Ocular Adnexal Lymphoproliferative Disorders Research Articles

Local Control of Ocular Adnexal Lympho-Proliferative Disorders (OALD): Similar Outcomes in MALT and Non-MALT Histologies

Background:Lympho-proliferative disorders are among the most common neoplasms affecting the ocular adnexa. OALD represents 1% of all lymphomas and 10-15% of extra nodal presentations. The outcomes of local radiation therapy (RT) in MALT vs. non-MALT histology are not known. Herein we present outcomes of local therapy in MALT vs. non-MALT OALD treated at a specialized lymphoma program.Methods:The analysis included 112 consecutive patients (pts) with OALD diagnosed at our institution between 1975- 2014. Patient characteristics, treatment modality and the response to treatment were retrospectively collected. Histology was reviewed by an expert hematopathologist. The primary objective of the study was to assess the failure free survival (FFS) in pts with marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) of ocular adnexa (OA) and non-MALT OA lymphomas treated with local radiation therapy. Complete remission was defined as absence of any disease by imaging. Local failure was defined as any failure within the OA; extra-orbital failure was either regional (within the radiation field) or distant (for cases with limited stage disease at presentation). FFS was defined as time from treatment to any failure (local, regional and distant) and overall survival (OS) as time from treatment to last follow up or death from any cause. FFS and OS were estimated using the Kaplan-Meier methods.Results:Baseline characteristics are shown in Table 1. Of 112, 71(57.7%) of the pts had ocular MALT, and 41(33.3%) had non-MALT (23 follicular, 8 diffuse large cell B cell lymphomas, 3 mantle cell, 6 small lymphocytic lymphoma and 1 T cell lymphoma). Unilateral eye involvement (83.9%) with mass/swelling (55.3%) was the most common presentation. Staging was performed with CT scan and bone marrow biopsy in select cases (n=63, 51%). PET scan was utilized in 33 (29.4%) pts. but was able to upstage in only 5 cases.For ocular MALT, 62(87.3%) received involved field radiation therapy (IFRT), 9(12.6%) chemotherapy. For non-MALT, 34(82.9%) had IFRT, 7(17%) chemotherapy. Among those who received IFRT, 55(75%) in MALT and 21(52%) in non-MALT had limited stage disease (I/II).Among OALD pts treated with only IFRT, 91.7% in ocular MALT and 90.9% in non-MALT achieved complete remission. Resolution of symptoms occurred in 83.3% and 93.3% of ocular MALT and non-MALT respectively. Failure rates of IFRT in ocular MALT vs. non-MALT were as follows: local (7% vs. 12.1%), regional (9.8% vs. 7.3%), and distant (5.6% vs 2.4%). Median follow-up was 3(1-22) years in each group. Median time to failure was 14 years for ocular MALT and 9 years for non-MALT. 3 year and 5 year failure-free survival was 88% and 81% for ocular MALT and 78% and 71% for non-MALT respectively (log rank p=0.26 for FFS) (Fig 1).Conclusions:Both the MALT and non-MALT OALD pts achieved excellent disease control with IFRT with no significant difference in local, regional and distant failure rates. 3 year and 5-year failure free survival were comparable between the two groups. PET scan resulted in upstaging in 5% of pts but did not alter treatment selection, indicating that PET had minimal utility in initial staging of OALD.Table 1Baseline characteristicsTOTAL, N=112MALT71(63.3%)NON-MALT41(36.6%)Age (median),years64 (22-84)66(25-87)Sex, M25 (35.2%)16(39%)Race, Caucasian63 (88%)34(83%)Symptoms at presentation - Mass/Swelling - Visual changes - Other35 (49.2%) 11 (15.4%) 2 (2.8%)27(66%) 11(27%) 1(2.4%)Site of origin - Orbital - Conjunctival - Lacrimal gland - Eyelid - Other31 (43.6%) 26 (36.6%) 10 (14%) 1 (1.4%) 4 (5.6%)14(34.1%) 14(34.1%) 10(24.3%) 3(7.3%) 0Unilateral Involvement60 (86%)34(83%)Stage at presentation - I - II - III - IV - Unknown60 (85%) 0 1 (1.4%) 8 (11.2%) 2(2.8%)24(59%) 4(9.7%) 2(4.8%) 7(17%) 4(9.7%) [Display omitted] DisclosuresHari:BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Spectrum: Consultancy. Fenske:Millennium/Takeda: Research Funding; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria; Celgene: Honoraria.

