# Masquerade Syndromes in Uveitis

## Introduction

Masquerade syndromes are conditions that mimic intraocular inflammation but are not primarily inflammatory in nature. They account for approximately 5% of uveitis referrals and represent a diagnostic pitfall. Delayed recognition can lead to inappropriate immunosuppression and loss of the window for effective treatment of the underlying condition, which is often malignant.

## Classification

### Neoplastic Masquerade Syndromes

**Primary vitreoretinal lymphoma (PVRL)**: most common neoplastic masquerade. **Primary central nervous system lymphoma** with ocular involvement. Uveal lymphoid infiltration. Retinoblastoma (pediatric population) Leukemia (acute lymphoblastic, acute myeloid) Uveal melanoma with secondary inflammation.

Metastatic carcinoma to the uveal tract (lung, breast) Paraneoplastic syndromes (cancer-associated retinopathy, melanoma-associated retinopathy)

### Non-Neoplastic Masquerade Syndromes

**Retained intraocular foreign body**: chronic low-grade inflammation. Retinal detachment (rhegmatogenous) with pigment release. Intraocular ischemia (ocular ischemic syndrome, neovascular glaucoma) Pigment dispersion syndrome. Juvenile xanthogranuloma. Drug reactions (rifabutin-associated uveitis, cidofovir)

Retinal degenerations (retinitis pigmentosa with vitreous cells) Amyloidosis.

| Masquerade Syndrome | Age Group | Key Clinical Clue | Diagnostic Test |
|---|---|---|---|
| Primary vitreoretinal lymphoma | >50 years | Vitritis unresponsive to steroids; sub-RPE deposits | Vitrectomy: IL-10:IL-6 >1; flow cytometry |
| Retinoblastoma | Pediatric | Leukocoria; pseudohypopyon | EUA + B-scan (calcification); NO biopsy |
| Leukemia | Any age | Spontaneous hyphema; Roth spots | CBC; known diagnosis |
| Uveal melanoma | Adults | Pigmented mass; sentinel vessels | B-scan: low reflectivity, acoustic hollowing |
| Retained IOFB | Any age | History of trauma; siderosis/chalcosis | CT orbit (no contrast) |
| Ocular ischemic syndrome | Elderly | Dilated non-tortuous veins; low IOP; NVI | Carotid Doppler |
| UGH syndrome | Pseudophakic | Recurrent hyphema; malpositioned IOL | Gonioscopy; UBM |

## Primary Vitreoretinal Lymphoma

### Epidemiology and Pathology

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Median age at presentation: 60-65 years; slight female predominance. Bilateral in 60-90% of cases, though may present asymmetrically. Strong association with **primary CNS lymphoma** (PCNSL): 50-80% develop CNS involvement.

### Clinical Features

Chronic vitritis unresponsive to corticosteroids (transient response may occur due to lymphocytolytic effect) Sub-RPE deposits: characteristic yellow-white lesions at the level of the RPE. Minimal anterior chamber inflammation relative to degree of vitritis. Retinal or subretinal infiltrates. **"Steroid-responsive but steroid-dependent"** pattern should raise suspicion.

### Diagnostic Workup

**Diagnostic vitrectomy**: undiluted vitreous specimen. Cytology: large atypical lymphoid cells with scanty cytoplasm, prominent nucleoli. Flow cytometry: monoclonal B-cell population (CD20+, CD19+) **IL-10:IL-6 ratio > 1** strongly supports lymphoma (IL-10 is a B-cell growth factor) Cytokine analysis is often more sensitive than cytology. Molecular: immunoglobulin heavy chain gene rearrangement (PCR), MYD88 L265P mutation.

MRI brain with gadolinium: evaluate for CNS involvement. Lumbar puncture with CSF cytology.

![Fundus photograph showing sub-RPE infiltrates in primary vitreoretinal lymphoma](images/pvrl-subrpe-deposits.jpg)

### Management

Multidisciplinary: ophthalmology, neuro-oncology, radiation oncology. **Intravitreal methotrexate** (400 mcg/0.1 mL): induction (twice weekly x 4 weeks), consolidation (weekly x 8 weeks), maintenance (monthly x 9 months) **Intravitreal rituximab** (1 mg/0.1 mL): alternative or adjunct. External beam radiation therapy to the globe. Systemic chemotherapy (high-dose methotrexate) if CNS involvement is present. Prognosis is guarded; 5-year survival 30-60%.

