Rare central nervous system lymphomas.

INTRODUCTION

Central nervous system (CNS) lymphomas are rare haematological malignancies. Primary CNS lymphomas (PCNSL) account for ~4% of all brain tumours and are formally classified by the World Health Organisation as diffuse large B‐cell lymphoma (DLBCL) isolated to the CNS (brain, spinal cord, cranial nerves, meninges, and/or eyes) without systemic involvement. 1 , 2 Secondary CNS lymphomas (SCNSL) are also typically DLBCL. These can present as synchronous systemic and CNS disease (at initial diagnosis or at recurrence) or as an isolated CNS relapse following previous treatment for systemic DLBCL.

The biological mechanisms underlying the tropism of DLBCL for the CNS are not fully understood. 3 , 4 Despite this, management strategies for primary and secondary CNS‐DLBCLs are relatively well characterised within the literature. Current consensus involves treating primary CNS‐DLBCL with induction chemoimmunotherapy incorporating a high‐dose methotrexate (HD‐MTX) backbone. 5 , 6 For suitably fit patients, remission induction treatment is followed by consolidation with high‐dose thiotepa‐based autologous stem cell transplantation (HDT‐ASCT) or whole brain radiotherapy (WBRT). 6 , 7 More recently, the MARIETTA study (ClinicalTrials.gov Identifier: NCT02329080 ) for patients with secondary CNS‐DLBCL described similarly intensive CNS‐directed chemotherapy and consolidation ASCT as an effective approach for this group of patients. 8

By comparison to DLBCL, other histopathological subtypes of CNS lymphoma are rare, with the published literature dominated by observational studies and isolated case reports describing these pathological entities. There is a lack of consensus on how to approach the diagnosis and management of this heterogeneous group of rare CNS lymphomas.

We undertook a literature review and narrative synthesis of the published data on rare CNS lymphomas, with the intention to provide a concise summary of the incidence, diagnostic features and challenges, management options, and anticipated clinical outcomes before suggesting a pragmatic clinical approach to these lymphoma entities. In order to address uncertainties presented by inconsistent staging procedures and to encompass a breadth of clinical scenarios, we included both rare primary CNS lymphomas and rare secondary CNS lymphomas, where the CNS presentation is described as the dominant clinical problem. Importantly, for many of these rare lymphoma subtypes, there is a paucity of high‐quality evidence informing clinical management strategies and we recognise the risk of positive reporting bias. As such, definitive conclusions on optimal treatment approaches are not possible and, hence, interpretation of published data also reflects consensus and clinical experience of the authors of this article.

DIAGNOSTIC APPROACHES AND CHALLENGES FOR CNS LYMPHOMAS

Cytological evaluation of cerebrospinal fluid (CSF) is a relatively straightforward diagnostic procedure but provides low sensitivity for diagnosis and typically does not permit accurate subclassification of CNS lymphomas. The combined sensitivity of CSF cytology, flow cytometry, CSF lactate dehydrogenase (LDH) isozyme 5, β2‐microglobulin, and immunoglobulin heavy (IGH) chain rearrangement studies (for B‐cell lymphomas) is superior to CSF cytology alone but even this integrated approach provides only moderate specificity. 9 More recently, there has been increased interest in the use of circulating tumour DNA (ctDNA) to aid diagnosis across lymphoma subtypes and improve the sensitivity of detecting disease recurrence. 10 , 11 A specific example is the diagnostic utility of the myeloid differentiation primary response 88 ( MYD88 ) L265P mutation given its presence in >80% of PCNSL cases. Indeed, one small study detected this mutation in the CSF ctDNA of 20/26 patients with CNS lymphoma. 12 Importantly, ctDNA analysis does not distinguish between DLBCL and lymphoplasmacytic histological subtypes. 11 Nevertheless, ctDNA (from blood and/or CSF) holds much promise for the diagnosis of CNS lymphoma and is likely to provide additional contributions to the differential diagnoses of less common CNS lymphoma entities.

The current diagnostic ‘gold standard’ remains histopathological diagnosis following biopsy of a CNS lesion. Nonetheless, biopsy poses a number of challenges, namely the procedural risks together with the diagnostic challenges presented by typically tiny fragments of tumour tissue. It is also well recognised that administration of corticosteroids prior to biopsy can cause rapid apoptosis and/or tissue necrosis, resulting in non‐diagnostic biopsies. Dural‐based lesions, although more easily accessible, can pose diagnostic difficulty due to crush artefact caused by dense fibrous tissue. As a diagnostic gold standard, detailed evaluation of the tissue biopsy using a wide range of immunohistochemical markers (supplemented where feasible by molecular diagnostics, fluorescent in situ hybridisation [FISH] studies and cytogenetics) and review by experienced haematopathologists is essential.

Intraoperative smear for any primary CNS space occupying lesion is a common initial procedure undertaken in many neurosurgical units. The cytological features of lymphoma are similar to those seen from other anatomical sites with a population of non‐cohesive cells and presence of numerous ‘naked’ nuclei as a result of loss of delicate cytoplasm from these lymphoid cells (Figure 1A ). Sometimes, the presence of numerous reactive astrocytes/reactive glial cells in the background can lead to misdiagnosis of a glial tumour (Figure 1B ). 13 The paucity of tumour cells within a non‐neoplastic background may be easily missed on cytology preparations (Figure 1C ) resulting in diagnostic delays with potential clinical sequelae.

SUBTYPES OF RARE CNS LYMPHOMA

Histopathological classification of rarer CNS lymphomas essentially follows the same diagnostic algorithms as their systemic counterparts. Figure 2 illustrates the essential histopathological delineation, focussing on the most frequent subtypes within this heterogeneous group of non‐DLBCL lymphomas that can present with dominant CNS disease.

Hodgkin lymphoma

Primary and secondary CNS involvement in Hodgkin lymphoma (CNS‐HL) occurs in an estimated ≤ 0.02%–0.5% of HL cases. 14 , 15 , 16 Secondary disease is more common than primary involvement. 17 The typical age at presentation of CNS‐HL appears to be 40–60 years. A large international multicentre case series, describing details of primary and secondary CNS‐HL, reported a median age of onset of 45 years. 17 However, other studies report older median ages for patients with only primary CNS‐HL. 18 For those with secondary involvement, CNS‐HL lesions presented at a median time of 11.7 months following initial diagnosis. 17

CNS‐HL commonly presents as parenchymal disease, although dural‐based lesions have been reported. 19 , 20 Most intracranial lesions are supratentorial but infratentorial (including cerebellar) lesions have also been described. 19 Similar to systemic HL, CNS‐HL may be associated with immunosuppressive states (including human immunodeficiency virus infection) and/or Epstein–Barr virus infection. 21 , 22 , 23 Due to limited data, it is difficult to conclude whether either of these virus co‐factors are associated with an increased risk of CNS‐HL. 17

The histopathological diagnosis of CNS‐HL is identical to that of systemic HL and reliant on identification of Hodgkin and Reed–Sternberg cells (expressing CD15, CD30, and multiple myeloma oncogene 1 [MUM1] with variable expression of B‐cell antigens) on a typical non‐neoplastic background comprising small lymphocytes, plasma cells, macrophages, and eosinophils. 18 , 24 In CNS‐HL, nodular sclerosing and mixed cellularity subtypes tend to predominate. 17 , 19 , 25

For patients with primary CNS‐HL, surgical resection followed by radiotherapy (RT) is commonly reported to result in favourable outcomes in case reports. A case series of 16 CNS‐HL patients reported that 12/16 (75%) were treated with surgical resection followed by RT; most received WBRT, whilst the remainder received focal RT to specific disease sites. 18 There was no evidence of residual or recurrent CNS‐HL in 90% of these patients with an average follow up time of 28 months. Indeed, one patient had no evidence of disease recurrence 10 years after local RT. 18 Three of the 16 patients received chemotherapy (cyclophosphamide, vincristine, procarbazine and prednisone or MTX) in addition to surgery and RT with no evidence of disease after a median follow up of 14 months. Favourable outcomes have also been described in more recent case reports of patients treated with similar strategies. 26 , 27

Reported treatment approaches for secondary CNS‐HL are similar to those for primary CNS‐HL, with a greater tendency to use chemotherapy (with or without RT). Immune checkpoint inhibitors, particularly programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) inhibitors, have an established role in the clinical management of relapsed and refractory systemic HL, raising the possibility of their utility in CNS‐HL. 28 Isolated case reports suggest that conventional HL chemotherapy protocols (including COPP/ABV [cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin, and vinblastine], ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] and ICE [ifosfamide, carboplatin, and etoposide]) in addition to intrathecal MTX (IT‐MTX) can confer complete remission for many patients. 17 , 29 , 30 However, further follow up in larger series is required to provide confidence in the rate and durability of the reported outcomes.

Non‐Hodgkin lymphoma

Low‐grade B‐cell lymphomas

Marginal zone lymphoma

Amongst the different subtypes of low‐grade lymphoma presenting with CNS disease, marginal zone lymphoma (CNS‐MZL) is considered to be the commonest. 31 A summary of recently published retrospective analyses of CNS‐MZL cases is presented in Table 1 , most of which focus on dural involvement by MZL.

By contrast to CNS‐DLBCL, which tends to present more commonly in males, a recent systematic review of the literature found that 77% of reported cases of CNS‐MZL affect female patients. 31 , 32 , 33 The estimated median age at diagnosis was 55 years (range: 18–78), considerably younger compared to patients with CNS‐DLBCL. 31 More recent retrospective analyses have suggested that median age at diagnosis may be younger in patients with primary CNS‐MZL (51 years) compared to those with secondary CNS disease (62 years). 34

Systemic MZL, particularly extra‐nodal subtypes outside the CNS, are often associated with chronic infectious or inflammatory processes (e.g. Helicobacter pylori infection in the stomach, Hashimoto's thyroiditis, and Sjögren's syndrome). Case reports have described instances of patients with CNS‐MZL who have these associated conditions, 35 although a causal link has not been established. One hypothesis is that CNS‐MZL may be a direct consequence of aseptic meningitis (caused by enteroviruses, herpes simplex virus‐2, autoimmune phenomena, amongst others) or trauma, which induces lymphocytic recruitment to the leptomeninges. 36 However, evidence to substantiate this hypothesis has not been forthcoming.

