Conjunctival Mucosa-associated Lymphoid Tissue Lymphoma Research Articles

Stromal area differences with epithelial-mesenchymal transition gene changes in conjunctival and orbital mucosa-associated lymphoid tissue lymphoma.

To examine the molecular biological differences between conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and orbital MALT lymphoma in ocular adnexa lymphoma. Observational case series. A total of 129 consecutive, randomized cases of ocular adnexa MALT lymphoma diagnosed histopathologically between 2008 and 2020.Total RNA was extracted from formalin-fixed paraffin-embedded tissue from ocular adnexa MALT lymphoma, and RNA-sequencing was performed. Orbital MALT lymphoma gene expression was compared with that of conjunctival MALT lymphoma. Gene set (GS) analysis detecting for gene set cluster was performed in RNA-sequence. Related proteins were further examined by immunohistochemical staining. In addition, artificial segmentation image used to count stromal area in HE images. GS analysis showed differences in expression in 29 GS types in primary orbital MALT lymphoma (N=5,5, FDR q-value <0.25). The GS with the greatest difference in expression was the GS of epithelial-mesenchymal transition (EMT). Based on this GS change, immunohistochemical staining was added using E-cadherin as an epithelial marker and vimentin as a mesenchymal marker for EMT. There was significant staining of vimentin in orbital lymphoma (P<0.01, N=129) and of E-cadherin in conjunctival lesions (P=0.023, N=129). Vimentin staining correlated with Ann Arbor staging (1 versus >1) independent of age and sex on multivariate analysis (P=0.004). Stroma area in tumor were significant difference(P<0.01). GS changes including EMT and stromal area in tumor were used to demonstrate the molecular biological differences between conjunctival MALT lymphoma and orbital MALT lymphoma in ocular adnexa lymphomas.

Fungal dysbiosis and decreased tear mucin at the conjunctiva in patients with conjunctival mucosa-associated lymphoid tissue lymphoma

ObjectiveThis study aimed to examine the differences in the fungal microbiome between patients with conjunctival mucosa-associated lymphoid tissue (MALT) and healthy controls using metagenomic analysis.Methods and analysisThis case-control study was...

Machine Learning Model with Texture Analysis for Automatic Classification of Histopathological Images of Ocular Adnexal Mucosa-associated Lymphoid Tissue Lymphoma of Two Different Origins

Purpose The purpose of this study was to develop artificial intelligence algorithms that can distinguish between orbital and conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas in pathological images. Methods Tissue blocks with residual MALT lymphoma and data from histological and flow cytometric studies and molecular genetic analyses such as gene rearrangement were procured for 129 patients treated between April 2008 and April 2020. We collected pathological hematoxylin and eosin-stained (HE) images of lymphoma from these patients and cropped 10 different image patches at a resolution of 2048 × 2048 from pathological images from each patient. A total of 990 images from 99 patients were used to create and evaluate machine-learning models. Each image patch of three different magnification rates at ×4, ×20, and ×40 underwent texture analysis to extract features, and then seven different machine-learning algorithms were applied to the results to create models. Cross-validation on a patient-by-patient basis was used to create and evaluate models, and then 300 images from the remaining 30 cases were used to evaluate the average accuracy rate. Results Ten-fold cross-validation using the support vector machine with linear kernel algorithm was identified as the best algorithm for discriminating between conjunctival mucosa-associated lymphoid tissue and orbital MALT lymphomas, with an average accuracy rate under cross-validation of 85%. There were ×20 magnification HE images that were more accurate in distinguishing orbital and conjunctival MALT lymphomas among ×4, ×20, and ×40. Conclusion Artificial intelligence algorithms can successfully distinguish HE images between orbital and conjunctival MALT lymphomas.

Feasibility of oral doxycycline as first-line therapy for conjunctival mucosa-associated lymphoid tissue lymphoma.

