Uveitis masquerade syndromes: A case series

Abstract

The aim of this series is to report challenges faced in diagnosis of three cases of recurrent or atypical uveitis not responding to conventional treatment. A high index of suspicion, aided by newer techniques, such as cytology, immunohistochemistry, flow cytometry of ocular fluids, and contrast-enhanced magnetic resonance imaging, may be necessary for a prompt diagnosis of uveitis masquerade syndromes.

Introduction

The uveitis masquerade syndromes (UMSs) are a group of ocular diseases that may mimic chronic intraocular inflammation. Malignancies such as primary intraocular lymphoma (IOL), leukemia, uveal melanoma, retinoblastoma, metastatic lesions, and paraneoplastic syndromes may masquerade as uveitis.

IOLs constitute <1% of all intraocular malignancies. They are classified as those arising primarily in the eye (vitreoretinal – primary vitreoretinal lymphoma [PVRL] or uveal origin – primary uveal lymphoma) or outside with subsequent ocular spread.[1] IOLs have varied presentations that mimic other forms of uveitis that delay diagnosis and hence are called “masquerades.”[2]

Here, we report our experience of diagnosing and managing three cases of IOL with varied presentations.

Case Reports

Case 1

A 65-year-old female presented gradual decline in vision in both eyes (OU) for the past 2 years. She had multiple courses of oral and periocular steroids given by her local doctor. On examination, best-corrected visual acuity (BCVA) was 6/18, N18 in the right eye (OD) and counting fingers at 50 cm in the left eye (OS). Slit lamp examination (SLE) revealed a quiet anterior chamber (AC) with two plus vitreous cells-OU. Fundus examination-OU revealed dense vitritis. Yellowish subretinal lesions were seen faintly at the posterior pole in OS [Figure 1a]. Complete uveitis workup was noncontributory. Aqueous fluid polymerase chain reaction (PCR) test showed positivity for both genomes of Mycobacterium tuberculosis (MTb-IS6110 and MPB64). Antitubercular therapy (ATT) and oral corticosteroids 1 mg/kg body weight were instituted. Four weeks later, she complained of deterioration of vision in OU. BCVA had dropped to 6/45, N24 OD and hand movements OS. Vitritis had worsened bilaterally with large confluent subretinal lesions noted at the posterior pole in OS [Figure 1b]. Diagnostic 25-gauge (25-G) vitrectomy was done. PCR testing was negative for both genomes of MTb. Cytopathologic testing of vitreous sample showed atypical lymphoid cells with necrotic background, suggestive of PVRL [Figure 1c]. PCR-based restriction fragment length polymorphism of vitreous aspirate showed MYD88 L265P mutation. Magnetic resonance imaging (MRI) brain revealed extensive lesions in the right frontal, left temporal lobes, left internal capsule, and left occipital cortex. Central nervous system (CNS) lymphoma was diagnosed. ATT and steroids were stopped. She was advised to undergo external beam radiotherapy and systemic chemotherapy.

Figure 1.

(a) Ultrawidefield fundus photograph (Optos PLC, Dunfermline, United Kingdom) of both eyes of case 1 at presentation showing vitreous haze in both eyes and yellow subretinal lesions at the posterior pole and along the inferior arcade in the Left eye. (b) Ultrawidefield fundus photograph-Optos of both eyes of case 1 after 4 weeks of antitubercular and steroid therapy showing extensive yellow subretinal lesions in the left eye compared to the previous visit. (c) Hematoxylin and eosin staining of the vitreous aspirate from the left eye showing atypical lymphoid cells (black arrows) with a necrotic background

Case 2

A 65-year-old male patient presented with sudden-onset pain, redness, and loss of vision in OS for 1 month and was on oral steroid therapy. He had a history of systemic non-Hodgkin's lymphoma (diffuse large B-cell lymphoma) and had completed six cycles of systemic chemotherapy. On examination, BCVA was 6/6, N6 in OD and perception of light OS. SLE-OS revealed granulomatous keratic precipitates with three plus AC cells [Figure 2a]. Fundus examination-OS revealed dense vitreous haze and three plus vitreous cells. Optic disc appeared pale [Figure 2b]. MRI brain showed T2 hyperintense signal in the left intraorbital optic nerve extending up to the orbital apex with no contrast enhancement. Diagnostic 25-G vitrectomy was done and cytopathology of vitreous specimen revealed inflammatory cells with few lymphoid cells; however, no abnormal cells were seen. Immunohistochemistry (IHC) was negative. One-month postvitrectomy OS was quiet, with pale optic disc and atrophic retina at posterior pole. Symptomatic therapy with close observation was advised.

Figure 2.

