Clinical patterns and prognostic outcomes of Asian ocular adnexal marginal zone lymphoma

Clinical patterns and prognostic outcomes of Asian ocular adnexal marginal zone lymphoma | 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 Article Clinical patterns and prognostic outcomes of Asian ocular adnexal marginal zone lymphoma Jason Yongsheng Chan, Rowena Lee Ying Kwan, Ryan Mao Heng Lim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6601029/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 Background Ocular adnexal marginal zone lymphoma (OAMZL) is the most common subtype of primary ocular lymphoma and has been rising in incidence in Asian populations. Methods We conducted a retrospective review of 95 patients diagnosed with OAMZL within a multi-ethnic cohort from Singapore. Clinical characteristics, survival outcomes including overall survival (OS) and progression-free survival (PFS), and SUVmax values on staging 18-FDG-PET/CT were investigated. Results The cohort comprised 60 males and 35 females, with a median age of 58 years (25–88). Median follow-up was 92 months. The most common sites involved were the orbit (49.5%) and lacrimal gland (23.2%). Most patients presented with stage 1 disease (72.6%). 5-year OS and PFS for the whole cohort was 94.9% and 84.1% respectively. Factors significantly associated with poorer OS included advanced (stage 2–4) disease (HR 6.26, 95% CI: 1.69–23.19, p = 0.0061), older age above 56 years (HR 13.48, 95% CI: 3.98–45.74, p < 0.0001), and higher MALT-IPI scores of 2–3 compared to low (0) and intermediate ( 1 ) scores (HR 9.28, 95% CI: 1.24–69.11, p < 0.0001 and HR 10.99, 95% CI: 1.34–89.94, p < 0.0001), respectively. Older age (HR 2.49, 95% CI: 1.12–5.55, p = 0.0260) and advanced disease (HR 2.47, 95% CI: 1.07–7.03, p = 0.0348) were significantly associated with poorer PFS. Median SUVmax of the lesions was 5.6 (2.1–9.6), with significantly higher values in advanced disease. Conclusion Our study illustrates the favourable prognosis of OAMZL in an Asian cohort, although particular factors may portend worse survival outcomes. Biological sciences/Cancer/Haematological cancer/Lymphoma Health sciences/Medical research/Epidemiology Ocular lymphoma rituximab prognostication positron emission tomography SUVmax Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Lymphoma of the ocular adnexa is estimated to account for 5–15% of all extranodal non-Hodgkin’s lymphoma ( 1 ), and is relatively less studied compared to other lymphoma subtypes. Among primary ocular adnexal lymphomas, ocular adnexal marginal zone lymphoma (OAMZL) is the most common subtype, representing up to 80% of all cases ( 2 ). For reasons unclear, it has been observed that there is a rising trend in the incidence of OAMZL, particularly in Asian countries ( 3 ). In Singapore for example, the incidence of marginal zone lymphoma has been increasing from 1998–2012, highlighting the growing clinical importance of these lymphomas in the region ( 4 ). The majority of cases arise from extranodal sites, with a peculiar predilection to the orbit, aside to the stomach, lung, skin, thyroid gland, salivary glands ( 5 ). In OAMZL, the application of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG-PET/CT) in staging assessment remains limited and its clinical utility is controversial. Its sensitivity in detecting OAMZL has been reported to range from 27–83.1%, depending on the study ( 3 , 6 ). Although SUVmax values have been suggested as a potential prognostic factor for OAMZL, research in this area remains limited. Furthermore, there is a notable lack of studies, particularly in Asian populations, that have documented the clinical characteristics and outcomes of patients with OAMZL, highlighting the need for further research in this field. This study aims to investigate the clinical characteristics and examine survival outcomes in a Southeast Asian patient cohort diagnosed with OAMZL, as well as to explore the relationship of SUVmax values on staging 18-FDG-PET/CT imaging with anatomical site and stage of disease. PATIENTS AND METHODS Study cohort Patients diagnosed with OAMZL and seen at the National Cancer Centre Singapore between 1998 and 2024 were retrospectively reviewed. Patients with marginal zone lymphoma (MZL) involving the ocular adnexa (OA), with or without metastatic spread, were included. A total of 95 patients were included in the final analysis. All data was obtained at the time of diagnosis or subsequent follow-up. The research study was carried out with approval from the SingHealth Centralised Institutional Review Board. Informed consent for the use of biospecimens was obtained in accordance with the Declaration of Helsinki. Participants and/or their legal guardians provided informed consent for their data to be used in this research. Demographic and clinicopathological analysis Demographical information available included age, sex and ethnicity. Clinical characteristics of each patient such as presenting symptoms, sites of disease involvement, serum lactate dehydrogenase (LDH) level, SUVmax values on FDG-PET/CT imaging, treatment regimens and response to treatment were included in the study. MALT-IPI score was calculated based on based on three key clinical parameters (1 point each): age ≥ 70 years, Ann Arbor Stage III or IV, and elevated LDH levels ( 7 ). Study Endpoints The outcomes of interest in this study were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed between the date of diagnosis till the date of relapse, progression, or death from any cause. OS was calculated from the date of diagnosis up till the date of death from any cause, or was censored at the date of last follow-up for survivors. Statistical Analysis Statistical analysis was carried out using methods as previously described ( 8 ). Continuous variables were compared using the Mann-Whitney U test or Kruskal-Wallis test. For each individual clinic-pathological parameter, Kaplan-Meier curves were plotted to estimate survival. The log-rank test was then used to calculate hazard ratios (HR), the corresponding 95% confidence intervals and the p -values. Clinicopathological parameters found to be significant on univariate analysis using a two-sided test with significance level of 0.05 were identified. All tests were performed using MedCalc statistical software for Windows version 19.0.4 (MedCalc Software, Ostend, Belgium). Data sharing statement The datasets created and analysed during this study are available from the corresponding author upon reasonable request. RESULTS Patient demographics and clinicopathological characteristics A total of 95 patients were included in this study. The median age of diagnosis was 58 years (range: 25 to 88 years). Sixty (63.2%) were male and 35 (36.8%) were female. The ethnicity groups of our patient population included Chinese (n = 76, 80.0%), Malay (n = 10, 10.5%) and others (n = 9, 9.5%). Most patients presented with stage 1 disease (n = 69, 72.6%), while the others presented with stage 2 (n = 8, 8.4%), stage 3 (n = 2, 2.1%) and stage 4 disease (n = 16, 16.8%). The lesions were mostly unilateral (n = 76, 80.0%). Bilateral lesions confined to the ocular adnexa were classified as stage 1 disease ( 9 ). The most frequent presenting symptoms were swelling (n = 31, 32.6%), presence of a lump (n = 20, 21.1%), and proptosis (n = 18, 18.9%). The most common site of disease involvement was the orbit (n = 47, 49.5%), followed by the lacrimal gland (n = 22, 23.2%), conjunctiva (n = 15, 15.8%), and eyelid (n = 11, 11.6%). Serum LDH level was elevated in 27 patients (28.4%). MALT-IPI scores were low (0) for 39 patients (41.1%), intermediate ( 1 ) for 38 patients (40.0%), and high ( 2 – 3 ) for 10 patients (10.5%). This information is summarised in Table 1 . Table 1 Demographic and clinical characteristics of patients with OAMZL. Characteristics n (%) Total patients 95 (100) Sex Male 60 (63.2) Female 35 (36.8) Age at presentation Median (Range) 58 (25–88) Mean ± SD 56.2 ± 14.0 Laterality Right 38 (40.0) Left 38 (40.0) Bilateral 19 (20.0) Ethnicity Chinese 76 (80.0) Malay 10 (10.5) Others 9 (9.5) Stage at presentation I 69 (72.6) II 8 (8.4) III 2 (2.1) IV 16 (16.8) Location in ocular adnexal region Orbit 47 (49.5) Conjunctiva 15 (15.8) Lacrimal gland 22 (23.2) Eyelid 11 (11.6) Symptoms Swelling 31 (32.6) Mass/lump 20 (21.1) Proptosis 18 (18.9) Erythema 8 (8.4) Ptosis 8 (8.4) Diplopia 5 (5.3) Decreased visual acuity 5 (5.3) Restricted eye movement 5 (5.3) Pain/Discomfort 4 (4.2) Watery eyes/tearing 3 (3.2) Not reported 31 (32.6) Serum LDH status Elevated 27 (28.4) Not elevated 60 (63.2) Unknown 8 (8.4) MALT IPI Score Low (0) 39 (41.1) Intermediate ( 1 ) 38 (40.0) High ( 2 – 3 ) 10 (10.5) Unknown 8 (8.4) Treatment outcomes and survival analyses The median follow-up duration for all patients was 92 months. The 5-year OS and PFS rates were 94.9% and 84.1% respectively. Median OS was not reached, while the median PFS was 194 months (Fig. 1 ). The majority of patients (n = 69, 72.5%) received orbital radiotherapy as initial treatment. A smaller proportion received rituximab alone (n = 4, 4.2%), R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) (n = 4, 4.2%), rituximab combined with radiotherapy (n = 2, 2.1%), or other radiation or chemotherapy (n = 6, 6.3%). The remaining patients were treated with excision only (n = 2, 2.1%), or underwent watchful waiting (n = 8, 8.4%). Best treatment response achieved after initial treatment included complete response for most patients (n = 74, 77.9%), while the rest had progression or relapse of disease (n = 21, 22.1%), which included 2 patients who underwent watchful waiting (2.1%) (Table 2 ). Table 2 First-line management of patients with ocular lymphoma in the study cohort. Management strategy n (%) Radiation therapy alone 69 (72.6) Rituximab alone 4 (4.2) Rituximab + radiation therapy 2 (2.1) R-CVP 4 (4.2) Other radiation and chemotherapy* 6 (6.3) Excision alone 2 (2.1) Watchful waiting 8 (8.4) Abbreviation: R-CVP, rituximab, cyclophosphamide, vincristine, prednisone *Other radiation and chemotherapy: CP (chlorambucil, prednisone) (n = 2), R-CP (rituximab, chlorambucil, prednisone) (n = 1), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (n = 1), R-B (rituximab, bendamustine) (n = 2) Prognostic factors for overall survival In univariate analyses, patients with stage 2–4 disease had significantly poorer OS than patients with stage 1 disease (HR 6.26, 95% CI: 1.69–23.19, p = 0.0061). Median survival for stage 1 was not reached, while for stage 2–4 it was 169 months. 5-year survival was 96.6% in stage 1 and 90.5% in stage 2–4. Patients who were above the mean age of 56 years at diagnosis had significantly poorer OS than patients aged 56 years and below (HR 13.48, 95% CI: 3.98–45.74, p < 0.0001). Median survival was 155 months for patients above age 56 years and not reached for the younger group. The 5 year OS rate was 90.0% in older patients and 100% in younger patients (Fig. 2 A-B). Patients with stage 2–4 disease had significantly poorer PFS than patients with stage 1 disease (HR 2.47, 95% CI: 1.07–7.03, p = 0.0348). Median PFS was 224 months for stage 1 disease, and 99 months for stage 2–4. 5-year PFS was 88.0% for stage 1 and 71.9% for stage 2–4. Patients who were above the mean age of 56 years at diagnosis had significantly lower PFS than those aged 56 years and below (HR 2.49, 95% CI: 1.12–5.55, p = 0.0260). Median PFS was 129 months in the older group compared to 224 months in the younger group. The 5-year PFS was 79.1% in older patients and 89.3% in younger patients (Fig. 2 C-D). There was no significant difference in OS or PFS when comparing patients with unilateral and bilateral disease. MALT-IPI risk groups and survival outcomes In terms of MALT-IPI score, patients with high scores ( 2 – 3 ) had significantly worse OS than patients with low (0) and intermediate ( 1 ) scores (HR 9.28, 95% CI: 1.24–69.11, p < 0.0001 and HR 10.99, 95% CI: 1.34–89.94, p < 0.0001) respectively. Median survival was 130 months for patients with high MALT-IPI scores and not reached for those with low and intermediate scores. 5-year OS was 97.0% for patients with low and intermediate MALT-IPI scores, and 76.2% for patients with high scores (Fig. 2 E). There was no significant difference in PFS of patients with low (0), intermediate ( 1 ) and high ( 2 – 3 ) scores (Fig. 2 F). SUVmax values on 18-FDG PET/CT and clinical characteristics In an exploratory analysis, 18-FDG PET/CT images of OAMZL at diagnosis were retrieved and SUVmax values were collated. Representative images of selected cases based on anatomical location are shown (Fig. 3 A-D). The median level of SUVmax of the lesions was 5.6 (range: 2.1–9.6). We observed that patients with stage 2–4 disease (median: 7.8, range: 2.1–9.6) had significantly higher SUVmax values compared to patients with stage 1 disease (median: 4.4, range: 2.4–6.8) ( p = 0.035). Interestingly, although there was no significant difference between SUVmax values across different tumour sites, eyelid tumours had numerically higher uptake values ( p = 0.18, Kruskal-Wallis test) (Fig. 3 E-F). The median SUVmax values for eyelid, lacrimal gland, orbit and conjunctival tumours were 7.8, 6.1, 5.5 and 4.0 respectively. An overview of studies on 18FDG-PET/CT in OAMZL, from 2010 to 2025, is included in Supplementary Table 1. DISCUSSION This study investigates the outcomes of ocular lymphoma in a Southeast Asian population in Singapore. The median age of presentation in our cohort was 58 years, which is similar to Chinese patients (median: 57, n = 166), but younger than the median age of 66 in American patients (n = 23) and 62 years in an international cohort (n = 689) ( 10 – 12 ). The 5-year OS and PFS for Stage 1 OAMZL was 96.6% and 88.0% respectively, in contrast to the Chinese study where OS and PFS was 99% and 76% respectively for Stage 1 disease ( 10 ). 5-year OS and PFS for the entire cohort was 94.9% and 84.1% respectively, similar to 96% and 79% in an American population (n = 87) and higher than the OS of 83% reported in an international population ( 12 , 13 ). These findings suggest that the earlier age of presentation in Asian populations may not have negative implications on OS and PFS. The most common sites of disease involvement in our cohort were the orbit (49.5%) and lacrimal gland (23.2%). Other larger studies in predominantly Caucasian populations have reported that ocular lymphomas primarily present in the orbit followed by conjunctiva, with the lacrimal gland being a less common site of involvement ( 14 , 15 ). Similarly, a Taiwanese study (n = 112) identified the orbit, followed by conjunctiva and lacrimal gland (35.5%, 31.6% and 27.6% respectively) as the three most common sites of disease ( 16 ). Interestingly, our findings align with a Thai study (n = 121), which reported the orbit, followed by lacrimal apparatus being the most common sites of disease (46.3% and 34.7% respectively) ( 17 ). This observation could potentially suggest different patterns of disease involvement in Southeast Asian populations. The most common sites of disease relapse after treatment were the lacrimal gland and lung (n = 5 each), followed by cervical lymph nodes and the orbit (n = 4 each). This is in line with findings from a Danish study which reported the most common sites of relapse to be the eye, followed by lymph nodes and the lung ( 18 ). The MALT-IPI (International