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Journal Français d'Ophtalmologie
Volume 36, n° 5
pages 431-434 (mai 2013)
Doi : 10.1016/j.jfo.2012.11.005
Received : 14 Mars 2012 ;  accepted : 11 November 2012
Intravitreal injection of anti-VEGF and diagnosis of primary intraocular central nervous system lymphoma
Injections intravitréennes d’anti-VEGF et diagnostic de lymphome oculocérébral
 

J. Gambrelle a, , G. Missotten b, S. Delhoum a, L. Desjardins c
a Service d’ophtalmologie, CHU de Brest, 2, avenue Foch, 29609 Brest, France 
b Service d’ophtalmologie, université Catholique de Louvain, place de l’Université, 1, bte L0.01.08, 1348, Louvain-la-Neuve, Belgium 
c Service d’ophtalmologie, institut Curie, 26, rue d’Ulm, 75005 Paris, France 

Corresponding author.
Summary

We report a case of primary intraocular central nervous system (CNS) lymphoma in a patient previously treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections for age-related macular degeneration (AMD). An 88-year-old woman, with past medical history significant for bilateral age-related macular degeneration (AMD) treated with intravitreal ranibizumab injections for 1year, was referred to our department for bilateral vitritis diagnosed 10days after the last anti-VEGF injection. A complete uveitis work-up including aqueous humour analysis, brain MRI and vitreous biopsy enabled us to confirm the diagnosis of primary intraocular CNS lymphoma. To the best of our knowledge, this is the first report of the diagnosis of primary intraocular CNS lymphoma in a patient treated with anti-VEGF for AMD. The differential diagnosis of vitritis in elderly patients is relatively broad. Endophthalmitis and uveitis have been described after anti-VEGF injections. In such a situation, there is actually a risk of missing the diagnosis of intraocular lymphoma in the mistaken belief that the observed vitritis may be a reaction to administered anti-VEGFs. If no direct time-relationship with the anti-VEGF injections can be found, a classic vitritis work-up should be performed. Our observation suggests that ranibizumab, at the dosage used for AMD, does not impede the spread of CNS lymphoma in the eye nor interfere with cytological diagnosis.

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Résumé

Nous rapportons un cas de lymphome oculocérébral (LOC) survenu chez un patient traité par injection intravitréenne (IVT) d’anti-Vascular Endothelial Growth Factor (VEGF) pour une dégénérescence maculaire liée à l’âge (DMLA). Une femme âgée de 88ans, aux antécédents marqués par une DMLA bilatérale traitée par IVTs de ranibizumab depuis un an nous a été adressée pour une hyalite bilatérale diagnostiquée dix jours après la dernière IVT d’anti-VEGF. Un bilan d’uvéite complet, incluant une analyse de l’humeur aqueuse, une IRM cérébrale et un examen cytologique sur biopsie du vitrée, nous a permis de confirmer le diagnostic de LOC. À notre connaissance, il s’agit de la première observation rapportant le diagnostic de LOC chez un patient traité par anti-VEGF pour la DMLA. Les diagnostics à évoquer devant une hyalite chez la personne âgée sont relativement nombreux. Endophtalmies et uvéites ont été rapportées après injections d’anti-VEGF. Dans cette situation, il existe un risque réel de méconnaître le diagnostic de LOC en pensant à tort que l’hyalite est réactionnelle à l’IVT d’anti-VEGF. Si aucune relation de cause à effet évidente entre l’injection d’anti-VEGF et la hyalite ne peut être démontrée, un bilan d’uvéite classique doit être effectué. Notre observation montre que le ranibizumab, aux doses utilisées dans la DMLA, n’empêche ni la dissémination intraoculaire du LOC ni son diagnostic cytologique sur la biopsie du vitré.

The full text of this article is available in PDF format.

Keywords : Primary intraocular central nervous system lymphoma, Ranibizumab, Vitreous biopsy

Mots clés : Lymphome oculocérébral, Ranibizumab, Biopsie du vitré


Over the years, anti-VEGF strategies have become an important therapeutic modality for solid tumors. The precise role of angiogenesis in lymphoma pathogenesis is still under active investigation. Non-Hodgkin lymphoma (NHL) growth and progression seem to be potentiated by angiogenic mechanisms implicating both the microenvironment (paracrine stimulation) and the lymphoma cells themselves (autocrine stimulation). Increased expression of VEGF in NHL has been correlated with more aggressive lymphoma subtypes and also with poorer prognosis. However, in pilot studies, bevacizumab has shown only modest clinical activity in lymphoma as a single agent in the setting of relapsed aggressive NHL or in combination with rituximab-CHOP (RCHOP) in upfront treatment [1].

The effect on lymphoma cells of anti-VEGFs designed for ARMD treatment is unknown. We report the case of a patient combining both bilateral ARMD treated by anti-VEGF injections for 1year and a primary intraocular CN lymphoma.

