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Extranodal Marginal Zone Lymphoma of the Central Nervous System
Accepted Manuscript Extra-Nodal Marginal Zone Lymphoma Of The Central Nervous System Adanma Ayanambakkam, Sami Ibrahimi, Khalid Bilal, Mohamad A. Cherry PII:
S2152-2650(17)31012-1
DOI:
10.1016/j.clml.2017.09.012
Reference:
CLML 1010
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 25 July 2017 Accepted Date: 15 September 2017
Please cite this article as: Ayanambakkam A, Ibrahimi S, Bilal K, Cherry MA, Extra-Nodal Marginal Zone Lymphoma Of The Central Nervous System, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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EXTRA-NODAL MARGINAL ZONE LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM Adanma Ayanambakkam 1, Sami Ibrahimi2, Khalid Bilal 2, Mohamad A Cherry
2
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1. Department of Internal Medicine, University of Oklahoma Health Sciences Center 2. Department of Hematology and Oncology, University of Oklahoma Health Sciences Center
:
1579
(Excluding references and tables)
Total pages
:
10
(Title page, main text and references)
References
:
Page 7 - 10
Tables
:
Table 1: Treatment outcomes.
Supplement
:
Description of 70 cases of CNS EMZBL
Abstract (words)
:
249
Key words
:
Extranodal marginal zone lymphoma, central nervous system, MALT lymphoma.
Corresponding Author
:
Mohamad. A Cherry, MD, MS Associate professor of medicine Stephenson’s Cancer center University of Oklahoma Health Sciences Center [email protected] Phone number: 405-271-8299
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Total words
ABSTRACT
BACKGROUND: Extranodal marginal zone lymphoma of the central nervous system (CNS EMZBL) is a rare disease. We present a review of the literature and describe the presentation, differential diagnosis, treatment options and outcomes of CNS EMZBL.
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METHODS:
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Systematic search of PUBMED, Medline and EMBASE databases via OVID engine for primary articles and case reports yielded 37 unduplicated peer reviewed articles of CNS EMZBL. We identified 69 cases in these articles and 1 unreported case at our institution, which were included for the analysis in this review. RESULTS:
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Median age of diagnosis was 55 years (range 18 - 78) with a female preponderance 77% (n=54). Most common presenting symptoms were headaches in 43% (n=30), seizures in 31% (n=22) and visual defects in 27% (n=19). The most common treatment modalities were localized therapies used in 67% (n=47) of cases. These included, radiotherapy in 27% (n=19), radiotherapy with surgery in 24% (n=17) and surgery alone in 16% (n=11). 90% (n=63) of patients had a median follow up of 23 months. Complete remission was achieved in 77% (n=49) of patients and 22% (n= 14) were alive with disease. Three patients had evidence of relapse and one patient died.
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CONCLUSION:
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CNS EMZBL is an indolent, low-grade, radiosensitive lymphoma with good treatment outcomes and prognosis. It is an important differential to consider in extra-axial dural based masses. Individualized management plans with preference to localized treatment options, should be considered after factoring in the site and extent of disease, resectability and expected adverse effects of systemic therapy.
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INTRODUCTION:
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Marginal Zone B-Cell Lymphoma (MZBL) is a non-Hodgkin lymphoma (NHL) arising from the postgerminal center marginal zone B cells. MZBL is further sub classified into extra-nodal marginal zone B cell lymphoma (EMZBL), nodal marginal zone B cell lymphoma and splenic marginal zone B cell lymphoma (SMZBL) (1). A multi centric study of 1378 cases of NHL revealed that MZBL accounts for 5% to 17% of all NHLs (2). Primary NHLs of the CNS, which account for less than 1% of all NHL cases, are usually aggressive lymphomas and have a poor prognosis (16). They usually present as masses in hemispheric white or deep gray matter and very rarely occur as isolated meningeal lesions. CNS EMZBL on the other hand, most commonly occurs as extra-axial dural-based masses. It is the most common primary CNS low-grade lymphoma and has a good prognosis regardless of treatment modality.
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Given the rarity of this entity, no randomized or prospective trials exist to evaluate different treatment options. Management of CNS EMZBL is currently extrapolated from the management of this disease occurring at other sites of the body. A literature review of CNS EMZBL to better understand the etiology, epidemiology and treatment outcomes was undertaken.
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METHODS:
RESULTS: Presenting features:
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A systematic search of PUBMED, Medline and EMBASE databases via OVID engine for primary articles and case reports yielded 37 unduplicated peer reviewed articles of CNS EMZBL. Search keywords included “Extranodal marginal zone lymphoma”, “Central nervous system” and “MALT lymphoma” used in different combinations. The search included publications before January 2017 and was limited to cases reported in the English language. We identified 69 published cases with available references and 1 unreported case at our institution, which were included for the analysis in this review. Cases reported within review articles without available references were not included in this study to avoid duplication of cases. A detailed clinical summary of each of the 70 cases is provided in Table 2. supplementary appendix. We used descriptive statistics to report the epidemiology, presenting features, treatment modalities and clinical outcomes.
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A significant female preponderance was identified (77% females, n=54). Median age of diagnosis was 55 years with a range from 18 to 78 years. A proportional increase in incidence with advancing age was noticed. Age < 20 (n=1), age 21-30 (n=2), age 31-40 (n=11), age 41-50 (n=16), age 51-60 (n=18) and age ≥ 61 (n=22). Patients presented with a wide range of clinical symptoms. Most common were, headaches in 43% of the cases (n=30), Seizures in 31% of the cases (n=22) and vision changes in 27% of the cases (n=19). Other presenting features included both focal signs (paresthesia, motor deficits, and ataxia) and non-focal signs (memory deficits and dizziness).
Site of involvement:
CNS EMZBL occurred at various sites ranging from dura to deep parenchyma. The most common location was within the dura (80%, n=56). Parenchymal involvement was the next most common location (n=6). Other less common sites of involvement included, cavernous sinus (n=4), choroid plexus (n=3) and cerebellopontine angle (n=2). Evidence of leptomeningeal involvement was found in 3 patients (Intraventricular mass n=1, and optic nerve n=2). Only one case of extracranial spread with multifocal involvement was identified (spinous involvement) (41). 19 cases were evaluated for
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cerebrospinal fluid involvement among which 5 were positive. Systemic disease at the time of diagnosis was not reported in any case. Diagnosis:
Immunohistochemistry (IHC) & molecular studies:
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Diagnosis of CNS EMZBL was established based on histopathologic findings. Misdiagnosis based on morphologic features on brain imaging was common. The most common misdiagnosis was meningioma (54%, n=38). Seven cases including 1 case at our institution were initially diagnosed as a subdural hematoma. Less common misdiagnosis included glioma, vasculitis, schwannoma, inflammatory pseudotumor and multiple sclerosis.
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Clinicopathologic and genetic profiling data are based on a study by Tu PH et al. (18) In this study, partial or complete trisomy of chromosome 3 was the most common numerical chromosomal abnormality, which was found in six out of the twelve cases tested. Despite the association with trisomy 3, no significant association with Bcl-6 has been established (18). Ki67 was consistently below 15% in all cases that were tested. No significant association with recurrent translocations or infectious etiologies was established in any of the cases. Treatment modalities:
The analysis of outcomes of different treatment modalities was performed and presented in Table 1. Surgery, chemotherapy and radiotherapy have been utilized in various combinations to treat CNS EMZBL. Localized treatment options including radiotherapy alone (n=19), radiotherapy with surgery (n=17) and surgery alone (n=11) were the most commonly used treatment options (67%, n=47). Various chemotherapy regimens including combinations of systemic and intrathecal chemotherapy have been utilized as detailed in the supplementary appendix.
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Outcomes
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Outcome data was available on 90% (n=63) cases. After a median follow up of 23 months, complete remission (CR) was achieved in 77% of patients and 22% of patients were alive with evidence of disease at follow up. Among the 47 patients that received localized therapies CR was achieved in 79% and 21% were alive with disease at follow up. In 22/23 patients who received systemic treatment, CR was achieved in 73% and 22% were alive with disease at follow up. Three cases of recurrence have been documented, of which 2 were local recurrences (18,31) and 1 was recurrence of EMZBL in the pelvis (39). One recurrence occurred following surgery and chemotherapy and a second CR was achieved with chemotherapy (39). Another recurrence occurred following surgery, chemotherapy and radiotherapy. Chemotherapy was used as second line treatment but patient died due to complications from sepsis (31).