Prognostic Index) divides patients into low, intermediate, and high-risk groups ( 7 ). This index has been shown to be a valuable tool in predicting the prognoses of MALT lymphoma patients ( 19 ). In our study, patients with higher IPI scores had significantly lower OS but not PFS. This is in contrast to a Korean study that showed significantly lower PFS but not OS for patients with higher MALT-IPI scores ( 20 ). A total of 22 patients underwent PET/CT scans at the point of staging, and SUVmax values of their ocular tumours were recorded. In patients with bilateral disease, the higher value was taken into account. Patients with Stage 2–4 disease had significantly higher SUVmax than those with Stage 1 disease. Eyelid tumours had the highest mean SUVmax (8.1 ± 1.2), although this was not statistically significant. This differs from a Korean study which showed orbit and lacrimal gland tumours having the highest and lowest mean SUVmax values respectively ( 3 ). It has been found that SUVmax values of the single most metabolically active lesion can be useful in response evaluation and prognosis prediction in indolent lymphomas ( 21 ). However, in our study, survival analysis was unable to be performed based on SUVmax values due to insufficient data. Our exploratory analysis of OAMZL patients that underwent PET/CT scans during staging showed that patients with advanced disease had significantly higher PET/CT SUVmax scores of their primary ocular tumour as compared to those with localized disease. Although no study has reviewed the correlation between SUVmax score and prognostic stage in OAZML, other studies involving solid tumours such as lung adenocarcinomas ( 22 ) and breast ( 23 ) cancers have found that higher SUVmax scores correlated with increased prognostic stage in these cancers. Conversely, while our study found that OAMZL tumours arising from the eyelid had non-significantly higher mean SUVmax values as compared to other orbital sites, both Park et al. ( 3 ) and Wang et al. ( 24 ) reported that SUVmax of orbital masses were significantly elevated as compared to other sites such as conjunctiva, lacrimal gland and eyelid. This could suggest that the relationship between SUVmax values and tumour site is less apparent, or that these results may be non-conclusive due to the relatively small sample sizes of each study. Other recent studies investigating the utility of SUVmax values in assessing treatment response and prognosis showed that OAMZL tumours had a decrease in SUVmax values after effective treatment 5 , and that PET/CT FDG-avid OAMZL tumours are more likely to achieve complete remission as compared to non-FDG-avid tumours ( 24 ). As our study was unable to perform survival analysis with regard to PET/CT FDG-avidity and SUVmax values for FDG-avid tumours due to insufficient data, further follow-up studies should be performed to validate these findings so as to improve prognostication at diagnosis and across treatment for OAMZL patients. Finally, as some studies have shown that CT and/or MRI scans have a higher sensitivity of detecting ocular adnexal lymphoproliferative disease as compared to PET/CT scan ( 25 , 26 ), the role of PET/CT scan may be best suited for prognostication of survival and treatment response, as well as in further staging ( 3 ), as compared to making a primary diagnosis of OAMZL. Our study has certain limitations inherent to its retrospective nature, including gaps in data collection. Additionally, due to the small number of patients who underwent PET/CT scans and subsequently progressed or relapsed, survival analysis based on SUVmax values could not be performed. Furthermore, information on subsequent relapse and treatment may be unavailable for patients lost to follow-up. In conclusion, our study illustrates the favourable survival outcomes of OAMZL and demonstrates certain similarities in the presentation of OAMZL among Asian populations, such as age of presentation and site of disease involvement, when compared to Western populations. Declarations Conflict of Interest Statement The authors declare no competing financial interests. Author Contributions RLK, RML and JYC analysed the data and drafted the manuscript; RLK and JYC obtained patient data; JYC designed the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript. Acknowledgements This work was supported by the Singapore Ministry of Health’s National Medical Research Council Research Transition Award (TA21jun-0005), Large Collaborative Grant (OFLCG-23May0039), and TETRAD II Collaborative Centre Grant (CG21APR2002), SingHealth Duke-NUS AM/ACP-Designated Philanthropic Fund Grant Award (08/FY2023/EX/27-A65), as well as the Khoo Bridge Funding Award (Duke-NUS-KBrFA/2025/0090) provided by Duke-NUS Medical School and the “Estate of Tan Sri Khoo Teck Puat”. References Raderer M, Kiesewetter B, Ferreri AJM. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CA: A Cancer Journal for Clinicians. 2016;66(2):152–71. Stefanovic A, Lossos IS. Extranodal marginal zone lymphoma of the ocular adnexa. Blood. 2009;114(3):501–10. Park HL, O JH, Park SY, Jung SE, Park G, Choi BO, et al. 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Value of 18FDG PET scan in staging of ocular adnexal lymphomas: a large single-center experience. Hematology. 2012;17(2):76–84. English JF, Sullivan TJ. The Role of FDG-PET in the Diagnosis and Staging of Ocular Adnexal Lymphoproliferative Disease. Orbit. 2015;34(5):284–91. Nasser QJ, Pfeiffer ML, Romaguera J, Fowler N, Debnam JM, Samaniego F, et al. Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma. Leuk Lymphoma. 2014;55(5):1013–7. Thuro BA, Ning J, Peng SA, Pace ST, Dudeja G, Ozgur O, et al. Rates of Positive Findings on Positron Emission Tomography and Bone Marrow Biopsy in Patients With Ocular Adnexal Lymphoma. Ophthalmic Plast Reconstr Surg. 2017;33(5):355–60. Fujii H, Tanaka H, Nomoto Y, Harata N, Oota S, Isogai J, et al. Usefulness of 18F-FDG PET/CT for evaluating response of ocular adnexal lymphoma to treatment. Medicine (Baltimore). 2018;97(17):e0543. Additional Declarations There is no conflict of interest Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6601029","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":456970131,"identity":"dbb0d49a-fb4c-4924-b766-b3b262b85b54","order_by":0,"name":"Jason Yongsheng Chan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYBACxgYInQDl25CuJY1422BaDhNWytx+/OHjAga7PP7ZDWwSDH/O5/G3H3/A8KNiG4N8/wLsDuvJMTaewZBcLHHnAJsEY9vtYokzOQaMPWduMxjceIBdS0MOmzQPw4HEhhsJQC0NtxM3SPAwMAP1MhhIHMCupf/5M7CW+SAtDH/OAbWwPwBrkZ+BQ8uMBDOwlg1gLWxAhgSDAVgLw/kGHFreGBvzGCQnbryR2GyR2JacOAPol4NAv/AY3MAeYob96Q8f81TYJc67kXzwxoc/don9wDB88KPitpx8P3aHGYItNwBb2CKRABUFqeVhgHNRgTwSm/kDqhw/dltGwSgYBaNgxAEAY0ZfcM62+cgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4801-3703","institution":"National Cancer Centre Singapore","correspondingAuthor":true,"prefix":"","firstName":"Jason","middleName":"Yongsheng","lastName":"Chan","suffix":""},{"id":456970132,"identity":"f22182e4-3e4f-41c8-a69d-d4b114f39426","order_by":1,"name":"Rowena Lee Ying Kwan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rowena","middleName":"Lee Ying","lastName":"Kwan","suffix":""},{"id":456970133,"identity":"c230662c-bccd-43ef-973b-6d82adc3c9e5","order_by":2,"name":"Ryan Mao Heng Lim","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"Mao Heng","lastName":"Lim","suffix":""}],"badges":[],"createdAt":"2025-05-06 08:55:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6601029/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6601029/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84506386,"identity":"a23ef6f5-b3b4-4861-95dd-2ebabe62ec7f","added_by":"auto","created_at":"2025-06-12 18:51:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70865,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier survival curves for overall survival (OS) and progression-free survival (PFS) in the overall cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) \u0026nbsp;The 5-year OS was 94.9%, and the median survival was not reached.