Primary central nervous system lymphoma (PCNSL) is a lymphoma that originates in the brain, spinal cord, eye or soft meninges. Patients with PCNSL mainly present with altered mental status, increased intracranial pressure, such as headache, nausea, vomiting, and watery eyes. vomiting, and optic papilloedema, as well as symptoms of local compression, including seizures, memory loss, unsteadiness in walking, visual field disturbances, blurred speech, and mild hemiparesis. In addition to brain involvement, 10% to 20% of patients have ocular involvement, manifested by blurred vision or complaints of “floating objects”.
I. Diagnosis of PCNSL
1.Cranial imaging
Cranio-cerebral imaging is important for the clinical diagnosis and differential diagnosis of PCNSL. The MRI features of PCNSL are equal or slightly low signal in T1WI, slightly low, equal or {signal in T2WI, single or multiple homogeneous lesions, more limited, irregular margins, 90% of the lesions are surrounded by different degrees of edema, the enhancement of tumor is obviously homogeneous and consistent after enhancement is the characteristic of this disease. 60% – 70% of patients have a single tumor. The tumor is a single lesion in 60% – 70% of patients, and 80% – 90% of the lesions are located in the cerebellar curtain. In immunodeficient patients, multiple foci with ring-like enhancement are seen. 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.
The imaging examination of PCNSL has certain characteristics, but the imaging examination 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 examinations are needed to confirm the diagnosis.
2.Stereotactic biopsy
Stereotactic biopsy is the most effective method for definitive diagnosis, and the sensitivity of biopsy has been reported to be over 90%, which is the main means to confirm the diagnosis of PCNSL, but biopsy can lead to bleeding or even more serious complications, especially for peri-brainstem lesions. Tumor cells from PCNSL patients express B-cell surface markers (e.g. CD19, CD20, CD79a). Immunohistochemical analysis revealed that 55.5% expressed Bcl-6, 92.6% expressed multiple myeloma oncogenic protein-1 (MUM-1), 51.2% expressed both Bcl-6 and MUM1, 40.2% expressed only MUM1, and none of them expressed plasma cell markers (e.g. CD38, CD138). 50% – 70%, even more than 90%. The tumor cells generally grow diffusely and infiltrate the surrounding normal brain tissue, and they can also be seen forming cuffs around small blood vessels in normal brain tissue, a sign unique to PCNSL.
3.Cerebrospinal fluid cytopathological examination
Cerebrospinal fluid cytopathological examination is one of the ancillary diagnostic measures for PCNSL, such as cytopathology and flow cytometry analysis, protein markers and miRNA detection. Careful evaluation is required before the examination, and caution should be exercised for patients with increased intracranial pressure {lumbar puncture may lead to complications such as brain herniation.
II. Treatment of PCNSL
PCNSL is sensitive to radiotherapy and chemotherapy, and it is possible to obtain complete remission in stages after treatment, but the results are still unsatisfactory compared with other lymphomas.
1.Surgery
Surgical removal of the tumor can temporarily relieve neurological symptoms in the brain, but the prognosis is not affected. Patients with PCNSL diagnosed by clinical imaging can have their tumor nature confirmed by stereotactic biopsy surgery and neuropathology.
2.Radiotherapy
The complete remission rate of whole brain radiation therapy (WBRT) alone for PCNSL is 80% – 90%, with a median overall survival of 12 – 16 months, with 10% – 29 percent of patients achieve a 5-year survival. The complete remission rate for PCNSL with combined radiotherapy and chemotherapy was 69%–87%, with a median progression-free survival (PFS) of 24–40 months. However, severe neurological damage (e.g., dementia) occurs in elderly patients treated with the combination of radiation and chemotherapy. randomized phase III (551 patients) clinical results in patients with PCNSL showed no statistically significant difference in overall survival after high-dose methotrexate (HD-MTX) treatment with or without administration of whole brain irradiation (32.4 months vs. 37.1 months, = 0.700).