To investigate the long-term outcomes of oral doxycycline as first-line treatment in patients with conjunctival extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In this case series, the medical records of 67 patients with conjunctival MALT lymphoma who received doxycycline as their primary treatment and were followed up for at least 5 years were retrospectively reviewed. Progression-free survival (PFS) was analysed at 3, 5, and 10 years after the initial doxycycline treatment. A Cox proportional hazards model was used to assess the independent risk factors for progression. After the initial treatment, 25 patients (37.3%) achieved a complete response, 8 patients (11.9%) achieved a partial response, 30 patients (44.8%) showed stable disease, and 4 patients (6.0%) showed disease progression. The median PFS in all patients was 168 months, and the 3-, 5- and 10-year PFS rates for all patients were 70%, 65%, and 62%, respectively. No further progression was observed 6 years after the initial doxycycline treatment. Younger age and TNM stage T1c were significant risk factors for the time to progression in the multivariate Cox regression analysis (p < 0.05). Additional doxycycline (>2 cycles) showed no benefit. There were no serious adverse events associated with doxycycline therapy, and most patients were successfully salvaged by second-line treatments, including radiotherapy and chemotherapy. In this case series, oral doxycycline treatment yielded acceptable long-term PFS with minimal complications. Especially in patients with stage T1a or T1b conjunctival MALT lymphoma, first-line doxycycline treatment could be considered under close monitoring for at least 6 years.

Effect of miR-184 and miR-205 on the tumorigenesis of conjunctival mucosa associated lymphoid tissue lymphoma through regulating RasL10B and TNFAIP8.

To explore the effect of miR-184 and miR-205 on the proliferation and metastasis of conjunctival mucosa associated lymphoid tissue (MALT) lymphoma. Tissue of tumor and adjacent normal control from 5 patients with conjunctival MALT was included. RPMI8226 cell line was selected to verify the effect of miRNAs in B cells. The function of microRNA on the RPMI8226 cell apoptosis, migration and invasion was evaluated by apoptosis assay and Transwell assay. The mRNA and protein expression were examined by quantitative RT-PCR and Western blotting. The effect of microRNA on regulation of downstream gene expression was evaluated by luciferase report assay. A decreased level of miR-184 and miR-205 was observed in MALT lymphoma tissue. Exogenous miR-184 and miR-205 analogues promoted apoptosis, and inhibited the survival, migration, and invasion of RPMI8226 cells. miR-184 and miR-205 inhibitor reversed the process. The RNA and protein level of RasL10B and TNFAIP8 were downregulated in MALT lymphoma tissue. The exogenous of miR-184 and miR-205 promoted the expression of RasL10B and TNFAIP8. Meanwhile, inhibition of miR-184 and miR-205 repressed the expression of target gene, RasL10B and TNFAIP8. miR-184 and miR-205 suppresses the tumorigenesis of conjunctival MALT lymphoma through regulating RasL10B and TNFAIP8.

Treatment of MALT lymphoma of the conjunctiva with intralesional rituximab supplemented with autologous serum

AbstractPatients with indolent conjunctival lymphomas exhibit good prognosis, with exceptional cases of dissemination, and are suitable candidates for intralesional therapies. We report the first prospective phase 2 trial using intralesional rituximab supplemented with autologous serum in adults with relapsed/refractory indolent CD20+ lymphoma of the conjunctiva (NCT01514344). Patients received 4 weekly intralesional injections of rituximab, followed by 6 monthly injections; 500 μL of autologous serum was added to rituximab in patients with lymphoma unresponsive to weekly doses. Safety, activity, and antitumor effect of autologous serum were investigated. Twenty patients with mucosa-associated lymphoid tissue (MALT)–type lymphoma were enrolled. Tolerability was excellent, with only 3 mild local reactions. After weekly injections, 11 patients achieved tumor regression, 8 had stable disease, and 1 experienced progressive disease; 9 patients received autologous serum, with response improvement in 4 cases (3 complete responses, 1 partial response). At the end of treatment, 12 patients achieved a complete remission, and 1 achieved a partial response, with an overall response rate of 65% (95% confidence interval, 45-85). At a median follow-up of 42 months (range, 10-78), 12 patients remain relapse free, with 5-year progression-free survival and time-to-next-treatment rates of 59% ± 11% and 69% ± 11%, respectively. Three patients with local relapse were retreated with intralesional rituximab and serum; 2 achieved a complete response that lasted 25+ and 38+ months. Thus, intralesional rituximab is a safe and active therapy in patients with relapsed conjunctival MALT lymphoma. The addition of autologous serum improves response in some cases. Retreatment of local relapses can result in a second durable remission.

