to be elucidated. Statements and Declarations Acknowledgments The authors thank Junghoon Noh and Jihwan Moon (Department of Pathology, Korea University Anam and Guro Hospitals) for their technical assistance. We would like to thank Editage (www.editage.co.kr) for English language editing. The authors would like to thank Editage (www.editage.co.kr) for English language editing. Funding information The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Declaration of competing interest: The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study. Ethics statement This study was approved by the Institutional Review Board (IRB) of Korea University Hospital (N0.2024AN0418). Author contributions Conceptualization: YSK, TSJ, JMS and YHK. Data curation: YSK. Formal analysis: TSJ. Writing of the original draft: YSK. Writing, review, editing: TSJ, YHK, HSK, YNS, KKW, and JMS. Approval of the final manuscript: all authors. Statement of significance This study reports a rare case of simultaneous T-cell antigen expression and monoclonal TCR gene rearrangement in PEL, a phenomenon rarely discussed in the existing literature. It provides a concise overview of other instances of lineage infidelity, with a particular focus on EBV and other potential underlying causes. This report provides valuable insights for both diagnostic and clinical research. Presenting a case of lymphoma with mixed immunophenotypic and genetic features highlights the challenges in diagnosing hematologic malignancies and expands the understanding of the relationship between EBV and gene regulation mechanisms. These findings are likely to attract significant interest from hematologists, oncologists, and molecular pathologists studying hematologic malignancies involving lineage infidelity. Patient consent statement Written informed consent was obtained from the patient’s family to publish this case report. No personal details that could identify the patient were included in the submission. Ethics statement Written informed consent was obtained from the patient’s family to publish this case report. No personal details that can identify the patient were included in the submission. Data availability statement No data was used for the research described in the article. 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Am J Surg Pathol 26:724–732 Hansson M, Jerkeman M, Dictor M (2007) Biphenotypic bigenotypic lymphoma with simultaneous expression of PAX5/BSAP and B- and T-cell markers. Eur J Haematol 79:159–165 Arai H, Maki K, Tadokoro J et al (2012) [CD20-positive peripheral T-cell lymphoma, not otherwise specified]. Rinsho Ketsueki 53:705–709 Hirata Y, Yokote T, Kobayashi K et al (2009) Rituximab for the treatment of CD20-positive peripheral T-cell lymphoma, unspecified. Leuk Res 33:e13–16 Matnani RG, Stewart RL, Pulliam J et al (2013) Peripheral T-cell lymphoma with aberrant expression of CD19, CD20, and CD79a: case report and literature review. Case Rep Hematol. ; 2013: 183134 Tan SY, Chuang SS, Tang T et al (2013) Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8alphaalpha phenotype. Leukemia 27:1688–1696 Huang Y, Chen S, Wei R et al (2020) CD20-positive extranodal NK/T cell lymphoma: clinicopathologic and prognostic features. 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Cite Share Download PDF Status: Published Journal Publication published 19 Sep, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Accepted 28 Apr, 2025 Reviews received at journal 27 Apr, 2025 Reviewers agreed at journal 12 Apr, 2025 Reviews received at journal 11 Apr, 2025 Reviewers agreed at journal 11 Apr, 2025 Reviewers invited by journal 10 Apr, 2025 Submission checks completed at journal 08 Apr, 2025 First submitted to journal 31 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6062454","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":442072533,"identity":"d5396643-036b-4d5d-a1ac-8c6124dae9dc","order_by":0,"name":"Taesung Jeon","email":"","orcid":"","institution":"Korea University Guro Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taesung","middleName":"","lastName":"Jeon","suffix":""},{"id":442072534,"identity":"ebb7e75a-04b8-431e-bc17-0b11069ffd52","order_by":1,"name":"Young-Hyeh Ko","email":"","orcid":"","institution":"Cheju Halla General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Young-Hyeh","middleName":"","lastName":"Ko","suffix":""},{"id":442072535,"identity":"478d65f1-9f85-477a-82b3-17b7a802a6cc","order_by":2,"name":"You-Na Sung","email":"","orcid":"","institution":"Korea University Anam Hospital","correspondingAuthor":false,"prefix":"","firstName":"You-Na","middleName":"","lastName":"Sung","suffix":""},{"id":442072536,"identity":"ff0bd236-dd35-47bc-a76a-a54c235a3b6b","order_by":3,"name":"Hyunsung Kim","email":"","orcid":"","institution":"Hanyang University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hyunsung","middleName":"","lastName":"Kim","suffix":""},{"id":442072537,"identity":"feba1c24-43eb-4dae-8a01-2df02cf032af","order_by":4,"name":"Ka-Won Kang","email":"","orcid":"","institution":"Korea University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ka-Won","middleName":"","lastName":"Kang","suffix":""},{"id":442072538,"identity":"3db1a9b1-9c03-4040-b73c-07863774e67e","order_by":5,"name":"Jong-Min