Ophthalmology – Vitreoretinal Lymphoma

What the Disorder Represents

Vitreoretinal lymphoma (VRL) is an aggressive lymphoid malignancy involving the:

• Vitreous
• Retina
• Subretinal space
• Retinal pigment epithelium (RPE)

Most primary cases are:

Diffuse large B-cell lymphoma (DLBCL)

and are closely related biologically to primary central nervous system lymphoma (PCNSL).

The preferred term is:

Primary vitreoretinal lymphoma (PVRL)

when the disease arises within the eye/CNS compartment rather than representing secondary spread from systemic lymphoma.

Why “Primary Intraocular Lymphoma” Is Less Precise

The older term:

Primary intraocular lymphoma

is potentially confusing because several distinct lymphomas can occur inside the eye.

These include:

• Primary vitreoretinal lymphoma – aggressive, high-grade, strongly linked to PCNSL
• Choroidal lymphoma – usually indolent, low-grade B-cell lymphoma
• Secondary intraocular involvement from systemic lymphoma

These disorders differ substantially in:

• Clinical appearance
• Biology
• CNS association
• Prognosis
• Treatment

Who Is Most Often Affected

PVRL occurs predominantly in:

• Older adults
• Typically sixth to seventh decade or later

It can occur in:

• Immunocompetent individuals
• Immunocompromised patients

Disease in children is exceptionally rare.

Relationship to the Central Nervous System

The most important systemic association is:

Primary CNS lymphoma.

PVRL is generally regarded as part of the PCNS lymphoma spectrum.

Patients may present with:

• Eye disease alone
• CNS disease alone
• Both simultaneously

A substantial proportion of patients who initially have apparently isolated ocular disease later develop:

CNS lymphoma.

This is why long-term neurologic surveillance is essential.

Bilateral Disease Is Common

PVRL is frequently:

Bilateral

but involvement may be:

• Asymmetric
• Sequential

One eye can therefore appear minimally involved while the fellow eye contains obvious disease.

What Causes It

The precise cause is not fully understood.

Most tumors arise from malignant B lymphocytes with characteristic molecular abnormalities.

Important modern molecular findings include:

• MYD88 L265P mutation
• CD79B pathway abnormalities
• B-cell receptor/NF-κB pathway activation
• Immunoglobulin gene clonality

These findings are diagnostically useful.

Important Modern Correction About Infection

Older literature proposed that:

• Epstein-Barr virus
• Herpesviruses
• Toxoplasma gondii

might directly cause PVRL.

In modern practice, these are:

Not considered established causes of typical PVRL in immunocompetent patients.

EBV is more relevant to certain lymphomas arising in severe immunosuppression.

How the Tumor Reaches Ocular Tissues

Malignant lymphocytes preferentially infiltrate:

• Vitreous
• Retina
• Sub-RPE space

rather than primarily involving the choroid.

This explains the classic combination of:

Vitreous cellular infiltration + creamy sub-RPE/retinal lesions.

What Patients Usually Notice

Typical symptoms include:

• Floaters
• Painless blurred vision
• Reduced contrast
• Hazy vision

Less commonly:

• Photopsias
• Visual field disturbances

Pain, severe redness, and photophobia are generally:

Less prominent than in ordinary inflammatory uveitis.

Why Diagnosis Is Often Delayed

PVRL frequently masquerades as:

Chronic intermediate or posterior uveitis.

Patients may initially be diagnosed with:

• Idiopathic vitritis
• Autoimmune uveitis
• Infectious uveitis

Transient improvement with corticosteroids may further delay the diagnosis.

The Classic Vitreous Appearance

The vitreous commonly contains:

• Sheets of cells
• Clumps of cells
• Fine particulate cellular haze

The appearance may resemble inflammatory vitritis but often has:

Dense cells with surprisingly little anterior-segment inflammation.

Characteristic Subretinal and Sub-RPE Lesions

A key finding is:

Creamy yellow-white infiltrates at or beneath the RPE.

They may appear as:

• Tiny dots
• Round lesions
• Plaques
• Confluent infiltrates

Early lesions can resemble:

• Drusen
• White-dot syndromes
• Inflammatory chorioretinal lesions

What Happens After Lesions Regress

Resolution of lymphoma infiltrates may leave:

• RPE mottling
• RPE atrophy
• Pigmentary disturbance
• Outer retinal loss

These residual changes can permanently reduce vision when the macula is involved.

Other Possible Ocular Findings

Less common findings include:

• Mild anterior chamber cells
• Keratic precipitates
• Retinal vascular sheathing
• Retinal hemorrhage
• Optic disc edema
• Subretinal fluid
• Epiretinal membrane

Frank hypopyon is unusual.

Optical Coherence Tomography

OCT has become extremely useful in suspected PVRL.

Possible findings include:

• Hyperreflective sub-RPE deposits
• Nodular RPE elevations
• Hyperreflective infiltrates within the retina
• Outer retinal disruption
• Ellipsoid zone loss
• RPE irregularity
• Subretinal hyperreflective material

Serial OCT can help monitor:

Response and recurrence.

A Characteristic OCT Clue

Vertical or column-like hyperreflective lesions extending through retinal layers have been described in PVRL.

