Retinal Lymphoma

Slide 1 · Retinal Lymphoma

Clinicopathologic diagnosis, ocular imaging and CNS implications

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Localize neoplastic infiltrates to vitreous, neural retina and retinal pigment epithelium.

Recognize the clinical masquerade and select a diagnostic specimen.

Integrate cytology, immunophenotyping and molecular evidence with CNS evaluation.

Interpret contemporary treatment and follow-up principles without overclaiming evidence.

Slide 3 · Scope and terminology

Retinal lymphoma

Aggressive intraocular B-cell neoplasm

Predilection for neurosensory retina and RPE

Characteristically associated with brain disease

Contemporary clinical designation

Primary vitreoretinal lymphoma (PVRL)

Predominantly large B-cell lymphoma

Within the primary CNS lymphoma spectrum

Slide 4 · The eye as a CNS-associated compartment

Neurosensory retina

Retinal pigment epithelium

Vitreous sampling

CNS evaluation

The anatomic localization of ocular lesions guides sampling and staging; These steps are not a biological lineage.

Schematic

Slide 5 · Retinal layers relevant to lymphoma

Vitreous cavity

Neurosensory retina

Retinal pigment epithelium

Bruch membrane

Choroid

PVRL commonly involves vitreous, retina and the RPE interface; Choroidal lymphoma occupies a different anatomic compartment.

Schematic (not histology)

Slide 6 · Why the RPE interface matters

Lesions at or above the RPE

Sub-RPE deposits and retinal infiltrates

OCT: RPE nodularity or outer retinal signal

Supports the vitreoretinal pattern

Lesions deep to Bruch membrane

Primarily choroidal distribution

Different imaging contour/depth

Suggests a choroidal process in the differential

Slide 7 · Retinal lymphoma is not retinoblastoma

Retinal lymphoma

Typically older adult

Large B-cell hematolymphoid neoplasm

Common CNS association

Vitreous cytology often key

Retinoblastoma

Typically young child

Retinal embryonal neoplasm

RB1 pathway relevant

Retinal mass with rosettes in some tumors

Slide 8 · Age and host context

PVRL classically presents in older adults, but age alone never determines the diagnosis.

Immunocompromised patients warrant evaluation for CNS/ocular lymphoma and infectious mimics.

A prolonged “uveitis” history does not exclude malignancy.

Do not use patient age or steroid responsiveness as a substitute for tissue diagnosis.

Slide 9 · Histologic identity: Large B-cell lymphoma

Clonal mature B-cell proliferation

Large atypical lymphoid cells

Diffuse large B-cell morphology

Ocular/CNS clinical phenotype

Most cases are large B-cell lymphomas; Uncommon non–B-cell intraocular lymphomas require separate classification.

Schematic

Slide 10 · Lymphoma phenotype is not defined by one stain

Lineage markers such as CD20, PAX5 and CD79a support B-cell differentiation.

CD3 highlights accompanying T cells and helps assess reactive components.

An integrated morphology–immunophenotype–molecular interpretation is required.

Marker expression is supportive; Histologic subtype is a composite diagnosis.

Slide 11 · Molecular context: B-cell receptor signaling

MYD88 / CD79B activating alterations

BCR / innate immune signaling

NF-κB-associated survival signaling

Clonal B-cell persistence

Conceptual pathway only. Mutations are common in PVRL, but not present in every case and not sufficient alone for diagnosis.

Schematic

Slide 12 · MYD88 p.L265P: Role and limits

What a positive assay adds

Supports an ocular B-cell lymphoma

Useful on paucicellular specimens

May complement cytology and clonality

What it does not establish

Not positive in all confirmed cases

Does not independently localize tumor

Must be interpreted in the clinical context

Slide 13 · CNS connection defines the clinical stakes

Ocular presentation

Brain MRI and clinical assessment

Current CNS disease?

Longitudinal CNS vigilance

PVRL can precede, accompany or follow CNS lymphoma; The time sequence varies by patient.

Schematic

Slide 14 · The optic nerve as a route of extension

Neurosensory retina

Optic nerve head

Optic nerve

Intracranial visual pathway

Brain

Possible spread to the brain along the optic nerve; Clinical CNS disease can also reflect the broader PCNSL spectrum.

Schematic (not histology)

Slide 15 · Possible clinical trajectories

Ocular disease only at presentation

Ocular + CNS involvement

Brain involvement during follow-up

Alternative patterns are shown, not a deterministic progression for every patient.