Sim","email":"","orcid":"","institution":"Korea University Anam Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jong-Min","middleName":"","lastName":"Sim","suffix":""},{"id":442072539,"identity":"245cb63f-b3a3-4807-9067-f74ef667c3e3","order_by":6,"name":"Yeseul Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYFACNoYDIMqAvQFEWhCvRcKAB0QZSBCnhQGsRSIBTBPWYHD+WOKhmzvs6swln1/d8KNAgoG/vTsBv5YbaQcO555JlrCcnVN2swfoMIkzZzcQ0MLecDi3jVnC4HZO2g0eoBYDiVwCWs4fB2mplzC4eSbt5h+itBwAOaztsATQumO3ibJF8kZaAtAvxyU3nMlhuy1jIMFD0C98548Zf87dUc1vcPz4s5tv/tjI8bf34teicABIMDaAmDwGYBKvchCQb4BrYX9AUPUoGAWjYBSMTAAAbMRPVsy/5OQAAAAASUVORK5CYII=","orcid":"","institution":"Korea University Anam Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yeseul","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2025-02-19 09:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6062454/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6062454/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06396-w","type":"published","date":"2025-09-19T15:57:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80800696,"identity":"20ab3b1c-98af-43ad-9890-556fad00ea1f","added_by":"auto","created_at":"2025-04-17 08:31:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81675649,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Cytologic specimen revealing large, atypical lymphoid cells with prominent nucleoli, coarse chromatin, and basophilic cytoplasm. Malignant cells exhibiting plasmablastic features lying in a background of apoptotic debris. Large and atypical cells resembling Hodgkin cells were frequently observed as either uninucleated or multinucleated. (H\u0026amp;E, 400×)\u003c/p\u003e\n\u003cp\u003eImmunohistochemically, atypical lymphocytes expressed (B) CD3, (C) CD2, (D) CD4, (E) MUM-1, (F) OCT2, (G) BOB1, (H) CD30, and (I) HHV8, but not (J) CD20, (K) CD79a, (L) Pax5, or (M) CD138. EBER \u003cem\u003ein situ\u003c/em\u003e hybridization yielded positive results (N). The Ki-67 proliferation index was 60% (O). (H\u0026amp;E, 400x)\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6062454/v1/27ef5d15a1a93ee2ad2441a2.png"},{"id":80800695,"identity":"2c838b63-5a66-4519-b094-7e0c8360eeae","added_by":"auto","created_at":"2025-04-17 08:31:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52826901,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative double-labeling immunohistochemistry (IHC) of PEL highlighting neoplastic cells exhibiting co-expression.\u003c/p\u003e\n\u003cp\u003eNuclear staining of OCT2 (brown) and cytoplasmic staining of CD3 (red).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6062454/v1/f2dd413cb0eacd586574af61.png"},{"id":80800682,"identity":"8d0c81a1-2934-4346-8633-7fc217a4826a","added_by":"auto","created_at":"2025-04-17 08:31:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1338331,"visible":true,"origin":"","legend":"\u003cp\u003ePolymerase chain reaction analyses revealed monoclonal (A) \u003cem\u003eTRB\u003c/em\u003e, (B) \u003cem\u003eTRG\u003c/em\u003e, and (C) \u003cem\u003eIGH\u003c/em\u003e gene rearrangements.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6062454/v1/26331971e3bec20eea1e0818.png"},{"id":91889796,"identity":"9858420b-f878-4864-b289-f95ea7c7654c","added_by":"auto","created_at":"2025-09-22 16:02:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":123097385,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6062454/v1/68ff2205-67b9-4825-8d46-3d1be57eea8a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003ePrimary effusion lymphoma with biphenotypic and bigenotypic features of T-cell receptor and IGH genes in an HIV-negative patient with kidney transplant\u003c/p\u003e","fulltext":[{"header":"Highlights","content":"\u003cp\u003ePrimary effusion lymphoma typically lacks B-cell markers but involves immunoglobulin gene rearrangements, indicating a B-cell origin.\u003c/p\u003e\u003cp\u003eThis case highlights the unusual co-expression of T-cell antigens and clonal gene rearrangements for both T- and B-cell lineages in PEL.\u003c/p\u003e\u003cp\u003eThe findings underscore the complex lineage infidelity in PEL, making diagnosis challenging.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003ePrimary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma that primarily presents as a malignant effusion in the pleural, pericardial, or peritoneal cavities [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In some cases, it can manifest as a solid mass, and an extracavitary form of PEL has also been recognized [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While PEL predominantly occurs in patients with human immunodeficiency virus (HIV) and is less common in other immunosuppressed individuals, including solid organ transplant recipients and those with neoplastic diseases, autoimmune diseases, or cirrhosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePEL is defined by the presence of human herpes virus-8 (HHV-8), and co-infection with Epstein-Barr virus (EBV) is common, although some cases may be EBV-negative. The malignant cells typically harbor clonally rearranged and hypermutated immunoglobulin genes. however, they lack phenotypic evidence of B-cell differentiation and do not express typical B-cell markers such as CD19, CD20, and CD79a.