Non-Hodgkin's lymphoma (NHL) includes a diverse group of diseases originating from lymphoid tissues, encompassing a wide range of histological subtypes and clinical presentations. In 85-90% of cases, NHL arises from B-cells, with less frequent occurrences from natural killer and T-cells. The pathogenesis of NHL is multifactorial, involving genetic, environmental and immunological factors. Chromosomal translocations, gene mutations and dysregulated signaling pathways, such as the B-cell receptor pathway, the NF-κB pathway, and the PI3K-AKT-mTOR pathway, contribute to the overall development of NHL. These alterations disrupt normal cellular processes, leading to uncontrolled proliferation and the survival of malignant lymphocytes (1).

As one of the most prevalent hematological conditions worldwide, NHL poses significant diagnostic and therapeutic challenges due to its heterogeneous nature and variable clinical courses. NHL accounts for 3-4% of all cancer cases annually, with notable geographic and ethnic variations in incidence, placing it among the top ten most common malignancies in developed countries. The overall incidence of NHL has continued to increase over the past few decades, partly due to improved diagnostic techniques and changes in risk factors (2). Moreover, NHL-associated deaths account for ~2.5% of all cancer-related deaths (3). While NHL commonly affects the lymph nodes, extranodal involvement may occur in various organs and tissues throughout the body, including the ocular adnexa. Among these extranodal sites, the lacrimal sac represents a rare, yet clinically significant location for NHL development (4).

The lacrimal sac, located in the medial canthal region of the orbit, is crucial for tear drainage into the nasolacrimal duct. Positioned within the anteromedial orbit wall, it resides within a concave fossa bordered by the anterior and posterior lacrimal crests, separated by the lacrimomaxillary suture (5). Notably, there are histological similarities with the nasolacrimal duct, and the conical portion within this fossa is identified as the lacrimal sac. Encased laterally by the lacrimal fascia and posteriorly by the common fascia of Horner's muscle, it forms the lacrimal diaphragm (6). The sac measures 9.8-11.0 mm in height, 7.5 mm in anteroposterior diameter and 3.0-4.9 mm in horizontal diameter, featuring a lining composed of stratified columnar epithelium with goblet cells, serous glands and cilia (7). Elastic fibers within the lamina propria aid in its function as a pump (8), while the submucosa contains lacrimal drainage-associated lymphoid tissue, contributing to the defense of the nasolacrimal system (9) (Fig. 1).

Primary NHL of the lacrimal sac is uncommon, with the majority of cases arising secondary to systemic lymphoproliferative disorders (10). NHL subtypes that affect the lacrimal sac include diffuse large B-cell lymphoma (DLBCL), extranodal marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Due to its proximity to the nasal cavity, the lacrimal sac is vulnerable to mucosa-associated lymphoid tissue (MALT) lymphoma, a subset of extranodal MZL. Despite its small size, the lacrimal sac accumulates lymphoid tissue and participates in immune surveillance, predisposing it to MALT lymphoma (11). The clinical presentation of lacrimal sac NHL is often indicative of a benign condition, such as dacryocystitis or nasolacrimal duct obstruction, leading to complexities in diagnosis and delayed identification. In addition, the effective management of lacrimal sac NHL requires a multidisciplinary approach, involving ophthalmologists, otolaryngologists, oncologists, pathologists and radiation oncologists, to ensure accuracy in diagnosis, staging and treatment.

The present review aimed to provide a comprehensive overview of lacrimal sac NHL, encapsulating the epidemiology, clinical manifestations, diagnostic modalities, histopathological features, treatment strategies and prognosis. Through the analysis of previous literature and clinical experience, the present review aimed to provide current insight into this disease, and determine potential future investigations to improve patient outcomes.

In the early stages of NHL, patients may not experience symptoms. However, the majority of patients with NHL typically present with concurrent lymphadenopathy and potential B symptoms. Notably, pain is not commonly reported. Additional symptoms may manifest depending on the organ involved (25).