Extra‐nodal MZLs of the CNS predominantly present as dural‐based lesions, although parenchymal masses are also recognised, particularly in the context of secondary disease. 31 , 34 Tumour margins are often well defined on magnetic resonance imaging (MRI). Dural masses commonly display variable signal intensity on diffusion‐weighted MR sequences in relation to adjacent white matter. 37

Given their anatomical predilection for the dura, CNS‐MZL are commonly mistaken for meningiomas on initial diagnostic imaging. 38 , 39 , 40 However, the differential diagnosis for dural‐based lesions is wide, encompassing subdural haematomas, other tumours (e.g. dural metastases, glioma, leiomyosarcoma, plasmacytoma, schwannoma), and inflammatory lesions (e.g. pseudotumours, vasculitides, neurosarcoidosis). 31 , 41 As such, biopsy is required for a conclusive diagnosis particularly if there is no history of systemic MZL. It should be noted that composite meningiomas and CNS‐MZL have been described, with evidence of MZL invasion of the meningioma, 42 further underscoring the importance of histopathological diagnosis of dural‐based lesions.

Histopathological diagnosis of low‐grade B‐cell CNS lymphomas is often more challenging than for DLBCL, requiring more extensive immunohistochemistry panels for accurate sub‐classification. This is reflected in the largest series reported to date where a large majority (62.5%) were unclassifiable due to lack of adequate tissue. 43 Perivascular patterns of infiltration, well described in primary CNS‐DLBCL, are also observed in low‐grade disease (Figure 3 ).

Similar to their systemic counterparts, marginal zone B cells express pan B‐cell markers (CD20, CD79A, CD19, CD22 and paired box 5 [PAX5]) and are typically CD5 and CD10 negative. 44 Expression of immune receptor translocation‐associated protein 1 (IRTA1) has been reported as a useful marker for differentiating MZL from CD10‐negative follicular lymphoma. 45 MZL outside the CNS frequently features IGH locus gene translocations, resulting in chimeric genes that can be identified within neoplastic B cells via FISH. 46 , 47 , 48 By comparison, one of the largest studies on CNS‐MZL reported trisomy 3 as a common genetic abnormality in primary CNS‐MZL rather than IGH translocation. 41

Active observation only (often referred to as ‘watch and wait’) may be appropriate for a number of years in asymptomatic patients with primary dural CNS‐MZL. 40 Symptomatic primary disease has often been managed using surgical resection with or without RT. 44 , 49 , 50 Complete surgical resection may be feasible for single discrete lesions, particularly if dural‐based, mindful of surgical risks and recognising that RT (focal or WBRT) can be highly effective. Moderate total radiation doses (e.g. 20–24 Gy) can achieve good responses whilst minimising neurotoxicity. 51 Reported survival outcomes for patients treated with resection and/or RT are encouraging. In one study of 26 patients with primary dural CNS‐MZL (of whom 54% were treated with both RT and surgery, and 23% with RT alone), 3‐year progression‐free survival (PFS) was 89% (95% confidence interval [CI] 0.64–0.97) and all patients were alive at last follow‐up. 44 These data are supported by a more recent report that described 2‐year overall survival (OS) rates of 100%, although this included a small number of patients treated with chemotherapy (BR [bendamustine and rituximab], R‐CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone] or rituximab +/− MTX) in addition to those who received surgery and RT. 34

Treatment approaches for parenchymal disease, CNS‐MZL at relapse, or those with concurrent systemic disease are less well characterised in the literature. By contrast to published patterns of care for primary dural CNS‐MZL, treatment approaches for secondary CNS‐MZL have commonly included pharmacological therapies with or without surgical intervention. 34 , 44 A recent case series of secondary CNS‐MZL reported data from seven cases treated heterogeneously including RT, IT therapy (MTX, rituximab), combination systemic chemotherapy (CHOP, CVP [cyclophosphamide, vincristine, and prednisolone]), systemic high‐dose MTX, and intravenous rituximab in various combinations and schedules. 52 Five out of seven patients achieved complete responses to treatment for ≥10 months. 52 Earlier published studies on secondary CNS‐MZL describe a largely indolent clinical course with many patients free from disease progression for several years after treatment. 52 , 53 , 54 However, a more recent observational study has highlighted inferior 2‐year OS rates for secondary CNS‐MZL (58%) compared to primary CNS disease (100%), underscoring the need for more data on this rare lymphoma subtype. 34

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a distinct clinicopathological entity with heterogeneous clinical behaviour. A proportion of patients undergo an aggressive disease course, whilst the vast majority experience disease recurrence after a period of remission following therapy. 55 Most cases of CNS disease involving MCL occur in the context of relapsed disease with an estimated reported frequency at relapse of 4.1%–7.8%. 56 , 57 , 58 Typically, CNS‐MCL occurs as a relatively late event following initial therapy. Estimated median times from first diagnosis to CNS‐MCL range from 12 to 61 months. 56 , 59 , 60

Both parenchymal and leptomeningeal CNS‐MCL have been reported. 56 , 59 , 61 Risk factors for developing CNS relapse include blastoid histology, 56 , 58 raised serum LDH and high proliferative index. 56 , 62 Although CNS prophylaxis is not routinely recommended, some experts suggest this may be considered for patients with risk factors for CNS relapse. 55 , 57 , 62 However it should be recognised that younger patients typically receive high‐dose cytarabine (HD‐AraC), integral to many first‐line treatment protocols. 55 , 63

CNS‐MCL, similar to its systemic counterpart, consists of a CD5 + B‐cell population expressing Cyclin D1 (encoded by the CCND1 gene) as demonstrated in Figure 4A . 64 FISH analysis for t (11;14)(q13;q32) involving the IGH and CCND1 genes is recommended, particularly when morphology or immunophenotype is atypical (Figure 4B ). 65

Treatment approaches and clinical outcomes described in the literature have evolved over time. Earlier studies reported very poor outcomes, with a median survival in the order of 3–4 months from diagnosis of CNS relapse. 56 , 57 An international retrospective study of 57 patients with CNS‐MCL from fourteen different centres reported that 72% of patients received chemotherapy alone (HD‐MTX and/or AraC alone, or as part of R hyper‐CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone, MTX, and AraC] or maxi‐CHOP). 57 The remainder received chemotherapy and RT, RT alone or palliative care. IT administration of chemotherapy also featured commonly within reported regimens. A proportion of patients underwent ASCT as consolidation using carmustine (BCNU)‐etoposide‐AraC‐melphalan (BEAM) or bulsulfan‐melphalan conditioning. 57 In the context of CNS‐MCL, superior OS rates (hazard ratio [HR] for death 0.42, 95% CI 0.19–0.91, p = 0.03) and sustained remission for >12 months were observed in patients consolidated with ASCT compared to non‐transplanted patients, although transplanted patients were generally younger with a superior baseline performance status. 57 Based on these limited data, a reasonable treatment option for suitably fit patients with CNS‐MCL may include consolidation with high‐dose CNS‐penetrant chemotherapy (e.g. thiotepa, BCNU, or busulfan) and ASCT, extrapolating from experience with CNS‐DLBCL. However, it must be acknowledged that ASCT (typically with BEAM conditioning) is an established consolidative strategy in first response for many patients aged <65 years with systemic MCL. 55

More recently the Bruton's tyrosine kinase inhibitor (BTKi), ibrutinib, approved for the treatment of relapsed/refractory MCL, 66 has been explored as a possible treatment option for CNS‐MCL given its ability to cross the blood–brain barrier. 61 A recent summary of five cases treated with ibrutinib (560 mg once daily) alone, or in combination with other chemotherapeutic agents and/or steroids, described objective clinical responses in all patients within 2 weeks. However, the durability of response was short (median duration of response: 4 months). 67 Other data indicate more encouraging outcomes with sustained complete response rates for up to 2 years. 61 , 68 Although these data are preliminary, it appears that ibrutinib may be an effective and well‐tolerated treatment alternative for CNS‐MCL, acknowledging the lack of durability in most cases. 67

Follicular lymphoma

Descriptions of primary and secondary CNS follicular lymphomas (CNS‐FL) are scarce within the literature. In common with the other rare CNS lymphomas described in this review, case reports dominate the literature on CNS‐FL.

Both primary and secondary CNS‐FL 69 , 70 , 71 , 72 , 73 have been described, although transformation into high‐grade B‐cell non‐Hodgkin lymphoma (B‐NHL) must always be considered in the context of secondary CNS disease. 70 , 71 Similar to CNS‐MZL, most cases of low‐grade CNS‐FL describe a dural pattern of involvement, such that they may be mistaken for meningiomas. 37 , 74 , 75 However, FLs represent a low proportion of dural lymphomas overall; these are predominantly CNS‐MZL. 76 , 77

Histopathologically, CNS‐FL can manifest as a nodular or diffuse pattern and show a mixed population of centrocytes and centroblasts that typically co‐express CD10 and BCL6. BCL2 overexpression, the hallmark of FL, is seen commonly in low‐grade disease or can at times be negative. 78

Treatment approaches adopted for CNS‐FL have typically included surgical resection followed by chemotherapy and/or RT. 75 By corollary to early‐stage low‐grade systemic FL, often treated with RT alone, isolated dural tumours have been treated with RT as a single modality, associated with good survival outcomes. 69 , 79 Transformation of FL into high‐grade B‐NHL of the CNS is usually treated using existing CNS‐DLBCL protocols. For patients with concurrent CNS and systemic involvement by low‐grade FL, intravenous (with/without IT) chemotherapy has been associated with favourable clinical outcomes. Regimens reported in the literature include various combinations of HD‐MTX, IT‐MTX, AraC, rituximab, CHOP, and CVP with or without RT. 70 , 72 , 75 Anthracycline‐containing regimens alternating with MTX have been employed to target both systemic and CNS disease respectively. 72 , 80 However, it should be recognised that, given the typically low proliferation rate of low‐grade FL cells, anti‐metabolite chemotherapy agents such as MTX and AraC may be less effective than for CNS‐DLBCL. Bendamustine, commonly used for systemic FL, is a potentially effective option due to its ability to cross the blood–brain barrier, although this is not frequently described as a therapy in the published literature for CNS‐FL. 81 Similarly, combination lenalidomide (a CNS‐penetrating agent) and rituximab, already used in relapsed and refractory systemic FL, may be a reasonable option in secondary CNS‐FL. 82 , 83 Some clinicians report using maintenance rituximab due to superior PFS rates observed in systemic FL. 80 , 84 Of the few cases of concurrent systemic and CNS‐FL reported in the literature, most patients achieved clinical remission. 70 , 72 , 75 , 80

