Neutrophil-to-Lymphocyte Ratio as a Promising Marker in Lacrimal Gland Pathologies: Differentiating MALT Lymphoma from Dacryoadenitis

Neutrophil-to-Lymphocyte Ratio as a Promising Marker in Lacrimal Gland Pathologies: Differentiating MALT Lymphoma from Dacryoadenitis | 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 Neutrophil-to-Lymphocyte Ratio as a Promising Marker in Lacrimal Gland Pathologies: Differentiating MALT Lymphoma from Dacryoadenitis Yasuhiro Takahashi, Muhammad Abumanhal This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7666025/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/Objectives: To investigate the role of the neutrophil-to-lymphocyte ratio (NLR) in differentiating lacrimal gland pathologies, specifically mucosa-associated lymphoid tissue (MALT) lymphoma, immunoglobulin G4 (IgG4)-related dacryoadenitis, and non-specific chronic dacryoadenitis. Subjects/Methods: This retrospective chart review included 54 patients with only lacrimal gland lesions who underwent lacrimal gland biopsy. Eligible cases were those with confirmed diagnoses of lacrimal gland MALT lymphoma (7 patients), definite IgG4-related dacryoadenitis (26 patients), or non-specific chronic dacryoadenitis (21 patients). Clinical data, imaging findings, laboratory results, and histopathological reports were reviewed. NLR was calculated from blood counts at presentation. Results: Mean NLR values were 3.21 ± 2.31 in MALT lymphoma, 2.03 ± 0.67 in IgG4-related dacryoadenitis, and 2.23 ± 1.09 in non-specific chronic dacryoadenitis. Although the overall difference did not reach statistical significance (P = 0.061), post-hoc analysis revealed a significantly higher NLR in MALT lymphoma, compared with IgG4-related dacryoadenitis (P = 0.049). In IgG4-related dacryoadenitis, NLR tended to be lower in bilateral cases (P = 0.118) and in patients with systemic lesions (P = 0.107), though these differences were not statistically significant. Conclusion: NLR may serve as a simple biomarker to help distinguish lacrimal gland MALT lymphoma from dacryoadenitis, particularly IgG4-related dacryoadenitis. These results, while promising, should be validated through large-scale, prospective studies to better define the diagnostic and prognostic utility of NLR in lacrimal gland pathologies. Health sciences/Biomarkers/Predictive markers Health sciences/Diseases/Immunological disorders/Autoimmune diseases neutrophil-to-lymphocyte ratio mucosa-associated lymphoid tissue lymphoma immunoglobulin G4-related dacryoadenitis non-specific chronic dacryoadenitis Figures Figure 1 INTRODUCTION Neutrophils-to-lymphocytes ratio (NLR) is a simple index calculated from the differential white blood cell count, reflecting the balance between the innate (neutrophils) and adaptive (lymphocytes) immune responses. 1 Initially described by Zahorec in the early 2000s as a prognostic marker in cardiovascular disease, 2 NLR has since emerged as a widely studied biomarker across diverse medical fields, including oncology, infectious diseases, and autoimmune disorders. 1 – 6 Studies have demonstrated a significant correlation between NLR and established inflammatory markers, such as C-reactive protein. 7 , 8 Owing to its simplicity, low cost, and accessibility, NLR has gained recognition as a potential and attractive tool for early diagnosis, risk stratification, treatment monitoring, and clinical decision-making. 2 NLR has been investigated in a variety of ocular diseases with an inflammatory component. In thyroid eye disease (TED), elevated NLR correlates with disease activity and severity, supporting differentiation between active and inactive phases. 9 In uveitis, including idiopathic and HLA-B27–associated anterior uveitis, higher NLR values have been associated with both disease severity and systemic involvement. 10 , 11 Recently, NLR was reported as a potential prognostic factor for surgical intervention in pediatric patients with orbital cellulitis complicated by subperiosteal abscess. 12 However, to date, its role in lacrimal gland pathologies has not been investigated. This study aims to evaluate the differences in NLR values at presentation among patients with three major lacrimal gland pathologies: 13 lacrimal gland mucosa-associated lymphoid tissue (MALT) lymphoma, immunoglobulin G4 (IgG4)-related dacryoadenitis, and non-specific chronic dacryoadenitis. METHODS Ethics Approval The institutional review board (IRB) of Aichi Medical University Hospital approved this study, which was conducted in accordance with the tenets of the Declaration of Helsinki and its later amendments (approval number, 2025 − 116). The IRB granted a waiver of informed consent for this study based on the ethical guidelines for medical and health research involving human subjects established by the Japanese Ministry of Education, Culture, Sports, Science, and Technology; and by the Ministry of Health, Labour, and Welfare. The waiver was granted because the study was not an interventional study. Nevertheless, at the request of the IRB, an outline of the study was published on the Aichi Medical University website that was available for public viewing, which also gave the patients an option to refuse to participate in the study, although none did. Personal identifiers were removed from the records prior to data analysis. Study Design This study was a retrospective chart review of consecutive patients who underwent incisional lacrimal gland biopsy from June 2018 to August 2025. Complete blood counts, including neutrophils and lymphocytes values, were routinely obtained from June 2018 onward at our hospital. Imaging of all patients revealed an “almond-shaped” appearance of the lacrimal gland, indicating either lacrimal gland inflammation or lymphoma (Fig. 1 ). 