Primary central nervous system lymphoma (PCNSL) is a lymphoma that originates in the brain, spinal cord, eye, or soft meninges, and most PCNSLs are of B-cell origin with morphologic and pathologic features similar to diffuselarge B-cell lymphoma (DLBCL). PCNSL accounts for 3% of brain tumors and more than 95% of them are DLBCL, which usually occurs in people aged 50-70 years and the time between onset and consultation is usually within 2-3 months. Patients with PCNSL mainly present with altered mental status, increased intracranial pressure such as headache, nausea and vomiting, and optic papilledema, as well as local compression symptoms, including epilepsy, memory loss, unstable walking, visual field disturbance, blurred speech, and mild hemiparesis. In addition to brain involvement, 10-20% of patients have ocular involvement, which may be manifested by blurred vision or complaints of “floaters”.
Since the incidence of PCNSL of T-cell origin and other types of PCNSL is extremely low and mostly limited to case reports, in this paper, we review the diagnostic and therapeutic advances of DLBCL in CNS.
I. Diagnosis of PCNSL
(A) Imaging
Cranial imaging plays an important role in the clinical diagnosis and differential diagnosis of PCNSL. The following is a description of several major examination methods.
MRI: MRI of PCNSL is characterized by equal or slightly low signal in TIWI, slightly low, equal or high signal in T2WI, single or multiple homogeneous lesions, more limited, with irregular margins, 90% of the lesions are surrounded by edema of different degrees, usually accessible to the surface of cerebrospinal fluid, and the tumor is obviously uniformly enhanced after enhancement, which is the characteristic of the disease, as a result of the destruction of the blood-brain barrier and the penetration of contrast agent into the extracellular space. This is the result of the disruption of the blood-brain barrier, which allows the contrast agent to penetrate into the extracellular space.
Necrosis, marginal enhancement, hemorrhage, and calcification are uncommon. In immunodeficient patients, multiple foci with circumferential enhancement are seen. 60%-70% of patients have a single tumor, and 80%-90% of foci are located in the cerebellar vermis. The clinical presentation of immunodeficient patients differs from that of immunocompetent patients in that the former have multiple foci and are almost always associated with multisystem damage.
Perfusion- weightedimaging (PWI): PWI can accurately reflect the degree of tumor angiogenesis, and PCNSL is a lack of vascular tumor, so the characteristic performance of PWI is that the tumor has a significant contrast enhancement without a significant increase in perfusion, but a significant increase in permeability. It can be distinguished from high-grade neuroepithelial tumor.
Diffusion- weighted imaging (DWI) and apparent diffusioncoefflcient (ADC): influenced by the characteristics of tumor cells, such as large nucleoplasmic ratio, dense tumor cells and small extracellular space, which reduce diffusion, DWI shows high signal and ADC shows iso- or low signal. The ADC value of PCNSL is lower than that of high-grade glial tumor.
4. magnetic resonance spectroscopy (MRS): MRS can detect the energy metabolism of living tissues and organs semi-quantitatively and is superior to conventional MRI in showing the biochemical characteristics of tissues. lactate and choline peaks are increased, which are not specific but have some significance for prognostic assessment.
5. 18Fluoro-deoxyglucose PET (18FDG-PET): 18FDG-PET has a 2.5-fold higher uptake of typical PCNSL tissue than normal brain white matter and is usually able to identify tumor tissue visually. FDG uptake can identify PCNSL and other malignant brain tumors, especially glioblastoma, however, 18FDG-PET is less sensitive for atypical PCNSL such as diffuse damage.1 FDG-PET is useful for evaluating treatment response after early initial treatment of patients.
Imaging of PCNSL has certain characteristics, but imaging has its limitations, especially in atypical cases it is difficult to differentiate from other intracranial tumors and diseases. For patients with imaging suggestive of PCNSL, stereotactic biopsy and other tests are still needed to confirm the diagnosis.
