Discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma in the brain and mantle cell lymphoma in the colon, rectum, and bone marrow.

Discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma in the brain and mantle cell lymphoma in the colon, rectum, and bone marrow. | 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 Discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma in the brain and mantle cell lymphoma in the colon, rectum, and bone marrow. Kyosuke Yamaguchi, Go Yamamoto, Otoya Watanabe, Kosei Kageyama, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5296962/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Mar, 2025 Read the published version in Brain Tumor Pathology → Version 1 posted 4 You are reading this latest preprint version Abstract We describe a rare case of discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma (DLBCL) in the brain and mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow. A 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography scan and contrast-enhanced magnetic resonance imaging showed a mass in the right temporal lobe and rectal wall thickening. Brain biopsy revealed DLBCL, and bone marrow and rectum biopsy showed MCL. According to a polymerase chain reaction analysis of immunoglobulin heavy-chain gene rearrangements using brain and bone marrow specimens, the two lesions were clonally unrelated lymphomas. After five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy and three cycles of R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy, the patient received autologous hematopoietic stem cell transplantation using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen after bridging therapy with ibrutinib. In addition, he received whole-brain irradiation at a dose of 40 Gy in 20 fractions as consolidation therapy. He did not relapse within 3 years of transplantation. To the best of our knowledge, this is the first case report of DLBCL and MCL coexistence. Central nervous system lymphoma discordant lymphoma Diffuse large B-cell lymphoma (DLBCL) Mantle cell lymphoma (MCL) hematopoietic stem cell transplantation (HSCT) Figures Figure 1 Figure 2 Figure 3 Introduction Discordant lymphoma is defined as the coexistence of two or more different types of malignant lymphomas in different anatomic sites. Meanwhile, composite lymphoma is defined as the presence of two or more distinct types of lymphoma in a single anatomic site. Both conditions are rare. The incidence of and number of previous reports on discordant lymphoma were lower than those of composite lymphoma. Research often focused on the association and origin and treatment of different types of lymphoma in various sites. Herein, we present an extremely rare case of discordant lymphoma characterized by the coexistence of Diffuse large B-cell lymphoma (DLBCL) in the brain and Mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow. Clinical summary and pathological findings A 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography (CT) scan revealed a mass lesion in the right temporal lobe and peritumoral brain edema extending to the midbrain, frontal lobe, and parietal lobe (Fig. 1 (A)). Head contrast-enhanced magnetic resonance imaging (MRI) showed a tumor with a diameter of 39 mm in the right temporal lobe with midline shift, and the size was about 39 mm in diameter (Fig. 1 (B)-(D)). Blood tests revealed elevated serum lactate dehydrogenase (335 IU/L) and serum soluble interleukin-2 receptor (953 U/mL) levels. Brain biopsy was performed. Histopathological examination of the biopsy specimen showed diffuse proliferation of large-atypical lymphocytes (Fig. 2 (A)). Immunohistochemistry revealed that the neoplastic cells tested positive for CD5, CD20, MUM1, BCL2, and BCL6 and negative for CD3, CD10, and BCL1. These results indicated diffuse large B-cell lymphoma with a non-germinal center B-cell origin according to the Hans algorithm [ 1 ]. The SOX11 expression in the brain was relatively weak and believed to be false-positive. The Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization was negative, and the Ki-67 labeling index was approximately 90%. Chromosomal analysis revealed near tetraploid complex karyotypes with add(3)(p21), add(5)(p15.3), add(6)(q13), add(17)(p11.2), and add(19)(p13.3) abnormality, not with t(11;14)(q13;q32). Paraffin-embedded tissue section-fluorescence in situ hybridization (PS-FISH) analysis using break-apart probes showed negativity for MYC, BCL2, and BCL6. The whole-body CT scan revealed rectal wall thickening. Colonoscopy showed rectal mucosa thickening with redness and erosion (Fig. 1 (E)-(F)). Repeated enteric and rectal biopsies showed diffuse infiltration of the lamina propria by small- to medium - sized atypical lymphocytes (Fig. 2 (B)). Immunohistochemical staining revealed that the abnormal cells tested positive for