We thank Dr. Bijnya Birajita PANDA for the thought-ful comments regarding our article and for the opportunity to further discuss the diagnostic challenges associated with ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) and IgG4-related ophthalmic disease (IgG4-ROD).
We are pleased that the correspondence highlights several issues that are highly consistent with the conclusions and limitations discussed in our study. As correctly noted by Dr. Panda, the distinction between OAML and IgG4-ROD remains challenging in selected patients because substantial overlap may exist in clinical presentation, imaging findings, and serologic features. Indeed, this diagnostic ambiguity was one of the primary motivations for our investigation. Although our study identified characteristic patterns favoring each disease entity, we emphasized that no single clinical, laboratory, or radiologic feature is sufficient for definitive diagnosis and that histopathologic examination remains the diagnostic reference standard.
We appreciate the authors’ observation that lesions strongly suggestive of lymphoma on clinical and radiologic grounds may ultimately be diagnosed as IgG4-ROD following histopathologic evaluation. We fully agree, and indeed this diagnostic uncertainty was one of the principal motivations for our study. The substantial overlap in clinical presentation, imaging characteristics, and even selected laboratory findings between OAML and IgG4-ROD makes reliable prebiopsy differentiation challenging in routine practice. Rather than suggesting that clinical or imaging findings alone can establish a definitive diagnosis, our study sought to identify features that may improve diagnostic discrimination while acknowledging that histopathologic examination remains the reference standard. Therefore, we view the authors’ clinical experience as complementary to, rather than divergent from, the central message of our study.
The correspondence further highlights the biologic overlap between OAML and IgG4-ROD. Notably, our study identified a subset of OAML cases with elevated serum IgG4 levels and prominent IgG4-positive plasma-cell infiltration despite lacking the characteristic histopathologic features required for the diagnosis of IgG4-ROD. These findings support the possibility that chronic immune stimulation and lymphoid neoplasia may, in selected cases, share overlapping pathogenic mechanisms. We agree that this area warrants further investigation through integrated molecular, immunologic, and translational studies.
Regarding artificial intelligence, we fully concur that AI should be regarded as a complementary tool rather than a substitute for tissue diagnosis. Importantly, our pathology-informed multimodal framework was not designed to replace biopsy. Instead, its purpose is to provide decision support in clinically ambiguous cases and to improve prebiopsy risk stratification. As acknowledged in our manuscript, the retrospective single-center design and absence of external validation represent important limitations, and prospective multicenter studies will be necessary before broader clinical implementation can be considered.
We sincerely thank Dr. Panda for the constructive comments and for emphasizing the continued importance of multidisciplinary evaluation in orbital lymphoproliferative disease.
CRediT authorship contribution statement
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