The Diagnosis and Treatment of Primary CNS Lymphoma
An Interdisciplinary Challenge
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Background: Primary central nervous system lymphoma is a diffuse large B-cell lymphoma with exclusive manifestation in the central nervous system (CNS), leptomeninges, and eyes. Its incidence is 0.5 per 100 000 persons per year. Currently, no evidence-based standard of care exists.
Methods: This review is based on pertinent publications (2000–2017) retrieved by a selective search in PubMed.
Results: The clinical and neuroradiological presentation of primary CNS lymphoma is often nonspecific, and histopathological confirmation is obligatory. The disease, if left untreated, leads to death within weeks or months. If the patient’s general condition permits, treatment should consist of a high-dose chemotherapy based on methotrexate (HD-MTX) combined with rituximab and other cytostatic drugs that penetrate the blood–brain barrier. Long-term survival can be achieved in patients under age 70 by adding non-myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HD-AST) to the induction therapy. Clinical trials comparing the efficacy and toxicity of these two treatment strategies are currently underway. Consolidation whole-brain radiotherapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment. Some 30% of patients are refractory to primary treatment, and at least 50% relapse. In patients who are still in good general condition, relapse can be managed with HD-AST. Re-exposure to conventional HD-MTX–based polychemotherapy is another option, if the initial response was durable. The 5-year survival rate of all treated patients is 31%, according to registry data.
Conclusion: Current recommendations for the treatment of primary CNS lymphoma are based on only a small number of prospective clinical trials. Patients with this disease should be treated by interdisciplinary teams in experienced centers, and preferably as part of a controlled trial.
Primary central nervous system lymphomas (PCNSL) are aggressive brain tumors. They are a form of extranodal non-Hodgkin lymphoma (NHL) with exclusive manifestation in the brain, leptomeninges, and spinal cord. Ocular involvement (vitreoretinal lymphoma) is seen in 10% of patients and leptomeningeal tumor spread is found in about 15% of patients (1–3). Only highly proliferative, diffuse large B-cell lymphomas without systemic manifestation are categorized as PCNSL according to the most recent WHO classification (4).
PCNSLs account for 2% to 4% of all primary brain tumors (5). The incidence is about 0.5/100 000 persons per year, with over-65-year-olds being more commonly affected and a rising incidence in this age group. Men are more commonly affected than women (sex ratio 1.35 : 1) (6, 7). Immunosuppression is one of the risk factors for PCNSL; in this situation, PCNSL is typically associated with Epstein–Barr virus (EBV) (8).
Even though the prognosis of PCNSL has significantly improved over the last decades (median survival improved from 2.5 to 26 months) (7) and intensive treatments can achieve long-term remission in young patients, no evidence-based standard of care exists. Treatment recommendations are based on retrospective case series and few larger prospective studies. Among older patients, highly effective treatments are often associated with serious adverse events and the prognosis in this age group is significantly less favorable with median survival rates between 7 to 19 months, regardless of treatment (7, 9).
PCNSL is a rare cancer that is easily overlooked in the differential diagnosis and that is managed differently from other brain tumors. We therefore set out to provide a summary of the currently available evidence on its diagnosis and treatment.
We performed a PubMed search for the years 2000–2017, using the search algorithm: “primary central nervous system lymphoma“ AND/OR “pcnsl“; filters activated: “meta-analysis“, “systematic reviews“, “randomized controlled trial“, “guideline“, “clinical trial“, “abstract“, “humans“, “English“, “German“. The search yielded 1175 results. After evaluating the abstracts (LB), 85 high-quality sources, including some older articles, were selected as relevant for our paper and included in our analysis on a consensus basis with the other authors.
Clinical signs and symptoms
The signs and symptoms of PCNSL are nonspecific and rapidly progressive. Frequently (50–70% of cases), patients present with personality changes and cognitive impairments; in addition, 50% of patients experience focal neurological deficits. Signs and symptoms of increased intracranial pressure are less commonly observed at the time of diagnosis. These include headache, nausea, decreased alertness, seizures or, in case of vitreoretinal involvement, ocular symptoms (vitreous floaters, visual impairment).