14 The study included patients with confirmed clinical and pathological diagnosis of extranodal marginal zone lymphoma of MALT type, definite IgG4-related dacryoadenitis, or non-specific chronic dacryoadenitis. Definite IgG4-related dacryoadenitis was defined, based on the 2023 revised diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD), 15 as satisfaction of 1) imaging findings compatible with IgG4-ROD, 2) elevated serum IgG4 level (> 135 mg/dL), and 3) histopathological evidence, results including an IgG4-positive/IgG-positive cell ratio ≥ 40% or more than 50 IgG4-positive cells per high-power field (× 400). Non-specific chronic dacryoadenitis was diagnosed, based on chronic disease course (≥ 1 month), slow progression without acute inflammatory sign, and exclusion of other pathology of lacrimal gland enlargement, such as epithelial neoplasms, lymphoma, IgG4-ROD, sarcoidosis, Sjögren syndrome, TED, and anti-neutrophil cytoplasmic antibody-related diseases. 16 Exclusion criteria included other types of orbital lymphomas, IgG4-positive MALT lymphomas, possible or probable IgG4-related dacryoadenitis (without marked IgG4 positive cell infiltration or without elevation of serum IgG4 level), a history of steroid treatment, or incomplete clinical data. Since the main purpose of this study was to investigate the role of the NLR in differentiating lacrimal gland pathologies, patients with orbital lesions outside the lacrimal gland were excluded. For example, infraorbital nerve involvement is highly suggestive of IgG4-ROD, 17 and in such cases, NLR might play a weak role in the differential diagnosis. Similarly, cases with other lacrimal gland pathologies were excluded due to the small number of patients encountered in the study period, which would not provide sufficient statistical power. Data Collection Data collected included age, sex, laterality, blood test results, histopathological findings, and concomitant systemic involvement in MALT lymphomas and IgG4-related dacryoadenitis. Laterality was confirmed by both the medical records and imaging studies (computed tomography [CT] or magnetic resonance imaging) (Fig. 1 ). Pre-biopsy blood tests were performed to assess autoimmune antibodies and overall systemic status. NLR was calculated as neutrophil counts divided by lymphocyte count (). Systemic work-up was done using CT and/or positron emission tomography (PET). Statistical Analyses Patient data and measurement results were expressed as means ± standard deviations. Patient age and NLR were compared between patients with MALT lymphoma, IgG4-related dacryoadenitis, and non-specific chronic dacryoadenitis using one-way ANOVA and Tukey post-hoc test. The Mann–Whitney U test was applied to compare NLR values between groups stratified by sex, laterality (unilateral vs. bilateral), and the presence or absence of systemic lesions. All statistical analyses were performed using SPSS™ version 26 software (IBM Japan, Tokyo, Japan). Two-tailed P values < 0.05 were deemed to indicate statistical significance. RESULTS Patient characteristics, NLR values, and statistical results are summarized in Tables 1 – 3 . Out of 125 patients who underwent lacrimal gland biopsy during the study period, 54 met the inclusion criteria: 7 with MALT lymphoma, 26 with IgG4-related dacryoadenitis, and 21 with non-specific chronic dacryoadenitis. A total of 71 patients were excluded: 37 patients with other pathologies, 24 patients with orbital lesions outside the lacrimal gland, 2 patients with other types of orbital lymphomas, 2 patients with IgG4-positive MALT lymphomas, 5 patients with possible IgG4-ROD, and 1 patient with a history of steroid treatment. The mean patient age was 70.7 ± 15.3 years in MALT lymphoma, 56.2 ± 13.8 years in IgG4-related dacryoadenitis, and 49.3 ± 14.9 years in non-specific chronic dacryoadenitis. Patients with MALT lymphomas tended to be older than those with IgG4-ROD (P = 0.056) and non-specific chronic dacryoadenitis (P = 0.004). Unilateral involvement was observed in 2 patients with MALT lymphoma, 12 patients with IgG4-related dacryoadenitis, and 12 patients with non-specific chronic dacryoadenitis (P = 0.407). Systemic lesions were identified more in IgG4-related dacryoadenitis cases (P = 0.009). Table 1 Data on patient demographics, clinical characteristics and neutrophil-to-lymphocyte ratio (NLR) values. MALT lymphoma IgG4-related dacryoadenitis Non-specific dacryoadenitis P value Number of patients 7 26 21 Patient age (years) 70.7 ± 15.3 56.2 ± 13.8 49.3 ± 14.9 0.003 M/L 3/4 12/14 4/17 0.139 Unilateral/bilateral 2/5 12/14 12/9 0.407 Systemic lesions [(w/)/(w/o)] 1/6 9/17 0/21 0.009 NLR 3.209 ± 2.305 2.027 ± 0.667 2.232 ± 1.089 0.061 M, male; F, female; w/, with; w/o, without; MALT lymphoma, mucosa-associated lymphoid tissue lymphoma; IgG4, immunoglobulin G4 Table 2 Results of Tukey post-hoc test Age MALT lymphoma IgG4-related dacryoadenitis IgG4-related dacryoadenitis 0.056 - Non-specific dacryoadenitis 0.004 0.241 NLR MALT lymphoma IgG4-related dacryoadenitis IgG4-related dacryoadenitis 0.049 - Non-specific dacryoadenitis 0.133 0.815 MALT lymphoma, mucosa-associated lymphoid tissue lymphoma; IgG4, immunoglobulin G4 Table 3 Statistical comparison of neutrophil to lymphocyte ratio (NLR) values between the subgroups in immunoglobulin G4 (IgG4)-related dacryoadenitis Unilateral Bilateral P value NLR (IgG4-related dacryoadenitis) 2.241 ± 0.599 1.844 ± 0.687 0.118 Systemic lesion (-) Systemic lesion (+) P value 2.173 ± 0.728 1.751 ± 0.444 0.107 The mean NLR was 3.209 ± 2.305 in MALT lymphoma, 2.027 ± 0.667 in IgG4-related dacryoadenitis, and 2.232 ± 1.089 in non-specific chronic dacryoadenitis. Although the difference in NLR among the diseases did not reach statistical significance (P = 0.061), the post-hoc test revealed significantly higher NLR in MALT lymphoma, compared with IgG4-related dacryoadenitis (P = 0.049). Based on this result, NLR was compared between unilateral and bilateral cases, and between cases with and without systemic lesions in IgG4-related dacryoadenitis. We did not analyze them in MALT lymphomas because of inclusion of a small number of unilateral cases and cases with systemic lesions. Within IgG4-related dacryoadenitis group, NLR tended to be lower in bilateral than unilateral cases (1.844 ± 0.687 vs. 2.241 ± 0.599; P = 0.118) and in cases with compared to those without systemic lesions (1.751 ± 0.444 vs. 2.173 ± 0.728; P = 0.107), although these differences were not statistically significant. DISCUSSION NLR has emerged as a promising biomarker across multiple diseases including autoimmune, infectious and neoplastic conditions. 