\u003c/p\u003e\n\u003cp\u003e(B) \u0026nbsp;The 5-year PFS was 84.1%, with a median PFS of 194 months.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6601029/v1/84cd073075b46045069266e5.png"},{"id":84506390,"identity":"6c6ed713-3324-43a2-b423-4ff8d46c0bbb","added_by":"auto","created_at":"2025-06-12 18:51:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":175465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier survival curves for overall survival (OS) and progression-free survival (PFS) stratified by Ann Arbor stage, age at diagnosis and MALT-IPI score.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Patients with stage 2-4 disease had significantly poorer survival than patients with stage 1 disease (HR 6.26, 95% CI: 1.69-23.19, \u003cem\u003ep\u003c/em\u003e = 0.0061).\u003c/p\u003e\n\u003cp\u003e(B) Older patients above age 56 years had significantly lower survival than younger patients (HR 13.48, 95% CI: 3.98-45.74, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.0001).\u003c/p\u003e\n\u003cp\u003e(C) Patients with stage 2-4 disease had a significantly poorer PFS than patients with stage 1 disease (HR 2.47, 95% CI: 1.07-7.03, \u003cem\u003ep\u003c/em\u003e = 0.0348).\u003c/p\u003e\n\u003cp\u003e(D) Patients above age 56 years had a significantly lower PFS than younger patients (HR 2.49, 95% CI: 1.12-5.55, \u003cem\u003ep\u003c/em\u003e= 0.0260).\u003c/p\u003e\n\u003cp\u003e(E) OS for low vs intermediate vs high MALT-IPI score. Patients with high MALT-IPI score had significantly worse OS than patients with low and intermediate IPI scores (HR=9.28, 95% CI: 1.24-69.11, p\u0026lt;0.0001, and HR=10.99, 95% CI: 1.34-89.94, p\u0026lt;0.0001) respectively.\u003c/p\u003e\n\u003cp\u003e(F) PFS for low vs intermediate vs high MALT-IPI score.. There was no significant difference in PFS of patients with different MALT-IPI scores.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6601029/v1/6d9cdeb0a20887b084821e53.png"},{"id":84506385,"identity":"aacdde26-d9a3-49f8-824a-911f9617622f","added_by":"auto","created_at":"2025-06-12 18:51:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":154081,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative 18-FDG PET/CT images of ocular marginal zone lymphoma based on anatomical location, and SUVmax values at diagnosis stratified by Ann Arbor stage and tumour site.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Bilateral enlarged and FDG-avid lacrimal glands (left, SUVmax 3.1; right, SUVmax 8.8).\u003c/p\u003e\n\u003cp\u003e(B) Bilateral FDG-avid lower eyelid masses (left, SUVmax 7.8; right, SUVmax 4.0).\u003c/p\u003e\n\u003cp\u003e(C) FDG-avid mass over medial-superior aspect of the left globe (SUVmax 5.5)\u003c/p\u003e\n\u003cp\u003e(D) FDG-avid nodular lesion on the left orbit (SUVmax 4.4). Red arrows indicate site of disease.\u003c/p\u003e\n\u003cp\u003e(E) Patients with stage 2-4 disease had significantly higher SUVmax values compared to patients with stage 1 disease (\u003cem\u003ep\u003c/em\u003e = 0.035, Mann-Whitney U test).\u003c/p\u003e\n\u003cp\u003e(F) There was no significant difference between SUVmax values across different tumour sites, though eyelid tumours had numerically higher uptake values (\u003cem\u003ep\u003c/em\u003e = 0.18, Kruskal-Wallis test).\u003c/p\u003e","description":"","filename":"Figure314.png","url":"https://assets-eu.researchsquare.com/files/rs-6601029/v1/9400d91c4d5b9954e15992c8.png"},{"id":84902865,"identity":"184bc8b5-40cf-49ae-b32b-94d1cea3da01","added_by":"auto","created_at":"2025-06-18 15:19:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1399960,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6601029/v1/c9e97fe9-740c-4dde-962f-6d333a51e31d.pdf"},{"id":84506384,"identity":"7255f8e7-1cef-4a4c-a43b-c41242cbc35a","added_by":"auto","created_at":"2025-06-12 18:51:21","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21397,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6601029/v1/8a86018aa111da3c949e4d75.docx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Clinical patterns and prognostic outcomes of Asian ocular adnexal marginal zone lymphoma","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eLymphoma of the ocular adnexa is estimated to account for 5\u0026ndash;15% of all extranodal non-Hodgkin\u0026rsquo;s lymphoma (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), and is relatively less studied compared to other lymphoma subtypes. Among primary ocular adnexal lymphomas, ocular adnexal marginal zone lymphoma (OAMZL) is the most common subtype, representing up to 80% of all cases (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). For reasons unclear, it has been observed that there is a rising trend in the incidence of OAMZL, particularly in Asian countries (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In Singapore for example, the incidence of marginal zone lymphoma has been increasing from 1998\u0026ndash;2012, highlighting the growing clinical importance of these lymphomas in the region (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The majority of cases arise from extranodal sites, with a peculiar predilection to the orbit, aside to the stomach, lung, skin, thyroid gland, salivary glands (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn OAMZL, the application of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG-PET/CT) in staging assessment remains limited and its clinical utility is controversial. Its sensitivity in detecting OAMZL has been reported to range from 27\u0026ndash;83.1%, depending on the study (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although SUVmax values have been suggested as a potential prognostic factor for OAMZL, research in this area remains limited. Furthermore, there is a notable lack of studies, particularly in Asian populations, that have documented the clinical characteristics and outcomes of patients with OAMZL, highlighting the need for further research in this field.\u003c/p\u003e \u003cp\u003eThis study aims to investigate the clinical characteristics and examine survival outcomes in a Southeast Asian patient cohort diagnosed with OAMZL, as well as to explore the relationship of SUVmax values on staging 18-FDG-PET/CT imaging with anatomical site and stage of disease.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort\u003c/h2\u003e \u003cp\u003ePatients diagnosed with OAMZL and seen at the National Cancer Centre Singapore between 1998 and 2024 were retrospectively reviewed. Patients with marginal zone lymphoma (MZL) involving the ocular adnexa (OA), with or without metastatic spread, were included. A total of 95 patients were included in the final analysis. All data was obtained at the time of diagnosis or subsequent follow-up. The research study was carried out with approval from the SingHealth Centralised Institutional Review Board. Informed consent for the use of biospecimens was obtained in accordance with the Declaration of Helsinki. Participants and/or their legal guardians provided informed consent for their data to be used in this research.