CD5, CD20, BCL2, and BCL1 and negative for CD3, CD10, BCL6, and MUM1. Additional SOX11 staining had positive results. The EBV-encoded small RNA in situ hybridization had negative results, and the Ki-67 labeling index was approximately 5%. Bone marrow aspiration and biopsy revealed that 2.4% of the cells were abnormal lymphocytes (Fig. 2 (C)). Flow cytometric analyses of the bone marrow specimen tested positive for CD5, CD19, CD20, CD22, and kappa and negative for CD10 and lambda, indicating bone marrow infiltration of lymphoma cells. Chromosomal analysis revealed the karyotype 46,XY in 20/20 of the metaphases examined. FISH analysis using the IGH :: CCND1 probes revealed positivity for 7.0% of the cells (Fig. 2 (D)). According to a polymerase chain reaction (PCR) analysis of immunoglobulin heavy (IGH) chain rearrangement, the brain and bone marrow lymphoma cells were clonally unrelated (Fig. 3 (A)-(C)). The DLBCL in the brain was aggressive and severe. Thus, five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy was started for the treatment of the primary central nervous system lymphoma (PCNSL). The patient’s level of consciousness improved, and the lesion size significantly decreased. However, the mass still remained. R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy was administered as a bridging therapy to auto- hematopoietic stem cell transplantation (HSCT). Peripheral blood progenitor cells were harvested after two cycles of R-ESHAP therapy with granulocyte colony - stimulating factor. The number of CD34-positive cells in the harvested product was 3.1×10 6 cells/kg of body weight. After three cycles of R-ESHAP therapy, contrast-enhanced brain MRI revealed that the contrast-enhanced lesion disappeared. Moreover, IGH :: CCND1 rearrangement was not detected in the bone marrow specimen based on the FISH analysis. However, biopsies of the ileum, cecum, ascending colon, transverse colon, descending colon, and rectum via colonoscopy revealed residual MCL. The auto-HSCT was postponed for approximately 2 months because of the coronavirus disease-2019 pandemic. Ibrutinib was used as a bridging therapy to auto-HSCT. The patient received auto-HSCT using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen. The number of transplanted CD34-positive cells was 2.07×10 6 /kg. The patient achieved neutrophil engraftment on post-transplant day 13 without infection, and he was discharged on post-transplant day 31. After transplantation, the MCL in the rectum disappeared. The patient received whole-brain irradiation with a dose of 40 Gy in 20 fractions as consolidation therapy without additional radiation boost. The patient did not develop severe complications, and he achieved complete metabolic response based on 18 F-fluorodeoxyglucose positron emission tomography/CT scan. Further brain MRI revealed that the contrast-enhanced lesion had disappeared. IGH :: CCND1 rearrangement was not detected in the peripheral blood and bone marrow specimen based on the FISH analysis. Hence, the lesions were successfully treated without maintenance therapy, and the patient did not relapse within 3 years of transplantation. Discussion Herein, we present an extremely rare case of discordant lymphoma characterized by the coexistence of DLBCL in the brain and MCL in the colon, rectum, and bone marrow. There are only a few cases of composite DLBCL and MCL [ 2 , 3 ]. To the best of our knowledge, this is the first case report of discordant lymphoma characterized by the coexistence of DLBCL and MCL. MCL and DLBCL were both non-Hodgkin B-cell lymphomas. However, their histological and chromosomal features differed. MCL is characterized by small- to medium-sized lymphoid cells with the CD5 + , CD20 + , CD10 − , CD23 − phenotype, and is defined by the IGH :: CCND1 fusion associated with the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression [ 4 , 5 ]. DLBCL is characterized by a diffuse proliferation of large and mature B cells, morphologically and genetically a heterogeneous group of large B-cell lymphoma. In some cases, DLBCL transforms from follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. De-novo CD5-positive DLBCL account for 5–10% of all DLBCL cases, and it is characterized by a high incidence of central nervous system relapse after standard immunochemotherapy [ 6 ]. Cyclin-D1 nuclear expression is an important diagnostic clue of MCL. However, previous research has reported about cyclin-D1-negative MCL [ 7 ] and cyclin D1-positive DLBCL [ 8 ]. Patients with MCL present with the overexpression of SOX11, a neural transcription factor [ 9 ]. SOX11 expression can be a valuable diagnostic tool for B-cell lymphoma and is useful in differentiating cyclin D1-positive DLBCL from MCL [ 10 ]. In the current case, the cyclin D1-negative cells in the brain were large, had a high Ki-67 labeling index, and did not present with