The molecular hallmarks of primary and secondary vitreoretinal lymphoma

• Published in: Blood advances Vol. 6; no. 5; pp. 1598 - 1607
• Main Authors: Bonzheim, Irina, Sander, Philip, Salmerón-Villalobos, Julia, Süsskind, Daniela, Szurman, Peter, Gekeler, Florian, Spitzer, Martin S., Steinhilber, Julia, Kohler, Esther, Büssgen, Melanie, Schittenhelm, Jens, Salaverria, Itziar, Campo, Elias, Coupland, Sarah E., Quintanilla-Martinez, Leticia, Fend, Falko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-03-2022; American Society of Hematology
• Subjects: Cell-Free Nucleic Acids - metabolism; Central Nervous System Neoplasms - metabolism; Humans; Lymphoid Neoplasia; Lymphoma, Large B-Cell, Diffuse - diagnosis; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Non-Hodgkin - pathology; Retinal Neoplasms - diagnosis; Retinal Neoplasms - genetics; Retinal Neoplasms - pathology; Uveitis - metabolism; Uveitis - pathology; Vitreous Body - metabolism; Vitreous Body - pathology
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2021004212

Vitreoretinal lymphoma (VRL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) considered a variant of primary central nervous system lymphoma (PCNSL). The diagnosis of VRL requires examination of vitreous fluid, but cytologic differentiation from uveitis remains difficult. Because of its rarity and the difficulty in obtaining diagnostic material, little is known about the genetic profile of VRL. The purpose of our study was to investigate the mutational profile of a large series of primary and secondary VRL. Targeted next-generation sequencing using a custom panel containing the most frequent mutations in PCNSL was performed on 34 vitrectomy samples from 31 patients with VRL and negative controls with uveitis. In a subset of cases, genome-wide copy number alterations (CNAs) were assessed using the OncoScan platform. Mutations in MYD88 (74%), PIM1 (71%), CD79B (55%), IGLL5 (52%), TBL1XR1 (48%), ETV6 (45%), and 9p21/CDKN2A deletions (75%) were the most common alterations, with similar frequencies in primary (n = 16), synchronous (n = 3), or secondary (n = 12) VRL. This mutational spectrum is similar to MYD88mut/CD79Bmut (MCD or cluster 5) DLBCL with activation of Toll-like and B-cell receptor pathways and CDKN2A loss, confirming their close relationship. OncoScan analysis demonstrated a high number of CNAs (mean 18.6 per case). Negative controls lacked mutations or CNAs. Using cell-free DNA of vitreous fluid supernatant, mutations present in cellular DNA were reliably detected in all cases examined. Mutational analysis is a highly sensitive and specific tool for the diagnosis of VRL and can also be applied successfully to cell-free DNA derived from the vitreous.
•Primary and secondary vitreoretinal lymphomas show the same genetic profile and belong to the MCD/C5 cluster of DLBCL.•Mutational analysis of vitreous fluid is a sensitive and specific tool for diagnosis of vitreoretinal lymphoma.
[Display omitted]