PCNSL accounts for approximately 3% of all neoplasms and 4% to 6% of all extranodal lymphomas.280 It is an aggressive form of non-Hodgkin lymphoma that develops within the brain, spinal cord, eye, or
leptomeninges without evidence of systemic involvement. The overall incidence of PCNSL in immunocompetent patients is 0.47 per 100,000 person-years, with higher incidence in males than in females and an increasing incidence with age.280 The greatest increase in incidence has been reported in older adults with 1.8 per 100,000 patient-years reported in patients aged 65 years or older and 1.9 in patients aged 75 years or older, indicating that, in immunocompetent patients, PCNSL is a disease of older adults.280,281 Non-immunosuppressed patients have a better prognosis than AIDS-related cases,282 and survival of this group has improved over the years with treatment advances.283,284 For more guidance on treatment of patients with PCNSL who are living with HIV, see the NCCN Guidelines for Cancer in People Living with HIV (available at www.NCCN.org).
Pathologically, PCNSL is an angiocentric neoplasm composed of a dense monoclonal proliferation of lymphocytes, usually diffuse large B cells.285 More than 90% of these primary CNS diffuse large B-cell lymphoma cases are of the activated B-cell–like (ABC) subtype.286 The tumor is infiltrative and typically extends beyond the primary lesion, as shown by CT or MRI scans, into regions of the brain with an intact BBB.286 The brain
parenchyma is involved in more than 90% of all PCNSL patients, and the
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-25 condition can be multifocal in more than 50% of cases. Leptomeningeal
involvement may occur, either localized to adjacent parenchymal sites or in diffuse form (that is, positive cytology) in up to 30% of patients. Ocular involvement may develop independently in 10% to 20% of patients.
Patients with PCNSL can present with various symptoms because of the multifocal nature of the disease. In a retrospective review of 248
immunocompetent patients, 43% had mental status changes, 33%
showed signs of elevated intracranial pressure, 14% had seizures, and 4%
suffered visual symptoms at diagnosis.287
PCNSL occurs in about 7% to 15% of patients with post-transplant lymphoproliferative disorders (PTLD)288-291 and is associated with poor prognosis.290,292,293 PTLDs are a heterogeneous group of lymphoid neoplasms associated with immunosuppression following solid organ transplantation (SOT) or allogeneic hematopoietic stem cell
transplantation (HSCT).294-296 For guidance on managing transplant recipients, see the Post-Transplant Lymphoproliferative Disorders sub-algorithm in the NCCN Guidelines for Diffuse Large B-Cell Lymphoma (available at www.NCCN.org).
Treatment Overview Steroid Administration
Steroids can rapidly alleviate signs and symptoms of PCNSL and improve PS. However, as these drugs are cytolytic, they can significantly decrease enhancement and size of tumors on CT and MRI scans as well as affect the histologic appearance. In the absence of significant mass effect, it is recommended that steroids be withheld or used judiciously until diagnostic tissue can be obtained if PCNSL is suspected.
Stereotactic Biopsy
In contrast to the principles previously outlined for invasive astrocytomas and other gliomas, the surgical goals for PCNSL are different, with the
main goal being establishment of diagnosis under minimal risk of morbidity. Currently, most authors recommend biopsy rather than resection.297 This approach stems from the fact that data do not
demonstrate a survival advantage for patients who have had a complete resection or extensive STR when compared with those who have had only a stereotactic biopsy. In addition, STR is associated with risk for
postoperative neurologic deficits.287 Systemic Therapy
Methotrexate is the most effective agent against PCNSL. It is commonly used in combination with other drugs such as procarbazine, vincristine, cytarabine, rituximab, and temozolomide.298-311 High doses of intravenous methotrexate are necessary (3.5 g/m2 or higher) to overcome the BBB and achieve therapeutic levels in the CSF. Intrathecal methotrexate can be useful where CSF cytology yields positive findings and when patients cannot tolerate systemic methotrexate at 3.5 g/m2 or higher. Other intrathecal chemotherapy options in this setting include cytarabine312 and rituximab.313 Phase II trials in the United States and Europe have shown that high-dose chemotherapy with autologous stem cell transplantation following high-dose methotrexate-based chemotherapy is feasible and well-tolerated, with little evidence of neurotoxicity.307,314-321
Renal dysfunction induced by high-dose methotrexate therapy is a
potentially lethal medical emergency due to heightened toxicities resulting from a delay in methotrexate excretion. Early intervention with
glucarpidase, a recombinant bacterial enzyme that provides an alternative route for methotrexate clearance, has shown efficacy in rapidly reducing plasma concentrations of methotrexate and preventing severe
toxicity.322,323
It has become clear that consolidative therapy can result in significant and sometimes lethal neurotoxic effects from consolidation RT, especially in patients older than 60 years of age.301,324,325 Complete response to
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-26 chemotherapy ranges from 42% to 61%, with OS ranging between 14 and
55 months. A number of phase II trials have adopted the approach of chemotherapy without planned RT.298,301,326-330 However, a high fraction of patients who have forgone initial RT—typically older or with significant comorbidities—may fail to achieve complete response to chemotherapy.