IGH :: CCND1 rearrangement. Moreover, the SOX11 expression in the brain was negative, but sparsely positive existed. Hence, a diagnosis of DLBCL was made. The cyclin D1-positive cells in the rectum were small to medium in size and had a low Ki-67 index. Further, they presented with IGH :: CCND1 rearrangements based on the FISH analysis using bone marrow specimens. Thus, a diagnosis of MCL was made. The pathogenesis and development of discordant lymphoma remain unclear. EBV infection [ 11 ] and anti-tumor therapy against the first lymphoma caused discordant lymphoma [ 12 ]. Patients with EBV infection can present with transformation from MCL to DLBCL [ 13 ]. In a previous case of composite lymphoma, PCR analysis of the IGH chain and immunoglobulin kappa light-chain gene rearrangements was performed to confirm if two lesions were clonally unrelated neoplasms [ 3 ]. In our case, both sites tested negative for EBV, and PCR analysis of the IGH chain gene rearrangements showed that the two lesions were clonally unrelated lymphomas. The optimal treatment strategies for discordant lymphoma are not completely elucidated. The first-line therapy often differs based on the histological type, localization, and severity of lymphoma. Further, which type of lymphoma should be treated initially has not been confirmed. Patients with PCNSL, receiving R-MPV therapy combined with consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine had a high response rate [ 14 ]. Upfront auto-HSCT after conditioning with busulfan and thiotepa in patients newly diagnosed with PCNSL treated with R-MVP had a significantly better progression-free and overall survival [ 15 ]. However, the efficacy of radiotherapy or auto-HSCT as consolidation therapy for PCNSL remains unclear. Ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase, had significant CNS penetration, and reported the efficacy and toxicity for PCNSL [ 16 ]. There is no standard frontline therapy for MCL, and intensive combination therapies incorporating rituximab and cytarabine are recommended to fit patients. Upfront auto-HSCT is recommended as consolidation therapy for patients with newly diagnosed MCL (without TP53 mutation or bi-allelic deletion) who are in complete remission or partial remission after the first-line therapies [ 17 ]. R-BEAM regimen (Carmustine, Etoposide, Aracytine, Melphalan) is widely used as conditioning therapy. Ibrutinib monotherapy for relapsed or refractory MCL also reported [ 18 ]. Rituximab, high-dose cytarabine, and ibrutinib seem to be effective for both PCNSL and MCL. In the current case, DLBCL in the brain was aggressive and severe. Thus, R-MPV therapy was used as the initial therapy with consideration of PCNSL. R-ESHAP therapy which contains rituximab and high-dose cytarabine and known as a harvest regimen [ 19 ] was conducted subsequently. After three cycles of R-ESHAP therapy, DLBCL in the CNS disappeared, h owever MCL in the colon and rectum did not disappear. MCL had a higher need for auto-HSCT than PCNSL, hence ranimustine-based R-MEAM regimen was applied as conditioning therapy [ 20 ], because intravenous carmustine was not available in Japan. For CNS lymphoma, whole-brain irradiation was used as consolidation therapy. The patient did not develop severe complications, and he achieved complete metabolic response. Further, he did not relapse within 3 years of transplantation. Declarations Conflict of Interest The authors declare that they have no conflict of interest. A written informed consent was obtained from the patient. Funding This research did not receive any source of support. Author Contributions K. Yamaguchi collected the data and wrote the first draft of the manuscript. H. Uruga, S. Ito and Y. Takazawa diagnosed the patient and collected images. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability Statement All data generated or analyzed during this study were included in this article. Further inquiries can be directed to the corresponding author. References Hans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282 Andhavarapu S, Crozier JA, Jiang L, Sher T (2014) Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma. Eur J Haematol 93:537–542 Mohammad F, Garcia G, Kedia S et al (2017) Composite Diffuse Large B-cell and Mantle Cell Lymphoma: A Case Report. Cureus 9:e963 Campo E, Swerdlow SH, Harris NL et al (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117:5019–5032 Jain P, Wang M (2019) Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol 94:710–725 Yamaguchi M, Seto M, Okamoto M et al (2002) De novo CD5 + diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients. Blood 99:815–821 Salaverria I, Royo C, Carvajal-Cuenca A et al (2013) CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma. 