(a) Slit lamp photograph of the left eye of case 2 showing granulomatous keratic precipitates on the corneal endothelium. (b) Ultrawidefield fundus photograph-Optos of the left eye showing vitreous floater, pale disc, and chorioretinal atrophic patches in the nasal retina

Case 3

A 49-year-old male presented with sudden blurring of vision in OD for the past 3 weeks and was started on oral steroids locally. On presentation, BCVA OD was 6/15, N36 and OS 6/6, N6. Fundus examination-OD revealed a yellow subretinal lesion at the macula [Figure 3a]. Complete uveitis tests including tuberculosis workup were negative. A diagnosis of unilateral acute idiopathic choroiditis was considered, and oral steroids were continued. The macular lesion resolved with scarring within 1 month of steroid therapy [Figure 3b]. Optical coherence tomography at presentation showed a dome-shaped elevation of retinal pigment epithelium (RPE) with subretinal hyperreflective echoes [Figure 3c], and at 1 month, the lesion had flattened but bumpy RPE and sub-RPE deposits persisted [Figure 3d]. MRI brain was advised as the patient reported a seizure episode which showed a space-occupying lesion in the frontoparietal lobe and cingulate gyrus. Biopsy IHC studies showed positive reaction to B-cell markers CD20, CD79a, Bcl-2, and Bcl-6. Bone marrow aspiration showed a hypercellular marrow, lymphocytes 3%, and blast cells 2%. Primary CNS lymphoma of diffuse B-cell phenotype with aggressive histology was diagnosed. The patient was started on systemic chemotherapy and radiotherapy. In retrospect, we concluded that the ocular findings were that of IOL masquerading as a macular lesion which responded to systemic steroids. Diagnostic vitrectomy for cytopathology could not be done as the patient succumbed to his systemic disease.

Figure 3.

(a) Fundus photograph of posterior pole of the right eye of case 3 showing a yellowish subretinal lesion at the macula with surrounding yellowish precipitates. (b) Fundus photograph of posterior pole of the right eye of case 3 showing scarred lesion at the macula after 1 month of treatment with oral corticosteroids. (c) Optical coherence tomography of the right eye case 3 (at presentation) showing subretinal hyper-reflective echoes at fovea with bumpy retinal pigment epithelium and retinal pigment epithelium atrophy in the right eye, with central foveal thickness of 96 μ. (d) Optical coherence tomography of the right eye (after 1 month) showing subretinal exudates (decreased) noted at foveal region with foveal thinning and a central foveal thickness of 80 μ

Discussion

IOL is a rare lymphoproliferative disorder. Ocular findings may include keratic precipitates, AC reaction, pseudohypopyon, vitreous haze, vitreous infiltration by lymphoma cells, creamy deep retinal/subretinal infiltrates, exudative retinal detachment, RPE atrophy with subretinal fibrosis, and rarely, disciform scarring at the macula. Secondary IOLs are known to present with granulomatous anterior uveitis.[3]

Clinical diagnosis of IOL masquerading as uveitis is a challenge as demonstrated by our three cases. We would like to highlight the role of multitargeted evaluation of aqueous and/or vitreous fluid by cytopathology, IHC, flow cytometry, cytokine analysis, and imaging to aid in diagnosis of IOL. The key findings of all these techniques are highlighted in Table 1.[4] Recently, Cani et al. have demonstrated the role of next-generation sequencing to detect MYD88 gain-of-function mutations, which are highly specific for PVRL.[5] We were able to identify this mutation in our first case. In the second case, although cytology and IHC were both negative, a diagnosis of presumed IOL was considered, as both prior chemotherapy and concurrent steroid use possibly affected the vitreous biopsy result. Studies have reported that the paucity of the cells in the biopsy specimens may be the result of corticosteroid treatment, which must be discontinued for at least 2 weeks before the procedure.[6] In the third case, the MRI brain, biopsy IHC studies, and bone marrow pathology clinched the diagnosis.

Table 1.

Key findings of various investigations in intraocular lymphomas

Investigative modality	Key findings
Cytology	Pleomorphic, medium-large sized cells with minimal cytoplasm, indented or folded nucleoli, prominent nucleoli Background of necrotic T-cells
IHC	Specific B-cell markers such as CD 20+, CD 79a+, BCL-2, MUM1/IRF4+, BCL 6+
Flow cytometry	Restricted expression of κ:ƛ light chain κ:ƛ ratio >3 or <0.6
Molecular	IgH gene rearrangements, BCL-2 proto-oncogene translocations
Cytokine profile analysis	Elevated IL-10 levels in vitreous aspirates IL-10: IL-6 ratio >1

IHC: Immunohistochemistry, BCL: B-cell lymphoma, IL: Interleukin

A high degree of clinical suspicion, coupled with targeted diagnostic tests, is necessary for early detection of IOLs, especially in recurrent, intractable, or atypical intermediate or posterior uveitis. Diagnosis of UMS should be considered in all patients with idiopathic recurrent corticosteroid-resistant chronic uveitis. Timely diagnosis and treatment may improve prognosis and sometimes gain control over this potentially lethal disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.