1 – 6 Our study extends this concept to lacrimal gland pathologies by evaluating the NLR in patients with lacrimal gland MALT lymphoma, IgG4-related dacryoadenitis, and non-specific chronic dacryoadenitis. Our findings indicate that NLR may differ among these conditions, showing a trend toward higher values in MALT lymphoma, compared with inflammatory dacryoadenitis, and reaching statistical significance when compared with IgG4-related dacryoadenitis. These results are consistent with previous reports identifying NLR as a marker of systemic and local inflammation and suggest its potential utility as an adjunctive tool for clinical assessment and risk stratification in lacrimal gland disorders. Systemic lymphoproliferative disorders have been consistently associated with elevated NLR levels. 18 , 19 An NLR cutoff of 2.3–4.2 at presentation has been identified as a predictive factor for poor prognosis, 20,21 and higher values have been significantly linked to disease stage, early-stage risk scoring, and treatment response. 20 A large meta-analysis further demonstrated that elevated NLR is strongly associated with worse overall and progression-free survival in patients with diffuse large B-cell lymphoma. To our knowledge, this is the first study to evaluate NLR in lacrimal gland MALT lymphoma. Despite the limited number of MALT cases in our cohort, our findings align with previous reports on systemic lymphomas, showing elevated NLR values (3.2) in lacrimal gland MALT lymphoma. Further large-scale studies are warranted to validate these observations and to assess the utility of NLR in monitoring disease progression and treatment response. The differentiation of lacrimal gland MALT lymphoma from inflammatory dacryoadenitis often presents a diagnostic challenge due to overlapping clinical and radiological features. In this context, our study introduces NLR as a potential supplementary bio-marker that could contribute to early risk stratification. While imaging and histopathology remain the gold standard, the simplicity and low cost of NLR make it an attractive adjunct in routine practice. The observation of higher NLR values in MALT lymphoma compared with IgG4-related and non-specific chronic dacryoadenitis emphasizes its possible role in raising clinical suspicion and guiding the decision to pursue biopsy. This may be particularly relevant in patients with subtle or indeterminate imaging findings, where invasive procedures are not immediately indicated. Interestingly, we observed that NLR tended to be lower in bilateral cases and in patients with systemic lesions among those with IgG4-related dacryoadenitis patients. These findings ae unexpected, as systemic inflammation is generally associated with higher NLR. This discrepancy may be attributable to the small sample size of our study, and the possibility of statistical variability. Another possible explanation is that systemic involvement may reflect a more chronic course with long-standing inflammation, where immune responses shift toward lymphocyte-predominant regulation. On the other hand, unilateral or isolated localized lacrimal gland disease could be an earlier or more acute stage dominated by neutrophils, thereby resulting in higher NLR values. This study has several limitations, including its retrospective design and the small sample size, particularly in the MALT lymphoma subgroup. Despite these limitations, our study provides new insights into the potential role of NLR in lacrimal gland pathologies. Larger, prospective studies are needed to further evaluate the utility of NLR as a diagnostic, prognostic, and treatment-response biomarker. In conclusion, our study demonstrates that NLR differs among lacrimal gland pathologies, with significantly higher values observed in MALT lymphoma, compared with IgG4-related dacryoadenitis, and a trend toward higher values than non-specific chronic dacryoadenitis. These findings suggest that NLR may serve as a simple marker to help distinguish lymphoproliferative from inflammatory lacrimal gland diseases. Declarations Funding: None. Conflicts of interest: Yasuhiro Takahashi received speaker and consultant honoraria from Amgen Inc., Chugai Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. The other author has no financial or conflicts of interest to disclose. Authors’ contributions: Conceptualization , Muhammad Abumanhal and Yasuhiro Takahashi; methodology , Muhammad Abumanhal and Yasuhiro Takahashi; data curation , Yasuhiro Takahashi; validation , Yasuhiro Takahashi; formal analysis , Yasuhiro Takahashi; investigation , Yasuhiro Takahashi; writing-original draft preparation , Muhammad Abumanhal; writing-review and editing , Yasuhiro Takahashi; supervision , Yasuhiro Takahashi; project administration , Yasuhiro Takahashi. All authors have read and agreed to the published version of the manuscript. No one contributed to the work who did not meet our authorship criteria. Meeting Presentation: None. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Declaration of Generative AI in scientific writing: The authors did not use generative AI and AI-assisted technologies in the writing process. 