CD5 positive marginal zone lymphoma of the lacrimal gland: case report and review of literature

CD5 positive marginal zone lymphoma of the lacrimal gland: case report and review of literature | 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 CD5 positive marginal zone lymphoma of the lacrimal gland: case report and review of literature - Safaa Mahmoud Mohamed Abd El Khalek1,2 (Abd El Khalek1,2 SMM) This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6231538/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Extra nodal Marginal Zone Lymphoma (EMZL) of the lacrimal gland, also known as mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare type of non-Hodgkin lymphoma (NHL). Environmental factors, autoimmune diseases, and infections have been identified as risk factors, with a notable increase in incidence over recent decades. This condition typically affects individuals around 65 years of age, with a higher prevalence in females. On average, the time from symptom onset to diagnosis is about 6–7 months. Case Report We present a case of a 43-year-old female patient who presented to an outpatient clinic with 6-month painless slowly progressive swelling in the superolateral region of the orbit bilaterally history revealed diabetes mellitus, though with no known autoimmune disease. On examination, the visual acuity was within normal limits in both eyes. Orbital contrast-enhanced MR. biopsy and immunohistochemical panel confirm the diagnosis of extra nodal al marginal zone B-cell lymphoma (EMZL) of the lacrimal gland six cycles of R-CHOP were utilized and led to partial remission. Conclusion This study presents a case of CD5 + extra nodal marginal zone lymphoma (ENMZL) of the lacrimal gland and provides a comprehensive review of its clinical features, pathology, and management, with the goal of deepening clinicians' understanding of CD5 + ENMZL Oncology Extra nodal marginal zone B-cell lymphoma Lacrimal gland lymphoma Ocular adnexal lymphoma Ocular malignancy Figures Figure 1 Figure 2 Figure 3 Background Typically, EMZL follows an indolent course, presenting as a localized tumour with a good prognosis. However, newly diagnosed cases of marginal zone lymphoma that display a CD5+ immunophenotype have challenged this assumption of indolence. These cases are often associated with disseminated lymphadenopathy, which raises concerns about their clinical course, prognosis, and appropriate treatment Although orbital adnexal lymphoma (OAL) is infrequent, accounting for approximately 8% of extra nodal NHLs, lymphoma remains one of the most prevalent malignancies affecting the ocular adnexa, comprising 55% of such cases (3). Introduction Extra nodal Marginal Zone Lymphoma (EMZL) of the lacrimal gland, also known as mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare type of non-Hodgkin lymphoma (NHL). Environmental factors, autoimmune diseases, and infections have been identified as risk factors, with a notable increase in incidence over recent decades. This condition typically affects individuals around 65 years of age, with a higher prevalence in females. On average, the time from symptom onset to diagnosis is about 6–7 months ( 1 ). The morphological and immunophenotypic characteristics of EMZL include the expansion of centrocytes, monocytosis cells, and small lymphocytes. Immunophenotypic markers typically show positivity for CD20, CD79a, IgM, and BCL-2, while markers such as CD3, CD5, and CD10 are negative. In around 55% of cases, PCR analysis reveals monoclonal immunoglobulin heavy chains and somatic hypermutations ( 2 ). Typically, EMZL follows an indolent course, presenting as a localized tumour with a good prognosis ( 1 ). However, newly diagnosed cases of marginal zone lymphoma that display a CD5 + immunophenotype have challenged this assumption of indolence. These cases are often associated with disseminated lymphadenopathy, which raises concerns about their clinical course, prognosis, and appropriate treatment ( 3 ). This study presents a case of CD5 + extra nodal marginal zone lymphoma (ENMZL) of the lacrimal gland and provides a comprehensive review of its clinical features, pathology, and management, with the goal of deepening clinicians' understanding of CD5 + ENMZL. Case Presentation A 43-year-old woman presented to the outpatient clinic with a complaint of 6-month painless, slowly progressive swelling in the superolateral region of the orbit bilaterally, with mild ptosis and orbital discomfort. Her history revealed diabetes mellitus, though with no known autoimmune disease. On examination, the visual acuity was within normal limits in both eyes. There was mild bilateral ptosis, with the corneal light reflex displaced by approximately 3 mm. Restricted eye movement was noted in the right eye, particularly in elevation and abduction. Firm, non-tender masses were palpated over both upper orbital rims, corresponding to the lacrimal glands. Visual