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Bone Marrow Transpl 57:641–648 Soussain C, Choquet S, Blonski M et al (2019) Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. Eur J Cancer 117:121–130 Munshi PN, Hamadani M, Kumar A et al (2021) ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma. Bone Marrow Transpl 56:2911–2921 Wang ML, Blum KA, Martin P et al (2015) Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 126:739–745 Lee JL, Kim S, Kim SW et al (2005) ESHAP plus G-CSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin's lymphoma: comparison with high-dose cyclophosphamide plus G-CSF. Bone Marrow Transpl 35:449–454 Koresawa-Shimizu R, Suzuki R, Uehara Y et al (2023) Comparison of MEAM, MCEC and LEED high-dose chemotherapy followed by autologous stem cell transplantation in relapsed/refractory diffuse large B-cell lymphoma: data from the Japan Society for Hematopoietic and Cellular Therapy Registry. Bone Marrow Transpl 59:125–127 Cite Share Download PDF Status: Published Journal Publication published 18 Mar, 2025 Read the published version in Brain Tumor Pathology → Version 1 posted Reviewers agreed at journal 01 Nov, 2024 Reviewers invited by journal 01 Nov, 2024 Editor assigned by journal 21 Oct, 2024 First submitted to journal 19 Oct, 2024 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. 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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-5296962","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":372928613,"identity":"939c4d11-cd29-4095-9e5a-e6b560444473","order_by":0,"name":"Kyosuke 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Byoin","correspondingAuthor":false,"prefix":"","firstName":"Shuichi","middleName":"","lastName":"Taniguchi","suffix":""}],"badges":[],"createdAt":"2024-10-20 06:06:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5296962/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5296962/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10014-025-00499-y","type":"published","date":"2025-03-18T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70951523,"identity":"52448c25-9e46-427d-95b0-d190116abb38","added_by":"auto","created_at":"2024-12-09 13:44:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":969870,"visible":true,"origin":"","legend":"\u003cp\u003eA non-contrast-enhanced CT scan of the head (A) revealed a mass in the right brain. Axial contrast-enhanced MRI of the head (B) showed a tumor with a diameter of approximately 39 mm in the right temporal lobe. Axial (C) and coronal (D) FLAIR images of the brain revealed a huge space-occupying lesion of the right temporal lobe with midline shift. Colonoscopy revealed mucosal edema in the terminal ileum (E) and mucosal edema, redness, and erosion in the rectum (F). CT, computed tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery\u003c/p\u003e","description":"","filename":"Fig.1DiscordantLymphoma1.png","url":"https://assets-eu.researchsquare.com/files/rs-5296962/v1/61ba0713cb4cbe820f47612c.png"},{"id":70951522,"identity":"9bc76421-523e-41d0-a36d-b07338f921d6","added_by":"auto","created_at":"2024-12-09 13:44:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1111430,"visible":true,"origin":"","legend":"\u003cp\u003eMorphologic and immunophenotypic findings of the brain (A), rectum (B), and bone marrow (C). The atypical lymphocytes in the brain were large (H\u0026amp;E staining, ×400). They tested positive for CD20 and CD5 and negative for cyclin-D1 (×400) (A). The rectal mucosa was infiltrated with small- to medium-sized atypical lymphocytes (H\u0026amp;E staining, ×400). It tested positive for CD20, CD5, and cyclin-D1 (×400) (B). H\u0026amp;E-stained section of the bone marrow biopsy showed infiltration of lymphoma cells (H\u0026amp;E staining, ×400). Fluorescence in situ hybridization analysis of bone marrow aspirate showed fusion signals of \u003cem\u003eIGH-CCND1\u003c/em\u003e rearrangement using a dual-color, dual-fusion rearrangement probe (D). H\u0026amp;E, hematoxylin and eosin\u003c/p\u003e","description":"","filename":"Fig.2DiscordantLymphoma1.png","url":"https://assets-eu.researchsquare.com/files/rs-5296962/v1/9692a90d48c3de70c2b30cfc.png"},{"id":70951521,"identity":"af9326ee-db8a-4c7a-a2ea-b911e44e84f6","added_by":"auto","created_at":"2024-12-09 13:44:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77837,"visible":true,"origin":"","legend":"\u003cp\u003ePolymerase chain reaction (PCR) for IgH gene rearrangement using a multiplex primer method based on the BIOMED-2 strategy. The expression patterns of the brain and bone marrow differ in the VH (FR1)/JH(A), VH (FR2)/JH(B), and VH (FR3)/JH regions (C). DLBCL in the brain presented with IgH gene rearrangement in the VH (FR1)/JH region. MCL in the bone marrow showed IgH gene rearrangement in the VH (FR1)/JH and VH (FR3)/ regions. IgH, immunoglobulin heavy chain; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.