Contrast-enhanced cranial magnetic resonance imaging (cMRI) is the most useful imaging modality (2, 10); however, nonspecific findings are not uncommon. It reveals unifocal or, in 35% of patients, multifocal, mainly supratentorial periventricular space-occupying lesions. Contrast enhancement is intense and generally homogeneous, but in 6% to 17% of patients inhomogeneous or missing (<2%) (10, 11). Typically, PCNSLs show significant diffusion restriction due to cell density and appear hypointense on T2-weighted imaging and iso-/hypointense on T1-weighted imaging (10, 11) (Figure 1). Regions of the brain with normal imaging morphology are usually also involved (12).
Imaging alone does not allow reliable discrimination from other malignant brain tumors (CNS metastasis, malignant glioma) or space-occupying inflammatory lesions (multiple sclerosis, sarcoidosis, vasculitis), more rarely of infectious nature (abscess, opportunistic CNS infections and toxoplasma encephalitis, progressive multifocal leukoencephalopathy) (3, 10); therefore, PCNSL should always be included in the differential diagnosis of space-occupying lesions of the brain. Regression of clinical and imaging findings of variable duration (usually weeks to months, rarely longer) is observed under steroid treatment in 40% to 80% of cases (13, 14). The histological picture is dominated by nonspecific inflammatory and reactive changes, while tumor cells are missing (3, 15). Therefore, in patients with suspected PCNSL, steroid treatment should be avoided before biopsies for histology have been taken.
Confirmation of diagnosis
Histopathological confirmation of the diagnosis is essential and should be sought without delay, given the aggressive course of the disease (2). Confirmation is typically achieved by stereotactic serial biopsies which are associated with a low peri-interventional risk for the patient (16). In the case of leptomeningeal or ocular involvement, lymphoma cells can only rarely be detected in the cerebrospinal fluid (CSF) or in the vitreous body aspirate using (immuno)cytological, flow cytometric or molecular biology methods. However, the latter does not allow definite classification of the lymphoma according to the WHO criteria which require immunohistochemistry for confirmation (4). Currently, diagnostic biomarkers (proteins, RNA, DNA) in the cerebrospinal fluid do not play an established role in clinical routine (17).
In case steroid treatment was started before histology samples were obtained, the medication should be tapered off as soon as possible and then biopsies should be taken, because the diagnosis can only be established in 50% to 85% of patients under steroid treatment (15, 18). However, in case of persisting contrast enhancement and a rapidly progressive clinical course or threat to the patient’s life, the biopsy should not necessarily be delayed. In case of inconclusive findings, imaging follow-ups should be performed at close intervals to ensure that patients showing signs of progression undergo a re-biopsy (2).
If a PCNSL is diagnosed, it is recommended to perform a standardized diagnostic evaluation (Figure 1) (19). In addition to spinal tap and ophthalmological examination, patients should undergo whole-body computed tomography (CT), or positron emission tomography CT (PET-CT), to rule out any systemic manifestation which is found in 10% of patients with cerebral lymphoma (20).
Additionally, the guidelines recommend a bone marrow aspiration to rule out bone marrow involvement, even though it does not change the treatment approach and may be dispensable (21).
Since more than 80% of patients with isolated vitreoretinal lymphoma develop CNS involvement over the course of the disease, cMRI and spinal tap should always be performed. In all patients, clinical chemistry testing (liver and kidney function tests), HIV testing, and hepatitis serology should be undertaken (19).
Histopathology and molecular pathophysiology
PCNSLs are mature B-cell lymphomas characterized by the expression of pan B-cell markers (CD20 and CD79a) (Figure 2) . Typically, they have a high proliferation rate (Ki-67 proliferative index >70%). The tumor cells express germinal center markers, predominantly BCL6 and MUM1/IRF4, but no plasma cell markers (CD38, CD138). They show light-chain restriction and express IgM, but not IgG (22). Frequently, B-cell receptor, Toll-like receptor and NF-κB signaling pathways are activated by changes in regulating genes (23–25), stimulating the proliferation of lymphoma cells and preventing their apoptosis.
