Ocular Marginal Zone B-cell Lymphoma Research Articles

Ocular marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue masquerading as chalazion: a case report

A case of ocular marginal zone non-Hodgkin B-cell lymphoma of mucosa-associated lymphoid tissue of the conjunctiva masquerading as chalazion is reported in a 57-year-old Chinese man, known to have diabetes mellitus. He presented with painless swelling of the lower lid and redness in the right eye for 3 months duration. A diagnosis of chalazion was made, and incision and curettage were performed by a general ophthalmologist. The swelling worsened and spread to the whole lower lid. Magnetic resonance imaging showed a lesion involving the right periorbital region limited to the anterior orbital septum that was hypointense on T1 and hyperintense on T2. A diagnosis of periorbital cellulitis with possibility of lymphoma was suggested.
 When he came to our eye clinic for expert opinion, his visual acuity, anterior segment and fundus were normal except early cataract changes in both eyes. There was a hard, non-tender, immobile mass within the lower eyelid associated with conjunctival injection and chemosis. Histopathology of the conjunctival biopsy showed features of low-grade non-Hodgkin B-cell lymphoma and the immunohistochemistry report was suggestive of marginal zone lymphoma. He was treated with chemotherapy (cyclophosphamide, vincristine, prednisolone) and radiotherapy, following which the swelling resolved.
 When patients do not respond to treatment as expected after incision and curettage of chalazion, a high index of possibility of malignancy should be kept in mind whenever a recurrence of hard swelling is observed at the same site in the eyelid. All suspicious lesions should be biopsied to find out the correct diagnosis.

Multiple mucosa-associated lymphoid tissue organs involving marginal zone B cell lymphoma: organ-specific relationships and the prognostic factors. Consortium for improving survival of lymphoma study

According to a previous review, multiple mucosa-associated lymphoid tissue (MALT)-organs involving marginal zone B cell lymphomas (MZLs) are present in 10-30% of patients. However, the clinical features and specific relationships among involved organs are yet to be clearly identified. In this study, we conducted retrospective analyses of multiple MALT organs involving MZLs (MM-MZLs) to identify their clinical features, treatment, prognosis, and specific relationships among involved organs. For analysis, between June 1987 and June 2009, a total of 55 patients from 17 different institutions in Korea, all of whom were histologically diagnosed with MM-MZL, were included in this study. MM-MZL was defined as MZL involving more than 2 different MALT organs. Multiple involvements within one MALT organ (e.g. both side ocular lesions, multiple lung nodules, and multiple stomach lesions, etc.) were excluded from this study. The male/female ratio of the 55 patients was 41/14. The median age of our subjects was 59 years (range 30-82 years). MM-MZL without lymph node (LN) was detected only in 9 patients (36.2%). Bone marrow (BM) involvement was observed in 17 patients (30.9%). The most common site of involvement was the gastrointestinal (GI) tract (25 patients, 45.5%) followed by the lung (40%), Waldeyer's ring (WR) (27.3%), and ocular area (25.5%). Ocular MZLs were commonly accompanied with WR- or lung-MZLs. GI-MZLs were WR or GI-MZLs. Lung-MZLs were frequently observed with ocular and GI-MZLs. WR-MZLs were ocular or GI-MZLs. A total of 53 patients were treated, and 2 on watchful wait. As much as 48 patients received chemotherapy-based treatment. Among them, CR or PR was achieved in 38 patients (79.2%, 95% CI 67-91%). Median time to progression (TTP) was 2.3 years (95% CI 1.4-3.2 years). Cause-specific overall survival (OS) did not reach the median value. The 5-year OS rate was 84.9%. MM-MZLs tend to be an indolent disease, characterized by prolonged survival with frequent relapses. The majority of cases could be controlled effectively via chemotherapy-based treatment, and prolonged survival was achieved in those patients. The GI, lung, WR, and ocular area were commonly presented with other MALT site MZLs, and an organ-specific relationship appears to be relevant to MM-MZLs.

Central nervous system manifestations of marginal zone B-cell lymphoma

Primary or secondary central nervous system (CNS) involvement by marginal zone B-cell lymphoma (MZBCL) is rare. A retrospective analysis of patients was done with MZBCL involving the CNS, diagnosed and treated at our institution between 2004 and 2010. We identified 10 MZBCL patients with primary (six) or secondary (four) CNS involvement. Five patients presented with primary dural lymphoma and were treated with surgical resection, whole-brain radiation, or systemic chemotherapy. Only one patient had CNS relapse 5 years later. A single patient with primary intraocular lymphoma achieved clinical remission with ocular radiotherapy and systemic chemotherapy. Four patients had ocular MZBCL within 5 years of the initial diagnosis of primary ocular adnexal MZBCL and primary splenic MZBCL. There was no evidence of local recurrence in all but one who developed systemic relapse after 3 years of follow-up. Primary or secondary CNS involvement by MZBCL display indolent clinical behavior and have a generally favorable prognosis, underlining the importance of their differentiation from aggressive lymphomas that more commonly involve the CNS.

TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas

AbstractThe constitutive activation of nuclear factor-κB (NF-κB) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-κB pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in Epstein-Barr virus–infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-κB activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-κB pathways may be advantageous for treatment.

Ocular Adnexal Marginal Zone B Cell Lymphoma Has Characteristic Deletion at Chromosome Band 6q23.3-24.1 Whose Target Is TNFAIP3.

Marginal zone B cell lymphoma (MZBCL) occupies a distinct disease entity in WHO classification, and it has been suggested that recurrent chromosomal aberrations, such as t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32) are associated with its lymphomagenesis. However, the frequency of chromosomal alteration in marginal zone B cell lymphomas varies according to the anatomical region, and genetic abnormalities other than recurrent translocations involved in the pathogenesis of MZBCL have not yet been fully identified. In this study, we aimed to investigate genomic aberrations in ocular MZBCL and to compare them with those of tumors from other anatomical sites by using genome-wide array comparative genomic hybridization (CGH). The study population comprised 24 cases of primary ocular MZBCL, 11 of pulmonary MZBCL, and seven of nodal MZBCL. FISH analysis for MALT1 gene alteration was performed for ocular and nodal MZBCL and RT-PCR for the detection of API2-MALT1 transcript was performed for pulmonary MZBCL. The recurrent genomic alterations of ocular MZBCL were losses of chromosomes 6q23.3(9/24, 38%), and gains of 3(9/24, 38%), 15(4/24, 16%), 18q(4/24, 16%). T(11;18)(q21;q21) was not detected. The genomic alteration of pulmonary MZBCL included recurrent loss of 13q34 (2/11, 19%). Fusion transcript of t(11;18)(q21;q21) was detected in five out of eight cases (63%). Nodal MZBCL showed neither recurrent genome alteration nor any change in MALT1 gene copy number. In conclusion of genome-wide array CGH analysis, the array CGH profile of ocular MZBCL is distinct from those of pulmonary and nodal MZBCL. The novel finding was recurrent deletion in the 2.9 Mb region at chromosome band 6q23.3–q24.1 including homozygous loss in ocular adnexal marginal zone B cell lymphoma. These findings suggest that deletion of chromosome band 6q23.3–24.1 may constitute a crucial genetic alteration in the lymphomagenesis of ocular MZBCL. For a further examination, we used contig bacterial artificial chromosome (BAC) array CGH, containing the 24 BAC clone to cover the 2.9 Mb region, to analyze nine cases with chromosome band 6q23.3–q24.1 loss. We narrowed the minimal common region down to a length of 586 kb with two genes and four expressed sequence tags (ESTs). All of these genes and ESTs were subjected to RT-PCR and real-time quantitative RT-PCR, and correlation between genomic loss and expression level was found only in TNFAIP3. We thus concluded that the TNFAIP3 gene is the candidate gene for this deleted region. TNFAIP3 is an inhibitor of NF-kB signaling so that loss of this gene may result constitutive activation of NF-kB which was also implicated in MALT lymphomas with t(11;18)(q21;q21) or t(14;18)(q32;q21). Thus, TNFAIP3 may act as a tumor suppressor gene in ocular adnexal marginal zone B cell lymphoma.

Genome‐wide array‐based comparative genomic hybridization of ocular marginal zone B cell lymphoma: Comparison with pulmonary and nodal marginal zone B cell lymphoma

The genetic changes in marginal zone B cell lymphomas (MZBCL) vary according to the anatomical region. This study aimed to investigate genomic aberrations in ocular MZBCL and to compare them with those of tumors from other anatomical sites. The study population comprised 24 cases of primary ocular MZBCL, 11 pulmonary MZBCL, and seven nodal MZBCL. For array CGH, fresh tumor tissues were analyzed with a genome-wide scanning array containing 2,304 BAC/PAC clones which cover the whole human genome at a resolution of 1.3 Mb. FISH analysis for MALT1 gene alteration was performed for ocular and nodal MZBCL and RT-PCR for the detection of API2-MALT1 transcripts was performed for pulmonary MZBCL. The recurrent genomic alterations in ocular MZBCL were losses of chromosome bands 6q23.3 (9/24, 38%), 7q36.3 (2/24, 8%), and 13q34 (2/24, 8%), and gains of chromosomes 3 (9/24, 38%), and 15 (4/24, 16%), and chromosome arms 18q (4/24, 16%), and 6p (2/24, 8%). The t(11;18)(q21;q21) was not detected. The genomic alterations of pulmonary MZBCL included recurrent loss of 18q21 (2/11, 19%). A t(11;18)(q21;q21) fusion transcript was detected in five out of eight cases (63%). Nodal MZBCL showed neither recurrent genome alterations nor any change in MALT1 gene copy number. In conclusion, the array CGH profile of ocular MZBCL is distinct from those of pulmonary and nodal MZBCL. Deletion of chromosome band 6q23.3 in ocular MZBCL is a novel finding and may constitute a crucial genetic alteration in the pathogenesis of ocular MZBCL.