Although not pathognomonic, such findings in an older patient with chronic unexplained vitritis should raise suspicion for:

Vitreoretinal lymphoma.

Fundus Autofluorescence

FAF may show a characteristic granular pattern of:

• Hyperautofluorescent spots
• Hypoautofluorescent spots

reflecting:

• Active RPE stress
• Infiltration
• RPE atrophy

A mottled “leopard-spot” pattern can occur.

Fluorescein Angiography

FA may demonstrate:

• RPE window defects
• Staining
• Blockage from infiltrates
• Vascular leakage
• Patchy hypofluorescent and hyperfluorescent lesions

It is supportive rather than diagnostic.

Indocyanine Green Angiography

ICGA may show:

• Hypofluorescent spots
• Areas of choroidal perfusion abnormality

but is generally less central to diagnosis than:

• OCT
• FAF
• Tissue/fluid analysis

Ultrasound Findings

B-scan may show:

• Vitreous opacities
• Mild focal retinal/choroidal thickening

It is mainly useful when:

Media opacity prevents fundus visualization.

Why MRI of the Brain Is Essential

Every patient with suspected or confirmed PVRL should undergo:

Contrast-enhanced MRI of the brain

to evaluate for:

• PCNS lymphoma
• Leptomeningeal disease
• Other CNS lesions

MRI is preferred over CT for detecting CNS lymphoma.

Typical CNS Lymphoma Findings

PCNS lymphoma often produces:

• Homogeneously enhancing lesions
• Deep periventricular lesions
• Corpus callosum involvement
• Basal ganglia or deep white matter lesions

However, the CNS MRI can be normal when ocular disease first appears.

Neurologic Symptoms to Ask About

Patients should be questioned about:

• Cognitive change
• Personality change
• Headache
• Seizures
• Weakness
• Gait disturbance
• Cranial nerve symptoms

New neurologic symptoms in a patient with PVRL require:

Prompt CNS reassessment.

Role of Lumbar Puncture

CSF analysis may include:

• Cytology
• Flow cytometry
• Molecular studies

It is particularly useful when:

• MRI shows suspicious CNS lesions
• Leptomeningeal involvement is suspected
• Neurologic symptoms are present

An important correction is that:

Lumbar puncture is not invariably required in every patient before the diagnosis of PVRL can be established.

It is performed according to the neurologic and oncologic assessment.

Why the Diagnosis Can Be Difficult

Lymphoma cells are:

Fragile

and may rapidly degenerate after specimen collection.

Diagnostic difficulty is increased by:

• Small samples
• Low tumor-cell concentration
• Abundant reactive inflammatory cells
• Previous corticosteroid treatment

Multiple tests and sometimes repeat biopsies are required.

Vitreous Biopsy

When PVRL is strongly suspected, a:

Diagnostic pars plana vitrectomy

is often the preferred method for obtaining adequate vitreous material.

The specimen should be handled rapidly and coordinated with:

• Cytopathology
• Hematopathology
• Molecular laboratory

before surgery.

Why Laboratory Coordination Matters

The surgeon should communicate with the laboratory in advance because vitreous must often be divided for:

• Cytology
• Flow cytometry
• Cytokine analysis
• Molecular testing

Improper handling can markedly decrease diagnostic yield.

Cytology

The traditional diagnostic cornerstone is identification of malignant lymphoid cells.

Typical cells are:

• Large
• Pleomorphic
• High nuclear-to-cytoplasmic ratio
• Prominent nucleoli
• Irregular nuclei

Most PVRL represents:

Large B-cell lymphoma.

Immunophenotyping

Typical B-cell markers include:

• CD20
• CD19
• CD79a
• PAX5

Demonstration of a clonal B-cell population supports lymphoma.

Flow cytometry may also evaluate:

Kappa/lambda light-chain restriction.

MYD88 Mutation Testing

One of the most useful modern diagnostic advances is detection of:

MYD88 L265P

in ocular fluid.

The mutation is present in a large proportion of PVRL and PCNS lymphoma cases.

Testing may be performed on:

• Vitreous
• Aqueous humor

Detection strongly supports the diagnosis in the appropriate clinical setting.

Why Aqueous Humor Is Increasingly Useful

Modern molecular techniques can detect:

• MYD88 mutation
• Tumor-derived DNA
• Cytokines

from small aqueous samples.

This provides a:

Less invasive adjunct to vitreous biopsy

although a negative aqueous test does not exclude PVRL.

Immunoglobulin Gene Rearrangement

PCR demonstrating clonal:

Immunoglobulin heavy-chain gene rearrangement

supports B-cell lymphoma.

However, false-negative and occasional false-positive results can occur.

It should be interpreted alongside:

• Cytology
• Clinical findings
• Other molecular testing

IL-10 and IL-6

PVRL cells frequently produce large amounts of:

Interleukin-10 (IL-10).

Inflammatory uveitis tends to produce more:

Interleukin-6 (IL-6).

An:

IL-10:IL-6 ratio >1

supports lymphoma but is:

Not sufficiently specific to establish the diagnosis by itself.

Absolute IL-10 concentration may also be informative.

Modern Cell-Free DNA Testing

Next-generation sequencing and analysis of:

cell-free tumor DNA

in ocular fluid are emerging as highly useful tools.