When the lacrimal sac is affected, specific symptoms often include epiphora, persistent edema or a mass in the medial canthal region, redness or irritation of the eye, discharge from the inner corner of the eye (clear, mucoid or purulent), recurrent eye infections, pain or discomfort around the eye and eyelid ptosis (26). Occasionally, initial symptoms may manifest as acute dacryocystitis (27) or individuals may experience recurrent episodes of dacryocystitis (28). In the case that lacrimal sac NHL extends into adjacent structures of the eye or the nose, or involves blood vessels within the lacrimal sac area, additional symptoms may be experienced by patients. These symptoms may include decreased visual accuracy, diplopia/visual disturbances, proptosis/displacement of the eye, retrobulbar resistance or chemosis, as well as symptoms affecting the nasal cavity, such as sinusitis, nasal obstruction and epistaxis (Table II) (29).

The diagnosis of lacrimal sac tumors may be challenging. In the absence of a palpable mass, experienced ophthalmologists may negate various factors. Lymphoma may originate from lacrimal drainage-associated lymphoid tissue, potentially causing epiphora without a palpable mass in the early stages (30). Dacryocystography (DCG) is used to reveal a filling defect indicative of a lacrimal sac tumor (31), while blood-stained discharge is often indicative of advanced disease stages. A palpable mass or edema, particularly above the medial canthal tendon, is a key indicator of a lacrimal tumor.

Conditions affecting the lacrimal sac exhibit considerable variation, yet their symptomatology often remains consistent across cases. A diverse range of tumor types may occur within this system, broadly classified into three groups; namely, primary epithelial, primary non-epithelial and inflammatory lesions. Primary epithelial tumors commonly include squamous cell carcinoma, papilloma and transitional cell carcinoma. Primary non-epithelial tumors include malignant lymphoma, fibrous histiocytoma and malignant melanoma. Inflammatory lesions often consist of sarcoidosis, Wegener granulomatosis and pyogenic granuloma (32).

Given the nature of lacrimal sac pathologies, a comprehensive medical history and thorough physical examination are essential for an accurate diagnosis. Ancillary diagnostic tools, such as DCG, CT and magnetic resonance imaging (MRI), are crucial in guiding diagnosis and for treatment planning by providing detailed anatomical information (33). However, an incisional biopsy of the lesion for histopathological and cytological examination remains the gold standard for a definitive diagnosis, particularly in suspected tumor cases (34). This approach is crucial for guiding the formulation of the most appropriate treatment strategy.

The early detection and diagnosis of lacrimal sac NHL are crucial for optimizing treatment outcomes, preserving the quality of life and improving the overall prognosis of patients. Timely intervention enables healthcare providers to develop personalized treatment plans, prevent disease progression and minimize complications, such as local invasion, the requirement for reconstruction and metastasis to distant sites. With early diagnosis, patients may have a higher chance of achieving complete remission and may experience fewer symptoms. Moreover, early detection may reduce healthcare costs associated with aggressive late-stage treatments, and provide patients and their families with timely counseling, improving their overall understanding of the condition. Therefore, regular eye examinations and the prompt evaluation of any concerning symptoms are essential for individuals who are at risk of developing lacrimal sac NHL, such as those with a history of chronic dacryocystitis, previous radiation therapy to the head and neck, immunodeficiency disorders, or a family history of lymphoproliferative diseases (2).

The prognosis of lacrimal sac NHL is dependent on tumor type, malignancy, disease stage, tumor grade and the overall health of the patient. IPI is a useful tool for outcome predictions, as stated by the International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993(35). This project accounts for several factors, including age (as patients >60 years of age may exhibit a poorer prognosis), performance status (as a poorer performance status may be indicative of a worse prognosis), stage of disease, serum lactate dehydrogenase (LDH) levels, with elevations associated with a poorer prognosis, and number of extranodal sites involved, as the involvement of multiple extranodal sites may be indicative of a worse prognosis. Each of these factors is assigned a score, and the total score is used to categorize patients into low-, intermediate- or high-risk groups (35). Patient grouping aids clinicians in determining appropriate treatment strategies and predicting patient outcomes.