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DISCUSSION:
Despite being classified as a single disease entity, there appears to be increasing evidence to support a significant clinical, pathological and etiological difference among MZBLs occurring at different anatomic sites (4,5). A population based incidence study in the United States, identified distinctive MZBL incidence patterns by primary site of disease and supported the etiological diversity suggested in prior clinical series (6). Extra-nodal marginal zone B cell lymphoma, otherwise known as mucosa associated lymphoid tissue (MALT) lymphoma, is the most common MZBL. Extra-nodal marginal zone B cell lymphoma accounts for approximately 70% of all MZBL (3) and is the third most common NHL (2). Extra-nodal marginal zone B cell lymphoma is more common in females with a median age of onset of 60 years (2). First described in the GI tract in 1983 (7), it has subsequently been described in various non-mucosal sites such as the lung, bladder, salivary glands, conjunctiva, lacrimal glands and the central nervous system. The
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association of EMZBL with various infectious and autoimmune etiologies has been frequently demonstrated (8-15). Zinzani et al hypothesized that chronic, auto antigenic stimulation results in lymphoid infiltrates at extra nodal sites normally devoid of lymphoid tissue (3). Remission of disease following treatment of these inflammatory conditions in certain cases provides further evidence to this hypothesis.
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Despite the absence of mucosal tissue or MALT tissue in the CNS, numerous cases of EMZBL in the CNS presenting as extra-axial dural-based masses have been reported. Kumar et al. hypothesized that meningothelial cells are similar to the epithelia at other sites, and are the cells of origin of CNS EMZBL (17) . Meningothelial cells are also the cells of origin for meningiomas, which could explain the common site of occurrence of CNS EMZBL and meningiomas.
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Extra-nodal marginal zone B cell lymphoma has been associated with multiple genetic abnormalities. Trisomy 3 is the most common numeric chromosomal abnormality. It is hypothesized that trisomy 3 results in over-expression of proto-oncogene Bcl-6, located at 3q. BCL-6 has been implicated in germinal center proliferation and subsequent tumorigenesis in EMZBL. Four recurrent translocations are associated with EMZBL. Translocations t(11;18) (q21;q21), t(14;18) (q32;q21) and t(1;14) (p22;q32) result in activation of NF-kappa B through the BCL-10/MALT1 signaling complex (54). Translocation t(3;14) (p13;q32) with FOXP1 gene expression has been well described and is associated with poor prognosis (55). These common translocations occurring in EMZBL at various other sites have not been reported in CNS EMZBL.
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The majority of cases reported in the literature show that complete remission could be achieved with localized therapies including radiotherapy and surgery. Moreover, Fabio et al. demonstrated that whole brain radiotherapy with doses as low as 20 grays can also result in complete remission (44). An important finding was the presence of malignant cells in the cerebrospinal fluid (CSF) in 5 out of 19 cases tested on presentation. Currently the role of intrathecal chemotherapy either prophylactically or therapeutically is unknown. The added benefit of adjuvant systemic therapy remains unclear and the number of cases using systemic therapy as primary treatment is too small to draw any definitive conclusions.
CONCLUSION:
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Central nervous system EMZBL is an indolent, low-grade, radiosensitive lymphoma with good treatment outcomes and prognosis. It is an important entity to consider in the differential diagnosis of patients presenting with extra-axial dural-based masses that are commonly misdiagnosed as meningioma. Definitive diagnosis of CNS EMZBL is based on histopathologic findings and not radiographic imaging. Despite EMZBL at other sites being associated with infectious and chromosomal abnormalities, such associations have not been reported in CNS EMZBL.
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Individualized management plans with preference to localized treatment options, should be considered after factoring in the site and extent of disease, surgical resectability and expected adverse effects of systemic therapy. Evaluation for CSF involvement at presentation and the addition of systemic therapy with either rituximab alone or with combination of systemic chemotherapy should be considered. Future prospective studies are needed to define high-risk features that would warrant the added toxicity from systemic therapy.
CONFLICTS OF INTEREST: The authors declare that they have no conflict of interest.
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Oct;32(5):384-92. doi: 10.5414/NP300579. (36) A 44-year old male with right-sided facial numbness. Dura-associated extranodal marginal zone B cell lymphoma (MALT lymphoma). Neidert MC et al., Brain Pathol. 2015 Jan;25(1):113-4. doi: 10.1111/bpa.12234.
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TABLE 1 - ANALYSIS OF TREATMENT OUTCOMES IN CNS EMZBL
Not Evaluated
FOLLOW UP
Complete Response
Alive with disease
Recurrence
DEATHS
Radiotherapy
19
-
Median: 12 months Range: 1 – 64 months
14
5
-
-
Surgery
11
5
Median: 23 months Range: 18 - 48 months
4
2
-
-
Chemotherapy
3
-
Median: 23 months Range: 22 - 24 months
1
2
-
-
Radiotherapy + Surgery
17
-
Median: 23 months Range: 1 – 36 months
Chemotherapy + Surgery
4
-
Median: 2 months Range: 1 – 33 months
Chemotherapy + Radiotherapy
9
1
Surgery + Chemotherapy + Radiotherapy
7
-
70
6
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2
-
-
2
2
1
-
Median: 25 months Range: 6 - 86 months
8
-
-
-
Median: 47 months Range: 20 - 78 months
5
1
2
1
49
14
3
1
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TREATMENT
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INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
OUTCOME
REF
Right cavernous sinus
Meningioma
Lambda light chain restriction
NR
NED at 63mo
17
Left tentorial mass
Meningioma
Lambda light chain restriction
NR
NED at 9 mo
17
Seizures
Left anterior falx cerebri
Meningioma
+VJ PCR Ig heavy chain rearrangement
NR
NED at 14 mo
17
F
Vision changes
Dura, Cerebellar tentorium
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 45 mo
18
59
F
Vision changes Unsteady gait
Dura, Falx cerebri
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 32 mo
18
6
53
F
Headache Vision changes
Dura, Sella, suprasellar
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 11 mo
18
7
18
M
Hemiparesis Dysarthria , dizziness
Left basal ganglia
Glioma
CD 20 & CD 79a positive. CD3, CD5, CD10, BCL6, CD23 negative. MUM1, ALK1 and cyclin D1 negative. EBV negative
Negative
NED at 12 mo
19
8
70
F
Headache, Ataxia Vision changes
Diffuse dural thickening with fat infiltration of left orbit
Vasculitis
L26 Ab positive. CD3, CD5, CD10, cyclin-D1, and TdT negative. EBV negative
Negative
AWD at 12 mo
22
9
57
F
Vision changes
Right cavernous sinus
Schwannoma
Small B-Cell kappa restricted monoclonal cells that were CD10 and CD5 negative.
Negative
NED at 24 mo
23
10
48
M
Seizures
Left frontal subcortex
Glioma
CD20 and BCL 2 positive. CD5, CD10, CD23, CD43 & cyclin D1 negative. FISH IGH BCL2 & IGH CCND negative. Ki67 2-5%
Negative
NED at 15 mo
26
11
39
F
Headache Vision changes
Posterior fossa
NR
Kappa light chain restriction
NR
AWD at 12 mo
27
12
62
F
Headache
Left parieto-occipital lobe
Meningioma with subdural hematoma
CD 20 & CD 79a positive. CD5, CD10, CD11c, CD23 and CD 43 negative. Rearrangement of Ig heavy chain focus
NR
AWD at 6 mo
28
13
60
F
Headache Numbness
LT parieto-occipital dura
Meningioma with subdural hematoma
CD20, CD79 and BCL-2 positive. CD3, CD5, CD10, CD23 and BCL-6 negative. Monoclonal Ig heavy chain rearrangement
NR
NED at 24 mo
35
14
45
M
Seizures Hemiparesis, dysarthria
Right parietal sulci
Carcinomatous meningitis
CD20 positive. Scattered CD3 positivity. Strong lambda light chain staining
Negative
NED at 64 mo
38
43
F
3
57
F
4
70
5
SC
2
Numbness Vision changes Headache, Numbness Vision changes
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40
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PRESENTING SYMPTOMS
AC C
SEX
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SITE
AGE
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TABLE 2.1 - PATIENTS TREATED WITH RADIOTHERAPY ALONE (CONTD)
AGE
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
15
51
F
Headache
Dural, Bifrontal lobe
NR
16
50
F
Seizures, headache Vision changes
Dural, Right frontal lobe
NR
17
59
M
Dysarthria, numbness
Left posterior temporal lobe abutting dura
NR
18
63
F
Seizures, dysarthria
Dural, falx cerebri with meningeal amyloid deposition
NR
19
61
F
Dizziness, nausea vomitting
Dura, posterior cranial fossa
REF
CD20, CD79a and BCL-2 positive. CD3, CD5, CD10, Cyclin D1 negative.
Negative
NED at 8 mo
44
CD20 and CD79a positive. CD3, CD5, CD10, Cyclin D1 and BCl-2 negative
Negative
NED at 5 mo
44
CD 20 CD79a positive. cyclin D1 negative CD3, CD5, CD21, CD23, CD10 negative. FISH IgH MALT 1 positive. t(14:18) (q32;21).
