A Rare Case of Composite Dural Extranodal Marginal Zone Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background Primary extranodal marginal zone lymphoma (MZL) of the dura is a rare neoplastic entity in the central nervous system (CNS). Methods We used literature searches to identify previously reported cases of primary dural MZL. We also reviewed clinical, pathologic, and radiographic data of an adult patient with concurrent dural MZL and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Results We identified 104 cases of dural MZL in the literature. None of them presented concurrently with another type of non-Hodgkin lymphoma. This is the first report of composite lymphoma consisting of dural MZL and CLL/SLL in the bone marrow and lymph nodes. Conclusion Primary dural MZL is a rare, indolent low-grade CNS lymphoma, with a relatively good prognosis. Its treatment is multidisciplinary and often requires surgical intervention due to brain compression, along with low to moderate doses of radiotherapy and/or systemic chemotherapy.

common site, extranodal MZL also occurs in the mucosa of other organs, including lung, salivary glands, bladder and lacrimal glands, as well as tissues without mucosa, such as thyroid gland, breast, skin, and less frequently the CNS (7)(8)(9).
A small number of cases have been reported on dural MZL, all of which were confined to the meninges with no systemic spread at the time of presentation. In this study, we review the literature on dural MZL and present clinical, pathologic, and radiographic data of an adult male with newly diagnosed primary dural MZL and simultaneous chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The patient subsequently developed lymph node infiltration by both MZL and SLL lymphomas. This case represents the first report of composite lymphoma consisting of dural MZL and CLL/SLL. Composite lymphoma is a rare phenomenon that is defined as the presence of two distinct types of lymphomas in the same patient (10).

Literature Search
Using PubMed searches, we identified 104 cases of dural MZL worldwide. The case we encountered at our institution is the 105th and the first to present concurrently with CLL/SLL in the bone marrow and peripheral blood investigations.

Flow Cytometry and immunohistochemistry (iHC)
Specimens including the patient tumor, peripheral blood, and bone marrow biopsy were submitted for flow cytometry and IHC.

immunoglobulin (ig) Gene Rearrangement Analysis
Heavy chain Ig gene rearrangement studies were performed by polymerase chain reaction (PCR) on genomic DNA extracted from tissue. Specific oligonucleotide primers recognizing framework 2 and 3 and the joining (Jh) regions of the human heavy chain were used. PCR products were then electrophoresed on agarose gels. Kappa light chain Ig gene rearrangement analysis was performed using the Invivoscribe IGK Gene Clonality Assay.