These can detect combinations of:

• MYD88
• CD79B
• Other lymphoma-associated mutations

and may improve diagnostic sensitivity when cytology is nondiagnostic.

Availability varies by center.

Why Steroids Can Interfere With Diagnosis

Corticosteroids can cause:

Rapid apoptosis of lymphoma cells.

This may temporarily improve:

• Vitritis
• Vision
• Retinal infiltrates

while reducing biopsy yield.

When clinically safe:

Avoid or minimize corticosteroids before diagnostic sampling.

What to Do If the First Biopsy Is Negative

A negative vitreous biopsy does:

Not exclude PVRL.

If suspicion remains high:

• Repeat vitreous biopsy
• Test the fellow eye if involved
• Perform aqueous molecular testing
• Consider retinal/sub-RPE biopsy in exceptional cases
• Reassess CNS imaging

may be necessary.

Why Retinal Biopsy Is Rarely First-Line

Retinal or chorioretinal biopsy can provide diagnostic tissue but carries risks including:

• Retinal detachment
• Hemorrhage
• Permanent scotoma

It is generally reserved for:

Persistently unexplained cases despite less invasive testing.

The Classic Masquerade Syndrome

PVRL is one of the most important causes of:

Masquerade uveitis

especially in an older adult with:

• Chronic vitritis
• Poor or transient steroid response
• Recurrent inflammation
• Sub-RPE infiltrates

Persistent “idiopathic uveitis” in this setting should trigger reconsideration of the diagnosis.

Important Differential Diagnoses

These include:

• Syphilitic posterior uveitis
• Tuberculosis
• Toxoplasmosis
• Viral retinitis
• Sarcoidosis
• Birdshot chorioretinopathy
• Multifocal choroiditis
• Other white-dot syndromes
• Endogenous endophthalmitis
• Choroidal lymphoma
• Choroidal metastasis

Distinguishing PVRL From Choroidal Lymphoma

These are biologically different diseases.

Vitreoretinal Lymphoma

• High-grade DLBCL
• Dense vitreous cells common
• Retinal/sub-RPE infiltration
• Strong association with PCNS lymphoma

Choroidal Lymphoma

• Usually low-grade B-cell lymphoma
• Diffuse or multifocal yellow choroidal thickening
• Little vitritis
• May produce extrascleral “salmon-patch” extension
• More closely related to systemic marginal-zone lymphoma than PCNS lymphoma

Distinguishing It From Choroidal Metastasis

Choroidal metastases typically appear as:

• Yellow choroidal masses
• Often with subretinal fluid

They generally lack the characteristic combination of:

Dense vitreous cellular infiltration and sub-RPE lymphoma deposits.

Systemic cancer history can provide an additional clue.

Establishing the Extent of Disease

Once PVRL is diagnosed, evaluation should determine whether disease is:

• Eye only
• Eye + CNS
• Rarely related to systemic lymphoma

This generally involves:

• Neuro-oncology/hematology assessment
• Brain MRI
• CSF evaluation when appropriate
• Systemic staging when clinically indicated

Treatment Requires Multidisciplinary Care

Management should involve:

• Ocular oncology or uveitis/retina specialist
• Hematology-oncology
• Neuro-oncology
• Radiation oncology when appropriate

The ocular disease cannot be managed in isolation because CNS relapse is the major determinant of survival.

Treatment When CNS Disease Is Present

When PVRL accompanies PCNS lymphoma, treatment generally includes:

Systemic CNS-penetrating chemotherapy

centered around:

High-dose methotrexate (HD-MTX).

Additional agents may include:

• Rituximab
• Cytarabine
• Thiotepa
• Other CNS-directed chemotherapy

Regimen selection depends on:

• Age
• Performance status
• Renal function
• Treatment center

Modern PCNS Lymphoma Therapy

Contemporary induction regimens frequently combine:

High-dose methotrexate with other CNS-penetrating agents and rituximab.

For suitable patients, consolidation may include:

High-dose chemotherapy followed by autologous stem-cell transplantation.

This has reduced reliance on routine whole-brain radiotherapy in many patients.

Why Whole-Brain Radiation Is Used More Selectively

Whole-brain radiotherapy can control lymphoma but may cause:

Delayed neurocognitive toxicity, especially in older adults.

Therefore modern management often favors:

• Chemotherapy-based induction
• Stem-cell-based consolidation in eligible patients

with radiation reserved for selected situations.

Treatment of Isolated Ocular Disease

Options include:

• Intravitreal methotrexate
• Intravitreal rituximab
• Ocular radiotherapy
• Systemic CNS-directed treatment in selected patients
• Combination approaches

There is no single universally accepted regimen for every patient with isolated PVRL.

Intravitreal Methotrexate

Intravitreal methotrexate is one of the most established local therapies.

A commonly used dose is:

400 µg/0.1 mL

Treatment usually involves:

• Induction injections
• Consolidation
• Maintenance

although schedules vary substantially.

Methotrexate Ocular Toxicity

Repeated injections can cause:

• Corneal epitheliopathy
• Punctate keratopathy
• Epithelial defects
• Cataract
• Macular toxicity rarely

Corneal toxicity is one of the major dose-limiting complications.

Reducing Methotrexate Keratopathy

Strategies may include:

• Reducing injection frequency
• Temporary treatment interruption
• Intensive lubrication
• Folinic acid approaches in selected protocols

while maintaining adequate lymphoma control.