NR
AWD at 1 mo
45
NR
NR
AWD at 8 mo
48
CD 20 and CD79a positive. CD5, CD10, CD23 and CD43 negative. Kappa light chain restriction, EBV negative
NR
NED at 6 mo
50
SC
OUTCOME
M AN U
TE D
AC C
EP
NR
CSF
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TABLE 2.2 - PATIENTS TREATED WITH SURGERY ALONE
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
OUTCOME
REF
1
56
F
NR
Dura, Falx
Meningioma
CD 20 positive, CD3 negative. MALT 1 negative, Trisomy 3 positive
NR
NR
18
2
55
F
NR
Dura, Posterior fossa
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
3
45
F
NR
Dura, Middle cranial fossa
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
4
68
F
NR
NR
Meningioma
CD 20 positive, CD3 negative Trisomy 3 positive
NR
NR
18
5
61
F
Headache Nausea and vomitting
Dura, Frontotemporal lobe
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 21 mo
18
6
47
M
Facial droop, numbness, Dysarthria
Parietal dura
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
7
56
F
Seizures Dizziness
Frontal lobe
Meningioma
CD 20 and CD 43 positive. Light chain restriction
NR
AWD at 18 mo
21
8
28
F
Tinnitus Nausea and vomitting
Left Cerebellopontine angle
Inflammatory pseudotumor
CD 20 and CD 43 positive. BCL 2 positive in some follicular centers
NR
NED at 24 mo
25
9
39
F
Hearing loss Facial pain
Cerebello-pontine angle
Meningioma with subdural hematoma
CD 20 & CD 79a positive. CD5 CD10 CD11c CD23 and CD 43 negative. Kappa light chain restriction
NR
AWD at 48 mo
28
10
67
F
Hemiparesis Dysphasia
Fronto-parietal lobe
Convexity menigioma
CD 20 and CD 43 positive. BCL 2 positive. CD3 CD5 CD10 and CD23 negative. EMA negative. Lambda light chain restriction
NR
NED at 36 mo
30
11
56
F
Seizures Dizziness
Dural, right frontal lobe
NR
NR
NR
NED at 18 mo
49
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M AN U
SC
AGE
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TABLE 2.3 - PATIENTS TREATED WITH CHEMOTHERAPY ALONE
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
62
F
Seizures
Biparietal dural thickening
Meningioma
+VJ PCR Ig heavy chain rearrangement Lambda light chain restriction.
NR
Systemic fludrabine
NED at 22mo
17
Frontal lobe sulci
Multiple sclerosis
Lambda restricted plasmacytoid cells
Positive
Systemic Methotrexate + Intrathecal Methotrexate and cytrarabine
AWD at 24 mo
40
Occipital lobe, temporal lobe and spinal cord (multiple lesions)
NR
CD20 and CD38 positive. CD3 CD5 and CD10 negative. EBV RNA and EBV IgM negative
Negative
Systemic Methotrexate and Cytarabine
AWD at 24 mo
41
53
M
Memory deficits Unsteady gait Urinary incontinence
SC
3
M AN U
F
TE D
39
EP
2
Vision defects Nystagmus
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SEX
AC C
1
AGE
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TABLE 2.4 - PATIENTS TREATED WITH SURGERY AND RADIOTHERAPY
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
1
66
M
Seizures
Frontal lobe
NR
2
29
F
NR
Dura, Subdural
Meningioma
3
62
F
Ataxia
Dura, Occipital lobe
Meningioma
4
66
F
Seizures, Syncope
Parietal lobe
5
64
F
Hemiparesis
Right frontoparietal dura
6
46
F
7
44
M
8
35
M
9
70
F
10
44
F
Headache Nausea and vomitting
11
55
F
Seizures
12
39
F
13
49
F
14
47
M
Visual loss Focal paraesthesia Seizures Focal paraesthesia Seizures, visual changes Memory deficits
15
53
M
Headache, seizures
16
63
F
Headaches, Ataxia
17
78
M
Headaches, leg weakness
Meningioma
Fronto-parietal lobe
NR
Right frontal convexity
NR
Inter hemispheric cissura
NR NR
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Trigonal choroid plexus
Meningioma en plaque
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Left frontal lobe adjacent to dura Dural, Left frontal and Right sphenoidal Dural, Right parietal lesion
CD 20 positive, CD3 negative. Trisomy 3 positive.MALT1 & IgH translocation negative CD 20 positive, CD3 negative. MALT 1 translocation negative CD 20 positive, CD3 negative. Trisomy 3 positive.MALT1 & IgH translocation negative CD 20 positive
CD 20 positive. CD5, CD23 and cyclin D1 negative. MNF116 negative, Ki-67 6.19% L26 positive. Kappa light chain restriction. +VJ PCR Ig heavy chain gene rearrangement
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Cavernous sinus
NR NR
Left tentorial lesion
Meningioma
Choroid plexus
NR
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Headache Vision changes Facial numbness Involuntary muscle movement Headaches Sezures, night sweats Headache, diplopia Vertigo
Meningioma with subdural hematoma Meningioma with subdural hematoma
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
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SEX
SC
AGE
Dura, anterior falx
Meningioma
Dura, corpus callosum
Meningioma
CD20, CD45, CD79a and BCL2 positive. CD34, CD99, EMA and TDT negative. Ki67 10%.
CD20, BCL 2 positive, CD10, CyclinD1 negative. Trisomy 3 negative. IgH-MALT1 negative CD20, BCL 2 positive, CD10, CyclinD1 negative. Trisomy 3 negative. IgH-MALT1 negative CD 20 positive. CD3, CD5, CD10, CD23, CD27, CD43 negative DBA44, TCL-1, T-bet and cyclin D1 negative. CD 20 positive. Rare CD3 positive lymphocytes CD 5 CD 10 CD 23 and cyclin D1 negative. CD20 positive. CD3, CD5, CD10, CD23 and Cyclin D1 negative. CD20 positive. CD5, CD10, Cyclin D1 and BCL-2 negative CD20and CD79a positive. CD5, CD10, CD3 and CD23 negative FISH normal, no trisomy 3 CD 20 positive. BCL2 negative. IgG lambda chain restricted CD 19 and CD20 positive
TABLE 2.5 - PATIENTS TREATED WITH CHEMOTHERAPY AND SURGERY
CSF
OUTCOME
REF
NR
NED at 13 mo
18
NR
NED at 36 mo
18
NR
NED at 25 mo
18
NR
NED at 12 mo
20
NR
NED on Rx
24
NR
AWD at 15 mo
32
NR
NED at 24 mo
36
NR
NED at 36 mo
39
NR
NED at 12 mo
39
NR
AWD at 25 mo
42
NR
NED at 36 mo
43
NR
NED at 5 mo
44
Positive
NED at 7 mo
44
Negative
NED at 27 mo
44
NR
NED at 12 mo
47
Negative
NED at 23 mo
53
Negative
NED at 48 mo
53
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SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
49
M
Seizures
Dura, Frontal lobe
Meningioma
CD 20 positive, CD3 negative. Trisomy 3 positive. MALT1 & IgH translocation negative
NR
Methotrexate. Recurrence treated with Fludrabine
Rec at 4mo, NED after Rx
18
2
56
M
Headache, memory deficits, vision changes
Dura, frontal lobe extending to ethmoidal sinus
Meningioma
NR
Methotrexate and rituximab
AWD at 1 mo
33
Meningioma
CD20, bcl-2, and MUM-1 positive. CD3, CD5, CD10, cyclin D1 negative BCL- 6 negative. Ki-67 15%
Negative
Cyclophosphamide + Vincristine + Prednisone
NED at 33 mo
34
NR
CD10, CD23, BCL-1 (cyclin D1) negative BCL-6 negative.
NR
Rituximab and bendamustine
AWD at 2mo
37
Headache
4
77
F
Headache Aggression
Bilateral frontal lobe extra-axial mass
SC
M
M AN U
69
CD20 positive. Plasma cells immunoglobulin G positive
AC C
EP
TE D
3
Frontal mass with dural attachment to falx cerebri and superior sagittal sinus
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AGE
TABLE 2.6 - PATIENTS TREATED WITH CHEMOTHERAPY AND RADIOTHERAPY
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SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
52
F
Seizures Focal numbness
Frontal lobe
Meningioma
Kappa light chain restriction. +VJ PCR Ig heavy chain rearrangement
NR
Cytarabine + methotrexate and Intrathecal methotrexate
NED at 7 mo
17
2
36
F
Seizures Headache
Parietal lobe & Falx cerebri
meningioma
NR
High dose methotrexate
NR
29
3
33
F
Seizure Vision Changes
Dural, Frontotemporal Intraventricular
NR
NR
Intrathecal Methotrexate and Cytarabine
NED at 86 mo
44
4
35
M
Headache Numbness Focal paresthesia
Dural, Frontoparietal
NR
Positive
Methotrexate+ vincristine, temozolomide + rituximab and Intrathecal thiotepa
NED at 53 mo
44
5
38
F
Headache
Frontoparietal
Meningioma
NR
NR
NR
NR
NR
Subdural hematoma
CD19 and CD10 positive. CD5, CD10, CD23 and Cyclin D1 negative. Ki67 5-10%
NR
NR
NED at 6 mo
51
NR
NR
Systemic methotrexate and intrathecal chemotherapy
NED at 36 mo
52
CD20 positive. CD10 and BCL-2 negative. Lambda chain restricted IgG
Positive
Rituximab
NED at 25 mo
53
F
Headache
Meningioma
7
45
F
Seizures, Dysphasia
8
75
F
Behavioral disorder, memory deficit, aphasia
Dural, Frontal
NR
9
61
F
Headaches, Vision deficits
Cavernous sinus and optic nerve
NR
SC
M AN U
45
NR
AC C
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6
CD20 positive. CD34 negative. EMA positive. Kappa light chain restriction. Ki67 <10%. CD20 positive. CD3, CD23, Cyclin D1 negative. BCL2 positive CD20, BCL2 positive CD3, CD5, CD10, CD23 Cyclin D1 negative.
