Malignant intraocular lymphoma is subcategorized by the structures it affects. The two main subdivisions are vitreoretinal (VRL) and uveal. In this article, we focus on vitreoretinal lymphoma.
VRL is characterized by the involvement of the vitreous, retinal, subretinal space, and/or optic nerve head.1 Most commonly, however, VRL presents with isolated vitritis with or without subretinal involvement.1
In contrast, uveal lymphoma is a less common and indolent disease found in the choroid with possible transscleral and/or orbital extension. VRL must be distinguished from choroidal lymphoma (CL), which is commonly low-grade extra nodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT).1,2
In addition to their differing intraocular distribution, VRL and CL differ in their associations with central nervous system (CNS) and visceral lymphoma, respectively. Clinically speaking, VRL patients present with a quiet eye, multifocal yellow subretinal pigment epithelial deposits, vitritis, and possible CNS disease. In contrast, uveal lymphoma presents as a sizeable subretinal tumor(s), with no vitritis, transscleral extension, and possible visceral disease.2
Overview of primary vitreoretinal lymphoma
VRL is considered a variant of primary CNS lymphoma (PCNSL), of which around 90 to 95% is classified as diffuse large B-cell lymphoma (DLBCL).1 More recently, VRL has been termed PCNSL-ophthalmic variant (PCNSL-O) to emphasize that this is a variant of primary CNS lymphoma.3
Two-thirds of patients with VRL develop CNS disease within 29 months (about 2.5 years) of diagnosis.4 PCNSL patients have an estimated 5-year overall survival of 33% based on Surveillance, Epidemiology, and End Rates (SEER) registry data.5
Due to its rare occurrence and variable presentations, often simulating uveitis, VRL's natural history is poorly understood. Like other rare cancers, the literature is composed of case reports, limited case series, and an occasional review. These small numbers and divided treatments by uveitis, retina, and ophthalmic oncology subspecialists have made the development of clinical trials difficult.
Risk factors for primary vitreoretinal lymphoma
Patient age and immunodeficiency are the two major risk factors for primary vitreoretinal lymphoma. Among immunocompetent patients, most cases of VRL develop after 40, most commonly in the 5th and 6th decades of life.
In cases of immunodeficiency and superimposed Epstein-Barr virus (EBV) infection, PCNSL and VRL develop most commonly in the 3rd and 4th decades. VRL has no known predilection for gender or race.7
Clinical features of primary vitreoretinal lymphoma
Masquerade is when one “pretends to be someone else by mask or costume.” VRL is a masquerade syndrome in that its subtle clinical signs and presenting symptoms can mimic other ocular conditions. In practice, this usually results in delays in diagnosis and difficulty making the diagnosis.
Patients commonly present with painless decreased vision and floaters without redness and photophobia, which sometimes may be diagnosed as typical age-related floaters or posterior vitreous detachment. Synchronous bilateral involvement is seen in 80% of patients; however, asymmetric or metachronous presentation is not uncommon.1
The anterior and posterior segments may be involved on examination, but anterior findings are less common. Sometimes, this can lead to an initial diagnosis of intermediate uveitis or pars planitis. One distinguishing feature of uveitis, as opposed to VRL, is that uveitis may present with iris depigmentation and anterior or posterior synechiae, not typically seen in VRL.7
Posterior segment findings in VRL
There is a range of posterior segment findings in VRL that present a challenge when faced with arriving at the correct diagnosis. Certain clues may help distinguish VRL from uveitis.
Vitritis is the most common, and sometimes only finding in VRL, with tumor cells depositing along the vitreous fibrils to give a characteristic “aurora borealis” or “string of pearls” appearance (Figure 1).1,7 The tumor cells in VRL are larger than ordinary nonmalignant inflammatory cells and often deposit in sheets and clusters.
Vitreous haze may also be subdued, with superior and peripheral densities that do not reflect the gravitationally-dependent inflammatory aggregation seen in cases of intermediate uveitis.7
Figure 1 shows a patient with VRL and depicts large lymphoma cells connected by vitreous fibrils in a “string of pearls” pattern. Unlike other causes of vitritis, VRL vitreous cells are larger and more likely to aggregate.
Figure 1: Reproduced, with permission, from Kim SJ et al.