\u003c/p\u003e \u003cp\u003eLymphomas are broadly classified into B-, T-, and NK-cell lineages based on their histomorphology, immunophenotype, immunoglobulin heavy locus (IGH), and T cell receptor (TCR)\u003cem\u003eTCR\u003c/em\u003e gene rearrangements. CD20 and CD3 are markers commonly used to determine B- and T-cell lineages, respectively. However, owing to the malignant nature of neoplasms, deviations in antigen expression patterns often occur in certain lymphomas compared with their benign counterparts. The acquisition of specific antigens is referred to as aberrant expression, and cross-lineage expression is often observed in certain types of mature B-cell lymphomas/leukemias. Nevertheless, co-expression of CD3 in mature B-cell lymphoma is uncommon [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMolecular analysis of clonal rearrangements aids in determining the B- or T-cell lineages, complementing histomorphology and immunohistochemistry. In some studies, simultaneous rearrangement of both \u003cem\u003eIGH\u003c/em\u003e and \u003cem\u003eTCR\u003c/em\u003e has been observed in immature cell populations, and its occurrence has been reported in mature B-cell lymphomas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, simultaneous rearrangement in PEL is rare, with only two cases reported to date [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Here, we present the case of a patient with PEL who expressed both B- and T-cell-associated antigens and exhibited rearrangement of both the B- and T-cell receptor genes.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eAn 81-year-old Asian man with a medical history of chronic kidney disease and kidney transplantation 20 years prior presented with underlying conditions including type 2 diabetes mellitus, retinopathy, hypertension, and tuberculous pleurisy. He reported symptoms associated with general weakness, edema, dyspnea on exercise, and recent melena. Their initial vital signs were within normal limits, but physical examination revealed pitting edema.\u003c/p\u003e \u003cp\u003eComplete blood counts revealed bicytopenia with normocytic normochromic anemia (hemoglobin 5.3 g/dL), and thrombocytopenia (platelet count of 67 \u0026times;10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L). The white blood cell count and morphology were normal. The creatinine level was consistent with previous trends at 2.42 mg/dL, and the BNP (brain natriuretic peptide) level was elevated at 5081 pg/mL; however, echocardiography revealed no heart failure. Serum protein electrophoresis revealed a small dense band in the lambda antisera, suggesting lambda-type monoclonal gammopathy. HIV and hepatitis tests were negative. Chest computed tomography (CT) revealed bilateral pleural effusion with passive atelectasis without enlarged lymph nodes or mass-like lesions.\u003c/p\u003e \u003cp\u003eThoracentesis revealed an exudate containing 73.8% lymphoid cells. The pleural fluid tested negative for fungi, acid-fast bacilli, and bacteria using staining techniques and anaerobic culture. Cytological smears revealed numerous large atypical lymphoid cells with plasmablastic features, pleomorphic nuclei, vesicular appearance, prominent nucleoli, a high nuclear/cytoplasmic ratio, amphophilic cytoplasm, karyorrhectic debris, and mitotic figures (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Immunohistochemical staining revealed strong human herpesvirus-8 (HHV-8) positivity and positive \u003cem\u003ein situ\u003c/em\u003e hybridization results for EBER (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eN).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the clinical findings, morphological features, and HHV-8 positivity, a diagnosis of PEL was made. The antibodies used in this study are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Immunohistochemical staining of cell blocks yielded positive findings for the T-cell markers CD2, CD3, and CD4, and the B-cell markers OCT2 (octamer-binding transcription factor 2), and BOB1 (B-cell-specific coactivator of octamer-binding transcription factors 1). In addition, the tumor cells expressed MUM-1. However, tests for other T-cell markers (CD5, CD7, and CD8) and B-cell markers (CD20 and CD79a) were negative. Vs38 and CD138 were not detected in this study. In-situ hybridization revealed lambda light-chain restriction. To clarify the biphenotypic features of the tumor cells, we performed double staining for the T-cell antigen CD3 and B-cell transcription factor OCT2 and confirmed dual staining of the two markers in the same tumor cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Polymerase chain reaction analysis revealed monoclonal peaks for T-cell receptor beta locus (TRB), T-cell receptor gamma locus (TRG) and \u003cem\u003eIGH\u003c/em\u003e genes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\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\u003eList and details of the immunohistochemical antibody markers used in this study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntibody\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDilution\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSource\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMRQ-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePolyclonal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell Marque\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSp57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eL26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell Marque\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD79a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePax5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBOB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSP92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell Marque\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOCT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMRQ-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCell Marque\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUM-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMUM1p\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDako\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVs38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eNA\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDako\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDako\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKi-67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIB-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1:80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDako\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHHV8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13B10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRTU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRoche\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eRTU, ready-to-use; NA, Not available\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient declined chemotherapy and opted for supportive care while continuing the cyclosporine therapy. Five months later, they presented with fever and dyspnea and died of pneumonia.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMost PEL cases lack expression of common B-cell markers and instead frequently express markers of terminal B-cell differentiation (CD138, CD38, and MUM-1). This immunophenotypic profile is supported by transcriptomic studies that have revealed similarities between the gene expression profiles of PEL and plasma cells [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although PEL is classified as a B-cell neoplasm, it often exhibits aberrant expression of T-cell markers, especially CD3. According to WHO 5th edition, aberrant expression of T-cell marker is observed in approximately 30% of PEL cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAberrant expression of lineage markers has been documented in various hematolymphoid neoplasms, particularly in immature neoplasms, including precursor cell leukemia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, such aberrant expression has also been observed in mature B- and T-cell neoplasms. In classic Hodgkin lymphoma, expression of T-cell associated antigens has been reported [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and several case reports and small series have described T-cell marker expression in mature B-cell neoplasm [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Conversely, aberrant expression of B-cell markers in T-cell lymphomas has also been observed. To date, 48 cases of CD20-positive PTCL-NOS have been reported [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and CD20 expression has been identified in 24% (14/60) of cases of type II enteropathy associated T-cell lymphoma [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. CD20-positive NK/T-cell lymphomas have also been documented, including 10.3% (4/39) of testicular extranodal NK/T-cell lymphoma [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong B-cell neoplasms, those associated with EBV, such as plasmablastic lymphoma, PEL, and diffuse large B-cell lymphoma associated with chronic inflammation, frequently exhibit biphenotypic features, especially downregulation of B-cell antigens [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. EBV promotes phenotypic infidelity by disrupting host gene expression control mechanisms, including those related to T-cell antigens. This disruption can activate genes that are normally silenced or repressed and that are related to T-cell differentiation. Viral proteins interfere with the expression of specific genes in the host cells [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], thereby disrupting normal gene regulation. Additionally, neoplastic transformation at the progenitor cell level, upregulation of genetic repression during neoplastic transformation, and neoplastic proliferation of a subset of B-cell clones expressing T-cell antigens have been proposed to explain the phenotypic infidelity observed in EBV-positive malignant lymphoma [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have described CD3 staining patterns in large B-cell lymphomas with aberrant CD3 expression. In a series of 21 cases of B-cell lymphoma with aberrant CD3 expression, all cases with plasma cell differentiation exhibited a cytoplasmic staining pattern\u0026rsquo; and 10 out of 13 expressed CD3 as the sole aberrant T-cell antigen [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], similar to the present case. Although previously reported cases of aberrant CD3 expression were polyclonal for \u003cem\u003eTCR\u003c/em\u003e rearrangements, the present case involved a monoclonal \u003cem\u003eTCR\u003c/em\u003e rearrangement, which makes our case unique.