Conjunctival dysbiosis in mucosa-associated lymphoid tissue lymphoma

To investigate the conjunctival microbiota and the association between the development of conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and dysbiosis, DNA samples were collected from 25 conjunctival MALT lymphoma patients and 25 healthy controls. To compare the microbiota, samples were collected from the following four body locations: conjunctiva, meibomian gland, periocular skin and hand. Extracted DNA was analyzed by 16S rRNA sequences, and libraries were sequenced on an Illumina MiSeq sequencer. The differences in bacteria were characterized by using principal coordinate analysis of metagenomics data, and the differences in bacterial compositions were evaluated by linear discriminant analysis effect size. The conjunctival microbiota of MALT lymphoma patients was compositionally different from that of healthy controls. For the conjunctival MALT lymphoma patients, alterations in the microbial composition were detected, and a remarkable change was detected at the conjunctiva. Detailed analysis showed that a specific population of the microbiota, the genus Delftia, was significantly more abundant in conjunctival MALT lymphoma patients, and the genera Bacteroides and Clostridium were less abundant in the MALT lymphoma patients. A specific microbiota on the ocular surface in conjunctival MALT lymphoma patients was detected, and dysbiosis may play an important role in the pathophysiology of conjunctival MALT lymphoma.

An Unusual Presentation of Pediatric Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma

Ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma is uncommon in the pediatric population. Initial misdiagnosis is common and there is lacking consensus regarding the optimal approach to treatment. Herein, we report an atypical presentation of pediatric conjunctival MALT lymphoma and review the presentation and management of this rare condition.

Refractory follicular conjunctival lesions: overlook as just inflammation or not?

PurposeTo report the clinical manifestations of 199 patients with suspected conjunctival lymphoma, the associations between these features and the pathological diagnoses, and the prognosis of conjunctival lesions during long-term follow-up.MethodsWe...

Immunoglobulin G4 (IgG4)-Positive Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma and Idiopathic Orbital Inflammation.

To report clinical and pathological characteristics of idiopathic orbital inflammation and ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma with immunoglobulin G4 (IgG4)-positive plasma cells. A retrospective histopathological review and clinical case series. A total of 51 biopsy samples from January 2005 to December 2015 were used in this study, including 21 cases of biopsy-confirmed idiopathic orbital inflammation and 30 cases of biopsy-confirmed ocular adnexal MALT lymphoma. Most cases of ocular adnexal lymphoma were conjunctival tissue. Retrospective immunohistochemical studies were performed to estimate the IgG4 and IgG4/IgG ratios. Histopathologic features, demographic and clinical data, radiologic findings, treatment, and follow-up information for each patient were analyzed. Among idiopathic orbital inflammation, 6 (28.6%) of the 21 patients were diagnosed as "probable" ocular adnexal IgG4-related diseases and 13 (43.3%) of the 30 patients were diagnosed as MALT lymphoma with IgG4-positive plasma cells. Six cases of 13 IgG4-positive MALT lymphoma group had contralateral chronic inflammatory lesions infiltrated by IgG4-positive plasma cells, which was significantly (p = 0.007) higher than that in the IgG4-negative group. Conjunctival involvement was 69% of the IgG4-positive MALT lymphoma cases. Bilateral involvement of the ocular adnexa was significantly (p = 0.02) more frequent among IgG4-positive MALT lymphoma patients than that in IgG4-positive idiopathic orbital inflammation patients. Recurrence rate in the IgG4-positive group was higher (p = 0.05) than that in the IgG4-negative group but not significantly. This study presented an unusual framework of ocular adnexal IgG4-related inflammation, in conjunctiva. It is important to understand contralateral chronic inflammatory lesions and their relationship with IgG4-positive MALT lymphoma. Tissue biopsy and IgG4 immunostaining are required for all cases because IgG4-positive MALT lymphoma can arise from a pre-existing IgG4-positive chronic inflammatory lesions. This is the first study that performs IgG4 immunostaining for tissue from a relatively large number of conjunctival MALT lymphomas in a single center. Therefore, it will help to diagnose conjunctival lymphoproliferative disease.

