Jawad Ahmad

Learning Points

• Ocular lymphoma encompasses ocular adnexal lymphoma (OAL) and intraocular lymphoma, which differ in biology, investigation and management (1,2).
• OAL represents a small but important subset of non-Hodgkin lymphoma and most commonly involves the orbit, followed by conjunctiva, eyelids and lacrimal gland (2,3).
• The predominant subtype is extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), typically indolent but prone to late relapse (1–3).
• Primary vitreoretinal lymphoma (PVRL) is usually a high-grade diffuse large B-cell lymphoma and is strongly associated with central nervous system (CNS) disease (4,8,9).
• Early biopsy with immunophenotyping, appropriate systemic staging, and multidisciplinary management are critical to optimise visual and survival outcomes (1–3,6).

Summary

Ocular lymphoma comprises a spectrum of lymphoid malignancies affecting the ocular adnexa and intraocular compartments. The most frequent form is ocular adnexal lymphoma (OAL), usually extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), which typically presents with painless periocular swelling or a salmon-coloured conjunctival mass (1–3,5). Primary vitreoretinal lymphoma (PVRL), in contrast, is an aggressive diffuse large B-cell lymphoma that often mimics chronic uveitis and is closely linked to central nervous system (CNS) lymphoma (4,8,9). Diagnosis relies on high clinical suspicion, targeted imaging, and timely biopsy with immunohistochemistry and molecular studies (1–3,5–7). Localised OAL is highly radiosensitive, with excellent local control and survival, whereas advanced or high-grade disease requires systemic chemo-immunotherapy (1,2,6,8,11,12). In selected regions, Chlamydia psittaci-directed antibiotic therapy may be considered as an adjunct in MALT-type OAL (4,7,11). This overview summarises current understanding of the epidemiology, pathophysiology, clinical features, diagnostic work-up, and management principles for ocular lymphoma.

Introduction

Ocular lymphomas are malignant proliferations of lymphoid cells involving the orbit, eyelids, lacrimal gland, conjunctiva, or intraocular structures. The majority are ocular adnexal lymphomas (OAL), which are predominantly B-cell non-Hodgkin lymphomas (NHL). OAL accounts for approximately 1–2% of all NHL and 5–10% of extranodal NHL in large series (1–3).

Ocular lymphomas are broadly divided into:

– Primary OAL, arising in the ocular adnexa;
– Secondary ocular involvement, as part of systemic lymphoma; and
– Primary intraocular lymphoma, most often primary vitreoretinal lymphoma (PVRL), a form of primary CNS lymphoma (4,5).

Accurate classification and staging are essential, as management and prognosis vary substantially with subtype and extent of disease.

Epidemiology

OAL typically affects middle-aged and elderly adults, with a median age at diagnosis in the sixth decade (1–3). Many cohorts show a slight female predominance (1).

The most frequent histologic subtype is extranodal marginal zone B-cell lymphoma of MALT type, which constitutes roughly 60–80% of OAL in contemporary series (1–3,6). Less common subtypes include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma.

In terms of anatomical distribution, the orbit is the most common primary site, followed by conjunctiva, eyelids and lacrimal gland (2,3,6,7). Conjunctival disease often presents earlier because of its visible, superficial location.

Primary intraocular lymphoma is rarer than OAL and most often represents a PVRL arising within the retina, vitreous, or optic nerve head, frequently associated with CNS lymphoma (4,8,9).

Pathophysiology

The pathogenesis of OAL reflects chronic antigenic stimulation of lymphoid tissue within the ocular adnexa. Several lines of evidence support an antigen-driven model, particularly for MALT-type disease (1,2,6,7).

In some geographic regions, infectious agents (most notably Chlamydia psittaci) have been associated with OAL (4,7). Prevalence of C. psittaci DNA in tumour tissue and clinical response to doxycycline, however, vary markedly between cohorts and regions, suggesting environmental and host-specific factors (4,7).

