A case of non-Hodgkin lymphoma diagnosed after 35-month of initial presentation as recurrent vitritis with multiple negative biopsies.

To report a case of non-Hodgkin lymphoma (NHL) that was diagnosed 35-month of initial ocular manifestation. Retrospective chart review. A 53-year-old male presented with painless diminution of vision in both eyes. He subsequently underwent extensive laboratory investigations including multiple vitreous biopsies with a suspicion of intraocular lymphoma. Cytology from the vitreous aspirate failed to diagnose any relevant pathology. After 35-month from the onset of his ocular symptom, a brain biopsy revealed a round cell tumor suggestive of NHL. Even with high index of suspicion, consultation with ocular oncologist, imaging, and diagnostic vitrectomy, the diagnosis of lymphoma remains challenging. Copyright:

Introduction

Intraocular lymphoma is a rare malignancy that accounts for 0.01% of ophthalmic conditions. It includes primary intraocular lymphoma (PIOL) with or without primary central nervous system lymphoma (PCNSL).[1] The majority of the patients are elderly individuals, usually aged over 50 years.[2] Because of the potential lethality of this condition, rapid and accurate diagnosis is crucial and may increase the survival, especially if diagnosed before central nervous system (CNS) involvement.[13] PIOL can have a plethora of presentations; most commonly, it masquerades as an intermediate and/or posterior uveitis.[3] Oncologists usually depend on the cytologic evidence of malignant lymphocytes on vitreous specimens before initiating treatment. We describe a case, in which, in spite of a high index of suspicion, a definitive diagnosis could not be established by vitreous biopsies until the patient developed CNS involvement.

Case Report

A 53-year-old male who presented with gradual painless diminution of vision in both eyes for 2 months. His best-corrected visual acuity was counting fingers close face in the right eye and 20/50 in the left eye. Examination of the right eye showed fine, small keratic precipitates inferiorly, cells 0.5+ in the anterior chamber. His intraocular pressures (IOP) were 40 and 20 mm Hg in the right and left eye, respectively. Fundus examination of the eyes revealed vitritis, which was marked in the right eye and glaucomatous disc in both eyes [Figure 1a and b]. Polymerase chain reaction (PCR) from aqueous aspirate was negative for herpes viruses and mycobacteria. He was started on topical and oral corticosteroid (1 mg/kg body weight/day) and anti-glaucoma medication.

Figure 1

(a and b) Fundus photograph of the both eyes showing vitritis, more marked in the right eye and glaucomatous disc in both eyes. (c and d) Fundus examination of both eyes 35 months after the onset of ocular symptoms, showing glaucomatous discs through severe vitritis in both eyes

Subsequently, his IOP returned to normal in both eyes, but there was very minimal improvement in vitreous haze in both eyes. The fundus examination was within normal limit and swept-source optical coherence tomography failed to reveal any abnormality. In view of persistent vitritis, he underwent diagnostic vitrectomy in the right eye after a month of stopping oral corticosteroid. Cytology and PCR from undiluted vitreous aspirate were inconclusive. Magnetic resonance imaging (MRI) of the brain and orbit was normal. He was again started on tapering doses of topical and oral steroids. Subsequently, he developed steroid-induced cataract and underwent cataract extraction in both the eyes at an interval of 5 months. A strong suspicion of intraocular lymphoma was maintained. However, another vitreous biopsy from the left eye failed to show the presence of neoplastic cells on cytologic analysis. Consultation with a neurologist did not help as a repeat MRI of the brain did not reveal any lesion.