The IPI was structured around patients receiving cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine) and prednisone (CHOP) chemotherapy. Notably, the addition of the chimeric anti-CD20 monoclonal antibody, rituximab, to traditional CHOP chemotherapy (R-CHOP) may be used in some patients (36). The restructuring of the IPI parameters into a revised version (R-IPI) yields a more clinically insightful prognosis. The R-IPI stratifies patients into three distinct prognostic groups, namely, very favorable [4-year progression-free survival (PFS), 94%; overall survival (OS), 94%]; favorable (4-year PFS, 80%; OS, 79%); and unfavorable (4-year PFS, 53%; OS, 55%) outcomes (37).

The pathogenesis of lacrimal sac NHL is characterized by a dysregulated lymphocyte proliferation within the lacrimal sac, culminating in tumor formation. While the precise etiology remains elusive, a complex interplay of factors contributes to its development. Immunodeficiency, stemming from conditions, such as HIV/AIDS (38) or post-organ transplantation immunosuppression (39), creates a conducive environment for lymphoma emergence. Chronic inflammation, often associated with conditions such as chronic dacryocystitis, may exacerbate lymphocyte activation and proliferation, thus promoting tumorigenesis (40). Infectious agents, including Epstein-Barr virus and human herpesvirus 8, are implicated in the pathogenesis of NHL, with the potential to direct stimulate lymphocyte proliferation and malignant transformation (41).

Genetic predisposition also plays a role, with alterations in lymphocyte regulatory genes promoting uncontrolled cell growth and tumor initiation. Notably, various genetic susceptibility loci for DLBCL have been identified through genome-wide association studies, and these have highlighted the role of pathways associated with immune recognition and immune function (42). Moreover, environmental factors, such as exposure to certain toxins or chemicals, may contribute to the development of NHL; however, this notion remains to be fully elucidated.

Risk factors, such as advanced age, may increase the susceptibility to lacrimal sac NHL development, due to immunosenescence and accumulated genetic mutations. Females also exhibit a higher predisposition to this disease. In addition, individuals with a previous history of lymphoma or other hematologic malignancies may also be at an increased risk, as a result of hormonal factors and potential shared genetic predispositions. Autoimmune diseases, such as Sjögren's syndrome, which involve chronic inflammation and immune dysregulation, further increase the susceptibility to lacrimal sac NHL development (43). In addition, systemic immunosuppression and certain medications may compromise immune surveillance, promoting lymphoma development. Occupational exposures with potential carcinogenic agents, such as pesticides, solvents, dyes, engine exhaust, wood dust, wood finishing chemicals and various microbes, are also associated with an increased risk of this disease. The identification of specific agents remains challenging (44).

Overall, the pathogenesis and risk factors for lacrimal sac NHL are multifaceted, encompassing a dynamic interplay of immunological, environmental, genetic and infectious elements. Understanding these complex mechanisms is crucial for elucidating disease progression and developing targeted therapeutic interventions.

Numerous factors have been identified as independent predictive indicators of a poor OS in cases of ocular NHL. Factors include a patient age of >59, elevated LDH levels, advanced tumor stage, high-grade histological subgroups and the presence of B symptoms. Specifically, in ocular adnexal DLBCL, concurrent bone marrow involvement is recognized as an independent adverse prognostic factor (45). Furthermore, p53 expression levels are associated with the presence of the Ki-67 antigen, and this association is indicative of clinical outcomes (46).

Disease localization may affect the survival rates of patients, with a notably high 5-year survival rate of 90.9% when the disease is confined to one area. However, prognosis is less favorable in patients with advanced-stage disease, with a 5-year survival rate of 23.5% (47). In the broader category of lacrimal sac lymphomas, the overall 5-year survival rate is 65% (14). Notably, female patients with lymphoma affecting the lacrimal drainage system may experience more pronounced symptoms and demonstrate a heightened likelihood of disease recurrence. However, the precise association between this tumor and hormonal response remains to be established (48,49).