field testing showed indices of 98% in the right eye and 96% in the left eye. Orbital contrast-enhanced MRI demonstrated a uniformly abnormal signal in the outer upper quadrant of the orbit, extraconal in position with maximum cross-sectional dimensions of 2 × 1.3 cm. Signal characteristics on T1WI demonstrated isointense appearance with enhancement, which was uniform and well demarcated (Fig. 1 ). A whole-body F18-FDG PET/CT scan was done to further evaluate the extent of the disease. Bilateral bulky, metabolically active lacrimal glands, 2 × 1.3 cm, SUV of 4.4 were noted. Deep cervical, left supraclavicular, and peritracheal lymph nodes showed enlargement. The infra-diaphragmatic pelvic and abdominal lymph nodes showed enlargement. There was enlargement of the spleen with mild diffuse activity. A biopsy was performed, and histopathological examination disclosed infiltration of the lacrimal gland by an expansile, nodular lymphoid infiltrate composed of small to medium-sized cells with slightly irregular nuclei, moderately dispersed chromatin, and inconspicuous nucleoli. No plasmacytic differentiation or lymphoepithelial lesions were identified (Fig. 2 ). Initial panel of immunohistochemical stains was applied. The neoplastic cells were diffusely positive for CD20 and BCL2, and negative for CD3 with high lightening of background T cells. Ki67 staining revealed a low proliferation index of 8%. Based on these preliminary results, a preliminary diagnosis of low-proliferation-rate B-cell non-Hodgkin lymphoma was favored and an extended immunohistochemical panel was requested. Upon performance of the extended panel, Results showed diffuse positivity for CD5 and negative staining for CD3, CD10, BCL6, CD48, and CD138. CD23 was negative in neoplastic cells but highlighted a distorted expanded meshwork of follicular dendritic cells corresponding to colonized follicles (Fig. 3 ). Cyclin D1 showed scattered weak positivity. The final diagnosis was CD5-positive marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type of the lacrimal gland. The clinical presentation of disseminated nodal involvement along with splenomegaly and diffuse CD5 positivity raised mantle cell lymphoma in the differential diagnosis. A second opinion was sought from another histopathology lab, and the same immunohistochemical panel was repeated with identical results. Additional staining for SOX11 and LEF1 showed negativity in the neoplastic lymphoid infiltrate, hence confirming the diagnosis of CD5-positive marginal zone lymphoma. The patient was then referred to oncology, where she received six cycles of R-CHOP chemotherapy separated by 21-day intervals. Rituximab was infused on Day 1, and the other components of the R-CHOP regimen-cyclophosphamide, doxorubicin, vincristine, and prednisone-were given in the same cycle, but prednisone was taken orally for several days after the infusion. Dosages were as follow; cyclophosphamide 750 mg/m2 D1, doxorubicin 50 mg/m2 D1, vincristine 2 mg D1, and methyl prednisolone 100 mg/d D1-5. Follow-up PET/CT showed a regressive course, although complete remission was not achieved. The lacrimal mass shrank down to 0.7 cm. Regression in the extent of splenic enlargement also continued. Moreover, the supra- and infra-diaphragmatic lymph nodes remained, though smaller in comparison. Another six cycles of R-CHOP were advised. However, the patient refused continued treatment and was lost to further follow-up care. Discussion Although orbital adnexal lymphoma (OAL) is infrequent, accounting for approximately 8% of extra nodal NHLs, lymphoma remains one of the most prevalent malignancies affecting the ocular adnexa, comprising 55% of such cases ( 4 ). The overwhelming majority of OALs are of B-cell lineage, with lacrimal gland extra nodal marginal zone lymphoma (EMZL) or mucosa associated lymphoid tissue lymphoma (MALT) representing the most common subtype followed by follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and mantle cell lymphoma (MCL) ( 2 ). The clinical manifestations and prognosis of orbital adnexal lymphomas (OALs) can vary significantly depending on the specific subtype, making it essential to distinguish between different types of lymphomas to determine therapeutic decisions that starts from watchful follow up to bone marrow transplantation. Biopsy followed by histologic and immunohistochemical evaluation is pivotal in differentiating lymphoma subtypes ( 5 ). On histologic basis, EMZL is a small cell lymphoma with nodular pattern that may acquire plasmacytic and/or monocytoid differentiation ( 2 ). However, the pattern of EMZL as a small cell lymphoma necessitates its distinction from other small cell lymphomas The immunophenotype signature of EMZL is usually CD20+, CD97a+, CD5-, CD10-, CD23-, CD43+/-and CD11c+/- (week) ( 6 ). An infrequent subset of marginal zone lymphoma was reported to be CD5+. Such subset can cause a diagnostic dilemma with