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDemographic and clinicopathological analysis\u003c/h3\u003e\n\u003cp\u003eDemographical information available included age, sex and ethnicity. Clinical characteristics of each patient such as presenting symptoms, sites of disease involvement, serum lactate dehydrogenase (LDH) level, SUVmax values on FDG-PET/CT imaging, treatment regimens and response to treatment were included in the study. MALT-IPI score was calculated based on based on three key clinical parameters (1 point each): age\u0026thinsp;\u0026ge;\u0026thinsp;70 years, Ann Arbor Stage III or IV, and elevated LDH levels (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eStudy Endpoints\u003c/h3\u003e\n\u003cp\u003eThe outcomes of interest in this study were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed between the date of diagnosis till the date of relapse, progression, or death from any cause. OS was calculated from the date of diagnosis up till the date of death from any cause, or was censored at the date of last follow-up for survivors.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was carried out using methods as previously described (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Continuous variables were compared using the Mann-Whitney U test or Kruskal-Wallis test. For each individual clinic-pathological parameter, Kaplan-Meier curves were plotted to estimate survival. The log-rank test was then used to calculate hazard ratios (HR), the corresponding 95% confidence intervals and the \u003cem\u003ep\u003c/em\u003e-values. Clinicopathological parameters found to be significant on univariate analysis using a two-sided test with significance level of 0.05 were identified. All tests were performed using MedCalc statistical software for Windows version 19.0.4 (MedCalc Software, Ostend, Belgium).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData sharing statement\u003c/h3\u003e\n\u003cp\u003eThe datasets created and analysed during this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient demographics and clinicopathological characteristics\u003c/h2\u003e \u003cp\u003eA total of 95 patients were included in this study. The median age of diagnosis was 58 years (range: 25 to 88 years). Sixty (63.2%) were male and 35 (36.8%) were female. The ethnicity groups of our patient population included Chinese (n\u0026thinsp;=\u0026thinsp;76, 80.0%), Malay (n\u0026thinsp;=\u0026thinsp;10, 10.5%) and others (n\u0026thinsp;=\u0026thinsp;9, 9.5%). Most patients presented with stage 1 disease (n\u0026thinsp;=\u0026thinsp;69, 72.6%), while the others presented with stage 2 (n\u0026thinsp;=\u0026thinsp;8, 8.4%), stage 3 (n\u0026thinsp;=\u0026thinsp;2, 2.1%) and stage 4 disease (n\u0026thinsp;=\u0026thinsp;16, 16.8%). The lesions were mostly unilateral (n\u0026thinsp;=\u0026thinsp;76, 80.0%). Bilateral lesions confined to the ocular adnexa were classified as stage 1 disease (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The most frequent presenting symptoms were swelling (n\u0026thinsp;=\u0026thinsp;31, 32.6%), presence of a lump (n\u0026thinsp;=\u0026thinsp;20, 21.1%), and proptosis (n\u0026thinsp;=\u0026thinsp;18, 18.9%). The most common site of disease involvement was the orbit (n\u0026thinsp;=\u0026thinsp;47, 49.5%), followed by the lacrimal gland (n\u0026thinsp;=\u0026thinsp;22, 23.2%), conjunctiva (n\u0026thinsp;=\u0026thinsp;15, 15.8%), and eyelid (n\u0026thinsp;=\u0026thinsp;11, 11.6%). Serum LDH level was elevated in 27 patients (28.4%). MALT-IPI scores were low (0) for 39 patients (41.1%), intermediate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) for 38 patients (40.0%), and high (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) for 10 patients (10.5%). This information is summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of patients with OAMZL.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (100)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (63.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (36.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at presentation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (25\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaterality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (80.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (9.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage at presentation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (72.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (16.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocation in ocular adnexal region\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (49.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConjunctiva\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (15.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal gland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (23.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEyelid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (11.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwelling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (32.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMass/lump\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (21.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProptosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (18.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePtosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiplopia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased visual acuity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRestricted eye movement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain/Discomfort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWatery eyes/tearing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (32.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum LDH status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (28.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot elevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (63.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMALT IPI Score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (41.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment outcomes and survival analyses\u003c/h3\u003e\n\u003cp\u003eThe median follow-up duration for all patients was 92 months. The 5-year OS and PFS rates were 94.9% and 84.1% respectively. Median OS was not reached, while the median PFS was 194 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The majority of patients (n\u0026thinsp;=\u0026thinsp;69, 72.5%) received orbital radiotherapy as initial treatment. A smaller proportion received rituximab alone (n\u0026thinsp;=\u0026thinsp;4, 4.2%), R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) (n\u0026thinsp;=\u0026thinsp;4, 4.2%), rituximab combined with radiotherapy (n\u0026thinsp;=\u0026thinsp;2, 2.1%), or other radiation or chemotherapy (n\u0026thinsp;=\u0026thinsp;6, 6.3%). The remaining patients were treated with excision only (n\u0026thinsp;=\u0026thinsp;2, 2.1%), or underwent watchful waiting (n\u0026thinsp;=\u0026thinsp;8, 8.4%). Best treatment response achieved after initial treatment included complete response for most patients (n\u0026thinsp;=\u0026thinsp;74, 77.9%), while the rest had progression or relapse of disease (n\u0026thinsp;=\u0026thinsp;21, 22.1%), which included 2 patients who underwent watchful waiting (2.1%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFirst-line management of patients with ocular lymphoma in the study cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManagement strategy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69 (72.