What Is the Typical Clinical Presentation of a Patient With Intraocular Lymphoma?
Wendy M.
Smith,
MD
H. Nida
Sen,
MD MHSc
Intraocular lymphoma is a rare entity, although the incidence in the United States has increased 3-fold during the past 2 decades.1 Lymphoma can manifest in the eye as a primary malignancy of the retina, the vitreous, and the choroid, in which case it is called primary intraocular lymphoma (PIOL). It can also occur secondarily as a metastasis from an invasive systemic disease. Here, we are going to focus on PIOL, a subset of primary central nervous system lymphoma (PCNSL), which is typically a B-cell non-Hodgkin’s lymphoma. Approximately 2000 to 3000 patients are diagnosed with PCNSL each year in the United States.2 At the time of initial diagnosis, there may not be any other focus of lymphoma outside the eye; however, 50% to 80% of PIOL patients will go on to develop central nervous system (CNS) involvement. The median survival of PCNSL patients is 1 to 4 years depending on treatment, so it is important to make the diagnosis as soon as possible in order to initiate appropriate therapy.3
The diagnosis of intraocular lymphoma is often delayed due to its similarity to chronic posterior uveitis. When you approach a patient with vision loss and ocular inflammation, you should keep a high index of suspicion for intraocular lymphoma, especially if the uveitis is resistant to steroid treatment and the patient is older than 50 years of age. The typical patient will be male or female between the ages of 50 and 70 years with no previous history of uveitis. If the patient is younger, he or she might have a history of immunosuppression or immunodeficiency. There is no racial predominance. The vision loss is often gradual, progressive, painless, and accompanied by an increase in floaters. The eyes are usually quiet without pain or photophobia. Initially, only one eye may be symptomatic, but eventually up to 75% to 80% of cases are bilateral. A less common symptom is metamorphopsia. If there is preceding or concurrent CNS involvement, the patient may experience neurological symptoms, such as changes in personality or mental status, new-onset seizures, hemiparesis, or ataxia. Patients may have no visual complaints if the diagnosis of CNS lymphoma has precipitated the ophthalmic exam.
On exam, the most characteristic finding is a hazy vitritis with sheets and clumps of vitreous cells (Figure 46-1). Anterior chamber reaction is usually absent or mild with nongranulomatous keratic precipitates and aqueous cell and flare. In the posterior segment, you might observe scattered white retinal lesions or multiple cream-colored subretinal or sub-retinal pigment epithelium (RPE) infiltrates that may mimic sarcoidosis, viral retinitis, or a white dot syndrome. As the sub-RPE infiltrates enlarge and coalesce, multiple overlying pigment epithelium detachments may convey a “leopard spot” appearance (Figure 46-2).3 If the sub-RPE lesions spontaneously regress, the remaining atrophic scars can resemble the “punched-out” lesions seen in presumed ocular histoplasmosis, sarcoidosis, or the geographic atrophy found in many degenerative or postinflammatory conditions (Figure 46-3). Fluorescein angiography (FA) may reveal hypofluorescent areas due to blocking by the sub-RPE lesions and hyperfluorescence from subretinal lesions or window defects in areas of atrophy (Figure 46-4; also see Figure 46-2). Interestingly, cystoid macular edema is uncommon in PIOL, and patients may have disproportionately good vision in contrast to the degree of vitritis and retinitis. Table 46-1 summarizes the common and rare findings.
Figure 46-1. Hazy vitritis (OD) in a 67-year-old Asian man with a history of treated biopsy-proven PCNSL prior to development of ocular symptoms. Intraocular lymphoma was confirmed with a vitreous tap.
Figure 46-2. A 67-year-old man with a 15-week history of decreased vision in the left eye. Visual acuity was 20/32. Color fundus photo shows macular mottling and large cream/white subretinal lesion temporally. Fluorescein angiography shows hyperfluorescence of the subretinal lesion and small areas of hypofluorescence throughout the macula. Note the spotty “leopard-skin”-like appearance on the fluorescein angiogram.
