Ocular Adnexal Extranodal Marginal Zone Research Articles

Chinese expert consensus on the diagnosis and management of ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (2023 edition)

Ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (OAML) is a common malignant tumor that affects the ocular adnexal region. The incidence of OAML is increasing due to the aging population. The tumor invades the ocular adnexal region, which can result in abnormal ocular appearance and function, thereby reducing the quality of life. Currently, there is no standardized diagnosis and management guideline for OAML. To enhance the standardization of diagnosis and management in OAML, a collaborative effort was undertaken by esteemed organizations in China. The Cellular Immune Therapy Committee of China Association for Promotion of Health Science and Technology, the Ocular Tumor Committee of Chinese Medical Doctor Association for Ophthalmologist Branch, the Imaging Medicine Branch of Chinese International Exchange and Promotion Association for Medical and Healthcare, the Tumor and Microecology Professional Committee of China Anti-cancer Association, and the Lymphoma Immunotherapy Committee of Beijing Cancer Prevention Society jointly convened a panel of experts to develop the inaugural "Chinese Expert Consensus on the Diagnosis and Management of ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (2023 edition)"..

Multi‐omics and case‐control analyses identify immunoglobulin M as a tumour‐derived serum biomarker of ocular adnexal extranodal marginal zone lymphoma

Multi‐omics and case‐control analyses identify immunoglobulin M as a tumour‐derived serum biomarker of ocular adnexal extranodal marginal zone lymphoma

MYC-targeted genes predict distant recurrence in patients with ocular adnexal extranodal marginal zone lymphoma.

Ocular adnexal extranodal marginal zone lymphoma (OA-EMZL) is the most frequent subtype of ocular adnexal lymphoma, with a high propensity for recurrence. Distant recurrence (DR) as an essential prognostic event has unique clinical risk factors, but whether distinct molecular features exist remains poorly understood. Here, we identified potential biomarkers using proteomic analysis of 27 OA-EMZL samples. The MYC-targeted genes PCNA, MCM6, and MCM4 were identified as candidates. MYC-targeted genes were further identified as the most significantly activated gene set in patients with DR. The candidate genes were verified in samples from 11 patients with DR and 33 matched controls using immunohistochemistry. The 3-year and 5-year AUC values of MCM6 (0.699 and 0.757) were higher than those of Ki-67 (0.532 and 0.592). High expressions of MCM6 and MCM4 were significantly associated with shorter distant recurrence-free survival (Log-rank p = 0.017, Log-rank p = 0.0053). Multivariate Cox regression identified MCM6 expression as an independent risk factor for DR (HR, 6.86; 95% CI, 1.32-35.79; P = 0.02). Knockdown of c-Myc in B cells resulted in decreased MCM6 and MCM4 expression and reduced proliferative capacity. Our results suggest that activation of the MYC-targeted gene is a distinct molecular feature of DR in OA-EMZL. MYC-targeted gene, MCM6, is a promising pathological biomarker for DR.

Epidemiology and Prognostic Index of Ocular Adnexal Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) in Thailand: Results from the Thai Lymphoma Study Group (TLSG)

Introduction Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is the most common subtype of marginal zone lymphoma (MZL) in Thailand. Results from the TLSG showed that almost half of the patients were ocular adnexal subtype (49.2%). However, there has been no validated prognostic index to predict outcome in these patients. Objectives This study aimed to describe epidemiology and develop prognostic index for ocular adnexa MALT lymphoma in Thai population. Methods Data from the TLSG were collected during January 2007 to March 2022. Patients who were diagnosed with ocular adnexa MALT lymphoma were enrolled. Demographic data including age, performance status (Eastern Cooperative Oncology Group; ECOG), stage of disease, lactate dehydrogenase (LDH), number of extranodal sites, presence of B symptoms and hepatitis profile were collected. Univariate and multivariate analyses were performed by using Cox regression. Parameters found to be associated with progression-free survival (PFS) and overall survival (OS) in multivariate analysis were used to perform prognostic index. Kaplan-Meier survival curves were analyzed to predict PFS and OS stratified by this prognostic index. Results Two hundred twenty-five patients were enrolled to this study. Male was predominantly affected (60.4%). Median age at diagnosis was 59 years (range: 28-87). Most of the patients (216, 96%) had good performance status (ECOG 0-1). Thirty-three patients (14.3%) had more than 1 extranodal sites. Thirty-five patients (15.6%) had high LDH at first diagnosis of lymphoma. Approximately half of the patients (116, 51.6%) were treated with chemotherapy. Twenty-three patients (10.2%) received immunotherapy (rituximab). Seventy-eight patients (34.7%) were radiated alone but only 3 patients (1.3%) in this registry underwent only surgery for treatment of ocular adnexa MALT lymphoma. Three parameters (age >65 years, ECOG 2-4, and advanced stage) were found to be potentially affecting survival in multivariate analysis. The prognostic index was categorized into low, intermediate, and high risk, according to the number of these parameters (0, 1, ≥ 2, respectively). Estimated 4-year OS for low-, intermediate- and high-risk groups were 97.4%, 90.9% and 77.9%, respectively, as shown in figure 1A (p-value=0.011). Estimated 4-year PFS for low-, intermediate- and high-risk groups were 82.5%, 69.2% and 55.4%, respectively (p-value=0.053), as shown in figure 1B. Conclusions This prognostic index can statistically discriminate among patients with ocular adnexa MALT lymphoma into low-, intermediate- and high-risk groups by OS. Although PFS can be stratified into 3 groups from this prognostic index, it has no statistical significance. Longer time of follow-up and more numbers of patients may result in statistical significance in near future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predicting the risk of distant and local recurrence for patients with ocular adnexal extranodal marginal zone lymphoma: a matched case–control study

