Lymphomas of the ocular adnexa account for approximately 1% to 2% of non-Hodgkin lymphomas and approximately 8% of extranodal lymphomas.1,2 It is the most common malignant neoplasm of the ocular adnexa.1–4 Most ocular adnexa lymphomas (OALs) are primary extranodal neoplasms with 10% to 32% arising as secondary tumors from disseminated disease.1,3,5 More than 95% of these OALs are of B-cell origin, and of those, approximately 80% are low-grade lymphomas.1 The most common subtype is extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT), which accounts for 35% to 80% of OALs, followed by follicular lymphoma (20%), diffuse large B-cell (8%) lymphoma, and less common, mantle cell lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma.1,3 Some studies report an incidence of MALT lymphoma to be as high as 86% of all non-Hodgkin lymphomas of the ocular adnexa.6
The most common sites of ocular involvement are the orbit (40%), conjunctiva (35% to 40%), lacrimal gland (10% to 15%), and the eyelid (∼10%) and are bilateral in 10% to 15% of cases.1,3 Extranodal marginal B-zone lymphoma of MALT is generally considered to have an indolent natural history, with a favorable prognosis that responds well to local radiation therapy (RT), although it may be associated with disseminated disease.2,4,5,7
A 58-year-old black woman presented for a comprehensive examination, with the chief complaint of ocular discomfort and stinging in both eyes. She described the discomfort as being moderate and occurring daily for a period of at least 3 weeks. The patient reported hypercholesterolemia and hypertension, which were controlled with Crestor and atenolol, respectfully. She had an unremarkable ocular history. The patient did report smoking nearly a pack of cigarettes a day for 40 years.
Best corrected visual acuity (BCVA) was 20/20 OD and OS. Pupil testing, confrontation fields, and motility were all unremarkable. Anterior segment biomicroscopy revealed multiple salmon-colored lesions in the superior and inferior bulbar and palpebral conjunctiva of both eyes (Figs. 1, 2A, 3A). The cornea and limbus were clear in both eyes. Her intraocular pressure (IOP) was 19 mm Hg OD and 18 mm Hg OS with Goldman tonometry. Her dilated fundus examination revealed moderate cupping of 0.7/0.7 OD and 0.6/0.6 OS. The remainder of her retinal examination was normal.
The patient was diagnosed as having conjunctival lesions consistent with ocular lymphoma and a glaucoma suspect based on her moderate C/D ratio. The patient was referred to her primary care physician (PCP) for evaluation of suspected systemic lymphoma and referred for biopsy and histopathology of her conjunctival lesions. A baseline glaucoma evaluation was to be initiated after the assessment and treatment of her conjunctival lesions.
The patient returned 4 weeks later for follow-up. She had not been to her PCP for blood work or been seen by an ophthalmologist at that time. Her BCVA was still 20/20 OD and OS. Her IOP was 18 mm Hg in each eye. Her pachymetry was 538 and 530 μm. Her conjunctival lesions seemed unchanged at this visit. Additional glaucoma testing was deferred at the patient’s request. The importance of secondary consultation was emphasized, and the patient was referred again for biopsy and systemic evaluation. She was reappointed after 2 weeks for additional testing.
The patient returned as scheduled 2 weeks later for repeat anterior segment photography and review of blood work. She did not bring the results of her blood work with her but claims that she was informed that it was “normal.” She reported that she did consult her PCP, but she had not yet been to ophthalmology because she was attempting to recertify her medical coverage. Her BCVA was still 20/20 OD and OS. Her conjunctival lesions on the right and left inferior conjunctiva seemed to have enlarged with intralesion hemorrhaging in both eyes (Figs. 2B, 3B). In addition, she seemed to have a new lesion of her right medial bulbar conjunctiva (Fig. 4). Her IOP was 15 mm Hg in each eye. Another communication was sent to the PCP that the ophthalmology consultation was urgent with a high suspicion of malignant conjunctival lesions OU based on the change in appearance in a relatively short period.
The patient was not seen again for 5 months; however, telephone conversation revealed that she had seen an ophthalmologist 2 months after her initial examination. She had lesions surgically removed approximately 3.5 months from her initial examination, and the specimen was sent for flow cytometry. Her flow cytometry results revealed monoclonal B cells and CD19+, CD20+, CD22+, CD23+, CD45+, CD5−, CD10−, CD25−, FMC7−. She was diagnosed as having marginal zone lymphoma (MALT) and was negative for mantle cell lymphoma, small lymphocytic lymphoma (CLL), follicular lymphoma, and hairy cell leukemia, although at that time, a CD5-negative variant of mantle cell lymphoma could not be ruled out. Additional studies were ordered to rule out mantle cell lymphoma and were eventually determined to be negative. She tested negative for Chlamydophila psittaci. The patient was scheduled for a scan of her orbits and body.