Case Presentation
A left-handed 59-year-old male presented at our institution with headaches, imbalance, and a left pronator drift on examination. Brain MRI showed a 6-cm enhancing right temporal mass causing severe brain compression, massive amounts of vasogenic edema and significant right-to-left midline shift ( Figure 1A). The mass appeared extra-axial and dural based. The mass also showed diffusion restriction on diffusion-weighted imaging ( Figure 1A). He also had a smaller right frontal convexity dural-based lesion with mild local mass effect on the underlying brain parenchyma ( Figure 1A). The MRI indicated diffuse pachymeningeal enhancement, especially over the right hemisphere. Given the size of the lesions, as well as the brain compression and the need for diagnosis, we offered the patient a right frontotemporal craniotomy for resection of the two extra-axial lesions. The differential diagnosis preoperatively included multiple meningiomas, metastatic disease, IgG4 disease, and lymphoma. Intraoperatively, we found that both masses were densely adherent to the dura. We performed gross total resection of both lesions ( Figure 1B). The convexity dura attached to the lesions was excised. The dura along the floor of the right middle fossa, where the large temporal mass was attached, was thoroughly coagulated. We used meticulous microdissection to develop the margins of the temporal tumor from the adjacent temporal lobe. Frozen sections from both lesions came back suggestive of atypical lymphoid tissue generating this tumor. Postoperative MRI confirmed gross total resection of both lesions. The patient was started on steroids postoperatively and was discharged to home 3 days after surgery, with complete resolution of his preoperative symptoms. MRI done 6 weeks later showed no recurrence and dramatic improvement in the surrounding vasogenic edema ( Figure 1C).
Pathologic examination of the tumors showed dural infiltration by small-sized lymphocytes (Figures 2A,B). Vague germinal centers were seen, which were colonized by the neoplastic lymphocytes. On flow cytometry and immunohistochemical stains, the neoplastic cells were positive for the B cell markers CD19, CD20, and CD79a (Figures 2C,D) and negative for CD5, CD10 (a marker of germinal center B cells). Tumor cells were κ light chain-restricted. CD3 immunostaining (a marker of T cells) showed few reactive T cells within the tumors ( Figure 2E). CD21 highlighted few residual follicular dendritic meshworks. Staining for Epstein-Barr virus (EBV) was negative. MIB1 (Ki-67) immunolabeling was overall low (20%), but high in residual germinal centers ( Figure 2F). The findings were diagnostic for extranodal MZL.
Bone marrow biopsy and aspirate showed a scant low-grade B-cell lymphoma that coexpressed the B cell markers CD19 and CD20, as well as the CLL markers CD5 and CD23, but lacked CD10 or CD38. This immunophenotype was consistent with CLL/SLL. The cells were dimly κ light chain-restricted, and the population represented about 5% of overall bone marrow cellularity. Flow cytometry of peripheral blood confirmed the diagnosis. Molecular analysis comparing the dural MZL to the CLL/SLL component in bone marrow and peripheral blood was requested. Ig gene rearrangement of the dural tumor detected a κ light chain clone of the same size (Jk) as that seen in the peripheral blood. Although these lymphomas were phenotypically different and also presented at different sites, the analysis of Ig gene rearrangement raised the possibility that the two of them shared the same clonal origin.
Starting at approximately 2 months after surgery, the patient received local proton beam radiotherapy (RT) to the right frontal and temporal fields, as well as four cycles of prophylactic intrathecal cytarabine. Multiple lumbar punctures over a 6-month period following surgery showed no evidence of tumor cells. However, 5 months after surgery, he presented with swollen right supraclavicular lymph nodes. CT of the chest and abdomen showed lymph node involvement in the right supraclavicular area and left axilla. Flow cytometry immunophenotyping of supraclavicular lymph node aspirate demonstrated two abnormal B cell populations. The larger one comprised 58% of all cells, consisted of small to medium-sized cells. It was CD45+ (pan-leukocyte marker), CD19+ (B cell marker), CD20+ (B cell marker), CD5−, CD10− (a marker of germinal center B cells), and surface kappa light chain strongly+, consistent with MZL lymph node. A second smaller cell population represented 6.3% of all cells and consisted of small cells with the following immunophenotype: CD45+, CD19+, CD20+, CD5+, CD10−, CD23+, CD38−, and surface kappa weakly+. This phenotype indicated the CLL presentation in the lymph node (also known as SLL). These two populations were compatible with the previously diagnosed dural MZL and CLL/SLL, respectively. Moreover, the presence of both MZL and SLL cells in the lymph node confirmed the diagnosis of composite lymphoma. Because both neoplastic processes are considered low-grade, the patient did not receive any additional treatment. On his most recent follow-up, 10 months after surgery, he had no new symptoms, fevers, night sweats, or additional lymph node involvement.