Background/aimsExtranodal marginal zone lymphoma of ocular adnexa (OA-EMZL) is the most frequent type of ocular adnexal lymphomas, with a high rate of disease recurrence. Precise patient stratification based on disease...

Long-term survival outcomes of patients with primary ocular adnexal MALT lymphoma: A large single-center cohort study.

Primary ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (OAML) is a rare subtype of non-Hodgkin's lymphoma, and no consensus has been defined concerning the optimal treatment strategies. This study aims to investigate the associations of disease characteristics and different treatments with long-term outcomes of patients with localized OAML. A large retrospective cohort study was conducted in a single-center of China, and 166 patients with newly diagnosed primary localized OAML were enrolled. Detailed data of disease characteristics at diagnosis and treatments were collected for all patients. We compared treatment response and progression-free survival (PFS) among patients with different characteristics and treatments. Of the 166 patients, 52 received complete resection of neoplasm, whereas 114 had residual lesion after surgery. Among the 114 patients, 61 underwent watchful waiting and 53 received further treatment including localized radiotherapy, chemotherapy, or combined radiotherapy and chemotherapy. Median follow-up was 49 months. A total of 31 patients had disease progression or relapse, including four patients with such event more than five years after initial treatment. The 5-year PFS was 73.9%, 70.6%, and 85.9%, whereas the 10-year PFS was 69.3%, 59.2%, and 79.3%, among patients with complete resection of neoplasm, patients in the watchful waiting group and patients with further treatment, respectively. Patients with further treatment had longer PFS, compared with patients in the watchful waiting group (p=0.011). Bilateral involvement at diagnosis was associated with significantly inferior PFS (p=0.029), whereas age, IPI score, or TNM staging were not associated with PFS. No serious adverse reaction was reported among patients with further treatment. Bilateral involvement was associated with poor prognosis. Among patients with residual lesions after surgery, further treatment was associated with improved survival. Patients with OAML might experience disease progression or relapse more than five years after initial treatment.

Treatment and prognosis of primary ocular adnexal extranodal marginal zone mucosa-associated lymphoid tissue lymphoma: a report from a single center

目的探讨局限于眼附属器黏膜相关淋巴组织结外边缘区淋巴瘤（OAML）患者应用不同初始治疗方案对长期预后的影响。方法对2008年4月至2019年4月首都医科大学附属北京同仁医院血液科收治的109例初发OAML患者进行疗效评估及随访，对初始治疗方案与预后进行分析。结果36例患者经手术完全切除病灶，73例术后存在残留病灶，其中37例选择观察等待，36例选择治疗，治疗方案包括局部放疗和系统性治疗（化疗、免疫化疗、放化疗联合等），选择系统性治疗患者未发生严重不良反应。中位随访时间61（10～142）个月，单眼受累患者5年、10年无进展生存（PFS）率分别为78.2％和76.0％，双眼受累患者5年、10年PFS率分别为64.4％和23.5％，单眼、双眼受累患者PFS的差异有统计学意义（P＝0.010）。残留病灶观察组患者和残留病灶治疗组患者5年PFS率分别为71.4％和90.1％，10年PFS率分别为63.5％和75.1％，两组患者PFS率的差异有统计学意义（P＝0.046）。OAML患者超过5年仍有疾病进展风险。结论双眼受累OAML患者预后差，治疗可以降低复发或进展风险。系统性治疗可作为OAML患者的一线治疗选择之一。OAML需要长期随访。

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing.

