Thi is a prospective and low-intervention clinical trial. We propose to design a panel of "core" genetic alterations by sequencing Cerebral Spinal Fluid (CSF) DNA in patients with confirmed or suspicious Primary Central Neurvous System Lymphoma (PCNSL) with the aim to improve diagnostic sensitivity, response assessment and monitoring early CNS relapse in routine practice.

Enrolled patients will receive conventional treatments according to well-established international guidelines, DNA assessments will not influence the treatment choices.

Inclusion Criteria for study population:

1. Age ≥18 years
2. Newly diagnosed PCNSL with available clinical and radiological data, CSF and histopathological brain biopsy material fresh and/or formalin fixed and paraffin embedded;
3. No contraindications to stereotactic or open brain biopsy and lumbar puncture;
4. No formal contraindications to intravenous chemo-immunotherapy or whole-brain irradiation;
5. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice.

Exclusion Criteria for study population:

1. Patients with concomitant CNS and systemic involvement at presentation (potentially eligible as "control"; see below)
2. Patients with CNS lymphoma other than DLBCL subtype
3. Any other serious medical condition which could impair the ability of the patient to participate in the trial
4. Pregnant and lactating female patients. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation.
5. Previous or concurrent malignancies at other sites diagnosed or relapsed within the last 3 years before PCNSL diagnosis. Patients with surgically cured in situ carcinomas and basal cell carcinoma of the skin are allowed.
6. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Inclusion criteria for controls:

1. Age ≥18 years
2. Newly diagnosed DLBCL with a high risk for relapse/progression in the CNS or High-grade B-cell (HGBC) lymphoma with available clinical and radiological data, CSF and diagnostic histopathological specimen. 3. Newly diagnosed and/or relapsed SCNSL with available clinical and radiological data, CSF and diagnostic histopathological specimen. 4. Newly diagnosed lymphoma confined to CNS other than DLBC subtype 5. Neoplastic and non-neoplastic neurological disorders (neurodegenerative and neuroinflammatory disorders, toxic or infective encephalitis, primary CNS tumors other than lymphomas (mainly gliomas)) with available clinical and radiological data, CSF samples and, where possible, histo-pathological brain biopsy material formalin fixed and paraffin embedded.

6. No contraindications to stereotactic or open brain biopsy and lumbar puncture; 7. Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice.

Exclusion criteria for controls:

1. Patients with extra-CNS lymphoma other than DLBC or HGBC subtypes, and not classified as high risk of CNS relapse;
2. Any other serious medical condition which could impair the ability of the patient to participate in the trial;
3. Pregnant and lactating female patients. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation;
4. Previous or concurrent malignancies at other sites diagnosed or relapsed within the last 3 years of follow-up. Patients with surgically cured in situ carcinomas and basal cell carcinoma of the skin are allowed;
5. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.