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Prognostic significance of pretreatment meutrophil/lymphocyte ratio and platelet/lymphocyte ratio in patients with diffuse large B-cell lymphoma. Biomed Res Int. 2018;2018:9651254. Additional Declarations There is conflict of interest 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. 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1","display":"","copyAsset":false,"role":"figure","size":3621111,"visible":true,"origin":"","legend":"\u003cp\u003eComputed tomographic images. \u003cstrong\u003ea. \u003c/strong\u003eUnilateral extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type. \u003cstrong\u003eb.\u003c/strong\u003eBilateral immunoglobulin G4-related dacryoadenitis. \u003cstrong\u003ec. \u003c/strong\u003eBilateral non-specific chronic dacryoadenitis. All lesions show almond-shaped appearance.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7666025/v1/440707f0a4bce4a058eb82c7.png"},{"id":100679779,"identity":"1e2dc9bc-f786-4b7c-b385-3419f4a19c6b","added_by":"auto","created_at":"2026-01-20 11:49:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3966086,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7666025/v1/529d41c9-f2cf-442b-9d6b-6c17cef78a8f.pdf"}],"financialInterests":"There is conflict of interest","formattedTitle":"Neutrophil-to-Lymphocyte Ratio as a Promising Marker in Lacrimal Gland Pathologies: Differentiating MALT Lymphoma from Dacryoadenitis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNeutrophils-to-lymphocytes ratio (NLR) is a simple index calculated from the differential white blood cell count, reflecting the balance between the innate (neutrophils) and adaptive (lymphocytes) immune responses.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Initially described by Zahorec in the early 2000s as a prognostic marker in cardiovascular disease,\u003csup\u003e2\u003c/sup\u003e NLR has since emerged as a widely studied biomarker across diverse medical fields, including oncology, infectious diseases, and autoimmune disorders.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Studies have demonstrated a significant correlation between NLR and established inflammatory markers, such as C-reactive protein.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Owing to its simplicity, low cost, and accessibility, NLR has gained recognition as a potential and attractive tool for early diagnosis, risk stratification, treatment monitoring, and clinical decision-making.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNLR has been investigated in a variety of ocular diseases with an inflammatory component. In thyroid eye disease (TED), elevated NLR correlates with disease activity and severity, supporting differentiation between active and inactive phases.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e In uveitis, including idiopathic and HLA-B27\u0026ndash;associated anterior uveitis, higher NLR values have been associated with both disease severity and systemic involvement.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Recently, NLR was reported as a potential prognostic factor for surgical intervention in pediatric patients with orbital cellulitis complicated by subperiosteal abscess.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, to date, its role in lacrimal gland pathologies has not been investigated.\u003c/p\u003e\u003cp\u003eThis study aims to evaluate the differences in NLR values at presentation among patients with three major lacrimal gland pathologies:\u003csup\u003e13\u003c/sup\u003e lacrimal gland mucosa-associated lymphoid tissue (MALT) lymphoma, immunoglobulin G4 (IgG4)-related dacryoadenitis, and non-specific chronic dacryoadenitis.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eEthics Approval\u003c/h2\u003e\u003cp\u003e The institutional review board (IRB) of Aichi Medical University Hospital approved this study, which was conducted in accordance with the tenets of the Declaration of Helsinki and its later amendments (approval number, 2025\u0026thinsp;\u0026minus;\u0026thinsp;116). The IRB granted a waiver of informed consent for this study based on the ethical guidelines for medical and health research involving human subjects established by the Japanese Ministry of Education, Culture, Sports, Science, and Technology; and by the Ministry of Health, Labour, and Welfare. The waiver was granted because the study was not an interventional study. Nevertheless, at the request of the IRB, an outline of the study was published on the Aichi Medical University website that was available for public viewing, which also gave the patients an option to refuse to participate in the study, although none did. Personal identifiers were removed from the records prior to data analysis.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eThis study was a retrospective chart review of consecutive patients who underwent incisional lacrimal gland biopsy from June 2018 to August 2025. Complete blood counts, including neutrophils and lymphocytes values, were routinely obtained from June 2018 onward at our hospital. Imaging of all patients revealed an \u0026ldquo;almond-shaped\u0026rdquo; appearance of the lacrimal gland, indicating either lacrimal gland inflammation or lymphoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The study included patients with confirmed clinical and pathological diagnosis of extranodal marginal zone lymphoma of MALT type, definite IgG4-related dacryoadenitis, or non-specific chronic dacryoadenitis. Definite IgG4-related dacryoadenitis was defined, based on the 2023 revised diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD),\u003csup\u003e15\u003c/sup\u003e as satisfaction of 1) imaging findings compatible with IgG4-ROD, 2) elevated serum IgG4 level (\u0026gt;\u0026thinsp;135 mg/dL), and 3) histopathological evidence, results including an IgG4-positive/IgG-positive cell ratio\u0026thinsp;\u0026ge;\u0026thinsp;40% or more than 50 IgG4-positive cells per high-power field (\u0026times; 400). Non-specific chronic dacryoadenitis was diagnosed, based on chronic disease course (\u0026ge;\u0026thinsp;1 month), slow progression without acute inflammatory sign, and exclusion of other pathology of lacrimal gland enlargement, such as epithelial neoplasms, lymphoma, IgG4-ROD, sarcoidosis, Sj\u0026ouml;gren syndrome, TED, and anti-neutrophil cytoplasmic antibody-related diseases.