Figure 46-3. A 52-year-old woman with a 1-year history of decreased vision and choroidal lesions. Best-corrected visual acuity was 20/25 in the right and 20/800 in the left (seen in Figure 46-2). Color fundus montage shows actively appearing subretinal lesions superior to disc and atrophic “punched out” areas inferiorly.
Figure 46-4. Color fundus photos with correlating fluorescein angiography in the right and left eyes of a patient with PIOL. In the upper panel, there is hyperfluorescence from infiltrates and window defects. The lower panel shows a large hypofluorescent area due to blocking from a subretinal lesion as well as smaller hyperfluorescent infiltrates.
The inflammation associated with PIOL may initially respond to steroid treatment because the majority of vitreous cells are “reactive” lymphocytes. Eventually, the disease will recur and progress despite steroids. To confirm the clinical suspicion of PIOL, you must obtain ocular fluid (preferably a vitreous biopsy via tap or vitrectomy) or a chorioretinal biopsy for examination by an experienced cytopathologist. Careful handling of the specimen is crucial in order to obtain accurate results from immunohistochemical and flow cytometric studies. Testing for cytokines interleukin (IL)-10 and IL-6 as well as for immunoglobulin heavy chain (IgH) gene rearrangements can be very informative, enabling earlier diagnosis and hence earlier implementation of effective therapy. B cells secrete high levels of IL-10, whereas IL-6 is higher in uveitis. Because the majority of intraocular lymphomas are B cell-derived, a ratio of IL-10:IL-6 greater than 1.0 is highly suggestive of PIOL.2 PCR with primers aimed at searching for IgH gene rearrangements performed on cells from the vitreous can determine if they share a common IgH gene rearrangement, thus confirming their monoclonality (another feature of lymphoma).2 You may need multiple vitreous biopsies in order to isolate malignant cells because they can be low in number and very sensitive to steroid therapy or sample mishandling.4 If the patient has not been previously diagnosed with PCNSL, he or she should also have a complete neurological exam, magnetic resonance imaging (MRI) of the brain and spine, and a lumbar puncture to obtain cerebrospinal fluid (CSF) for cytology. If the CSF shows malignant cells unequivocally, we don’t pursue vitrectomy for diagnosis (Figure 46-5).2
Figure 46-5. Vitreous biopsy from a patient with PIOL. The lymphoma cells are large with scant basophilic cytoplasm, large, multi-lobulated nuclei, and prominent nucleoli (Giemsa). (Reprinted with permission from Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17:133-141.)
High-dose methotrexate is the most effective treatment for PCNSL/PIOL but it is not curative. Adjunct treatments include anti-B cell therapy (rituximab, trade name Rituxan) or radiotherapy, which has the downside of severe neurologic side effects especially in patients older than 60 years of age. Even with treatment, the median survival ranges from 2 to 4 years. Patients require close monitoring with regular eye exams and MRI/light perception. Isolated ocular recurrences can be treated with an intravitreal injection of methotrexate (400 mcg/0.1 mL) and/or Rituximab (1 mg/0.1 mL). Although this does not treat or prevent CNS recurrence, in some cases, it is preferred over systemic treatment to avoid the side effects of chemotherapy or radiotherapy.
Summary
Intraocular lymphoma is classified as one of the masquerade syndromes due to its similarity to chronic posterior uveitis. In general, keep PIOL in mind in an elderly or immunocompromised patient with steroid-resistant chronic posterior uveitis, and consider further investigations for intraocular lymphoma.
References
1. Mochizuki M, Singh AD. Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm. 2009;17:69-72.
2. Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17:133-141.
3. Choi JY, Kafkala C, Foster CS. Primary intraocular lymphoma: a review. Semin Ophthalmol. 2006;21:125-133.
4. Coupland SE, Chan CC, Smith J. Pathophysiology of retinal lymphoma. Ocul Immunol Inflamm. 2009;17:227-237.
The opinions expressed in this chapter are those solely of the authors and do not represent the views or official policies of the National Eye Institute or the United States National Institutes of Health.