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Background: Central nervous system lymphomas are aggressive tumors requiring a prompt diagnosis for successful treatment. Stereotactic biopsy remains the standard procedure, but the time needed for histopathology is usually over 2 days. We evaluated the contribution of cytomorphology and flow cytometry to histopathology of the brain biopsy in particular on the rinse fluid usually removed., Methods: Eighteen patients with suspected localized brain lymphoma underwent stereotactic brain biopsy. Brain biopsy tissue sample and/or brain biopsy rinse fluid were analyzed by cytomorphology combined with flow cytometry. Histopathology was used as a reference., Results: Histopathology characterized ten diffuse large B-cell lymphomas and eight other diseases. Cytomorphology and flow cytometry showed lymphoma cells in nine out of the ten lymphomas. Three cytomorphology or flow cytometry negative results were reported for lymphomas in tissue samples due to low cellularity and biopsy sample conditioning. No lymphomatous cells were found by cytomorphology or flow cytometry in the eight other diseases. Rinse fluid results were consistent with histology in all cases studied (sensitivity and specificity, 100%). The median time to result was 4.5 days (range, 2-10 days) for histopathology, while 5 h (range, 3-20 h) were required for both cytomorphology and flow cytometry., Conclusions: Brain biopsy rinse fluid alleviates problems of tissue sample distribution compared to tissue sample. Its analysis performs the diagnosis of B-cell lymphoma in a few hours and, associated with histopathology, allows a multidisciplinary diagnosis. This study shows that cytomorphology combined with flow cytometry on brain biopsy rinse fluid is a new, fast, and useful strategy. © 2016 International Clinical Cytometry Society., (© 2016 International Clinical Cytometry Society.)

Primary central nervous system lymphomas (PCNSLs) classically remain confined within the CNS throughout their evolution for unknown reasons. Our objective was to analyse the rare extracerebral relapses of PCNSL in a nationwide population-based study. We retrospectively selected PCNSL patients who experienced extracerebral relapse during their follow-up from the French LOC database. Of the 1968 PCNSL included in the database from 2011, 30 (1.5%, median age 71 years, median KPS 70) presented an extracerebral relapse, either pure (n = 20) or mixed (both extracerebral and in the CNS) (n = 10), with a histological confirmation in 20 cases. The median delay between initial diagnosis and systemic relapse was 15.5 months [2-121 months]. We found visceral (n = 23, 77%), including testis in 5 (28%) men and breast in 3 (27%) women, lymph node (n = 12, 40%), and peripheral nervous system (PNS) (n = 7, 23%) involvement. Twenty-seven patients were treated with chemotherapy, either with only systemic targets (n = 7) or mixed systemic and CNS targets (n = 20), 4 were consolidated by HCT-ASCT. After systemic relapse, the median progression-free survival and overall survival (OS) were 7 and 12 months, respectively. KPS > 70 and pure systemic relapses were significantly associated with higher OS. Extracerebral PCNSL relapses are rare, mainly extranodal, and frequently involve the testis, breast, and PNS. The prognosis was worse in mixed relapses. Early relapses raise the question of misdiagnosed occult extracerebral lymphoma at diagnostic workup that should systematically include a PET-CT. Paired tumour analysis at diagnosis/relapse would provide a better understanding of the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5-82.5) and median Karnofsky performance status (KPS) was 60 (range, 40-80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2-6.2), and median overall survival was 8.2 months (95%CI: 0.6-15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions. • Multi-omic data consensus clustering reveals four molecular subtypes of PCNSL with prognostic relevance. • RNA-seq data alone and a publicly accessible algorithm can be used to assign the multi-omic defined PCNSL subtypes. • PCNSL molecular subtyping can improve future clinical stratification and suggest rational subtype-based targeted therapies. [ABSTRACT FROM AUTHOR]