SLL/CLL and the more aggressive MCL ( 7 ). MCL exhibits positive CD5, cyclin D1 and Sox 11. However, some MCL are negative for cyclin D1 adding more complexity for diagnosis. Sox 11 positive staining can help in confirmation of diagnosis of cyclin D1 negative MCL ( 8 ). While CD5- EMZL have an indolent course, are slow to disseminate and rare to recur, more needs to be explored about the nature of CD5 + MZL and its clinical course ( 1 ). We hereby characterize a case of CD5 + EMZL of lacrimal gland which shows disseminated Lymphadenopathy and splenomegaly at time of presentation. The case reflects poor prognosis in terms of incomplete tumour response after R-CHOP. Despite the scarcity of comprehensive studies on CD5 + EMZL, it is posited that this variant of lymphoma exhibits a significantly higher incidence of disseminated lymphadenopathy at the time of initial presentation. A case series encompassing fourteen patients reported that up to 64% of cases demonstrated disseminated lymphadenopathy ( 3 ). However localized presentations have also been documented in MALT lymphoma of lacrimal gland ( 9 ) and appendix ( 10 ). Notably, disseminated lymphadenopathy is more frequently observed in non-gastric locations ( 3 ). Furthermore, CD5 + EMZL is associated with an increased propensity for relapse ( 11 ). Additionally, a case report has established a potential link between CD5 + EMZL and thrombophilia ( 10 ). In terms of treatment responses, the literature reflects a broad spectrum of outcomes among affected individuals. Some patients with CD5 + EMZL may remain asymptomatic and require no intervention ( 3 ), while others achieve complete remission following chemotherapy ( 3 , 12 ) or localized radiotherapy ( 9 ). In contrast, our case did not exhibit a complete response to R-CHOP therapy, which may indicate the necessity for adjunctive therapeutic approaches. Noteworthy in this regard is a study by Hsu et al., which suggested that the addition of bendamustine to rituximab could augment treatment efficacy and promote complete remission in patients ( 13 ). Regarding survival outcomes, data indicate that patients with CD5 + EMZL exhibit a five-year survival rate comparable to that of their CD5-negative counterparts, particularly when treated with chemotherapy ( 9 , 6 , 10 ). Regarding survival, data have shown that patients with CD5 + ENMZL reported 5-year survival like CD5- counterparts especially with chemotherapy ( 3 , 10 , 11 ). Genetic analyses of ocular marginal zone lymphoma have identified several mutations, including those in the JAK3, TNFAIP3, and MYD88 genes, as well as alterations in pathways like NF-kB, chromatin modification, and B lymphocyte differentiation ( 14 ). Environmental factors, autoimmune diseases, and infections, notably Chlamydia psittaci , have been associated with OAML, with the latter implicated in the disease’s pathogenesis ( 5 ). However, more studies are still needed to differentiate the genetic background between CD5- and CD5 + marginal Zone lymphoma. Whether CD5 + ENMZL, Nodal MZL or splenic MZL sharing the same clinical course and prognosis or not is still an issue of debate. Transformation to diffuse large b cell lymphoma is more prevalent in the CD5 + nodal MZL ( 1 ). In addition, patients with CD5 + splenic MZL was more prone to B symptoms, peripheral lymphadenopathy, extra nodal and bone marrow infiltration as well as high Ann Arbor stage ( 15 ). Conclusion In conclusion, CD5 + EMZL of the lacrimal gland presents diagnostic and therapeutic challenges due to its overlap with other small cell lymphomas and vague clinical course. While it follows good prognosis, the case discussed highlights a more complicated presentation with disseminated lymphadenopathy and a poor response to R-CHOP therapy. CD5 + EMZL is associated with a higher likelihood of relapse and may require alternative treatments differ from CD- EMZL. Further research into its genetic profile and clinical behaviour is needed to improve diagnosis and treatment strategies. Declarations Ethical approval the study was approved by Ain shams committee for ethical approval. Informed consent : informed consent was obtained prior to use the patient data. Consent for publication was taken. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors . References Xia Y, Ge J, Sun Z, Nan F, Wan W, Xu D, Zhang M, Fu X (2022) CD5-positive marginal zone lymphoma: Clinicopathological features and survival outcomes. Leuk Res 117:106840. 10.1016/j.leukres.2022.106840 Epub 2022 Apr 12. PMID: 35468520 Who Jaso J, Chen L, Li S et al (2012) CD5-positive mucosa-associated lymphoid tissue (MALT) lymphoma: a clinicopathologic study of 14 cases. Hum Pathol 43(9):1436–1443. 10.1016/j.humpath.2011.11.004 Pancetti S, Broggi G, Caltabiano R, Cimino L, Mecucci C, Ascani S (2023) CD5-Negative Primary Mantle Cell Lymphoma Presenting with a Bilateral Conjunctival Mass: A Potential Diagnostic Pitfall. Curr Oncol 30(1):824–831. 