Studies investigating the efficacy of methotrexate-based regimens as induction therapy for patients with PCNSL have utilized WBRT, including reduced WBRT following cytarabine as consolidation treatment.300-302 There are currently no conclusive prospective data published comparing consolidation with high-dose chemotherapy regimens or high-dose chemotherapy with autologous stem cell transplantation versus
maintenance therapy or observation, and there are different approaches at different institutions. Consolidation with high-dose chemotherapy and autologous stem cell transplant is frequently considered for fitter patients.
Eligibility criteria used in the respective trials that studied these regimens need to be carefully considered when considering this approach, and referral to centers with subspecialty expertise in PCNSL should be considered.
Cytarabine combined with etoposide as high-dose consolidation therapy following induction treatment with methotrexate, temozolomide, and rituximab was evaluated in the multicenter Alliance 50202 trial.331 This protocol was feasible and generally well-tolerated, with one treatment-related death.
High-dose chemotherapy with autologous stem cell transplantation in the relapsed/refractory setting has been tested with some success in two phase 2 European trials,332,333 although evidence of its advantage over conventional treatment is lacking. The German Cooperative PCNSL Study Group evaluated the safety and efficacy of rituximab, high-dose
cytarabine, and thiotepa followed by autologous stem cell transplantation in 39 patients with relapsed or refractory PCNSL with previous high-dose
methotrexate-based treatment.333 A complete response was achieved in 56% of the patients. Out of the remaining patients, only one had
progressive disease (18% of the patients had a partial response or stable disease). However, median OS was not reached, with a 2-year OS rate of 56.4%. Median PFS was 12.4 months, with a 2-year PFS rate of 46%. A phase 2 trial from France evaluated the efficacy of high-dose cytarabine and etoposide followed by autologous stem cell transplantation in 43 patients with relapsed or refractory PCNSL with previous high-dose methotrexate-based treatment.332 Out of the 27 patients who completed autologous stem-cell rescue, median OS was 58.6 months (2-year OS was 69%) and median PFS was 41.1 months (2-year PFS was 58%).
High-dose chemotherapy and autologous stem cell transplantation as part of initial treatment has now been explored in several trials. High complete response rates and 2-year PFS have been demonstrated.307,334 Whether high-dose chemotherapy and autologous stem cell rescue provides any additional benefit over consolidative conventional-dose chemotherapy or not is being investigated in two trials currently in progress. Consolidative conventional dose chemotherapy (NCTNA51101, MATRIX)335 or
consolidative WBRT (ANOCEF-GOELAMS, IELSG32)336 have resulted in equivalent 2-year PFS in randomized phase II trials. Toxicities differ and might be a basis for individual patient selection. Of note, longitudinal neurocognitive assessment in the IELSG32 study showed persistent neurocognitive impairment in the consolidative WBRT group, but not in the high-dose chemotherapy group. The extent to which the patient selection inherent in high-dose chemotherapy trials underlies these favorable outcomes remains to be determined.
Unfortunately, even for patients who initially achieved complete response, half will eventually relapse. Re-treatment with high-dose methotrexate may produce a second response in patients who achieved complete response with prior exposure.337 Rituximab as well as ibrutinib may be used in
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-27 combination with high-dose methotrexate retreatment.338 Several other
regimens, including ibrutinib,339,340 rituximab,341 TMZ with or without rituximab,342-345 lenalidomide with or without rituximab,346 high-dose cytarabine,347 pomalidomide,348 and pemetrexed349 have also shown activity in the relapsed/refractory disease setting, but none has been established as a standard of care.