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Exclusion criteria included other types of orbital lymphomas, IgG4-positive MALT lymphomas, possible or probable IgG4-related dacryoadenitis (without marked IgG4 positive cell infiltration or without elevation of serum IgG4 level), a history of steroid treatment, or incomplete clinical data. Since the main purpose of this study was to investigate the role of the NLR in differentiating lacrimal gland pathologies, patients with orbital lesions outside the lacrimal gland were excluded. For example, infraorbital nerve involvement is highly suggestive of IgG4-ROD,\u003csup\u003e17\u003c/sup\u003e and in such cases, NLR might play a weak role in the differential diagnosis. Similarly, cases with other lacrimal gland pathologies were excluded due to the small number of patients encountered in the study period, which would not provide sufficient statistical power.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eData collected included age, sex, laterality, blood test results, histopathological findings, and concomitant systemic involvement in MALT lymphomas and IgG4-related dacryoadenitis. Laterality was confirmed by both the medical records and imaging studies (computed tomography [CT] or magnetic resonance imaging) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Pre-biopsy blood tests were performed to assess autoimmune antibodies and overall systemic status. NLR was calculated as neutrophil counts divided by lymphocyte count (). Systemic work-up was done using CT and/or positron emission tomography (PET).\u003c/p\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003ePatient data and measurement results were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Patient age and NLR were compared between patients with MALT lymphoma, IgG4-related dacryoadenitis, and non-specific chronic dacryoadenitis using one-way ANOVA and Tukey post-hoc test. The Mann\u0026ndash;Whitney U test was applied to compare NLR values between groups stratified by sex, laterality (unilateral vs. bilateral), and the presence or absence of systemic lesions. All statistical analyses were performed using SPSS\u0026trade; version 26 software (IBM Japan, Tokyo, Japan). Two-tailed \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were deemed to indicate statistical significance.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003ePatient characteristics, NLR values, and statistical results are summarized in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Out of 125 patients who underwent lacrimal gland biopsy during the study period, 54 met the inclusion criteria: 7 with MALT lymphoma, 26 with IgG4-related dacryoadenitis, and 21 with non-specific chronic dacryoadenitis. A total of 71 patients were excluded: 37 patients with other pathologies, 24 patients with orbital lesions outside the lacrimal gland, 2 patients with other types of orbital lymphomas, 2 patients with IgG4-positive MALT lymphomas, 5 patients with possible IgG4-ROD, and 1 patient with a history of steroid treatment. The mean patient age was 70.7\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3 years in MALT lymphoma, 56.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8 years in IgG4-related dacryoadenitis, and 49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9 years in non-specific chronic dacryoadenitis. Patients with MALT lymphomas tended to be older than those with IgG4-ROD (P\u0026thinsp;=\u0026thinsp;0.056) and non-specific chronic dacryoadenitis (P\u0026thinsp;=\u0026thinsp;0.004). Unilateral involvement was observed in 2 patients with MALT lymphoma, 12 patients with IgG4-related dacryoadenitis, and 12 patients with non-specific chronic dacryoadenitis (P\u0026thinsp;=\u0026thinsp;0.407). Systemic lesions were identified more in IgG4-related dacryoadenitis cases (P\u0026thinsp;=\u0026thinsp;0.009).\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\u003eData on patient demographics, clinical characteristics and neutrophil-to-lymphocyte ratio (NLR) values.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMALT lymphoma\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIgG4-related dacryoadenitis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNon-specific dacryoadenitis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient age (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70.7\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3/4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4/17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.139\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnilateral/bilateral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12/9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.407\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystemic lesions [(w/)/(w/o)]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9/17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNLR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.209\u0026thinsp;\u0026plusmn;\u0026thinsp;2.305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.027\u0026thinsp;\u0026plusmn;\u0026thinsp;0.667\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.232\u0026thinsp;\u0026plusmn;\u0026thinsp;1.089\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.061\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eM, male; F, female; w/, with; w/o, without; MALT lymphoma, mucosa-associated lymphoid tissue