Dural lymphomas in particular have a good prognosis with complete surgical resection. 79 A database analysis of >4000 patients with primary CNS lymphoma diagnosed between 1998 and 2014 suggest that the 5‐year OS rate for patients with primary CNS‐FL is significantly higher compared to those with primary CNS‐DLBCL (66% [95% CI 54%–76%] vs. 30% [95% CI 28%–32%]). This was confirmed in multivariate analysis, adjusted for age and treatment type (HR 0.32, 95% CI 0.23–0.46, p < 0.001 – compared to DLBCL), 85 although survival outcomes for CNS‐DLBCL have improved in recent years. 5 , 86

Lymphoplasmacytic lymphoma (Waldenström macroglobulinaemia)

Lymphoplasmacytic lymphoma (LPL) or Waldenström macroglobulinaemia (WM) is a low‐grade lymphoproliferative disorder, resulting in the production of a monoclonal immunoglobulin M (IgM) paraprotein by lymphoplasmacytoid cells that infiltrate the bone marrow. 87 Although neurological signs and symptoms may occur in the context of LPL, they are not always the direct result of neoplastic infiltration into the CNS. The spectrum of neurological features in LPL/WM includes: IgM neuropathy: a demyelinating neuropathy caused by monoclonal IgM activity against myelin associated glycoprotein, resulting in proprioceptive and sensory dysfunction. 88 Hyperviscosity syndrome: high levels of IgM paraprotein in the plasma resulting in increased viscosity, manifesting as headaches, retinopathy, seizures, and altered conscious level. 89 Transformation to CNS high‐grade B‐NHL: typically a subacute presentation akin to PCNSL and treated with CNS‐DLBCL protocols. Bing–Neel syndrome (BNS): neoplastic lymphoplasmacytic cells directly invade the blood–brain barrier, often with leptomeningeal involvement, causing a spectrum of central neurological phenomena. Primary CNS‐LPL (PCNS‐LPL): characterised by lymphoplasmacytoid cells within the CNS without evidence of LPL in the bone marrow.

IgM neuropathy, hyperviscosity syndrome, and transformation to high‐grade lymphoma are outside the scope of this review. Thus, we have focussed on BNS and PCNS‐LPL.

Bing–Neel syndrome

Bing–Neel syndrome may be the first presentation of LPL or, more commonly, appear later in the disease course. Estimates of median time from LPL diagnosis to the development of BNS are around 3–4 years. 90 , 91

Contrast‐enhanced MRI of the neuroaxis commonly reveals leptomeningeal enhancement in ~80% of cases of BNS but is not pathognomonic. 92 Mass lesions within the brain parenchyma are less common, but are recognised in the context of BNS. 93 , 94 Particularly where mass lesions are present, it is important to exclude histopathological transformation to an aggressive B‐cell lymphoma.

Diagnosis of BNS requires the demonstration of clonal lymphoplasmacytoid cells within CSF and/or tissue biopsy of a mass within the CNS demonstrating features of LPL. 93 Confirmation of LPL infiltration in the bone marrow is also helpful in securing the diagnosis. 92 Microscopically, lymphoplasmacytoid cells typically display characteristic intranuclear Ig inclusions (Dutcher bodies) (Figure 5 ). 89 They express pan‐B‐cell antigens (CD19, CD20, CD22, CD79a and PAX5), whilst being negative for CD5 and CD10. The plasma cells in LPL are CD138 positive as well as CD19, CD45 and PAX5 positive, unlike in plasma cell myeloma where the cells do not express CD45 or PAX5. 89 Elevated IgM within the CSF and serum may also be observed in addition to a monoclonal IgM paraprotein on serum electrophoresis. 92 Molecular analysis of cells within the CSF often reveals IGH gene rearrangements and MYD88 mutations (L256P). Importantly, this must be correlated with clinical and radiological features as MYD88 mutations are common in patients with primary CNS‐DLBCL and are also described in MCL and chronic lymphocytic leukaemia. 91 , 92 , 95

Similar to other low‐grade B‐NHL subtypes, asymptomatic BNS may not require treatment and close monitoring is considered an acceptable management approach. 92 Historically, conventional chemotherapy, often empirically adopted from PCNSL protocols, has been employed for symptomatic BNS, e.g. HD‐AraC and HD‐MTX. However, the toxicity of these anti‐metabolite chemotherapy agents may not be warranted, particularly given the lack of strong rationale for the treatment of indolent B‐NHL with low proliferative rates. Purine‐analogue and related agents (e.g. fludarabine, bendamustine), with established efficacy for systemic LPL, have also been employed for BNS often in combination with rituximab, but these regimens can be potently immunosuppressive and are usually reserved for relapsed disease in fitter patients. 92 , 96 , 97 One study estimated an overall response rate of 70% after treatment with chemoimmunotherapy with an OS of 71% at 5 years, 90 although treatment approaches were very heterogeneous and no clear conclusions could be made regarding the relative efficacy of the different management strategies. Some clinicians propose that ASCT may prolong remission after first‐line treatment for BNS. A recent review found that of 14 patients who underwent ASCT (with either BEAM or thiotepa‐based conditioning regimens), 13 remained in remission after a median follow up of 35 months. 98

More recently, ibrutinib, licensed for the treatment of systemic LPL, has emerged as a potential treatment option for BNS, owing to its efficacy, oral administration and ability to penetrate the blood–brain barrier. 99 , 100 , 101 , 102 In one study, 2‐year event‐free survival (measured from the time of treatment initiation to disease progression, treatment toxicity or death from any cause) was 80%. 92 Although second‐generation BTKi have shown promise in treating systemic LPL, 103 we found no reported data on these agents in the context of BNS.

Primary CNS‐LPL

Distinct from BNS is PCNS‐LPL, where lymphoplasmacytoid cells are present in the CNS but not elsewhere systemically, including the bone marrow. 104 Combined morphological and immunophenotypic assessments have improved the ability to exclude lymphoplasmacytic infiltration into the bone marrow. 105 More recently, this has been enhanced with the development of specific polymerase chain reaction assays used to detect MYD88 mutations in bone marrow cell populations, with high sensitivity. 106 Descriptions of PCNS‐LPL within the literature are rare when compared to BNS and, as such, there is no consensus on treatment strategies. Several case reports describe successful treatment with WBRT alone 104 , 107 but the frequent leptomeningeal involvement with LPL cells may not be sufficiently addressed by this strategy. Another report described successful treatment with surgical resection, chemotherapy and RT, inducing complete remission for 4 years. 108

High‐grade B‐cell lymphomas

Intravascular large B‐cell lymphoma

Intravascular large B‐cell lymphoma (IVL) is a rare high‐grade B‐cell malignancy characterised by an almost exclusive growth of malignant cells within peripheral blood vessels. 109 Estimated incidence is <1 case per million per annum. 110 Up to 61% of IVL cases with CNS involvement are diagnosed post‐mortem, implying late presentation and/or diagnosis with rapidly progressive neurological deterioration. 111

CNS involvement has been described in 30%–40% of patients at diagnosis (although this may be an underestimate given the potential for subclinical disease), whilst a further 25% develop CNS disease during follow‐up. 112 Neurological manifestations are usually accompanied by systemic phenomena, of which skin infiltration is the most frequent. 113

There are no typical diagnostic radiological findings. MRI is frequently normal, but may show diffuse multifocal white matter involvement, infarct‐like lesions, meningeal and focal nodular parenchymal enhancement. 114 , 115 , 116 , 117 As such, IVL with CNS involvement should be included in the differential of rapidly progressive neurological symptoms with ischaemic MRI changes in the absence of cardiovascular risk factors. 118 Positron emission tomography has been described as a potentially useful diagnostic tool, 119 particularly the 11 C‐methionine radionuclide, which seems to be able to identify IVL CNS lesions when MRI appearances resemble vasculitis. 120

CSF examination offers little aid in diagnosis, as neoplastic cells are frequently absent. 121 , 122 Brain biopsy histopathology reveals arrays of intravascular CD20 cells with MUM1 expression in 75%–80% of cases (Figure 6 ). 113 Recent reports have highlighted the potential use of CD79B Y196H and MYD88 L256P mutations as diagnostic aids using plasma ctDNA (detected in 26% and 44% of IVL cases respectively). 123

Given the disease biology and need for rapid clearance of tumour cells, systemic chemotherapy is often the preferred treatment modality. R‐CHOP is most frequently used, demonstrating good outcomes; within a cohort of 10 patients in which half had CNS disease, 3‐year OS rates were 81%. 124 , 125 A recent population‐based analysis described 5‐year OS rates of 46%. 126 Systemic CNS‐directed therapy of isolated CNS‐IVL has been reported with the use of the MTX‐containing Bonn‐Protocol (MTX, ifosfamide, procarbazine, AraC, vincristine, dexamethasone, and rituximab), 127 BCNU‐AraC‐MTX, 128 HD‐MTX followed by RT, and the deAngelis protocol (MTX, vincristine, procarbazine, and rituximab). 129 RT has been seldom used in isolated CNS‐IVL, with disappointing results. 121 , 130 Although the number of reported cases is too small to conclude that WBRT is ineffective, this is not considered a rational approach given the biology of IVL.

For patients without CNS disease at IVL diagnosis, CNS prophylaxis remains a key aspect of IVL management. Although data are limited; delivery of CNS prophylaxis is justified given the prevalence and risk of CNS disease in IVL.

