1. Overview: Brain lymphoma (also known as primary central nervous system lymphoma (PCNSL)) is a rare malignant tumor, specifically malignant lymphoma originating from the brain, soft meninges, spinal cord or eye, accounting for about 3% of the malignant tumors of the central nervous system. The incidence of brain lymphoma is slowly increasing in recent years, and human immunodeficiency virus (HIV) infection is said to be a major risk factor for the development of brain lymphoma. The main pathological type of brain lymphoma is diffuse large B-cell lymphoma (DLBCL), which accounts for about 90% of cases. About half of the patients present with psychoneurological symptoms, and about 1/3 of the patients present with increased cranial pressure or seizures. A small number of patients have an ocular or spinal occupancy, with corresponding ocular symptoms or spinal cord compression. Compared with other malignant tumors of the central nervous system, cerebral lymphoma is sensitive to radiotherapy and chemotherapy, but the long-term survival rate is significantly lower than that of other malignant lymphomas originating from outside the lymph nodes. Brain lymphoma diagnosis: Brain lymphoma imaging has certain characteristics, and the tumor lesions are usually located deep in the brain and are often multiple; however, the diagnosis must be differentiated from multiple sclerosis, nodal disease and certain gliomas. The diagnosis of cerebral lymphoma must be established by pathology rather than by a single imaging diagnosis. The diagnosis of cerebral lymphoma relies on a histologic pathology and is obtained primarily by stereotactic biopsy of the tumor lesion. The diagnosis can be established by orbital mass biopsy or CSF cytology if the tumor lesion is ocularly or cerebrospinal fluid (CSF) involved; lumbar puncture for CSF cytology should be performed 1 week before or after surgery to avoid false positive results. Patients with spinal cord symptoms require full spinal magnetic resonance imaging (MRI). PET/CT examinations can detect central and systemic lesions and help exclude peripheral lymph node enlargement or other extra-nodal lesions. 3. Pre-treatment evaluation of cerebral lymphoma A comprehensive baseline examination and evaluation should be performed before treatment of cerebral lymphoma. To establish the diagnosis of cerebral lymphoma, peripheral lymph node enlargement or other extra-nodal lesions should be excluded. Especially for elderly men, the testes should be examined for the presence of occult lesions to exclude the involvement of the central nervous system by malignant lymphoma originating in the testes. The incidence of a diagnosis of cerebral lymphoma with an occult systemic lesion is approximately 8%. The protein content of cerebrospinal fluid (CSF) on lumbar puncture is a prognostic correlate, with a poor prognosis for high protein concentrations. Ophthalmologic examination with slit lamp, including dilated fundus examination, should be performed to exclude vitreous, retinal or optic nerve involvement. The patient’s cognitive function should be assessed prior to treatment to facilitate comparison with post-treatment and follow-up to determine the effect of treatment on neurocognitive function. All patients should be tested for HIV. 4. Brain lymphoma treatment Brain lymphoma treatment mainly includes hormone therapy, chemotherapy and radiotherapy. Brain lymphoma is sensitive to hormone therapy. After brain lymphoma is treated with hormone therapy, the tumor partially regresses, edema is reduced and symptoms are relieved, but the efficacy of hormone therapy alone cannot last. Patients with cerebral lymphoma who have not yet obtained pathological histological diagnosis should withhold the use of hormone because hormone can make lymphocytes lyse and cause difficulties in pathological diagnosis. Surgical resection is not the main treatment, because tumor lesions are usually located deep in the brain with infiltrative growth and multiple lesions, which may involve soft meninges and eyes. Patients do not benefit from surgery alone. Radiotherapy is the mainstay of treatment for cerebral lymphoma; based on the fact that cerebral lymphoma is usually multifocal, the traditional treatment is whole-cranial radiotherapy, which has a high near-term remission rate (about 90%), but a short remission period, usually recurring after several months. The median survival for those treated with radiotherapy alone is 12–18 months, with a 5-year OS rate of 18%–35%. Long-term follow-up results show that the neurotoxicity from total cranial radiotherapy partially offsets the benefit of treatment, especially in older PCNSL patients >60 years of age who do not benefit from total cranial radiotherapy. In a randomized phase III study in Germany (551 primary patients) randomized to chemotherapy combined with radiotherapy or chemotherapy alone, 318 of them complied with the treatment regimen of MTX (4 g/m2) followed by IFO (1.5 g/m2); the radiotherapy dose was 45 Gy; those who did not receive radiotherapy received Ara-c if they did not achieve CR; the results showed that the median OS in the combined radiotherapy group and the chemotherapy alone group was 0.5 g/m2. The median OS period was 32.4 months and 37.1 months (P=0.71, HR=1.06), and the median PFS period was 18.3 months and 11.9 months (P=0.14) in the combined radiotherapy and chemotherapy alone groups, respectively. Treatment-related neurotoxicity occurred at a higher rate in the radiotherapy group (49% versus 26%), and the benefit of PFS may be reduced by long-term neurotoxicity. The study results did not meet the study design HR=0.9 assumption. In recent years, the authors explored the application of whole-brain intensity-modulated radiotherapy (IMRT) incremental technique + temozolomide oral chemotherapy for the treatment of cerebral lymphoma, and preliminary results showed that whole-brain incremental intensity-modulated radiotherapy + temozolomide showed significant advantages in terms of local remission rate and survival compared with conventional whole-cranial radiotherapy alone. Chemotherapy Although some chemotherapy regimens are effective, they are in transient remission because the blood-brain barrier makes it difficult for most chemotherapeutic agents to cross the blood-brain barrier and develop effective drug concentrations. Most of the drugs traditionally used to treat malignant lymphoma do not cross the blood-brain barrier and are ineffective against brain lymphoma, with high-dose methotrexate (MTX) being the main effective drug. The only known high-dose MTX can cross the blood-brain barrier, and many clinical trials have demonstrated that high-dose MTX + cyclophosphamide (CF) rescue therapy can improve the remission rate of brain lymphoma with long-lasting efficacy, which is the widely accepted standard chemotherapy regimen for brain lymphoma in current protocols; the most common dose of high-dose MTX is 3 – 3.5 g/m2. It is worth noting that patients’ blood levels should be monitored when high-dose MTX is administered so that CF relief can be given more accurately and serious toxicity can be avoided. The complete remission (CR) rate was 18% and 46% (P=0.005), the efficiency rate was 40% and 69% (P=0.009), the 3-year failure-free survival (FFS) rate was 21% and 38% (P=0.01), and the 3-year OS rate was 32% and 46% (P=0.07) in the single-agent and combination groups, respectively; however, the hematologic toxicity of patients in the combination group was significantly greater than that of the single-agent group. Brain lymphoma is rare and it is very difficult to conduct randomized clinical trials. Therefore, it is not clear which combination of high-dose MTX and chemotherapeutic agents is most effective. Other drugs include isocyclophosphamide cetepe, nitrosoureas, and temozolomide. The value of the targeted drug melphalan (rituximab) for the treatment of B-cell lymphoma has been demonstrated, but it has not been shown to be used in the treatment of brain lymphoma because of the blood-brain barrier.