epidemiological Data
Analysis of prior literature revealed that dural MZL exhibits a marked female predilection with an approximate female:male ratio of 3:1 (76% of the cases were females). The reason behind this female predominance is unknown. The median age at presentation was 51 years (range: 28-78) (11,12), with the majority being middle-aged females. In all but one case, MZL involved the cranial dura, while in one case it was localized to the thoracic dura (13). Patients presented with a group of symptoms that include: persistent headaches (45%), seizures (30%), visual loss (25%), dizziness (10%), ataxic gait (10%), speech deficits (8%), and hearing deficits (5%). Most of the cases were immunocompetent, and tests for EBV and human immunodeficiency virus were negative when performed (14). Four cases (4%) had an underlying autoimmune or infectious disease, including hepatitis C with immunosuppression after liver transplantation (15), Sjogren's syndrome (16), Graves' disease (17), and multiple sclerosis (14). In two cases, the dural MZL arose after other neoplasms [meningioma (18) and inflammatory breast cancer (19)]. In our case, CLL/SLL was diagnosed concurrently in the bone marrow and peripheral blood. We consider this to be the first reported case of composite lymphoma of dural MZL and CLL.  Table 1). MIB1 (Ki-67) staining is usually low, ranging from 10 to 30%, which correlates with the indolent nature of this lymphoma. All these markers are essential to distinguish MZL from other types of lymphomas, such as CLL/ SLL (CD5+ and CD23+), mantle cell lymphoma (CyclinD1+, CD5+, CD23−), and follicular lymphoma (CD10+ and Bcl6+). Immunophenotypically, MZL is closely related to Waldenstrom macroglobulinemia (WM), another indolent NHL. Both entities express CD19 and CD20; however, WM mainly arises in the bone marrow and has a higher CD25 expression. Moreover, MYD88 gene mutation is detected in 90% of WM patients, while being rarely found in MZL (20). The pathogenesis of dural MZL is not well delineated. In the CNS, there is no MALT tissue. However, it has been hypothesized that meningothelial cells are analogous to epithelial cells at sites where extranodal MZL arises (16,21,40). Meningothelial cells are found throughout the arachnoid membrane and are concentrated in the arachnoid villi adjacent to the dural venous sinuses. Indeed, convexity dura is the most common site of dural MZL (12).

Cytogenetic and Molecular Studies
Extranodal MZL, especially in the gastric, intestinal, and pulmonary tissues, has a characteristic t(11;18)(q21;q21) translocation (54,55), where the 3′ end of the MALT1 gene on chromosome 18 is fused to the 5′ portion of API2, located on chromosome 11. This translocation is considered the most common chromosomal aberration in extranodal MZL (55); however, it is not found in the nodal and splenic types (14,54,55). Another common abnormality is the t(14;18)(q32;q21) translocation, which occurs in 15-20% of extranodal MZL, especially in nongastrointestinal sites (54). It brings the MALT1 gene under the control of the Ig heavy chain enhancer on chromosome 14 (55, 56). These two translocations lead to upregulation of BCL10, a protein component of a signaling complex that activates NF-κB and promotes the growth and survival of B cells. Trisomy of chromosomes 3, 7, 12, and 18 can be found in all types of MZL (14,57), but their effect on lymphomagenesis is still unclear (58). In our review of dural MZL, we observed that trisomy 3 is the most common chromosomal aberration (14,59), followed by t(14;18)(q32;q21) (40). Interestingly, none of the reported cases had t(11;18).

imaging Studies
Dural-based MZL is often misdiagnosed as meningioma on imaging studies, because, both tumors appear as enhancing extra-axial lesions. By contrast, the diffuse large B-cell lymphoma (DLBCL) variant of primary CNS high-grade lymphoma typically localizes to the brain parenchyma. Dural MZL frequently shows a "dural tail" sign on gadolinium-enhanced MRI, a finding classically seen with meningioma (48). It can also induce vasogenic edema, mass effect, and ventricular compression. Although the anatomic location of dural involvement is variable, MZL most commonly arises at the hemispheric convexities, interhemispheric falx, tentorium, and cavernous sinus.