(B) Stereotactic biopsy
Stereotactic biopsy is the most effective method for definitive diagnosis, and the sensitivity of biopsy has been reported to be more than 90%, but it is worth noting that glucocorticoids must be avoided before the examination to avoid reducing the detection rate. The immunohistochemical analysis of tumor cells from 83 patients with PCNSL revealed that 55.5% expressed Bcl-6, 92.6% expressed multiplemyeloma oncogene protein l (MUM-1), and 51.2% expressed both Bcl-6 and MUM1, which were considered to be the source of “activated 40.2% expressed only MUM1 and none of them expressed plasma cell markers (e.g. CD38, CD138). PCNSL has a high proliferative activity, with Ki-67 positivity index of 50-70% and even over 90%. Tumor cells generally grow diffusely, infiltrating the surrounding normal brain tissue, and forming cuffs around small blood vessels in normal brain tissue, a sign unique to PCNSL. The tumor cells are often surrounded by reactive inflammatory exudates such as CD4+CD8+ T cells, non-neoplastic B cells, macrophages, activated microglia and activated astrocytes. This method is the primary means of confirming the diagnosis of PCNSL, but biopsy can lead to hemorrhage or even more serious complications, and special attention should be paid to peri-brainstem lesions in particular.
(iii) Cerebrospinal fluid analysis
In some cases, biopsy cannot be performed due to the location of the lesion. Since PCNSL is a highly aggressive tumor, identification of markers in the cerebrospinal fluid becomes one of the means to clarify the diagnosis as soon as possible.
1. Cytopathological and flow cytometric analysis: Cerebrospinal fluid cytopathological analysis is the gold standard for the diagnosis of meningeal malignancies. 80% of patients with PCNSL have soft meningeal involvement; however, the sensitivity and specificity of cytopathological examination with Pappenheim staining are low, and repeated lumbar punctures are required for possible diagnosis. Therefore, immunocytochemical methods (e.g., detection of B-cell surface markers including CD20, CD10, Bcl-6, MUM1, and Ki-67) are still required in most patients to aid in the diagnosis.
Flow cytometry testing is currently an important method for the diagnosis of many hematologic malignancies. This method also has the advantage of requiring a smaller number of cells in the sample and is able to distinguish between lymphoma cells and reactive lymphocytes based on cell size, intracellular granule complexity, and surface antigen analysis. In a retrospective study that included 35 patients with lymphoproliferative disorders involving the CNS, a combination of flow cytometric immunophenotyping and cytopathological examination resulted in a 50% increase in cerebrospinal fluid detection compared with cytopathological examination alone. Another study also showed that the use of flow cytometry improved the detection rate of malignant lymphomas. A recent investigator examined the cerebrospinal fluid of 30 patients with PCNSL and found that the sensitivity of flow cytometry was 23.3% compared to 13.3% for cytopathological methods.
2.Protein markers: Cerebrospinal fluid protein analysis including antithrombin, soluble CD27, and immunoglobulin light chain may assist in the diagnosis of PCNSL. high expression of MYC, Bcl-2 and Bcl-6 in tumor tissue may indicate poor prognosis.
3. miRNA: Abnormal expression of miRNA has been found in many tumors including leukemia and lymphoma patients. miRNAs have also been found in cerebrospinal fluid. miRNAs in cerebrospinal fluid have higher stability than cells, and it has been reported that mir-21, mir-19Bl, mir92Al are significantly higher in cerebrospinal fluid of PCNSL patients compared to inflammatory CNS disease or other neurological diseases, so it can be used as one of the methods for differential diagnosis.
Cerebrospinal fluid cytopathology and other tests are one of the ancillary diagnostic measures for PCNSL. Careful evaluation is required before examination, and caution should be exercised in patients with increased intracranial pressure, and lumbar puncture may lead to complications such as brain herniation.
II. Treatment of PCNSL
Since PCNSL is sensitive to both chemotherapy and radiotherapy, complete remission in stages is possible. However, compared with other lymphomas, the results are still unsatisfactory. The effectiveness of treatment for PCNSL is currently evaluated by retrospective studies, case studies and uncontrolled phase II clinical trials.
(i) Surgery
Surgical removal of the tumor may temporarily relieve neurological symptoms but does not contribute to the prognosis. Currently, the nature of the tumor is clarified by stereotactic biopsy and neuropathological analysis for patients considered to have PCNSL on imaging. Prior to stereotactic biopsy, hormonal drugs should be avoided as they may interfere with the histopathological diagnosis of PCNSL. However, for conditions such as intracranial hypertension that may be life-threatening, hormones may be used before biopsy.
(ii) Radiotherapy
In the 1990s, whole brain radiation therapy (WBRT) alone was used as the basic treatment for patients with PCNSL, with complete remission rates of 80-90%; however, even with irradiation doses up to 60 Gy, almost all patients still relapse, with a median overall survival of only 12-16 months and up to 5 years in 10%-29% of patients. Subsequently, clinical trials found that treatment with whole-brain radiotherapy followed by high-dose methotrexate (HD-MTX) was more effective and prolonged patient survival, with complete remission rates of 69-87% and median progression-free survival (PFS) of 24-40 months in patients treated with the combination of radiotherapy and chemotherapy.