When she was examined again approximately 6 months from her initial examination, she reported that “some” lesions had been surgically removed. She had also been diagnosed as having glaucoma by the ophthalmologist and placed on travoprost (Travatan Z, Alcon, Fort Worth, TX) OU QHS. She claimed that she had a magnetic resonance imaging (MRI) scan, a computed tomographic (CT) scan, and a positron emission tomographic (PET) scan, and the results were free of disseminated disease. She was scheduled to see an oncologist for a bone marrow biopsy and ocular RT later in the week. Her IOP was 14 mm Hg OD and 13 mm Hg OS on Travatan Z. She still had superiorly located salmon-colored conjunctival lesions in both eyes and scar tissue in the left inferior cul-de-sac from surgical excision of the lesion in this area. She was instructed to continue with her drops as prescribed elsewhere.
The patient called the office with the results of her bone marrow testing, which were negative for lymphoproliferative disease, and she was presumed to have ocular lymphoma with no dissemination identified on CT, PET scan, or bone marrow biopsy. A review of her blood work revealed slightly elevated lymphocytes. She was to be scheduled for ocular RT of her conjunctival lesions.
The patient was reexamined at our facility 13 months after her initial examination. She claimed to have completed 19 sessions of ocular RT, which was completed approximately 3 months previously. She reported with the complaint of severe pain in both eyes. She had been prescribed Ciloxan ointment and Tobradex drops by her oncologist for conjunctivitis and discomfort after RT. She was still using the Tobradex drops approximately twice a day for the pain; however, she claimed that the drops burned as well and she only used them when the pain was severe. She was also still using Travatan Z OU QHS. On examination, she did not seem to have any remaining or new conjunctival lesions. However, there was mild to moderate periorbital and conjunctival edema remaining. There was no indication of discharge or conjunctivitis. The cornea revealed trace staining OU. Her IOP was 17 mm Hg OD and 14 mm Hg OS with medication. The remainder of her anterior and posterior examination was unremarkable. There was no evidence of posterior segment complications secondary to the RT. She was diagnosed as having ocular inflammation and dry eyes after RT. We discussed the possibility of switching her IOP medication from Travatan Z to an alternate medication because of her ocular pain after her RT, as the patient noted an increase in her symptoms with the use of the medication. In addition, there was minimal efficacy of the medication (IOP 15 to 18 mm Hg untreated). She was prescribed Pred Forte 1% OU QID and artificial tears and was to return in 1 week. A record review revealed that she had received 2850 cGy (28.50 Gy) of total radiation within 19 sessions and had completed her treatment.
When the patient returned 1 week later, she noted improvement with Pred Forte and was experiencing less pain. Her BCVA was still 20/20 OD and OS. She was instructed to continue the use of the topical steroid and the artificial tears, and a steroid taper was discussed and initiated. She agreed to continue the Travatan Z as prescribed by the ophthalmologist. She was also to continue the use of her artificial tears. She was to return in 2 weeks to assess her comfort.
On her return, she complained of pain when she tapered and discontinued the topical steroid. She resumed use of the Pred Forte 1% on her own. She was still using Travatan Z as prescribed elsewhere. Her anterior segment examination seemed unchanged. Her IOP was 14 mm Hg OD and OS. She had no new or relapsing conjunctival lesions and no evidence of additional ocular complications from the RT other than radiation-induced inflammation and dry eyes. She was switched from Pred Forte to Lotemax OU QID and advised to continue using her artificial tears QID and rescheduled for 3 weeks.
At follow-up, the patient claimed that she had tapered herself off the topical steroid and discontinued the Travatan Z on her own. She noted improvement and did not report pain at this time. She was using only artificial tears. Her BCVA was still 20/20 OD and OS. Her IOP was 15 mm Hg OD and OS without medication. She had no relapse of her conjunctival lesions and no evidence of additional anterior or posterior segment complications from RT. She was informed to continue with the artificial tears and to continue with her discontinuation of the IOP medication until her next visit.
