Management of primary CNS lymphomas including vitreoretinal lymphomas
Authors: Trneny Marek 
Published: December 2022

Primary CNS lymphomas (PCNSL) are represented in almost all cases by diffuse large B‐cell lymphomas (DLBCL). WHO 2017 defines “Primary DLBCL of CNS as DLBCL arising within the brain, spinal cord, leptomeninges or eye”. Those sites together with testes are characterized as “immune sanctuaries”. CNS DLBCL accounts <1% of all lymphomas and 2–3% of brain tumours. Approximately 15% of patients (pts) have ocular involvement and approximately 75% of pts with vitreoretinal lymphomas (VRL) develop contralateral and/or parenchymal CNS lesions. The aetiology in immunocompetent patients is unknown. The majority of DLBCL cases shows nongerminal center immunophenotype. The significant proportion reveals MYD88 and CD79b mutations. Copy number gains at chromosome 9p24.1 lead to PD‐L1/2 overexpression are frequently found. Cognitive dysfunction, psychomotor slowing, different neurological symptoms including seizures are among the leading symptoms. The median age at diagnosis is around 60 years and significant proportion of patients have worse performance status based on ECOG scale. The diagnosis is established on immunohistochemical examination of biopsy. Corticosteroid administration leads to the lymphoma regression and biopsy is therefore recommended before it. MRI, eye and cerebrospinal fluid (CSF) examination is recommended as essential for the staging. The neurosurgical tumour removal is generally not recommended. The CNS DLBCL is usually chemosensitive and combined immunochemotherapy consisted of rituximab and high dose methotrexate (HD MTX) up to 8 g/m2 (usually 3.5 g/m2) based chemotherapy is recommended. Several combinations are used, especially for younger patients, combine HD MTX with HD cytarabine and thiotepa, or procarbazine, lomustine. Intrathecal administration of methotrexate is omitted if the CSF is negative. The therapy goal is to achieve complete remission. The relapse rate is, however, high and consolidation therapy is necessary. The radiation therapy is a standard with the dose of 40Gy, but it seems to cause long‐term cognitive impairment especially in elderly patients with the age above 60 years. The dose reduction and even radiotherapy omitting has been tested in patient with complete remission at the end of induction. The high dose therapy with autologous stem cell transplantation is increasingly used in younger population. The prognosis has been significantly improved during last 10–15 years. At the time of relapse immunochemotherapy with radiotherapy (if it was not part of 1st line treatment) could be used. The targeted therapy or immunotherapy based on molecular biological findings is tested. Brutone tyrosine kinase inhibitor ibrutinib (active in lymphoproliferations dependent on BCR signalling and presence of MYD88 mutations) is tested. Immune checkpoint inhibitors nivolumab and pembrolizumab (active in lymphoproliferations with PD1/PDL‐1,2 axis activation) are tested in prospective trials and results awaited. Imids (lenalidomide, pomalidomide), mTOR inhibitors (temsirolimus) among others are tested. VRL is considered to be CNS DLBCL subtype as mentioned above. The diagnosis is challenging because the tumour tissue is usually not available and it is established on morphology, flow cytometry and currently on mutations of MYD88 and other genes. The same systemic therapy is recommended as in classical CNS DLBCL, intraocular methotrexate administration is used in some centers. A new drugs are tested in the relapse setting.