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Molekulare Diagnostik des vitreoretinalen Lymphoms

Molecular diagnostics for vitreoretinal lymphoma

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Zusammenfassung

Das primäre vitreoretinale Lymphom (PVRL) stellt einen Subtyp der intraokularen Lymphome bzw. der malignen Lymphome des Auges dar. Das PVRL gilt als Sonderform des primären diffusen großzelligen Lymphoms (DLBCL) des zentralen Nervensystems (ZNS) (PCNSL) und entsteht primär oder sekundär bei einem ZNS-Lymphom. Nach der COO-Klassifikation („cell of origin“) des DLBCL gehören PVRL größtenteils zum aktivierten B‑Zell-Typ (ABC) des DLBCL. Nach einer kürzlich erstellten genetisch-biologischen Klassifizierung von DLBCL gehören PCNSL und damit auch PVRL zu einer Gruppe von DLBCL des MCD- oder Cluster-5-Subtyps, der häufig extranodale Manifestationen und MYD88- und CD79A-Mutationen sowie CDKN2A-Deletionen aufweist.

Die PVRL-Diagnostik ist oft kompliziert, da es sich um ein klassisches Maskeradesyndrom handelt. Aufgrund des in der Regel geringen Materials mit oft großer Anzahl reaktiver Lymphozyten und/oder degenerativer Veränderungen der Zellen sind die Ergebnisse diagnostischer Tests schwer zu interpretieren. Zu den klassischen diagnostischen Tests gehören die Zytologie von Glaskörperaspiraten, die Immunzytochemie und die Klonalitätsanalyse.

Neue Erkenntnisse über das Spektrum der genetischen Veränderungen von vitreoretinalen Lymphomen (VRL) bestätigen die enge Verwandtschaft mit PCNSL und könnten die pathologische Diagnose erheblich verbessern. NGS-Panel-basierte Diagnostik ermöglicht die Bestätigung der VRL-Diagnose mit wenig DNA bei fast 100 % der Patienten in Fällen mit unzureichendem zytologischem Nachweis oder fehlendem Klonalitätsnachweis. PVRL sowie sekundäre vitreoretinale Lymphome nach PCNSL oder extrazerebralem DLBCL weisen hohe Mutationshäufigkeiten in charakteristisch mutierten Genen bei PCNSL oder MCD/Cluster-5-Typ-DLBCL auf. Zur Unterstützung der Diagnostik kann der Mutationsnachweis auch an zellfreier DNA aus dem Glaskörperüberstand erfolgen.

Abstract

Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered a special form of primary diffuse large cell lymphoma (DLBCL) of the CNS (central nervous system) (PCNSL) and arises primary or secondary to PCNSL. According to the cell of origin (COO) classification of DLBCL, PVRL largely belongs to the activated B‑cell (ABC) type of DLBCL. Based on a recently established genetic-biological classification of DLBCL, PCNSL and thus also PVRL belong to a group of DLBCL of the MYD88/CD79B-mutated (MCD) or cluster 5 subtype, which often shows extranodal manifestations and MYD88 and CD79A mutations as well as CDKN2A deletions.

PVRL diagnostics is often complicated as it represents a classic masquerade syndrome. Due to the usually limited material with often large numbers of reactive lymphocytes and/or degenerative changes in the cells, the results of diagnostic tests are difficult to interpret. Classic diagnostic tests include cytology on vitreous aspirates, immunocytochemistry, and clonality analysis.

New insights into the spectrum of genetic alterations of vitreoretinal lymphomas (VRL) confirm the close relationship to PCNSL and could significantly improve pathological diagnosis. Next-generation sequencing panel-based diagnostics allow VRL diagnosis confirmation with little DNA in almost 100% of patients in cases with insufficient cytological evidence or lack of clonality detection. PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant.

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Literatur

  1. Fend F, Ferreri AJ, Coupland SE (2016) How we diagnose and treat vitreoretinal lymphoma. Br J Haematol 173(5):680–692

    Article  PubMed  Google Scholar 

  2. Sobolewska B et al (2021) Vitreoretinal Lymphoma. Cancers (basel) 13(16)

  3. Grimm SA et al (2007) Primary intraocular lymphoma: an international primary central nervous system Lymphoma collaborative group report. Ann Oncol 18(11):1851–1855

    Article  CAS  PubMed  Google Scholar 

  4. Swerdlow S et al (2017) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC, Lyon (ed. S. Swerdlow, et al.)

    Google Scholar 

  5. Soussain C, Malaise D, Cassoux N (2021) Primary vitreoretinal lymphoma: a diagnostic and management challenge. Blood 138(17):1519–1534

    Article  CAS  PubMed  Google Scholar 

  6. Coupland SE, Damato B (2008) Understanding intraocular lymphomas. Clin Exp Ophthalmol 36(6):564–578

    Article  PubMed  Google Scholar 

  7. Bonzheim I et al (2015) High frequency of MYD88 mutations in vitreoretinal B‑cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates. Blood 126(1):76–79

    Article  CAS  PubMed  Google Scholar 

  8. Coupland SE et al (2005) Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 46(10):3507–3514

    Article  PubMed  Google Scholar 

  9. Bodor C et al (2020) Molecular subtypes and genomic profile of primary central nervous system Lymphoma. J Neuropathol Exp Neurol 79(2):176–183