Burkitt lymphoma

Burkitt lymphoma (BL) is a distinct clinicopathological B‐cell lymphoma entity with aggressive clinical behaviour, associated with a high risk of CNS involvement (CNS‐BL) ranging from 5% to 40%. 131 , 132 , 133 Standard therapy for systemic BL involves blood–brain barrier penetrating systemic chemotherapy and IT chemotherapy e.g. R‐CODOX‐M/R‐IVAC (rituximab, cyclophosphamide, vincristine, doxorubicin, MTX, ifosfamide, etoposide, and AraC). 134 Isolated CNS‐BL has been reported in <40 cases in the literature to date. 135 , 136 Gadolinium enhancing white matter lesions are frequently reported on MRI, although other unusual manifestations have been described, such as oculomotor nerve palsy in the absence of radiological or CSF manifestations. 137 , 138 Cases reported to date have predominantly employed HD‐MTX‐based treatment. However, the optimal combination regimen remains unknown. Disease‐free intervals of the reported cases range from 4 to 48 months. 139 , 140 , 141 , 142 , 143 , 144

T‐cell lymphomas

Primary CNS T‐cell lymphomas (PCNS‐TCL) account for between 2% and 8.5% of all primary lymphomas within the CNS, 145 , 146 , 147 with a reported higher incidence in Eastern countries. 148 Estimates of average age at diagnosis range from 55.8 to 60 years. 149 , 150 Interestingly, a recent systematic review described a much lower median age at diagnosis for those with primary CNS anaplastic large cell lymphoma (PCNS‐ALCL), at 21 years (range 1–82 years). 151

Mature peripheral TCLs comprise a spectrum of biologically and clinically heterogeneous malignancies. In two large retrospective studies of primary and secondary CNS‐TCL, the commonest histopathological subtype was peripheral TCL‐not otherwise specified (PTCL‐NOS) (83% and 54% respectively), with other subtypes also described; ALCL, angioimmunoblastic lymphoma, adult TCL/leukaemia, and extra‐nodal natural killer TCL. 147 , 152 , 153 Due to extensive heterogeneity across the spectrum of secondary CNS‐TCLs, we have focussed our discussion on primary disease and PTCL‐NOS and ALCL subtypes, which constitute the majority of CNS‐TCL cases. 147

There are no specific radiological features which clearly delineate CNS‐TCL from B‐NHL within the CNS. PCNS‐TCL may occur within the brain parenchyma or the leptomeninges. In particular, ALCL has a predilection for the meninges with one review suggesting 80% of reported PCNS‐ALCLs exhibit meningeal involvement. 151 Morphologically, PCNS‐PTCL‐NOS can be difficult to distinguish from reactive T‐cell infiltrates and B‐cell lymphomas; these neoplasms may be CD4 or CD8 positive. 147 By contrast, ALCL may manifest as large pleomorphic populations of cells with horse‐shoe shaped or multi‐lobated nuclei with vesicular chromatin and prominent eosinophilic nucleoli (Figure 7A ). The diagnostic immunophenotype of ALCL is that of uniform cytoplasmic and Golgi staining with CD30 and loss of numerous T‐cell antigens. 147 Similar to their systemic counterparts, PCNS‐ALCL may be anaplastic lymphoma kinase (ALK) positive or negative (Figure 7B ). 151

Owing to their rarity, no standard treatment protocol has been established for PCNS‐TCL. Similar to CNS‐DLBCL, most regimens described within the literature include systemic HD‐MTX and/or IT‐MTX. 148 , 151 , 154 , 155 Intravitreal MTX and local RT have been reported as treatment options for ocular involvement. 155 For PCNS‐DLBCL, HDT‐ASCT has demonstrable efficacy as the preferred consolidation strategy. Accordingly, HDT‐ASCT represents a viable consolidative strategy in the context of PCNS‐TCL. 7

Despite treatment, PCNS‐TCL confers a very poor prognosis. A large case series comprising a range of histopathological subtypes estimated patients with PCNS‐TCL have a short median OS of 8 months with a 3‐year OS of 32.8%. 150 Specifically for patients with PCNS‐ALCL, a systematic review of reported cases found that ALK‐positive tumours were associated with superior 2‐year OS rates compared to ALK‐negative neoplasms (71% vs. 22%). 151 However, this observation may be confounded by age; the ALK‐positive group was significantly younger than the ALK‐negative cohort (17.5 vs. 63 years). 151

A PRAGMATIC CLINICAL APPROACH TO RARE CNS LYMPHOMAS

For patients presenting with these rare primary and secondary CNS lymphoma entities, a diagnosis may not be immediately forthcoming. In Table 2 , we summarise a non‐exhaustive list of possible signs and symptoms that may prompt clinicians to consider neuroimaging and/or CSF examination, particularly in patients with established systemic lymphoma. Additionally, we have summarised recommended investigations and staging procedures. Mindful of the fragile evidence‐base underpinning clinical management decisions for many of these rare lymphomas, we present rational treatment options informed by the available literature and our clinical experience of these entities.

CONCLUSIONS AND OUTLOOK

In this review, we have summarised the epidemiology, diagnostic features, reported management strategies, and anticipated survival outcomes across the rare CNS lymphomas. It is clear that there is substantial clinical, radiological and histopathological heterogeneity which, together with the rarity of these entities, presents a weak evidence‐base to support clinical decision‐making.

Approaches to clinical management of the low‐grade B‐cell CNS lymphomas, particularly CNS‐MZL and CNS‐MCL, are relatively better characterised due to larger numbers of published cases. However, conclusions regarding optimal management strategies for these and other rarer CNS lymphoma subtypes are limited by study design, small case numbers, potential for selection and publication bias, and heterogeneity of treatment approaches. As such, current management is often informed by existing protocols for their systemic lymphoma counterparts and/or empirically adopted from CNS‐DLBCL, together with rational application of chemotherapeutic agents known to penetrate the blood–brain barrier.

Looking ahead, emerging technologies such as ctDNA in plasma and CSF offer great promise as a paradigm‐shift in biological classification, as well as offering an opportunity for individualised, dynamic assessment of treatment response. 11 Moreover, ctDNA should provide much greater sensitivity for the detection of concomitant subclinical disease in both systemic and CNS compartments. Importantly, ctDNA and sequencing technology, together with enhanced potential for discovery science on small and/or fixed tissue specimens, promises further opportunities to develop biologically‐rational therapies informed by a more precise understanding of subtype specific pathobiology.

Interventional studies specifically designed for distinct rare CNS lymphomas may be considered too challenging to deliver. Nevertheless, inclusion of such CNS cohorts within subtype‐specific systemic lymphoma protocols, with biologically rational therapies, is an important and achievable goal.

CONFLICT OF INTEREST

Christopher Paul Fox has received speaker and consultancy fees from Roche, Adienne, Janssen, Astrazeneca and research funding from BeiGene.

AUTHOR CONTRIBUTIONS

Christopher Paul Fox initiated and supervised the review. Furqaan Ahmed Kaji undertook the literature review. Furqaan Ahmed Kaji, Vishakha Sovani, Nicolás Martinez‐Calle and Christopher Paul Fox reviewed the literature summary, critically revised the manuscript and approved the final version.

ACKNOWLEDGEMENTS

Christopher Paul Fox is grateful for funding support through research grants from Cancer Research UK, Blood Cancer UK and Cure Leukaemia.

REFERENCES

1 Swerdlow SH , Campo E , Harris NL , Jaffe ES , Pileri SA , Stein H , et al. (Eds.) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Revised ( 4th ed. ). Lyon, France : IARC Press ; 2017 .

2 Gibson AW , Bonm AV , Barber J , Graber JJ . Seasonal variation in the incidence of primary CNS lymphoma . Neurooncol Pract . 2020 ; 7 : 620 – 5 . 33312676 10.1093/nop/npaa038 PMC7716177

3 Rubenstein JL . Biology of CNS lymphoma and the potential of novel agents . Hematology Am Soc Hematol Educ Program . 2017 ; 2017 : 556 – 64 . 29222305 10.1182/asheducation-2017.1.556 PMC6053314

4 Deckert M , Engert A , Brück W , Ferreri AJ , Finke J , Illerhaus G , et al. Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma . Leukemia . 2011 ; 25 : 1797 – 807 . 21818113 10.1038/leu.2011.169

5 Ferreri AJ , Cwynarski K , Pulczynski E , Ponzoni M , Deckert M , Politi LS , et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group‐32 (IELSG32) phase 2 trial . Lancet Haematol . 2016 ; 3 : e217 – 27 . 27132696 10.1016/S2352-3026(16)00036-3

6 Fox CP , Phillips EH , Smith J , Linton K , Gallop‐Evans E , Hemmaway C , et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B‐cell lymphoma . Br J Haematol . 2019 ; 184 : 348 – 63 . 30467845 10.1111/bjh.15661

7 Ferreri AJ , Cwynarski K , Pulczynski E , Fox CP , Schorb E , La Rosée P , et al. Whole‐brain radiotherapy or autologous stem‐cell transplantation as consolidation strategies after high‐dose methotrexate‐based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group‐32 phase 2 trial . Lancet Haematol . 2017 ; 4 : e510 – 23 . 29054815 10.1016/S2352-3026(17)30174-6

8 Ferreri AJ , Doorduijn JK , Re A , Cabras MG , Smith J , Ilariucci F , et al. MATRix‐RICE therapy and autologous haematopoietic stem‐cell transplantation in diffuse large B‐cell lymphoma with secondary CNS involvement (MARIETTA): an international, single‐arm, phase 2 trial . Lancet Haematol . 2021 ; 8 : e110 – 21 . 33513372 10.1016/S2352-3026(20)30366-5 PMC7844712

9 Scott BJ , Douglas VC , Tihan T , Rubenstein JL , Josephson SA . A systematic approach to the diagnosis of suspected central nervous system lymphoma . JAMA Neurol . 2013 ; 70 : 311 – 9 . 23319132 10.1001/jamaneurol.2013.606 PMC4135394

10 Bobillo S , Crespo M , Escudero L , Mayor R , Raheja P , Carpio C , et al. Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B‐cell lymphomas . Haematologica . 2021 ; 106 : 513 – 21 . 32079701 10.3324/haematol.2019.241208 PMC7849551

11 Poynton E , Okosun J . Liquid biopsy in lymphoma: is it primed for clinical translation? eJHaem . 2021 ; 2 : 616 – 27 . 35844685 10.1002/jha2.212 PMC9175672

12 Watanabe J , Natsumeda M , Okada M , Kobayashi D , Kanemaru Y , Tsukamoto Y , et al. High detection rate of MYD88 mutations in cerebrospinal fluid from patients with CNS lymphomas . JCO Precis Oncol . 2019 ; 3 : 1 – 13 . 10.1200/PO.18.00308 35100686

13 Sugita Y , Terasaki M , Nakashima S , Ohshima K , Morioka M , Abe H . Intraoperative rapid diagnosis of primary central nervous system lymphomas: advantages and pitfalls . Neuropathology . 2014 ; 34 : 438 – 45 . 24750231 10.1111/neup.12126

14 Akyüz C , Yalcin B , Atahan IL , Varan A , Kutluk MT , Büyükpamukçu M . Intracranial involvement in Hodgkin's disease . Pediatr Hematol Oncol . 2005 ; 22 : 589 – 96 . 16166052 10.1080/08880010500198863

15 Sapozink MD , Kaplan HS . Intracranial Hodgkin's disease. A report of 12 cases and review of the literature . Cancer . 1983 ; 52 : 1301 – 7 . 6883291 10.1002/1097-0142(19831001)52:7<1301::aid-cncr2820520728>3.0.co;2-5

16 Re D , Fuchs M , Schober T , Engert A , Diehl V . CNS involvement in Hodgkin's lymphoma . J Clin Oncol . 2007 ; 25 : 3182 . 10.1200/JCO.2007.12.5088 17634503

17 Gerstner ER , Abrey LE , Schiff D , Ferreri AJ , Lister A , Montoto S , et al. CNS Hodgkin lymphoma . Blood . 2008 ; 112 : 1658 – 61 . 18591379 10.1182/blood-2008-04-151563 PMC3710443

18 Kresak JL , Nguyen J , Wong K , Davis R . Primary Hodgkin lymphoma of the central nervous system: two case reports and review of the literature . Neuropathology . 2013 ; 33 : 658 – 62 . 23530967 10.1111/neup.12035

19 Gessi M , Kuchelmeister K , Kellner U , Ritter M , Morgner A , Urbach H , et al. Unusual clinico‐pathological features in primary Hodgkin's lymphomas of the central nervous system . Acta Neurochir (Wien) . 2013 ; 155 : 19 – 24 . 23139103 10.1007/s00701-012-1535-6

20 Szelemej PA , Bigder MG , Krcek J . Treatment and long‐term follow‐up of primary CNS classical Hodgkin's lymphoma—a case report and review of the literature . Interdiscip Neurosurg . 2017 ; 9 : 30 – 3 .