However, long-term follow-up has revealed severe neurological damage (e.g., dementia) and death in elderly patients treated with the combination of radiation and chemotherapy. Results of a randomized phase III clinical trial of 551 patients with PCNSL showed no statistically significant difference in overall survival after HD-MTX treatment with or without the administration of whole brain irradiation (32.4 months versus 37.1 months, P=0.700).
(iii) Chemotherapy
Chemotherapy has an important place in the treatment of PCNSL, however, the presence of the blood-to-cerebrospinal fluid barrier (BBB) in CNS makes the effectiveness of chemotherapy somewhat limited. Compared with peripheral lymphoma, treatment should pay attention to: (i) relatively large doses; (ii) choosing drugs that can pass the BBB. Drugs can be divided into three groups according to their ability to pass the BBB: (1) drugs that can barely pass the BBB and have very limited effects, such as anthracyclines, vincristine and cyclophosphamide; (2) drugs that have moderate ability to pass the BBB and can be used in large doses to achieve therapeutic concentrations in the CNS, such as MTX and ara-C; (3) drugs that can achieve therapeutic concentrations in the CNS using conventional concentrations, such as glycocorticosteroids and temozolomide. corticosteroids and temozolomide.
CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) regimens are virtually ineffective in PCNSL, and the addition of CHOP regimens does not improve prognosis compared with HD-MTX alone. Patients should be aware of hematological adverse effects and other organ function impairment during high-dose chemotherapy, and liver and kidney function and serum lactate dehydrogenase levels should be tested regularly.
1.HD-MTX: HD-MTX is the main treatment for PCNSL. Some investigators explored the efficacy of three different doses of MTX: MTX 1g/m2 given before WBRT, the overall survival rate of patients at 3 years was 45%-50%; MTX 3.5g/m2 given every 2-3 weeks before WBRT, once every 3 weeks, maintained for 2-4 cycles, the overall survival rate of resting patients at 3 years was 32 %-47%; MTX 8 g/m2 given every 2 weeks before WBRT, the patients’ 3-year overall survival rate was 33%-35%. Of note, 45% of patients on MTX 8 g/m2 had to have their dose reduced due to impaired creatinine clearance, whereas almost no patients in the MTX 3.5 g/m2 group required a dose reduction. Therefore, the MTX 3.5 g/m2 regimen is the best choice when weighing the safety and efficacy of dosing. Maintaining effective MTX concentration in cerebrospinal fluid and tumor tissues is one of the prognostic factors to improve the therapeutic effect. For this reason, intravenous administration of MTX is currently advocated to maintain 4-6h dosing time, while some investigators advocate maintaining 3-4h dosing time.
2. High-dose Ara-C (HD-Ara-C): Some investigators advocate adding HD-Ara-C to MTX. a recent randomized trial of 79 patients with PCNSL showed that four cycles of HD-MTX (3.5g/m2) given alone or with HD-Ara-C (2g/m2, twice a day, day 2-3), followed by both WBRT was given, with complete remission rates of 18% and 46% (P=0.006) and 3-year overall survival rates of 32% and 46% (P=0.070), respectively, indicating that the combination of HD-Ara-C significantly improved the survival of PCNSL patients. It is worth noting that the combination of MTX and HD-Ara-C will result in an increase in hematological adverse effects, and attention should be paid to the prevention of complications such as infection and bleeding. It is recommended that the specific use of the drug should be adjusted according to the patient’s condition and conditions.
3. Rituximab: Since PCNSL is predominantly a B-cell tumor, rituximab may be effective. However, as a large protein, rituximab is difficult to access to the CNS. German investigators conducted a retrospective analysis of 1
A retrospective analysis of 222 patients showed that rituximab combined with CHOP regimen was able to inhibit the infiltration of tumor cells into the CNS in patients with DLBCL. However, French investigators did not reach a consistent conclusion in a study of 399 patients. Feugier et al. treated 30 patients with PCNSL with rituximab in combination with HD-MTX and achieved a complete remission rate of 78% and an overall patient survival rate of 67% at 2 years. The exact role of rituximab in PCNSL is still debatable.