lymphoma; IgG4, immunoglobulin G4\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\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\u003eResults of Tukey post-hoc test\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMALT lymphoma\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIgG4-related dacryoadenitis\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG4-related dacryoadenitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.056\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-specific dacryoadenitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.241\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNLR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMALT lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIgG4-related dacryoadenitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG4-related dacryoadenitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-specific dacryoadenitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.133\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.815\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eMALT lymphoma, mucosa-associated lymphoid tissue lymphoma; IgG4, immunoglobulin G4\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStatistical comparison of neutrophil to lymphocyte ratio (NLR) values between the subgroups in immunoglobulin G4 (IgG4)-related dacryoadenitis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnilateral\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBilateral\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eNLR (IgG4-related dacryoadenitis)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.241\u0026thinsp;\u0026plusmn;\u0026thinsp;0.599\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.844\u0026thinsp;\u0026plusmn;\u0026thinsp;0.687\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.118\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSystemic lesion (-)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSystemic lesion (+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.173\u0026thinsp;\u0026plusmn;\u0026thinsp;0.728\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.751\u0026thinsp;\u0026plusmn;\u0026thinsp;0.444\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.107\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe mean NLR was 3.209\u0026thinsp;\u0026plusmn;\u0026thinsp;2.305 in MALT lymphoma, 2.027\u0026thinsp;\u0026plusmn;\u0026thinsp;0.667 in IgG4-related dacryoadenitis, and 2.232\u0026thinsp;\u0026plusmn;\u0026thinsp;1.089 in non-specific chronic dacryoadenitis. Although the difference in NLR among the diseases did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.061), the post-hoc test revealed significantly higher NLR in MALT lymphoma, compared with IgG4-related dacryoadenitis (P\u0026thinsp;=\u0026thinsp;0.049). Based on this result, NLR was compared between unilateral and bilateral cases, and between cases with and without systemic lesions in IgG4-related dacryoadenitis. We did not analyze them in MALT lymphomas because of inclusion of a small number of unilateral cases and cases with systemic lesions. Within IgG4-related dacryoadenitis group, NLR tended to be lower in bilateral than unilateral cases (1.844\u0026thinsp;\u0026plusmn;\u0026thinsp;0.687 vs. 2.241\u0026thinsp;\u0026plusmn;\u0026thinsp;0.599; P\u0026thinsp;=\u0026thinsp;0.118) and in cases with compared to those without systemic lesions (1.751\u0026thinsp;\u0026plusmn;\u0026thinsp;0.444 vs. 2.173\u0026thinsp;\u0026plusmn;\u0026thinsp;0.728; P\u0026thinsp;=\u0026thinsp;0.107), although these differences were not statistically significant.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNLR has emerged as a promising biomarker across multiple diseases including autoimmune, infectious and neoplastic conditions.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Our study extends this concept to lacrimal gland pathologies by evaluating the NLR in patients with lacrimal gland MALT lymphoma, IgG4-related dacryoadenitis, and non-specific chronic dacryoadenitis. Our findings indicate that NLR may differ among these conditions, showing a trend toward higher values in MALT lymphoma, compared with inflammatory dacryoadenitis, and reaching statistical significance when compared with IgG4-related dacryoadenitis. These results are consistent with previous reports identifying NLR as a marker of systemic and local inflammation and suggest its potential utility as an adjunctive tool for clinical assessment and risk stratification in lacrimal gland disorders.\u003c/p\u003e\u003cp\u003eSystemic lymphoproliferative disorders have been consistently associated with elevated NLR levels.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e An NLR cutoff of 2.3\u0026ndash;4.2 at presentation has been identified as a predictive factor for poor prognosis,\u003csup\u003e20,21\u003c/sup\u003e and higher values have been significantly linked to disease stage, early-stage risk scoring, and treatment response.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e A large meta-analysis further demonstrated that elevated NLR is strongly associated with worse overall and progression-free survival in patients with diffuse large B-cell lymphoma. To our knowledge, this is the first study to evaluate NLR in lacrimal gland MALT lymphoma. Despite the limited number of MALT cases in our cohort, our findings align with previous reports on systemic lymphomas, showing elevated NLR values (3.2) in lacrimal gland MALT lymphoma. Further large-scale studies are warranted to validate these observations and to assess the utility of NLR in monitoring disease progression and treatment response.