At 20 months from her initial ocular examination and nearly 1 year from finalizing her RT, the patient has a clear anterior segment evaluation at this time. Her IOPs seem stable without ocular medication. Her visual fields and imaging testing have been performed, and the patient has chosen to continue with the discontinuation of topical IOP medications at this time and agreed to close follow-up. She did report to her oncologist with a new scalp lesion that was “the size of a golf ball.” She was referred as a cautionary measure to dermatology for excision and biopsy, although it was not believed to be a lymphoma lesion manifesting cutaneously.
Most cases of OALs are seen in the fifth to seventh decade of life with an average age of 65 years.1,8 The condition is considered rare in young adults, although it has been reported.3 Patients may present with ocular irritation or have no symptoms at all, with lesions being discovered on routine examination. Conjunctival lesions typically appear as pink or “salmon-pink patch”–colored lesions that cause swelling, redness, and ocular irritation. Orbital lymphoid lesions are palpable masses causing progressive proptosis, palpable masses, periorbital edema, decreased visual acuity, restrictive ophthalmoplegia, and diplopia. Lacrimal gland lesions in the superior orbit may lead to inferior and nasal displacement of the globe, and lid lesions may present with ptosis.1,8
Morphology and Immunohistology
Benign conjunctival lymphoid hyperplasia and lymphoma cannot be diagnosed by microscopic examination alone.9 Before the advent of immunophenotyping and molecular diagnostic techniques such as flow cytometry and polymerase chain reaction, ocular adnexa MALT may have been frequently misdiagnosed as benign reactive lymphocytic hyperplasia.9,10 Histologically, the monotypical expression of immunoglobulin light chains in the cell cytoplasm or on cell membrane will distinguish the diagnosis of OAL from reactive lymphocytic hyperplasia.11 The morphology is described as monocytoid B cells or small lymphocytes with numerous secondary follicles and broadening of the marginal zone by small centrocyte-like cells with occasional blasts, plasmacellular differentiation, and infiltrated reactive B-cell follicles.1,11–13 Immunophenotypically, MALT lymphoma consist of CD20+, CD79a+, IgM+ with light-chain restriction, PAX5+, BCL2+, TCL1+, CD11+/−, CD43+/−, CD21+/−, CD35+/−, IgD−, CD3−, CD5−, CD10−, CD23−, cyclin D1−, BCL6−, and MUM1− cells.8,12,13 It is necessary to distinguish it from mantel cell lymphoma (CD5+, CD23−, cyclin D1+), small lymphocytic B-cell lymphoma/chronic lymphocytic leukemia (CD5+, CD23+), and follicular lymphoma (CD10+, BCL 6+) because these conditions may require a different treatment regimen and carry a different prognosis for the patient.1,7,8 There have been some reports of CD5 reactivity, although rare, posing diagnostic challenges.1,8
Association with an Antigenic Stimulus
Ocular adnexa lymphomas are similar to other MALT lymphomas and arise in tissues normally devoid of the innate immune system.8 It has been proposed that an OAL develops after a trigger of preexisting chronic inflammation, persistent infection, or autoimmune disease, and the chronic antigenic stimulation predisposes the site for the development of MALT lymphoma.10,14 This has been demonstrated in the association of Helicobacter pylori in association with the development of gastric MALT lymphoma.8 The DNA of C. psittaci has been reported to be detected in many OAL patients and is believed by many to contribute to the development of this condition. Patients may be tested for this condition and, if testing positive, may be treated with a course of doxycycline, which may aid in tumor regression for small-cell lymphoma. Chlamydophila psittaci is a gram-negative intracellular parasite transmitted by respiratory inhalation of secretions of birds. This bacteria causes an atypical and potentially life-threatening pneumonia in patients and is typically treated with tetracycline or macrolide medications. This condition should not be confused with Chlamydia trachomatis, which is also a gram-negative intracellular parasite but a sexually transmitted disease causing symptoms of urethritis, cervicitis, salpingitis, oropharyngeal disease, and pelvic inflammatory disease and typically treated with azithromycin. The patient presented tested negative for C. psittaci, and therefore, no treatment was prescribed. Associations have also been made with autoimmune diseases, such a thyrotoxicosis or Sjögren syndrome, although this is more uncommon.8
Staging of the Disease