21 Biagi J , MacKenzie RG , Lim MS , Sapp M , Berinstein N . Primary Hodgkin's disease of the CNS in an immunocompetent patient: a case study and review of the literature . Neuro Oncol . 2000 ; 2 : 239 – 43 . 11265233 10.1093/neuonc/2.4.239 PMC1920596

22 Massarweh S , Udden MM , Shahab I , Kroll M , Sears DA , Lynch GR , et al. HIV‐related Hodgkin's disease with central nervous system involvement and association with Epstein‐Barr virus . Am J Hematol . 2003 ; 72 : 216 – 9 . 12605396 10.1002/ajh.10288

23 Martinez DL , Gujrati M , Geoffroy F , Tsung AJ . Isolated CNS Hodgkin's lymphoma: implications for tissue diagnosis . CNS Oncol . 2014 ; 3 : 383 – 7 . 25438809 10.2217/cns.14.45 PMC6113894

24 Cozzolino I , Vitagliano G , Caputo A , Montella M , Franco R , Ciancia G , et al. CD15, CD30, and PAX5 evaluation in Hodgkin's lymphoma on fine‐needle aspiration cytology samples . Diagn Cytopathol . 2020 ; 48 : 211 – 6 . 31825183 10.1002/dc.24366

25 Morawa E , Ragam A , Sirota R , Nabhan C . Hodgkin's lymphoma involving the CNS . J Clin Oncol . 2007 ; 25 : 1437 – 8 . 17416864 10.1200/JCO.2006.10.1691

26 Alfaseh A , Rajeh MN , Hamed G . Primary central nervous system Hodgkin Lymphoma: A case discussion and a hypothesis on the etiology . Avicenna J Med . 2019 ; 9 : 28 – 31 . 30697523 10.4103/ajm.AJM_104_18 PMC6335883

27 Williamson TJ , Wang M , Clark J , Williams J , Drnda A . Primary intradural Hodgkin lymphoma of the conus medullaris and cauda equina: case report . CNS Oncol . 2020 ; 9 : CNS52 . 32990023 10.2217/cns-2020-0002 PMC7546171

28 Kline J , Godfrey J , Ansell SM . The immune landscape and response to immune checkpoint blockade therapy in lymphoma . Blood . 2020 ; 135 : 523 – 33 . 31790142 10.1182/blood.2019000847

29 Maka VV , Chitrapur R , Kilara N , Prabhu VM , Krishnamoorthy N . Management of Hodgkin's lymphoma with midbrain involvement: a case report and review of literature . Hematology . 2015 ; 20 : 272 – 5 . 25133862 10.1179/1607845414Y.0000000190

30 Ahmed S , Irfan B , Raza M , Ghulam H . Atypical involvement of central nervous system in classic Hodgkin lymphoma: a case report . J Med Case Rep . 2021 ; 15 : 532 . 34711281 10.1186/s13256-021-03118-4 PMC8555165

31 Ayanambakkam A , Ibrahimi S , Bilal K , Cherry MA . Extranodal marginal zone lymphoma of the central nervous system . Clin Lymphoma Myeloma Leuk . 2018 ; 18 : 34 – 7.e8 . 29103980 10.1016/j.clml.2017.09.012

32 Villano JL , Koshy M , Shaikh H , Dolecek TA , McCarthy BJ . Age, gender, and racial differences in incidence and survival in primary CNS lymphoma . Br J Cancer . 2011 ; 105 : 1414 – 8 . 21915121 10.1038/bjc.2011.357 PMC3241537

33 Houillier C , Soussain C , Ghesquières H , Soubeyran P , Chinot O , Taillandier L , et al. Management and outcome of primary CNS lymphoma in the modern era: an LOC network study . Neurology . 2020 ; 94 : e1027 – 39 . 31907289 10.1212/WNL.0000000000008900 PMC7238921

34 Sunderland AJ , Steiner RE , Al Zahrani M , Pinnix CC , Dabaja BS , Gunther JR , et al. An international multicenter retrospective analysis of patients with extranodal marginal zone lymphoma and histologically confirmed central nervous system and dural involvement . Cancer Med . 2020 ; 9 : 663 – 70 . 31808316 10.1002/cam4.2732 PMC6970027

35 Itoh T , Shimizu M , Kitami K , Kamata K , Mitsumori K , Fujita M , et al. Primary extranodal marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue type in the CNS . Neuropathology . 2001 ; 21 ( 3 ): 174 – 80 . 11666014 10.1046/j.1440-1789.2001.00392.x

36 Weis S , Llenos IC . Primary leptomeningeal B‐cell lymphoma of MALT‐type in statu nascendi: a case report and review of the literature . Clin Neurol Neurosurg . 2008 ; 110 : 732 – 8 . 18499338 10.1016/j.clineuro.2008.04.005

37 Karschnia P , Batchelor TT , Jordan JT , Shaw B , Winter SF , Barbiero FJ , et al. Primary dural lymphomas: clinical presentation, management, and outcome . Cancer . 2020 ; 126 : 2811 – 20 . 32176324 10.1002/cncr.32834

38 Venkataraman G , Rizzo KA , Chavez JJ , Streubel B , Raffeld M , Jaffe ES , et al. Marginal zone lymphomas involving meningeal dura: possible link to IgG4‐related diseases . Mod Pathol . 2011 ; 24 : 355 – 66 . 21102421 10.1038/modpathol.2010.206 PMC7425666

39 Douleh DG , Morone PJ , Forbes JA , Thompson RC . Intracranial marginal zone B‐cell lymphoma mimicking meningioma . World Neurosurg . 2016 ; 91 : 676.e9 – 12 . 10.1016/j.wneu.2016.04.106 27155383

40 Villeneuve A , Rubin F , Bonfils P . Meningeal marginal zone B‐cell lymphoma: the meningioma trap . Eur Ann Otorhinolaryngol Head Neck Dis . 2018 ; 135 ( 2 ): 131 – 2 . 29331570 10.1016/j.anorl.2017.12.002

41 Tu PH , Giannini C , Judkins AR , Schwalb JM , Burack R , O'Neill BP , et al. Clinicopathologic and genetic profi le of intracranial marginal zone lymphoma: a primary low‐grade CNS lymphoma that mimics meningioma . J Clin Oncol . 2005 ; 23 : 5718 – 27 . 16009945 10.1200/JCO.2005.17.624

42 Martin SE , Khalidi HS , Hattab EM . Marginal zone B‐cell lymphoma involving a longstanding fibrous meningioma: an initial manifestation of systemic disease . Hum Pathol . 2013 ; 44 : 2609 – 13 . 23850496 10.1016/j.humpath.2013.04.016

43 Jahnke K , Korfel A , O'Neill BP , Blay JY , Abrey LE , Martus P , et al. International study on low‐grade primary central nervous system lymphoma . Ann Neurol . 2006 ; 59 : 755 – 62 . 16586496 10.1002/ana.20804

44 de la Fuente MI , Haggiagi A , Moul A , Young RJ , Sidani C , Markoe A , et al. Marginal zone dural lymphoma: the Memorial Sloan Kettering Cancer Center and University of Miami experiences . Leuk Lymphoma . 2017 ; 58 : 882 – 8 . 27649904 10.1080/10428194.2016.1218006 PMC5576515

45 Ikeda JI , Kohara M , Tsuruta Y , Nojima S , Tahara S , Ohshima K , et al. Immunohistochemical analysis of the novel marginal zone B‐cell marker IRTA1 in malignant lymphoma . Hum Pathol . 2017 ; 59 : 70 – 9 . 27666766 10.1016/j.humpath.2016.09.011

46 Murga Penas EM , Hinz K , Röser K , Copie‐Bergman C , Wlodarska I , Marynen P , et al. Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas . Leukemia . 2003 ; 17 : 2225 – 9 . 12931213 10.1038/sj.leu.2403122

47 Streubel B , Lamprecht A , Dierlamm J , Cerroni L , Stolte M , Ott G , et al. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma . Blood . 2003 ; 101 : 2335 – 9 . 12406890 10.1182/blood-2002-09-2963

48 Streubel B , Vinatzer U , Lamprecht A , Raderer M , Chott A . T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma . Leukemia . 2005 ; 19 : 652 – 8 . 15703784 10.1038/sj.leu.2403644

49 Tsang RW , Gospodarowicz MK , Pintilie M , Wells W , Hodgson DC , Sun A , et al. Localized mucosa‐associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome . J Clin Oncol . 2003 ; 21 : 4157 – 64 . 14615444 10.1200/JCO.2003.06.085

50 Iwamoto FM , Abrey LE . Primary dural lymphomas: a review . Neurosurg Focus . 2006 ; 21 ( 5 ): E5 . 10.3171/foc.2006.21.5.6 17134121

51 Iwamoto FM , DeAngelis LM , Abrey LE . Primary dural lymphomas: a clinicopathologic study of treatment and outcome in eight patients . Neurology . 2006 ; 66 : 1763 – 5 . 16769960 10.1212/01.wnl.0000218284.23872.eb