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.

A prevalence study of IgG4-related ophthalmic disease in Japan

Immunoglobulin (Ig)G4-related ophthalmic disease belongs to a category of ocular adnexal lymphoproliferative disorders, the most frequent group of orbital tumors and simulating lesions. The aim of this study was to elucidate the number of IgG4-related diseases of orbital lymphoproliferative disorders and correlate ages and sex of such patients from 18 centers in Japan. One thousand and fourteen patients with orbital lymphoproliferative disorders were enrolled in this study. All had pathologically diagnosed lymphoproliferative disorders with surgical samples of ocular adnexal tissue. Patients with conjunctival lesions and intraocular lymphoma were excluded. Of the 1,014 cases of orbital lymphoproliferative disorders 404 (39.8%) had extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, 156 (15.4%) had other malignant lymphomas, 191 (18.8%) had non-IgG4 orbital inflammation, 219 (21.6%) had IgG4-related orbital inflammation, and 44 (4.3%) had IgG4-positive MALT lymphoma. Median age of the IgG4-related orbital inflammation group was 62years, which is significantly lower than that of the MALT lymphoma group (median 66years) and higher than the non-IgG4 orbital inflammation group (median 57years). The male/female ratio was 105/114 in the IgG4-related orbital inflammation group. Nearly a quarter of orbital lymphoproliferative disorders in Japan are related to IgG4.

Ocular adnexal lymphoproliferative disorders in an ophthalmic referral center in Saudi Arabia

PurposeTo study the pattern of ocular adnexal lymphoproliferative disorders (OALD) in an ophthalmic referral center in Saudi Arabia and to review their, histopathological characteristics with clinical correlation. MethodsRetrospective chart review of 40 cases of patients who underwent incisional biopsy with the suspected diagnosis of periocular and/or adnexal lymphoid lesions over the period: 2000–2012 at the King Khaled Eye Specialist Hospital (KKESH), Riyadh, Saudi Arabia. The routine histopathologic slides are reviewed by a single pathologist to identify cases of Benign Reactive Lymphoid Hyperplasia (RLH), Atypical Lymphoid Hyperplasia and probable lymphoma. The identification of the specific types of lymphoma is performed at a tertiary general hospital: King Faisal Specialist Hospital and Research Centre (KFSH&RC). ResultsForty patients are included with an age range of 11–91years and a median of 36years. The males constitute 70% and females 30% of the cases. The right eye and/or orbit are involved in 48%. The left eye is involved in 45% while a bilateral disease is found in 7.5%. The median duration of symptoms is 5months. The site distribution is conjunctiva (42.5%), orbit (25%), lacrimal gland (12.5%), eyelid (10%), lacrimal sac (7.5%) and caruncle (2.5%). One case is excluded after histopathologic diagnosis of malignant melanoma. Diagnosis in the remaining 39 cases includes: RLH in 14 cases (35%), atypical lymphoid hyperplasia in three cases (9%), and lymphoma in 22 cases (56%). Classification of the lymphoma group is: extranodal marginal zone lymphoma (EMZL) in 9/22 cases (41%), diffuse large B cell lymphoma (DLBCL) in 4/22 cases (18%), Castelman’s disease in 3/22 cases (14%), Burkitt’s lymphoma in 2/22 cases (9%), follicular lymphoma and T cell-rich B cell lymphoma: one case each (4.5%).Two cases remain unclassified. ConclusionWe have a wide age range which is comparable to other studies. Our results show male predominance and the commonest site of involvement is conjunctival, however if RLH cases are excluded, the commonest site for lymphoma is orbit/lacrimal gland in 45% followed by conjunctival in 23%. The commonest type of lymphoma is: EMZL in 41% followed by DLBCL in 18% then other types of lymphoma including follicular lymphoma.