4. Other drugs: glucocorticoids and other alkylating agents with good CNS penetration, such as temozolomide, isocyclophosphamide, nitrosourea, and mebendazole, have been incorporated into PCNSL combination chemotherapy regimens. Steroids can induce malignant B-cell apoptosis and affect the diagnosis so they should be avoided before biopsy and should only be used if the patient has brain herniation that may be immediately life-threatening. Care should also be taken to prevent immunosuppression due to long-term steroid use. Temozolomide is an oral alkylating agent with a good safety profile and can be passed by the BBB, and has been shown to achieve a complete remission rate of 25% in patients with relapsed/refractory PCNSL. The results showed that patients treated with this regimen had a complete remission rate of 85%, a partial remission rate of 15%, and a 5-year survival rate of 77%, with acceptable adverse drug effects, but whether it can be used as a first-line treatment option for PCNSL needs to be confirmed in larger clinical trials. Isocyclophosphamide may improve the rate of complete remission and inhibit tumor progression, but has a high incidence of adverse effects and is not suitable for elderly patients in particular. Tiotipine can be used in combination with HD-MTX, HD-Ara-C, desoxorubicin and WBRT. In phase II clinical trials, patients had a median PFS of 13 months and a 5-year survival rate of 41%, but some patients had serious adverse effects and a drug-related mortality rate of 10%. Mebendazole combined with HD-MTX and vincristine is widely used in PCNSL combination chemotherapy regimens followed by WBRT and HD-Ara-C, and the 5-year survival rate of patients was 32%. Bis-chloroethylnitrosourea can be used as part of combination chemotherapy or as pretreatment for leukosomal stem cell transplantation. Topotecan, a topoisomerase II inhibitor, has good CNS bioavailability with both temozolomide and shows good promise in the treatment of relapsed/refractory PCNSL, with a complete remission rate of 19% and an overall patient survival rate of 39% at 1 year. Therefore, temozolomide with topotecan is a good choice for relapsed/refractory PCNSL. the treatment of PCNSL remains a difficult problem, and treatment varies from place to place. the 2013 NCCN guidelines have been newly modified for the treatment of PCNSL: those with a Karnofsky functional status (KPS) score ≥ 40 are given HD-MTX-based chemotherapy, based on the disease response to response to treatment and the patient’s general condition to decide whether to perform WBRT, with the caveat that WBRT may increase neurotoxicity, especially in older patients >60 years of age.
Intrathecal chemotherapy should be considered if there is an increase in malignant cells on cerebrospinal fluid examination or positive findings on spinal MRI; if the ocular examination is positive (e.g., malignant uveitis), whole brain radiation or intraocular chemotherapy should be considered. For those with KPS score <40 even after hormone therapy should be given wbrt, which helps induce responsiveness to treatment, reduce the incidence of cns, and improve the quality of life of patients; if lumbar puncture or spinal mri is positive, intrathecal chemotherapy + local spinal radiotherapy should be considered. < p="">
PCNSL patients with disease progression or relapse after treatment should be considered for further chemotherapy (systemic or intrathecal), reirradiation or given optimal supportive therapy, or high-dose chemotherapy sequential hematopoietic stem cell transplantation may be considered.
III. Prognosis of PCNSL
Age and physical status are important factors affecting the prognosis of PCNSL patients, and the results of a multicenter retrospective study suggest that the five factors with poor prognosis include: ① age > 60 years; ② physical status of 2-4 on the EasternCooperativeOncology Group (ECOG) scale; ③ serum (3) increased serum lactate dehydrogenase; (4) increased cerebrospinal fluid protein content; (5) deep brain parenchyma involvement. Some studies have also suggested that only age and physical status are relevant for prognostic judgments. In terms of pathomorphology, vascular hyperplasia suggests a poor prognosis and reactive perivascular T-cell infiltration suggests a good prognosis.
In conclusion, the understanding of PCNSL has been lagging behind other sites of lymphoma due to the specificity of the site and the relatively low incidence. Currently, the classification of PCNSL is based on the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, in which DLBCL is the main type. MRI, PET-CT and other imaging examinations have a preliminary diagnostic role, and targeted biopsy is the main means to confirm the diagnosis.
According to the 2013 NCCN guidelines and related literature, HD-MTX and/or HD-Ara-C are the main treatments for PCNSL patients, and whole brain radiotherapy can be used as a complementary and rescue option. More information needs to be accumulated for hematopoietic stem cell transplantation and biologically targeted therapy. Early antiviral therapy should be administered to HIV-infected patients, which may help to prevent the occurrence of PCNSL. although there are many advances in the diagnosis and treatment of PCNSL, there are still many challenges, and in future work, multi-center cooperation is recommended to find new ways for the diagnosis and treatment of PCNSL.