PURPOSE: The aim of this study was to briefly review the clinical and diagnostic features of vitreoretinal lymphoma (VRL) and to introduce the recent introduction of metagenomic deep sequencing in this ocular lymphomatous disease.

DESIGN AND METHODS: Review and description of the process of using metagenomic deep sequencing for ocular specimens at the Proctor Foundation, University of California, San Francisco, CA.

RESULTS: VRL masquerades as a uveitis, but clinical signs of subretinal lesions, and vitritis should prompt the inclusion of VRL in a differential diagnosis. Imaging features such as hyporeflective infiltrative lesions between the retinal pigment epithelium and Bruch's membrane are compatible with VRL, but diagnosis requires satisfying specific cytopathological and immunohistochemical or molecular features. Diagnosis, then, is subject to the cellularity, viability, and volume of the specimen submitted for these tests. Metagenomic deep sequencing has the ability to detect numerous lymphoma-associated mutations and is able to utilize minute volume samples and cell-free nucleic acid, so is well-suited for ocular tissues.

CONCLUSIONS: Metagenomic deep sequencing may offer an additional tool in the future with which to diagnose VRL.