Nasal dissemination of a single-clone IgH-rearranged conjunctival MALT lymphoma through the nasolacrimal duct: A case report.

The aim of the present study was to report a rare case of single-clone, immunoglobulin heavy chain (IgH)-rearranged mucosa-associated lymphoid tissue (MALT) lymphoma in the conjunctiva, with nasal cavity dissemination through the nasolacrimal duct. A 24-year-old female was diagnosed with MALT lymphoma of the nasal cavity at the Department of Otolaryngology, Wan Fang Medical Center, Taipei Medical University (Tapei, Taiwan) in October 2008. A biopsy of the relapsing conjunctival lesion revealed a MALT lymphoma by pathological staining, while a single-clone, IgH-rearranged tumor lesion in the nasal cavity and conjunctiva was confirmed using continuous sinus computed tomography scans and polymerase chain reaction. Tumor lesions were negative for Helicobacter pylori and Chlamydia infection, but exhibited bilateral neck lymph node dissemination. A combination of radiation therapy (a total dosage of 46.8 Gray, in two phases covering the left lacrimal sac, nasal cavity and bilateral neck region) and topical ciprofloxacin plus steroid (0.3% ciprofloxacin 4 times a day and betamethasone eye ointment before sleep for 1 month) was provided as an effective therapeutic strategy, and no recurrence was found in the next 3 years. The nasolacrimal duct serves as a channel for conjunctival tumor spreading and is easily neglected. IgH-involved translocation in MALT lymphoma is a factor in the progression of the disease, and aggressive combination therapy is essential for a high-risk, disseminated IgH-rearranged MALT lymphoma.

Genome-Wide Analysis of Ocular Adnexal Lymphoproliferative Disorders Using High-Resolution Single Nucleotide Polymorphism Array.

We identified the genomic signature of ocular adnexal lymphoproliferative disorders (LPDs), especially ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma, IgG4-related ophthalmic disease (IgG4-ROD), reactive lymphoid hyperplasia (RLH), and diffuse large B-cell lymphoma (DLBCL). We included 52 subjects with ocular adnexal LPDs (13 orbital MALT lymphomas, 16 conjunctival MALT lymphomas, 13 IgG4-RODs, 4 RLHs, and 6 DLBCLs) who had been treated at the Tokyo Medical University Hospital from 2008 to 2012. Genomic DNA was extracted from the tumor tissues and subjected to high-resolution single nucleotide polymorphism array (SNP-A) karyotyping using GeneChip Human Mapping 250K SNP arrays. The array data were investigated using Copy Number Analysis for GeneChips (CNAG) software. In ocular adnexal MALT lymphomas, the most frequent copy number (CN) gain region was trisomy 3 detected in 31% (9/29), followed by trisomy 18 in 17% (5/29), and 6p and 21q in 14% (4/29). The most frequent CN loss regions were 6q and 9p, detected in 7% (2/29). Uniparental disomy was detected on 6q in 14% (4/29), followed by 3q in 10% (3/29). Copy number variations (CNVs) were not detected in IgG4-RODs and RLHs. Conversely, CNVs were more frequent in DLBCLs than in ocular adnexal MALT lymphomas. Copy number variations were detected in 77% (10/13) of orbital MALT lymphomas and in 67% (11/16) of conjunctival MALT lymphomas. High-resolution single nucleotide polymorphism array is a useful method for discriminating ocular adnexal lymphomas from benign LPDs. The differences in the chromosomal abnormality patterns may reflect the activity of ocular adnexal LPDs.