PCNSLs are highly malignant lymphomas with a median survival of weeks to months if treatment is only symptomatic; however, with anticancer therapy 5-year survival is 31% (6). Old age and poor clinical performance status have the strongest negative impact on prognosis; besides these, increased LDH levels, elevated CSF protein levels, and involvement of deeper brain regions are summarized in the International Extranodal Lymphoma Study Group (IELSG) score (Figure 2) and associated with a poorer prognosis. In low-risk patients, the 2-year survival is 80%, in moderate-risk patients 48%, and in high-risk patients only 15% (26).
Available study data
PCNSL is sensitive to radiation and chemotherapy. Due to the low incidence of PCNSL, it is challenging to conduct large randomized studies. The current treatment recommendations are based on a few prospective treatment studies (Figure 2 and 3, Table). Given the heterogeneity of these studies, the small sample sizes, and the different endpoints, these studies are difficult to compare.
A subgroup analysis of the largest PCNSL study conducted so far indicated that tumor resection may improve progression-free survival in patients with single PCNSL lesions (27). However, involvement of deeper brain structures, which is a contraindication for resection, is associated with a poorer prognosis and this was not taken into account. Thus, there is no established role of resection in the management of infiltrative PCNSL (2, 28).
The first-line treatment for PCNSL is systemic chemotherapy. Chemotherapy regimens for the treatment of systemic lymphoma are ineffective in PCNSL as these drugs do not readily pass the blood–brain barrier. Based on the currently available data, the following treatment strategies can be recommended:
High-dose methotrexate (HD-MTX; ≥ 3 g/m² body surface, given as a 4-hour IV infusion) is the most effective single active agent and a key component of all combination regimens (2). Outside of clinical trials and without subsequent consolidation, HD-MTX–based polychemotherapy should be administered over at least 6 cycles together with adequate supportive care (hydration, urine alkalinization, leucovorin rescue, and monitoring of MTX levels) (2).
HD-MTX monotherapy achieves complete remissions in only 30% to 40% of patients and is comparatively well tolerated (moderate toxicity in <10% of cases) (29, 30). Adverse events include renal failure, blood count abnormalities, liver function abnormalities, pneumonitis, mucositis, and, in the long term, clinically relevant leukoencephalopathy, especially in older patients (31).
Combination chemotherapies with other cytostatic agents capable of crossing the blood–brain barrier, for example high-dose cytarabine (HD-AraC), thiotepa or ifosfamide, increase the overall response rate along with increased toxicity, while treatment-associated mortality remains unchanged (30, 32).
Treatment response to HD-MTX/AraC was further improved by adding rituximab, an anti-CD20 antibody, to the regimen; however, the effect was only significant if thiotepa (MATRIX protocol, [eTable 2]) was also added (overall response rate: 53% versus 74% versus 86%). Even though hematologic adverse events occurred more commonly in the intensified treatment arm, no significant differences were found with regard to the rate of serious infectious complications and treatment-associated mortality (33). However, a point of criticism is that only 54% of all patients reached the consolidation phase of the study. This was due to inadequate stem cell collection, prolonged adverse events, and neurological deterioration despite tumor regression, among others (34). The most commonly used protocols and currently recruiting studies are listed in the eSupplement and in eTable 1 and eTable 2.
In the majority of patients, percutaneous fractionated whole-brain radiotherapy leads to fast and usually complete remission; however, recurrences occur early. Median survival is only 12 to 18 months (35). With combined chemoradiotherapy, tumor control can be significantly improved and—in prospective studies—median survival times of 31 to 90 months have been achieved (30, 36–40, e1). However, neurotoxicity occurring over a time course of months to years has emerged as a very serious problem. Affected patients show marked leukoencephalopathy, leading to cortical/subcortical atrophy and, in some cases, to severe cognitive deficits, gait abnormalities, incontinence, and need for nursing care (e2). The 5-year incidence of overt neurotoxicity is 12% to 65%; it is associated with mortality rates of 16% to 66% and primarily affects patients aged >60 years (30, 36–40, e1, e3–5). Delayed neurotoxicity is also observed in patients receiving intensive chemotherapy (e1, e6); however, extensive neurocognitive analyses showed that, especially irradiation, has a negative impact on cognitive performance and quality of life (e5, e7).