\u003c/p\u003e \u003cp\u003eIn a gene rearrangement study using total tumor samples, dual genotypes were observed in 13% of B-cell lymphomas and 11% of T-cell lymphomas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In mature B-cell lymphomas with aberrant CD3 expression, dual \u003cem\u003eTCR\u003c/em\u003e and \u003cem\u003eIGH\u003c/em\u003e rearrangements were observed in 4 of 24 (16.7%) cases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The high number of double genotypes was mostly attributed to background non-neoplastic cells. For example, in nodal T-follicular helper cell lymphoma, the angioimmunoblastic type, formerly known as angioimmunoblastic T-cell lymphoma, in addition to the \u003cem\u003eTCR\u003c/em\u003e monoclonal peak originating from tumor T cells, non-neoplastic B cells expanded by EBV infection exhibit oligo-or monoclonal peaks [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Therefore, determining whether these cases are truly bigenotypic is difficult. Only a few studies to date have demonstrated simultaneous rearrangements of the \u003cem\u003eTCR\u003c/em\u003e and \u003cem\u003eIGH\u003c/em\u003e genes in the same cell using single-cell PCR. In our case, we confirmed the co-expression of the B-cell transcription factor OCT2 and the T-cell antigen CD3 within the same tumor cells using double-staining techniques, providing morphological evidence of a biphenotypic population. In addition, PCR analysis demonstrated monoclonal rearrangements of both the \u003cem\u003eTCR\u003c/em\u003e and \u003cem\u003eIGH\u003c/em\u003e genes, supporting the bigenotypic nature of the tumor. However, a key limitation of this case is that we were unable to confirm whether the B-cell and T-cell clonalities originated from the same individual tumor cell. Further studies employing cell sorting method and single-cell analysis will be necessary in future cases to overcome this limitation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, aberrant expression of CD3 and monoclonal rearrangement of the \u003cem\u003eTCR\u003c/em\u003e gene in PEL are rare but can occur. This phenotypic and genotypic infidelity makes the diagnosis difficult and warrants caution when interpreting laboratory data at the time of diagnosis. While EBV is one of the well-known contributors to such lineage infidelity, additional genetic and epigenetic mechanisms likely play a role and remain to be elucidated.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Junghoon Noh and Jihwan Moon (Department of Pathology, Korea University Anam and Guro Hospitals) for their technical assistance. We would like to thank Editage (www.editage.co.kr) for English language editing.\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Editage (www.editage.co.kr) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of Korea University Hospital (N0.2024AN0418).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: YSK, TSJ, JMS and YHK. Data curation: YSK. Formal analysis: TSJ. Writing of the original draft: YSK. Writing, review, editing: TSJ, YHK, HSK, YNS, KKW, and JMS. Approval of the final manuscript: all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of significance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study reports a rare case of simultaneous T-cell antigen expression and monoclonal TCR gene rearrangement in PEL, a phenomenon rarely discussed in the existing literature. It provides a concise overview of other instances of lineage infidelity, with a particular focus on EBV and other potential underlying causes. This report provides valuable insights for both diagnostic and clinical research. Presenting a case of lymphoma with mixed immunophenotypic and genetic features highlights the challenges in diagnosing hematologic malignancies and expands the understanding of the relationship between EBV and gene regulation mechanisms. These findings are likely to attract significant interest from hematologists, oncologists, and molecular pathologists studying hematologic malignancies involving lineage infidelity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient\u0026rsquo;s family to publish this case report. No personal details that could identify the patient were included in the submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient\u0026rsquo;s family to publish this case report. No personal details that can identify the patient were included in the submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data was used for the research described in the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCesarman E, Chang Y, Moore PS et al (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332:1186\u0026ndash;1191\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArber DA (2025) The International Consensus Classification of Myeloid and Lymphoid