Schematic

Slide 16 · Early symptoms are nonspecific

Floaters and painless blurred vision are characteristic presenting complaints.

Symptoms may fluctuate despite persistent neoplastic disease.

Unilateral symptoms do not exclude bilateral involvement on careful examination.

Persistent unexplained floaters plus posterior segment inflammation warrant a malignancy-aware differential.

Slide 17 · A classic masquerade: Chronic uveitis

Features that resemble uveitis

Vitreous cells and haze

Blurred vision and floaters

Variable retinal inflammation-like lesions

Features that raise suspicion

Older patient with atypical course

Relapsing or treatment-resistant disease

Creamy outer retinal/RPE infiltrates

Limited macular edema despite vitritis

Slide 18 · Corticosteroids can obscure the diagnosis

Empirical corticosteroid exposure

Transient clinical improvement

Reduced or altered tumor-cell yield

Potential diagnostic delay

Consensus recommends withholding systemic corticosteroids before diagnostic vitrectomy when clinically feasible; Coordinate this decision with treating specialists.

Schematic

Slide 19 · Slit-lamp observations

Vitreous cells may appear in sheets, clusters or dense haze.

Anterior segment inflammation may be relatively modest compared with vitreous infiltration.

Evaluate both eyes; Absence of striking retinal lesions does not exclude lymphoma.

A normal-appearing fundus through dense vitritis is not reassuring.

Slide 20 · Fundus: Creamy retinal and subretinal lesions

Creamy or yellow-white lesions

RPE mottling or focal atrophy

Retinal or sub-RPE infiltration

Imaging and biopsy correlation

Findings are suggestive rather than pathognomonic; Avoid diagnosing lymphoma solely from fundus color.

Schematic

Slide 21 · Patterns beyond a discrete lesion

Optic disc edema, perivascular changes and serous retinal detachment may occur.

RPE pigment disturbance can persist after an active infiltrate resolves.

Retinitis-like presentations require exclusion of infection and other mimics.

Document anatomic distribution, not just the presence of “white spots”.

Slide 22 · Multimodal imaging has complementary roles

Modality

Primary information

Key limitation

Color fundus

Vitreous haze; Lesion distribution

Subtle lesions may be missed

OCT

Layer and sub-RPE localization

Imaging is not tissue proof

FAF

RPE metabolic disturbance

Signal varies with activity/damage

Angiography

Staining, blockage, leakage

Findings are nonspecific

Slide 23 · OCT: Anatomic localization

Inner retina

Outer retina

Subretinal space

RPE

Bruch membrane

Hyperreflective material may involve outer retina, subretinal space, or the sub-RPE interface. This drawing is schematic, not an OCT scan.

Schematic (not histology)

Slide 24 · OCT signs that increase suspicion

Nodular elevation or irregularity of the retinal pigment epithelium.

Outer retinal hyperreflective foci and subretinal infiltrative material.

Vitreous cellular echoes and occasional pigment epithelial detachment.

Interpret OCT in combination with fundoscopy, FAF and clinical context.

Slide 25 · Vertical hyperreflective columns

Localized retinal infiltrative focus

Vertical hyperreflective OCT signal

Possible microscopic tumor infiltration

Correlate with other modalities

Proposed association, not a stand-alone diagnostic sign; Exact mechanism remains inferential.

Schematic

Slide 26 · Fundus autofluorescence patterns

Hyperautofluorescence

May accompany active sub-RPE lesions

Related to disturbed RPE function

Often paired with OCT nodularity

Hypoautofluorescence

May reflect masking by infiltrate

Can follow RPE atrophy or injury

Does not alone establish inactivity

Slide 27 · Fluorescein angiography: What it adds

Granular or mottled RPE-level fluorescence changes may be seen.

Blocking and late staining can coexist at different lesion sites.

Angiography assesses morphology and activity but cannot classify lymphoid cells.

If imaging and clinical course remain suspicious, tissue-based evaluation is still necessary.