Radiation Therapy
Historically, WBRT was the treatment standard to cover the multifocal nature of the disease. The majority of studies demonstrated the limitation of high-dose RT and led to the recommended dose of 24 to 36 Gy in 1.8 to 2.0 Gy fractions to the whole brain, without a boost.300,302,350-353 Although RT alone is useful for initial tumor control, frequent and rapid relapse of the disease led to a short OS of 12 to 17 months.282,352 This dismal outcome has prompted the addition of pre-irradiation methotrexate-based combination chemotherapy in later studies. This approach yields
impressive response rates of up to 94% and improved OS ranging from 33 to 60 months.300-302,310,324,325,350,354,355 However, excessive grade 3 and 4 hematologic toxicity (up to 78%) as well as RT-induced delayed
neurotoxicity (up to 32%) sometimes leading to deaths are primary concerns, although most of these studies utilized a high RT dose of
greater than or equal to 40 Gy. Of note, younger patients (aged <60 years) consistently fare better, and there is a higher incidence of late neurotoxic effects in older patients, but significant neurotoxicity can also occur in younger adults.
Thiel and colleagues356 conducted a randomized, phase III, non-inferiority trial of high-dose methotrexate plus ifosfamide with or without WBRT in 318 patients with PCNSL. There was no difference in OS (HR, 1.06; 95%
CI, 0.80–1.40; P = .71), but the primary hypothesis (0.9 non-inferiority margin) was not proven. Patients who received WBRT had a higher rate of neurotoxicity than those who did not (49% vs. 26%). The panel currently
recommends that patients receiving WBRT because they are not
candidates for chemotherapy should receive a dose of 24 to 36 Gy with a boost to gross disease, for a total dose of 45 Gy.
Although WBRT alone is seldom sufficient as primary treatment and is primarily reserved for patients who cannot tolerate multimodal treatment, it may be a reasonable treatment option for patients not suitable for other systemic therapies or clinical trials. Results from a phase II trial showed that reduced-dose WBRT (23.4 Gy in 1.8 Gy/fraction) following a complete response to induction chemotherapy was associated with disease
response and long-term control, as well as low neurotoxicity.357 When administered after chemotherapy failure, WBRT has shown response rates reaching nearly 75%.358 Median PFS was 9.7 months overall, 57.6 months in patients who had achieved a CR with WBRT, and 9.7 months in patients with a PR. For patients who had a less than complete response to chemotherapy, a dosing schedule consistent with that used for induction treatment may be used, followed by a limited field to gross disease, or focal RT to residual disease.
NCCN Recommendations Initial Evaluation
Neuroradiologic evaluation is important in the diagnosis of PCNSL and to evaluate the effectiveness of subsequent therapy. With MRI, the tumor is often isointense or hypointense on T1- and T2-weighted images and enhances frequently.359 In addition, restricted diffusion can be seen in the area of the enhancing abnormality on diffusion-weighted imaging
sequences. On a CT scan, PCNSL is usually isodense or hyperdense compared to the brain and enhances in most cases. Hallmark features include a periventricular distribution, ring enhancement, multiple lesions, and a smaller amount of edema than might otherwise be expected from a similar-sized metastatic tumor or glioma. If contrast-enhanced brain MRI (or contrast-enhanced CT if MRI is contraindicated) suggests PCNSL,
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-28 clinicians are advised to hold the use of steroids if possible before
diagnosis is established, since the imaging and histologic features of PCNSL can be profoundly affected by these drugs.
Patients with an enhancing brain lesion consistent with PCNSL should receive a biopsy (if lesion is amenable to biopsy), as this is the most direct and rapid route to achieve a pathologic diagnosis. Because the role of maximal surgical resection is limited to alleviating symptoms of raised intracranial pressure or preventing herniation,287 stereotactic biopsy is generally preferred to minimize invasiveness.297 Even with molecular marker testing, however, a biopsy can occasionally be falsely negative, particularly if the patient had been treated previously with steroids. Thus, if a biopsy is nondiagnostic, the panel recommends that the steroids be tapered and that the patient be followed closely, both clinically and radiographically. If and when the lesion recurs, there should be a prompt repeat CSF evaluation or rebiopsy before the initiation of steroids. If, on the other hand, no definitive diagnosis of lymphoma is made from biopsy and the patient has not received steroid therapy, workup for other
diagnoses (for example, inflammatory processes) or repeat CSF evaluation/rebiopsy is recommended.