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5–10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.

High-throughput sequencing reveals no viral pathogens in eight cases of ocular adnexal extranodal marginal zone B-cell lymphoma

The purpose of the present study was to perform a next-generation sequencing (NGS) based analysis of viruses in ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL). Eight patients with extraocular EMZL were identified in the archives of Department of Ophthalmology, Copenhagen University Hospital. All cases were validated according to the World Health Organization classification. We subjected samples to enrichment of virion-associated (encapsidated) nucleic acids which included sample homogenization, filtration, and nuclease treatment. Both DNA and RNA were sequenced, and we analyzed the sequencing data for the presence of viral sequences. We detected no pathogenic viruses likely to be associated to development of EMZL. In one case, we detected human polyomavirus 7 and traces of Epstein-Barr virus (EBV) (human herpesvirus 4 (HHV4)) and a human papillomavirus. In conclusion, no viral pathogens were consistently detected in the extraocular EMZL samples when applying NGS-based methods.

Clinical presentation and treatment outcomes of primary ocular adnexal MALT lymphoma in Thailand.

BackgroundPrimary ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (POML) is the most common subtype of lymphoma involving the eyes in Thailand. We sought to assess the characteristics and treatment outcomes of patients with POML in Thailand.MethodsWe retrospectively reviewed patient data and included patients diagnosed with POML between January 2004 and December 2016 at Chiang Mai University Hospital and King Chulalongkorn Memorial Hospital, Thailand. We collected and analyzed patients' clinical characteristics and treatment outcomes.ResultsAmong 146 patients with lymphoma involving the eyes, 121 (82%) were diagnosed with POML. Sixty-four (52.9%) were women with median age 58 (range, 22–86) years. The most common presenting symptom was orbital mass (71.1%). Common sites of origin were the orbit (46.3%) and lacrimal gland (34.7%). At presentation, 22.3% of patients had bilateral eye involvement. About half of patients had stage I disease (N=59, 56.2%) and 20% had stage IV. Most patients (73.3%) had a low-risk International Prognostic Index. Radiotherapy was the main treatment for patients with limited-stage disease (66.7% in stage I and 56.5% in stage II). The overall response rate was 100% with complete response rates 80%, 77.3%, and 64.7% for stages I, II, and IV, respectively. Five-year progression-free survival (PFS) and overall survival were 66.1% and 94.0%, respectively. For patients with limited-stage disease, radiotherapy significantly improved PFS compared with treatment not involving radiotherapy (5-year PFS 89.9% vs. 37.3%, P=0.01).ConclusionWe revealed that POML has good response to treatment, especially radiotherapy, with excellent long-term outcome.

Characteristics of primary extranodal marginal zone B-cell lymphoma in Korea: conjunctiva versus other ocular adnexa

AimsTo compare the clinical characteristics and prognosis of primary conjunctival versus other ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL).MethodsRetrospective review of clinical records for all consecutive patients with primary...

Clinicopathological Analysis of Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma with IgG4-Positive Cells.

This study aims to analyze clinical and pathological characteristics of ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL) accompanying IgG4-positive cells. Fifty patients with a diagnosis of primary non-conjunctival ocular adnexal EMZL were enrolled in this study. The number of IgG4-positive cells and the ratio of IgG/IgG4 were evaluated by immunohistochemistry in the biopsy specimens. The patients were divided into two groups based on the absolute number and the ratio of IgG4-positive cells (IgG4-posivite vs IgG4-negative groups). The demographic data, clinical staging at diagnosis, histopathological characteristics, and response to initial treatment were comparatively analyzed between the 2 groups. Five (10%) of 50 patients were defined as IgG4-positive group, and all the cases showed characteristic histological features such as extensive plasma cell infiltration and dense fibrosis. Most of these patients (4 of 5 patients) had lymphoma of the lacrimal gland. The patients from the IgG4-positive group showed a lower response rate to initial treatment (87.5 vs 33%, p = 0.03) than IgG4-negative group with a median follow-up period of 38 months. A part of the ocular adnexal EMZLs were accompanied with IgG4-positive cells. Significantly, most IgG4-positive ocular adnexal EMZLs occurred in the lacrimal gland, and can be related with a more frequent treatment failure.

Chlamydophila psittaci-negative ocular adnexal marginal zone lymphomas express self polyreactive B-cell receptors.

The pathogenesis of Chlamydophila psittaci-negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B-cell receptor (BCR) may have a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase high-performance liquid chromatography nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (for example, galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings indicate that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall, our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci-negative OAEMZLs.

