Uveitis Masquerade Syndromes (UMS) are a group of diseases presenting with intraocular infiltrating cells not due to immune-mediated or infectious processes. In 1967, Theodore first used the term “masquerade syndrome” for a case of conjunctival carcinoma presenting as chronic conjunctivitis. Suspect this condition when uveitis is refractory to steroid therapy or recurs after temporary improvement.
The frequency of UMS in tertiary uveitis clinics is reported to be 2.5–5%5, 9). Epidemiological statistics in the 2019 Uveitis Clinical Practice Guidelines also show that intraocular malignant lymphoma accounts for 1.0% and masquerade syndrome accounts for 2.5%5). Rothova (2001) reported that 40 out of 828 patients (5%) were diagnosed with UMS, of whom 48% had intraocular malignancy9).
QWhat diseases is masquerade syndrome often mistaken for?
A
It mimics common ocular inflammatory diseases such as sarcoidosis, toxoplasmosis, syphilis, tuberculosis, intermediate uveitis, acute retinal necrosis, and birdshot retinochoroidopathy. In particular, a temporary response to steroids can delay diagnosis9). UMS should be actively considered in the differential diagnosis in elderly patients, those with a history of malignancy, or immunocompromised individuals.
Symptoms of UMS vary depending on the underlying cause but are generally indistinguishable from uveitis.
Blurred vision: due to vitreous opacity or subretinal infiltration. Most common symptom
Floaters: due to cellular infiltration in the vitreous. Prominent in PVRL
Decreased vision: Slowly progressive painless vision loss is characteristic of PVRL
Eye pain: Metastatic iris tumors may present with severe eye pain due to secondary glaucoma1). During intraocular recurrence of PVRL, eye pain with elevated intraocular pressure may also occur2)
Redness: Associated with anterior segment infiltration or secondary glaucoma
The major clinical findings of neoplastic UMS by cause are shown below.
PVRL
Vitreous opacity: Characterized by veil-like diffuse opacity. Lymphoma cells align along the peripheral vitreous fibers in a band-like or cord-like pattern, showing a unique pattern radiating from the posterior pole to the periphery2, 12).
Subretinal infiltration: Creamy to yellowish-white infiltration resembling sarcoidosis or white dot syndrome.
Keratic precipitates: More frequent at intraocular recurrence than at initial onset (47.4% vs 29.4%)2). They appear stellate or mutton fat-like.
Anterior chamber cells: Mimics anterior uveitis.
Metastatic tumor/Leukemia
Choroidal mass: Creamy white to pale yellow mass with subretinal fluid. The most common form of ocular metastasis.
Iris nodules: Small nodules scattered on the iris surface. Associated with secondary glaucoma1).
Pseudohypopyon: Characteristic of leukemia. Bilateral, viscous, often bloody.
Angle mass: Small mass or peripheral anterior synechiae seen on gonioscopy1).
Intraocular malignant lymphoma shows a characteristic combination of relatively mild iritis and severe vitreous opacity, with a veiled vitreous opacity that helps differentiate it from the clumped vitreous opacity of fungal endophthalmitis.
QWhat are the ocular manifestations of leukemia?
A
Ocular involvement has been reported in up to 90% of leukemia patients. Anterior segment findings include pseudohypopyon and iris infiltration, while posterior segment findings include cotton-wool spots, Roth spots-like white-centered retinal hemorrhages, and tortuous dilation of retinal veins. It may also cause serous retinal detachment, mimicking Vogt-Koyanagi-Harada disease or posterior scleritis. In adult T-cell leukemia/lymphoma (ATL), a unique uveitis-like condition associated with HTLV-1 infection is known5).
PVRL: The annual incidence is approximately 1 per 100,000 population. The average age at diagnosis is 63 years, with a slight female predominance. Immunodeficiency and immunosuppression are risk factors. Histologically, almost all cases (98%) are non-Hodgkin B-cell lymphoma, corresponding to diffuse large B-cell lymphoma (DLBCL). The disease is classified into four types: (1) eye and central nervous system, (2) intraocular only, (3) eye plus other organs, and (4) eye plus other organs plus central nervous system. Type (1) is the most common, accounting for about 60% of all cases. Ocular symptoms are seen in 15–20% of central nervous system lymphomas, and the majority of patients presenting with ocular involvement alone later develop CNS lymphoma10, 12).
Adult T-cell leukemia/lymphoma (ATL): A T-cell hematologic malignancy caused by HTLV-1 virus infection, presenting with uveitis-like ocular infiltration and contributing to masquerade syndrome5). It is relatively common in regions with high HTLV-1 infection rates, such as Kyushu and Okinawa.
Metastatic solid tumors: Ocular involvement is observed in approximately 8–10% of patients with metastatic disease. In about 30%, ocular metastasis is the first sign of systemic tumor dissemination. Iris metastasis accounts for 8% of all metastatic uveal tumors1). Common primary sites are breast and lung cancers.