Evaluation for Extent of Disease
Once the diagnosis of PCNSL is established, the patient should undergo a thorough staging workup detailed by The International PCNSL
Collaborative Group.297 This workup involves a complete CNS evaluation including imaging of the entire neuraxis (MRI of the spine with contrast). If possible, this should be done before CSF analysis is attempted to avoid post-lumbar puncture artifacts that can be mistaken for leptomeningeal disease on imaging.
A lumbar puncture with evaluation of CSF (15–20 mL of spinal fluid) should be considered, if it can be done safely and without concern for herniation from increased intracranial pressure, and if it will not delay
diagnosis and treatment. A delay in treatment may compromise patient outcomes.331 Caution should be taken in patients who are anticoagulated, thrombocytopenic, or who have a bulky intracranial mass. CSF analysis should include flow cytometric analysis, CSF cytology, and cell count. The yield for a positive diagnostic test can be increased by the use of
molecular markers of monoclonality, such as an immunoglobulin gene rearrangement.
Since disease is sometimes detected in the retina and optic nerve, a full ophthalmologic exam should be done, which should include a slit-lamp eye examination. In some cases, the diagnosis of lymphoma is made by vitrectomy; in this case, flow cytometric analysis is recommended. In addition, blood work (CBC and chemistry panel) and a contrast-enhanced body CT or PET/CT360 are required to rule out systemic involvement.
Elevated lactate dehydrogenase (LDH) serum level is associated with worse survival in patients with PCNSL,361,362 and LDH should be evaluated as part of the workup for this disease. Bone marrow biopsy is a category 2B option that may be considered. In men older than 60 years of age, testicular ultrasound may be considered (category 2B). In these patients, regular testicular examination is encouraged. If both testicular examination and CT or PET/CT imaging are negative, then testicular ultrasound may not be necessary.
An HIV blood test should also be performed, because both prognosis and treatment of patients with HIV-related PCNSL may be different than that of patients who are otherwise immunocompetent. HIV-positive patients should receive highly active retroviral therapy in addition to their cancer therapy.
Newly Diagnosed Disease
Induction treatment should be initiated as soon as possible following confirmation of diagnosis. The International PCNSL Collaborative Group has published treatment response criteria for complete response,
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-29 unconfirmed complete response, partial response, progressive disease,
and relapsed disease.297 Given the dramatic effect of steroids on symptom relief, they are commonly administered concurrently with workup. A high-dose methotrexate-containing regimen is the recommended induction treatment. In the case of methotrexate-induced renal dysfunction, consider glucarpidase to aid clearance. Non–methotrexate-based regimens may be used if the patient cannot tolerate methotrexate, usually those with
impaired renal function.
If a patient is found to have malignant uveitis, orbital RT may be
considered because of poor penetration of systemic chemotherapy into the uveal fluid. However, there are reports of clearance of ocular lymphoma in patients who were treated with systemic high-dose methotrexate.298 Therefore, for a patient with PCNSL who has
asymptomatic ocular involvement, a reasonable strategy is to delay RT to the globe in order to see if high-dose methotrexate is effective. Referral to a neuro-ophthalmologist or ophthalmologic oncologist for intraocular injection of chemotherapy (category 2B) is also an option.
WBRT may be used in patients who are not candidates for chemotherapy.
For a patient treated with WBRT, consideration of intra-CSF
chemotherapy plus focal spinal RT are treatment options if the lumbar puncture or spinal MRI are positive. Intrathecal chemotherapy options include methotrexate, cytarabine, and rituximab.
Treatment following induction high-dose methotrexate-based therapy depends on disease response.297 Given the rarity of this disease, there are few high-quality studies to inform treatment decision-making. For patients who have a complete or unconfirmed complete response, consolidation therapy options that may be considered include high-dose chemotherapy (carmustine/thiotepa or thiotepa/busulfan/cyclophosphamide [TBC]) with stem cell rescue307,314-320 or low-dose WBRT. However, WBRT in this setting may increase neurotoxicity,356,363 especially in patients older than
60 years.301,324,325 High-dose cytarabine with or without etoposide is also a consolidation treatment option for patients who had a complete response to induction high-dose methotrexate-based therapy (this regimen may also be considered in patients who do not have a complete response).300-302,331
If there is not a complete or unconfirmed complete disease response following induction therapy, it is recommended to pursue another systemic therapy or WBRT in order to rapidly induce a response, diminish
neurologic morbidity, and optimize quality of life. Best supportive care is another option for patients with residual disease following methotrexate-based treatment who are not candidates for other reasonable rescue therapies.