During a clinical examination, distinguishing between benign and malignant lymphoid lesions remains challenging. Thus, obtaining a tumor biopsy is imperative for accurate diagnosis and the initiation of required systemic assessments.

Due to cost and limited accessibility, the implementation of molecular approaches in routine clinical practice is challenging. As an alternative, immunohistochemistry (IHC)-based algorithms have gained attention due to their user-friendly and practical application in pathology laboratories. These techniques allow pathologists to analyze tissue samples obtained through biopsy or surgical excision, providing valuable insight into the histological subtype, grade and immunophenotype of the tumor. IHC aids in the identification of specific cell markers and protein expression patterns, which ultimately leads to the classification of NHL subtypes and differentiation from other benign or malignant conditions.

Several markers are measured in NHL to aid in diagnosis, prognosis and treatment planning. Commonly assessed markers include CD20, CD3, CD5, CD10, BCL6, BCL2, Ki-67, MYC and cyclin D1. These markers aid in identifying the type of lymphoma, assessing tumor aggressiveness and guiding treatment decisions (57).

The method devised by Hans et al (58), which used IHC, was initially carried out for the categorization of DLBCL into GC and non-GC subtypes. This algorithm utilizes the expression of CD10, BCL6 and MUM1 proteins. This method requires only three widely available antibodies, thus leading to its widespread use compared with alternate subtyping algorithms for DLBCL. Moreover, that study demonstrated a strong association between the Hans algorithm and gene expression profiles, revealing distinct survival outcomes between the GCB and ABC DLBCL groups (58). However, subsequent investigations yielded varying results, with some affirming the prognostic value of the Hans algorithm, and others failing to identify statistically significant differences between subgroups (59).

Through the combination of imaging, clinical assessment and immunophenotypic analysis, clinicians may achieve a comprehensive understanding of the disease. Following the diagnosis of lacrimal sac NHL, patients undergo an extensive oncologic workup, which includes imaging that covers areas beyond the lacrimal sac region. Moreover, laboratory analyses and bone marrow biopsies are integral components of the diagnostic process, ensuring a thorough assessment of the extent of the disease and any associated characteristics.

There are no standardized treatment protocols for the management of lacrimal sac NHL. However, several crucial factors are used to guide the initial assessment and tailor optimal treatment strategies. These factors include the following: i) the specific histopathological subtype of the lymphoma; ii) the extent of disease involvement both locally in the ocular region and systemically; iii) prognostic indicators relevant to both the patient and the disease itself; and iv) the impact of the lymphoma on visual function. Typically, a multimodal approach involving surgery, chemotherapy, radiotherapy, immunotherapy or targeted therapy is used. However, total surgical resection of orbital lymphoma is generally discouraged due to the potential risk of ocular damage and subsequent vision loss. Surgery is typically reserved for diagnostic purposes rather than therapeutic intervention. Consequently, treatment decisions are highly individualized, and these vary from one patient to another (Fig. 2).

In conclusion, lacrimal sac NHL is a rare malignancy originating in the lymphoid tissue of the lacrimal drainage system. Diagnosis often involves clinical evaluation, imaging studies and tissue biopsy. Treatment options may include surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy or a combination of the aforementioned strategies, depending on the severity and characteristics of the disease. Surgical excision combined with chemotherapy typically yields favorable outcomes, with adjuvant radiotherapy applied in some cases. Advanced imaging techniques aid in accurate disease staging and treatment planning, contributing to improved patient outcomes. Despite advances in research, the diagnosis and treatment of lacrimal sac NHL remains challenging due to the rarity of the disease. Thus, multidisciplinary approaches are required. Further research into the molecular mechanisms underlying lacrimal sac NHL and potential targeted therapies is crucial for refining clinical strategies. Further understanding of treatment efficacy and the importance of individualized approaches tailored to patient characteristics and disease stage is critical for improving care and prognosis. Continued efforts and collaborations in this field are essential to enhance diagnostic and therapeutic methods, ultimately leading to improved patient outcomes and quality of life.