Molecular and genomic aberrations in Chlamydophila psittaci negative ocular adnexal marginal zone lymphomas

The etiology and pathogenesis of ocular adnexal extranodal marginal zone lymphoma (OAEMZL) are still unknown and the association with Chlamydophila psittaci (C. psittaci) has been shown in only some geographic regions. Herein, we comprehensively examined the frequency of chromosomal translocations as well as CARD11, MYD88 (L265P), and A20 mutations/deletions in 45 C. psittaci negative OAEMZLs. t(14;18)(q32;q21) IGH-MALT1 and t(11;18)(q21;q21) API2-MALT1 were not detected in any of the analyzed tumors while three tumors harbored IGH translocations to an unidentified partner. CARD11 mutations were not found in all analyzed tumors, while the MYD88 L265P mutation was detected in three (6.7%) tumors. A20 mutations and deletions were each detected in seven (15.6%) and six (13.3%) tumors, respectively. Therefore, the observed genetic aberrations could account for the activation of the nuclear factor (NF)-kB signaling pathway in only a minority of the cases. Further studies are needed to identify the molecular mechanisms underlying the pathogenesis of OAEMZL.

The Effect of Rituximab, Cyclophosphamide, Vincristine, and Prednisolone (R-CVP) Chemotherapy in Patients with Ocular Adnexal Extranodal Marginal Zone B Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

The Effect of Rituximab, Cyclophosphamide, Vincristine, and Prednisolone (R-CVP) Chemotherapy in Patients with Ocular Adnexal Extranodal Marginal Zone B Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

MicroRNA profiling in ocular adnexal extranodal marginal zone lymphoma and diffuse large B‐cell lymphoma

AbstractPurpose To investigate changes in microRNA (miR) expression in ocular adnexal extranodal marginal zone lymphoma (EMZL) and diffuse large B‐cell lymphoma (DLBCL), and to perform a pathway analysis of differentially expressed miRs.Methods Global miR expression profiling was performed using miRCURYTM LNA miR‐arrays, v. 11.0, (Exiqon) on formalin‐fixed paraffin‐embedded tissue from 18 ocular adnexal EMZLs and 25 DLBCLs. The result of microarray was confirmed using quantitative real time (RT)‐PCR. Predicted and validated targets of the significantly differentially expressed miRs were obtained from MiR‐walk. Transcription factor (TF)‐miR interactions were obtained from the TransmiR database.Results The microarray results revealed two up‐regulated and 41 down‐regulated miRs in the DLBCLs compared to the EMZLs. Further, the differentially expressed miRs separated EMZLs and DLBCLs into two distinct entities using a supervised clustering analysis. These findings were confirmed by quantitative RT‐PCR. Five of the down‐regulated miRs (let‐7g, miR‐26a, miR‐29a, miR‐29c and miR‐221) were identified to be regulated negatively by MYC. A small set of miRs (let‐7g, miR‐199a‐5, miR‐26a, miR‐27a* and miR‐342‐3p) that regulate NFKB1 were all down‐regulated in the DLBCLs compared to the EMZL samples. Further, the NFKB1 regulated miRs (miR‐29a/b/c and miR‐125b) were down‐regulated significantly in the DLBCLs compared with the EMZLs (log2 fold‐changes: miR‐29a/b/c < ‐1.9 and ‐1.1 for miR‐125b).Conclusion We demonstrated that fundamental differences in miR expression exist between ocular adnexal EMZLs and DLBCLs, mainly due to differences in MYC and NF‐kB regulatory pathways.

Orbital MALT Lymphoma, Abdominal Hodgkin lymphoma, and Systemic Diffuse Large B-cell Lymphoma Develop Sequentially in One Patient

In February 2002, a 42-year-old woman developed ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), MALT lymphoma, in the bilateral orbits involving lacrimal glands. She underwent 30 Gy external beam irradiation to the orbital lesions on both sides. She was well until November 2008 when she developed abdominal lymphadenopathy and transabdominal excisional biopsy showed mixed cellularity classical Hodgkin lymphoma at stage II. She underwent standard combination chemotherapy. In July 2010, she developed systemic lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma (DLBCL) by cervical lymph node biopsy. She underwent rituximab monotherapy and finally allogeneic hematopoietic stem cell transplantation in October 2010, but died of renal failure in February 2011. Amplification by polymerase chain reaction of the immunoglobulin heavy chain gene gave rise to dominant discrete fragments of the same size between the orbital lesion with MALT lymphoma in 2002 and the cervical lymph node lesion with DLBCL in 2010. The sequential development of MALT lymphoma, Hodgkin lymphoma, and DLBCL in the long-term course of this patient suggests the common origin of the neoplastic cells, changing their pathological faces in response to irradiation and combination chemotherapy.

