Signs and Symptoms
While basal cell carcinoma, sebaceous cell carcinoma and malignant melanoma are the most common malignancies of the periocular skin, lymphoma represents the most common malignant neoplasm of the ocular adnexa, and the conjunctiva is the site of involvement in about 35% to 40% of cases.1 This condition can be seen as an isolated entity (primary lymphoma), or it may arise as a localized manifestation of systemic disease (secondary lymphoma).2 Conjunctival lymphomas most often present as rapidly-growing mass lesions of the superficial ocular surface. The typical appearance is that of one or more pink, “fleshy” masses arising from within the fornix and extending toward the cornea. Alternatively, they may present as smaller, solitary lesions of the bulbar conjunctiva.3 Classically, lymphomas of the conjunctiva are described, based on their color, as “salmon-patch lesions.”1,3 They may present bilaterally in 7% to 24% of patients.1,4 Affected individuals are usually in the fifth to seventh decade of life, with a median age of 65 at the time of diagnosis.1-4 Patients are also predominantly female.1,2,4 Individuals with conjunctival lymphoma often have cosmetic concerns regarding chronic redness and occasionally report dryness, irritation, or both, but rarely experience substantial ocular pain.5 Vision may be variably impacted, depending upon the location and extent of the lesion.
Lymphoid tissue is present in most organs throughout the body. The lymph tissues are producers of immune cells. They are connected by channels and conduits to regional lymph nodes, located primarily in the neck, axillae, groin and abdomen. The primary function of the lymphatic system is to serve as a collection reservoir for interstitial fluid and to provide a conduit for the return of this fluid back to the vascular system. Lymphoma represents an abnormal, malignant growth of lymphoid tissue. It is classified as a cancer of the various elements of the lymphatic system. From an ocular point of view, primary lymphoma can manifest as a mass lesion of the external eye, localizing to the conjunctiva, the orbit, lacrimal gland or eyelid.6 Alternatively, patients may present with primary intraocular lymphoma, demonstrating choroidal infiltration with secondary vitritis, infiltrative optic neuropathy, or both.6,7 Secondary lymphoma can likewise be extraocular or intraocular, but these lesions are far less common than primary lymphomas of the eye.2
Throughout the years, a number of classification systems have been developed to describe lymphoid tumors, including the Rappaport classification, Kiel classification, Lukes-Collins classification, Working Formulation, British National Lymphoma Investigation classification and Revised European-American Lymphoma (REAL) classification.8 These systems were based on either the histological appearance of tumor growth (nodular or diffuse), size of cells (small, medium or large) or cell immunophenotype (B, T, natural killer [NK] or null).8 Today, the accepted standard is the World Health Organization (WHO) classification, established in 2001 and revised in 2008.9,10 The WHO classification is based on morphology, immunophenotype and genetic, molecular and clinical features.11 This system recognizes five broad categories: precursor B- and T-cell neoplasms, mature B-cell neoplasms, mature T/NK-cell neoplasms, Hodgkin’s lymphoma and immunodeficiency-associated lymphoproliferative disorders.10 It then further subdivides these into numerous specific entities based on the aforementioned criteria, ultimately yielding nearly 60 unique clinical diagnoses.11
Most conjunctival lymphomas fall into the category of B-cell neoplasms of the non-Hodgkin’s variety.12 These are frequently broken down further into mucosa-associated-lymphoid-tissue (MALT) lymphomas and non-MALT lymphomas. MALT lymphomas a more prevalent and generally follow a more indolent course, while non-MALT lesions are considered highly malignant and invasive.3,13
Although conjunctival lymphomas often have a characteristic appearance, it is important to differentiate them from other benign tumors of the ocular surface such as squamous papilloma, pyogenic granuloma and lymphangiectasis. Additional differential considerations should include benign reactive lymphoid hyperplasia, episcleritis, scleritis, ectopic lacrimal gland, chronic follicular conjunctivitis, ocular surface squamous neoplasia and amelanotic melanoma.14 It is not possible to differentiate between benign and malignant lymphoid tumors (or MALT vs. non-MALT lymphomas) simply on the basis of clinical presentation. Hence, tissue biopsy is crucial to establish a definitive diagnosis via flow cytometry and formalin-fixed tissue analysis.14 In addition, any patient with biopsy-proven lymphoma warrants a complete medical evaluation to determine if systemic lymphoma is present. Ideally, this should be done upon referral to or in coordination with a board-certified oncologist. Testing should include careful palpation of peripheral lymph nodes, complete blood count with differential, liver function tests, bone marrow biopsy and CT scans of the orbit, chest, abdomen and pelvis.15
Therapy for conjunctival lymphoma depends on the disposition of the tumor and whether there is disseminated lymphoma elsewhere in the body. Isolated conjunctival lymphoma (i.e., involving the conjunctiva but no other ocular or systemic structures) is most often treated with external beam radiation therapy (EBRT), on the order of 25 to 30 Gy (gray units).1,16,17 Dosage and exposure tends to be higher for more aggressive non-MALT lymphomas, though care must be taken to minimize long-term complications of ocular radiation such as xerophthalmia, cataract formation, ischemic retinopathy, optic atrophy and neovascular glaucoma.15-18 Alternative or adjunctive therapeutic options may include intralesional injection of interferon-, intralesional injection of Rituxan (rituximab, Genentech) (anti-CD20 antibody), oral doxycycline (as an association with infection by Chlamydia psittaci has been noted for ocular lymphoma), or simple observation following excisional biopsy.18-22 Those patients with invasive or disseminated lymphoma may require systemic chemotherapy in addition to local treatment. The standard regimen for non-Hodgkin’s lymphoma is a combination of Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone, referred to in oncologic circles as R-CHOP.23-27
• Conjunctival lymphoma should be part of the differential in all cases of sudden onset, rapidly growing lesions of the fornix, particularly those that are highly vascularized and fleshy in nature. Never assume these lesions to be benign; the most prudent course of action is to obtain a prompt biopsy.
• Staging and histologic subtyping are essential in the design of a therapeutic regimen and determination of prognosis, since about 15% of cases present with disseminated disease.
• Though conjunctival lymphoma may be associated with systemic lymphoma, the ocular lesions have not been shown to metastasize to any significant degree. The five-year survival rate for primary MALT lymphomas is excellent.
• Localized therapy for conjunctival lymphoma may not be required in those individuals with secondary, disseminated lymphoma who are already undergoing systemic chemotherapy.
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