Primary Intraocular Lymphoma
An update on pathology and treatments.
Primary intraocular lymphoma (PIOL) is a rare malignancy. It is estimated to represent less than 1% of non-Hodgkin's lymphomas and less than 1% of intraocular tumors.1 Clinically, the disease has often been classified as a subcategory of primary central nervous system (CNS) lymphoma.2 Recent molecular studies, however, suggest differences in disease pathogenesis.3 Many authors have discussed the confusing nature of the PIOL terminology, and some have proposed that the disease be referred to on the basis of its origin in the retina, ciliary body, choroid, or iris.4 PIOL is typically a high-grade B-cell malignancy.
PIOL is characterized clinically by malignant lymphocytic invasion of the vitreous, retina, or optic nerve, and may occur either as an isolated finding before involvement of the neuraxis is apparent or as a component of concomitantly or previously diagnosed CNS disease. The disease is more often bilateral, but can present asymmetrically. It is not known if the malignant transformation of these cells occurs within or outside the eye. Some authors hypothesize that the initial malignant transformation occurs outside the eye and then the malignant cells become trapped in the "immune privileged" enclosed structures of the eye, which permit tumor growth while the systemic clone is eliminated by the intact immune system. Other authors speculate that PIOL originates from lymphocytes that are chronically activated, selected, and transformed by exposure to a pathogen or antigen within the eye.
There has been an increase in the incidence of PIOL in the older immunocompetent population over the past 20 years or so, which is not thought to be accounted for by improved neuroimaging or stereotactic neurosurgery.5 The incidence of primary CNS lymphoma had increased over the past 30 years in part due to the increased incidence of AIDS.5 Since the mid-1990s and increased availability of antiretroviral therapies, however, the incidence appears to have stabilized in this population of young patients.6
PRESENTING SIGNS AND SYMPTOMS
Patients with PIOL (Figure 1) frequently present to a retina specialist because they may manifest a variety of ophthalmic signs that can easily mimic other intraocular conditions. In a review of more than 800 uveitis patients in a large referral center, this diagnosis represented the most common masquerade syndrome accounting for one-third of all masquerade syndromes, although it represented only 1.6% of all uveitis.7 PIOL must always be considered whenever uveitis does not respond to steroids in older patients.4 Patients can present with many findings, listed in Table 1.
Because patients with PIOL often present with a chronic idiopathic uveitis-like presentation, definitive tissue diagnosis is often required. Pars plana vitrectomy (PPV), the most commonly used and most effective sampling technique, can provide both diagnostic and therapeutic results. The advantage of PPV is that the surgeon can obtain a large volume fluid sample and targeted tissue biopsy, facilitating cytological analysis.2 Recently, the advent of the 23-gauge PPV system has enabled a sutureless procedure while keeping the specimen yield at least comparable with traditional 20-gauge techniques.
Most clinicians routinely send an undiluted specimen for cytology and molecular analysis with polymerase chain reaction (PCR) amplification with or without cytokine level analysis and antibody determination. Diluted vitreous specimens are typically sent for flow cytometry and bacterial/fungal/viral cultures. Even when performed properly, diagnostic vitrectomies are often negative.8 This can occur because of minimal involvement of the vitreous or degeneration of the cells. As a result, patients often require multiple procedures before a definitive diagnosis is identified.
B-cell malignancies can secrete high levels of interleukin-10 (IL-10), an immunosuppressive cytokine, whereas inflammatory processes are associated with high levels of IL-6.8 IL-10:IL-6 rations greater than 1 have been reported to be suggestive of PIOL and useful for following response to treatment.9 Recently, researchers from France have reported that the measurement of IL-10 levels in aqueous can serve as a screening tool for primary intraocular lymphoma.10 A cutoff of 50 pg/mL in the aqueous was associated with a sensitivity of 0.89 and a specificity of 0.93.