Feasibility of the TNM‐based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma)

The American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system to overcome the limitations of the Ann Arbor staging system for ocular adnexal lymphoma. We performed this study to evaluate the feasibility of the TNM staging system for ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (OAML). The data form 66 total eyes from 54 patients with biopsy-confirmed OAML according to World Health Organization classification were retrospectively analyzed. Using the TNM staging system, we reclassified all patients into two categories: (1) T1N0M0 stage group (n = 26), for patients with lymphoma involving only the conjunctiva; and (2) above T1N0M0 or bT1N0M0 stage group (n = 28), for patients with lymphoma extending to the orbit, eyelid, or adjacent structures, and/or bilateral OAML. After a 24-month median follow-up period for all patients, the T1N0M0 group revealed higher progression-free survival (PFS) than the above T1N0M0 or the bT1N0M0 group (P = 0.041). In a separate analysis of only 50 patients categorized as Ann Arbor stage IE, the T1N0M0 group demonstrated higher PFS (100%) than the above T1N0M0 or the bT1N0M0 group (84.7%; P = 0.067). Our data show that the poor prognostic group classified as Ann Arbor stage IE can be further distinguished by using the TNM staging system. Thus, further studies to develop treatment strategies for reducing relapse after treatment for OAML should use the TNM staging system.

Local Recurrence as Immunoglobulin G4 (IgG4)-Related Disease 10 Years after Radiotherapy to Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

In 2000, a 48-year-old woman developed a left orbital mass with lacrimal gland involvement and then, in 2003, a right orbital mass with lacrimal gland involvement, both of which were diagnosed as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). She underwent 30 Gy external beam radiation to bilateral orbital lesions. The lymphoma cells in both lesions did not share the same clonality, as shown by amplification by polymerase chain reaction of the immunoglobulin heavy chain gene. Immunoglobulin light chain analysis by immunohistochemistry and messenger RNA in situ hybridization showed λ chain monotype in the left orbital lesion but κ chain monotype in the right orbital lesion. She developed recurrent left orbital mass with high uptake on fluorodeoxyglucose positron emission tomography fused with computed tomography in 2010, and excisional biopsy disclosed the formation of follicles and infiltration with immunoglobulin G4 (IgG4)-positive plasma cells mainly in interfollicular areas. The immunoglobulin light chain analysis showed the λ chain and κ chain bitype. With the immunohistopathological diagnosis of IgG4-related disease, the serum IgG4 level was found to show elevation at 376 mg/dL, and the patient chose observation. This is the first reported case of development of IgG4-related disease after bilataral orbital MALT lymphoma with external beam radiotherapy.

Ocular Adnexal Lymphoma Associated With IgG4+ Chronic Sclerosing Dacryoadenitis: A Previously Undescribed Complication of IgG4-related Sclerosing Disease

IgG4-related sclerosing disease is a recently recognized inflammatory lesion frequently involving pancreas, submandibular gland, lacrimal gland, and lymph node. We report 3 cases of ocular adnexal lymphoma arising in IgG4-related chronic sclerosing dacryoadenitis, a phenomenon that has not been previously reported. The patients presented with bilateral or unilateral ocular adnexal mass usually present for many years. One patient also had asymptomatic diffuse lymphadenopathy. Two patients had biopsy-proven IgG4-related chronic sclerosing dacryoadenitis before the current presentation, and 1 had systemic involvement by IgG4-related sclerosing disease as evidenced by increased IgG4+ cells in a prior nasopharyngeal biopsy. Two cases showed features of extranodal marginal zone lymphoma of mucosa-associated lymphoid-tissue type (1 with large cell transformation) and 1 follicular lymphoma. Thus, the lymphoid hyperplasia of IgG4-related sclerosing disease can provide a substrate for the emergence of lymphoma. In addition, we report 3 cases of ocular adnexal extranodal marginal zone B-cell lymphoma that show sclerosing inflammation in the background and numerous IgG4+ monotypic plasma cells. In the absence of prior biopsies or information on serum IgG4 titer, it is unclear whether these cases represent lymphoma complicating IgG4-related sclerosing disease or de novo lymphoma. Nonetheless, these cases are distinctive in that the neoplastic cells express IgG4 (light chain restricted), whereas unselected cases of ocular adnexal lymphomas do not show IgG4 expression.