Slide 28 · An imaging finding is not a tumor diagnosis

Imaging can

Locate abnormalities by retinal layer

Map burden and possible response

Select an accessible biopsy target

Imaging cannot

Establish B-cell clonality alone

Replace cytologic/molecular analysis

Prove absence of microscopic disease

Slide 29 · Differential: Inflammatory posterior uveitis

Question

Inflammatory uveitis

PVRL concern

Course

Often follows recognized syndrome

Chronic atypical or relapsing

Vitreous

Inflammatory cells

Clumped atypical cells possible

Retina

Inflammatory/chorioretinal lesions

Creamy infiltrates / RPE deposits

Next step

Cause-directed tests

Ocular biopsy if unexplained

Slide 30 · Differential: Infectious retinitis

Infectious considerations

Herpetic necrotizing retinitis

Toxoplasma retinochoroiditis

Opportunistic infection in at-risk hosts

Why lymphoma remains in the differential

Retinitis-like lesions may occur

Nonresponse despite adequate antimicrobial therapy

Negative pathogen evaluation with atypical course

Slide 31 · Differential: Choroidal lymphoma

Neural retina

RPE

Bruch membrane

Choroidal stroma

Sclera

A primarily choroidal lymphoma is centered below Bruch membrane; PVRL often occupies retinal and sub-RPE compartments.

Schematic (not histology)

Slide 32 · Differentiate primary from secondary ocular disease

Lymphoma identified in ocular specimen

Review systemic lymphoma history

MRI brain / CNS evaluation

Systemic staging as indicated

Assign clinical disease context

PVRL is used for eye-predominant disease in the PCNSL spectrum after appropriate evaluation; Secondary intraocular involvement is a separate context.

Schematic

Slide 33 · When to proceed to diagnostic vitrectomy

Sustained suspicion persists despite noninvasive evaluation and appropriate differential testing.

Sampling should be planned with ophthalmology and an experienced cytopathology laboratory.

Specimen volume, priorities, transport conditions and ancillary tests should be agreed before surgery.

A vitrectomy intended for diagnosis is a coordinated tissue-acquisition procedure.

Slide 34 · The diagnostic specimen is fragile

Vitrectomy planning

Fresh undiluted vitreous allocation

Immediate cytology processing

Ancillary testing in parallel

Neoplastic cells can degenerate quickly; Fixation and handling must follow local ocular-cytopathology protocols.

Schematic

Slide 35 · Vitreous cytology: Hallmark morphology

Large atypical lymphoid cells with irregular nuclear contours and prominent nucleoli.

Variable cytoplasmic volume, apoptosis and background necrotic debris may be present.

Reactive small lymphocytes and macrophages can obscure sparse malignant cells.

The diagnosis is morphological and multimodal; This slide does not substitute for a real cytology image.

Slide 36 · Why diagnostic yield may be low

Low neoplastic cellularity

Prior steroid exposure or apoptosis

Cell degeneration during handling

Nondiagnostic cytology

False-negative vitreous cytology does not exclude lymphoma when clinical suspicion remains high.

Schematic

Slide 37 · The core immunocytochemical panel

Marker

Interpretive use

Caution

CD20 / PAX5

B-cell lineage

Expression can vary

CD3

Reactive T-cell component

Not equivalent to tumor lineage

CD79a

Additional B-lineage support

Integrate with phenotype

Ki-67

Proliferation pattern

Not independently diagnostic

Slide 38 · Typical immunophenotypic pattern

Many tumors express B-cell markers with MUM1/IRF4 and other activated B-cell–associated features.

BCL2 and BCL6 may be expressed; CD10 is often absent.

There is no single immunophenotypic profile that replaces integrated classification.

Phenotypic expectations should guide, not dictate, interpretation of an individual small specimen.

Slide 39 · Flow cytometry: Strength and limitation

Strengths

Detects aberrant B-cell populations

Can assess light-chain restriction

Phenotypes multiple markers in parallel

Limitations

Needs viable, adequate cellular material

May miss sparse or fragile tumor cells

Clonality alone is not whole diagnosis

Slide 40 · Interleukin-10 and interleukin-6

Collect ocular fluid appropriately

Measure IL-10 and IL-6

High IL-10 / IL-6 ratio supports suspicion

Correlate with tumor cells and other testing

An IL-10:IL-6 ratio >1 is a consensus-supported indicator, not independently definitive proof.

Schematic

Slide 41 · Interpret a cytokine-positive sample carefully

Reasonable conclusion

Lymphoma becomes more likely

Prioritize morphology and clonality

Reassess imaging and CNS staging

Unwarranted conclusion

Ratio alone proves malignancy

Specimen handling is irrelevant

Negative cytology can be ignored

Slide 42 · MYD88 mutation testing

Targeted detection of MYD88 p.L265P can reinforce suspicion for PVRL.

The mutation is absent from a meaningful subset of confirmed cases.

Positive testing should be integrated with morphology, lineage and presentation.

A negative result is not a rule-out test; Mutation positivity alone is not sufficient.