Long-Term Outcomes after Cryotherapy for Conjunctival Mucosa-Associated Lymphoid Tissue Lymphomas

Purpose: To evaluate long-term outcomes after cryotherapy for conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas. Methods: We retrospectively analyzed 11 eyes of 8 patients who underwent cryotherapy with a confirmed histopathological diagnosis of conjunctival MALT lymphoma between January 2006 and December 2010 and were followed up for at least a year. Results: The mean patient age was 36.8 years and the average follow-up was 4.1 years. Complete remission was achieved in 3 patients (4 eyes) and recurrence occurred in 5 patients (7 eyes) after the first cryotherapy. After the third cryotherapy, complete remission was achieved in 2 patients (2 eyes) and recurrence occurred in 3 patients (5 eyes). Therefore, 3 patients (5 eyes) underwent radiotherapy and finally achieved complete remission. After cryotherapy, significant complications were not observed except mild symblepharon in 4 patients (6 eyes). Conclusions: Cryotherapy, although having a higher recurrence rate than radiotherapy, is a simple treatment modality with fewer complications for patients. In the conjunctival MALT lymphoma patients who cannot undergo radiotherapy, cryotherapy should be considered as an alternative treatment modality. J Korean Ophthalmol Soc 2015;56(11):1653-1660

Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma

The objective of this study was to assess the value of magnetic resonance imaging (MRI) of the orbit for conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. The yield of other staging tests at baseline were also evaluated. Twenty-one consecutive patients treated for conjunctival MALT lymphoma were retrospectively studied. Lymphoma was staged according to both the Ann Arbor system and the seventh edition of the AJCC [American Joint Committee on Cancer] cancer staging manual. Findings on MRI of the orbit, whole-body positron emission tomography/computed tomography (PET/CT), CT of the chest/abdomen/pelvis, bone marrow (BM) biopsy and gastrointestinal (GI) endoscopy were recorded. Seventeen patients had orbital MRI. Fourteen of 17 patients (82%) with obvious conjunctival MALT lymphoma on clinical examination had a negative MRI scan. Only three patients had subtle conjunctival enhancement on orbital MRI. Ann Arbor stage at presentation was as follows: stage IE (15 patients), stage IIE (two patients) and stage IV (four patients). Eighteen of 21 patients had total-body PET/CT; four patients (22%) had hypermetabolic activity evident on PET scan. All 21 patients had bilateral BM biopsies. Fifteen of 21 patients (71%) had GI endoscopy. None of the patients had a positive BM biopsy or findings on GI endoscopy. Our data suggest that orbital MRI has a very low yield for identification of conjunctival MALT lymphoma. Clinical examination is critical in diagnosing and assessing treatment response in conjunctival MALT lymphoma. The yield for GI endoscopy and BM biopsy may also be low in staging of conjunctival MALT lymphoma.

Intra-lesional interferon injection for recurrent conjunctival MALT lymphoma

Sir, Conjunctival mucosa-associated lymphoid tissue (MALT) lymphomas are localized low-grade extra-nodal tumours that are managed with radiotherapy, cryotherapy, surgical excision, or even observation. Intra-lesional interferon injection for conjunctival lymphomas was first cited as early as 1996 by Cellini et al;1 its successful use has been reported since then.2, 3 We report a case where its use has been invaluable in a patient with recurrent conjunctival MALT lymphoma following external beam radiation.

Clarithromycin-Therapie eines B-Zell-MALT-Lymphoms

Presentation of a 34-year-old patient with a conjunctival tumor of the left upper circumference of the eyeball clinically presenting as a salmon-pink colored conjunctival tumor. The incisional biopsy and immunohistochemical work-up revealed an extranodal conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma of the marginal zone B cell type. The therapy comprised a currently experimental therapy scheme with 500 mg clarithromycin 3 times per day for 21 days. This therapy achieved a significant tumor regression.