52 Angelopoulou MK , Vassilakopoulos TP , Konstantinou E , Boutsikas G , Asimakopoulos JV , Triantafyllou EF , et al. Central nervous system involvement in primary bone marrow or splenic marginal zone lymphoma: report of two cases and review of the literature . Hematol Oncol . 2019 ; 37 : 219 – 22 . 30592785 10.1002/hon.2571

53 Arai A , Taomoto K , Yokoyama M , Kudo H , Nishisaki H , Kajimoto K . A case of CNS metastasis from gastric MALT lymphoma . No Shinkei Geka . 2009 ; 37 : 1235 – 40 . 19999557

54 Bayraktar S , Stefanovic A , Montague N , Davis J , Murray T , Lossos IS . Central nervous system manifestations of marginal zone B‐cell lymphoma . Ann Hematol . 2010 ; 89 : 1003 – 9 . 20440502 10.1007/s00277-010-0976-3

55 McKay P , Leach M , Jackson B , Robinson S , Rule S . Guideline for the management of mantle cell lymphoma . Br J Haematol . 2018 ; 182 : 46 – 62 . 29767454 10.1111/bjh.15283

56 Ferrer A , Bosch F , Villamor N , Rozman M , Graus F , Gutiérrez G , et al. Central nervous system involvement in mantle cell lymphoma . Ann Oncol . 2008 ; 19 : 135 – 41 . 17962207 10.1093/annonc/mdm447

57 Cheah CY , George A , Giné E , Chiappella A , Kluin‐Nelemans HC , Jurczak W , et al. Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network . Ann Oncol . 2013 ; 24 : 2119 – 23 . 23616279 10.1093/annonc/mdt139

58 Conconi A , Franceschetti S , Lobetti‐Bodoni C , Stathis A , Margiotta‐Casaluci G , Ramponi A , et al. Risk factors of central nervous system relapse in mantle cell lymphoma . Leuk Lymphoma . 2013 ; 54 : 1908 – 14 . 23339449 10.3109/10428194.2013.767454

59 Oinonen R , Franssila K , Elonen E . Central nervous system involvement in patients with mantle cell lymphoma . Ann Hematol . 1999 ; 78 : 145 – 9 . 10211757 10.1007/s002770050491

60 Gill S , Herbert KE , Prince HM , Wolf MM , Wirth A , Ryan G , et al. Mantle cell lymphoma with central nervous system involvement: frequency and clinical features . Br J Haematol . 2009 ; 147 : 83 – 8 . 19694718 10.1111/j.1365-2141.2009.07835.x

61 Bernard S , Goldwirt L , Amorim S , Brice P , Brière J , de Kerviler E , et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse . Blood . 2015 ; 126 : 1695 – 8 . 26239089 10.1182/blood-2015-05-647834 PMC4591793

62 Chihara D , Asano N , Ohmachi K , Nishikori M , Okamoto M , Sawa M , et al. Ki‐67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL) . Ann Oncol . 2015 ; 26 : 966 – 73 . 25712457 10.1093/annonc/mdv074

63 Le Gouill S , Beldi‐Ferchiou A , Alcantara M , Cacheux V , Safar V , Burroni B , et al. Molecular response after obinutuzumab plus high‐dose cytarabine induction for transplant‐eligible patients with untreated mantle cell lymphoma (LyMa‐101): a phase 2 trial of the LYSA group . Lancet Haematol . 2020 ; 7 : e798 – 807 . 32971036 10.1016/S2352-3026(20)30291-X

64 McKay P , Leach M , Jackson B , Robinson S , Rule S . A British Society for haematology good practice paper on the diagnosis and investigation of patients with mantle cell lymphoma . Br J Haematol . 2018 ; 182 : 63 – 70 . 29882587 10.1111/bjh.15281

65 Vandenberghe E , De Wolf‐Peeters C , van den Oord J , Wlodarska I , Delabie J , Stul M , et al. Translocation (11;14): a cytogenetic anomaly associated with B‐cell lymphomas of non‐follicle centre cell lineage . J Pathol . 1991 ; 163 : 13 – 8 . 2002419 10.1002/path.1711630104

66 Wang ML , Rule S , Martin P , Goy A , Auer R , Kahl BS , et al. Targeting BTK with ibrutinib in relapsed or refractory mantle‐cell lymphoma . N Engl J Med . 2013 ; 369 : 507 – 16 . 23782157 10.1056/NEJMoa1306220 PMC4513941

67 Tucker DL , Naylor G , Kruger A , Hamilton MS , Follows G , Rule SA . Ibrutinib is a safe and effective therapy for systemic mantle cell lymphoma with central nervous system involvement – a multi‐centre case series from the United Kingdom . Br J Haematol . 2017 ; 178 : 327 – 9 . 27197509 10.1111/bjh.14122

68 Alsuliman T , Belghoul M , Choufi B . Ibrutinib treatment through nasogastric tube in a comatose patient with central nervous system localization of mantle cell lymphoma . Case Rep Hematol . 2018 ; 2018 : 5761627 . 30186643 10.1155/2018/5761627 PMC6116396

69 Beriwal S , Hou JS , Miyamoto C , Garcia‐Young JA . Primary dural low grade BCL‐2 negative follicular lymphoma: a case report . J Neurooncol . 2003 ; 61 : 23 – 5 . 12587792 10.1023/a:1021244228163

70 Spectre G , Gural A , Amir G , Lossos A , Siegal T , Paltiel O . Central nervous system involvement in indolent lymphomas . Ann Oncol . 2005 ; 16 : 450 – 4 . 15642707 10.1093/annonc/mdi076

71 Grupka NL , Seinfeld J , Ryder J , Lillehei KO , Kleinschmidt‐Demasters BK . Secondary central nervous system involvement by follicular lymphoma: case report and review of the literature . Surg Neurol . 2006 ; 65 : 590 – 4 . 16720183 10.1016/j.surneu.2005.08.027

72 Costa R , Costa R , Costa R . Follicular lymphoma presenting with leptomeningeal disease . Case Rep Hematol . 2014 ; 2014 : 767621 . 25544910 10.1155/2014/767621 PMC4269308

73 Hafeez S , Cho WC , Shen P . Leptomeningeal involvement by relapsed follicular lymphoma detected by flow cytometry despite exceedingly low white blood cell counts in cerebrospinal fluid: a case report . Indian J Pathol Microbiol . 2020 ; 63 : 131 – 3 . 32031143 10.4103/IJPM.IJPM_67_19

74 Hamilton DK , Bourne TD , Ahmed H , Cousar JB , Mandell JW , Sheehan JP . Follicular lymphoma of the dura: case report . Neurosurgery . 2006 ; 59 : E703 – 4 . 16955025 10.1227/01.NEU.0000229057.50372.06

75 Karadurmus N , Ataergin S , Erdem G , Cakar M , Emer O , Ozaydin S , et al. A rare presentation of follicular lymphoma: cerebellar involvement, successfully treated with a combination of radiotherapy and chemotherapy . Cancer Res Treat . 2013 ; 45 : 234 – 8 . 24155683 10.4143/crt.2013.45.3.234 PMC3804736

76 Kumar S , Kumar D , Kaldjian EP , Bauserman S , Raffeld M , Jaffe ES . Primary low‐grade B‐cell lymphoma of the dura: a mucosa associated lymphoid tissue‐type lymphoma . Am J Surg Pathol . 1997 ; 21 : 81 – 7 . 8990144 10.1097/00000478-199701000-00009

77 Rottnek M , Strauchen J , Moore F , Morgello S . Primary dural mucosa‐associated lymphoid tissue‐type lymphoma: case report and review of the literature . J Neurooncol . 2004 ; 68 : 19 – 23 . 15174517 10.1023/b:neon.0000024704.70250.42

78 McNamara C , Davies J , Dyer M , Hoskin P , Illidge T , Lyttelton M , et al. Guidelines on the investigation and management of follicular lymphoma . Br J Haematol . 2012 ; 156 : 446 – 67 . 22211428 10.1111/j.1365-2141.2011.08969.x

79 Tandon R , Mukherjee U , Abrari A , Patir R , Tandon A , Bansal B . Primary dural follicular lymphoma masquerading as meningioma: a case report . Br J Neurosurg . 2012 ; 26 : 905 – 6 . 22616798 10.3109/02688697.2012.685783

80 MacCann R , Gleeson JP , Aird JJ , Beausang A , Breathnach O , Morris PG , et al. An unusual presentation of a low grade follicular lymphoma masquerading as a meningioma . Ann Hematol Oncol . 2018 ; 5 : 1211 .

81 Nahi H , Svedmyr E , Lerner R . Bendamustine in combination with high‐dose radiotherapy and thalidomide is effective in treatment of multiple myeloma with central nervous system involvement . Eur J Haematol . 2014 ; 92 : 454 – 5 . 24330308 10.1111/ejh.12247

82 Flowers CR , Leonard JP , Fowler NH . Lenalidomide in follicular lymphoma . Blood . 2020 ; 135 : 2133 – 6 . 32236519 10.1182/blood.2019001751 PMC7290094

83 Gribben JG , Fowler N , Morschhauser F . Mechanisms of action of lenalidomide in B‐cell non‐Hodgkin lymphoma . J Clin Oncol . 2015 ; 33 : 2803 – 11 . 26195701 10.1200/JCO.2014.59.5363 PMC5320950

84 Salles G , Seymour JF , Offner F , López‐Guillermo A , Belada D , Xerri L , et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial . Lancet . 2011 ; 377 : 42 – 51 . 21176949 10.1016/S0140-6736(10)62175-7

85 Chihara D , Fowler NH , Oki Y , Fanale MA , Nastoupil LJ , Westin JR , et al. Impact of histologic subtypes and treatment modality among patients with primary central nervous system lymphoma: a SEER database analysis . Oncotarget . 2018 ; 9 : 28897 – 902 . 29988979 10.18632/oncotarget.25622 PMC6034756

86 Kaji FA , Martinez‐Calle N , Bishton MJ , Figueroa R , Adlington J , O'Donoghue M , et al. Improved survival outcomes despite older age at diagnosis: an era‐by‐era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom . Br J Haematol . 2021 ; 195 : 561 – 70 . 34368948 10.1111/bjh.17747