Intravitreal Rituximab

Rituximab, an anti-CD20 monoclonal antibody, can be given intravitreally.

A commonly used dose is:

1 mg/0.1 mL.

It may be used:

• Alone
• With methotrexate

and is particularly useful when methotrexate causes significant corneal toxicity.

Ocular Radiotherapy

External-beam radiotherapy can provide excellent local control.

Typical contemporary doses depend on treatment strategy but are usually considerably lower than historic tumoricidal doses used for many other malignancies.

Potential adverse effects include:

• Cataract
• Dry eye
• Radiation retinopathy
• Optic neuropathy
• Keratopathy

Risk depends on dose and field.

Bilateral Ocular Disease

When both eyes are involved, treatment options include:

• Bilateral local therapy
• Systemic CNS-directed therapy
• Combination treatment

Treatment should account for:

• Existing CNS disease
• Likelihood of CNS progression
• Patient age
• Ocular disease burden

Does Systemic Therapy Prevent CNS Lymphoma?

This remains an area of ongoing investigation.

Because ocular-only PVRL carries substantial risk of later CNS disease, some centers use:

Systemic CNS-directed therapy even when MRI is initially negative.

However, the optimal strategy remains debated and individualized.

Role of Vitrectomy Beyond Diagnosis

Vitrectomy may also:

• Clear visually significant vitreous haze
• Improve visual function
• Reduce cellular burden

but:

Vitrectomy alone is not curative.

Residual lymphoma cells remain in the retina and sub-RPE compartment.

Monitoring Treatment Response

Follow-up should include:

• Visual acuity
• Slit-lamp examination
• Vitreous cellular assessment
• Dilated retinal examination
• OCT
• FAF
• Fundus photography

Molecular or cytokine testing may occasionally assist in monitoring selected patients.

What Ocular Recurrence Can Look Like

Recurrence may present with:

• New floaters
• Increasing vitreous cells
• New sub-RPE deposits
• Recurrent outer retinal infiltration
• New RPE abnormalities

Because recurrence can be subtle, imaging should be compared carefully with:

Baseline studies.

CNS Surveillance

Patients with apparently isolated PVRL require:

Long-term neurologic surveillance.

This usually includes:

• Clinical neurologic review
• Serial brain MRI

The exact frequency is individualized according to:

• Initial disease pattern
• Treatment
• Oncology protocol

Why Long-Term Follow-Up Is Essential

PVRL can recur:

• In either eye
• In the CNS
• Years after initial therapy

Therefore apparent ocular remission does not mean the patient is:

Cured of the overall lymphoma risk.

Expected Visual Outcome

Vision depends on:

• Macular involvement
• Optic nerve involvement
• Degree of RPE/outer retinal destruction
• Treatment toxicity
• Recurrence

Vitritis alone may clear with good visual recovery.

Extensive macular sub-RPE infiltration may leave:

Permanent RPE and photoreceptor atrophy.

Systemic Prognosis

Prognosis is determined primarily by:

CNS involvement and response to lymphoma therapy.

Older literature often quoted survival of only 2–3 years.

This is no longer universally applicable because modern:

• High-dose methotrexate-based regimens
• Rituximab
• Intensive consolidation
• Autologous stem-cell transplantation

have improved outcomes in appropriately selected patients.

High-Yield Takeaways

• Primary vitreoretinal lymphoma is an aggressive diffuse large B-cell lymphoma of the vitreous, retina, and sub-RPE space and belongs to the primary CNS lymphoma spectrum.
• The older term “primary intraocular lymphoma” is less precise because choroidal lymphoma is a distinct intraocular lymphoma.
• PVRL typically affects older adults and is frequently bilateral but asymmetric.
• The classic presentation is painless blurred vision and floaters with chronic vitreous cells plus creamy yellow-white sub-RPE or retinal infiltrates.
• PVRL is a classic masquerade syndrome and should be considered in an older patient with chronic unexplained posterior uveitis.
• Temporary improvement with corticosteroids does not exclude lymphoma and can delay diagnosis.
• Avoid corticosteroids before biopsy when clinically feasible, because lymphoma cells are highly steroid-sensitive and diagnostic yield can fall substantially.
• OCT may show sub-RPE hyperreflective deposits, retinal infiltrates, outer retinal disruption, and RPE nodularity.
• Brain MRI with contrast is essential because of the strong association with PCNS lymphoma.
• CSF testing is useful when clinically indicated, but lumbar puncture is not an absolute prerequisite in every ocular presentation.
• Diagnostic vitrectomy requires careful advance coordination because lymphoma cells are fragile and rapidly degenerate.
• Cytology remains important but has limited sensitivity; diagnosis is increasingly strengthened by flow cytometry, IL-10 analysis, immunoglobulin clonality, and molecular testing.
• MYD88 L265P testing of vitreous or aqueous humor is a major modern diagnostic tool.
• Aqueous humor molecular testing and cell-free DNA analysis can provide useful less-invasive diagnostic evidence, although negative tests do not exclude PVRL.
• An IL-10:IL-6 ratio >1 supports lymphoma but cannot independently establish the diagnosis.
• Most PVRL is CD20-positive DLBCL.
• PVRL must be distinguished from choroidal lymphoma, which is usually low-grade, has little vitritis, and is not strongly associated with PCNS lymphoma.
• When CNS lymphoma is present, treatment centers on high-dose methotrexate-based systemic therapy, usually with modern multidrug regimens and often rituximab.
• Autologous stem-cell transplantation is now an important consolidation strategy for selected fit patients with PCNS lymphoma.
• Whole-brain radiotherapy is used more selectively because of delayed neurotoxicity, particularly in older adults.
• Local ocular treatment includes intravitreal methotrexate, intravitreal rituximab, and/or ocular radiotherapy.
• Repeated intravitreal methotrexate frequently causes corneal epitheliopathy, whereas rituximab can be useful as an alternative or adjunct.
• Vitrectomy can improve vitreous haze but is diagnostic and debulking, not curative.
• Patients with apparently isolated ocular disease remain at substantial risk of later CNS lymphoma and require long-term neurologic and MRI surveillance.
• Ocular prognosis depends mainly on macular/RPE damage, while overall survival depends predominantly on CNS disease and response to modern lymphoma therapy.

Why “Primary Intraocular Lymphoma” Is Less Precise The older term: Primary intraocular lymphoma is potentially confusing because several distinct lymphomas can occur inside the eye. These include:  Primary vitreoretinal lymphoma – aggressive, high-grade, strongly linked to PCNSL Choroidal lymphoma – usually indolent, low-grade B-cell lymphoma Secondary intraocular involvement from systemic lymphoma  These disorders differ substantially in:  Clinical appearance Biology CNS association Prognosis Treatment

Who Is Most Often Affected PVRL occurs predominantly in:  Older adults Typically sixth to seventh decade or later  It can occur in:  Immunocompetent individuals Immunocompromised patients  Disease in children is exceptionally rare.

Relationship to the Central Nervous System The most important systemic association is: Primary CNS lymphoma. PVRL is generally regarded as part of the PCNS lymphoma spectrum. Patients may present with:  Eye disease alone CNS disease alone Both simultaneously  A substantial proportion of patients who initially have apparently isolated ocular disease later develop: CNS lymphoma. This is why long-term neurologic surveillance is essential.

Bilateral Disease Is Common PVRL is frequently: Bilateral but involvement may be:  Asymmetric Sequential  One eye can therefore appear minimally involved while the fellow eye contains obvious disease.

What Causes It The precise cause is not fully understood. Most tumors arise from malignant B lymphocytes with characteristic molecular abnormalities. Important modern molecular findings include:  MYD88 L265P mutation CD79B pathway abnormalities B-cell receptor/NF-κB pathway activation Immunoglobulin gene clonality  These findings are diagnostically useful.

Important Modern Correction About Infection Older literature proposed that:  Epstein-Barr virus Herpesviruses Toxoplasma gondii  might directly cause PVRL. In modern practice, these are: Not considered established causes of typical PVRL in immunocompetent patients. EBV is more relevant to certain lymphomas arising in severe immunosuppression.

How the Tumor Reaches Ocular Tissues Malignant lymphocytes preferentially infiltrate:  Vitreous Retina Sub-RPE space  rather than primarily involving the choroid. This explains the classic combination of: Vitreous cellular infiltration + creamy sub-RPE/retinal lesions.

What Patients Usually Notice Typical symptoms include:  Floaters Painless blurred vision Reduced contrast Hazy vision  Less commonly:  Photopsias Visual field disturbances  Pain, severe redness, and photophobia are generally: Less prominent than in ordinary inflammatory uveitis.

Why Diagnosis Is Often Delayed PVRL frequently masquerades as: Chronic intermediate or posterior uveitis. Patients may initially be diagnosed with:  Idiopathic vitritis Autoimmune uveitis Infectious uveitis  Transient improvement with corticosteroids may further delay the diagnosis.

The Classic Vitreous Appearance The vitreous commonly contains:  Sheets of cells Clumps of cells Fine particulate cellular haze  The appearance may resemble inflammatory vitritis but often has: Dense cells with surprisingly little anterior-segment inflammation.

Characteristic Subretinal and Sub-RPE Lesions A key finding is: Creamy yellow-white infiltrates at or beneath the RPE. They may appear as:  Tiny dots Round lesions Plaques Confluent infiltrates  Early lesions can resemble:  Drusen White-dot syndromes Inflammatory chorioretinal lesions

What Happens After Lesions Regress Resolution of lymphoma infiltrates may leave:  RPE mottling RPE atrophy Pigmentary disturbance Outer retinal loss  These residual changes can permanently reduce vision when the macula is involved.

Other Possible Ocular Findings Less common findings include:  Mild anterior chamber cells Keratic precipitates Retinal vascular sheathing Retinal hemorrhage Optic disc edema Subretinal fluid Epiretinal membrane  Frank hypopyon is unusual.

Optical Coherence Tomography OCT has become extremely useful in suspected PVRL. Possible findings include:  Hyperreflective sub-RPE deposits Nodular RPE elevations Hyperreflective infiltrates within the retina Outer retinal disruption Ellipsoid zone loss RPE irregularity Subretinal hyperreflective material  Serial OCT can help monitor: Response and recurrence.