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRituximab alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRituximab\u0026thinsp;+\u0026thinsp;radiation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR-CVP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther radiation and chemotherapy*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExcision alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWatchful waiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviation: R-CVP, rituximab, cyclophosphamide, vincristine, prednisone\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Other radiation and chemotherapy: CP (chlorambucil, prednisone) (n\u0026thinsp;=\u0026thinsp;2), R-CP (rituximab, chlorambucil, prednisone) (n\u0026thinsp;=\u0026thinsp;1), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (n\u0026thinsp;=\u0026thinsp;1), R-B (rituximab, bendamustine) (n\u0026thinsp;=\u0026thinsp;2)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic factors for overall survival\u003c/h2\u003e \u003cp\u003eIn univariate analyses, patients with stage 2\u0026ndash;4 disease had significantly poorer OS than patients with stage 1 disease (HR 6.26, 95% CI: 1.69\u0026ndash;23.19, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0061). Median survival for stage 1 was not reached, while for stage 2\u0026ndash;4 it was 169 months. 5-year survival was 96.6% in stage 1 and 90.5% in stage 2\u0026ndash;4. Patients who were above the mean age of 56 years at diagnosis had significantly poorer OS than patients aged 56 years and below (HR 13.48, 95% CI: 3.98\u0026ndash;45.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Median survival was 155 months for patients above age 56 years and not reached for the younger group. The 5 year OS rate was 90.0% in older patients and 100% in younger patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatients with stage 2\u0026ndash;4 disease had significantly poorer PFS than patients with stage 1 disease (HR 2.47, 95% CI: 1.07\u0026ndash;7.03, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0348). Median PFS was 224 months for stage 1 disease, and 99 months for stage 2\u0026ndash;4. 5-year PFS was 88.0% for stage 1 and 71.9% for stage 2\u0026ndash;4. Patients who were above the mean age of 56 years at diagnosis had significantly lower PFS than those aged 56 years and below (HR 2.49, 95% CI: 1.12\u0026ndash;5.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0260). Median PFS was 129 months in the older group compared to 224 months in the younger group. The 5-year PFS was 79.1% in older patients and 89.3% in younger patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC-D). There was no significant difference in OS or PFS when comparing patients with unilateral and bilateral disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMALT-IPI risk groups and survival outcomes\u003c/h2\u003e \u003cp\u003eIn terms of MALT-IPI score, patients with high scores (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) had significantly worse OS than patients with low (0) and intermediate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) scores (HR 9.28, 95% CI: 1.24\u0026ndash;69.11, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and HR 10.99, 95% CI: 1.34\u0026ndash;89.94, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) respectively. Median survival was 130 months for patients with high MALT-IPI scores and not reached for those with low and intermediate scores. 5-year OS was 97.0% for patients with low and intermediate MALT-IPI scores, and 76.2% for patients with high scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). There was no significant difference in PFS of patients with low (0), intermediate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and high (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSUVmax values on 18-FDG PET/CT and clinical characteristics\u003c/h2\u003e \u003cp\u003eIn an exploratory analysis, 18-FDG PET/CT images of OAMZL at diagnosis were retrieved and SUVmax values were collated. Representative images of selected cases based on anatomical location are shown (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-D). The median level of SUVmax of the lesions was 5.6 (range: 2.1\u0026ndash;9.6). We observed that patients with stage 2\u0026ndash;4 disease (median: 7.8, range: 2.1\u0026ndash;9.6) had significantly higher SUVmax values compared to patients with stage 1 disease (median: 4.4, range: 2.4\u0026ndash;6.8) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035). Interestingly, although there was no significant difference between SUVmax values across different tumour sites, eyelid tumours had numerically higher uptake values (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.18, Kruskal-Wallis test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE-F). The median SUVmax values for eyelid, lacrimal gland, orbit and conjunctival tumours were 7.8, 6.1, 5.5 and 4.0 respectively. An overview of studies on 18FDG-PET/CT in OAMZL, from 2010 to 2025, is included in Supplementary Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study investigates the outcomes of ocular lymphoma in a Southeast Asian population in Singapore. The median age of presentation in our cohort was 58 years, which is similar to Chinese patients (median: 57, n\u0026thinsp;=\u0026thinsp;166), but younger than the median age of 66 in American patients (n\u0026thinsp;=\u0026thinsp;23) and 62 years in an international cohort (n\u0026thinsp;=\u0026thinsp;689) (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The 5-year OS and PFS for Stage 1 OAMZL was 96.6% and 88.0% respectively, in contrast to the Chinese study where OS and PFS was 99% and 76% respectively for Stage 1 disease (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). 5-year OS and PFS for the entire cohort was 94.9% and 84.1% respectively, similar to 96% and 79% in an American population (n\u0026thinsp;=\u0026thinsp;87) and higher than the OS of 83% reported in an international population (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These findings suggest that the earlier age of presentation in Asian populations may not have negative implications on OS and PFS.\u003c/p\u003e \u003cp\u003eThe most common sites of disease involvement in our cohort were the orbit (49.5%) and lacrimal gland (23.2%). Other larger studies in predominantly Caucasian populations have reported that ocular lymphomas primarily present in the orbit followed by conjunctiva, with the lacrimal gland being a less common site of involvement (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Similarly, a Taiwanese study (n\u0026thinsp;=\u0026thinsp;112) identified the orbit, followed by conjunctiva and lacrimal gland (35.5%, 31.6% and 27.6% respectively) as the three most common sites of disease (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Interestingly, our findings align with a Thai study (n\u0026thinsp;=\u0026thinsp;121), which reported the orbit, followed by lacrimal apparatus being the most common sites of disease (46.3% and 34.7% respectively) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This observation could potentially suggest different patterns of disease involvement in Southeast Asian populations.