Orbital Lymphoma

Lymphoma arising in the orbit, conjunctiva, lacrimal gland, or eyelid (ocular adnexal lymphoma). It is the commonest orbital malignancy in adults over 60 and accounts for 10 to 15 percent of orbital tumours and about 1 to 2 percent of all non-Hodgkin lymphomas.

• Subtypes: extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (about 60 to 70 percent, indolent), follicular lymphoma (about 10 to 15 percent), diffuse large B-cell lymphoma (about 10 percent, aggressive), mantle cell lymphoma (rare, aggressive), and others (T-cell, plasmacytoma, Burkitt, in children and HIV).
• Associations: chronic antigenic stimulation (Chlamydia psittaci infection in some regions, Helicobacter pylori, hepatitis C virus), autoimmune disease (Sjogren syndrome, Hashimoto thyroiditis), and immunosuppression (HIV, transplant).
• Lymphoid proliferations span a spectrum from reactive hyperplasia and atypical lymphoid hyperplasia to lymphoma; IgG4-related disease and idiopathic orbital inflammation are mimics.
• Systemic disease is present at diagnosis in about 30 to 40 percent (higher for orbital than conjunctival primaries), and dissemination risk is about 20 to 30 percent over 5 to 10 years.

• Painless slowly progressive swelling, proptosis, globe displacement (usually inferior or inferomedial), ptosis, a palpable firm mass in the anterior orbit or upper lid, and diplopia; pain is unusual, and inflammation is absent in most.
• Conjunctival lymphoma: "salmon patch" fleshy pink lesion in the fornix or on the bulbar conjunctiva.
• Lacrimal gland: swelling of the superolateral lid with an S-shaped ptosis, bilateral in 10 to 20 percent.
• Aggressive subtypes: rapid growth, pain, orbital apex involvement, optic neuropathy, and constitutional (B) symptoms (fever, night sweats, weight loss).
• Visual loss is uncommon in indolent disease; bilateral involvement in 10 to 20 percent.

• CT orbits (well defined homogeneous soft tissue mass moulding to the globe and orbital walls without bone destruction) and MRI (isointense to muscle on T1, intermediate on T2, homogeneous enhancement, restricted diffusion), imaging extent and optic nerve involvement.
• Incisional biopsy with fresh tissue (not fixed in formalin only) for histology, immunohistochemistry (CD20, CD79a, CD10, BCL2, BCL6, cyclin D1, Ki-67), flow cytometry, and molecular testing (immunoglobulin gene rearrangement, MYC, BCL2 and BCL6 translocations); avoid fine needle aspiration alone.
• Staging: whole body PET-CT or CT of chest, abdomen and pelvis, bone marrow biopsy (for aggressive subtypes and when indicated), lactate dehydrogenase, beta-2 microglobulin, full count, liver and renal function, hepatitis B and C, HIV, and serum protein electrophoresis; gastroscopy with Helicobacter pylori testing in marginal zone disease; polymerase chain reaction for Chlamydia psittaci on tissue in endemic regions.
• Disease stage by extent: stage IE (confined to the orbit or adnexa), with higher stages when nodal or distant disease is present.

• Localised indolent disease (marginal zone, follicular grade 1 to 2, stage IE):
  • Radiotherapy to the orbit: 24 to 30 Gy in 12 to 15 fractions (local control above 95 percent); low dose radiotherapy 4 Gy in 2 fractions is an option for follicular and marginal zone disease with fewer side effects. Lens shielding and techniques that reduce cataract, dry eye, radiation retinopathy and optic neuropathy risk.
  • Doxycycline 100 mg orally twice daily for 3 weeks for Chlamydia psittaci associated disease (response in about 20 to 65 percent).
  • Rituximab 375 mg/m2 IV weekly for 4 weeks, with or without chlorambucil 6 mg/m2 daily for 6 weeks or bendamustine (90 mg/m2 days 1 and 2 every 28 days with rituximab) for bilateral or extra adnexal disease or for patients unsuitable for radiotherapy.
  • Intralesional rituximab and observation (watch and wait) in selected asymptomatic patients.
• Systemic or advanced indolent disease: chemoimmunotherapy (rituximab with bendamustine or CHOP-like regimens), with treatment of Helicobacter pylori (clarithromycin 500 mg, amoxicillin 1 g, and a proton pump inhibitor twice daily for 14 days) when positive.
• Diffuse large B-cell lymphoma: R-CHOP every 21 days for 6 cycles (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 maximum 2 mg, all on day 1, with prednisolone 100 mg daily for 5 days), with involved site radiotherapy (30 to 36 Gy); central nervous system prophylaxis (intrathecal or high dose methotrexate) for high risk disease; referral to haemato oncology.
• Monitor with clinical examination and MRI every 3 to 6 months for 2 years, then yearly; relapse occurs in 20 to 30 percent (often at distant extranodal sites), and late relapse is possible beyond 10 years.
• Prognosis: 5-year disease specific survival above 90 percent for indolent adnexal lymphoma, 60 to 70 percent for large cell lymphoma.
• Manage radiation complications (cataract, dry eye, retinopathy) and provide supportive care.