Intralesional Interferon-α for Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma: Long-term Results

To report the long-term therapeutic results for patients with conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma who were treated with intralesional injections of interferon-α (IFN-α). Prospective, nonrandomized, interventional case series. Twenty eyes of 16 patients with histologically proven conjunctival MALT lymphoma in the absence of systemic disease. Patients were given 1,500,000 international units (IU) of IFN-α (Roferon-A; Roche s.p.a., Milano, Italy) subconjunctivally inside the lesion 3 times weekly for 4 weeks. If there was even a minimal response, a further cycle of 1,000,000 IU 3 times weekly for 4 weeks was administered. Patients were followed up clinically using slit-lamp examination to determine evidence of tumor disappearance or recurrence. In 10 eyes, an incisional biopsy was performed 6 months after therapy to verify the histologic absence of the lesion. A complete response was obtained in 15 eyes (75%) at the end of first cycle treatment, and in 5 eyes (25%) after further cycles. Seventeen eyes (85%) showed no local recurrence after a median follow-up of 65 months (range, 15-136 months). Three eyes (15%) demonstrated recurrence at variable points after treatment. One patient with stage IIA lymphoma exhibited systemic lymphoma progression. Local immunotherapy with IFN-α seems to be an effective and lasting treatment method and provides an alternative to radiotherapy for conjunctival MALT lymphomas. Very few transient side effects were detected.

Lack of association of conjunctival MALT lymphoma with Chlamydiae or Helicobacter pylori in a cohort of Chinese patients

SummaryBackgroundThis study was conducted to detect microbial pathogens in conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma specimens in an attempt to determine possible associations between conjunctival MALT lymphoma and microbial infections.Material/MethodsUsing PCR technique, freshly obtained tumor specimens from 16 cases of conjunctival MALT lymphoma, as confirmed by postoperative pathology, were analyzed for DNA of Chlamydia psittaci (C. psittaci), Chlamydia trachomatis (C. trachomatis), Chlamydia pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori). Synthetic C. psittaci, C. trachomatis, C. pneumoniae and H. pylori DNA were used as positive control, and blank plasmid DNA as negative control.ResultsElectrophoresis showed that no bands corresponding to the positive control were observed in the specimens, indicating that no DNA of the 4 microorganisms was detected in the specimens of the 16 cases of conjunctival MALT lymphoma.ConclusionsThe PCR technique was able to detect the positive control quickly and accurately, but the results of PCR in analyzing the 16 specimens were negative, indicating that there is no association between conjunctival MALT lymphoma and the 4 microorganisms in Chinese patients.

MicroRNA-200 is commonly repressed in conjunctival MALT lymphoma, and targets cyclin E2

Aberrant microRNA expression is implicated in cancer initiation and progression. We sought to identify dysregulated miRNAs in conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma, and investigated their biological significance. The profiles of miRNAs in conjunctival MALT lymphoma and normal adjacent tissues were investigated by microRNA microarray of four pairs of surgically removed conjunctival MALT lymphoma tissues and matched controls. The results of microarray were further confirmed in 14 paired conjunctival MALT lymphoma samples (including the former four pairs) using quantitative RT-PCR. The functional effect of miR-200 was examined further. A luciferase reporter assay was performed to confirm the predicted target. The microarray results revealed upregulated miR-150/155, and downregulated miR-184, miR-200a, b, c, and miR-205. These findings were confirmed by quantitative RT-PCR. Targetscan analysis suggested cyclin E2 as potential target of miR-200a, b, c. Luciferase reporter assay using vectors containing the 3'UTR of cyclin E2 showed that miR-200a, b, c could suppress luciferase activities. RT-PCR and immunoblotting studies revealed that overexpression of miR-200a, b, c reduced the mRNA and protein levels of cyclin E2 respectively. We demonstrated that miRNAs were dysregulated in conjunctival MALT lymphoma, and dysregulation of the miR-200 family could be involved in the pathogenesis and progression of the disease.

Giant Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma

Giant Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma