Vitreoretinal lymphoma

Primary Intraocular Lymphoma (PIOL)

Primary Intraocular Lymphoma (PIOL) is a devastating intraocular malignancy and a distinct subset of Primary Central Nervous System Lymphoma (PCNSL). Over $95\%$ of cases are high-grade Diffuse Large B-cell Lymphomas (DLBCL); T-cell intraocular lymphomas represent $<5\%$.

Clinical Presentation: The Uveitis "Masquerade Syndrome"

PIOL characteristically arises in elderly patients (median age 60-70 years) with a slight female predominance. It is the classic masquerade syndrome, frequently misdiagnosed as chronic, non-infectious, steroid-resistant posterior or intermediate uveitis:

• Laterality: Bilateral in $60-80\%$ of patients, though frequently asymmetrical at onset.
• Dense Vitritis: Vitreous cells arranged in distinctive sheets, clumps, debris, or "strings of pearls", characteristically disproportional to mild anterior chamber cellular activity.
• Sub-RPE Infiltrates: Multifocal, elevated, creamy yellowish-white infiltrates located beneath the retinal pigment epithelium (sub-RPE deposits), giving rise to a "leopard-spotting" pattern with overlying RPE detachments.
• Absence of Macular Oedema: A critical negative diagnostic sign: despite dense vitreous haze and extensive cellular infiltration, cystoid macular oedema (CMO) is often less prominent than expected. Its presence does not exclude lymphoma; integrate sub-RPE lesions, course and tissue findings.
• Steroid Responsiveness: Systemic or periocular steroids induce transient, dramatic clinical improvement by triggering apoptosis of neoplastic B-cells; however, relapse can occur and apparent steroid responsiveness does not establish an inflammatory diagnosis.
• CNS Association: Up to $60-80\%$ of patients presenting with PIOL will develop intracranial CNS lymphoma during their lifetime. Conversely, 15-25% of patients presenting with PCNSL have occult intraocular involvement.

Diagnostic Vitrectomy & Vitreous Biomarkers

Diagnosis commonly uses planned vitreous sampling, but the approach depends on the lesion and previous results. Coordinate cytology, flow and molecular testing before surgery; selected retinal/choroidal sampling or repeat investigation may be required, and no single negative vitreous test excludes disease.

1. Specimen Handling: An undiluted vitreous sample ($0.5-1.0\text{ mL}$) must be obtained under manual suction, transported immediately to the laboratory, and processed without delay, as lymphomatous cells rapidly undergo spontaneous cytolysis.
2. Cytopathology: Neoplastic lymphoid cells are characteristically large (2-3 times normal lymphocyte size) with a high nuclear-to-cytoplasmic ratio, hyperchromatic indented nuclei, and prominent multiple nucleoli.
3. Flow Cytometry: Confirms B-cell lineage ($CD19^+$, $CD20^+$, $CD22^+$, $CD79a^+$) and demonstrates monoclonal kappa or lambda light chain restriction.
4. Molecular Genetics: Detection of MYD88 L265P gene mutations (present in $>70-80\%$ of vitreoretinal DLBCL) and immunoglobulin heavy chain (IgH) gene rearrangement by PCR.
5. Cytokine Biomarker Analysis:
   • Interleukin-10 (IL-10) to Interleukin-6 (IL-6) Ratio: Neoplastic B-cells secrete high levels of immunosuppressive IL-10, whereas inflammatory T-cells in uveitis secrete IL-6. A vitreous IL-10:IL-6 ratio $> 1.0$ exhibits high sensitivity and specificity for B-cell PIOL.

Management Protocols

• Isolated Intraocular Disease: Local therapy consisting of repeated intravitreal injections of Methotrexate ($400\;\mu\text{g}/0.1\text{ mL}$) or Rituximab ($1\text{ mg}/0.1\text{ mL}$) on an induction and maintenance schedule, or low-dose ocular external beam radiation (30-40 Gy).
• Concurrent CNS Lymphoma: High-dose systemic intravenous methotrexate-based chemotherapy regimens (e.g. MATRix protocol) coordinated with neuro-oncology.

Comprehensive Summary: Uveal Melanoma vs Retinoblastoma vs Primary Intraocular Lymphoma

Genetic and Sampling Limits

Most retinoblastoma involves RB1 inactivation, but rare MYCN-amplified cases do not follow the classic two-hit pattern. Heritable disease can be unilateral and may reflect a new mutation in the child; no family history does not establish non-heritable disease. Genetic counselling addresses mosaicism, relatives, future children and second-tumour risk. Avoid intraocular biopsy of suspected retinoblastoma.

PVRL usually involves large B cells and may temporarily improve with steroids; cystoid oedema can occur. IL-10/IL-6 and MYD88 results support diagnosis but cytology, molecular tests and clinical evidence must be integrated. Plan unfixed material promptly for cytology/flow with the laboratory before vitrectomy; formalin destroys the ability to perform some tests. Negative sampling can require repeat investigation. Assess CNS disease and discuss local versus systemic therapy through a lymphoma team. COMS evidence does not mandate enucleation for every large melanoma; selected large lesions may receive specialist eye-preserving radiation.