Treatment and Prognosis
The optimal management of non-gastric extranodal MZL, and particularly dural MZL is not clearly defined. Surgery, chemotherapy, and RT alone or in combination have been used (60). MZL is indolent in nature and thus has a favorable prognosis. Treatment paradigms for dural MZL have varied ( Table 2), probably due to the paucity of cases compared with the gastric and the other extranodal sites.   All patients in our review underwent some form of surgical intervention, either biopsy to obtain tissue and establish diagnosis or resection of the tumor. The resection was complete in many cases; however, partial resection was done in some cases due to neuroanatomic constraints. RT has been shown to significantly prolong overall survival (OS) in both gastric and non-gastric extranodal MZL and was used in 70% of the dural MZL patients (61). Chemotherapy was also utilized in the management of 35% of the cases, where methotrexate was the most commonly used agent, either alone or as part of combinatorial therapy (41). Rituximab, a monoclonal antibody against CD20, has also been frequently used in treating dural MZL. It has shown significant activity and tolerability in both gastric and non-gastric extranodal MZL (62). Most of the patients (64%) were treated with two modalities including resection and RT (72%); resection and chemotherapy (17%) or RT plus chemotherapy (11%). On the other hand, 27% were treated with a single modality like resection (44%), RT (37%), or chemotherapy (19%) alone. Finally, only 9% of patients are treated with all three modalities combined.
Dural MZL has an excellent prognosis. In the 105 patients we reviewed, the median follow-up time was 23 months (range 1-336 months). There was disease recurrence in 12 cases: 4 were at the same site (13,14,38,52), while another 4, including this case, were extracranial and with no evidence of CNS involvement (7,35,41). The information of the other four relapsed cases was unavailable. The median and average time to relapse was 12 and 40 months, respectively. However, the majority of patients achieved complete remission on further follow-up. Three patients expired, either due to toxicity from the treatment or due to causes other than MZL. One of the cases was diagnosed with a recurrence and died from pneumonia and sepsis secondary to adjuvant therapy (38), while the other two cases succumbed after 2 and 6 months of treatment, respectively. Their death was attributed to causes other than lymphoma (12,35).
A study on non-gastric MZL, which did not include the dural variant, reported that the 5-year OS and progression-free survival (PFS) were 90 and 60%, respectively (60). Our analysis of previous published dural MZL cases (n = 93) showed that the 5-year OS and PFS were 96.7 and 81.2%, respectively (Figure 3), suggesting a better prognosis compared with extranodal MZL in other tissues.

Comparison with Other Lymphomas
High-grade DLBCL of brain parenchyma is the most common type of primary CNS lymphomas, followed by Burkitt lymphoma (63). Low-grade CNS lymphomas are much less common and are associated with a better prognosis compared with DLBCL. Dural MZL is the most common type of low-grade CNS lymphoma. It occurs in immune-competent patients, and middle-aged females are predominantly affected, in contrast to the immunocompromised state and male predilection seen in CNS DLBCL (14). Most of the large studies on non-gastric MZL (55,58,60) did not include dural-based tumors, likely due to the rarity of such cases. Interestingly, dural MZL was not associated with an infectious etiology like the stomach, intestine, ocular adnexa, and skin extranodal MZL (58,64). Moreover, only 5% of the dural cases were associated with chronic inflammatory or autoimmune conditions.

Composite Lymphoma
The case we encountered is unique in its presentation as a composite lymphoma. When two distinct types of lymphomas occur in the same patient, the disease state is termed composite lymphoma. This term was introduced in 1954 by Muller-Hermelink et al. (65) and then refined by Kim et al. (66). Composite lymphomas can be composed of a Hodgkin's lymphoma and an NHL, or two distinct NHL tumors. It may occur in one lymph node or multiple sites in one patient. There can be sharp or diffuse borders or even partial mixtures of infiltrates of various lymphoma types if they occur at the same site. Most of the reported cases of composite NHLs were mantle cell or follicular cell lymphomas associated with CLL or DLBCL (10,66,67). In most reported cases, the two lymphomas were not clonally related. However, in a few cases, Ig gene rearrangement analysis suggested a common clonal origin of two morphologically distinct types (10,67), as occurred in this case. With advances in next-generation sequencing and molecular pathology, the question of a common origin in composite lymphoma can be definitively addressed in the future.
The case we present here is the first report of composite lymphoma consisting of dural MZL and CLL/SLL. The two components initially presented at different sites, but then concurrently invaded systemic lymph nodes.

CONCLUSiON
Primary dural extranodal MZL is a low-grade NHL. Appropriate pathology and immunophenotyping by IHC and flow cytometry are essential for establishing the diagnosis and distinguishing this neoplasm from other lymphomas or primary brain tumors. Combinations of surgical resection, RT, and chemotherapy are effective in producing complete remission in most cases. Cases of composite lymphoma, where the dural MZL spreads concurrently with another lymphoma, require monitoring of both neoplastic processes.

AUTHOR CONTRiBUTiONS
MB and DP conceived the study, collected data, and wrote the manuscript. BL, DZ, and CL provided pathology data and helped write the manuscript. TS, DG, and BR provided clinical data and helped write the manuscript.