\u003c/p\u003e","description":"","filename":"Fig.3DiscordantLymphoma1.png","url":"https://assets-eu.researchsquare.com/files/rs-5296962/v1/02c2f81df11bc1cb5825d700.png"},{"id":79120598,"identity":"108b7499-4e1d-43b1-b207-1c59be2a9892","added_by":"auto","created_at":"2025-03-24 16:10:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2641429,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5296962/v1/b03eea48-f52b-49ed-98da-742f4ebc7916.pdf"}],"financialInterests":"","formattedTitle":"Discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma in the brain and mantle cell lymphoma in the colon, rectum, and bone marrow.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiscordant lymphoma is defined as the coexistence of two or more different types of malignant lymphomas in different anatomic sites. Meanwhile, composite lymphoma is defined as the presence of two or more distinct types of lymphoma in a single anatomic site. Both conditions are rare. The incidence of and number of previous reports on discordant lymphoma were lower than those of composite lymphoma. Research often focused on the association and origin and treatment of different types of lymphoma in various sites. Herein, we present an extremely rare case of discordant lymphoma characterized by the coexistence of Diffuse large B-cell lymphoma (DLBCL) in the brain and Mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow.\u003c/p\u003e\n\n "},{"header":"Clinical summary and pathological findings","content":"\u003cp\u003eA 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography (CT) scan revealed a mass lesion in the right temporal lobe and peritumoral brain edema extending to the midbrain, frontal lobe, and parietal lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (A)). Head contrast-enhanced magnetic resonance imaging (MRI) showed a tumor with a diameter of 39 mm in the right temporal lobe with midline shift, and the size was about 39 mm in diameter (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (B)-(D)). Blood tests revealed elevated serum lactate dehydrogenase (335 IU/L) and serum soluble interleukin-2 receptor (953 U/mL) levels. Brain biopsy was performed. Histopathological examination of the biopsy specimen showed diffuse proliferation of large-atypical lymphocytes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (A)). Immunohistochemistry revealed that the neoplastic cells tested positive for CD5, CD20, MUM1, BCL2, and BCL6 and negative for CD3, CD10, and BCL1. These results indicated diffuse large B-cell lymphoma with a non-germinal center B-cell origin according to the Hans algorithm [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The SOX11 expression in the brain was relatively weak and believed to be false-positive. The Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization was negative, and the Ki-67 labeling index was approximately 90%. Chromosomal analysis revealed near tetraploid complex karyotypes with add(3)(p21), add(5)(p15.3), add(6)(q13), add(17)(p11.2), and add(19)(p13.3) abnormality, not with t(11;14)(q13;q32). Paraffin-embedded tissue section-fluorescence in situ hybridization (PS-FISH) analysis using break-apart probes showed negativity for MYC, BCL2, and BCL6. The whole-body CT scan revealed rectal wall thickening. Colonoscopy showed rectal mucosa thickening with redness and erosion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (E)-(F)). Repeated enteric and rectal biopsies showed diffuse infiltration of the lamina propria by small- to medium\u003cem\u003e-\u003c/em\u003esized \u003cem\u003eatypical\u003c/em\u003e lymphocytes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (B)). Immunohistochemical staining revealed that the abnormal cells tested positive for CD5, CD20, BCL2, and BCL1 and negative for CD3, CD10, BCL6, and MUM1. Additional SOX11 staining had positive results. The EBV-encoded small RNA in situ hybridization had negative results, and the Ki-67 labeling index was approximately 5%. Bone marrow aspiration and biopsy revealed that 2.4% of the cells were abnormal lymphocytes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (C)). Flow cytometric analyses of the bone marrow specimen tested positive for CD5, CD19, CD20, CD22, and kappa and negative for CD10 and lambda, indicating bone marrow infiltration of lymphoma cells. Chromosomal analysis revealed the karyotype 46,XY in 20/20 of the metaphases examined. FISH analysis using the \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e probes revealed positivity for 7.0% of the cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (D)). According to a polymerase chain reaction (PCR) analysis of immunoglobulin heavy (IGH) chain rearrangement, the brain and bone marrow lymphoma cells were clonally unrelated (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e (A)-(C)).