\u003c/p\u003e\u003cp\u003eThe differentiation of lacrimal gland MALT lymphoma from inflammatory dacryoadenitis often presents a diagnostic challenge due to overlapping clinical and radiological features. In this context, our study introduces NLR as a potential supplementary bio-marker that could contribute to early risk stratification. While imaging and histopathology remain the gold standard, the simplicity and low cost of NLR make it an attractive adjunct in routine practice. The observation of higher NLR values in MALT lymphoma compared with IgG4-related and non-specific chronic dacryoadenitis emphasizes its possible role in raising clinical suspicion and guiding the decision to pursue biopsy. This may be particularly relevant in patients with subtle or indeterminate imaging findings, where invasive procedures are not immediately indicated.\u003c/p\u003e\u003cp\u003eInterestingly, we observed that NLR tended to be lower in bilateral cases and in patients with systemic lesions among those with IgG4-related dacryoadenitis patients. These findings ae unexpected, as systemic inflammation is generally associated with higher NLR. This discrepancy may be attributable to the small sample size of our study, and the possibility of statistical variability. Another possible explanation is that systemic involvement may reflect a more chronic course with long-standing inflammation, where immune responses shift toward lymphocyte-predominant regulation. On the other hand, unilateral or isolated localized lacrimal gland disease could be an earlier or more acute stage dominated by neutrophils, thereby resulting in higher NLR values.\u003c/p\u003e\u003cp\u003eThis study has several limitations, including its retrospective design and the small sample size, particularly in the MALT lymphoma subgroup. Despite these limitations, our study provides new insights into the potential role of NLR in lacrimal gland pathologies. Larger, prospective studies are needed to further evaluate the utility of NLR as a diagnostic, prognostic, and treatment-response biomarker.\u003c/p\u003e\u003cp\u003eIn conclusion, our study demonstrates that NLR differs among lacrimal gland pathologies, with significantly higher values observed in MALT lymphoma, compared with IgG4-related dacryoadenitis, and a trend toward higher values than non-specific chronic dacryoadenitis. These findings suggest that NLR may serve as a simple marker to help distinguish lymphoproliferative from inflammatory lacrimal gland diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e Yasuhiro Takahashi received speaker and consultant honoraria from Amgen Inc., Chugai Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. The other author has no financial or conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions:\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConceptualization\u003c/strong\u003e, Muhammad Abumanhal and Yasuhiro Takahashi; \u003cstrong\u003emethodology\u003c/strong\u003e, Muhammad Abumanhal and Yasuhiro Takahashi; \u003cstrong\u003edata curation\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003evalidation\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003eformal analysis\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003einvestigation\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003ewriting-original draft preparation\u003c/strong\u003e, Muhammad Abumanhal;\u003cstrong\u003e\u0026nbsp;writing-review and editing\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003esupervision\u003c/strong\u003e, Yasuhiro Takahashi; \u003cstrong\u003eproject administration\u003c/strong\u003e, Yasuhiro Takahashi. All authors have read and agreed to the published version of the manuscript. No one contributed to the work who did not meet our authorship criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeeting Presentation:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Generative AI in scientific writing:\u0026nbsp;\u003c/strong\u003eThe authors did not use generative AI and AI-assisted technologies in the writing process.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBuonacera A, Stancanelli B, Colaci M \u0026amp; Malatino L. Neutrophil to lymphocyte ratio: An emerging marker of the relationships between the immune system and diseases. Int J Mol Sci. 2022;23:3636.\u003c/li\u003e\n\u003cli\u003eZahorc R. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy. 2001;102:5\u0026ndash;14.\u003c/li\u003e\n\u003cli\u003eHolub M, Beran O, Kaspř\u0026iacute;kov\u0026aacute; N \u0026amp; Chalupa P. Neutrophil to lymphocyte count ratio as a biomarker of bacterial infections. Cent Eur J Med\u003cem\u003e. \u003c/em\u003e2012;7:258\u0026ndash;261.\u003c/li\u003e\n\u003cli\u003eLiu X, Shen Y, Wang H, Ge Q, Fei A \u0026amp; Pan S. Prognostic significance of neutrophil-to-lymphocyte ratio in patients with sepsis: A prospective observational study. Mediat Inflamm. 2016:201;8191254.\u003c/li\u003e\n\u003cli\u003eMazaki J, Katsumata K, Kasahara K, Tago T, Wada T, Kuwabara H, et al. Neutrophil-to-lymphocyte ratio is a prognostic factor for colon cancer: a propensity score analysis. BMC Cancer. 2020;20:922.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Amico E, Zangh\u0026igrave; A, Romano A, Sciandra M, Palumbo GAM \u0026amp; Patti F. The neutrophil-to-lymphocyte ratio is related to disease activity in relapsing remitting multiple sclerosis. Cells. 2019;8:1114.\u003c/li\u003e\n\u003cli\u003eArshad RG \u0026amp; Toori KU. Correlation between neutrophil to lymphocyte ratio and C-reactive protein in diverse disease states in hospitalized patients. Pak J Med Sci. 2024;40:1989\u0026ndash;1993.\u003c/li\u003e\n\u003cli\u003eBeberashvili I, Omar MA, Nizri E, Stav K \u0026amp; Efrati S. Combined use of CRP with neutrophil-to-lymphocyte ratio in differentiating between infectious and noninfectious inflammation in hemodialysis patients. Sci Rep. 2023;13:5463.\u003c/li\u003e\n\u003cli\u003eZhang X, Han C, Wang H, Sun X, Dou X, He X, et al. The correlation of the neutrophil-lymphocyte ratio to clinical and imaging parameters in patients with thyroid eye disease. Endocr Connect. 