3, Chemotherapy
Although chemotherapy has an important role in the treatment of PCNSL, the presence of the blood-brain barrier in the central nervous system limits the effectiveness of chemotherapy; compared with peripheral lymphoma, chemotherapy treatment for PCNSL should consider: choosing drugs that can cross the blood-brain barrier and relatively high drug doses. The CHOP regimen (cyclophosphamide, adriamycin, vincristine, prednisone) is almost ineffective in PCNSL and the addition of CHOP regimen does not improve the prognosis compared to HD-MTX alone. The current study data show that HD-MTX is the main treatment for PCNSL, and the efficacy of different doses of MTX: the overall survival rate of patients at 3 years was 45% – 50% when MTX 1g/m2 was given before WBRT; every 2 – MTX 3.5g/m2 given every 3 weeks for 2–4 cycles before WBRT, the overall survival rate of patients at 3 years was 32%–47%; MTX 8g/m2 given every 2 weeks before WBRT, the overall survival rate of patients at 3 years was 33%–35%. —35%. During high-dose chemotherapy, patients should be aware of hematological adverse effects and other organ function impairment, and liver and kidney function and serum lactate dehydrogenase levels should be tested regularly. Therefore, the MTX 3.5g/m2 regimen is the best choice in terms of safety and efficacy. Maintaining effective MTX concentrations in the 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 4–6 h dosing time, and some investigators advocate maintaining 3–4 h dosing time. In a recent randomized trial of 79 PCNSL cases, four cycles of HD-MTX (3.5 g/m2) given alone or with HD-Ara-C (2 g/m2 twice daily on days 2–3), all followed by WBRT, resulted in complete remission rates of 18% and 46%, respectively (p= The combination of MTX and HD-Ara-C may increase the hematological adverse effects, so it is recommended to adjust the medication according to the patient’s condition and conditions, and pay attention to the prevention of complications such as infection and bleeding.
4.Other drugs
Rituximab: Feugier et al. treated 30 patients with PCNSL with the combination of rituximab and HD-MTX and achieved a complete remission rate of 78%, with an overall survival rate of 67% at 2 years. The exact role of rituximab in PCNSL is debatable.
Temozolomide is an oral alkylating agent that has a good safety profile and crosses the blood-brain barrier, and has been shown to achieve a complete remission rate of 25% in patients with relapsed/refractory PCNSL. The results showed 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. However, the use of temozolomide in combination with HD-Ara-C and MTX as a first-line treatment option for PCNSL needs to be confirmed in larger clinical trials.
The treatment of PCNSL remains a challenge, and the 2013 NCCN guidelines have been newly modified for the treatment of PCNSL: HD-MTX-based chemotherapy is given to those with a Kamofsky functional status (KPS) score of more than 40, and the decision to perform WBRT is based on the disease response to treatment and the patient’s general condition, with the caveat that WBRT may increase neurotoxicity , especially in elderly patients aged >60 years. WBRT should be given to those with KPS score <40 even after hormone therapy, which helps to induce responsiveness to treatment, reduce the incidence of cns and improve {patients' quality of life; if lumbar puncture or spinal mri is positive, intrathecal chemotherapy + local spinal radiotherapy should be considered. If the cerebrospinal fluid examination has increased malignant cells or the spinal mri has positive findings, both should be considered intrathecal chemotherapy; if the eye examination is positive (such as malignant uveitis), whole brain radiotherapy or intraocular chemotherapy should be considered.
III. Prognosis of PCNSL
Age and physical status are important factors affecting the prognosis of PCNSL patients, and a multicenter retrospective study suggests that the prognosis is worse when the following five factors are present.
① Age > 60 years.
②ECOG scale evaluation of physical fitness status of 2 – 4.
(iii) increased serum lactate dehydrogenase.
④ increased cerebrospinal fluid protein content.
⑤ Deep brain parenchyma involvement.
In terms of pathomorphology, vascular hyperplasia suggests a poor prognosis and reactive perivascular T-cell infiltration suggests a good prognosis.
In conclusion, the recognition of PCNSL has been lagging behind other sites of lymphoma due to the specificity of the site and the relatively low incidence. According to the 2013 NCCN guidelines and related literature, HD-MTX and/or HD-Ara-C are the primary treatment for patients with PCNSL, and whole-brain radiotherapy can be used as a complementary and rescue option. although there are many advances in the diagnosis and treatment of PCNSL, many challenges still exist, and multicenter cooperation is recommended in future work to seek new ways for the diagnosis and treatment of PCNSL.