Primary central nervous system (CNS) lymphoma is one of the most controversial topics in neuro-oncology due to its complexity and limited treatment options. Back in 2013, the European Neuro-Oncology Society developed evidence-based guidelines for the treatment of immunocompetent primary CNS lymphoma through a multidisciplinary collaboration. The guidelines were recently updated with the latest evidence-based medical evidence and published in the journal Lancet oncology.
Primary CNS lymphoma is a very aggressive disease that primarily involves the brain, spinal cord, eyes, meninges, and cranial nerves, with little systemic involvement. Most (>90%) primary CNS lymphomas have the same histology as diffuse large B-cell lymphoma.
Statistically, primary CNS lymphomas account for approximately 1% of all lymphomas, 4%-6% of extranodal lymphomas, and 3% of CNS tumors. Epidemiological data show that after a sustained increase in the 1980s and 1990s, its incidence has declined in developed countries, especially among young AIDS patients. In contrast, the incidence of primary CNS lymphoma continues to rise in older patients, who also account for the majority of immunocompetent primary CNS lymphomas.
Although the prognosis of primary CNS lymphoma remains poor, it has improved considerably in the last two decades due to the availability of new treatment options. Primary CNS lymphoma is sensitive to both chemotherapy and radiotherapy, but the duration of remission is usually short and the blood-brain barrier prevents many chemotherapeutic agents from reaching the center. In addition, elderly patients are at high risk of severe treatment-related neurotoxic side effects, which makes treatment very challenging.
Current recommendations or consensus for the treatment of this disease are largely derived from evidence-based evidence, with only three completed clinical studies demonstrating effectiveness in the treatment of primary CNS lymphoma: a phase 3 clinical study and two phase 2 clinical trials. The purpose of this guideline is to provide clinicians with evidence-based recommendations and expert consensus opinions, with a primary focus on immunocompetent populations.
Diagnosis
Cranial MRI neuroimaging using fluid-attenuated inversion recovery and T1-weighted series before and after contrast injection is the method of diagnosis and follow-up. Diffuse, dynamic sensitivity contrast, proton-energy spectroscopy MRI and fluorodeoxyglucose-PET can be used for differential diagnosis but with insufficient specificity.
Histopathologic confirmation of primary CNS lymphoma is mandatory prior to treatment, and its biopsy should be performed by stereotactic or navigation-guided puncture. Clinically, the use of steroids prior to biopsy is generally not recommended. Although steroids can rapidly shrink the mass and improve symptoms, steroids can mask pathologic features and compromise the diagnosis. For patients who have been on steroids prior to biopsy, are in remission at the time of biopsy or have non-specific inflammation suggested by biopsy, repeat biopsy is recommended when serial MRI monitoring suggests mass growth.
Diagnosis of primary CNS lymphoma is based on WHO 2008 classification and must be based on immunohistochemical findings, with key markers including all B-cell markers (CD19, CD20, PAX5), BCL6, MUM1/IRF4, and CD10. In difficult cases, such as patients previously treated with steroids, immunoglobulin gene family PCR analysis may be helpful.
If primary CNS lymphoma is suspected, all patients must have at least one HIV test, one lumbar puncture (performed without contraindications) and one eye examination (fundoscopic slit lamp examination), including patients without ocular symptoms.
The presence of lymphocytes in the cerebrospinal fluid or vitreous fluid is highly suggestive of primary CNS lymphoma on clinical and imaging examination and may not require a further stereotactic brain biopsy to confirm the diagnosis. In general, it may be difficult to diagnose primary CNS lymphoma by cytology, at which point a pathologist may be consulted to help make the diagnosis. If there is still doubt, then a brain biopsy should be performed. Immediate immunophenotyping of cells collected from cerebrospinal fluid or vitreous fluid may increase the sensitivity of the diagnosis.
The presence of B-cell monoclonality in atypical or suspicious cells and sequences, and PCR analysis of immunoglobulin gene rearrangements in the cerebrospinal fluid may lead to false-positive results. Therefore, clonal evidence of lymphocytes is not sufficient to diagnose primary CNS lymphoma except in the presence of patients with a high clinical suspicion of CNS lymphoma.
If a specimen with a monoclonal clone of B cells shows atypical or suspicious cells and PCR analysis of cerebrospinal fluid or vitreous fluid suggests an immunoglobulin gene rearrangement, this may be a false positive result. Therefore, denial of a lymphocyte clone is not sufficient to diagnose primary CNS lymphoma unless it is highly clinically considered.
Staging
Systematic staging takes into account the following factors.
Physical examination, bone marrow biopsy, ultrasound scan of the testes, CT scan of the chest, abdomen and pelvis.
In addition, whole-body fluorodeoxyglucose-PET may be superior to whole-body CT scans and testicular ultrasound scans.
Prognosis
Age and physical condition are treatment-independent prognostic factors. Prior to treatment, individual risk should be assessed based on available prognostic scores. Older patients are defined as approximately 60C65 years of age.