Extranodal marginal zone B-cell lymphoma of MALT is a subset of the non-Hodgkin B-cell neoplasms and is recognized as a distinct type of lymphoma by the Revised European-American Lymphoma (REAL) Classification and by the World Health Organization Classification.15 Most are primary extranodal neoplasms, although 10% to 32% may be secondary tumors with disseminated lymphoma.1 A large study performed on OALs reported that 18% of patients with MALT had previous or concurrent systemic disease at the time of diagnosis.16 Additional studies have reported that 19% of patients with MALT lymphoma of the ocular adnexa had stage III or IV disseminated disease at the time of diagnosis, emphasizing the importance of staging evaluation in patients with OALs.17 Although primary marginal zone B-cell lymphoma in the adnexa is generally believed to be an indolent disease, the OAL found in patients with disseminated disease tended to be secondary lesions.13 Stage III and IV disseminated disease may also be associated with diffuse large B-cell lymphoma, systemic T-cell lymphoma, follicle center lymphoma, and hairy cell leukemia. In accordance to the Ann Arbor Classification, bilateral orbital lymphoma without systemic manifestation is referred to as stage IE versus disseminated disease of stages II, III, and IV.2,7,12,13,18,19
On suspicion of a possible OAL, initial assessment requires tissue sampling for histopathologic diagnosis. Additional staging should follow, including physical examination; complete blood count; lactate dehydrogenase level; chest x-ray; CT of chest, abdomen, and pelvis; and bone marrow biopsy.1,2,7 A CT and/or MRI of the brain and orbit should also be included to distinguish size and location, although they cannot distinguish benign from malignant lesions.2,6 They are also used in posttreatment assessment of the patient. In addition, a PET scan may be used to detect distant disease and is more sensitive than a CT scan. The addition of PET imaging to CT and MRI has been reported to be beneficial in establishing the proper stage at the time of initial diagnosis and, therefore, the proper therapeutic course for the patient.20 The treatment plan for localized IE disease involved local radiation, whereas advanced or systemic disease may require systemic chemotherapy.6 Nonconjunctival lesions, advanced disease stage, nodal involvement, age older than 60 years, B symptoms, and elevated lactate dehydrogenase levels have been reported to be identified as negative prognostic factors.1,16,17
Local RT is the treatment of choice for most OALs. Localized lymphomas of the conjunctiva, eyelid, and lacrimal gland are treated with a direct electron beam using a lens shield, whereas retrobulbar tumors are treated with photon beam radiation.1 Radiation therapy alone typically leads to high control rates of 85% to 100%, although these reports vary in total radiation, fraction sizes, and whether the radiation is applied to the entire orbit. The treated area, or clinical target volume, is generally the entire orbit and both bulbar and palpebral conjunctiva.2,7 The relapse rate may be higher in partial orbit RT versus whole-orbit RT, and reducing the RT volume did not decrease the rate of side effects; therefore, treatment of the entire conjunctiva or whole orbit is recommended.7 Radiation therapy for lymphoma is described in Gray units (or Gy), where 1 Gy is 1 unit of absorbed radiation energy. It seems that the average radiation dose, with a successful control rate and low complications, is approximately 30 Gy divided into several fractions of approximately 1.5 to 2.0 per session.1,5 Dosing greater than 30 Gy seemed to increase the possibility of radiation toxicity and with no proven added benefit in control rate.1,5,21 Therefore, in the patient presented, the total dose of 28.5 Gy was an adequate typical dose for this condition. There are conflicting reports on survival rate for various treatments and/or staging of the disease at the time of treatment.2,5 Tanimoto et al22 found no difference in survival rates between treated and observed patients. Tanimoto et al22 also reported that 10% of the patients with orbital MALT lymphoma had distant involvement at the time of diagnosis and 5% to 16% developed disseminated disease after treatment. Thieblemont et al23 reported no difference in survival rate regardless of the presence or absence of disseminated disease, and for that reason, risky treatments that may induce significant complications are not indicated in patients with MALT lymphoma. Although there are conflicting data reported on the impact of disease stage at the time of diagnosis, most reports agree that stage I localized disease determined through staging is an essential first step in making therapeutic decisions for the patient because most of these patients are rendered disease-free with RT alone.1
Potential Complications and Posttreatment Care of the Patient
Short-term or acute reactions associated with RT include periorbital erythema and edema, conjunctival infection, excessive tearing, ocular irritation, and keratitis.2,5,7 Long-term complications may include cataract formation, xerophthalmia and dry eye, ischemic retinopathy, optic atrophy, corneal ulceration, neovascular glaucoma, and macular edema.2 Shielding is used when possible to protect the lens of the eye, particularly with higher doses of RT, with caution not to hinder the treatment area. Cataract formation is the most common long-term complication and is seen to occur approximately 3 years after treatment.2,5,7 Radiation retinopathy may be seen in doses higher than 30 to 40 Gy and neovascular glaucoma in doses more than 50 Gy.7 Significant complications are rare with less than 30 Gy of RT.7 Radiation therapy applied to the orbit and lacrimal gland may be likely to result in severe dry eye after treatment. Amifostine is a medication used as an adjunct therapy with radiation for other forms of lymphoma, and it has been proposed that it may also be beneficial to patients undergoing treatment in the head and neck area. This medication is a chemoprotectant agent that selectively protects nonaffected healthy tissues from radiation toxicity. Small pilot studies and animal studies are being conducted to investigate the benefit of this medication in patients treated with radiation to the orbit in the prevention of radiation-induced dry eye.24