\u003c/p\u003e \u003cp\u003eThe most common sites of disease relapse after treatment were the lacrimal gland and lung (n\u0026thinsp;=\u0026thinsp;5 each), followed by cervical lymph nodes and the orbit (n\u0026thinsp;=\u0026thinsp;4 each). This is in line with findings from a Danish study which reported the most common sites of relapse to be the eye, followed by lymph nodes and the lung (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe MALT-IPI (International Prognostic Index) divides patients into low, intermediate, and high-risk groups (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). This index has been shown to be a valuable tool in predicting the prognoses of MALT lymphoma patients (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In our study, patients with higher IPI scores had significantly lower OS but not PFS. This is in contrast to a Korean study that showed significantly lower PFS but not OS for patients with higher MALT-IPI scores (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA total of 22 patients underwent PET/CT scans at the point of staging, and SUVmax values of their ocular tumours were recorded. In patients with bilateral disease, the higher value was taken into account. Patients with Stage 2\u0026ndash;4 disease had significantly higher SUVmax than those with Stage 1 disease. Eyelid tumours had the highest mean SUVmax (8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2), although this was not statistically significant. This differs from a Korean study which showed orbit and lacrimal gland tumours having the highest and lowest mean SUVmax values respectively (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It has been found that SUVmax values of the single most metabolically active lesion can be useful in response evaluation and prognosis prediction in indolent lymphomas (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However, in our study, survival analysis was unable to be performed based on SUVmax values due to insufficient data.\u003c/p\u003e \u003cp\u003e Our exploratory analysis of OAMZL patients that underwent PET/CT scans during staging showed that patients with advanced disease had significantly higher PET/CT SUVmax scores of their primary ocular tumour as compared to those with localized disease. Although no study has reviewed the correlation between SUVmax score and prognostic stage in OAZML, other studies involving solid tumours such as lung adenocarcinomas (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and breast (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) cancers have found that higher SUVmax scores correlated with increased prognostic stage in these cancers. Conversely, while our study found that OAMZL tumours arising from the eyelid had non-significantly higher mean SUVmax values as compared to other orbital sites, both Park et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and Wang et al. (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) reported that SUVmax of orbital masses were significantly elevated as compared to other sites such as conjunctiva, lacrimal gland and eyelid. This could suggest that the relationship between SUVmax values and tumour site is less apparent, or that these results may be non-conclusive due to the relatively small sample sizes of each study.\u003c/p\u003e \u003cp\u003eOther recent studies investigating the utility of SUVmax values in assessing treatment response and prognosis showed that OAMZL tumours had a decrease in SUVmax values after effective treatment\u003csup\u003e5\u003c/sup\u003e, and that PET/CT FDG-avid OAMZL tumours are more likely to achieve complete remission as compared to non-FDG-avid tumours (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). As our study was unable to perform survival analysis with regard to PET/CT FDG-avidity and SUVmax values for FDG-avid tumours due to insufficient data, further follow-up studies should be performed to validate these findings so as to improve prognostication at diagnosis and across treatment for OAMZL patients. Finally, as some studies have shown that CT and/or MRI scans have a higher sensitivity of detecting ocular adnexal lymphoproliferative disease as compared to PET/CT scan (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), the role of PET/CT scan may be best suited for prognostication of survival and treatment response, as well as in further staging (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), as compared to making a primary diagnosis of OAMZL.\u003c/p\u003e \u003cp\u003eOur study has certain limitations inherent to its retrospective nature, including gaps in data collection. Additionally, due to the small number of patients who underwent PET/CT scans and subsequently progressed or relapsed, survival analysis based on SUVmax values could not be performed. Furthermore, information on subsequent relapse and treatment may be unavailable for patients lost to follow-up.\u003c/p\u003e \u003cp\u003eIn conclusion, our study illustrates the favourable survival outcomes of OAMZL and demonstrates certain similarities in the presentation of OAMZL among Asian populations, such as age of presentation and site of disease involvement, when compared to Western populations.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e \u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eRLK, RML and JYC analysed the data and drafted the manuscript; RLK and JYC obtained patient data; JYC designed the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003e This work was supported by the Singapore Ministry of Health\u0026rsquo;s National Medical Research Council Research Transition Award (TA21jun-0005), Large Collaborative Grant (OFLCG-23May0039), and TETRAD II Collaborative Centre Grant (CG21APR2002), SingHealth Duke-NUS AM/ACP-Designated Philanthropic Fund Grant Award (08/FY2023/EX/27-A65), as well as the Khoo Bridge Funding Award (Duke-NUS-KBrFA/2025/0090) provided by Duke-NUS Medical School and the \u0026ldquo;Estate of Tan Sri Khoo Teck Puat\u0026rdquo;.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRaderer M, Kiesewetter B, Ferreri AJM. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CA: A Cancer Journal for Clinicians. 2016;66(2):152\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStefanovic A, Lossos IS. Extranodal marginal zone lymphoma of the ocular adnexa. Blood. 2009;114(3):501\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark HL, O JH, Park SY, Jung SE, Park G, Choi BO, et al. Role of F-18 FDG PET/CT in non-conjunctival origin ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphomas. EJNMMI Research. 2019;9(1):99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim RBT, Loy EY, Lim GH, Zheng H, Chow KY, Lim ST. Gender and ethnic differences in incidence and survival of lymphoid neoplasm subtypes in an Asian population: Secular trends of a population-based cancer registry from 1998 to 2012. Int J Cancer. 2015;137(11):2674\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeo YH, Teo YN, Khoo LP, Chang EWY, Tan YH, Chiang J, et al. Clinicopathological factors affecting prognosis in marginal zone lymphoma in Asian patients: a cohort study. Leuk Lymphoma. 2022;63(11):2723\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValenzuela AA, Allen C, Grimes D, Wong D, Sullivan TJ. Positron Emission Tomography in the Detection and Staging of Ocular Adnexal Lymphoproliferative Disease. Ophthalmology. 2006;113(12):2331\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThieblemont C, Cascione L, Conconi A, Kiesewetter B, Raderer M, Gaidano G, et al. A MALT lymphoma prognostic index. Blood. 2017;130(12):1409\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan KM, Chia B, Lim JQ, Khoo LP, Cheng CL, Tan L, et al. A clinicohaematological prognostic model for nasal-type natural killer/T-cell lymphoma: A multicenter study. Sci Rep. 2019;9(1):14961.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee SE, Paik JS, Cho WK, Choi BO, Lee SN, Jung SE, et al. Feasibility of the TNM-based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Am J Hematol. 2011;86(3):262\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang Y, Fu RY, Liu XL, Liu X di, Piao YS, Ma JM, et al. Long-term survival outcomes of patients with primary ocular adnexal MALT lymphoma: A large single-center cohort study. Cancer Med. 2023;12(3):2514\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharlotte F, Doghmi K, Cassoux N, Ye H, Du MQ, Kujas M, et al. Ocular adnexal marginal zone B cell lymphoma: a clinical and pathologic study of 23 cases. Virchows Arch. 2006;448(4):506\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHinds\u0026oslash; TG, Esmaeli B, Holm F, Mikkelsen LH, Rasmussen PK, Coupland SE, et al. International multicentre retrospective cohort study of ocular adnexal marginal zone B-cell lymphoma. Br J Ophthalmol. 