Relapsed or Refractory Disease
Patients should be followed using brain MRI. Imaging of the spine and CSF sampling may be done as clinically indicated for patients with spine disease. If there is ocular involvement, ophthalmologic exams may also be carried out.
For patients who are treated with prior WBRT and ultimately relapse, they may consider further chemotherapy (systemic and/or intrathecal), focal reirradiation, or palliative/best supportive care.
For patients who were initially treated with high-dose methotrexate-based chemotherapy but did not receive WBRT, the decision about whether to use other systemic therapy or proceed to RT at the time of relapse depends on the duration of response to initial chemotherapy. If a patient had experienced a relatively long-term response of one year or more, then treating either with the same (in most cases, high-dose methotrexate-based therapy) or another regimen is reasonable. However, for patients who either have no response or relapsed within a very short time after systemic therapy, recommendations include WBRT, switching to a different chemotherapy regimen, or involved-field RT with or without
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-30 chemotherapy.358 In either case, palliative/best supportive care remains an
option.
High-dose chemotherapy with stem cell rescue may also be considered as treatment for relapsed/refractory disease in patients who did not previously receive this treatment (ie, patients who were treated with high-dose
methotrexate-based therapy or with WBRT) (category 2B). Regardless of primary treatment received, stem cell rescue should only be used for relapsed/refractory disease if there is a complete or partial response to re-induction high-dose chemotherapy.
For patients previously treated with high-dose chemotherapy with stem cell rescue, retreatment may be considered if there was a previous
disease response and if time to relapse was at least one year. For patients who did not have a response to high-dose chemotherapy with stem cell rescue, and the time to relapse was less than one year, treatment options include RT to the whole brain or to the involved field. Regardless of time to relapse, using a different systemic therapy regimen (without stem cell rescue) and best supportive care are also options.
As there is no uniform standard of care for the treatment of refractory or relapsed PCNSL, participation in clinical trials is encouraged.
Primary Spinal Cord Tumors
Spinal tumors are classified according to their anatomic location as extradural, intradural-extramedullary, and intradural-intramedullary.
Extradural tumors are primarily due to metastatic disease and are discussed in the section Metastatic Spinal Tumors. This section focuses on intradural primary spinal tumors.
Primary spinal cord tumors are a histologically diverse set of diseases that represent 2% to 4% of all primary CNS tumors. The overall incidence is 0.74 per 100,000 person-years with a 10-year survival rate of 64%.364
Extramedullary lesions, most commonly benign meningiomas, account for 70% to 80% of spinal cord tumors.365 Astrocytomas (more prevalent in children) and ependymomas (more prevalent in adults) are the most common intramedullary tumors. Clinicians are advised to refer to the corresponding sections in these guidelines for further details regarding these subtypes, as intracranial and spinal lesions are biologically similar.
Individuals with type I neurofibromatosis, type II neurofibromatosis, and von Hippel-Lindau syndrome are predisposed to form, respectively, spinal astrocytomas, spinal peripheral nerve sheath tumors, spinal
ependymomas, and intramedullary hemangioblastomas.
Since 70% of primary spinal cord tumors are low-grade and slow-growing,364 it is common for patients to suffer from pain for months to years before diagnosis. Pain that worsens at night is a classic symptom for intramedullary lesions. Progressive motor weakness occurs in half of the patients, and patients may experience sensory loss with late autonomic dysfunction (incontinence).
Treatment Overview Observation
Many asymptomatic primary tumors of the spinal cord, especially grade I meningiomas and peripheral nerve sheath tumors, follow an indolent course and can be followed by observation without immediate intervention.
Surgery
Surgery is the preferred primary treatment when the tumor is symptomatic and amenable to surgical resection. For lesions that are radiographically well defined, such as ependymoma, WHO grade I astrocytoma,
hemangioblastoma, schwannoma, and WHO grade I meningioma, potentially curative, maximal, safe resection is the goal. En bloc total resection yielded excellent local control rates of more than 90%.366-369