\u003c/p\u003e\u003cp\u003eThe DLBCL in the brain was aggressive and severe. Thus, five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy was started for the treatment of the primary central nervous system lymphoma (PCNSL). The patient’s level of consciousness improved, and the lesion size significantly decreased. However, the mass still remained. R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy was administered as a bridging therapy to auto- hematopoietic stem cell transplantation (HSCT). Peripheral blood progenitor cells were harvested after two cycles of R-ESHAP therapy with granulocyte colony\u003cem\u003e-\u003c/em\u003estimulating factor. The number of CD34-positive cells in the harvested product was 3.1×10\u003csup\u003e6\u003c/sup\u003e cells/kg of body weight. After three cycles of R-ESHAP therapy, contrast-enhanced brain MRI revealed that the contrast-enhanced lesion disappeared. Moreover, \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e rearrangement was not detected in the bone marrow specimen based on the FISH analysis. However, biopsies of the ileum, cecum, ascending colon, transverse colon, descending colon, and rectum via colonoscopy revealed residual MCL. The auto-HSCT was postponed for approximately 2 months because of the coronavirus disease-2019 pandemic. Ibrutinib was used as a bridging therapy to auto-HSCT. The patient received auto-HSCT using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen. The number of transplanted CD34-positive cells was 2.07×10\u003csup\u003e6\u003c/sup\u003e/kg. The patient achieved neutrophil engraftment on post-transplant day 13 without infection, and he was discharged on post-transplant day 31. After transplantation, the MCL in the rectum disappeared. The patient received whole-brain irradiation with a dose of 40 Gy in 20 fractions as consolidation therapy without additional radiation boost. The patient did not develop severe complications, and he achieved complete metabolic response based on \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose positron emission tomography/CT scan. Further brain MRI revealed that the contrast-enhanced lesion had disappeared. \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e rearrangement was not detected in the peripheral blood and bone marrow specimen based on the FISH analysis. Hence, the lesions were successfully treated without maintenance therapy, and the patient did not relapse within 3 years of transplantation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerein, we present an extremely rare case of discordant lymphoma characterized by the coexistence of DLBCL in the brain and MCL in the colon, rectum, and bone marrow. There are only a few cases of composite DLBCL and MCL [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To the best of our knowledge, this is the first case report of discordant lymphoma characterized by the coexistence of DLBCL and MCL.\u003c/p\u003e \u003cp\u003eMCL and DLBCL were both non-Hodgkin B-cell lymphomas. However, their histological and chromosomal features differed. MCL is characterized by small- to medium-sized lymphoid cells with the CD5\u003csup\u003e+\u003c/sup\u003e, CD20\u003csup\u003e+\u003c/sup\u003e, CD10\u003csup\u003e\u0026minus;\u003c/sup\u003e, CD23\u003csup\u003e\u0026minus;\u003c/sup\u003e phenotype, and is defined by the \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e fusion associated with the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. DLBCL is characterized by a diffuse proliferation of large and mature B cells, morphologically and genetically a heterogeneous group of large B-cell lymphoma. In some cases, DLBCL transforms from follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. De-novo CD5-positive DLBCL account for 5\u0026ndash;10% of all DLBCL cases, and it is characterized by a high incidence of central nervous system relapse after standard immunochemotherapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Cyclin-D1 nuclear expression is an important diagnostic clue of MCL. However, previous research has reported about cyclin-D1-negative MCL [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and cyclin D1-positive DLBCL [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Patients with MCL present with the overexpression of SOX11, a neural transcription factor [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. SOX11 expression can be a valuable diagnostic tool for B-cell lymphoma and is useful in differentiating cyclin D1-positive DLBCL from MCL [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the current case, the cyclin D1-negative cells in the brain were large, had a high Ki-67 labeling index, and did not present with \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e rearrangement. Moreover, the SOX11 expression in the brain was negative, but sparsely positive existed. Hence, a diagnosis of DLBCL was made. The cyclin D1-positive cells in the rectum were small to medium in size and had a low Ki-67 index. Further, they presented with \u003cem\u003eIGH\u003c/em\u003e::\u003cem\u003eCCND1\u003c/em\u003e rearrangements based on the FISH analysis using bone marrow specimens. Thus, a diagnosis of MCL was made.