Clinical Aspects of IgG4-Related Orbital Inflammation in a Case Series of Ocular Adnexal Lymphoproliferative Disorders

The most frequent ocular adnexal tumors and simulating lesions are lymphoproliferative disorders (LPDs), including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration. IgG4-related orbital inflammation (IgG4-ROI) often involves lacrimal glands and other orbital tissues and is an important differential diagnosis. The present study evaluated clinical aspects of IgG4-ROI in a case series of orbital LPD. Sixty-two consecutive cases of orbital LPD, pathologically diagnosed from November, 2004, through March, 2011, were investigated. Histological types were 22 cases with MALT lymphoma, 11 cases with diffuse large B-cell lymphoma (DLBCL), 3 cases with other malignant lymphomas, 16 cases with IgG4-ROI, and 10 cases with non-IgG4-ROI. Ages of the IgG4-ROI group (56 ± 10 yrs) were significantly lower than the MALT lymphoma (71 ± 12 yrs) and DLBCL (75 ± 14 yrs) groups. Orbital lesions other than lacrimal glands were present in six cases including extraocular muscle swelling, mass lesions surrounding the optic nerve, and supraorbital and infraorbital nerves enlargements. Although none of the malignant lymphomas were related to IgG4, previous evidence suggested that malignant lymphomas can arise from IgG4-ROI. Based on this study (26%) and another report (33%), it is likely that nearly a quarter of orbital LPD are IgG4-ROI.

No evidence of a correlation between BCL10 expression and API2-MALT1 gene rearrangement in ocular adnexal MALT lymphoma.

In the present study, 62 cases of ocular adnexal lymphoproliferative disorders were reviewed clinicopathologically. Of them, 51 were extranodal marginal zone B-cell lymphoma (MALT lymphoma), five were diffuse large B-cell lymphoma (DLBCL), one was peripheral T-cell lymphoma, one was NK/T cell lymphoma, nasal type, and four were reactive lymphoid hyperplasia. These lymphoma cases showed a favorable clinical course and localized disease, except for the case of NK/T cell lymphoma, although 19 cases (32.8%) had a recurrence of disease. To clarify the correlation between BCL10 protein expression and API2-MALT1 gene rearrangement, the 51 cases of MALT lymphoma and 5 cases of DLBCL were analyzed by immunohistochemical and RT-PCR methods. Nuclear BCL10 expression was identified in 58% of MALT lymphoma cases, but not in any DLBCL cases. There was no evidence of a correlation between aberrant nuclear BCL10 expression and the clinical parameters examined in the present study. API2-MALT1 transcription was not demonstrated in either the MALT lymphoma cases or the DLBCL cases studied using a multiplex one-tube reverse transcriptase-PCR method. These findings indicate that the nuclear expression of BCL10 is unlikely to correlate with the API2-MALT1 fusion gene in ocular adnexal MALT lymphoma.

Involvement of the Chromosomal Translocation t(11;18) in Some Mucosa-Associated Lymphoid Tissue Lymphomas and Diffuse Large B-Cell Lymphomas of the Ocular AdnexaEvidence from Multiplex Reverse Transcriptase-Polymerase Chain Reaction and Fluorescence In Situ Hybridization on Using Formalin-Fixed, Paraffin-Embedded Specimens

