The evaluation and treatment of primary intraocular lymphoma

Primary intraocular lymphoma (PIOL) is a relatively rare form of Non-Hodgkin’s Lymphoma arising in the lymphoid tissues of the eye. It is highly correlated with primary CNS lymphoma (PCNSL) and it is estimated that up to 80% of patients presenting with PIOL will eventually manifest intracranial malignancy, which is the largest contributor to mortality. Most patients present with nonspecific visual symptoms, including floaters and blurry vision, and are often initially diagnosed with uveitis or retinitis. Definitive diagnosis requires biopsy of malignant tissues with demonstration of malignant lymphoid cells. Optimal therapy is to this point undefined, and the available literature is limited to case reports and retrospective series. Currently employed therapies include the use of localized external beam radiation therapy (EBRT), whole brain radiation therapy (WBRT), systemic chemotherapy, intrathecal chemotherapy, and, most recently, direct intravitreal (IVT) chemotherapy. While radiation therapy and chemotherapy can produce a high response rate, they have not been shown to effectively prevent relapse or the incidence of CNS spread. Methotrexate has been the most popular therapy used for the treatment of intraocular lymphoma. It has been administered systemically, intrathecally or intravitreally. However due to multiple mechanisms of resistance developed by lymphoma cells against methotrexate, this drug has been unable to prevent disease recurrence. The newest, and perhaps most promising, reported therapy includes the use of rituximab anti-CD20 monoclonal antibody either alone or in combination chemotherapy via intrathecal or IVT administration. Most cases in the literature employ combinations of available therapies, and there are no comparative studies of significant power to date. Multicenter collaboration will be required to determine the true relative efficacy and adversity of the therapeutic options available. keywords: Primary intraocular lymphoma, methotrexate, intravitreal rituximab © 2013Alexandru et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Primary intraocular lymphoma (PIOL), also known as primary vitreoretinal lymphoma (PVRL), is a rare subset of primary central nervous system lymphoma (PCNSL) arising in the retina, vitreous, subretinal pigment epithelium, or optic nerve head [1]. Intraocular lymphoma can arise primarily within the lymphoid tissues of the eye or due to metastatic spread of hematopoietic malignancy from the CNS. The disease is classified as PIOL if, at the time of diagnosis, the disease is limited to the eye with no intracranial involvement [2]. Vitreoretinal lymphoma with concomitant CNS disease is classified as PCNSL with ocular involvement [2]. It has been shown that up to 80% of patients with PIOL will be subsequently diagnosed brain lymphoma, and among those presenting with PCNSL up to 25% have concomitant ocular involvement [3]. For this reason it is thought that definitive management of PIOL may improve morbidity and mortality by preventing spread to the brain and leptomeninges [4]. Given its rarity, PIOL has been difficult to study. To date, no formal standards exist for the treatment of this condition, but many therapies have been experimentally employed. For those with no concomitant CNS disease, high dose intravenous (IV) methotrexate with adjuvant local radiation [5,6] and intraocular methotrexate injections [7-9] have been popular in the literature. For those with comorbid CNS malignancy, whole brain radiation therapy (WBRT) and IV or intrathecal (IT) chemotherapy in conjunction with intravitreal chemotherapy have been used [10-12]. The most novel therapy for the treatment of PIOL involves the use of rituximab, a humanized antibody targeting CD20+ B cells, in either IV or intravitreal administration [13,14]. Because several treatment modalities have been reported in the literature, many authors have called for further research into the comparative effectiveness of the available treatments and the establishment of treatment guidelines thereof [1,15,16]. This paper provides an up-to-date review of the multiple interventions currently employed in PIOL management, and to our knowledge contains the most comprehensive meta-analysis of case reports and retrospective series of novel therapies to date. With this we hope to better guide further investigation into the comparative effectiveness of novel methods for treating PIOL. Incidence and Distribution PIOL is the most common lymphoma of the eye [17]. A 20-year retrospective study at a large Canadian hospital estimated the incidence of PIOL in British Columbia to be between 0.017-0.048 per 100,000 people between 1990 and 2010 [18]. Still, since no national registry or central database for intraocular lymphoma exists, the true incidence of PIOL is unknown. PCNSL is both Journal of Cancer Therapeutics & Research