    Article  CAS  PubMed  Google Scholar 

  10. Bonzheim I et al (2022) The molecular hallmarks of primary and secondary vitreoretinal lymphoma. Blood Adv 6(5):1598–1607

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chapuy B et al (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127(7):869–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee J et al (2020) Whole exome sequencing identifies mutational signatures of vitreoretinal lymphoma. Haematologica 105(9):e458–e460

    Article  PubMed  PubMed Central  Google Scholar 

  13. Montesinos-Rongen M et al (2008) Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell. Leukemia 22(2):400–405

    Article  CAS  PubMed  Google Scholar 

  14. Ho KG, Grommes C (2019) Molecular profiling of primary central nervous system lymphomas—predictive and prognostic value? Curr Opin Neurol 32(6):886–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nayyar N et al (2019) MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B‑cell lymphomas. Blood Adv 3(3):375–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chapuy B et al (2018) Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24(5):679–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmitz R et al (2018) Genetics and pathogenesis of diffuse large B‑cell Lymphoma. N Engl J Med 378(15):1396–1407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Salomao DR et al (2013) Vitreoretinal presentation of secondary large B‑cell lymphoma in patients with systemic lymphoma. JAMA Ophthalmol 131(9):1151–1158

    Article  PubMed  Google Scholar 

  19. Morin RD, Scott DW (2020) DLBCL subclassification: divide and conquer? Blood 135(20):1722–1724

    Article  CAS  PubMed  Google Scholar 

  20. Behdad A et al (2019) High frequency of MYD88 L265P mutation in primary ocular adnexal marginal zone lymphoma and its clinicopathologic correlation: a study from a single institution. Arch Pathol Lab Med 143(4):483–493

    Article  CAS  PubMed  Google Scholar 

  21. Cani AK et al (2017) Next generation sequencing of vitreoretinal lymphomas from small-volume intraocular liquid biopsies: new routes to targeted therapies. Oncotarget 8(5):7989–7998

    Article  PubMed  Google Scholar 

  22. Hiemcke-Jiwa LS et al (2018) Potential diagnosis of vitreoretinal lymphoma by detection of MYD88 mutation in aqueous humor with ultrasensitive droplet digital polymerase chain reaction. JAMA Ophthalmol 136(10):1098–1104

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tan WJ et al (2019) Single-cell MYD88 sequencing of isolated B cells from vitreous biopsies aids vitreoretinal lymphoma diagnosis. Blood 134(8):709–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen X et al (2022) Diagnostic value of genetic mutation analysis and mutation profiling of cell-free DNA in intraocular fluid for vitreoretinal lymphoma. Cancer Commun 42(11):1217–1221

    Article  Google Scholar 

  25. Wang X et al (2022) A pilot study of the use of dynamic analysis of cell-free DNA from aqueous humor and vitreous fluid for the diagnosis and treatment monitoring of vitreoretinal lymphomas. Haematologica 107(9):2154–2162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bobillo S et al (2021) Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B‑cell lymphomas. Haematologica 106(2):513–521

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Pathologie und Neuropathologie, Abt. Allgemeine und Molekulare Pathologie, Universitätsklinikum Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Deutschland

    Irina Bonzheim, Leticia Quintanilla-Martinez & Falko Fend

  2. Hematopathology Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spanien

    Julia Salmerón-Villalobos, Itziar Salaverria & Elias Campo

  3. Department für Augenheilkunde, Universitätsklinikum Tübingen, Tübingen, Deutschland

    Daniela Süsskind & Florian Gekeler

  4. Augenklinik Sulzbach, Sulzbach, Deutschland

    Peter Szurman

  5. Augenklinik, Klinikum Stuttgart, Stuttgart, Deutschland

    Florian Gekeler

  6. Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Deutschland

    Martin S. Spitzer

  7. Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, Großbritannien

    Sarah E. Coupland

Authors
  1. Irina Bonzheim
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  2. Julia Salmerón-Villalobos
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  3. Daniela Süsskind
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  4. Peter Szurman
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  5. Florian Gekeler
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  6. Martin S. Spitzer
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  7. Itziar Salaverria
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  8. Elias Campo
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  9. Sarah E. Coupland
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  10. Leticia Quintanilla-Martinez
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  11. Falko Fend
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Corresponding author

Correspondence to Irina Bonzheim.

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Interessenkonflikt

I. Bonzheim, J. Salmerón-Villalobos, D. Süsskind, P. Szurman, F. Gekeler, M.S. Spitzer, I. Salaverria, E. Campo, S.E. Coupland, L. Quintanilla-Martinez und F. Fend geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Aufgrund der besseren Lesbarkeit wird im Text das generische Maskulinum verwendet. Gemeint sind jedoch immer alle Geschlechter.

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Bonzheim, I., Salmerón-Villalobos, J., Süsskind, D. et al. Molekulare Diagnostik des vitreoretinalen Lymphoms. Pathologie 44 (Suppl 3), 150–154 (2023). https://doi.org/10.1007/s00292-023-01251-z

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  • DOI: https://doi.org/10.1007/s00292-023-01251-z

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