10.3390/curroncol30010062 PMID: 36661711; PMCID: PMC9857961 Di Rocco A, Petrucci L, Assanto GM, Martelli M, Pulsoni A (2022) Extranodal Marginal Zone Lymphoma: Pathogenesis, Diagnosis and Treatment. Cancers (Basel) 14(7):1742. 10.3390/cancers14071742 PMID: 35406516; PMCID: PMC8997163 Kalogeropoulos D, Papoudou-Bai A, Kanavaros P, Kalogeropoulos C (2018) Ocular adnexal marginal zone lymphoma of mucosa-associated lymphoid tissue. Clin Exp Med 18(2):151–163. 10.1007/s10238-017-0474-1 Cheah CY, Seymour JF (2023) Marginal zone lymphoma: 2023 update on diagnosis and management. Am J Hematol 98(10):1645–1657. 10.1002/ajh.27058 Ok CY, Medeiros LJ Cyclin D1-negative mantle cell lymphoma. Hum Pathol. 2024 Nov 19:105698. 10.1016/j.humpath.2024.105698 . Epub ahead of print. PMID: 39571691 Mulay K, Honavar SG (2014) Lacrimal gland CD5-positive, primary, extra-nodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) - Type. Saudi J Ophthalmol 28(4):338–340. 10.1016/j.sjopt.2014.04.004 Epub 2014 Jun 21. PMID: 25473357; PMCID: PMC4250491 Grace Priyadarshini BN, Chander SPJ (2024) An Unusual Case of CD5-Positive Extranodal Marginal Zone Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT) Involving the Appendix. Cureus 16(8):e67883. 10.7759/cureus.67883 PMID: 39328717; PMCID: PMC11426931 Tanaka T, Kitabatake K, Iino M, Goto K (2011) Immunohistochemical comparison of CD5, lambda, and kappa expression in primary and recurrent buccal mucosa-associated lymphoid tissue (MALT) lymphomas. Diagn Pathol . ; 6:82. Published 2011 Sep 6. 10.1186/1746-1596-6-82 Palamar M, Ozsan N, Sahin F (2016) Bilateral Lacrimal Gland Lymphoma in Sjögren Syndrome. Case Rep Ophthalmol Med . ; 2016:2798304. 10.1155/2016/2798304 Hsu A, Kurt H, Zayac AS, Olszewski AJ (2022) CD5 expression in marginal zone lymphoma predicts differential response to rituximab or bendamustine/rituximab. Leuk Lymphoma 63(1):31–42 Epub 2021 Sep 1. PMID: 34467833 Johansson P, Klein-Hitpass L, Budeus B, Kuhn M, Lauber C, Seifert M, Roeder I, Pförtner R, Stuschke M, Dührsen U et al (2020) Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing. Cancers 12:986 Li Y, Wang G, Liu E, Zhang D, Zhang Y, Jian X, Zhao W, Li W (2024) Clinicopathological features of CD5-positive splenic marginal zone lymphoma. J Clin Pathol. ;77(6):421–425. 10.1136/jcp-2022-208603 . PMID: 36922019 Additional Declarations The authors declare no competing interests. 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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-6231538","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":429157141,"identity":"201e0b3f-4ffa-45d4-9ed2-1490e192cd3f","order_by":0,"name":"- Safaa Mahmoud Mohamed Abd El Khalek1,2 (Abd El Khalek1,2 SMM)","email":"","orcid":"","institution":"Ain shams university","correspondingAuthor":false,"prefix":"","firstName":"2","middleName":"SMM) 2 (Abd El Khalek1 - Safaa Mahmoud Mohamed Abd El","lastName":"Khalek1","suffix":""},{"id":429157142,"identity":"982bd069-e915-4db6-a2ce-2763dc759579","order_by":1,"name":"- Azza Mohamed Ahmed Said1","email":"","orcid":"","institution":"Ain shams univeristy","correspondingAuthor":false,"prefix":"","firstName":"-","middleName":"Azza Mohamed Ahmed","lastName":"Said1","suffix":""},{"id":429157143,"identity":"31e68116-a6ca-4b23-84df-a822083a07b1","order_by":2,"name":"-Ashraf Abdelsalam Kandeel Shaat1","email":"","orcid":"","institution":"Ain Shams Univeristy","correspondingAuthor":false,"prefix":"","firstName":"-Ashraf","middleName":"Abdelsalam Kandeel","lastName":"Shaat1","suffix":""},{"id":429157144,"identity":"7d8bb11d-b8e2-4654-aefd-0561b746e467","order_by":3,"name":"-Eman Hassan Ibrahim2, 3","email":"","orcid":"","institution":"gulf medical univeristy","correspondingAuthor":false,"prefix":"","firstName":"3","middleName":"-Eman Hassan","lastName":"Ibrahim2","suffix":""},{"id":429157145,"identity":"6f8f7874-dbb2-4ec7-ab48-c046d51181e6","order_by":4,"name":"Mona Quenawy Ramadan Mohammed1","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3534-9694","institution":"Ain Shams Univeristy","correspondingAuthor":true,"prefix":"","firstName":"Mona","middleName":"Quenawy Ramadan","lastName":"Mohammed1","suffix":""}],"badges":[],"createdAt":"2025-03-15 08:34:23","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6231538/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6231538/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78885113,"identity":"010fb0bb-9cd3-4761-bff1-3685f1b737bf","added_by":"auto","created_at":"2025-03-20 09:29:39","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20501,"visible":true,"origin":"","legend":"\u003cp\u003eAxial T1-weighted contrast-enhanced MRI shows homogeneous bilateral lacrimal gland enlargement (white arrows).