2020;104(3):357\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosado MF, Byrne GE, Ding F, Fields KA, Ruiz P, Dubovy SR, et al. Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci. Blood. 2006;107(2):467\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoslehi R, Devesa SS, Schairer C, Fraumeni JF. Rapidly increasing incidence of ocular non-hodgkin lymphoma. J Natl Cancer Inst. 2006;98(13):936\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesai A, Joag MG, Lekakis L, Chapman JR, Vega F, Tibshirani R, et al. Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study. Blood. 2017;129(3):324\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu CR, Chen YY, Yao M, Wei YH, Hsieh YT, Liao SL. Orbital and ocular adnexal lymphoma: a review of epidemiology and prognostic factors in Taiwan. Eye (Lond). 2021;35(7):1946\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeresirikachorn K, Norasetthada L, Ausayakhun S, Apivatthakakul A, Tangchittam S, Pruksakorn V, et al. Clinical presentation and treatment outcomes of primary ocular adnexal MALT lymphoma in Thailand. Blood Res. 2018;53(4):307\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSj\u0026ouml; LD, Heegaard S, Prause JU, Petersen BL, Pedersen S, Ralfkiaer E. Extranodal marginal zone lymphoma in the ocular region: clinical, immunophenotypical, and cytogenetical characteristics. Invest Ophthalmol Vis Sci. 2009;50(2):516\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong J, Cho J, Ko YH, Kim SJ, Kim WS. Validation of the Marginal Zone Lymphoma International Prognostic Index. Ann Hematol. 2019;98(2):457\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeon YW, Yang HJ, Choi BO, Jung SE, Park KS, O JH, et al. Comparison of Selection and Long-term Clinical Outcomes Between Chemotherapy and Radiotherapy as Primary Therapeutic Modality for Ocular Adnexal MALT Lymphoma. EClinicalMedicine. 2018;4\u0026ndash;5:32\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim HJ, Lee R, Choi H, Paeng JC, Cheon GJ, Lee DS, et al. Application of Quantitative Indexes of FDG PET to Treatment Response Evaluation in Indolent Lymphoma. Nucl Med Mol Imaging. 2018;52(5):342\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun X, Chen T, Xie C, Liu L, Lei B, Wang L, et al. Relationships between SUVmax of lung adenocarcinoma and different T stages, histological grades and pathological subtypes: a retrospective cohort study in China. BMJ Open. 2022;12(5):e056804.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMori M, Fujioka T, Kubota K, Katsuta L, Yashima Y, Nomura K, et al. Relationship between Prognostic Stage in Breast Cancer and Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. J Clin Med. 2021;10(14):3173.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang W, Ni X, Tang T, Wang J, Li Y, Song X. The role of 18F-FDG PET/CT in diagnosis and treatment evaluation for ocular adnexal mucosa-associated lymphoid tissue lymphoma. Br J Radiol. 2022;95(1130):20210635.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZanni M, Moulin-Romsee G, Servois V, Validire P, B\u0026eacute;namor M, Plancher C, et al. Value of 18FDG PET scan in staging of ocular adnexal lymphomas: a large single-center experience. Hematology. 2012;17(2):76\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnglish JF, Sullivan TJ. The Role of FDG-PET in the Diagnosis and Staging of Ocular Adnexal Lymphoproliferative Disease. Orbit. 2015;34(5):284\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNasser QJ, Pfeiffer ML, Romaguera J, Fowler N, Debnam JM, Samaniego F, et al. Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma. Leuk Lymphoma. 2014;55(5):1013\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThuro BA, Ning J, Peng SA, Pace ST, Dudeja G, Ozgur O, et al. Rates of Positive Findings on Positron Emission Tomography and Bone Marrow Biopsy in Patients With Ocular Adnexal Lymphoma. Ophthalmic Plast Reconstr Surg. 2017;33(5):355\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujii H, Tanaka H, Nomoto Y, Harata N, Oota S, Isogai J, et al. Usefulness of 18F-FDG PET/CT for evaluating response of ocular adnexal lymphoma to treatment. Medicine (Baltimore). 2018;97(17):e0543.\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":"Ocular lymphoma, rituximab, prognostication, positron emission tomography, SUVmax","lastPublishedDoi":"10.21203/rs.3.rs-6601029/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6601029/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOcular adnexal marginal zone lymphoma (OAMZL) is the most common subtype of primary ocular lymphoma and has been rising in incidence in Asian populations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe conducted a retrospective review of 95 patients diagnosed with OAMZL within a multi-ethnic cohort from Singapore. Clinical characteristics, survival outcomes including overall survival (OS) and progression-free survival (PFS), and SUVmax values on staging 18-FDG-PET/CT were investigated.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe cohort comprised 60 males and 35 females, with a median age of 58 years (25\u0026ndash;88). Median follow-up was 92 months. The most common sites involved were the orbit (49.5%) and lacrimal gland (23.2%). Most patients presented with stage 1 disease (72.6%). 5-year OS and PFS for the whole cohort was 94.9% and 84.1% respectively. Factors significantly associated with poorer OS included advanced (stage 2\u0026ndash;4) disease (HR 6.26, 95% CI: 1.69\u0026ndash;23.19, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0061), older age above 56 years (HR 13.48, 95% CI: 3.98\u0026ndash;45.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and higher MALT-IPI scores of 2\u0026ndash;3 compared to low (0) and intermediate (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) scores (HR 9.28, 95% CI: 1.24\u0026ndash;69.11, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and HR 10.99, 95% CI: 1.34\u0026ndash;89.94, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), respectively. Older age (HR 2.49, 95% CI: 1.12\u0026ndash;5.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0260) and advanced disease (HR 2.47, 95% CI: 1.07\u0026ndash;7.03, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0348) were significantly associated with poorer PFS. Median SUVmax of the lesions was 5.6 (2.1\u0026ndash;9.6), with significantly higher values in advanced disease.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOur study illustrates the favourable prognosis of OAMZL in an Asian cohort, although particular factors may portend worse survival outcomes.\u003c/p\u003e","manuscriptTitle":"Clinical patterns and prognostic outcomes of Asian ocular adnexal marginal zone lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-12 18:51:17","doi":"10.21203/rs.3.rs-6601029/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":"0d06a3a9-a6bc-4517-aabd-04b464fade62","owner":[],"postedDate":"June 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48567644,"name":"Biological sciences/Cancer/Haematological cancer/Lymphoma"},{"id":48567645,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2025-06-18T15:11:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-12 18:51:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6601029","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6601029","identity":"rs-6601029","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}