Slide 43 · Immunoglobulin gene rearrangements

Ocular specimen DNA

IGH / IGK clonality assay

Dominant rearrangement detected?

Interpret alongside cytology and phenotype

A clonality result supports an expanded population but must be evaluated against small-sample artifacts and biologic context.

Schematic

Slide 44 · Evidence integration rather than one-test diagnosis

Evidence level

Contribution

Interpretation

Direct malignant cytology

Morphologic evidence

Central to diagnosis

B-cell phenotype / clonality

Establish lineage and restricted clone

Strong corroboration

MYD88 / cytokines

Supportive molecular / soluble markers

Not sufficient in isolation

Imaging / clinical pattern

Localization and suspicion

Guides sampling

Slide 45 · When a vitreous biopsy is negative

Re-evaluate specimen adequacy

Review imaging and differential

Reconsider corticosteroid effect

Repeat/alternative ocular sampling if warranted

Continue CNS surveillance

Decisions require a multidisciplinary risk–benefit assessment; Do not declare lymphoma excluded on one negative sample.

Schematic

Slide 46 · Retinal/subretinal tissue biopsy

May be considered when vitreous testing is nondiagnostic and accessible retinal lesions persist.

Targets should correspond to the demonstrated site of disease.

Retinal biopsy has procedural risks and requires specialist planning.

Biopsy site and tissue allocation are clinical decisions, not automatic next steps.

Slide 47 · CNS evaluation is part of the diagnosis

Confirmed or strongly suspected PVRL

Contrast-enhanced brain MRI

Neurologic review ± CSF assessment

Neuro-oncology/hematology coordination

A normal initial MRI does not eliminate the need for subsequent surveillance.

Schematic

Slide 48 · Why systemic staging still matters

Primary vitreoretinal pattern

Ocular disease within PCNSL spectrum

No demonstrated systemic primary after assessment

CNS risk remains central

Secondary ocular lymphoma

Ocular infiltration by systemic lymphoma

Different staging and therapeutic context

Requires systemic disease evaluation

Slide 49 · Pathology report: Essential components

Specimen type, preservation and diagnostic adequacy.

Atypical-cell morphology, B-cell markers and cytologic interpretation.

Ancillary test results with assay-specific limitations.

Integrated diagnosis and recommendation for clinicoradiologic correlation.

Slide 50 · Clinical decision-making is multidisciplinary

Retina / uveitis specialist

Ocular cytopathology

Hematology / neuro-oncology

Neuroradiology

Individualized integrated plan

Eye control and CNS disease prevention/control are related but distinct clinical goals.

Schematic

Slide 51 · Treatment goals

Ocular objectives

Regress vitreoretinal infiltration

Preserve visual function

Monitor local relapse

Systemic / CNS objectives

Treat or prevent CNS progression when feasible

Address current CNS involvement

Balance toxicity against fitness

Slide 52 · Systemic therapy: 2024 guideline emphasis

EHA–ESMO recommends high-dose methotrexate–based induction for fit patients with PVRL.

Regimen selection parallels primary CNS lymphoma and depends on systemic fitness.

Evidence is limited by disease rarity; Recommendations include expert consensus.

Treatment choices should follow specialist multidisciplinary assessment, not a generic fixed regimen.

Slide 53 · Local ocular treatment

Modality

Clinical intent

Important trade-off

Intravitreal methotrexate

Rapid local tumor control

Injection burden / ocular toxicity

Intravitreal rituximab

Local CD20-targeted therapy

Limited comparative evidence

Ocular radiotherapy

Local consolidation / control

Potential late ocular toxicity

Slide 54 · Local control is not CNS assurance

Visible vitreoretinal response

Improved ocular appearance

CNS involvement may still emerge

Continue neuro-oncology follow-up

An apparently quiet eye does not establish systemic or CNS remission.

Schematic

Slide 55 · Treatment must reflect patient fitness

Fit for intensive systemic treatment

HD-MTX-based induction in guidelines

Consolidation discussed individually

Ocular treatment added when appropriate

Frailty or contraindications

Local treatment may play larger role

Alternative systemic approaches considered

Toxicity and visual goals prioritized

Slide 56 · Assessing response

Assessment

What it can track

Why it is insufficient alone

Slit lamp / fundus

Vitreous cells and visible lesions

Microscopic persistence possible

OCT / FAF

Retinal structure and RPE change

Damage may remain after control

MRI brain

Parenchymal CNS involvement

Does not replace ocular exam

Aqueous biomarkers

Potential molecular activity

Standardization varies

Slide 57 · Relapse and follow-up

Ocular and CNS disease require coordinated follow-up even after apparent response.