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Temporal, parieto-occipital Dural, frontotemporoparietal
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AGE
TABLE 2.7 - PATIENTS TREATED WITH SURGERY, CHEMOTHERAPY AND RADIOTHERAPY
NED at 24 mo NED at 12 mo
46 46
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SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
33
F
Seizures Headache Vision changes
Parietal convexity
Meningioma with subdural hematoma
CD5, CD10, CD20 and CD23 positive. BCL-2 negative. Ki67 <10%
Negative
Rituximab
NED at 12 mo
Our case
2
57
F
Arm pain
Dura, Frontoparietal
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
Procarbazine,+ vincristine + cytarabine + methotrexate
NED at 66 mo
18
3
48
F
Headache, ear pain
Dura, tentorium, falx
Meningioma
CD 20 positive, CD3 negative. Trisomy 3 positive MALT1 & IgH translocation negative
NR
Methotrexate + leucovorin
NED at 20 mo
18
Frontotemporoparietal dura
Meningioma
CD20 and BCL-2 positive. CD5, CD10, CD21, p53 and EMA negative. Lambda light chain restriction.
NR
Surgery, radiotherapy and chemotherapy. Recurrence Treated with adjuvant chemotherapy.
Rec at 12mo. Died at 24 mo due to sepsis
31
N/a
CD 20 and BCL 2 positive. CD 10 and cyclin D1 negative. FISH for trisomy 3 negative. IgH-MALT1 negative
NR
SX + XRT w. recurrence. Rituximab + cyclophosphamide + doxorubicin + vincristine
Recurrence in pelvis AWD at 47 mo
39
NED at 78 mo
44
NED at 30 mo
53
48
F
Headache Vision changes
Occipital and Parietal lobe
Dural, Temporoparietal lobe
N/a
Posterior fossa
N/a
64
F
7
74
F
Headache Dizziness
N/a
Positive
IgG lambda chain restricted
Negative
AC C
6
Headache Facial weakness
SC
5
M AN U
F
TE D
59
EP
4
Seizures Headache Facial weakness
KEY: AWD MO NR NED REF
: : : : :
RI PT
AGE
Alive with disease Months Not reported No evidence of disease Reference
Methotrexate + Vincristine + Procarbazine + Cytarabine ntrathecal methotrexate
Rituximab + Cyclophosphamide + Vincristine + Prednisone and Intrathecal methotrexate
S2152-2650(17)31012-1
DOI:
10.1016/j.clml.2017.09.012
Reference:
CLML 1010
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 25 July 2017 Accepted Date: 15 September 2017
Please cite this article as: Ayanambakkam A, Ibrahimi S, Bilal K, Cherry MA, Extra-Nodal Marginal Zone Lymphoma Of The Central Nervous System, Clinical Lymphoma, Myeloma and Leukemia (2017), doi: 10.1016/j.clml.2017.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
EXTRA-NODAL MARGINAL ZONE LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM Adanma Ayanambakkam 1, Sami Ibrahimi2, Khalid Bilal 2, Mohamad A Cherry
2
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1. Department of Internal Medicine, University of Oklahoma Health Sciences Center 2. Department of Hematology and Oncology, University of Oklahoma Health Sciences Center
:
1579
(Excluding references and tables)
Total pages
:
10
(Title page, main text and references)
References
:
Page 7 - 10
Tables
:
Table 1: Treatment outcomes.
Supplement
:
Description of 70 cases of CNS EMZBL
Abstract (words)
:
249
Key words
:
Extranodal marginal zone lymphoma, central nervous system, MALT lymphoma.
Corresponding Author
:
Mohamad. A Cherry, MD, MS Associate professor of medicine Stephenson’s Cancer center University of Oklahoma Health Sciences Center [email protected] Phone number: 405-271-8299
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Total words
ABSTRACT
BACKGROUND: Extranodal marginal zone lymphoma of the central nervous system (CNS EMZBL) is a rare disease. We present a review of the literature and describe the presentation, differential diagnosis, treatment options and outcomes of CNS EMZBL.
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METHODS:
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Systematic search of PUBMED, Medline and EMBASE databases via OVID engine for primary articles and case reports yielded 37 unduplicated peer reviewed articles of CNS EMZBL. We identified 69 cases in these articles and 1 unreported case at our institution, which were included for the analysis in this review. RESULTS:
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Median age of diagnosis was 55 years (range 18 - 78) with a female preponderance 77% (n=54). Most common presenting symptoms were headaches in 43% (n=30), seizures in 31% (n=22) and visual defects in 27% (n=19). The most common treatment modalities were localized therapies used in 67% (n=47) of cases. These included, radiotherapy in 27% (n=19), radiotherapy with surgery in 24% (n=17) and surgery alone in 16% (n=11). 90% (n=63) of patients had a median follow up of 23 months. Complete remission was achieved in 77% (n=49) of patients and 22% (n= 14) were alive with disease. Three patients had evidence of relapse and one patient died.
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CONCLUSION:
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CNS EMZBL is an indolent, low-grade, radiosensitive lymphoma with good treatment outcomes and prognosis. It is an important differential to consider in extra-axial dural based masses. Individualized management plans with preference to localized treatment options, should be considered after factoring in the site and extent of disease, resectability and expected adverse effects of systemic therapy.
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INTRODUCTION:
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Marginal Zone B-Cell Lymphoma (MZBL) is a non-Hodgkin lymphoma (NHL) arising from the postgerminal center marginal zone B cells. MZBL is further sub classified into extra-nodal marginal zone B cell lymphoma (EMZBL), nodal marginal zone B cell lymphoma and splenic marginal zone B cell lymphoma (SMZBL) (1). A multi centric study of 1378 cases of NHL revealed that MZBL accounts for 5% to 17% of all NHLs (2). Primary NHLs of the CNS, which account for less than 1% of all NHL cases, are usually aggressive lymphomas and have a poor prognosis (16). They usually present as masses in hemispheric white or deep gray matter and very rarely occur as isolated meningeal lesions. CNS EMZBL on the other hand, most commonly occurs as extra-axial dural-based masses. It is the most common primary CNS low-grade lymphoma and has a good prognosis regardless of treatment modality.
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Given the rarity of this entity, no randomized or prospective trials exist to evaluate different treatment options. Management of CNS EMZBL is currently extrapolated from the management of this disease occurring at other sites of the body. A literature review of CNS EMZBL to better understand the etiology, epidemiology and treatment outcomes was undertaken.
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METHODS:
RESULTS: Presenting features:
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A systematic search of PUBMED, Medline and EMBASE databases via OVID engine for primary articles and case reports yielded 37 unduplicated peer reviewed articles of CNS EMZBL. Search keywords included “Extranodal marginal zone lymphoma”, “Central nervous system” and “MALT lymphoma” used in different combinations. The search included publications before January 2017 and was limited to cases reported in the English language. We identified 69 published cases with available references and 1 unreported case at our institution, which were included for the analysis in this review. Cases reported within review articles without available references were not included in this study to avoid duplication of cases. A detailed clinical summary of each of the 70 cases is provided in Table 2. supplementary appendix. We used descriptive statistics to report the epidemiology, presenting features, treatment modalities and clinical outcomes.
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A significant female preponderance was identified (77% females, n=54). Median age of diagnosis was 55 years with a range from 18 to 78 years. A proportional increase in incidence with advancing age was noticed. Age < 20 (n=1), age 21-30 (n=2), age 31-40 (n=11), age 41-50 (n=16), age 51-60 (n=18) and age ≥ 61 (n=22). Patients presented with a wide range of clinical symptoms. Most common were, headaches in 43% of the cases (n=30), Seizures in 31% of the cases (n=22) and vision changes in 27% of the cases (n=19). Other presenting features included both focal signs (paresthesia, motor deficits, and ataxia) and non-focal signs (memory deficits and dizziness).