In the so far largest randomized phase III study, consolidation whole-brain radiotherapy did not improve overall survival compared to HD-MTX–based chemotherapy (e1). Thus, it should not be not be performed on a routine basis (1, 2).
Strategies to maintain long-term remission
Several strategies to intensify conventional chemotherapy have been evaluated in prospective studies, in some cases with promising results; they may be equally effective compared to chemoradiotherapy (34, e3).
Non-myeloablative consolidation chemotherapy achieved an efficacy comparable to that of chemoradiotherapy (median overall survival >59 months) (e8). Likewise, a HD-MTX–based polychemotherapy combined with intensive intraventricular chemotherapy via a reservoir (“Bonn protocol“, [eTable 2]) achieved long recurrence-free survival (>80 months), especially in younger patients (e9, e10). However, the regimen did not find widespread adoption due to the high rate of reservoir infections (19%). Without intraventricular chemotherapy, these good results could not be reproduced (e11). No controlled studies have yet been conducted to further explore the role of intrathecal treatment.
Lymphoma cells persisting in the CNS are reached by myeloablative, high-dose consolidation chemotherapy with autologous stem cell transplantation (HD-ASCT) as this strategy achieves very high drug levels in the CNS. The efficacy of HD-ASCT was evaluated in several phase II studies on younger patients without major comorbidities. In this selected patient population, HD-ASCT was a highly effective treatment option with curative potential (overall response 80–96%, median overall survival 64–104 months) (e12–14). More recent data indicate that HD-ASCT provides equal efficacy to consolidation whole-brain radiotherapy, but is associated with less neurotoxic adverse events (34). In prospective studies, HD-ASCT has been associated with a mortality of 0% to 12% (e13, e14), but, because of its toxicity, especially older patients are often not eligible for it. Thus, ongoing studies are evaluating an age-adapted HD-ASCT for patients aged >65 years (eTable 1). The value of the various consolidation strategies (non-myeloablative versus myeloablative) is being explored in randomized trials in Germany too (28, e15) (eTable 1). Until solid data have become available, no reliable conclusions can be drawn.
Management of recurrence
About one third of all PCNSL patients are primarily refractory to treatment and at least half of the patients with initial response to treatment experience a relapse (e16, e17). So far, no standard of care has been established for this situation; the majority of treatment recommendations are based on retrospective and a few prospective studies (28).
According to reviews, the overall response rates of recurrences range from 10% to 85%; however, remissions are short-lived (median progression-free survival [PFS] approx. three months) (28). In patients with long-lasting remission after initial treatment (median 24–26 months), re-exposure to HD-MTX–containing chemotherapy proved effective with a high response rate (85–91%) and a median survival of 41 to 62 months (e18, e19). For patients aged <65 years, promising data on HD-ASCT are available from the Freiburg ZNS-NHL study (2-year survival: 56%) which is now established in many German centers (e20) (eTable 2). With HD-ASCT, long-term remission was achieved even in cases with no response to HD-MTX–based induction (e20, e21). Other published regimens to treat recurrence include pemetrexed (e22), topotecan (e23), temozolomide in combination with rituximab (e24), the PCV regimen (procarbazine, CCNU, and vincristine) (e25), and rituximab and ifosfamide plus etoposide (e26). With response rates of 74% to 79% and a median survival of 10 to 16 months, whole-brain radiotherapy for recurrence is an effective treatment option (e27, e28). However, it should be used late in the course of the disease, if possible, as it is associated with a high rate of severe neurotoxic adverse events among patients with prior intensive chemotherapy (e28).