A Characteristic OCT Clue Vertical or column-like hyperreflective lesions extending through retinal layers have been described in PVRL. Although not pathognomonic, such findings in an older patient with chronic unexplained vitritis should raise suspicion for: Vitreoretinal lymphoma.

Fundus Autofluorescence FAF may show a characteristic granular pattern of:  Hyperautofluorescent spots Hypoautofluorescent spots  reflecting:  Active RPE stress Infiltration RPE atrophy  A mottled “leopard-spot” pattern can occur.

Fluorescein Angiography FA may demonstrate:  RPE window defects Staining Blockage from infiltrates Vascular leakage Patchy hypofluorescent and hyperfluorescent lesions  It is supportive rather than diagnostic.

Indocyanine Green Angiography ICGA may show:  Hypofluorescent spots Areas of choroidal perfusion abnormality  but is generally less central to diagnosis than:  OCT FAF Tissue/fluid analysis

Ultrasound Findings B-scan may show:  Vitreous opacities Mild focal retinal/choroidal thickening  It is mainly useful when: Media opacity prevents fundus visualization.

Why MRI of the Brain Is Essential Every patient with suspected or confirmed PVRL should undergo: Contrast-enhanced MRI of the brain to evaluate for:  PCNS lymphoma Leptomeningeal disease Other CNS lesions  MRI is preferred over CT for detecting CNS lymphoma.

Typical CNS Lymphoma Findings PCNS lymphoma often produces:  Homogeneously enhancing lesions Deep periventricular lesions Corpus callosum involvement Basal ganglia or deep white matter lesions  However, the CNS MRI can be normal when ocular disease first appears.

Neurologic Symptoms to Ask About Patients should be questioned about:  Cognitive change Personality change Headache Seizures Weakness Gait disturbance Cranial nerve symptoms  New neurologic symptoms in a patient with PVRL require: Prompt CNS reassessment.

Role of Lumbar Puncture CSF analysis may include:  Cytology Flow cytometry Molecular studies  It is particularly useful when:  MRI shows suspicious CNS lesions Leptomeningeal involvement is suspected Neurologic symptoms are present  An important correction is that: Lumbar puncture is not invariably required in every patient before the diagnosis of PVRL can be established. It is performed according to the neurologic and oncologic assessment.

Why the Diagnosis Can Be Difficult Lymphoma cells are: Fragile and may rapidly degenerate after specimen collection. Diagnostic difficulty is increased by:  Small samples Low tumor-cell concentration Abundant reactive inflammatory cells Previous corticosteroid treatment  Multiple tests and sometimes repeat biopsies are required.

Vitreous Biopsy When PVRL is strongly suspected, a: Diagnostic pars plana vitrectomy is often the preferred method for obtaining adequate vitreous material. The specimen should be handled rapidly and coordinated with:  Cytopathology Hematopathology Molecular laboratory  before surgery.

Why Laboratory Coordination Matters The surgeon should communicate with the laboratory in advance because vitreous must often be divided for:  Cytology Flow cytometry Cytokine analysis Molecular testing  Improper handling can markedly decrease diagnostic yield.

Cytology The traditional diagnostic cornerstone is identification of malignant lymphoid cells. Typical cells are:  Large Pleomorphic High nuclear-to-cytoplasmic ratio Prominent nucleoli Irregular nuclei  Most PVRL represents: Large B-cell lymphoma.

Immunophenotyping Typical B-cell markers include:  CD20 CD19 CD79a PAX5  Demonstration of a clonal B-cell population supports lymphoma. Flow cytometry may also evaluate: Kappa/lambda light-chain restriction.

MYD88 Mutation Testing One of the most useful modern diagnostic advances is detection of: MYD88 L265P in ocular fluid. The mutation is present in a large proportion of PVRL and PCNS lymphoma cases. Testing may be performed on:  Vitreous Aqueous humor  Detection strongly supports the diagnosis in the appropriate clinical setting.

Why Aqueous Humor Is Increasingly Useful Modern molecular techniques can detect:  MYD88 mutation Tumor-derived DNA Cytokines  from small aqueous samples. This provides a: Less invasive adjunct to vitreous biopsy although a negative aqueous test does not exclude PVRL.

Immunoglobulin Gene Rearrangement PCR demonstrating clonal: Immunoglobulin heavy-chain gene rearrangement supports B-cell lymphoma. However, false-negative and occasional false-positive results can occur. It should be interpreted alongside:  Cytology Clinical findings Other molecular testing

IL-10 and IL-6 PVRL cells frequently produce large amounts of: Interleukin-10 (IL-10). Inflammatory uveitis tends to produce more: Interleukin-6 (IL-6). An: IL-10:IL-6 ratio >1 supports lymphoma but is: Not sufficiently specific to establish the diagnosis by itself. Absolute IL-10 concentration may also be informative.

Modern Cell-Free DNA Testing Next-generation sequencing and analysis of: cell-free tumor DNA in ocular fluid are emerging as highly useful tools. These can detect combinations of:  MYD88 CD79B Other lymphoma-associated mutations  and may improve diagnostic sensitivity when cytology is nondiagnostic. Availability varies by center.

Why Steroids Can Interfere With Diagnosis Corticosteroids can cause: Rapid apoptosis of lymphoma cells. This may temporarily improve:  Vitritis Vision Retinal infiltrates  while reducing biopsy yield. When clinically safe: Avoid or minimize corticosteroids before diagnostic sampling.