Intraocular foreign body (IOFB): Found in 17–40% of penetrating ocular injuries. Retained iron or copper can cause retinal degeneration and vision loss.
Pigment dispersion syndrome (PDS): Incidence is approximately 4.8 per 100,000 population. Pigment release due to friction between the posterior iris surface and zonules mimics intraocular inflammation.
Medulloepithelioma: A rare pediatric tumor originating from the ciliary body. Secondarily causes cataract, glaucoma, and uveitis.
QCan adult T-cell leukemia/lymphoma also cause masquerade syndrome?
A
ATL (adult T-cell leukemia/lymphoma) is a T-cell neoplasm caused by HTLV-1 infection. Infiltration of lymphoma cells into the eye can present with uveitis-like conditions (anterior chamber inflammation, vitreous opacity, retinal infiltration) and contribute to masquerade syndrome5). It is histologically different from PVRL (T-cell type), and treatment response and prognosis also differ. In areas with high HTLV-1 infection rates, it should be considered in the differential diagnosis.
A high index of clinical suspicion is essential for diagnosing UMS. Differential diagnosis should be actively pursued, especially in elderly patients with first-onset uveitis, cases that temporarily respond to steroids but relapse, and patients with a history of malignant tumors. Screening tests based on the 2019 Uveitis Clinical Practice Guidelines should be performed5).
Vitreous biopsy is important for definitive diagnosis of PVRL5, 10).
Cytology: Identify pleomorphic cells with large hyperchromatic nuclei and scant basophilic cytoplasm. Perform after steroid discontinuation, as steroids may lyse lymphoma cells and cause false negatives3).
Flow cytometry: Evaluate the ratio of B cells (CD19+/CD20+) and T cells to confirm monoclonal proliferation6).
IL-10/IL-6 ratio: An IL-10 level higher than IL-6 in aqueous humor or vitreous fluid strongly suggests PVRL. IL-10 measurement has reported sensitivity of 85.7% and specificity of 81.1%2, 13).
MYD88 mutation detection: Detection of the MYD88 L265P mutation using cell-free DNA is gaining attention. It has been reported that the detection rate is approximately 30% higher than using cellular DNA3)
PCR immunoglobulin gene rearrangement: Used to confirm clonality5)
Tumor markers (in aqueous humor): For metastatic intraocular tumors, measurement of tumor markers (e.g., CEA) corresponding to the primary tumor in the aqueous humor is useful as an auxiliary diagnostic tool. In one case, the aqueous humor CEA level (75.6 ng/mL) was more than four times the serum level (17.3 ng/mL)1)
Clumped (not veil-like) vitreous opacities, IVH history
QWhy is the diagnosis of PVRL often delayed?
A
Because PVRL temporarily responds to steroids, it is often diagnosed as uveitis and steroid treatment is continued 3). Additionally, the positive rate of cytology in vitreous biopsy is low (30–50%), and prior steroid administration can cause lymphoma cells to lyse, making them harder to detect. Ancillary tests such as IL-10/IL-6 ratio measurement and MYD88 mutation detection contribute to improved diagnostic accuracy 13).
Treatment of UMS is based on identifying and treating the underlying disease. For neoplastic UMS, chemotherapy and radiotherapy for the primary disease are the mainstays.
External beam radiotherapy was previously the first choice, but due to severe side effects, it is now limited to patients with bilateral disease, elderly patients, or those who cannot tolerate frequent injections 3).
Local Ocular Treatment
Intravitreal MTX injection (first choice) 3, 7):
Dosing protocol: 400 μg/0.1 mL twice weekly for 4 weeks → once weekly for 8 weeks → once monthly for 9 months
The regimen by Frenkel 2008, based on 10 years of experience, is widely referenced 7)
Toxicity: MTX keratopathy (punctate superficial keratitis) may occur
Intravitreal rituximab injection: administered at 1 mg/0.1 mL5)
Efficacy has been reported in MTX-refractory cases and B-cell lymphoma
Radiation therapy: total dose of approximately 30 Gy to both eyes5)
Systemic treatment: Chemotherapy and molecular targeted therapy for the primary tumor are the mainstays. Advances in molecular targeted agents (e.g., osimertinib) have prolonged survival1)
Radiation therapy: External beam radiation therapy (41%) and plaque radiation therapy (24%) for iris metastases 1)
Surgery: Surgical resection for iris metastases accounts for only 5% of cases 1)
Konno et al. (2024) reported a case of masquerade syndrome due to metastatic iris tumor from lung adenocarcinoma 1). The iris tumor regressed after trabeculectomy, a single intravitreal injection of bevacizumab, and continued osimertinib administration, with intraocular pressure controlled at 8–10 mmHg. Quality of life was maintained for 2 years and 9 months from the initial visit.