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6231538/v1/4aa8299265434a6a2dae48c3.jpeg"},{"id":78885648,"identity":"2fba5971-df89-43b2-8774-e049b2fb445a","added_by":"auto","created_at":"2025-03-20 09:37:39","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":547581,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathologic features of Lacrimal gland swelling; Expansile nodules of lymphoid infiltrate (left) (H\u0026amp;E, 40) composed of small sized lymphocytes (right) (H\u0026amp;E, 200x).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6231538/v1/6ff0afc26280c7bb8607ad01.jpeg"},{"id":78885108,"identity":"311c5d91-c689-491c-acc6-37231802f477","added_by":"auto","created_at":"2025-03-20 09:29:39","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":702360,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical profile of the lymphoid infiltrate; A: Diffuse positive CD20 staining of the neoplastic cells denoting B cell lymphoma (CD20, 100x). B: Negative Cd3 in neoplastic lymphoid infiltrate with scattered positivity in background residual T cells (CD3, 100x). C: Ki67 immunostaining reveals less frequent positive nuclear staining of neoplastic cells (8%). The positivity is noted frequently in the background T cells (Ki67, 100x). D: CD5 immunostaining reveals diffuse positive staining of the CD20 positive cells (B cells) (CD5, 200x). E: Neoplastic cells show complete negativity for CD10 (CD10, 100x). F: CD23 immunostaining highlights the residual disrupted and expanded follicular dendritic cells while negative in the neoplastic lymphoid cells (CD23, 200x).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6231538/v1/47b39682b652db5644738f3d.jpeg"},{"id":78886596,"identity":"5f1fa1cf-8bc8-4369-89ce-0c7c13fb8a78","added_by":"auto","created_at":"2025-03-20 09:45:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1633141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6231538/v1/d41de400-658d-4911-a658-84f53fe70716.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCD5 positive marginal zone lymphoma of the lacrimal gland: case report and review of literature\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eTypically, EMZL follows an indolent course, presenting as a localized tumour with a good prognosis. However, newly diagnosed cases of marginal zone lymphoma that display a CD5+ immunophenotype have challenged this assumption of indolence. These cases are often associated with disseminated lymphadenopathy, which raises concerns about their clinical course, prognosis, and appropriate treatment Although orbital adnexal lymphoma (OAL) is infrequent, accounting for approximately 8% of extra nodal NHLs, lymphoma remains one of the most prevalent malignancies affecting the ocular adnexa, comprising 55% of such cases (3).\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eExtra nodal Marginal Zone Lymphoma (EMZL) of the lacrimal gland, also known as mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare type of non-Hodgkin lymphoma (NHL). Environmental factors, autoimmune diseases, and infections have been identified as risk factors, with a notable increase in incidence over recent decades. This condition typically affects individuals around 65 years of age, with a higher prevalence in females. On average, the time from symptom onset to diagnosis is about 6\u0026ndash;7 months (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe morphological and immunophenotypic characteristics of EMZL include the expansion of centrocytes, monocytosis cells, and small lymphocytes. Immunophenotypic markers typically show positivity for CD20, CD79a, IgM, and BCL-2, while markers such as CD3, CD5, and CD10 are negative. In around 55% of cases, PCR analysis reveals monoclonal immunoglobulin heavy chains and somatic hypermutations (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTypically, EMZL follows an indolent course, presenting as a localized tumour with a good prognosis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, newly diagnosed cases of marginal zone lymphoma that display a CD5\u0026thinsp;+\u0026thinsp;immunophenotype have challenged this assumption of indolence. These cases are often associated with disseminated lymphadenopathy, which raises concerns about their clinical course, prognosis, and appropriate treatment (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study presents a case of CD5\u0026thinsp;+\u0026thinsp;extra nodal marginal zone lymphoma (ENMZL) of the lacrimal gland and provides a comprehensive review of its clinical features, pathology, and management, with the goal of deepening clinicians' understanding of CD5\u0026thinsp;+\u0026thinsp;ENMZL.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 43-year-old woman presented to the outpatient clinic with a complaint of 6-month painless, slowly progressive swelling in the superolateral region of the orbit bilaterally, with mild ptosis and orbital discomfort. Her history revealed diabetes mellitus, though with no known autoimmune disease.