Retinal findings in VRL
Retinal and retinal pigment epithelium (RPE) involvement is typically present and may help guide the diagnosis. Lymphoma cells deposit underneath the RPE, growing along Bruch’s membrane and leading to focal detachments and atrophy of the RPE.7
These sub-RPE infiltrates are considered a pathognomonic feature of VRL. Sheets of yellow-white malignant cells can also develop, leading to persistent pigmentary alterations. As the disease progresses, creamy subretinal lesions may become more widespread, developing a “leopard spot” appearance that mimics findings seen in white dot syndromes, as illustrated in Figure 2.1
However, the distinct sub-RPE infiltrates seen in VRL may be evident in only 20 to 40% of patients on presentation.1 Choroidal invasion is atypical, as lymphoma cells seemingly cannot penetrate the Bruch’s membrane.9
Figure 2 demonstrates multimodal imaging of VRL:
- In A, a color fundus photograph (CFP) of the left eye of a patient with primary CNS lymphoma and recurrent VRL depicts diffuse “leopard spot” hypopigmented lesions.
- In B, fundus autofluorescence (FAF) of the left eye depicts corresponding hypo-autofluorescent spots.
- In C, optical coherence tomography (OCT) of the left eye depicts sub-RPE nodular lesions (red arrow), subjacent increased choroidal reflectivity, and ellipsoid zone irregularity (yellow arrows).
Figure 2: Reproduced with open access permission under Creative Commons Attribution 4.0 International License, from Xu LT et al.
Comparison of clinical findings in VRL and uveitis
Table 1 compares the clinical findings in primary vitreoretinal lymphoma and uveitis.1,11,12,13
| Vitreoretinal Lymphoma | Uveitis | |
|---|---|---|
| Anterior Segment | ||
| Conjunctival Injection | Rare | Common |
| Scleritis | Absent | Possible |
| Keratic Precipitates | Rare | Common |
| Hypopyon | Rare | Common |
| Anterior Chamber Inflammation | Rare | Common |
| Anterior Synechiae | Rare | Common |
| Posterior Synechiae | Rare | Common |
| Vitreous & Posterior Segment | ||
| Vitreous Cells | Common | Common |
| Snowbanking | Absent | Common |
| Vitreous Hemorrhage | Unlikely | Unlikely |
| Retina | Multifocal yellow sub-RPE tumors | Vasculitis, subretinal fluid, macular edema, retinal necrosis, etc. |
| Choroid | Rare | Common |
| Optic Nerve Edema | Common | Common |
Table 1: Courtesy of the authors.
Utilizing multimodal imaging to diagnose VRL
Multiple imaging modalities may provide characteristic findings to aid in the diagnosis of VRL. Color fundus photography allows for direct visualization of key manifestations, providing a valuable foundation for VRL diagnosis.
Vitreous haze and cream-colored subretinal lesions are common findings seen on fundus photography in VRL (Figure 2).8 Fundus photography also allows the clinician to evaluate treatment efficacy by monitoring for regression of subretinal deposits.
Fundus autofluorescence
Fundus autofluorescence is helpful in its ability to detect both diffuse and focal areas of RPE disruption.10 With FAF, one can see a granular pattern of hypo- or hyper-autofluorescence, in which hyper-autofluorescent lesions represent sub-RPE deposits of lymphoma cells.1,10
It has been proposed that lymphomatous sub-RPE proliferation alters the metabolism of the overlying RPE cells, producing melanolipofuscin-related hyperautofluorescence.10 Areas of hypo-autofluorescence are related to loss of the RPE in more mature lesions (seen in Figure 2).
Optical coherence tomography
OCT is particularly useful for monitoring treatment response in VRL. RPE nodularity (seen in Figure 2) is the most common finding in 63% of cases.10 Pigment epithelial detachments (PEDs) can be seen as a result of lymphomatous proliferation in 30 to 50% of cases.10
Nodular hyperreflective spots on OCT often correspond to areas of hyper-autofluorescence on FAF.1 Monitoring for a reduction in hyperreflective sub-RPE infiltrates can provide valuable insight into the efficacy of VRL treatment.10
Vertical hyperreflective columns (VHRLs), representing tumor infiltrates, extend from the inner retina to RPE and may be found in 58% of patients.10 The hyperreflective nodularity seen in VRL is limited to the space between the RPE and Bruch’s membrane, helping to distinguish VRL from choroidal pathology.1
Fluorescein angiography (FA)
Fluorescein angiography may also aid in analyzing the progression or resolution of disease. On FA, retinal lymphomatous infiltrates between Bruch’s and RPE can be seen as hypo-fluorescent “leopard spots.”1,10
The granular pattern of hyper-fluorescence and hypo-fluorescence seen with FA is the reverse of that seen with FAF.10 Areas of hypo-fluorescence are produced when the depositions of sub-RPE lymphomatous cells block choroidal fluorescence.10 FA analysis provides helpful clues to distinguish VRL from other causes of active uveitis.