What to Do If the First Biopsy Is Negative A negative vitreous biopsy does: Not exclude PVRL. If suspicion remains high:  Repeat vitreous biopsy Test the fellow eye if involved Perform aqueous molecular testing Consider retinal/sub-RPE biopsy in exceptional cases Reassess CNS imaging  may be necessary.

Why Retinal Biopsy Is Rarely First-Line Retinal or chorioretinal biopsy can provide diagnostic tissue but carries risks including:  Retinal detachment Hemorrhage Permanent scotoma  It is generally reserved for: Persistently unexplained cases despite less invasive testing.

The Classic Masquerade Syndrome PVRL is one of the most important causes of: Masquerade uveitis especially in an older adult with:  Chronic vitritis Poor or transient steroid response Recurrent inflammation Sub-RPE infiltrates  Persistent “idiopathic uveitis” in this setting should trigger reconsideration of the diagnosis.

Important Differential Diagnoses These include:  Syphilitic posterior uveitis Tuberculosis Toxoplasmosis Viral retinitis Sarcoidosis Birdshot chorioretinopathy Multifocal choroiditis Other white-dot syndromes Endogenous endophthalmitis Choroidal lymphoma Choroidal metastasis

Distinguishing PVRL From Choroidal Lymphoma These are biologically different diseases. Vitreoretinal Lymphoma  High-grade DLBCL Dense vitreous cells common Retinal/sub-RPE infiltration Strong association with PCNS lymphoma  Choroidal Lymphoma  Usually low-grade B-cell lymphoma Diffuse or multifocal yellow choroidal thickening Little vitritis May produce extrascleral “salmon-patch” extension More closely related to systemic marginal-zone lymphoma than PCNS lymphoma

Distinguishing It From Choroidal Metastasis Choroidal metastases typically appear as:  Yellow choroidal masses Often with subretinal fluid  They generally lack the characteristic combination of: Dense vitreous cellular infiltration and sub-RPE lymphoma deposits. Systemic cancer history can provide an additional clue.

Establishing the Extent of Disease Once PVRL is diagnosed, evaluation should determine whether disease is:  Eye only Eye + CNS Rarely related to systemic lymphoma  This generally involves:  Neuro-oncology/hematology assessment Brain MRI CSF evaluation when appropriate Systemic staging when clinically indicated

Treatment Requires Multidisciplinary Care Management should involve:  Ocular oncology or uveitis/retina specialist Hematology-oncology Neuro-oncology Radiation oncology when appropriate  The ocular disease cannot be managed in isolation because CNS relapse is the major determinant of survival.

Treatment When CNS Disease Is Present When PVRL accompanies PCNS lymphoma, treatment generally includes: Systemic CNS-penetrating chemotherapy centered around: High-dose methotrexate (HD-MTX). Additional agents may include:  Rituximab Cytarabine Thiotepa Other CNS-directed chemotherapy  Regimen selection depends on:  Age Performance status Renal function Treatment center

Modern PCNS Lymphoma Therapy Contemporary induction regimens frequently combine: High-dose methotrexate with other CNS-penetrating agents and rituximab. For suitable patients, consolidation may include: High-dose chemotherapy followed by autologous stem-cell transplantation. This has reduced reliance on routine whole-brain radiotherapy in many patients.

Why Whole-Brain Radiation Is Used More Selectively Whole-brain radiotherapy can control lymphoma but may cause: Delayed neurocognitive toxicity, especially in older adults. Therefore modern management often favors:  Chemotherapy-based induction Stem-cell-based consolidation in eligible patients  with radiation reserved for selected situations.

Treatment of Isolated Ocular Disease Options include:  Intravitreal methotrexate Intravitreal rituximab Ocular radiotherapy Systemic CNS-directed treatment in selected patients Combination approaches  There is no single universally accepted regimen for every patient with isolated PVRL.

Intravitreal Methotrexate Intravitreal methotrexate is one of the most established local therapies. A commonly used dose is: 400 µg/0.1 mL Treatment usually involves:  Induction injections Consolidation Maintenance  although schedules vary substantially.

Methotrexate Ocular Toxicity Repeated injections can cause:  Corneal epitheliopathy Punctate keratopathy Epithelial defects Cataract Macular toxicity rarely  Corneal toxicity is one of the major dose-limiting complications.

Reducing Methotrexate Keratopathy Strategies may include:  Reducing injection frequency Temporary treatment interruption Intensive lubrication Folinic acid approaches in selected protocols  while maintaining adequate lymphoma control.

Intravitreal Rituximab Rituximab, an anti-CD20 monoclonal antibody, can be given intravitreally. A commonly used dose is: 1 mg/0.1 mL. It may be used:  Alone With methotrexate  and is particularly useful when methotrexate causes significant corneal toxicity.

Ocular Radiotherapy External-beam radiotherapy can provide excellent local control. Typical contemporary doses depend on treatment strategy but are usually considerably lower than historic tumoricidal doses used for many other malignancies. Potential adverse effects include:  Cataract Dry eye Radiation retinopathy Optic neuropathy Keratopathy  Risk depends on dose and field.