87 Johnson SA , Birchall J , Luckie C , Oscier DG , Owen RG . Haemato‐Oncology Task Force of the British Committee for Standards in Haematology. Guidelines on the management of Waldenström macroglobulinaemia . Br J Haematol . 2006 ; 132 : 683 – 97 . 16487169 10.1111/j.1365-2141.2005.05948.x

88 Steck AJ , Stalder AK , Renaud S . Anti‐myelin‐associated glycoprotein neuropathy . Curr Opin Neurol . 2006 ; 19 : 458 – 63 . 16969155 10.1097/01.wco.0000245368.36576.0d

89 Owen RG , Pratt G , Auer RL , Flatley R , Kyriakou C , Lunn MP , et al. Guidelines on the diagnosis and management of Waldenström macroglobulinaemia . Br J Haematol . 2014 ; 165 : 316 – 33 . 24528152 10.1111/bjh.12760

90 Simon L , Fitsiori A , Lemal R , Dupuis J , Carpentier B , Boudin L , et al. Bing‐Neel syndrome, a rare complication of Waldenstrom macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO) . Haematologica . 2015 ; 100 : 1587 – 94 . 26385211 10.3324/haematol.2015.133744 PMC4666335

91 Castillo JJ , D'Sa S , Lunn MP , Minnema MC , Tedeschi A , Lansigan F , et al. Central nervous system involvement by Waldenstrom macroglobulinaemia (Bing‐Neel syndrome): a multi‐institutional retrospective study . Br J Haematol . 2016 ; 172 : 709 – 15 . 26686858 10.1111/bjh.13883 PMC5480405

92 Castillo JJ , Treon SP . How we manage Bing‐Neel syndrome . Br J Haematol . 2019 ; 187 : 277 – 85 . 31430829 10.1111/bjh.16167

93 Minnema MC , Kimby E , D'Sa S , Fornecker LM , Poulain S , Snijders TJ , et al. Guideline for the diagnosis, treatment and response criteria for Bing‐Neel syndrome . Haematologica . 2017 ; 102 : 43 – 51 . 27758817 10.3324/haematol.2016.147728 PMC5210231

94 Fitsiori A , Fornecker LM , Simon L , Karentzos A , Galanaud D , Outteryck O , et al. Imaging spectrum of Bing‐Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenström's macroglobulinemia? Eur Radiol . 2019 ; 29 : 102 – 14 . 29922935 10.1007/s00330-018-5543-7

95 Poulain S , Boyle EM , Roumier C , Demarquette H , Wemeau M , Geffroy S , et al. MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome . Br J Haematol . 2014 ; 167 : 506 – 13 . 25160558 10.1111/bjh.13078

96 Varettoni M , Marchioni E , Bonfichi M , Picchiecchio A , Arcaini L , Arbasino C , et al. Successful treatment with Rituximab and Bendamustine in a patient with newly diagnosed Waldenström's Macroglobulinemia complicated by Bing‐Neel syndrome . Am J Hematol . 2015 ; 90 : E152 – 3 . 25975811 10.1002/ajh.24059

97 Vos JM , Kersten MJ , Kraan W , Groeneveld ON , Linn C , Pals ST , et al. Effective treatment of Bing‐Neel Syndrome with oral fludarabine: a case series of four consecutive patients . Br J Haematol . 2016 ; 172 : 461 – 4 . 25944724 10.1111/bjh.13483

98 Simon L , Lemal R , Fornecker LM , Tournilhac O , Leblond V . High‐dose therapy with autologous stem cells transplantation in Bing‐Neel syndrome: a retrospective analysis of 14 cases . Am J Hematol . 2019 ; 94 : E227 – 9 . 31149742 10.1002/ajh.25547

99 O'Neil DS , Francescone MA , Khan K , Alobeid B , Bachir A , O'Connor OA , et al. A case of Bing‐Neel syndrome successfully treated with ibrutinib . Case Rep Hematol . 2018 ; 2018 : 8573105 . 30228918 10.1155/2018/8573105 PMC6136466

100 Tallant A , Selig D , Wanko SO , Roswarski J . First‐line ibrutinib for Bing‐Neel syndrome . BMJ Case Rep . 2018 ; 2018 : bcr2018226102 . 10.1136/bcr-2018-226102 PMC6169697 30279255

101 Hashmi H , Dhanoa JS , Emmons R . Rare case of Bing‐Neel syndrome treated successfully with ibrutinib . BMJ Case Rep . 2019 ; 12 : e230067 . 10.1136/bcr-2019-230067 PMC6605891 31243026

102 Plander M , Szendrei T , Vadvári Á , Iványi J . Standard dose of ibrutinib is effective in the treatment of Bing‐Neel syndrome . Pathol Oncol Res . 2020 ; 26 : 591 – 2 . 30357751 10.1007/s12253-018-0482-9

103 Ntanasis‐Stathopoulos I , Gavriatopoulou M , Fotiou D , Dimopoulos MA . Current and novel BTK inhibitors in Waldenström's macroglobulinemia . Ther Adv Hematol . 2021 ; 12 : 2040620721989586 . 33613931 10.1177/2040620721989586 PMC7874350

104 Abbi KK , Muzaffar M , Gaudin D , Booth RL Jr , Feldmeier JJ , Skeel RT . Primary CNS lymphoplasmacytic lymphoma: a case report and review of literature . Hematol Oncol Stem Cell Ther . 2013 ; 6 : 76 – 8 . 23791836 10.1016/j.hemonc.2013.06.002

105 Sah SP , Matutes E , Wotherspoon AC , Morilla R , Catovsky D . A comparison of flow cytometry, bone marrow biopsy, and bone marrow aspirates in the detection of lymphoid infiltration in B cell disorders . J Clin Pathol . 2003 ; 56 : 129 – 32 . 12560392 10.1136/jcp.56.2.129 PMC1769888

106 Xu L , Hunter ZR , Yang G , Zhou Y , Cao Y , Liu X , et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B‐cell lymphoproliferative disorders using conventional and quantitative allele‐specific polymerase chain reaction . Blood . 2013 ; 121 : 2051 – 8 . 23321251 10.1182/blood-2012-09-454355 PMC3596964

107 Shenkier TN . Unusual variants of primary central nervous system lymphoma . Hematol Oncol Clin North Am . 2005 ; 19 : 651 – 64 . 16083828 10.1016/j.hoc.2005.05.001

108 Carrasco CA , Rojas‐Z D , Chiorino R , González G . Primary pituitary lymphoma in immunocompetent patient: diagnostic problems and prolonged follow‐up . Pituitary . 2012 ; 15 : 93 – 6 . 20146099 10.1007/s11102-010-0219-6

109 Ponzoni M , Campo E , Nakamura S . Intravascular large B‐cell lymphoma: a chameleon with multiple faces and many masks . Blood . 2018 ; 132 : 1561 – 7 . 30111607 10.1182/blood-2017-04-737445

110 Zuckerman D , Seliem R , Hochberg E . Intravascular lymphoma: the oncologist's "great imitator" . Oncologist . 2006 ; 11 : 496 – 502 . 16720850 10.1634/theoncologist.11-5-496

111 Fonkem E , Dayawansa S , Stroberg E , Lok E , Bricker PC , Kirmani B , et al. Neurological presentations of intravascular lymphoma (IVL): meta‐analysis of 654 patients . BMC Neurol . 2016 ; 16 : 9 . 26849888 10.1186/s12883-015-0509-8 PMC4744383

112 Shimada K , Murase T , Matsue K , Okamoto M , Ichikawa N , Tsukamoto N , et al. Central nervous system involvement in intravascular large B‐cell lymphoma: a retrospective analysis of 109 patients . Cancer Sci . 2010 ; 101 : 1480 – 6 . 20412122 10.1111/j.1349-7006.2010.01555.x PMC11158344

113 Murase T , Yamaguchi M , Suzuki R , Okamoto M , Sato Y , Tamaru J , et al. Intravascular large B‐cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5 . Blood . 2007 ; 109 : 478 – 85 . 16985183 10.1182/blood-2006-01-021253

114 Liow K , Asmar P , Liow M , Spanaki M , Townsend JJ , Buys S , et al. Intravascular lymphomatosis: contribution of cerebral MRI findings to diagnosis . J Neuroimaging . 2000 ; 10 : 116 – 8 . 10800265 10.1111/jon2000102116

115 Song DK , Boulis NM , McKeever PE , Quint DJ . Angiotropic large cell lymphoma with imaging characteristics of CNS vasculitis . AJNR Am J Neuroradiol . 2002 ; 23 : 239 – 42 . 11847048 PMC7975247

116 Baehring JM , Henchcliffe C , Ledezma CJ , Fulbright R , Hochberg FH . Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system . J Neurol Neurosurg Psychiatry . 2005 ; 76 : 540 – 4 . 15774442 10.1136/jnnp.2003.033662 PMC1739607

117 Abe Y , Narita K , Kobayashi H , Kitadate A , Takeuchi M , Kikuchi Y , et al. Clinical value of abnormal findings on brain magnetic resonance imaging in patients with intravascular large B‐cell lymphoma . Ann Hematol . 2018 ; 97 : 2345 – 52 . 30141061 10.1007/s00277-018-3481-8

118 Cruto C , Taipa R , Monteiro C , Moreira I , Melo‐Pires M , Correia M , et al. Multiple cerebral infarcts and intravascular central nervous system lymphoma: a rare but potentially treatable association . J Neurol Sci . 2013 ; 325 : 183 – 5 . 23246010 10.1016/j.jns.2012.10.012

119 Shimada K , Kosugi H , Shimada S , Narimatsu H , Koyama Y , Suzuki N , et al. Evaluation of organ involvement in intravascular large B‐cell lymphoma by 18F‐fluorodeoxyglucose positron emission tomography . Int J Hematol . 2008 ; 88 : 149 – 53 . 18496649 10.1007/s12185-008-0102-7

120 Yomo S , Tsutsumi K , Yako T , Sato H , Hashimoto T , Oguchi K . Accurate detection of tumor infiltration by 11 C‐methionine positron emission tomography in a patient with central nervous system intravascular lymphoma: a case report . Case Rep Oncol . 2018 ; 11 ( 2 ): 577 – 84 . 30186143 10.1159/000492465 PMC6120372

121 Baehring JM , Longtine J , Hochberg FH . A new approach to the diagnosis and treatment of intravascular lymphoma . J Neurooncol . 2003 ; 61 : 237 – 48 . 12675317 10.1023/a:1022588812415

