Primary intraocular lymphoma: Current and future perspectives

Primary intraocular lymphoma (PIOL) is a rare disease characterized by infiltration of the retina, uveal tract, vitreous or optic nerve head. It is almost always of diffuse large B-cell lymphoma (DLBCL) histology with occasional reports of T-cell origin. By virtue of its rarity in the literature, its clinicopathological definition remains somewhat ill defined as does its place within the spectrum of primary central nervous system lymphoma (PCNSL). While considered by many to be a subset of PCNSL, the coand independent presentation of PIOL with PCNSL confounds the identification of its unique pathobiology and optimum treatment. Indeed, as the authors of the accompanying report note, PIOL by definition presents independently of PCNSL, but 60 – 85% of patients eventually develop intracranial involvement and some 15 – 25% of PCNSL have concomitant ocular disease. Important clinical and biological questions remain unanswered. Do cases which remain confined to the eye have a different microenvironment requirement compared to cases which spread to the CNS? Does PIOL have a distinct tumor biology and hence gene expression signature and if so, how does it differ from PCNSL? Is radiotherapy integral to the treatment of PIOL and what is the role of chemotherapy and/or novel drugs which could obviate the need for radiation and avoid ocular toxicity? Answers to such questions will enhance our understanding of PIOL and help guide new treatment approaches and the optimal management. The multi-institutional survey of PIOL reported by Isobe and colleagues in this issue [1] is a unique case series, given that all patients presented with PIOL, and can provide some new perspectives. While bilateral ocular involvement by disease in the current series is not a new finding, the high rate of 87% suggests a prominent role for the microenvironment in disease spread. Firm conclusions regarding optimal treatment of PIOL cannot be made from the current series but several observations are worthwhile. Two of nine patients who received prophylactic cranial irradiation (PCI) developed CNS spread, whereas one of four patients who did not receive PCI developed CNS spread, suggesting PCI is not useful. Indeed, as cranial radiation is rarely curative in PCNSL and causes significant cognitive toxicity, it would seem imprudent to recommend PCI for such patients at the present time [2]. Although the effectiveness of systemic chemotherapy on CNS spread cannot be determined from the study, none of three patients who received high-dose methotrexate developed CNS recurrence. This is not inconsistent with the success of methotrexate in PCNSL and reinforces the notion that systemic chemotherapy should be examined as a strategy to reduce CNS recurrence. The natural history of PIOL/PCNSL suggests they possess cellular mechanisms distinct from systemic diffuse large B-cell lymphomas (DLBCL). Indeed, it is known that systemic DLBCL is comprised of at least three molecular subtypes termed germinal center B-cell (GCB), activated Bcell (ABC) and primary mediastinal B-cell (PMBL) [3 – 5]. In addition to molecular differences, these subtypes possess differences in clinical presentation and prognosis [4]. Likewise, the confinement of PIOL/PCNSL to the CNS axis for almost all of their natural history suggests a unique pathobiology which reflects a dependency on the microenvironment and/or trafficking signals. Recent work has investigated both the immunohistochemical profile