Lymphoma is a malignant disease of the immune system that can involve virtually any part of the body, including all compartments of the eye and its adnexa. Considerable confusion exists within ophthalmology regarding lymphomatous diseases, likely due to their rarity and, at times, diagnostic difficulty.
Classification of lymphoma has a long history, beginning with its first description in 1832 by Thomas Hodgkin, MD.1 Considerable effort has been made to align modern nomenclature with the genetic and pathophysiologic characteristics of the disease, as reflected in the widely accepted World Health Organization classification, which can be challenging to navigate.2 For practical purposes in ophthalmology, lymphoma may be conceptualized as involving either central nervous system (CNS) tissues or mucosal tissues. CNS lymphomas tend to be aggressive and often lethal, whereas mucosal lymphomas are generally indolent but can be locally destructive or disfiguring.
CNS-involved lymphoma is of particular concern to retina specialists. It arises in immune-privileged sites, including the posterior segment of the eye, brain, and testis, and is typically high grade and commonly lethal.3 In the eye, it primarily affects the retina, vitreous, and retinal pigment epithelium (RPE). These cases are often described as primary vitreoretinal lymphoma or primary intraocular lymphoma. However, such terminology may incorrectly imply that the disease originates in the eye, vitreous, or retina, rather than reflecting the chemotactic migration of malignant cells from the bone marrow to immune-privileged tissues.4 Accordingly, high-grade CNS lymphomas involving the eye are more accurately referred to as primary central nervous system lymphoma—ophthalmic variant , which is most commonly a diffuse large B-cell lymphoma on histopathology.
Figure 1. Color fundus photo and fluorescein/indocyanine green angiogram images obtained from a 72-year-old male patient.
Another form of lymphoma affecting the eye arises from mucosal tissues. The most common type on tissue biopsy is extranodal marginal zone lymphoma (EMZL), although follicular, large B-cell, and mantle cell variants are also observed. Early-career ophthalmology residents may recognize these because a conjunctival “salmon patch” is a characteristic finding.5 Mucosal lymphomas may also manifest in the eyelid and orbit, both of which are contiguous with and directly connected to ocular surface mucosa. Collectively, the conjunctiva, orbit, and eyelids are considered the ocular adnexa, and lymphomas in these tissues are often referred to as adnexal lymphomas.6
This article will focus on mucosal lymphomas, otherwise known as adnexal lymphomas, that may be encountered by retina specialists. A case example will illustrate why retina specialists should be familiar with adnexal lymphoma.
Case Presentation
A 72-year-old male presented to an optometrist reporting difficulty seeing in bright light in the right eye. He noted that colors appeared less vivid while driving during the day. Additionally, the same eye became red, though without pain. Concerned by these symptoms, the patient sought care. He was initially diagnosed with episcleritis and treated with topical glucocorticoid drops.
Figure 2. Prototypical salmon patch is noted on eyelid eversion.
At a follow-up visit, the patient elected to undergo fundus photography for screening. Review of the images revealed concerning retinal findings, prompting referral to a retina specialist. The specialist examined the patient, obtained additional photographs, and performed angiography, leading to a diagnosis of birdshot chorioretinopathy (Figure 1). The patient was started on empiric high-dose oral glucocorticoid therapy while extensive laboratory testing, including HLA-A29 typing, was performed, which returned negative. Following these results, the patient was referred to a uveitis specialist.
On review of imaging and clinical examination, the uveitis specialist identified a salmon-colored lesion on the conjunctiva of the symptomatic eye (Figure 2). The patient was then referred to an ocular oncologist, who performed an incisional biopsy. Histopathology demonstrated findings consistent with extranodal marginal zone lymphoma. The patient underwent external beam radiotherapy, after which the retina and choroid returned to an age-appropriate appearance and thickness on optical coherence tomography (Figure 3).
Figure 3. Optical coherence tomography images showing the curvature of the macula in the patient’s first visit in the top panel. Note that the choroid is very thick, almost unmeasurable, and there is a convex-appearing macular surface. Following radiation treatment, the choroidal anatomy appears more appropriate, and the curvature of the macula returns to its normal concave shape.
Discussion
Adnexal lymphomas involve the orbit, eyelids, conjunctiva, lacrimal gland, and other structures of the lacrimal system. Retina specialists should recognize that the choroid is viewed by the immune system as contiguous with mucosal tissues. Because the choroid is a component of the uvea, some authors have described these entities as uveal lymphoma if the uvea is predominantly involved, even though malignancy of the iris and ciliary body is rarely observed.6-8
Historically, there has been considerable controversy regarding the clinical significance of this disease. In some reports, this form of lymphoma has been described as benign reactive lymphoid hyperplasia, based on observations that tumor growth may parallel systemic inflammatory states. However, most cases described in the literature demonstrate behavior that is anything but benign. Notably, even publications using “benign” terminology have reported severe complications, including acute angle-closure glaucoma and exudative retinal detachment.9
In a study reviewing cases of uveal lymphoma, most patients were male, lesions were predominantly located in the posterior pole, and extraocular extension was identified in more than 57% of cases. Indocyanine green angiography detected disease in all cases.5 In other series evaluating adnexal lymphoma more broadly, signs of uveal involvement were reported in 15.9% of patients.7 These findings underscore the importance of a complete ophthalmic examination, including dilation, when mucosal lymphoma is suspected—even when disease appears confined to the orbit. Characterizing the extent and laterality of involvement has important implications for staging and treatment.
Decreased visual acuity is the most common presenting symptom, although misdiagnosis is common. Patients are often initially told they have conjunctivitis, a dermoid tumor, choroidal metastases, or, most commonly, painless scleritis. In many cases, these diagnoses reflect the presence of conjunctival findings at presentation.
It is important to obtain a tissue specimen during the diagnostic evaluation process. Retina specialists may be less comfortable performing conjunctival or orbital biopsies; however, these sites are preferred for tissue sampling because excisional biopsy carries minimal risk to vital ocular structures. Diagnostic evaluation often begins with the retina specialist, as B-scan ultrasonography is more sensitive than MRI or CT scan for detecting orbital disease.5
Treatment typically involves radiation therapy using intensity-modulated radiation therapy or external beam radiation therapy. Uveal lymphoma is highly radiosensitive, although radiation dose and delivery are tailored based on histopathologic findings.10,11
Finally, close collaboration with medical oncology is essential, because mucosal lymphomas may occur at extraocular sites. In one review, nearly 22% of patients diagnosed with adnexal lymphoma were found to have systemic disease in other areas of the body.5 RP
References
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9. Gass JD. Retinal detachment and narrow-angle glaucoma secondary to inflammatory pseudotumor of the uveal tract. Am J Ophthalmol. 1967;64(3):612-621.
10. Baryla J, Allen LH, Kwan K, Ong M, Sheidow T. Choroidal lymphoma with orbital and optic nerve extension: case and review of literature. Can J Ophthalmol. 2012;47(1):79-81. doi:10.1016/j.jcjo.2011.12.017
11. Fung CY, Tarbell NJ, Lucarelli MJ, et al. Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes. Int J Radiat Oncol Biol Phys. 2003;57(5):1382-1391. doi:10.1016/s0360-3016(03)00767-3