2022;11:e220260.\u003c/li\u003e\n\u003cli\u003eOzgonul C, Sertoglu E, Ayyildiz O, Mumcuoglu T, Kucukevcilioglu M, Gokce G, et al. Novel biomarkers for patients with idiopathic acute anterior uveitis: neutrophil to lymphocyte ratio and platelet to lymphocyte ratio. Int J Ophthalmol. 2017;10:262\u0026ndash;266.\u003c/li\u003e\n\u003cli\u003eVaradisai V, Somkijrungroj T \u0026amp; Kongwattananon W. Diagnostic value of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in HLA-B27-associated acute anterior uveitis. Clin Ophthalmol. 2025;19:1467\u0026ndash;1474.\u003c/li\u003e\n\u003cli\u003eAbumanhal M, Leibovitch I, Niry D, Ahmad NS, Mezad-Koursh D, Zipori AB, et al. Management of subperiosteal orbital abscess in pediatric population: A comparative study. Can J Ophthalmol. 2025 Jul 14 (Online ahead of print).\u003c/li\u003e\n\u003cli\u003eChung SR, Kim GJ, Choi YJ, Cho KJ, Suh CH, Kim SC, et al. Clinical and radiological features of diffuse lacrimal gland enlargement: comparisons among various etiologies in 91 biopsy-confirmed patients. Korean J Radiol. 2022;23:976\u0026ndash;985.\u003c/li\u003e\n\u003cli\u003ePakdaman MN, Sepahdari AR \u0026amp; Elkhamary SM. Orbital inflammatory disease: Pictorial review and differential diagnosis. World J Radiol. 2014;6:106\u0026ndash;115.\u003c/li\u003e\n\u003cli\u003eTakahira M, Goto H \u0026amp; Azumi A. The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2024;68:293\u0026ndash;301.\u003c/li\u003e\n\u003cli\u003eMombaerts I, Bilyk JR, Rose GE, McNab AA, Fay A, Dolman PJ, et al. Consensus on diagnostic criteria of idiopathic orbital inflammation using a modified Delphi approach. JAMA Ophthalmol. 2017;135:769\u0026ndash;776.\u003c/li\u003e\n\u003cli\u003eOhshima K, Sogabe Y \u0026amp; Sato Y. The usefulness of infraorbital nerve enlargement on MRI imaging in clinical diagnosis of IgG4-related orbital disease. Jpn J Ophthalmol. 2012;56:380\u0026ndash;382. \u003c/li\u003e\n\u003cli\u003eWang J, Zhou X, Liu Y, Li Z \u0026amp; Li X. Prognostic significance of neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma: A meta-analysis. PLoS One. 2017 25;12:e0176008.\u003c/li\u003e\n\u003cli\u003eLee SF \u0026amp; Luque-Fernandez MA. Prognostic value of lymphocyte-to-monocyte ratio and neutrophil-to-lymphocyte ratio in follicular lymphoma: a retrospective cohort study. BMJ Open. 2017;7:e017904.\u003c/li\u003e\n\u003cli\u003eDogan A \u0026amp; Demircioglu S. Assessment of the neutrophil-lymphocyte ratio in classic Hodgkin lymphoma patients. Pak J Med Sci. 2019;35:1270\u0026ndash;1275.\u003c/li\u003e\n\u003cli\u003eWang S, Ma Y, Sun L, Shi Y, Jiang S, Yu K, et al. Prognostic significance of pretreatment meutrophil/lymphocyte ratio and platelet/lymphocyte ratio in patients with diffuse large B-cell lymphoma. Biomed Res Int. 2018;2018:9651254.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neutrophil-to-lymphocyte ratio, mucosa-associated lymphoid tissue lymphoma, immunoglobulin G4-related dacryoadenitis, non-specific chronic dacryoadenitis ","lastPublishedDoi":"10.21203/rs.3.rs-7666025/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7666025/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground/Objectives: \u003c/strong\u003eTo investigate the role of the neutrophil-to-lymphocyte ratio (NLR) in differentiating lacrimal gland pathologies, specifically mucosa-associated lymphoid tissue (MALT) lymphoma, immunoglobulin G4 (IgG4)-related dacryoadenitis, and non-specific chronic dacryoadenitis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubjects/Methods: \u003c/strong\u003eThis retrospective chart review included 54 patients with only lacrimal gland lesions who underwent lacrimal gland biopsy. Eligible cases were those with confirmed diagnoses of lacrimal gland MALT lymphoma (7 patients), definite IgG4-related dacryoadenitis (26 patients), or non-specific chronic dacryoadenitis (21 patients). Clinical data, imaging findings, laboratory results, and histopathological reports were reviewed. NLR was calculated from blood counts at presentation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eMean NLR values were 3.21 ± 2.31 in MALT lymphoma, 2.03 ± 0.67 in IgG4-related dacryoadenitis, and 2.23 ± 1.09 in non-specific chronic dacryoadenitis. Although the overall difference did not reach statistical significance (P = 0.061), post-hoc analysis revealed a significantly higher NLR in MALT lymphoma, compared with IgG4-related dacryoadenitis (P = 0.049). In IgG4-related dacryoadenitis, NLR tended to be lower in bilateral cases (P = 0.118) and in patients with systemic lesions (P = 0.107), though these differences were not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eNLR may serve as a simple biomarker to help distinguish lacrimal gland MALT lymphoma from dacryoadenitis, particularly IgG4-related dacryoadenitis. These results, while promising, should be validated through large-scale, prospective studies to better define the diagnostic and prognostic utility of NLR in lacrimal gland pathologies.\u003c/p\u003e","manuscriptTitle":"Neutrophil-to-Lymphocyte Ratio as a Promising Marker in Lacrimal Gland Pathologies: Differentiating MALT Lymphoma from Dacryoadenitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 16:15:20","doi":"10.21203/rs.3.rs-7666025/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":"243de497-590b-4ea9-aae7-ea99222e655f","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55676963,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":55676964,"name":"Health sciences/Diseases/Immunological disorders/Autoimmune diseases"}],"tags":[],"updatedAt":"2026-01-20T10:08:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-15 16:15:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7666025","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7666025","identity":"rs-7666025","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}