## Retinoblastoma

Most important masquerade in pediatric uveitis. May present with pseudohypopyon (tumor cells), vitritis, or anterior uveitis. **Leukocoria** and strabismus are the most common presenting signs. Aqueous or vitreous biopsy is **contraindicated** due to risk of extraocular seeding. Diagnosis is clinical with exam under anesthesia, B-scan ultrasound (calcification), and MRI. Aqueous humor cell-free DNA analysis is an emerging diagnostic tool.

## Leukemia

Can involve any ocular structure; anterior segment involvement may simulate iridocyclitis. Iris infiltration, **spontaneous hyphema**, pseudohypopyon of leukemic cells. Retinal findings: cotton-wool spots, hemorrhages, Roth spots, vessel infiltration. Diagnosis usually known; ophthalmic findings may herald relapse.

![Slit-lamp photograph of pseudohypopyon in a patient with intraocular lymphoma](images/masquerade-pseudohypopyon.jpg)

## Uveal Melanoma with Inflammation

Melanoma can incite secondary inflammation mimicking uveitis. Sentinel episcleral vessels, elevated pigmented or amelanotic mass. Exudative retinal detachment may be present. B-scan ultrasonography shows characteristic **acoustic hollowing** and choroidal excavation. Dilated fundus examination with indirect ophthalmoscopy and scleral depression is essential.

## Non-Neoplastic Masquerades

### Retained Intraocular Foreign Body

History of trauma or prior surgery; may be remote. Chronic granulomatous or non-granulomatous anterior uveitis. Siderosis (iron) or chalcosis (copper) if metallic. CT orbit without contrast is the imaging modality of choice (MRI contraindicated for metallic foreign bodies)

### Ocular Ischemic Syndrome

Carotid artery stenosis causing chronic ocular hypoperfusion. Dilated but non-tortuous retinal veins, mid-peripheral dot-blot hemorrhages. Flare out of proportion to cells in the anterior chamber. Low intraocular pressure; neovascularization of iris and disc.

### Pigment Dispersion and UGH Syndrome

Pigment dispersion syndrome: bilateral, young myopic males, Krukenberg spindle. UGH syndrome (uveitis-glaucoma-hyphema): associated with malpositioned or chafing IOL.

![CT scan demonstrating a metallic intraocular foreign body causing chronic inflammation](images/iofb-ct-masquerade.jpg)

## Approach to the Unresponsive Uveitis Patient

Re-evaluate the diagnosis when uveitis fails to respond to appropriate therapy. **Red flags** for masquerade: Age > 50 with new-onset vitritis. Unilateral disease unresponsive to corticosteroids. Sub-RPE deposits or retinal/subretinal infiltrates. Pseudohypopyon.

Progressive course despite adequate immunosuppression. Consider diagnostic vitrectomy with cytology, flow cytometry, and cytokine analysis. Obtain neuroimaging (MRI brain) in suspected lymphoma. Maintain a low threshold for biopsy in atypical presentations.

## Key Clinical Pearls

Primary vitreoretinal lymphoma is the most common neoplastic masquerade and should be suspected in any patient over 50 with chronic vitritis unresponsive to corticosteroids. An IL-10:IL-6 ratio greater than 1 in vitreous fluid supports a diagnosis of intraocular lymphoma. Never perform an intraocular biopsy in suspected retinoblastoma due to the risk of tumor seeding. Always reconsider the diagnosis when uveitis does not respond as expected to appropriate therapy.

## References

1. Faia LJ, Chan CC. Primary intraocular lymphoma. *Arch Pathol Lab Med*. 2009;133(8):1228-1232.
2. Cassoux N, Merle-Beral H, Leblond V, et al. Ocular and central nervous system lymphoma: clinical features and diagnosis. *Ocul Immunol Inflamm*. 2000;8(4):243-250.
3. Read RW, Zamir E, Rao NA. Neoplastic masquerade syndromes. *Surv Ophthalmol*. 2002;47(2):81-124.
4. Sagoo MS, Shields CL, Mashayekhi A, et al. Plaque radiotherapy for juxtapapillary choroidal melanoma. *Arch Ophthalmol*. 2007;125(10):1347-1352.