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.

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 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).

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.

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).

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.

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.