\u003c/p\u003e \u003cp\u003eThe pathogenesis and development of discordant lymphoma remain unclear. EBV infection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and anti-tumor therapy against the first lymphoma caused discordant lymphoma [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patients with EBV infection can present with transformation from MCL to DLBCL [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In a previous case of composite lymphoma, PCR analysis of the IGH chain and immunoglobulin kappa light-chain gene rearrangements was performed to confirm if two lesions were clonally unrelated neoplasms [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our case, both sites tested negative for EBV, and PCR analysis of the IGH chain gene rearrangements showed that the two lesions were clonally unrelated lymphomas.\u003c/p\u003e \u003cp\u003eThe optimal treatment strategies for discordant lymphoma are not completely elucidated. The first-line therapy often differs based on the histological type, localization, and severity of lymphoma. Further, which type of lymphoma should be treated initially has not been confirmed.\u003c/p\u003e \u003cp\u003ePatients with PCNSL, receiving R-MPV therapy combined with consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine had a high response rate [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Upfront auto-HSCT after conditioning with busulfan and thiotepa in patients newly diagnosed with PCNSL treated with R-MVP had a significantly better progression-free and overall survival [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the efficacy of radiotherapy or auto-HSCT as consolidation therapy for PCNSL remains unclear. Ibrutinib, an oral inhibitor of Bruton\u0026rsquo;s tyrosine kinase, had significant CNS penetration, and reported the efficacy and toxicity for PCNSL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is no standard frontline therapy for MCL, and intensive combination therapies incorporating rituximab and cytarabine are recommended to fit patients. Upfront auto-HSCT is recommended as consolidation therapy for patients with newly diagnosed MCL (without TP53 mutation or bi-allelic deletion) who are in complete remission or partial remission after the first-line therapies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. R-BEAM regimen (Carmustine, Etoposide, Aracytine, Melphalan) is widely used as conditioning therapy. Ibrutinib monotherapy for relapsed or refractory MCL also reported [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Rituximab, high-dose cytarabine, and ibrutinib seem to be effective for both PCNSL and MCL.\u003c/p\u003e \u003cp\u003eIn the current case, DLBCL in the brain was aggressive and severe. Thus, R-MPV therapy was used as the initial therapy with consideration of PCNSL. R-ESHAP therapy which contains rituximab and high-dose cytarabine and known as a harvest regimen [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] was conducted subsequently. After three cycles of R-ESHAP therapy, DLBCL in the CNS disappeared, h\u003cem\u003eowever\u003c/em\u003e MCL in the colon and rectum did not disappear. MCL had a higher need for auto-HSCT than PCNSL, hence ranimustine-based R-MEAM regimen was applied as conditioning therapy [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], because intravenous carmustine was not available in Japan. For CNS lymphoma, whole-brain irradiation was used as consolidation therapy. The patient did not develop severe complications, and he achieved complete metabolic response. Further, he did not relapse within 3 years of transplantation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003cp\u003e A written informed consent was obtained from the patient.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive any source of support.\u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eK. Yamaguchi collected the data and wrote the first draft of the manuscript. H. Uruga, S. Ito and Y. Takazawa diagnosed the patient and collected images. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability Statement\u003c/h2\u003e \u003cp\u003eAll data generated or analyzed during this study were included in this article. Further inquiries can be directed to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275\u0026ndash;282\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndhavarapu S, Crozier JA, Jiang L, Sher T (2014) Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma. Eur J Haematol 93:537\u0026ndash;542\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammad F, Garcia G, Kedia S et al (2017) Composite Diffuse Large B-cell and Mantle Cell Lymphoma: A Case Report. Cureus 9:e963\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampo E, Swerdlow SH, Harris NL et al (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117:5019\u0026ndash;5032\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain P, Wang M (2019) Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol 94:710\u0026ndash;725\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi M, Seto M, Okamoto M et al (2002) De novo CD5\u0026thinsp;+\u0026thinsp;diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients. 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Blood 126:739\u0026ndash;745\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee JL, Kim S, Kim SW et al (2005) ESHAP plus G-CSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin's lymphoma: comparison with high-dose cyclophosphamide plus G-CSF. Bone Marrow Transpl 35:449\u0026ndash;454\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoresawa-Shimizu R, Suzuki R, Uehara Y et al (2023) Comparison of MEAM, MCEC and LEED high-dose chemotherapy followed by autologous stem cell transplantation in relapsed/refractory diffuse large B-cell lymphoma: data from the Japan Society for Hematopoietic and Cellular Therapy Registry. Bone Marrow Transpl 59:125\u0026ndash;127\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"brain-tumor-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"btpa","sideBox":"Learn more about [Brain Tumor Pathology](http://link.springer.com/journal/10014)","snPcode":"10014","submissionUrl":"https://www.editorialmanager.com/btpa/default2.aspx","title":"Brain Tumor Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Central nervous system lymphoma, discordant lymphoma, Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), hematopoietic stem cell transplantation (HSCT)","lastPublishedDoi":"10.21203/rs.3.rs-5296962/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5296962/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe describe a rare case of discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma (DLBCL) in the brain and mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow. A 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography scan and contrast-enhanced magnetic resonance imaging showed a mass in the right temporal lobe and rectal wall thickening. Brain biopsy revealed DLBCL, and bone marrow and rectum biopsy showed MCL. According to a polymerase chain reaction analysis of immunoglobulin heavy-chain gene rearrangements using brain and bone marrow specimens, the two lesions were clonally unrelated lymphomas. After five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy and three cycles of R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy, the patient received autologous hematopoietic stem cell transplantation using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen after bridging therapy with ibrutinib. In addition, he received whole-brain irradiation at a dose of 40 Gy in 20 fractions as consolidation therapy. He did not relapse within 3 years of transplantation. To the best of our knowledge, this is the first case report of DLBCL and MCL coexistence.\u003c/p\u003e","manuscriptTitle":"Discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma in the brain and mantle cell lymphoma in the colon, rectum, and bone marrow.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 13:44:43","doi":"10.21203/rs.3.rs-5296962/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-11-01T10:15:42+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-01T09:41:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-21T06:58:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Brain Tumor Pathology","date":"2024-10-20T02:06:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"brain-tumor-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"btpa","sideBox":"Learn more about [Brain Tumor Pathology](http://link.springer.com/journal/10014)","snPcode":"10014","submissionUrl":"https://www.editorialmanager.com/btpa/default2.aspx","title":"Brain Tumor Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e113c28d-3cd1-4e75-b826-a90e89bf43fa","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-24T16:05:42+00:00","versionOfRecord":{"articleIdentity":"rs-5296962","link":"https://doi.org/10.1007/s10014-025-00499-y","journal":{"identity":"brain-tumor-pathology","isVorOnly":false,"title":"Brain Tumor Pathology"},"publishedOn":"2025-03-18 15:57:32","publishedOnDateReadable":"March 18th, 2025"},"versionCreatedAt":"2024-12-09 13:44:43","video":"","vorDoi":"10.1007/s10014-025-00499-y","vorDoiUrl":"https://doi.org/10.1007/s10014-025-00499-y","workflowStages":[]},"version":"v1","identity":"rs-5296962","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5296962","identity":"rs-5296962","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}