with a poor prognosis. This chapter will focus on patients presenting with primary intraocular lymphoma with no history of CNS involvement.

The most recent World Health Organization Classification of Lymphoma [1] is based on the Revised European American Lymphoma classification. The World Health Organization classification employs clinical as well as pathologic, immunologic, and genetic parameters.

A key lymphoma risk factor is increased age; the majority of patients present in their sixth or seventh decades. The elderly population is increasing, especially in western Europe and the United States. The incidence of NHL is also increasing in this growing population, which represents both a challenge and an opportunity for clinicians and researchers to effectively serve this expanding cohort [2].

39.2 Presentation and Diagnosis

Several recently published reviews have summarized the natural history and standard diagnostic and treatment strategies for intraocular lymphoma [3–8]. In primary intraocular lymphoma, patients present with recurrent vitritis or uveitis that may initially respond to topical steroids. Some complain of increased floaters or generalized blurry vision. The lack of other ocular findings and the initial response to topical anti-inflammatory drops often lead to a delayed diagnosis.

In patients with primary uveal lymphoma, clinicians may detect choroidal or subretinal infiltration. The differential diagnosis of vitritis is beyond the scope of this chapter, but other causes should be entertained and ruled out before lymphoma is considered; in particular, infectious etiologies should be ruled out. Pathologic assessment of the vitreous plays a key role in arriving at the correct diagnosis. While some clinicians advocate fine needle aspiration, most centers proceed with a pars plana vitrectomy. The surgeon should first confirm that there is enough cellular material in the vitreous to justify biopsy. A scant specimen is unlikely to yield enough tissue for the pathologist to arrive at a definitive diagnosis. It cannot be overemphasized how critical it is to coordinate such a procedure in advance with an ocular pathologist experienced in processing vitreous and choroidal specimens.

The core vitrectomy specimen should be obtained with the cutter on slow speed to minimize damage to the cells (please see Chapter 38). This specimen should be sent off separately from the rest of the tissue, which can be obtained from the vitrectomy cassette. A fresh specimen should be supplied to the pathologist, who can also perform appropriate stains to rule out infectious etiologies. Cytospin and liquid-based cytology studies are generally employed to increase the sensitivity of the testing. In some cases, the core vitrectomy specimen may demonstrate only reactive lymphocytes. It is the authors’ experience that in such patients, additional tissue from a choroidal infiltrate (if present) is very helpful in arriving at the correct diagnosis. The uveal biopsy may be performed using either an ab interno approach (via

antibody) for the treatment of CNS lymphoma with and without ocular involvement has been investigated. One study showed that for recurrent primary CNS lymphoma (n = 4) and for NHL with leptomeningeal involvement (n = 2), systemic administration of rituximab via a combination of intravenous and intraventricular injections, intraventricular injections alone, or intrathecal injections alone had some benefit in terms of clearing the leptomeningeal process but was less efficacious for solid parenchymal disease [12].

Given the blood–brain barrier, the efficacy of intravenous administration of immunotherapy is limited. Intrathecal administration of rituximab appears to overcome the penetration limitation of intravenous administration, as shown in a recent phase I trial in which intrathecal administration of rituximab at a dose ranging from 10 to 25 mg via an Ommaya reservoir over 5 weeks resulted in cytologic response in 6 of 10 patients with non-Hodgkin’s CNS lymphoma [13].

Some believe that intravitreal treatment of primary intraocular lymphoma with rituximab is ideal given the specificity of CD20-positive cells for primary intraocular lymphoma and the lack of CD20-positive cells in the normal eye, in particular in the neurons and glial tissues [14]. Intravitreal injection of rituximab has been studied in animals and in humans [15–18]. In rabbit studies, the half-life of rituximab 1 mg delivered by intravitreal injection was 4.7 days, and the drug was detectable up to 72 days, although the threshold dose needed for clinical efficacy is unclear [16]. In a small number of patients, no obvious toxicity was observed with intravitreal rituximab at a dose of 1 mg/0.1 ml, although longer term data from histologic and electrophysiologic studies are lacking [15, 16, 19, 20]. Further studies are warranted to evaluate the optimal conditions under which intravitreal rituximab may be of benefit to patients with primary intraocular lymphoma.

Other local therapies currently being considered include treatment with siRNA, anti-adhesion molecule therapy, anti-CD22 constructs, anti-angiogenic agents, and anti-interleukin-10 therapy [21]. Other broad areas for further research include identifying better prognostic factors, improving the sensitivity of diagnostic tools and imaging modalities, and increasing the use of animal models in testing preclinical local and systemic treatments [21].

39.5 Conclusions

At present, intraocular lymphoma remains a challenging disease to diagnose and cure. Early clinical recognition, core vitreous biopsy, and expert cytologic assessment are critical components in achieving improved clinical outcomes. Multidisciplinary treatment in consultation with experts on CNS lymphoma is the standard approach at our institution. Intensive systemic chemotherapy and ocular radiotherapy are often considered initially. Future studies using anti-CD20 monoclonal antibodies, such as rituximab, appear promising.

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