Indocyanine green angiography (ICGA)
Choroidal visualization via ICGA allows one to distinguish VRL from diseases with more prominent choroidal involvement, such as white dot syndromes, sarcoidosis, and choroidal or uveal lymphoma.
The most common ICGA finding in VRL is hypo-fluorescence, which corresponds to atrophic RPE and choriocapillaris areas.1,10 These hypo-fluorescent spots appear hypo-autofluorescent on FAF and hyperfluorescent in late stages of FA.10 Notably, ICGA is unremarkable in areas of active leakage on FA and acute RPE disruption.10
Diagnosis of VRL with pars plana vitrectomy
Pars plana vitrectomy (PPV) with vitreous sampling for cytologic and genetic analysis is the gold standard for tissue diagnosis.1 The biopsy sample may be analyzed with cytology and flow cytometry. Cytologic analysis alone presents challenges due to the fragility of lymphoma cells in vitreous tissue.1
Immunophenotyping via flow cytometry can reveal monoclonal B-cells with kappa or lambda light chain restriction and positive B-cell markers for CD20, CD79a, and PAX5.1 Although tissue sampling is the gold standard, poor cell preservation due to fragility of lymphoma cells negatively impacts and decreases the sensitivity of cytology and flow cytometry results.
Evaluating the cytokine profile
The cytokine profile of vitreous and aqueous fluid may help support a diagnosis of VRL. It is well established that interleukin 6 (IL-6) is an inflammatory cytokine predominant in the vitreous of patients with uveitis.
Conversely, interleukin 10 (IL-10) acts as a growth factor for malignant B-cells.1 An IL-10:IL-6 ratio of >1.0 suggests a lymphomatous rather than a uveitic process, with a sensitivity of 93 to 94% and specificity of 95 to 100%.1
Genetic testing for VRL
The MYD88 and CD79B mutations are the most frequently mutated genes in DLBCL.1 Genetic testing for MYD88 in vitreous or aqueous samples has 100% specificity for VRL, with greater sensitivity in vitreous (75%) than in aqueous (67%) samples.14
As part of the MYD88/CD79B-mutated (MCD) cluster, PIM-1, IGLL5, and BTG1/2 are among the other genes recently shown to be involved in both primary and secondary VRL.1
Recent studies have expanded the genetic profile available for testing in suspected cases of VRL via next-generation sequencing and digital droplet polymerase chain reaction of cell-free DNA.1
Staging of VRL
When VRL is suspected or biopsy-proven, comprehensive CNS and systemic staging is necessary to investigate further disease involvement.
A neuro-oncologist may pursue additional workup, including:
- Magnetic resonance imaging (MRI) of the brain and spine with contrast
- Lumbar puncture for evaluation of leptomeningeal involvement of lymphomatous cells via cytology and flow cytometry
- Systemic body imaging with PET (positron emission tomography) and CT (computerized tomography) of the chest, abdomen, and pelvis with contrast
Each component is critical to identifying disease and treating and longitudinally monitoring patients on therapy properly. Radiographic evidence of an intracranial lymphomatous process highlighted most often by homogenously enhancing and diffusion-restricted CNS lesions or positive CSF for a malignant clonal population of lymphoma cells is highly suggestive of VRL diagnosis.
Treatment of localized VRL
When VRL is localized to the eye, treatment approaches include multiple, periodic intravitreal drug injections (e.g., rituximab, methotrexate) or, alternatively, a less than 2-week long, single session of low dose (20 to 26Gy total, in 180 to 200cGy daily fractions) external beam radiation therapy.1,7,9,15
Intravitreal injections carry risks of infection and drug toxicity, and radiation can cause dose-dependent dry eye, cataract, and retinopathy. Antimetabolite systemic chemotherapy has not been an effective method to control intraocular disease.