Case report

An 88-year old female, with a medical history of bilateral ARMD treated by intravitreal injections of ranibizumab for 1year (four injections in the left eye and two in the right eye), was referred to our department for bilateral vitritis diagnosed 10days after the last anti-VEGF injection in the right eye.

There was no external sign of inflammation. Slit-lamp examination revealed very mild anterior segment inflammation in both eyes (Figure 1). Fundus examination showed mild vitritis in both eyes associated with disseminated punctate whitish retinal infiltrates. In the right eye, choroidal neovascularization was still active as demonstrated by fluorescein angiography and optical coherence tomography (Figure 2) whereas in the left eye we found a large inactive fibrovascular scar. A complete vitritis work-up including aqueous humour analysis and magnetic resonance imaging (MRI) of the brain was performed. Aqueous tap showed an increased Interleukin-10/Interleukin-6 ratio and MRI revealed a supratentorial and multicentric lesion of the CNS (Figure 3). The diagnosis of large B-cell non-Hodgkin primary intraocular CNS lymphoma was suspected.



Figure 1


Figure 1. 

Photography of the anterior segment of the right eye showing very mild inflammation.

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Figure 2


Figure 2. 

Fluorescein angiography (FA) and optical coherence tomography (OCT) of the right eye demonstrating that classic choroidal neovascularization (CNV) is still active after two intravitreous injections of ranibizumab: a: late-phase FA showing the intense leakage of the classic CNV and numerous punctate retinal infiltrates related to primary intraocular lymphoma. White arrow indicates the direction of the OCT-scan below; b: horizontal OCT-scan showing a discrete, elevated, hyperreflective, subretinal lesion above the retinal pigment epithelium corresponding to CNV with persistent subretinal fluid at its periphery (arrow).

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Figure 3


Figure 3. 

Brain MRI showing multiple contrast-enhancing lesions demonstrating the involvement of the temporal, occipital and frontal lobes by intraocular central nervous system (CNS) lymphoma.

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We performed a vitreous biopsy by three-port pars plana vitrectomy of the right eye 15days after the last anti-VEGF injection. Before commencing the infusion, 1mL of undiluted vitreous was collected by a syringe and immediately delivered to the cytology laboratory. Cytological examination found rare atypical lymphoid cells with basophilic cytoplasm and large prominent irregular nuclei corresponding to malignant B-cell lymphoma cells (Figure 4).



Figure 4


Figure 4. 

Cytological examination from undiluted vitreous showing rare atypical lymphoid cells with basophilic cytoplasm and large prominent irregular nuclei corresponding to malignant B-cell lymphoma cells.

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Discussion

The differential diagnosis of vitritis in elderly patients is relatively large. (Pseudo)-endophthalmitis or mild anterior uveitis/intermediate uveitis has been described after anti-VEGF injections [2]. If no direct time-relationship with the anti-VEGF injections can be found, a classic vitritis work-up should be performed. In such a situation, there is actually a risk of overlooking a diagnosis of intraocular lymphoma in the mistaken belief that the observed vitritis may be a reaction to administered anti-VEGFs.

In this case, the initial diagnosis of CNV related to ARMD could also be discussed. It is known that PIOL can mimic CNV related to ARMD and the fundus examination of our patient revealed neither drusen nor geographic atrophy [3].

A chimeric monoclonal antibody against the protein CD20, rituximab, has been assessed in PIOL [4, 5]. Because the protein CD20 is primarily found on the surface of B-cells, rituximab specifically destroys them and therefore is used for the treatment of lymphomas or autoimmune disorders. Though only isolated cases have been reported, rituximab, either given systemically or by intravitreal injection has provided promising results for the treatment of PIOL. Unlike to rituximab, neither bevacizumab nor ranibizumab proved any efficiency for the treatment of PIOL. The effect on lymphoma cells of anti-VEGFs designed for ARMD is unknown. To the best of our knowledge, it is the first report of the diagnosis of primary intraocular CNS lymphoma in a patient treated by anti-VEGF for ARMD. In our opinion, the occurrence of lymphoma was here coincidental and not due to the anti-VEGF injections. The interest of this case lies in the fact that 15days after the last intravitreal injection of ranibizumab in the right eye, the cytological examination performed in this eye was positive.

Conclusion

The precise place of anti-VEGF strategies in NHL treatment is still controversial. In spite of the dramatic differences between the use of anti-VEGF in oncology and in ophthalmology, our observation suggests that ranibizumab, used following the protocol of treatment for ARMD, did not halt spread of CNS lymphoma into the eye and did not impede cytological diagnosis.

Disclosure of interest

The authors declare that they have no conflict of interest concerning this article.


 This study has been presented at the 116th meeting of the French Ophthalmology Society in May 2010 and at the EVER 2010 Congress (Creta, Greece) in October 2010.

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Fardeau C., Lee C.P., Merle-Béral H., Cassoux N., Bodaghi B., Davi F., and al. Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-Hodgkin primary intraocular lymphoma Am J Ophthalmol 2009 ;  147 : 886-894
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