The chromosomal translocation t(11;18) is a unique chromosomal aberration associated with mucosa-associated lymphoid tissue lymphoma. API2 and MALT1 genes have been identified around this translocation. We attempted to find chromosomal abnormalities focusing mainly on the t(11;18) translocation in formalin-fixed, paraffin-embedded tissues of ocular adnexal lymphoproliferative disorders using multiplex reverse transcriptase-polymerase chain reaction and/or two-color interphase fluorescence in situ hybridization. By these methods, the t(11;18) translocation was detected in 1 of 8 patients with reactive lymphoid hyperplasia (13%), 3 of 23 with mucosa-associated lymphoid tissue lymphoma (13%), and 2 of 14 with diffuse large B-cell lymphoma with/without mucosa-associated lymphoid tissue lymphoma (14%). Moreover, we performed fluorescence in situ hybridization analysis to detect any numerical aberration of chromosomes 3, 7, 12, and 18 on some specimens nonselectively. No numerical chromosomal abnormalities were detected in 3 cases of reactive lymphoid hyperplasia, whereas three of four cases of mucosa-associated lymphoid tissue lymphoma and all four cases of diffuse large B-cell lymphoma with/without mucosa-associated lymphoid tissue lymphoma components exhibited one or more abnormalities. These findings indicate a possibility that at least in the ocular adnexa, some diffuse large B-cell lymphomas are derived from mucosa-associated lymphoid tissue lymphomas.

Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of MALT lymphoma and reactive lymphoid hyperplasias

Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of MALT lymphoma and reactive lymphoid hyperplasias

Clinical, Histopathological, and Immunogenetic Analysis of Ocular Adnexal Lymphoproliferative Disorders: Characterization of MALT Lymphoma and Reactive Lymphoid Hyperplasia

Malignant lymphomas and reactive lymphoid hyperplasia (RLH) in the ocular adnexa are sometimes difficult to differentiate morphologically and have often been categorized together as a lymphoproliferative disorder. Immunogenotypic characters of these diseases have not yet been well clarified. This study included 76 cases of ocular adnexal lymphoproliferative disorders. These consisted of 52 cases of malignant lymphoma (43 primary and 9 secondary), 22 of RLH, and 2 borderline cases. There were slightly more male than female subjects. Diagnoses were based on morphology and immunophenotypic characteristics. Clonalities were detected by means of polymerase chain reaction (PCR), and immunoglobulin heavy-chain variable region (VH) genes were sequenced in 10 cases of mucosa-associated lymphoid tissue (MALT) lymphoma. MALT lymphoma constituted 86% (37 cases) of the primary lymphomas. MALT lymphomas were more indolent, more rarely disseminated, and had a lower death rate than the other primary lymphomas. Two patients exhibited coexistence of MALT and diffuse large B-cell lymphoma. The average age of patients with RLH was 5.5 years younger than that of those with MALT lymphoma. One of the cases of RLH later progressed to malignant lymphoma. B-cell clonality was detected by PCR in 57%, 55%, and 0% of primary lymphomas, MALT lymphomas and RLHs, respectively. Sequencing of VH genes revealed that the VH3 family was the most commonly expressed germline VH family (70%) and that DP-63, DP-54 and DP-47 genes were frequently found in the MALT lymphomas examined. PCR analysis was useful for differentiation between MALT lymphoma and RLH. Sequence analysis of VH genes showed that an autoimmune mechanism may be involved in the lymphomagenesis of ocular adnexal MALT lymphoma.

Histopathologic, immunophenotypic and genotypic analyses in ocular adnexal lymphoproliferative disorders

This study reports on fourteen biopsies from patients presenting to our orbital and oncology service with ocular adnexal lymphoid proliferations between November 1988 to September 1991. The biopsies were studied using histologic, immunophenotypic and genotypic analyses. By histologic criteria, there were two reactive, five indeterminate and seven lymphomatous lesions. On immunophenotypic analysis, there were two monoclonal and 10 polyclonal lesions in the 12 specimens analysed. Genotypic analysis confirmed the histopathologic diagnoses for the reactive lesions by showing them to be germline. It also confirmed that both the histopathologic lymphomas and immunophenotypically monoclonal lesions were clonally rearranged. Genotypic analysis was able to separate the histologically indeterminate group into two subsets: clonally rearranged, of which there was one, and germline, of which there were four. In addition, it demonstrated that immunophenotypic polyclonality cannot always be equated with genotypic polyclonality as was the situation in four out of 10 lesions in our series. The significance of clonal arrangements in the histologically indeterminate and immunophenotypically polyclonal groups can only be determined by prospective study.