Extraocular PCNSL in the brain, spine, or CSF is traditionally treated with a poly-chemotherapy induction regimen based on high-dose methotrexate. Surgery does not provide a survival benefit. Whole brain radiation was previously utilized for treatment; however, its lack of durable response and early relapses have rendered it not standard of care in neuro-oncologic practice.
After induction, patients undergo consolidation therapy, which depends upon response rate, performance status, and age. Consolidation therapy occurs via either non-myeloablative chemotherapy such as Cytarabine, reduced whole brain radiation, or more aggressive novel treatments such as high-dose myeloablative chemotherapy followed by autologous stem cell transplant.
It is suggested that combination therapy with both systemic and local treatments may be effective in preventing VRL relapse.1 However, this effect remains controversial due to the difficulty in comparing homogenous treatment protocols across studies.1
Recent studies have provided encouraging results suggesting a decreased incidence of CNS relapse in patients treated with various combination therapies (local and systemic MTX or systemic chemotherapy and whole brain irradiation).1 A similar treatment approach with intravitreal chemotherapy and targeted radiation may be applied when treating recurrent VRL.7
Current research on treatments for primary VRL
In a recent attempt to repurpose effective treatments for DLBCL, targeted therapies with lenalidomide and ibrutinib have shown clinical activity in the eye during phase 1 and proof-of-concept phase 2 trials.16,17
The National Comprehensive Cancer Network (NCCN) also approved both lenalidomide and ibrutinib for patients with extra-ocular CNS lymphoma in the recurrent setting.
Single-agent therapy with oral temozolomide has also shown promise in retrospective studies of patients with VRL.18 Single-agent pembrolizumab therapy for patients with PCNSL and VRL is currently under investigation.19 Without medical evidence of cure, these authors suggest all patients be included in clinical trials.
Differential diagnosis for primary VRL
Primary vitreoretinal lymphoma remains an elusive masquerade diagnosis, mandating careful analysis of clinical history, imaging findings, and diagnostic criteria. VRL is often the first presentation of CNS lymphoma.
Additionally, VRL often mimics chronic steroid-resistant uveitis or idiopathic vitritis. The latter often obscures VRL’s retinal findings.1,7,9 For the posterior segment, it is essential to exclude infectious etiologies such as acute retinal necrosis secondary to viral retinitis, toxoplasmosis chorioretinitis, syphilitic retinitis, and tuberculosis.20
With a few exceptions, most autoimmune inflammatory conditions such as sarcoidosis and white dot inflammatory syndromes are initially present in younger populations than is seen with VRL.16 Eye doctors seeing patients with intermediate uveitis and floaters should always consider vitreoretinal lymphoma in the proper clinical setting.
In conclusion
VRL is considered the ophthalmic variant of PCNSL, now termed PCNSL-O. It most commonly presents in the 5th and 6th decades of life and has no predilection for gender. Younger age at presentation warrants workup for underlying immunodeficiency. Anterior segment findings are rare in VRL; the presence of anterior/posterior synechiae and/or iris depigmentation discourages lymphoma as a diagnosis.
Vitritis is the most common presentation of VRL, with superior/peripheral densities (non-gravitationally dependent) of vitreous haze signifying lymphomatous cell deposition along vitreous strands. Of note, vitritis may mask sub-RPE deposits, sub-RPE deposits in VRL exist between the RPE and Bruch’s membrane, and perivascular leakage on FA is uncommon.
ICGA and ultrasound imaging can help distinguish VRL from diseases with choroidal involvement. MRI brain and orbits with contrast, lumbar puncture, and systemic imaging with PET CT of the chest/abdomen/pelvis are crucial in diagnosing VRL due to the high rate of CNS involvement, requiring co-management with neuro-oncology.
While pars plana vitrectomy with vitreous biopsy for cytology is the gold standard for tissue diagnosis of VRL, its sensitivity is low. Genetic analysis further suggests diagnosis for the presence of MYD88 mutation and IL-10 to IL-6 ratio >1.0.
There exist no consensus guidelines for treatment; however, combination therapy with systemic/local chemotherapy and external beam radiation therapy is most commonly employed. A multicenter international data-sharing study is needed to determine the natural history of VRL, which can serve as a foundational element for clinical trials.