\u003c/p\u003e\n\u003cp\u003eOn examination, the visual acuity was within normal limits in both eyes. There was mild bilateral ptosis, with the corneal light reflex displaced by approximately 3 mm. Restricted eye movement was noted in the right eye, particularly in elevation and abduction. Firm, non-tender masses were palpated over both upper orbital rims, corresponding to the lacrimal glands. Visual field testing showed indices of 98% in the right eye and 96% in the left eye.\u003c/p\u003e\n\u003cp\u003eOrbital contrast-enhanced MRI demonstrated a uniformly abnormal signal in the outer upper quadrant of the orbit, extraconal in position with maximum cross-sectional dimensions of 2 \u0026times; 1.3 cm. Signal characteristics on T1WI demonstrated isointense appearance with enhancement, which was uniform and well demarcated (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). A whole-body F18-FDG PET/CT scan was done to further evaluate the extent of the disease. Bilateral bulky, metabolically active lacrimal glands, 2 \u0026times; 1.3 cm, SUV of 4.4 were noted. Deep cervical, left supraclavicular, and peritracheal lymph nodes showed enlargement. The infra-diaphragmatic pelvic and abdominal lymph nodes showed enlargement. There was enlargement of the spleen with mild diffuse activity.\u003c/p\u003e\n\u003cp\u003eA biopsy was performed, and histopathological examination disclosed infiltration of the lacrimal gland by an expansile, nodular lymphoid infiltrate composed of small to medium-sized cells with slightly irregular nuclei, moderately dispersed chromatin, and inconspicuous nucleoli. No plasmacytic differentiation or lymphoepithelial lesions were identified (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Initial panel of immunohistochemical stains was applied. The neoplastic cells were diffusely positive for CD20 and BCL2, and negative for CD3 with high lightening of background T cells. Ki67 staining revealed a low proliferation index of 8%. Based on these preliminary results, a preliminary diagnosis of low-proliferation-rate B-cell non-Hodgkin lymphoma was favored and an extended immunohistochemical panel was requested.\u003c/p\u003e\n\u003cp\u003eUpon performance of the extended panel, Results showed diffuse positivity for CD5 and negative staining for CD3, CD10, BCL6, CD48, and CD138. CD23 was negative in neoplastic cells but highlighted a distorted expanded meshwork of follicular dendritic cells corresponding to colonized follicles (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Cyclin D1 showed scattered weak positivity. The final diagnosis was CD5-positive marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type of the lacrimal gland. The clinical presentation of disseminated nodal involvement along with splenomegaly and diffuse CD5 positivity raised mantle cell lymphoma in the differential diagnosis.\u003c/p\u003e\n\u003cp\u003eA second opinion was sought from another histopathology lab, and the same immunohistochemical panel was repeated with identical results. Additional staining for SOX11 and LEF1 showed negativity in the neoplastic lymphoid infiltrate, hence confirming the diagnosis of CD5-positive marginal zone lymphoma.\u003c/p\u003e\n\u003cp\u003eThe patient was then referred to oncology, where she received six cycles of R-CHOP chemotherapy separated by 21-day intervals. Rituximab was infused on Day 1, and the other components of the R-CHOP regimen-cyclophosphamide, doxorubicin, vincristine, and prednisone-were given in the same cycle, but prednisone was taken orally for several days after the infusion. Dosages were as follow; cyclophosphamide 750 mg/m2 D1, doxorubicin 50 mg/m2 D1, vincristine 2 mg D1, and methyl prednisolone 100 mg/d D1-5.\u003c/p\u003e\n\u003cp\u003eFollow-up PET/CT showed a regressive course, although complete remission was not achieved. The lacrimal mass shrank down to 0.7 cm. Regression in the extent of splenic enlargement also continued. Moreover, the supra- and infra-diaphragmatic lymph nodes remained, though smaller in comparison. Another six cycles of R-CHOP were advised. However, the patient refused continued treatment and was lost to further follow-up care.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough orbital adnexal lymphoma (OAL) is infrequent, accounting for approximately 8% of extra nodal NHLs, lymphoma remains one of the most prevalent malignancies affecting the ocular adnexa, comprising 55% of such cases (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe overwhelming majority of OALs are of B-cell lineage, with lacrimal gland extra nodal marginal zone lymphoma (EMZL) or mucosa associated lymphoid tissue lymphoma (MALT) representing the most common subtype followed by follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and mantle cell lymphoma (MCL) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe clinical manifestations and prognosis of orbital adnexal lymphomas (OALs) can vary significantly depending on the specific subtype, making it essential to distinguish between different