At the molecular level, genetic alterations affecting NF-κB signalling, B-cell receptor pathways and immune regulation have been described, contributing to survival and proliferation of neoplastic B cells (1,2).

Intraocular lymphoma, particularly PVRL, is usually a high-grade DLBCL and shares many biological features with primary CNS lymphoma, including a predilection for immune-privileged sites and a high risk of CNS involvement (4,8,9).

Clinical Presentation

Ocular adnexal lymphoma

OAL often presents insidiously, with symptoms that may mimic benign inflammatory disease. Common features include (1–3,5–7):

– Painless periocular swelling or mass, often firm and slowly progressive;
– Proptosis, eyelid fullness or ptosis;
– Diplopia or ocular motility restriction due to extraocular muscle or orbital involvement;
– Less commonly, pain or compressive optic neuropathy in bulky orbital disease.

Conjunctival OAL typically manifests as a salmon-pink, smooth, mobile, subepithelial mass, which may be unilateral or bilateral (2,3,5,6). Recognition of this characteristic “salmon patch” is crucial to prompt biopsy.

Primary vitreoretinal lymphoma

PVRL frequently masquerades as chronic, treatment-refractory uveitis (4,8,9). Typical features include:

– Blurred vision and floaters from vitreous cellular infiltration;
– Creamy or yellow-white subretinal or retinal pigment epithelial infiltrates;
– Anterior chamber inflammation or vitritis that responds only partially or transiently to corticosteroids.

Up to 60–90% of patients with PVRL will have, or later develop, CNS lymphoma, underscoring the need for careful neuro-imaging and lumbar puncture as part of the work-up (4,8,9).

Because signs can be subtle and overlap with inflammatory conditions, both OAL and PVRL are prone to diagnostic delay.

Investigations

Imaging

MRI or CT of the orbits help define the location, size and extent of adnexal disease. Typical features of OAL include (6,10):

– A well-defined, homogeneous, moulded soft-tissue mass that conforms to orbital structures;
– Frequent lacrimal gland enlargement or extraconal/orbital apex involvement;
– Relative absence of bone destruction, which favours lymphoma over more aggressive neoplasms.

PET-CT or contrast-enhanced CT of chest, abdomen and pelvis is recommended for systemic staging and to identify nodal or extranodal disease elsewhere (1,2,6).

For suspected PVRL, investigations include (4,8,9):

– Optical coherence tomography (OCT);
– Fundus fluorescein and indocyanine green angiography;
– Brain and spine MRI;
– Sometimes PET-CT, particularly if systemic disease is suspected.

Histopathology and ancillary studies

Definitive diagnosis requires incisional or excisional biopsy of the lesion (1–3,5–8). Key features in MALT-type OAL include:

– Infiltrates of small to medium-sized CD20-positive B cells;
– Lymphoepithelial lesions;
– Low to moderate proliferative index on Ki-67.

Immunohistochemistry and flow cytometry help confirm B-cell lineage and light-chain restriction. Additional molecular studies, such as immunoglobulin heavy chain gene rearrangement or targeted mutational profiling, support clonality assessment and subtyping (1–3,5–7).

In suspected PVRL, diagnostic yield may be improved by combining vitreous biopsy with subretinal or retinal sampling where possible, alongside cytology, flow cytometry and molecular analysis (4,8,9).

Systemic evaluation

Staging follows principles used for other extranodal lymphomas (1–3,6). A typical work-up includes:

– Full blood count, biochemistry and lactate dehydrogenase (LDH);
– CT or PET-CT of chest, abdomen and pelvis;
– Bone marrow biopsy, particularly in non-MALT or advanced-stage disease;
– For PVRL, brain/spine MRI and CSF analysis to assess CNS involvement (4,8,9).

Management

Treatment is individualised according to histologic subtype, anatomical site and stage.

Localised (Stage I) OAL

For unilateral, localised MALT-type OAL, radiotherapy (RT) is considered the standard of care (1,2,6,8,11).