122 Mihaljevic B , Sternic N , Skender Gazibara M , Sretenovic A , Antic D , Terzic T , et al. Intravascular large B‐cell lymphoma of central nervous system—a report of two cases and literature review . Clin Neuropathol . 2010 ; 29 : 233 – 8 . 20569674 10.5414/npp29233

123 Schrader AMR , Jansen PM , Willemze R , Vermeer MH , Cleton‐Jansen AM , Somers SF , et al. High prevalence of MYD88 and CD79B mutations in intravascular large B‐cell lymphoma . Blood . 2018 ; 131 : 2086 – 9 . 29514783 10.1182/blood-2017-12-822817

124 Ferreri AJ , Campo E , Seymour JF , Willemze R , Ilariucci F , Ambrosetti A , et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant' . Br J Haematol . 2004 ; 127 : 173 – 83 . 15461623 10.1111/j.1365-2141.2004.05177.x

125 Ferreri AJ , Dognini GP , Bairey O , Szomor A , Montalbán C , Horvath B , et al. The addition of rituximab to anthracycline‐based chemotherapy significantly improves outcome in 'Western' patients with intravascular large B‐cell lymphoma . Br J Haematol . 2008 ; 143 : 253 – 7 . 18699850 10.1111/j.1365-2141.2008.07338.x

126 Rajyaguru DJ , Bhaskar C , Borgert AJ , Smith A , Parsons B . Intravascular large B‐cell lymphoma in the United States (US): a population‐based study using Surveillance, Epidemiology, and End Results program and National Cancer Database . Leuk Lymphoma . 2017 ; 58 : 1 – 9 . 10.1080/10428194.2017.1287363 28278725

127 Kebir S , Kuchelmeister K , Niehusmann P , Nelles M , Kim Y , Thanendrarajan S , et al. Intravascular CNS lymphoma: successful therapy using high‐dose methotrexate‐based polychemotherapy . Exp Hematol Oncol . 2012 ; 1 : 37 . 23217063 10.1186/2162-3619-1-37 PMC3533508

128 Prats‐Martin C , Franco‐Macias E , Morales‐Camacho RM , Pérez O , Vargas MT , de la Cruz VF , et al. Intravascular lymphoma: look through the small vessels . Ann Hematol . 2017 ; 96 : 517 – 9 . 27838775 10.1007/s00277-016-2874-9

129 Liu Z , Zhang Y , Zhu Y , Zhang W . Prognosis of Intravascular Large B Cell Lymphoma (IVLBCL): analysis of 182 patients from global case series . Cancer Manag Res . 2020 ; 12 : 10531 – 40 . 33122951 10.2147/CMAR.S267825 PMC7591067

130 Momota H , Narita Y , Miyakita Y , Shibui S . Intravascular lymphoma of the central nervous system presenting as multiple cerebral infarctions . Nagoya J Med Sci . 2012 ; 74 : 353 – 8 . 23092108 PMC4831244

131 Boehme V , Zeynalova S , Kloess M , Loeffler M , Kaiser U , Pfreundschuh M , et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma‐‐a survey of 1693 patients treated in protocols of the German High‐Grade Non‐Hodgkin's Lymphoma Study Group (DSHNHL) . Ann Oncol . 2007 ; 18 : 149 – 57 . 17018708 10.1093/annonc/mdl327

132 Oosten LE , Chamuleau ME , Thielen FW , de Wreede LC , Siemes C , Doorduijn JK , et al. Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens . Ann Hematol . 2018 ; 97 : 255 – 66 . 29209924 10.1007/s00277-017-3167-7 PMC5754407

133 Zayac AS , Evens AM , Danilov A , Smith SD , Jagadeesh D , Leslie LA , et al. Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study . Haematologica . 2021 ; 106 : 1932 – 42 . 33538152 10.3324/haematol.2020.270876 PMC8252937

134 Phillips EH , Burton C , Kirkwood AA , Barrans S , Lawrie A , Rule S , et al. Favourable outcomes for high‐risk Burkitt lymphoma patients (IPI 3‐5) treated with rituximab plus CODOX‐M/IVAC: results of a phase 2 UK NCRI trial . eJHaem . 2020 ; 1 : 133 – 41 . 35847742 10.1002/jha2.3 PMC9176097

135 Alabdulsalam A , Zaidi SZ , Tailor I , Orz Y , Al‐Dandan S . Primary burkitt lymphoma of the fourth ventricle in an immunocompetent young patient . Case Rep Pathol . 2014 ; 2014 : 630954 . 25254131 10.1155/2014/630954 PMC4164299

136 Shehu BB . Primary central nervous system Burkitt's lymphoma presenting with proptosis . Ann Trop Paediatr . 2003 ; 23 : 319 – 20 . 14738582 10.1179/027249303322705812

137 Pesin N , Lam C , Margolin E . Central nervous system burkitt lymphoma presenting as atypical Guillain‐Barre syndrome . Can J Neurol Sci . 2020 ; 47 : 145 – 7 . 31685043 10.1017/cjn.2019.310

138 Liang Y , Ding L , Li X , Wang W , Zhang X . Oculomotor nerve palsy as a preceding symptom of adult sporadic burkitt lymphoma: a case report and review of the literature . Oncol Lett . 2017 ; 13 : 1315 – 8 . 28454254 10.3892/ol.2017.5583 PMC5403323

139 Monabati A , Rakei SM , Kumar P , Taghipoor M , Rahimi A . Primary burkitt lymphoma of the brain in an immunocompetent patient . Case report. J Neurosurg . 2002 ; 96 : 1127 – 9 . 12066916 10.3171/jns.2002.96.6.1127

140 Patel PA , Anand AS , Parikh SK , Patel AD , Kulkarni RS . Primary central nervous system burkitt lymphoma in HIV positive pediatric patient: a rare case report . J Pediatr Neurosci . 2019 ; 14 : 86 – 9 . 31516626 10.4103/jpn.JPN_81_18 PMC6712912

141 Bower K , Shah N . Primary CNS burkitt lymphoma: a case report of a 55‐year‐old cerebral palsy patient . Case Rep Oncol Med . 2018 ; 2018 : 5869135 . 30034894 10.1155/2018/5869135 PMC6035833

142 Silfen ME , Garvin JH Jr , Hays AP , Starkman HS , Aranoff GS , Levine LS . Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism . J Pediatr Hematol Oncol . 2001 ; 23 : 130 – 3 . 11216706 10.1097/00043426-200102000-00013

143 Spath‐Schwalbe E , Genvresse I , Stein H , Gelderblom H , Lehmann R , Budach V , et al. Primary cerebral highly‐malignant B‐cell lymphoma of the Burkitt type . Dtsch Med Wochenschr . 1999 ; 124 : 451 – 5 . 10326601 10.1055/s-2007-1024333

144 Wilkening A , Brack M , Brandis A , Heidenreich F , Dengler R , Weibetaenborn K . Unusual presentation of a primary spinal Burkitt's lymphoma . J Neurol Neurosurg Psychiatry . 2001 ; 70 : 794 – 7 . 11385017 10.1136/jnnp.70.6.794 PMC1737392

145 Hayabuchi N , Shibamoto Y , Onizuka Y . Primary central nervous system lymphoma in Japan: a nationwide survey . Int J Radiat Oncol Biol Phys . 1999 ; 44 : 265 – 72 . 10760418 10.1016/s0360-3016(98)00564-1

146 Ferreri AJ , Reni M , Pasini F , Calderoni A , Tirelli U , Pivnik A , et al. A multicenter study of treatment of primary CNS lymphoma . Neurology . 2002 ; 58 : 1513 – 20 . 12034789 10.1212/wnl.58.10.1513

147 Menon MP , Nicolae A , Meeker H , Raffeld M , Xi L , Jegalian AG , et al. Primary CNS T‐cell lymphomas: a clinical, morphologic, immunophenotypic, and molecular analysis . Am J Surg Pathol . 2015 ; 39 : 1719 – 29 . 26379152 10.1097/PAS.0000000000000503 PMC4644095

148 Zing N , Fischer T , Federico M , Chiattone C , Ferreri AJ . Diagnosis, prevention and treatment of central nervous system involvement in peripheral t‐cell lymphomas . Crit Rev Oncol Hematol . 2021 ; 167 : 103496 . 34653598 10.1016/j.critrevonc.2021.103496

149 Shenkier TN , Blay JY , O'Neill BP , Poortmans P , Thiel E , Jahnke K , et al. Primary CNS lymphoma of T‐cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group . J Clin Oncol . 2005 ; 23 : 2233 – 9 . 15800313 10.1200/JCO.2005.07.109

150 Long H , Li S , Zhang Y , Li R , Fong T , Yang C , et al. Primary central nervous system T‐cell lymphoma: an analysis from the surveillance, epidemiology, and end results program . J Clin Neurosci . 2020 ; 79 : 74 – 9 . 33070923 10.1016/j.jocn.2020.07.020

151 Hirano Y , Miyawaki S , Tanaka S , Taoka K , Hongo H , Teranishi Y , et al. Clinical features and prognostic factors for primary anaplastic large cell lymphoma of the central nervous system. A systematic review . Cancers (Basel) . 2021 ; 13 : 4358 . 34503168 10.3390/cancers13174358 PMC8431692

152 Ellin F , Landström J , Jerkeman M , Relander T . Central nervous system relapse in peripheral T‐cell lymphomas: a Swedish Lymphoma Registry study . Blood . 2015 ; 126 : 36 – 41 . 25957393 10.1182/blood-2014-12-616961

153 Gurion R , Mehta N , Migliacci JC , Zelenetz A , Moskowitz A , Lunning M , et al. Central nervous system involvement in T‐cell lymphoma: a single center experience . Acta Oncol . 2016 ; 55 : 561 – 6 . 27046135 10.3109/0284186X.2015.1118656 PMC5376067

154 Nevel KS , Pentsova E , Daras M . Clinical presentation, treatment, and outcomes of patients with central nervous system involvement in extranodal natural killer/T‐cell lymphoma . Leuk Lymphoma . 2019 ; 60 : 1677 – 84 . 30648449 10.1080/10428194.2018.1551541 PMC7580871

155 Chaput F , Amer R , Baglivo E , Touitou V , Kozyreff A , Bron D , et al. Intraocular T‐cell lymphoma: clinical presentation, diagnosis, treatment, and outcome . Ocul Immunol Inflamm . 2017 ; 25 : 639 – 48 . 27002464 10.3109/09273948.2016.1139733