types of lymphomas to determine therapeutic decisions that starts from watchful follow up to bone marrow transplantation. Biopsy followed by histologic and immunohistochemical evaluation is pivotal in differentiating lymphoma subtypes (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn histologic basis, EMZL is a small cell lymphoma with nodular pattern that may acquire plasmacytic and/or monocytoid differentiation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, the pattern of EMZL as a small cell lymphoma necessitates its distinction from other small cell lymphomas\u003c/p\u003e \u003cp\u003eThe immunophenotype signature of EMZL is usually CD20+, CD97a+, CD5-, CD10-, CD23-, CD43+/-and CD11c+/- (week) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). An infrequent subset of marginal zone lymphoma was reported to be CD5+. Such subset can cause a diagnostic dilemma with SLL/CLL and the more aggressive MCL (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). MCL exhibits positive CD5, cyclin D1 and Sox 11. However, some MCL are negative for cyclin D1 adding more complexity for diagnosis. Sox 11 positive staining can help in confirmation of diagnosis of cyclin D1 negative MCL (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). While CD5- EMZL have an indolent course, are slow to disseminate and rare to recur, more needs to be explored about the nature of CD5\u0026thinsp;+\u0026thinsp;MZL and its clinical course (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe hereby characterize a case of CD5\u0026thinsp;+\u0026thinsp;EMZL of lacrimal gland which shows disseminated Lymphadenopathy and splenomegaly at time of presentation. The case reflects poor prognosis in terms of incomplete tumour response after R-CHOP.\u003c/p\u003e \u003cp\u003eDespite the scarcity of comprehensive studies on CD5\u0026thinsp;+\u0026thinsp;EMZL, it is posited that this variant of lymphoma exhibits a significantly higher incidence of disseminated lymphadenopathy at the time of initial presentation. A case series encompassing fourteen patients reported that up to 64% of cases demonstrated disseminated lymphadenopathy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). However localized presentations have also been documented in MALT lymphoma of lacrimal gland (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and appendix (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Notably, disseminated lymphadenopathy is more frequently observed in non-gastric locations (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Furthermore, CD5\u0026thinsp;+\u0026thinsp;EMZL is associated with an increased propensity for relapse (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Additionally, a case report has established a potential link between CD5\u0026thinsp;+\u0026thinsp;EMZL and thrombophilia (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of treatment responses, the literature reflects a broad spectrum of outcomes among affected individuals. Some patients with CD5\u0026thinsp;+\u0026thinsp;EMZL may remain asymptomatic and require no intervention (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), while others achieve complete remission following chemotherapy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) or localized radiotherapy (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In contrast, our case did not exhibit a complete response to R-CHOP therapy, which may indicate the necessity for adjunctive therapeutic approaches. Noteworthy in this regard is a study by Hsu et al., which suggested that the addition of bendamustine to rituximab could augment treatment efficacy and promote complete remission in patients (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding survival outcomes, data indicate that patients with CD5\u0026thinsp;+\u0026thinsp;EMZL exhibit a five-year survival rate comparable to that of their CD5-negative counterparts, particularly when treated with chemotherapy (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding survival, data have shown that patients with CD5\u0026thinsp;+\u0026thinsp;ENMZL reported 5-year survival like CD5- counterparts especially with chemotherapy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGenetic analyses of ocular marginal zone lymphoma have identified several mutations, including those in the JAK3, TNFAIP3, and MYD88 genes, as well as alterations in pathways like NF-kB, chromatin modification, and B lymphocyte differentiation (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Environmental factors, autoimmune diseases, and infections, notably \u003cem\u003eChlamydia psittaci\u003c/em\u003e, have been associated with OAML, with the latter implicated in the disease\u0026rsquo;s pathogenesis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, more studies are still needed to differentiate the genetic background between CD5- and CD5\u0026thinsp;+\u0026thinsp;marginal Zone lymphoma.