Although RT alone is the first-line regimen in most cases, systemic chemotherapy may be used as well for relapses, advanced disease states, or disseminated disease.2 Systemic treatment for nonlocalized disease may involve a chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone.2,7,8 Rituximab has also been used in the treatment of B-cell lymphoma because it targets the B-lymphocyte CD20 specifically.8
Patients should be seen within 4 to 8 weeks of the initial treatment to evaluate the response to treatment and determine whether the patient is experiencing toxicity to the RT. The ocular adnexa should be assessed for skin irritation and periorbital edema. The anterior segment evaluation should include conjunctival assessment for edema, injection, and conjunctivitis. The cornea should be carefully evaluated for keratitis or corneal melt. Schirmer testing and staining with NaFl and rose bengal can be performed if the patient presents with symptoms of dry eye and xerophthalmia is suspected, in which case, topical steroids may be prescribed. Posterior segment evaluation should be conducted periodically to rule out cataract formation, radiation retinopathy, ischemic neuropathy, and macular edema. After the initial assessment, ongoing examination should occur about every 3 months for the first year and approximately every 4 to 6 months thereafter for up to 3 years for relapses and long-term complications from radiation.2 However, closer follow-up evaluations will be necessary if pharmacological management is initiated.
In the patient presented, the ocular pain was the result of radiation-induced periorbital and conjunctival edema and inflammation, which gradually improved after treatment with topical management. She also has radiation-induced dry eye, which is slowly improving. A combination of these factors likely led to her complaints of pain. It is also possible that the Travatan Z was an additional contributing factor to her ocular discomfort because she had existing inflammation from treatment and the symptoms seemed to improve significantly when she discontinued the medication. Because patients undergoing RT for ocular lymphoma are likely to develop a significant amount of ocular surface irritation, dry eye, and inflammation, addition of topical IOP medications for the coexisting condition of glaucoma may prove challenging, particularly the addition of prostaglandin analogs. The necessity and benefit of addition of IOP medications during this period should be weighed and discussed with the patient.
Ocular lymphoma is the most common malignancy of the ocular adnexa and may present on routine examination or with relatively mild symptoms. Although it is most commonly a primary extranodal neoplasm, the condition may be associated with disseminated lymphoma and requires a thorough evaluation. Communication with the PCP, ophthalmologist, and oncologist will be necessary to obtain the necessary testing and determine the stage of the disease. The initial referral may be to the patient’s PCP or ophthalmologist for verification of the diagnosis of OAL with tissue sampling and immunophenotyping. Staging will involve coordinating a physical examination; blood work; chest x-ray; CT of chest, abdomen, and pelvis; bone marrow biopsy; CT and/or MRI of the brain and orbit; and possibly a PET. The patient should be followed closely during this process and after the delivery of RT to assess for any possible relapse of disease and identification of acute or long-term complications from ocular RT. Acute conditions of conjunctivitis, dry eye, and keratitis can be treated with topical antibiotic therapy, topical steroids, and artificial tears. Long-term complications, such as cataract, xerophthalmia, ischemic retinopathy, optic atrophy, corneal ulceration, neovascular glaucoma, and macular edema should be identified and care coordinated for management of these conditions. The primary eye care provider plays an important role not only in the identification of this condition and coordination of the patient’s care but also in the management of the patient after RT because it may improve the quality of the patient’s life while undergoing such treatment.
Nova Southeastern University
College of Optometry
3200 S. University Dr
Fort Lauderdale, FL 33328
The authors give a special acknowledgment to Ryan Schott, OD.
Received August 14, 2012; accepted November 14, 2012.
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