New floaters, reduced vision or new neurologic symptoms merit prompt reassessment.

Repeat imaging, biomarkers and tissue testing may be indicated depending on context.

Follow-up intervals and modalities are individualized; No single universal timetable is implied.

Slide 58 · Relapsed disease: Concept and limitations

Define local versus CNS recurrence

Review prior therapies and toxicity

Re-stage disease extent

Consider systemic salvage / selected local options

Guideline salvage choices depend on performance status, prior regimens and CNS involvement; Efficacy evidence remains heterogeneous.

Schematic

Slide 59 · Case A: An apparent posterior uveitis

A 71-year-old has 9 months of floaters, blurred vision, fluctuating vitreous haze, and recurrent “uveitis” after corticosteroids. OCT shows nodular RPE changes.

What is the highest-value next diagnostic action?

Arrange a planned diagnostic vitrectomy with ocular cytology and ancillary testing, while initiating CNS assessment. Treatable infections still require consideration.

Slide 60 · Case A: Dissect the decision

Finding

Interpretation

Action

Older adult + recurrent vitritis

Masquerade phenotype

Keep PVRL on differential

RPE nodularity

Anatomic clue

Guide multimodal imaging

Temporary steroid response

Not exclusionary

Plan appropriate sampling

CNS association

Potential systemic consequence

MRI and referral

Slide 61 · Case B: A nondiagnostic aspirate

A patient with multifocal creamy retinal lesions has nondiagnostic vitreous cytology. OCT remains suspicious. An ocular-fluid MYD88 assay is negative.

Does this exclude vitreoretinal lymphoma?

No. Reassess sample quality, previous treatment, imaging and mimics; Consider repeat or targeted retinal sampling after multidisciplinary review.

Slide 62 · Case B: Interpret discordant tests

What is known

Clinical localization remains suspicious

One ocular specimen lacked diagnostic cells

MYD88 assay did not detect the mutation

What remains unresolved

Whether tumor cells were sampled

Whether another subtype/molecular profile is present

Which specimen has best next yield

Slide 63 · Case C: Ocular control with later CNS lesion

After treatment, fundus lesions regress and vision stabilizes. Several months later, the patient develops new focal neurologic symptoms.

What is the most important clinical inference?

Ocular improvement does not exclude CNS lymphoma. Urgent neurological assessment and brain imaging are required.

Slide 64 · What the original textbook establishes

Primary retinal lymphoma targets neurosensory retina and RPE.

It usually presents in older individuals and can mimic uveitis.

Most cases are diffuse large B-cell lymphoma.

Brain involvement is frequent; Vitreous aspirate demonstrates malignant cells.

Slide 65 · What specialist literature adds

Diagnostic refinement

OCT / FAF and layer-specific signs

Coordinated vitrectomy specimen triage

MYD88, cytokines and clonality as adjuncts

Clinical management refinement

MRI and systemic context

Individualized CNS-directed / ocular therapy

Structured recurrence surveillance

Slide 66 · Diagnostic synthesis

Persistent suspicious vitritis / retinal infiltrates

Multimodal retinal localization

Planned ocular biopsy with integrated pathology

CNS evaluation and multidisciplinary care

Consider infection, inflammatory disease and alternative ocular lymphoma throughout the pathway.

Schematic

Slide 67 · Five defensible conclusions

Atypical “uveitis” may be an ocular presentation of large B-cell lymphoma.

The vitreous–retina–RPE distribution helps direct imaging and biopsy.

Cytology is central; Immunophenotype and molecular tests increase confidence.

Negative sampling does not automatically exclude the disease.

CNS evaluation and prolonged coordinated follow-up are integral.

Slide 68 · References and source hierarchy

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Ch 29, p 1206.

Ferreri AJM et al. EHA–ESMO guideline for primary CNS lymphomas. HemaSphere. 2024;8:e89.

Carbonell D et al. Diagnostic consensus. Ocul Immunol Inflamm. 2021;29:507–520.

Xu LT et al. Multimodal imaging in PVRL. Int J Retina Vitreous. 2022;8:58.

Diagnostic methods for PVRL: a systematic review. Surv Ophthalmol. 2024;69:456–464.

WHO Classification of Tumours of the Eye and Orbit, 5th edition — summary in Ocul Oncol Pathol. 2023.