PVRL has a high rate of intraocular recurrence. In one study, intraocular recurrence was observed in 14 of 51 cases (27.5%) during a mean follow-up period of 42.5 months 2). The most common finding at recurrence was vitreous opacity (84%). Regular ophthalmologic follow-up and IL-10 measurement are recommended for early detection of recurrence 2, 5). No history of intravitreal chemotherapy has been identified as an independent risk factor for intraocular recurrence (OR 7.72; 95% CI 1.37-43.6) 2).
PVRL is a rare type of central nervous system lymphoma that initially presents in the eye. Ultimately, about 80% of cases develop CNS lesions 4). It is thought that transformation of tumor cells occurs outside the CNS, after which they migrate into the immune-privileged intraocular space 4).
The presence of the blood-retinal barrier (BRB) plays an important role in the pathology of PVRL. The BRB limits the intraocular penetration of systemic chemotherapy, making it difficult to control intraocular lesions 2, 4). This is the rationale for the need for intravitreal chemotherapy.
Most intraocular lymphoma cells are DLBCL, which is highly malignant, and the prognosis is often poor when it occurs in the central nervous system. Visual function prognosis is relatively good if there is no tumor cell infiltration into the macula or optic nerve and if radiation-induced retinopathy or optic neuropathy does not occur. On the other hand, when retinal lesions are extensive or when macular atrophy or optic atrophy occurs, visual function is significantly reduced. The MYD88 L265P mutation (constitutive activation of Toll-like receptor signaling) is involved in tumor cell proliferation and survival 3).
Ocular metastases commonly occur in the vascular-rich uvea, especially the choroid. Iris metastases account for 8% of all uveal metastases and are rare, but they often present as uveitic masquerade syndrome 1). The mechanism of secondary glaucoma due to metastatic iris tumors is obstruction of aqueous outflow by tumor cell infiltration into the angle or peripheral anterior synechiae1). Although life prognosis has improved with high-dose MTX-based chemotherapy, many elderly-onset cases still have a poor prognosis.
Pigment dispersion syndrome: Pigment is released from the iris pigment epithelium due to friction between the posterior iris and the lens zonules, and is released into the anterior chamber.
Ocular ischemic syndrome: Elevated VEGF levels due to chronic hypoperfusion increase vascular permeability, triggering anterior chamber inflammation.
Retinitis pigmentosa: Secondary inflammatory reactions associated with degeneration of photoreceptors and retinal pigment epithelium are observed as vitreous cells.
In the diagnosis of PVRL, detection of MYD88 mutations using cell-free DNA in vitreous fluid has attracted attention3). The detection rate of MYD88 mutations using cell-free DNA is approximately 30% higher than that using cellular DNA, and it was effective even in highly diluted (100-fold or more) vitreous samples. Detection in aqueous humor samples is also possible, and it is expected to be a minimally invasive diagnostic tool.
A study by Kimura et al. (2012) involving 217 patients with intraocular lymphoma systematically evaluated the diagnostic accuracy of combinations of high IL-10, low IL-6, positive cytology, and positive gene rearrangement testing13).
Ibrutinib (a Bruton’s tyrosine kinase inhibitor) has shown efficacy against relapsed/refractory PCNSL (primary central nervous system lymphoma) and PVRL8, 11). The mechanism of action is based on MYD88 mutations maintaining BTK-dependent survival signals via activation of the NF-κB pathway.
Clinical trials of CAR-T (chimeric antigen receptor T-cell) therapy for CNS lymphoma are ongoing. Studies continue on its transfer into the central nervous system and effects within the eye. Overcoming the blood-ocular barrier remains a challenge for achieving local CAR-T administration for intraocular lesions.
Konno S, Yuzawa S, Kinouchi R. A case of masquerade syndrome caused by metastatic iris tumor diagnosed by a high CEA level in the aqueous humor and iris biopsy. Diagn Pathol. 2024;19:128.
Liu Y, Wang X, Chen K, et al. Intraocular recurrence in primary vitreoretinal lymphoma. Ophthalmol Retina. 2024;8:317-324.
Levy-Clarke GA, Chan CC, Nussenblatt RB. Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am. 2005;19(4):739-749.
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Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017;7(9):1018-1029.
Rothova A, Ooijman F, Kerkhoff F, et al. Uveitis masquerade syndromes. Ophthalmology. 2001;108(2):386-399.
Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lymphoma: a report from an International Primary CNS Lymphoma Collaborative Group symposium. Oncologist. 2011;16(11):1589-1599.
Soussain C, Choquet S, Fournier E, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma (iLOC): a phase 2 study. Eur J Cancer. 2019;117:121-130.
Kimura K, Usui Y, Goto H; Japanese Intraocular Lymphoma Study Group. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol. 2012;56(4):383-389.
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