Site of involvement:
CNS EMZBL occurred at various sites ranging from dura to deep parenchyma. The most common location was within the dura (80%, n=56). Parenchymal involvement was the next most common location (n=6). Other less common sites of involvement included, cavernous sinus (n=4), choroid plexus (n=3) and cerebellopontine angle (n=2). Evidence of leptomeningeal involvement was found in 3 patients (Intraventricular mass n=1, and optic nerve n=2). Only one case of extracranial spread with multifocal involvement was identified (spinous involvement) (41). 19 cases were evaluated for
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cerebrospinal fluid involvement among which 5 were positive. Systemic disease at the time of diagnosis was not reported in any case. Diagnosis:
Immunohistochemistry (IHC) & molecular studies:
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Diagnosis of CNS EMZBL was established based on histopathologic findings. Misdiagnosis based on morphologic features on brain imaging was common. The most common misdiagnosis was meningioma (54%, n=38). Seven cases including 1 case at our institution were initially diagnosed as a subdural hematoma. Less common misdiagnosis included glioma, vasculitis, schwannoma, inflammatory pseudotumor and multiple sclerosis.
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Clinicopathologic and genetic profiling data are based on a study by Tu PH et al. (18) In this study, partial or complete trisomy of chromosome 3 was the most common numerical chromosomal abnormality, which was found in six out of the twelve cases tested. Despite the association with trisomy 3, no significant association with Bcl-6 has been established (18). Ki67 was consistently below 15% in all cases that were tested. No significant association with recurrent translocations or infectious etiologies was established in any of the cases. Treatment modalities:
The analysis of outcomes of different treatment modalities was performed and presented in Table 1. Surgery, chemotherapy and radiotherapy have been utilized in various combinations to treat CNS EMZBL. Localized treatment options including radiotherapy alone (n=19), radiotherapy with surgery (n=17) and surgery alone (n=11) were the most commonly used treatment options (67%, n=47). Various chemotherapy regimens including combinations of systemic and intrathecal chemotherapy have been utilized as detailed in the supplementary appendix.
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Outcomes
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Outcome data was available on 90% (n=63) cases. After a median follow up of 23 months, complete remission (CR) was achieved in 77% of patients and 22% of patients were alive with evidence of disease at follow up. Among the 47 patients that received localized therapies CR was achieved in 79% and 21% were alive with disease at follow up. In 22/23 patients who received systemic treatment, CR was achieved in 73% and 22% were alive with disease at follow up. Three cases of recurrence have been documented, of which 2 were local recurrences (18,31) and 1 was recurrence of EMZBL in the pelvis (39). One recurrence occurred following surgery and chemotherapy and a second CR was achieved with chemotherapy (39). Another recurrence occurred following surgery, chemotherapy and radiotherapy. Chemotherapy was used as second line treatment but patient died due to complications from sepsis (31).
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DISCUSSION:
Despite being classified as a single disease entity, there appears to be increasing evidence to support a significant clinical, pathological and etiological difference among MZBLs occurring at different anatomic sites (4,5). A population based incidence study in the United States, identified distinctive MZBL incidence patterns by primary site of disease and supported the etiological diversity suggested in prior clinical series (6). Extra-nodal marginal zone B cell lymphoma, otherwise known as mucosa associated lymphoid tissue (MALT) lymphoma, is the most common MZBL. Extra-nodal marginal zone B cell lymphoma accounts for approximately 70% of all MZBL (3) and is the third most common NHL (2). Extra-nodal marginal zone B cell lymphoma is more common in females with a median age of onset of 60 years (2). First described in the GI tract in 1983 (7), it has subsequently been described in various non-mucosal sites such as the lung, bladder, salivary glands, conjunctiva, lacrimal glands and the central nervous system. The
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association of EMZBL with various infectious and autoimmune etiologies has been frequently demonstrated (8-15). Zinzani et al hypothesized that chronic, auto antigenic stimulation results in lymphoid infiltrates at extra nodal sites normally devoid of lymphoid tissue (3). Remission of disease following treatment of these inflammatory conditions in certain cases provides further evidence to this hypothesis.
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Despite the absence of mucosal tissue or MALT tissue in the CNS, numerous cases of EMZBL in the CNS presenting as extra-axial dural-based masses have been reported. Kumar et al. hypothesized that meningothelial cells are similar to the epithelia at other sites, and are the cells of origin of CNS EMZBL (17) . Meningothelial cells are also the cells of origin for meningiomas, which could explain the common site of occurrence of CNS EMZBL and meningiomas.
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Extra-nodal marginal zone B cell lymphoma has been associated with multiple genetic abnormalities. Trisomy 3 is the most common numeric chromosomal abnormality. It is hypothesized that trisomy 3 results in over-expression of proto-oncogene Bcl-6, located at 3q. BCL-6 has been implicated in germinal center proliferation and subsequent tumorigenesis in EMZBL. Four recurrent translocations are associated with EMZBL. Translocations t(11;18) (q21;q21), t(14;18) (q32;q21) and t(1;14) (p22;q32) result in activation of NF-kappa B through the BCL-10/MALT1 signaling complex (54). Translocation t(3;14) (p13;q32) with FOXP1 gene expression has been well described and is associated with poor prognosis (55). These common translocations occurring in EMZBL at various other sites have not been reported in CNS EMZBL.
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The majority of cases reported in the literature show that complete remission could be achieved with localized therapies including radiotherapy and surgery. Moreover, Fabio et al. demonstrated that whole brain radiotherapy with doses as low as 20 grays can also result in complete remission (44). An important finding was the presence of malignant cells in the cerebrospinal fluid (CSF) in 5 out of 19 cases tested on presentation. Currently the role of intrathecal chemotherapy either prophylactically or therapeutically is unknown. The added benefit of adjuvant systemic therapy remains unclear and the number of cases using systemic therapy as primary treatment is too small to draw any definitive conclusions.
CONCLUSION:
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Central nervous system EMZBL is an indolent, low-grade, radiosensitive lymphoma with good treatment outcomes and prognosis. It is an important entity to consider in the differential diagnosis of patients presenting with extra-axial dural-based masses that are commonly misdiagnosed as meningioma. Definitive diagnosis of CNS EMZBL is based on histopathologic findings and not radiographic imaging. Despite EMZBL at other sites being associated with infectious and chromosomal abnormalities, such associations have not been reported in CNS EMZBL.
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Individualized management plans with preference to localized treatment options, should be considered after factoring in the site and extent of disease, surgical resectability and expected adverse effects of systemic therapy. Evaluation for CSF involvement at presentation and the addition of systemic therapy with either rituximab alone or with combination of systemic chemotherapy should be considered. Future prospective studies are needed to define high-risk features that would warrant the added toxicity from systemic therapy.
CONFLICTS OF INTEREST: The authors declare that they have no conflict of interest.
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REFERENCES: (1) Swerdlow SH et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms., Blood. 2016;127(20):2375. PMID 26980727
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(2) A clinical evaluation of the international lymphoma study group classification of non-Hodgkin's lymphoma. the non-Hodgkin's lymphoma classification project. Blood 89(11):3909–3918. (3) Zinzani et al., The many faces of marginal zone lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:426-32. doi: 10.1182 (4) Racal et al., Site-specific morphologic differences in extranodal marginal zone B-cell lymphomas. Arch Pathol Lab Med. 2007 Nov;131(11):1673-8.
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(5) Traverse-Glehen et al., Splenic marginal zone B-cell lymphoma: a distinct clinico-pathological and molecular entity. Recent advances in ontogeny and classification. Curr Opin Oncol. 2011 Sep;23(5):4418.
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(6) Khalil MO et al., Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site. Br J Haematol. 2014 Apr;165(1):67-77. Epub 2014 Jan 12. (7) Isaacson P et al., Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983; 52:1410-6. (8) Regression of primary low grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Wotherspoon AC et al., Lancet 1993; 342:575-7.
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(9) Immunoproliferative small intestinal disease associated with Campylobacter Jejuni. Lecuit M et al.,N Engl J Med 2004; 350:239-48. (10) Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. Ferreri AJ et al., J Natl Cancer Inst 2006; 98:1375-82. (11) Borrelia burgdorferi associated cutaneous B cell lymphoma: clinical and immunohistologic characterization of four cases Garbe C et al., J Am Acad Dermatol 1991; 24:584-90.