Bilateral Ocular Disease When both eyes are involved, treatment options include:  Bilateral local therapy Systemic CNS-directed therapy Combination treatment  Treatment should account for:  Existing CNS disease Likelihood of CNS progression Patient age Ocular disease burden

Does Systemic Therapy Prevent CNS Lymphoma? This remains an area of ongoing investigation. Because ocular-only PVRL carries substantial risk of later CNS disease, some centers use: Systemic CNS-directed therapy even when MRI is initially negative. However, the optimal strategy remains debated and individualized.

Role of Vitrectomy Beyond Diagnosis Vitrectomy may also:  Clear visually significant vitreous haze Improve visual function Reduce cellular burden  but: Vitrectomy alone is not curative. Residual lymphoma cells remain in the retina and sub-RPE compartment.

Monitoring Treatment Response Follow-up should include:  Visual acuity Slit-lamp examination Vitreous cellular assessment Dilated retinal examination OCT FAF Fundus photography  Molecular or cytokine testing may occasionally assist in monitoring selected patients.

What Ocular Recurrence Can Look Like Recurrence may present with:  New floaters Increasing vitreous cells New sub-RPE deposits Recurrent outer retinal infiltration New RPE abnormalities  Because recurrence can be subtle, imaging should be compared carefully with: Baseline studies.

CNS Surveillance Patients with apparently isolated PVRL require: Long-term neurologic surveillance. This usually includes:  Clinical neurologic review Serial brain MRI  The exact frequency is individualized according to:  Initial disease pattern Treatment Oncology protocol

Why Long-Term Follow-Up Is Essential PVRL can recur:  In either eye In the CNS Years after initial therapy  Therefore apparent ocular remission does not mean the patient is: Cured of the overall lymphoma risk.

Expected Visual Outcome Vision depends on:  Macular involvement Optic nerve involvement Degree of RPE/outer retinal destruction Treatment toxicity Recurrence  Vitritis alone may clear with good visual recovery. Extensive macular sub-RPE infiltration may leave: Permanent RPE and photoreceptor atrophy.

Systemic Prognosis Prognosis is determined primarily by: CNS involvement and response to lymphoma therapy. Older literature often quoted survival of only 2–3 years. This is no longer universally applicable because modern:  High-dose methotrexate-based regimens Rituximab Intensive consolidation Autologous stem-cell transplantation  have improved outcomes in appropriately selected patients.

High-Yield Takeaways  Primary vitreoretinal lymphoma is an aggressive diffuse large B-cell lymphoma of the vitreous, retina, and sub-RPE space and belongs to the primary CNS lymphoma spectrum. The older term “primary intraocular lymphoma” is less precise because choroidal lymphoma is a distinct intraocular lymphoma. PVRL typically affects older adults and is frequently bilateral but asymmetric. The classic presentation is painless blurred vision and floaters with chronic vitreous cells plus creamy yellow-white sub-RPE or retinal infiltrates. PVRL is a classic masquerade syndrome and should be considered in an older patient with chronic unexplained posterior uveitis. Temporary improvement with corticosteroids does not exclude lymphoma and can delay diagnosis. Avoid corticosteroids before biopsy when clinically feasible, because lymphoma cells are highly steroid-sensitive and diagnostic yield can fall substantially. OCT may show sub-RPE hyperreflective deposits, retinal infiltrates, outer retinal disruption, and RPE nodularity. Brain MRI with contrast is essential because of the strong association with PCNS lymphoma. CSF testing is useful when clinically indicated, but lumbar puncture is not an absolute prerequisite in every ocular presentation. Diagnostic vitrectomy requires careful advance coordination because lymphoma cells are fragile and rapidly degenerate. Cytology remains important but has limited sensitivity; diagnosis is increasingly strengthened by flow cytometry, IL-10 analysis, immunoglobulin clonality, and molecular testing. MYD88 L265P testing of vitreous or aqueous humor is a major modern diagnostic tool. Aqueous humor molecular testing and cell-free DNA analysis can provide useful less-invasive diagnostic evidence, although negative tests do not exclude PVRL. An IL-10:IL-6 ratio >1 supports lymphoma but cannot independently establish the diagnosis. Most PVRL is CD20-positive DLBCL. PVRL must be distinguished from choroidal lymphoma, which is usually low-grade, has little vitritis, and is not strongly associated with PCNS lymphoma. When CNS lymphoma is present, treatment centers on high-dose methotrexate-based systemic therapy, usually with modern multidrug regimens and often rituximab. Autologous stem-cell transplantation is now an important consolidation strategy for selected fit patients with PCNS lymphoma. Whole-brain radiotherapy is used more selectively because of delayed neurotoxicity, particularly in older adults. Local ocular treatment includes intravitreal methotrexate, intravitreal rituximab, and/or ocular radiotherapy. Repeated intravitreal methotrexate frequently causes corneal epitheliopathy, whereas rituximab can be useful as an alternative or adjunct. Vitrectomy can improve vitreous haze but is diagnostic and debulking, not curative. Patients with apparently isolated ocular disease remain at substantial risk of later CNS lymphoma and require long-term neurologic and MRI surveillance. Ocular prognosis depends mainly on macular/RPE damage, while overall survival depends predominantly on CNS disease and response to modern lymphoma therapy.