Application Value Of Cerebrospinal Fluid Biomarkers In Primary Central Nervous System Lymphoma And Primary Intraocular Lymphoma

Background and ObjectivesPrimary central nervous system lymphoma(PCNSL)is a rare type of primary extra-nodal non-hodgkin's lymphoma,with poor prognosis and increasing incidence.Primary intraocular lymphoma(PIOL)is a special type of PCNSL,and is prone to central involvement,which is the main cause of death.The common features of PCNSL and PIOL are propensity for relapse,poor prognosis and difficulties in early diagnosis.Thus,it is of great clinical significance to earch for highly effective and sensitive indicators for diagnosis and disease monitoring.Previous studies have found cerebrospinal fluid(CSF)IL-10 with accurate diagnostic and monitoring value for PCNSL,but uclear for PIOL.Cell-free DNA(cfDNA),or liquid biopsy",has been a hot topic in recent years.Studies found cfDNA mutations detected in CSF consistent with those in tumor tissue from refractory/recurrence(R/R)PCNSL and value of disease monitoring value.However,the cfDNA mutation spectrum of CSF in newly diagnosed PCNSL or PIOL patients are unknown.Therefore,this study will monitor the CSF IL-10 and cfDNA mutations in newly diagnosed PCNSL or PIOL patients,to explore the diagnositic and monitoring values.Methods(1)Second-generation sequencing analysis was performed on CSF cfDNA and paraffin-embedded tumor tissues for PCNSL patients,as well as CSF cfDNA for other CNSL and PIOL patients.CSF cfNDA was dynamically monitored.Meanwhile,the relationship between CSF IL-10 level and cfDNA mutation was compared..(2)CSF IL-10 newly diagnosed PIOL patients were monitored and its dynamic changes were compared with disease course.(3)Patients diagnosed with PIOL,other intraocular lymphoma and suspected intraocular lymphoma were included.Baseline CSF cfDNA was sequenced in all the patients.CSF cfDNA mutations were monitored in PIOL patients and its monitoring value was compared with IL-10.Results1.The diagnositic and monitoring value of CSF cfDNA in PCNSL(1)Ten PCNSL patients,8 other CNSL patients and 3 PIOL patients newly diagnosed in Peking union medical college hospital from July 2018 to December 2019 were included.(2)The tumor tissues and CSF cfDNA mutations overlapped by 40%,and the overlap genes were MYD88 L265P and TBFRSF14 mutations.(3)Of 7 newly diagnosed PCNSL patients with baseline CSF,6 had more than one mutations in cfDNA,and some of the gene mutations were multi-point mutations,including PIM1 and ETV6.Three patients had postive MYD88 L265P mutation,with the variant allele frequency(VAF)to be 3.4%-71.5%.Only 1 patient had CD79B mutation.(4)The number of mutated genes and the VAF were much higher in newly diagnosed patients than those in patients with relapse.(5)The dynamic change of cfNDA mutations in CSF was significantly correlated with disease course,with the sensibility higher than IL-10.(6)There was a positive correlation between baseline CSF IL-10 level and the maximum VAF of CSF cfNDA.2.The monitoring value of CSF IL-10 in PIOL(1)In 15 newly diagnosed PIOL patients,13 patients(86.7%)had elevated baseline CSF IL-10 levels.(2)CSF IL-10 decreased or became negative after treatment,and increased again while recurrence or progression.Elevated CSF IL-10 could predates disease recurrence/progression,with a median lead time of 99 d(37-253 d).(3)The PFS of patients with CSF IL-10 elevating after becoming negative was better than that of those with persistently positive IL-10,but worse than those with IL-10 becoming persistently n egative,but with no statistical significance.3.The diagnositic and monitoring value of CSF cfDNA in PIOL(1)Ten patients with newly diagnosed PIOL,2 with other intraocular lymphoma and 1 with suspected intraocular lymphoma were included.(2)Of 4 newly diagnosed PIOL patients with baseline CSF,3 had positive MYD88 L265P mutation,with the VAF to be 21.3%-62%.Two had positive CD79B Y196 mutation,with the VAF to be 10.2-61.8%.The patient with suspected intraocular lymphoma had no mutations.(3)Patients with cfDNA becoming negative achieved complete remission,and those with cfDNA postive again or persistently postive relapsed.CSF cfDNA was less sensitive than IL-10 in disease monitoring.ConclusionCSF cfDNA can reflect the genomic information of tumor tissue to a certain degree,which may have a diagnostic value for PCNSL and PIOL.The dynamic changes of cfNDA mutations and IL-10 in CSF were significantly correlated with the disease course,which suggest that CSF IL-10 and cfDNA had monitoring value in PCNSL and PIOL.They cen even pridict progeresison or relapse much earlier than imageological examination.