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(12) Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT. Arcaini L et al., Ann Oncol 2007; 18:346-50
AC C
(13) Salivary gland mucosa associated lymphoid tissue lymphoma in 2 patients with Sjogren's syndrome: clinical and sonographic features with pathological correlation. Lewis K et al., J Clin Ultrasound 2007; 35:97-101. (14) Maltoma of the thyroid in a man with Hashimoto’s thyroiditis. Wozniak R et al., J Clin Endocrinol Metab 1999; 84:1206-9. (15) Primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in a patient with primary biliary cirrhosis. Ye MQ et al., Arch Pathol Lab Med 2000; 124:604-8. (16) Primary central nervous system lymphoma. O'Neill BP et al., Mayo Clin Proc 1989;64:1005-20. (17) Primary low-grade B-cell lymphoma of the dura: a mucosa associated lymphoid tissue-type lymphoma. Kumar et al ., Am J Surg Pathol 1997; 21:81-7. (18) Clinicopathologic and genetic profile of intracranial marginal zone lymphoma: a primary lowgrade CNS lymphoma that mimics meningioma. Tu PH et al., J Clin Oncol 2005; 23:5718-27.
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(19) Primary Central Nervous System Marginal Zone B-Cell Lymphoma of the Basal Ganglia Mimicking Low-Grade Glioma: A Case Report and Review of the Literature. Inkeun Park et al., Clin Lymphoma Myeloma. 2008 Oct;8(5):305-8. doi: 10.3816/CLM.2008.n.043.
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(20) Primary low grade B-cell lymphoma of the dura in an immunocompetent patient. Altundag MK et al., J Exp Clin Cancer Res. 2000 Jun;19(2):249-51. (21) 56-year-old female with right frontal tumor of the dura. Bódi I et al., Brain Pathol. 2003 Jul;13(3):417-8, 423. (22) Small B-cell lymphoma presenting as diffuse dural thickening with cranial neuropathies. Estevez M et al., J Neurooncol. 2002 Sep;59(3):243-7.
SC
(23) Management of neurotropic low-grade B-cell lymphoma: report of two cases. Garcia-Serra A et al., Head Neck. 2003 Nov;25(11):972-6.
M AN U
(24) Primary low-grade B-cell lymphoma of mucosa-associated lymphoid tissue of the dura mimicking the presentation of an acute subdural hematoma. Case report and review of the literature. Goetz P et al., J Neurosurg. 2002 Mar;96(3):611-4. (25) Primary extranodal marginal zone B- cell lymphoma of the mucosa-associated lymphoid tissue type in the CNS. Itoh et al., Neuropathology 2001; 21:174-80. (26) Primary CNS Marginal Zone Lymphoma: A Case Report and Review of the Literature. Barina Aqil et al., Open Journal of Pathology, 2013, 3, 55-59 55 Published Online April 2013
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(27) Teaching NeuroImages: Primary dural mucosa-associated lymphoid tissue lymphoma. Chen J et al., Neurology. 2015 Apr 7;84(14):e107-8. doi: 10.1212/WNL.0000000000001457. (28) Primary low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in dura. Kambham N et al., Clin Neuropathol. 1998 Nov-Dec;17(6):311-7. (29) Patients presenting with CNS lesions. Case 1. Primary low-grade mucosa-associated B-cell lymphoma of the dura. Lima VS et al., J Clin Oncol. 2003 Nov 1;21(21):4058-60.
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(30) Low-grade primary meningeal lymphoma: case report and review of the literature. Menniti A et al., Neurosurg Rev. 2005 Jul;28(3):229-33. Epub 2005 Jan 29.
AC C
(31) Primary low-grade MALT lymphoma of the dura. Saggioro FP, Colli BO, Paixao-Becker AN, et al. Histopathology 2006; 49:323-6. (32) Extranodal marginal zone B-cell lymphoma of malt type involving the cavernous sinus. Sanjeevi A, Krishnan J, Bailey PR, et al. Leuk Lymphoma 2001; 42:1133-7. (33) Intracranial Marginal Zone B-Cell Lymphoma Mimicking Meningioma. Douleh DG et al., World Neurosurg. 2016 May 4. pii: S1878-8750(16)30235-2. doi: 10.1016/j.wneu.2016.04.106. (34) Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Tissue Type Involving the Dura. Choi JY et al., Cancer Res Treat. 2016 Apr;48(2):859-63. doi: 10.4143/crt.2014.334. Epub 2015 Jul 17. (35) Primary extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in the central nervous system (MZBL CNS) presented as traumatic subdural hematoma and subarachnoid bleeding - case report. Jesionek-Kupnicka D et al., Clin Neuropathol. 2013 Sep-
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Oct;32(5):384-92. doi: 10.5414/NP300579. (36) A 44-year old male with right-sided facial numbness. Dura-associated extranodal marginal zone B cell lymphoma (MALT lymphoma). Neidert MC et al., Brain Pathol. 2015 Jan;25(1):113-4. doi: 10.1111/bpa.12234.
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(37) 77-year-old woman with a dural-based mass. Marginal zone B-cell lymphoma (MZBCL). Okimoto RA et al., Brain Pathol. 2015 Jan;25(1):111-2. doi: 10.1111/bpa.1223 (38) Rare case of cerebral MALToma presenting with stroke-like symptoms and seizures. Wei D et al., BMJ Case Rep. 2013 Apr 22;2013. pii: bcr2012008494. doi: 10.1136/bcr-2012-008494.
SC
(39) Extranodal marginal zone lymphoma of the cranial dura mater: report of three cases and systematic review of the literature. Beltrán BE et al., Leuk Lymphoma. 2013 Oct;54(10):2306-9. doi: 10.3109/10428194.2013.771399. Epub 2013 Mar 8.
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(40) Extranodal marginal zone lymphoma of the CNS arising after a long-standing history of atypical white matter disease. Schiefer et al., Leuk Res. 2012 Jul;36(7):e155-7. doi: 10.1016/j.leukres.2012.03.022. Epub 2012 Apr 18. (41) Central nervous system marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type involving the brain and spinal cord parenchyma. Ueba T et al., Neuropathology. 2013 Jun;33(3):30611. doi: 10.1111/j.1440-1789.2012.01350.x. Epub 2012 Sep 21. (42) Central nervous system marginal zone B-cell lymphoma associated with Chlamydophila psittaci infection. Ponzoni M et al., Hum Pathol. 2011 May;42(5):738-42. doi: 10.1016/j.humpath.2010.08.014. Epub 2011 Jan 15.
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(43) Primary central nervous system mucosa-associated lymphoid tissue lymphoma--case report. Kamoshima Y et al., Neurol Med Chir (Tokyo). 2011;51(7):527-30, .
(44) Primary dural lymphomas: A clinicopathologic study of treatment and outcome in eight patients. Fabio M. Iwamoto et al., NEUROLOGY 2006;66:1763–1765
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(45) Extranodal marginal zone lymphoma of the dura mater with IgH/MALT1 translocation and review of literature. Bhagavathi S, Greiner TC, Kazmi SA, et al. J Hematop 2008;1:131–137. (46) Primary dural lymphoma: a report of two cases with review of the literature. Benouaich et al., Rev Neurol (Paris). 2003 Jul;159(6-7 Pt 1):652-8.
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(47) Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising in the lateral ventricle. Kelly et al., Leuk Lymphoma 46:1423–1427 (48) Dural marginal zone lymphoma with massive amyloid deposition: rare low grade primary central system B-cell lymphoma. Lehman et al. Case report. J Neurosurg 96:368–372 (49) 56-years old female with right frontal tumor of the dura. Bodi I, Hussain A, Gullan RW et al . Brain Pathol 13:417–423 (50) Mucosa-associated lymphoma tissue of the dura presenting as meningioma. Shaia J, Kerr PB, Saini A, et al. South Med J 2010;103:950–952 (51) Primary dural lymphoma mimicking a subdural hematoma. Gocmen S, Gamsizkan M, Onguru O, et al. J Clin Neurosci 2010;17:380–382.
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(52) Primary intracranial dural lymphoma of mucosa-associated lymphoid tissue (MALT) type: report of one case and review of the literature. George AC, Ozsahin M, Janzer R, et al. Bull Cancer 2005;92:E51– E56.
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(53) Primary central nervous system mucosa-associated lymphoid tissue lymphoma: case report and literature review. Razaq W, Goel A, Amin A, et al. Clin Lymphoma Myeloma 2009;9:E5–E9. (54) The pathogenesis of MALT lymphomas: where do we stand?. Sagaert X et al., Leukemia. 2007;21(3):389.
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(55) Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas. Sagaert X et al., J Clin Oncol. 2006;24(16):2490.