Six-month after and 35 months from the onset of first ocular symptoms, the patient was admitted to a hospital with vomiting, difficulty in walking associated with speech disturbance. MRI brain with contrast at this point was suggestive of PCNSL. However, cerebrospinal fluid (CSF) examination whole-body positron emission tomography – computed tomography was inconclusive. He had nil perception of light in the right eye and was 20/30 in the left eye. Fundus examination revealed a hazily seen glaucomatous disc through severe vitritis in both eyes [Figure 1c and d]. A repeat vitreous biopsy from the left eye did not yield any positive result. However, this time MRI brain showed ill-defined hyperintense areas in the cerebellum and cerebral white matter [Figure 2a-c]. Frozen section from specimens of the right frontal corona radiata lesions obtained through a brain biopsy indicated a round cell tumor suggestive of non-Hodgkin lymphoma. Immunohistochemistry for leukocyte common antigen (LCA), B-cell markers (CD20 and CD79a), and other markers Bcl2, Bcl6, and MUM1 was positive [Figure 3]. MIB-1 proliferation index was high (>90%) suggesting a high-grade lymphoma. T-cell marker CD3 was negative. The patient was started on methotrexate. Chemotherapy with weekly rituximab along with whole-brain radiation was planned which the patient opted to have locally.

Figure 2

(a-c) Magnetic resonance imaging brain with contrast-flair axial images of the showing ill-defined hyperintense areas in the cerebellum and cerebral white matter. Diffusion-weighted images of the same patient showed restricted diffusion (bright signal). No appreciable postcontrast enhancement was seen which is atypical for lymphoma but highly suspected to be consistent with lymphomatosis cerebri

Figure 3

Frozen section from specimens of the right frontal corona radiata lesions obtained through a brain biopsy. On H and E stain (a, ×20 and b, ×40) showed a round cell suggestive of non-Hodgkin lymphoma. Immunohistochemistry for leukocyte common antigen (c, LCA - ×40), B-cell markers (d, CD20 - ×40); Bcl6 (e, ×40); MUM1 (f, ×40) was positive

Discussion

Diagnosis of PIOL requires a high index of suspicion and a multidisciplinary approach. PIOL is frequently masquerades and often misdiagnosed as uveitis.[4] Treatment with corticosteroid may help in transient reduction of inflammation in vitreous, mainly because of the lymphocytic nature of corticosteroid, which further adds to the misdiagnosis of uveitis. In the majority of cases, a diagnosis of intraocular lymphoma is considered when the presumed uveitis fails to respond to corticosteroid therapy. Thus, the ophthalmologist may play a very important role-to suspect PIOL, obtain adequate sample for the pathologist to confirm the diagnosis of PIOL and coordinate with an oncologist in planning management of PIOL.

Diagnosis of PIOL requires histopathologic evidence of the malignant lymphoma cells in tissue biopsy and in the absence of chorioretinal lesions, vitreous biopsy can be an ideal tool to obtain specimen for cytological analysis. It is also essential to rule out the CNS involvement with radiological imaging and cytologic analysis of the CSF obtained by a lumbar puncture. In the absence of negative cytologic analysis of CSF for PCNSL, vitreous aspirate has been found to be useful in diagnosis of PIOL.[5]

A PIOL is an important cause of masquerade syndrome. It can mimic intraocular inflammation and pose a significant challenge to the diagnosis. One needs to exclude the other causes of uveitis before confirming the diagnosis of masquerade syndrome. However, high index of suspicion in elderly individuals, especially those with first-episode intraocular inflammation should be investigated cautiously.

The index case is unusual in that multiple vitreous biopsies from two separate clinical settings failed to yield any positive result for the diagnosis of intraocular lymphoma. Finally, positive radiological findings and biopsy from corona radiata helped us to clinch the diagnosis of PCNSL. Even with suggestive radiology, vitreous biopsy and CSF analysis were inconclusive in our patient. Vitreous biopsy may often be negative due to the fact that the lymphoma cells are fragile and easily degenerate in the vitreous, but it is extremely difficult to explain why the cytologic analysis from three vitreous biopsies was not helpful in the current case. To conclude, the clinicians should recognize that PIOL can occur and manifest as PCNSL even when the vitreous biopsy and CSF analysis shows negative cytology.

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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.