TRADITIONAL AND INVESTIGATIVE TREATMENTS
Just as it is often difficult to diagnose, PIOL is challenging to treat. Because of the blood-retinal barrier, the concentrations of drug delivered to the vitreous via intravenous injection are low and unpredictable, requiring very high dosing of the chemotherapeutic agents. Traditionally, the mainstay of treatment was external beam radiation with a 30 Gy to 45 Gy treatment prescribed to both eyes; the historical 5-year survival rates with this treatment have been dismally low at 10% to 29%.5 Furthermore, morbidity due to neurotoxicity is common, especially in older patients, and can present as cognitive dysfunction, ataxia, and dementia.11 Better disease control combining radiation and methotrexate-based chemotherapy has been reported,12 but the combined strategy is not universally accepted, based on retrospective surveys of routine clinical practice.5
Newer therapeutic strategies have included high dose chemotherapy with autologous stem cell transplantation13 and intravitreal injections of methotrexate with or without thiotepa.14-16 In the largest of these studies, Smith et al16 treated 16 patients with a series of intravitreal methotrexate injections that were performed twice weekly for 1 month, then weekly for 1 month, then monthly for 1 year. Short-term remission (median, 18.5 months of follow-up) was achieved in all of the patients who completed the protocol, although six patients died of progression of intracranial disease. A major confounding factor in this study was the fact that the patients in the study received a wide range of additional treatments, including intraventricular and intravenous chemotherapy of varying regimens and ocular external beam radiation. This heterogeneity made it difficult to assess the efficacy of the intravitreal methotrexate in isolation. A group from Japan reported more recently that vitreous IL-10 levels were nondetectable after treatment in six patients treated with intravitreal methotrexate.17 A corneal epitheliopathy was observed in all cases, which resolved after the treatment period.
Intravitreal rituximab (Rituxan, Biogen Idec/Genentech, Inc.; distributed in Europe as MabThera, Roche) is an investigational strategy that has gained attention recently. Rituximab is a chimeric monoclonal antibody directed against the B-cell specific antigen CD20 and is efficient alone or in combination with chemotherapy in systemic non-Hodgkin's lymphoma.5,11 High doses of the drug can be safely administered intravenously in order to achieve higher concentrations in the cerebrospinal fluid.5
Pharmacokinetic study of intravitreal injections of rituximab in rabbits demonstrated a 4.7-day half-life of the drug in the vitreous.18 Extrapolation of this data suggested that a 1 mg intravitreal injection of the drug in humans might deliver vitreous drug levels that would remain above 10 ng/mL for 72 days. Drugs are known to be cleared more rapidly in previously vitrectomized eyes, however, and most patients who would be eligible for this therapy have previously undergone vitrectomy and possibly cataract surgery.18 The effect of these surgeries on the clearance of rituximab is not known. Kitzmann et al recently confirmed the lack of toxicity of intravitreal rituximab in rabbits.19
Kitzmann et al were also the first group to report the use of rituximab in humans. Five eyes of three patients were treated with one to four injections per eye. There were no signs of clinical toxicity, although no electroretinograms (ERGs) were performed. Clinical effectiveness of the drug could not yet be determined because all three patients in the study received either other additional ocular treatment or systemic treatment. Since this report, several other patients have been treated with success.20 Given that 95% of PIOL malignancies are B-cell in origin and express the CD20 antigen, rituximab appears to be an ideal intravitreal therapy.
Primary intraocular lymphoma is a rare malignancy that is a challenge to diagnose and treat. Treatments in the past such as whole brain radiation and chemo-therapy have had devastating side effects on the elderly patients whom the disease usually affects. New biological intravitreal therapies such as rituximab hold the potential promise of minimal systemic toxicity with a robust intraocular response. In the future, we are likely to see the use of combination intravitreal therapy targeted to the specific expression patterns of CD antigens for each individual patient.
Amy C. Schefler, MD, is at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine in Florida.
Daniel Gologorsky is a medical student at Dartmouth Medical School in Hanover, NH.
Timothy G. Murray, MD, MBA, FACS, is Professor of Ophthalmology and Radiation Oncology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. Dr. Murray is a consultant for Alcon Laboratories, Inc. He can be reached at +1 305 326 6000, ext. 6166; fax: +1 305 326 6147; or via e-mail at firstname.lastname@example.org.