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TABLE 1 - ANALYSIS OF TREATMENT OUTCOMES IN CNS EMZBL
Not Evaluated
FOLLOW UP
Complete Response
Alive with disease
Recurrence
DEATHS
Radiotherapy
19
-
Median: 12 months Range: 1 – 64 months
14
5
-
-
Surgery
11
5
Median: 23 months Range: 18 - 48 months
4
2
-
-
Chemotherapy
3
-
Median: 23 months Range: 22 - 24 months
1
2
-
-
Radiotherapy + Surgery
17
-
Median: 23 months Range: 1 – 36 months
Chemotherapy + Surgery
4
-
Median: 2 months Range: 1 – 33 months
Chemotherapy + Radiotherapy
9
1
Surgery + Chemotherapy + Radiotherapy
7
-
70
6
SC
2
-
-
2
2
1
-
Median: 25 months Range: 6 - 86 months
8
-
-
-
Median: 47 months Range: 20 - 78 months
5
1
2
1
49
14
3
1
M AN U
15
TE D EP AC C
TOTAL
RI PT
SAMPLE SIZE
TREATMENT
ACCEPTED MANUSCRIPT TABLE 2 – SUPPLEMENTARY APPENDIX TABLE 2.1- PATIENTS TREATED WITH RADIOTHERAPY ALONE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
OUTCOME
REF
Right cavernous sinus
Meningioma
Lambda light chain restriction
NR
NED at 63mo
17
Left tentorial mass
Meningioma
Lambda light chain restriction
NR
NED at 9 mo
17
Seizures
Left anterior falx cerebri
Meningioma
+VJ PCR Ig heavy chain rearrangement
NR
NED at 14 mo
17
F
Vision changes
Dura, Cerebellar tentorium
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 45 mo
18
59
F
Vision changes Unsteady gait
Dura, Falx cerebri
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 32 mo
18
6
53
F
Headache Vision changes
Dura, Sella, suprasellar
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 11 mo
18
7
18
M
Hemiparesis Dysarthria , dizziness
Left basal ganglia
Glioma
CD 20 & CD 79a positive. CD3, CD5, CD10, BCL6, CD23 negative. MUM1, ALK1 and cyclin D1 negative. EBV negative
Negative
NED at 12 mo
19
8
70
F
Headache, Ataxia Vision changes
Diffuse dural thickening with fat infiltration of left orbit
Vasculitis
L26 Ab positive. CD3, CD5, CD10, cyclin-D1, and TdT negative. EBV negative
Negative
AWD at 12 mo
22
9
57
F
Vision changes
Right cavernous sinus
Schwannoma
Small B-Cell kappa restricted monoclonal cells that were CD10 and CD5 negative.
Negative
NED at 24 mo
23
10
48
M
Seizures
Left frontal subcortex
Glioma
CD20 and BCL 2 positive. CD5, CD10, CD23, CD43 & cyclin D1 negative. FISH IGH BCL2 & IGH CCND negative. Ki67 2-5%
Negative
NED at 15 mo
26
11
39
F
Headache Vision changes
Posterior fossa
NR
Kappa light chain restriction
NR
AWD at 12 mo
27
12
62
F
Headache
Left parieto-occipital lobe
Meningioma with subdural hematoma
CD 20 & CD 79a positive. CD5, CD10, CD11c, CD23 and CD 43 negative. Rearrangement of Ig heavy chain focus
NR
AWD at 6 mo
28
13
60
F
Headache Numbness
LT parieto-occipital dura
Meningioma with subdural hematoma
CD20, CD79 and BCL-2 positive. CD3, CD5, CD10, CD23 and BCL-6 negative. Monoclonal Ig heavy chain rearrangement
NR
NED at 24 mo
35
14
45
M
Seizures Hemiparesis, dysarthria
Right parietal sulci
Carcinomatous meningitis
CD20 positive. Scattered CD3 positivity. Strong lambda light chain staining
Negative
NED at 64 mo
38
43
F
3
57
F
4
70
5
SC
2
Numbness Vision changes Headache, Numbness Vision changes
M AN U
F
TE D
40
EP
1
PRESENTING SYMPTOMS
AC C
SEX
RI PT
SITE
AGE
ACCEPTED MANUSCRIPT
RI PT
TABLE 2.1 - PATIENTS TREATED WITH RADIOTHERAPY ALONE (CONTD)
AGE
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
15
51
F
Headache
Dural, Bifrontal lobe
NR
16
50
F
Seizures, headache Vision changes
Dural, Right frontal lobe
NR
17
59
M
Dysarthria, numbness
Left posterior temporal lobe abutting dura
NR
18
63
F
Seizures, dysarthria
Dural, falx cerebri with meningeal amyloid deposition
NR
19
61
F
Dizziness, nausea vomitting
Dura, posterior cranial fossa
REF
CD20, CD79a and BCL-2 positive. CD3, CD5, CD10, Cyclin D1 negative.
Negative
NED at 8 mo
44
CD20 and CD79a positive. CD3, CD5, CD10, Cyclin D1 and BCl-2 negative
Negative
NED at 5 mo
44
CD 20 CD79a positive. cyclin D1 negative CD3, CD5, CD21, CD23, CD10 negative. FISH IgH MALT 1 positive. t(14:18) (q32;21).
NR
AWD at 1 mo
45
NR
NR
AWD at 8 mo
48
CD 20 and CD79a positive. CD5, CD10, CD23 and CD43 negative. Kappa light chain restriction, EBV negative
NR
NED at 6 mo
50
SC
OUTCOME
M AN U
TE D
AC C
EP
NR
CSF
ACCEPTED MANUSCRIPT
RI PT
TABLE 2.2 - PATIENTS TREATED WITH SURGERY ALONE
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
OUTCOME
REF
1
56
F
NR
Dura, Falx
Meningioma
CD 20 positive, CD3 negative. MALT 1 negative, Trisomy 3 positive
NR
NR
18
2
55
F
NR
Dura, Posterior fossa
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
3
45
F
NR
Dura, Middle cranial fossa
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
4
68
F
NR
NR
Meningioma
CD 20 positive, CD3 negative Trisomy 3 positive
NR
NR
18
5
61
F
Headache Nausea and vomitting
Dura, Frontotemporal lobe
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
NED at 21 mo
18
6
47
M
Facial droop, numbness, Dysarthria
Parietal dura
Meningioma
CD 20 positive, CD3 negative
NR
NR
18
7
56
F
Seizures Dizziness
Frontal lobe
Meningioma
CD 20 and CD 43 positive. Light chain restriction
NR
AWD at 18 mo
21
8
28
F
Tinnitus Nausea and vomitting
Left Cerebellopontine angle
Inflammatory pseudotumor
CD 20 and CD 43 positive. BCL 2 positive in some follicular centers
NR
NED at 24 mo
25
9
39
F
Hearing loss Facial pain
Cerebello-pontine angle
Meningioma with subdural hematoma
CD 20 & CD 79a positive. CD5 CD10 CD11c CD23 and CD 43 negative. Kappa light chain restriction
NR
AWD at 48 mo
28
10
67
F
Hemiparesis Dysphasia
Fronto-parietal lobe
Convexity menigioma
CD 20 and CD 43 positive. BCL 2 positive. CD3 CD5 CD10 and CD23 negative. EMA negative. Lambda light chain restriction
NR
NED at 36 mo
30
11
56
F
Seizures Dizziness
Dural, right frontal lobe
NR
NR
NR
NED at 18 mo
49
AC C
EP
TE D
M AN U
SC
AGE
ACCEPTED MANUSCRIPT
TABLE 2.3 - PATIENTS TREATED WITH CHEMOTHERAPY ALONE
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
62
F
Seizures
Biparietal dural thickening
Meningioma
+VJ PCR Ig heavy chain rearrangement Lambda light chain restriction.
NR
Systemic fludrabine
NED at 22mo
17
Frontal lobe sulci
Multiple sclerosis
Lambda restricted plasmacytoid cells
Positive
Systemic Methotrexate + Intrathecal Methotrexate and cytrarabine
AWD at 24 mo
40
Occipital lobe, temporal lobe and spinal cord (multiple lesions)
NR
CD20 and CD38 positive. CD3 CD5 and CD10 negative. EBV RNA and EBV IgM negative
Negative
Systemic Methotrexate and Cytarabine
AWD at 24 mo
41
53
M
Memory deficits Unsteady gait Urinary incontinence
SC
3
M AN U
F
TE D
39
EP
2
Vision defects Nystagmus
RI PT
SEX
AC C
1
AGE
ACCEPTED MANUSCRIPT
TABLE 2.4 - PATIENTS TREATED WITH SURGERY AND RADIOTHERAPY
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
1
66
M
Seizures
Frontal lobe
NR
2
29
F
NR
Dura, Subdural
Meningioma
3
62
F
Ataxia
Dura, Occipital lobe
Meningioma
4
66
F
Seizures, Syncope
Parietal lobe
5
64
F
Hemiparesis
Right frontoparietal dura
6
46
F
7
44
M
8
35
M
9
70
F
10
44
F
Headache Nausea and vomitting
11
55
F
Seizures
12
39
F
13
49
F
14
47
M
Visual loss Focal paraesthesia Seizures Focal paraesthesia Seizures, visual changes Memory deficits
15
53
M
Headache, seizures
16
63
F
Headaches, Ataxia
17
78
M
Headaches, leg weakness
Meningioma
Fronto-parietal lobe
NR
Right frontal convexity
NR
Inter hemispheric cissura
NR NR
TE D
Trigonal choroid plexus
Meningioma en plaque
EP
Left frontal lobe adjacent to dura Dural, Left frontal and Right sphenoidal Dural, Right parietal lesion
CD 20 positive, CD3 negative. Trisomy 3 positive.MALT1 & IgH translocation negative CD 20 positive, CD3 negative. MALT 1 translocation negative CD 20 positive, CD3 negative. Trisomy 3 positive.MALT1 & IgH translocation negative CD 20 positive
CD 20 positive. CD5, CD23 and cyclin D1 negative. MNF116 negative, Ki-67 6.19% L26 positive. Kappa light chain restriction. +VJ PCR Ig heavy chain gene rearrangement
M AN U
Cavernous sinus
NR NR
Left tentorial lesion
Meningioma
Choroid plexus
NR
AC C
Headache Vision changes Facial numbness Involuntary muscle movement Headaches Sezures, night sweats Headache, diplopia Vertigo
Meningioma with subdural hematoma Meningioma with subdural hematoma
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
RI PT
SEX
SC
AGE
Dura, anterior falx
Meningioma
Dura, corpus callosum
Meningioma
CD20, CD45, CD79a and BCL2 positive. CD34, CD99, EMA and TDT negative. Ki67 10%.