Involved-site RT to doses of 24–30 Gy achieves local control rates exceeding 95% in most series (1,6,8,11). Very low-dose RT (e.g. 4 Gy in 2 fractions) is used selectively in frail patients or for palliative intent, but long-term control is superior with conventional dosing (11).

Treatment planning aims to minimise radiation exposure to critical ocular structures, particularly the lens and lacrimal gland, to reduce cataract formation and dry eye.

Advanced, bilateral, or high-grade disease

Patients with bilateral, multifocal, nodal, or high-grade lymphoma generally require systemic therapy (1,2,6,8,12).

Chemo-immunotherapy with regimens such as R-CHOP or bendamustine-rituximab is commonly used for DLBCL or disseminated disease (1,2,6). Rituximab, an anti-CD20 monoclonal antibody, has significantly improved outcomes across B-cell lymphomas and is widely incorporated into regimens for OAL, either as monotherapy in selected indolent cases or combined with chemotherapy in aggressive or advanced disease (1,2,12).

In rare circumstances with low-tumour-burden MALT lymphoma and favourable prognostic features, a watch-and-wait strategy may be considered, as long-term series from some centres have demonstrated durable survival with delayed treatment (13). However, this approach must be individualised and balanced against the risk of local complications.

Antibiotic therapy

In regions where C. psittaci is frequently detected in OAL, doxycycline-based antibiotic therapy has been explored as a lymphoma-directed treatment (4,7,11).

A multicentre trial demonstrated meaningful response rates in C. psittaci–positive ocular adnexal MALT lymphoma following doxycycline (11). However, both the association with C. psittaci and the clinical efficacy of antibiotics vary geographically, and antibiotic therapy is not a universal standard of care (4,7,11).

Antibiotics, where used, should be considered as adjunctive or first-line therapy in carefully selected patients, with close monitoring and a low threshold to escalate to RT or systemic therapy when indicated.

Management of primary vitreoretinal lymphoma

PVRL requires coordination between ophthalmology, neurology and haematology/oncology (4,8,9).

Treatment strategies may include:

– High-dose systemic methotrexate–based chemotherapy, often combined with rituximab, as for primary CNS lymphoma;
– Intravitreal methotrexate and/or rituximab injections to achieve local ocular control;
– Ocular RT in selected cases, particularly for unilateral or refractory disease.

Given the strong association with CNS involvement, long-term neuro-oncological follow-up is mandatory.

Prognosis

For low-grade MALT-type OAL, prognosis is generally excellent, with 5-year overall survival rates >90% and high local control following appropriate RT or chemo-immunotherapy (2,3,6,8,11,13).

However, relapse can occur many years after initial treatment, often at distant extranodal or nodal sites (2,3,11,13). Certain features, such as non-MALT histology, lacrimal gland or eyelid involvement, bilateral disease, advanced stage, or transformation to DLBCL, are associated with a higher risk of systemic dissemination and worse outcomes (2,3,6).

By contrast, PVRL and CNS-associated disease carry a substantially poorer prognosis, with high rates of CNS relapse despite aggressive therapy (4,8,9).

These patterns underscore the importance of long-term surveillance of both ocular and systemic status in all patients with ocular lymphoma.

Conclusion

Ocular lymphoma is an uncommon but clinically important group of malignancies that should be considered in any patient with a persistent, painless orbital mass, salmon-coloured conjunctival lesion, or steroid-refractory uveitis. Distinguishing between ocular adnexal and intraocular disease, accurately subtyping on biopsy, and performing appropriate systemic staging are essential steps in guiding management. Localised OAL is highly radiosensitive and carries an excellent prognosis, whereas PVRL and high-grade or disseminated lymphoma require systemic chemo-immunotherapy and carry higher morbidity and mortality. Early recognition and coordinated multidisciplinary care between ophthalmologists, pathologists, radiation oncologists and haematologists are key to optimising visual and survival outcomes.

References

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