Neoplasms, 1th edn. LWW\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO Classification of Tumours Editorial Board (2024) Haematolymphoid Tumours: WHO Classification of Tumours, 5th edn. World Health Organization\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZanelli M, Sanguedolce F, Zizzo M et al (2021) Primary effusion lymphoma occurring in the setting of transplanted patients: a systematic review of a rare, life-threatening post-transplantation occurrence. BMC Cancer 21:468\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKropf J, Gerges M, Perez Perez A et al (2020) T cell primary effusion lymphoma in an HIV-negative man with liver cirrhosis. Am J Case Rep 21:e919032\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang J, Chen C, Lau S et al (2009) CD3-positive large B-cell lymphoma. Am J Surg Pathol 33:505\u0026ndash;512\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVergier B, Dubus P, Kutschmar A et al (2002) Combined analysis of T cell receptor gamma and immunoglobulin heavy chain gene rearrangements at the single-cell level in lymphomas with dual genotype. 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Blood 121:1795\u0026ndash;1804\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliveira JL, Grogg KL, Macon WR et al (2012) Clinicopathologic features of B-Cell lineage neoplasms with aberrant expression of CD3: a study of 21 cases. Am J Surg Pathol 36:1364\u0026ndash;1370\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetitjean B, Jardin F, Joly B et al (2002) Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol 26:724\u0026ndash;732\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHansson M, Jerkeman M, Dictor M (2007) Biphenotypic bigenotypic lymphoma with simultaneous expression of PAX5/BSAP and B- and T-cell markers. 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Am J Pathol 154:1857\u0026ndash;1866\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"primary effusion lymphoma, biphenotypic, bigenotypic, EBV-positive, HIV-negative, lineage infidelity","lastPublishedDoi":"10.21203/rs.3.rs-6062454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6062454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrimary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin lymphoma that primarily involves body cavities and is characterized by human herpes virus-8 (HHV-8) positivity and the presence of immunoblastic, plasmablastic or anaplastic cells. PEL typically lacks B-cell antigens, but involves immunoglobulin gene rearrangements, suggesting a B-cell origin. Here, we present a highly unusual case of PEL in which tumor cells expressed T-cell antigens but were also monoclonal for both T-cell receptor (TCR) and immunoglobulin heavy locus (IGH) gene rearrangements.\u003c/p\u003e\n\u003cp\u003eAn 81-year-old man with bilateral pleural effusions presented with atypical lymphoid cells. Immunohistochemistry revealed positivity for CD3, CD4, MUM-1, OCT2, BOB1, and HHV-8, but negativity for other T- and B-cell antigens. \u003cem\u003eIn situ\u003c/em\u003e hybridization identified Epstein-Barr virus and lambda light chain restriction. Gene rearrangement studies demonstrated monoclonal \u003cem\u003eTRB \u003c/em\u003e(T-cell receptor beta locus) and \u003cem\u003eTRG \u003c/em\u003e(T-cell receptor gamma locus) as well as \u003cem\u003eIGH\u003c/em\u003erearrangement.\u003c/p\u003e\n\u003cp\u003eThis unusual case of PEL with T-cell antigen expression and clonal rearrangement of both the \u003cem\u003eTCR\u003c/em\u003e and \u003cem\u003eIGH\u003c/em\u003e genes highlights the lineage complexity of this tumor.\u003c/p\u003e","manuscriptTitle":"Primary effusion lymphoma with biphenotypic and bigenotypic features of T-cell receptor and IGH genes in an HIV-negative patient with kidney transplant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 08:31:19","doi":"10.21203/rs.3.rs-6062454/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-04-28T13:09:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-27T23:53:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282614900735155497173928372172903831519","date":"2025-04-12T14:31:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-11T21:05:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306616601531428524947617183194555618491","date":"2025-04-11T20:54:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-10T06:44:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-08T07:47:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-03-31T08:34:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4fb74c1b-f2a4-4f5a-bdc1-3a4aef637770","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T15:58:44+00:00","versionOfRecord":{"articleIdentity":"rs-6062454","link":"https://doi.org/10.1007/s00277-025-06396-w","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-09-19 15:57:05","publishedOnDateReadable":"September 19th, 2025"},"versionCreatedAt":"2025-04-17 08:31:19","video":"","vorDoi":"10.1007/s00277-025-06396-w","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06396-w","workflowStages":[]},"version":"v1","identity":"rs-6062454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6062454","identity":"rs-6062454","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}