\u003c/p\u003e \u003cp\u003eWhether CD5\u0026thinsp;+\u0026thinsp;ENMZL, Nodal MZL or splenic MZL sharing the same clinical course and prognosis or not is still an issue of debate. Transformation to diffuse large b cell lymphoma is more prevalent in the CD5\u0026thinsp;+\u0026thinsp;nodal MZL (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In addition, patients with CD5\u0026thinsp;+\u0026thinsp;splenic MZL was more prone to B symptoms, peripheral lymphadenopathy, extra nodal and bone marrow infiltration as well as high Ann Arbor stage (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, CD5\u0026thinsp;+\u0026thinsp;EMZL of the lacrimal gland presents diagnostic and therapeutic challenges due to its overlap with other small cell lymphomas and vague clinical course. While it follows good prognosis, the case discussed highlights a more complicated presentation with disseminated lymphadenopathy and a poor response to R-CHOP therapy. CD5\u0026thinsp;+\u0026thinsp;EMZL is associated with a higher likelihood of relapse and may require alternative treatments differ from CD- EMZL. Further research into its genetic profile and clinical behaviour is needed to improve diagnosis and treatment strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003ethe study was approved by Ain shams committee for ethical approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e: \u0026nbsp;informed consent was obtained prior to use the patient data. Consent for publication was taken.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eXia Y, Ge J, Sun Z, Nan F, Wan W, Xu D, Zhang M, Fu X (2022) CD5-positive marginal zone lymphoma: Clinicopathological features and survival outcomes. 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PMID: 34467833\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohansson P, Klein-Hitpass L, Budeus B, Kuhn M, Lauber C, Seifert M, Roeder I, Pf\u0026ouml;rtner R, Stuschke M, D\u0026uuml;hrsen U et al (2020) Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing. Cancers 12:986\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Wang G, Liu E, Zhang D, Zhang Y, Jian X, Zhao W, Li W (2024) Clinicopathological features of CD5-positive splenic marginal zone lymphoma. J Clin Pathol. ;77(6):421\u0026ndash;425. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jcp-2022-208603\u003c/span\u003e\u003cspan address=\"10.1136/jcp-2022-208603\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 36922019\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Extra nodal marginal zone B-cell lymphoma, Lacrimal gland lymphoma, Ocular adnexal lymphoma, Ocular malignancy","lastPublishedDoi":"10.21203/rs.3.rs-6231538/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6231538/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExtra nodal Marginal Zone Lymphoma (EMZL) of the lacrimal gland, also known as mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare type of non-Hodgkin lymphoma (NHL). Environmental factors, autoimmune diseases, and infections have been identified as risk factors, with a notable increase in incidence over recent decades. This condition typically affects individuals around 65 years of age, with a higher prevalence in females. On average, the time from symptom onset to diagnosis is about 6–7 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe present a case of a 43-year-old female patient who presented to an outpatient clinic with 6-month painless slowly progressive swelling in the superolateral region of the orbit bilaterally history revealed diabetes mellitus, though with no known autoimmune disease. On examination, the visual acuity was within normal limits in both eyes. Orbital contrast-enhanced MR. biopsy and immunohistochemical panel confirm the diagnosis of extra nodal al marginal zone B-cell lymphoma (EMZL) of the lacrimal gland six cycles of R-CHOP were utilized and led to partial remission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study presents a case of CD5 + extra nodal marginal zone lymphoma (ENMZL) of the lacrimal gland and provides a comprehensive review of its clinical features, pathology, and management, with the goal of deepening clinicians' understanding of CD5 + ENMZL\u003c/p\u003e","manuscriptTitle":"CD5 positive marginal zone lymphoma of the lacrimal gland: case report and review of literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-20 09:29:34","doi":"10.21203/rs.3.rs-6231538/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8e193a9e-3e1c-4708-988b-3747bda47dbc","owner":[],"postedDate":"March 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":45719259,"name":"Oncology"}],"tags":[],"updatedAt":"2025-03-20T09:29:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-20 09:29:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6231538","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6231538","identity":"rs-6231538","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}