Treatment outcome and follow-up
According to the International Primary CNS Lymphoma Collaborative Group criteria (2005), the efficacy of treatment should be evaluated based on MRI, eye examination, cerebrospinal fluid examination, and steroid dosing.
There is no evidence that fluorodeoxyglucose-PET can be used to assess the efficacy of treatment for primary CNS lymphoma, and this tool is currently used primarily to assess the efficacy of treatment for other types of lymphoma.
Formal prospective neuropsychological testing is recommended at follow-up for patients with primary CNS lymphoma undergoing clinical trials.
Treatment
1. Surgery
To rapidly reduce intracranial pressure, surgery is indicated for patients with large intracranial masses and acute signs of brain herniation.
The panel did not reach consensus on whether surgery is recommended or requires tissue biopsy in patients with suspected primary CNS lymphoma as a single lesion and resectable lesions.
2. Chemotherapy
conventional CHOP regimens and other CHOP-like regimens are not recommended for the treatment of primary CNS lymphoma.
Chemotherapy regimens should include high-dose methotrexate (>3 g/m2) at cerebrospinal fluid cytotoxic levels because methotrexate can cross the blood-brain barrier. Methotrexate should be administered by intravenous infusion over 2-3 hours, with a minimum of 4-6 chemotherapy doses, and no more than 2-3 weeks apart.
High-dose methotrexate in combination with other chemotherapeutic agents may improve remission rates compared to single-agent high-dose methotrexate therapy.
High-dose methotrexate should be combined with chemotherapeutic agents that can cross the blood-brain barrier, such as high-dose cytarabine.
high-dose methotrexate may be used to treat elderly patients with good physical status and renal function
Rituximab in combination with other chemotherapy regimens is currently used only as experimental therapy in clinical trials.
3.Radiotherapy
whole brain radiotherapy (WBRT), high-dose methotrexate and combination therapy have a greater neurotoxic effect on patients
Consolidation WBRT after high-dose methotrexate chemotherapy remains controversial. the optimal dose of WBRT remains undetermined and should be selected based on the response to initial treatment.
irradiation at a dose of 40C45 Gy (1.8-2.0 Gy per fraction) is recommended for patients with disease progression or residual disease remaining after initial chemotherapy.
For patients <60 years of age who have achieved complete remission after induction therapy, the decision to continue WBRT (40C45 Gy at 1.8C2.0 Gy per fraction) should be discussed with the patient. Reduced-dose WBRT consolidation therapy (23?4C30?0 Gy at 1.8C2.0 Gy per segment) as a treatment option is currently only being evaluated in clinical trials.
In patients aged >60 years, the risk of delayed WBRT neurotoxicity is very high, especially after high-dose methotrexate therapy. This is when WBRT should be postponed or simply not done.
4. High-dose chemotherapy combined with autologous hematopoietic stem cell transplantation (HDC-ASCT)
HDC-ASCT is effective in the treatment of relapsed refractory CNS lymphoma.
HDC-ASCT only for the treatment of patients aged <60-65 years.
Pre-transplant treatment regimen with high-dose tiotipine based chemotherapy is superior to BEAM
HDC-ASCT as first-line consolidation therapy for the treatment of primary CNS lymphoma is currently limited to clinical trials and only in clinically experienced research centers.
5. Salvage therapy
Patients with relapsed refractory primary CNS lymphoma should be entered into phase 1 and phase 2 clinical trials.
What salvage therapy regimen is most appropriate should be judged based on the patient’s age, physical condition, comorbidities, site of relapse, and previous treatment regimen and duration of remission. Adverse reactions to the chemotherapeutic agent of choice should also be carefully evaluated.
Salvage WBRT may be applied prior to induction therapy and may be used in patients who have not received prior radiotherapy.
HDC-ASCT may be an option for patients aged <60-65 years with relapsed primary CNS lymphoma who are chemotherapy-sensitive.
Salvage therapy prior to WBRT or HDC-ASCT may be used as induction therapy or only to treat patients who are not candidates for WBRT or HDC-ASCT
for patients with relapsed primary CNS lymphoma for whom prior high-dose methotrexate therapy has been effective, treatment with methotrexate may be considered again
For isolated CNS extranodal lymphoma, treatment should be with an anthracycline-based chemotherapy regimen with or without HDC-ASCT.
6.Primary intraocular lymphoma
Primary intraocular lymphoma may be treated with a high-dose methotrexate-based chemotherapy regimen (with or without WBRT) or local therapy (intravitreal chemotherapy or local radiation therapy to the eye).
local treatment is an effective treatment for elderly patients with contraindications to systemic chemotherapy or recurrent intraocular disease.
Treatment options for concurrent intraocular and CNS lymphoma are the same as for primary CNS lymphoma.
If WBRT consolidation therapy is recommended, both eyes should be treated with radiotherapy
Treatment of relapsed refractory intraocular lymphoma should be selected based on patient characteristics and previous treatment options. These include: intravitreal methotrexate injection, local radiotherapy, WBRT, systemic chemotherapy and HDC-ASCT.