CD20, BCL 2 positive, CD10, CyclinD1 negative. Trisomy 3 negative. IgH-MALT1 negative CD20, BCL 2 positive, CD10, CyclinD1 negative. Trisomy 3 negative. IgH-MALT1 negative CD 20 positive. CD3, CD5, CD10, CD23, CD27, CD43 negative DBA44, TCL-1, T-bet and cyclin D1 negative. CD 20 positive. Rare CD3 positive lymphocytes CD 5 CD 10 CD 23 and cyclin D1 negative. CD20 positive. CD3, CD5, CD10, CD23 and Cyclin D1 negative. CD20 positive. CD5, CD10, Cyclin D1 and BCL-2 negative CD20and CD79a positive. CD5, CD10, CD3 and CD23 negative FISH normal, no trisomy 3 CD 20 positive. BCL2 negative. IgG lambda chain restricted CD 19 and CD20 positive
TABLE 2.5 - PATIENTS TREATED WITH CHEMOTHERAPY AND SURGERY
CSF
OUTCOME
REF
NR
NED at 13 mo
18
NR
NED at 36 mo
18
NR
NED at 25 mo
18
NR
NED at 12 mo
20
NR
NED on Rx
24
NR
AWD at 15 mo
32
NR
NED at 24 mo
36
NR
NED at 36 mo
39
NR
NED at 12 mo
39
NR
AWD at 25 mo
42
NR
NED at 36 mo
43
NR
NED at 5 mo
44
Positive
NED at 7 mo
44
Negative
NED at 27 mo
44
NR
NED at 12 mo
47
Negative
NED at 23 mo
53
Negative
NED at 48 mo
53
ACCEPTED MANUSCRIPT
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
49
M
Seizures
Dura, Frontal lobe
Meningioma
CD 20 positive, CD3 negative. Trisomy 3 positive. MALT1 & IgH translocation negative
NR
Methotrexate. Recurrence treated with Fludrabine
Rec at 4mo, NED after Rx
18
2
56
M
Headache, memory deficits, vision changes
Dura, frontal lobe extending to ethmoidal sinus
Meningioma
NR
Methotrexate and rituximab
AWD at 1 mo
33
Meningioma
CD20, bcl-2, and MUM-1 positive. CD3, CD5, CD10, cyclin D1 negative BCL- 6 negative. Ki-67 15%
Negative
Cyclophosphamide + Vincristine + Prednisone
NED at 33 mo
34
NR
CD10, CD23, BCL-1 (cyclin D1) negative BCL-6 negative.
NR
Rituximab and bendamustine
AWD at 2mo
37
Headache
4
77
F
Headache Aggression
Bilateral frontal lobe extra-axial mass
SC
M
M AN U
69
CD20 positive. Plasma cells immunoglobulin G positive
AC C
EP
TE D
3
Frontal mass with dural attachment to falx cerebri and superior sagittal sinus
RI PT
AGE
TABLE 2.6 - PATIENTS TREATED WITH CHEMOTHERAPY AND RADIOTHERAPY
ACCEPTED MANUSCRIPT
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
52
F
Seizures Focal numbness
Frontal lobe
Meningioma
Kappa light chain restriction. +VJ PCR Ig heavy chain rearrangement
NR
Cytarabine + methotrexate and Intrathecal methotrexate
NED at 7 mo
17
2
36
F
Seizures Headache
Parietal lobe & Falx cerebri
meningioma
NR
High dose methotrexate
NR
29
3
33
F
Seizure Vision Changes
Dural, Frontotemporal Intraventricular
NR
NR
Intrathecal Methotrexate and Cytarabine
NED at 86 mo
44
4
35
M
Headache Numbness Focal paresthesia
Dural, Frontoparietal
NR
Positive
Methotrexate+ vincristine, temozolomide + rituximab and Intrathecal thiotepa
NED at 53 mo
44
5
38
F
Headache
Frontoparietal
Meningioma
NR
NR
NR
NR
NR
Subdural hematoma
CD19 and CD10 positive. CD5, CD10, CD23 and Cyclin D1 negative. Ki67 5-10%
NR
NR
NED at 6 mo
51
NR
NR
Systemic methotrexate and intrathecal chemotherapy
NED at 36 mo
52
CD20 positive. CD10 and BCL-2 negative. Lambda chain restricted IgG
Positive
Rituximab
NED at 25 mo
53
F
Headache
Meningioma
7
45
F
Seizures, Dysphasia
8
75
F
Behavioral disorder, memory deficit, aphasia
Dural, Frontal
NR
9
61
F
Headaches, Vision deficits
Cavernous sinus and optic nerve
NR
SC
M AN U
45
NR
AC C
EP
6
CD20 positive. CD34 negative. EMA positive. Kappa light chain restriction. Ki67 <10%. CD20 positive. CD3, CD23, Cyclin D1 negative. BCL2 positive CD20, BCL2 positive CD3, CD5, CD10, CD23 Cyclin D1 negative.
TE D
Temporal, parieto-occipital Dural, frontotemporoparietal
RI PT
AGE
TABLE 2.7 - PATIENTS TREATED WITH SURGERY, CHEMOTHERAPY AND RADIOTHERAPY
NED at 24 mo NED at 12 mo
46 46
ACCEPTED MANUSCRIPT
SEX
PRESENTING SYMPTOMS
SITE
INITIAL DIAGNOSIS
IMMUNOHISTOCHEMISTRY & MOLECULAR STUDES
CSF
CHEMOTHERAPY
OUTCOME
REF
1
33
F
Seizures Headache Vision changes
Parietal convexity
Meningioma with subdural hematoma
CD5, CD10, CD20 and CD23 positive. BCL-2 negative. Ki67 <10%
Negative
Rituximab
NED at 12 mo
Our case
2
57
F
Arm pain
Dura, Frontoparietal
Meningioma
CD 20 positive, CD3 negative. MALT1 & IgH translocation negative
NR
Procarbazine,+ vincristine + cytarabine + methotrexate
NED at 66 mo
18
3
48
F
Headache, ear pain
Dura, tentorium, falx
Meningioma
CD 20 positive, CD3 negative. Trisomy 3 positive MALT1 & IgH translocation negative
NR
Methotrexate + leucovorin
NED at 20 mo
18
Frontotemporoparietal dura
Meningioma
CD20 and BCL-2 positive. CD5, CD10, CD21, p53 and EMA negative. Lambda light chain restriction.
NR
Surgery, radiotherapy and chemotherapy. Recurrence Treated with adjuvant chemotherapy.
Rec at 12mo. Died at 24 mo due to sepsis
31
N/a
CD 20 and BCL 2 positive. CD 10 and cyclin D1 negative. FISH for trisomy 3 negative. IgH-MALT1 negative
NR
SX + XRT w. recurrence. Rituximab + cyclophosphamide + doxorubicin + vincristine
Recurrence in pelvis AWD at 47 mo
39
NED at 78 mo
44
NED at 30 mo
53
48
F
Headache Vision changes
Occipital and Parietal lobe
Dural, Temporoparietal lobe
N/a
Posterior fossa
N/a
64
F
7
74
F
Headache Dizziness
N/a
Positive
IgG lambda chain restricted
Negative
AC C
6
Headache Facial weakness
SC
5
M AN U
F
TE D
59
EP
4
Seizures Headache Facial weakness
KEY: AWD MO NR NED REF
: : : : :
RI PT
AGE
Alive with disease Months Not reported No evidence of disease Reference
Methotrexate + Vincristine + Procarbazine + Cytarabine ntrathecal methotrexate
Rituximab + Cyclophosphamide + Vincristine + Prednisone and Intrathecal methotrexate