New active substances and immunotherapies
In refractory patients with multiple previous therapies, substances, such as temsirolimus (e29), lenalidomide (e30) and ibrutinib (e31), which interfere with B-cell receptor signaling and thus have an effect on proliferation and survival of lymphoma cells, and so-called checkpoint inhibitors (e32), which modulate T cell–mediated immune response, show activity, but are associated with significant toxicity in some patients. Should their efficacy and tolerability be confirmed in the currently recruiting studies, new treatment options for patients with PCNSL may become available.
Special patient populations
Management of older patients
The treatment of elderly patients is limited by comorbidities and the increased risk of treatment-related side effects. HD-MTX–based polychemotherapy is safe and effective as long as renal function is taken into account (dose reduction if creatinine clearance <100 mL/min) (29). Complete remissions are achieved in 36% to 60% of patients; however, median overall survival is only 14 to 31 months (e6, e33, e34) (Table). In the German-speaking countries, many centers have adopted the PRIMAIN protocol (rituximab, methotrexate, procarbazine, [eTable 2]) which was evaluated in a large, randomized, multicenter study (e33).
If HD-MTX is contraindicated, patients can be treated with temozolomide for which an overall response of 47% and overall survival of 21 months was found in a retrospective analysis (e35). Given the high risk of neurotoxic adverse events, whole-brain radiotherapy should only be used if other treatment alternatives are not available or have been exhausted (2).
See the eSupplement for the sections “Management of vitreoretinal lymphoma“ and “Management of immunocompromised patients“.
The follow-up should be based on neurological examination and cranial magnetic resonance imaging; other investigations are only recommended if specific abnormalities are suspected. The requirements for complete remission include the complete disappearance of contrast-enhancing lesions, the absence of malignant cells in the cerebrospinal fluid, and the complete disappearance of previous ocular involvement. All patients should undergo imaging and clinical follow-up examinations at 3-month intervals for 2 years, then at 6-month intervals for 3 years and finally at 1-year intervals for 5 years (2). Additional checks should be performed to assess any suspected abnormalities. With regard to potential neurotoxic late complications, it is advisable that patients receive follow-up care in a neuro-oncological center.
Because of its specific biological and clinical features, the diagnosis and treatment of PCNSL is challenging and requires an interdisciplinary approach. Thus, it is crucial that patients are preferably treated in centers experienced in the management of the disease and in the setting of a clinical study.
Conflict of interest statement
Prof. Illerhaus has received consultancy fees from Riemser. He has received fees for conference participation and reimbursement of travel and accommodation expenses from Riemser and Roche. He has been contracted and received fees for the conduction of clinical trials from Riemser.
Dr. Korfel has received consultancy fees and fees for preparing continuing medical education events from PIQUR, Mundipharma, and Riemser.
Prof. Schlegel has received lecture fees for Neuro-update from medupdate.
Prof. Dreyling has received consultancy fees from Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche, and Sandoz. He has received fees for preparing continuing medical education events from Bayer, Celgene, Gilead, Janssen, and Roche. He has received financial support from Celegne, Janssen, Mundipharma, and Roche for a research project that he initiated.
Dr. von Baumgarten and Prof. Deckert declare that no conflict of interest exists.
Manuscript received on 7 September 2017; revised version accepted on 6 March 2018
Translated from the original German by Ralf Thoene, M.D.
PD Dr. med. Louisa von Baumgarten
Neurologische Klinik und Poliklinik
Klinikum der Universität München
81377 München, Germany
For eReferences please refer to:
a long-term follow-up study. Ann Oncol 2012; 23: 2670–5.
PD Dr. med. Louisa von Baumgarten
Department of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center/Tumor Center Eva-Mayr-Stih, Klinikum Stuttgart: Prof. Dr. med. Gerald Illerhaus
Medical Department, Division of Oncology and Hematology, Charité – Universitätsmedizin Berlin: PD Dr. med. Agnieszka Korfel
Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum: Prof. Dr. med. Uwe Schlegel
Department of Neuropathology, University Hospital Cologne: Prof. Dr. med. Martina Deckert
Department of Internal Medicine III, Hospital of the University of Munich (LMU):
Prof. Dr. med. Martin Dreyling
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