The most prevalent malignant tumors of the conjunctiva tumors include ocular surface squamous neoplasia (OSSN) (14%), melanoma (12%), and lymphoma (7%) 1 Lymphomas are a malignant neoplasm derived from monoclonal proliferations of B or T lymphocytes. They are divided into 2 major groups, Hodgkin’s lymphoma and Non-Hodgkin’s lymphomas, named after the British pathologist Dr. Thomas Hodgkin, (1798-1866). Conjunctival lymphomas make up about ¼ of all ocular adnexal lymphomas, with nearly all (98%) of B-cell lineage. The most common subtypes are low grade extranodal marginal zone (81%), follicular (8%), high grade mantle cell and diffuse large B cell (3%) lymphoma. Typically, this is a disease of the elderly, but it has been identified in patients as young as 33 months. In general, the low grade subtypes (EMZL, FL) will present earlier than high grade subtypes.
Etiology and Risk Factors
There has been significant research regarding whether lymphomas, particularly extranodal marginal zone lymphoma, are caused by chronic antigen stimulation. This is because most EZML is preceded by a benign, chronic inflammation. Over time, prolonged antigen stimulation could lead to a loss of regulation of B-lymphocyte proliferation and differentiation. Recent studies have implicated immune deficiency (HIV), H. pylori, Chlamydia psittaci, and Hepatitis C as potential organisms.
Autoimmune disorders such as benign lymphoid hyperplasia, Sjogren’s and Hashimoto’s have also been suggested as a potential association,  although studies regarding this have not been conclusive.
There can be a wide range of clinical symptoms including irritation, dryness, tearing, ptosis, and redness, particularly in the low grade types. Low grade types often have symptom duration for 4-6 months prior to presentation, whereas some of the high grade subtypes prompt more rapid consultation. Occasionally, the lesions may be found incidentally on examination.
Examination can reveal a salmon colored mass or patch, chemosis, ptosis, hyperemia, dryness, and epiphora, among others. Distinct clinical clues may be suggestive of a subtype, such as EMZL demonstrating a mobile, non-lobulated salmon-pink patch or follicular lymphoma demonstrating a multinodular appearance. The lesions of diffuse large B cell lymphoma may have a grayish coloration.
The differential diagnosis of conjunctival lymphoma includes benign reactive lymphoid hyperplasia, benign ocular surface tumors such as pyogenic granuloma, papilloma, malignant tumors such as squamous cell carcinoma, foreign body granuloma, amyloid deposition, and chronic follicular conjunctivitis.
Diagnosis requires adequate tissue sampling, with 2 samples typically being sent - formalin fixed, and fresh. Formalin-fixed, paraffin embedded tissue sections are stained with typical hematoxylin-eosin stain to evaluate the morphology. Fresh tissue is analyzed with flow cytometry for specific immunohistochemical antibodies. Antibodies directed against CD3, CD5, CD20, and CD79 will help differentiate between B and T cell non-Hodgkin’s lymphomas. Further immunophenotyping will then help clarify sub-classifications.
It is important to note that B cell lymphoma is typically a primary disease (80%), where T cell NHL is usually a secondary disease (80%). Subtypes can vary however, such as mantle cell (B cell NHL), being a secondary disease in half of cases.
Once identified, complete staging may include a full body PET and CT, or MRI and bone marrow biopsy. Sensitivities of PET and CT are 85 and 70%, respectively. Additionally, a hematologic screening is necessary for these patients.
Treatment is multidisciplinary, with ophthalmologists, hematologists, and radiotherapists with treatment ranging from surgical resection, cryotherapy, radiotherapy, systemic chemotherapy, or targeted anti-B-cell therapy (rituximab).External beam radiotherapy (EBRT) is the treatment of choice when managing indolent EMZL and FL, but is only applied 20% in pts with high-grade B or T cells. Typically 20-50 Gy are used, with fractionated treatment over 15 sessions. With this therapy, 80% will not experience progression or recurrence during a 5 year follow-up period. Side effects are well tolerated, and include dry eye, cataract formation, orbital fat-tissue reduction, and rarely, radiation retinopathy. Lower dose radiation in two sessions has also been shown to have complete resolution of conjunctival lymphoma.
More aggressive types are primarily managed using chemotherapy, which has good efficacy, eliminating nearly three-quarters of high grade B and T cell lymphomas,but with a higher toxicity profile. Chemotherapy is often a combination regimen such as CVP (cyclophosphamide, vincristine, and prednisone) or CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone). Typical systemic side effects include hair loss, constipation, nausea, leukopenia, hematuria, neuropathy, myopathy, mood swings, and weight gain.
Other methods of treatment include the use of monoclonal antibodies such as Rituximab (anti-CD20) and Daclizumab (anti-CD25). These can be used if the correct B-lymphocyte antigens are present, and can be given systemically alone or with conventional chemotherapy or as an intralesional injection. Several small studies have shown that 75% of patients with isolated disease will have no progression or recurrence following intralesional Rituximab at 1 year. Local immunotherapy with interferon-alpha, is another treatment option that has been reported for the use of EMZL.
Less commonly Beta-ray brachytherapy may be utilized. This is performed with a bidirectional ophthalmic applicator, but doses are often higher than that used with EBRT. While effective, it can cause greater acute and late complications than EBRT.
Complete surgical excision can be performed, but due to tumor microfiltration, there is a higher rate of recurrence - one-third of patients demonstrate recurrence or progression at three years. Alternatively, observation without treatment can also be used for low grade lymphomas, and this is done in approximately 15% of EMZL patients. However this also has a higher recurrence and progression rates on par with surgical excision.
Finally, antibiotics, particularly doxycycline, have been recommended either alone or with combination therapy after discovery of the role of potential infectious agents in lymphomas. It is recommended that treatment be selective for those testing positive for infectious agents.
Lymphoma-related survival (5-year) depends on subtype and ranges from 97% (ENMZL) to 9% (MC
Overall, prognosis is generally good, with 90% of patients not experiencing progression or recurrence during one year follow-up periods. Low grade lymphomas have the lowest progression, followed by higher grade diffuse large B cell and mantle cell lymphomas. T cell lymphomas have the worst prognosis, with 50% of patients experiencing progression or recurrence. Age appears to be an important prognostic marker for T cell lymphomas, with those greater than 50 being three times more likely to progress or recur than those under age 50. Additionally and importantly, long-term follow-up is needed for these patients, as an increased risk of mortality is present many years later.
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