Lymphoproliferative Läsionen der okulären Adnexe

The ocular adnexal lymphomas represent the malignant end of the spectrum of lymphoproliferative lesions which occur in the conjunctiva, eyelids, lacrimal gland and orbit. The new “W.H.O. Classification of Tumours of Haemopoietic and Lymphoid Tissues” is the most suitable for subdividing the ocular adnexal lymphomas, whereby the extranodal marginal zone B-cell lymphoma (EMZL) represents the most common lymphoma subtype. Management of patients with ocular adnexal lymphomas includes a systemic medical examination to establish the clinical stage of the disease. Most patients have stage IE disease and current recommended therapy for this is radiotherapy, while disseminated disease is treated with chemotherapy. Despite usually demonstrating an indolent course, EMZLs are renowned for recurrence in extranodal sites, including other ocular adnexal sites. Furthermore, blastic transformation of EMZL with a corresponding aggressive clinical course has been described. Long-term follow-up with half-yearly examinations are therefore recommended. Major prognostic criteria for the ocular adnexal lymphomas include the age of the patient, anatomical location of the tumour, stage of disease at first presentation, serum lactate dehydrogenase level at the time of diagnosis, lymphoma subtype as determined using the W.H.O. lymphoma classification and the tumour cell growth rate. The clinical symptoms and the histopathological findings of the differential diagnoses of lymphoproliferative lesions of the ocular adnexa are discussed.     

Ocular adnexal lymphomas: five case presentations and a review of the literature

The ocular adnexal lymphomas represent the malignant end of the spectrum of lymphoproliferative lesions that occur in these locations. The Revised European and American Lymphoma (REAL) Classification and the new World Health Organization Classification of Tumors of Hemopoietic and Lymphoid Tissues are the most suitable for subdividing the ocular adnexal lymphomas, whereby the extranodal marginal zone B-cell lymphoma represents the most common lymphoma subtype. This review is based on five cases subtyped according to the above classifications-three "typical" lymphomas (an extranodal marginal zone B-cell lymphoma, a diffuse large cell B-cell lymphoma arising from an extranodal marginal zone B-cell lymphoma, and a follicular lymphoma) and two "atypical" lymphomas (a non-endemic Burkitt lymphoma in an immune competent elderly patient, and a primary Hodgkin lymphoma of the eyelid) of the ocular adnexa. Management of patients with ocular adnexal lymphomas includes a thorough systemic medical examination to establish the clinical stage of the disease. The majority of patients with ocular adnexal lymphoma have stage IE disease. Current recommended therapy in stage IE tumors is radiotherapy, while disseminated disease is treated with chemotherapy. Despite usually demonstrating an indolent course, extranodal marginal zone B-cell lymphomas are renowned for recurrence in extranodal sites, including other ocular adnexal sites. Long-term follow-up with 6-month examinations are therefore recommended. Major prognostic criteria for the ocular adnexal lymphomas include anatomic location of the tumor; stage of disease at first presentation; lymphoma subtype as determined using the REAL classification; immunohistochemical markers determining factors such as tumor growth rate; and the serum lactate dehydrogenase level.     

Orbital lymphoma

Orbital lymphomas constitute 50–60% of ocular adnexal lymphomas. A total of 2211 cases of orbital lymphoma with a known subtype have been reported in the last 24 years (1994–2017). The vast majority of orbital lymphomas are of B-cell origin (97%), of which extranodal marginal zone B-cell lymphoma (EMZL) (59%) is the most common subtype, followed by diffuse large B-cell lymphoma (23%), follicular lymphoma (9%), and mantle cell lymphoma (5%). Orbital lymphoma is primarily a disease of the elderly. Gender distribution varies according to lymphoma subtype. However, extranodal marginal zone B-cell lymphoma (53%) and follicular lymphoma (75%) show a female predominance, whereas diffuse large B-cell lymphoma shows an even gender distribution. Mantle cell lymphoma has a striking male predominance of 80%. The histopathological subtype and the clinical stage of the disease are the best indicators of prognosis and patient outcome. Low-grade lymphomas such as extranodal marginal zone B-cell lymphoma and FL have a good prognosis, whereas high-grade lymphomas (diffuse large B-cell lymphoma and mantle cell lymphoma) are associated with a poor prognosis. When managing solitary low-grade lymphomas, radiotherapy is the treatment of choice. Chemotherapy, with or without radiotherapy, should be chosen for disseminated and high-grade lymphomas.     

Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases

Background To determine the prognostic value of cell-cycle associated markers in ocular adnexal lymphoma (OAL).Methods Two hundred sixty-one consecutive cases of ocular adnexal lymphoproliferative lesions were subdivided into reactive lymphoid hyperplasia (RLH), atypical lymphoid hyperplasia (ALH) and OAL. The latter were sub-typed according to the new WHO Lymphoma Classification. All lesions were investigated applying standard immunohistochemical methods with antibodies specific for pRB, p53, p16, p21, BCL-6 and for multiple myeloma oncogene-1-protein (MUM1, also known as IRF4). The main endpoints included the development of a local recurrence, of systemic disease and of lymphoma-related death. The association of prognostic variables with endpoints was assessed by multiple logistic and Cox regression models, respectively.Results The ocular adnexal lymphoproliferative lesions were categorised as OAL (n=230; 88%), RLH (n=29; 11%), and ALH (n=2; 1%). The major lymphoma subtypes included 136 extranodal marginal zone B-cell lymphoma (EMZL), 31 diffuse large cell B-cell lymphomas, 27 follicular lymphomas, 9 plasmacytomas, 9 lymphoplasmocytic lymphoma/immunocytomas and 8 mantle cell lymphomas. The median follow-up time was 44.5 months. Most OAL patients had Stage IE disease and were treated with radiotherapy. Thirty-seven (25%) Stage IE patients had tumour relapses: these were significantly associated with an increased BCL6 blast percentage. Sixty-two (42%) Stage IE patients developed systemic disease: they had non-EMZL with large growth fractions and increased blast percentages for BCL6. Fifty-seven (25%) OAL patients died because of their lymphoma; lymphoma-related death was significantly associated on multivariable analysis with advanced clinical stage, an age >60 years and large tumour growth fractions.Conclusion Subtyping of OAL according to the new WHO Lymphoma Classification, the stage of disease and tumour cell growth fraction aided the prediction of (1) tumour relapse, (2) the development of systemic disease and (3) lymphoma-related death in OAL.     

Prognosis for patients in a Korean population with ocular adnexal lymphoproliferative lesions

PURPOSE: To analyze the clinical features, treatment outcomes, and prognostic factors associated with lymphoproliferative lesions of the ocular adnexa in a Korean population. METHODS: Data from 69 patients treated for adnexal lymphoproliferative disease in the 12-year period from 1991 to 2002 were retrospectively evaluated. RESULTS: The 69 patients had a median age of 46 years (range, 15-73 years); 60 of these patients were diagnosed with extranodal marginal zone B cell lymphomas (MALT lymphomas) and had 10 year cause specific survival and relapse free survival rates of 95.6% and 82.6%, respectively. Of 6 patients (8.7%) with concurrent systemic lymphoma, including 4 diagnosed with stage IV disease, 3 died from lymphoma. Only one patient with a primary ocular adnexal MALT lymphoma developed systemic lymphoma, which was treated with surgical resection. Local recurrence either at the primary site or in the fellow eye occurred in 11.6% of patients at a median follow-up time of 102 months (range, 79-132 months), and was controlled using repeat irradiation in all cases. Statistical analysis showed the presence of concurrent systemic lymphoma, bilateral disease, and an advanced stage at diagnosis, were linked to lymphoma-related death (Log-rank test, p < 0.05) and systemic progression (Fisher's exact test, p < 0.05), and that the tumor location was not a prognostic factor for lymphoma-related death or relapse at any site. CONCLUSIONS: Ocular adnexal lymphoproliferative disease in Koreans occurred at a relatively young age, and was mostly orbitally located and of the MALT subtype, which is highly localized and rarely associated with extraorbital relapse. Primary or secondary status, stage at presentation, and bilaterality were found to be prognostic factors.     

Plasmacellular differentiation in extranodal marginal zone B cell lymphomas of the ocular adnexa: an analysis of the neoplastic plasma cell phenotype and its prognostic significance in 136 cases

AIM: To determine (a) the expression of plasma cell related antigens in extranodal marginal zone B cell lymphomas (EMZL) of the ocular adnexa; and (b) the prognostic value of plasmacellular differentiation in these tumours. METHODS: A consecutive case series of 136 ocular adnexal EMZL obtained from three ocular pathology centres over 20 years was analysed retrospectively. An extensive immunohistochemical panel, including the plasma cell related antigens VS38c, CD38, CD138, multiple myeloma oncogene-1-protein (MUM1/IRF4), and CREB binding protein (CBP) was performed. EMZL were defined as "plasmacellular differentiated" on the basis of morphological features, evidence of cytoplasmic immunoglobulin, negativity for BSAP/PAX5, and expression of at least one of the investigated plasma cell related antigens. Controls included normal or hyperplastic lymphatic tissues. Detailed clinical data were collected for most patients, and compared with the results of immunohistochemistry. The end points considered for statistical analysis were development of local tumour recurrence, development of systemic disease, and lymphoma related death. RESULTS: 57 (42%) of the 136 ocular adnexal EMZL showed a plasmacellular differentiation; 45 of these plasmacytoid cases were primary tumours. In contrast with most admixed normal plasma cells, which displayed co-expression of MUM1/IRF4, Vs38c, CD38, CD138, and CBP, the plasmacellular differentiated EMZL tumour cells demonstrated co-expression of all five plasma cell related antigens in only six of 57 (11%) plasmacellular differentiated ocular adnexal EMZL. The most commonly expressed plasma cell related antigen was MUM1/IRF4, immunoreactivity being seen in 56/57 (98%) plasmacellular differentiated EMZL examined. Although the association of plasmacellular differentiation in primary ocular adnexal EMZL and disseminated disease was statistically significant on univariate analysis (p = 0.042), this was weaker on multivariate analysis. CONCLUSION: Plasmacellular differentiated tumour cells in EMZL demonstrate an aberrant immune profile for plasma cell related antigens when compared with normal plasma cells. On multivariate analysis, plasmacellular differentiation in ocular adnexal EMZL was not significantly associated with local recurrence, the development of systemic disease, or with lymphoma related death.     

Ocular adnexal lymphoproliferative disease: a series of 73 cases

Background : This study involved 73 patients with lymphoproliferative lesions of the ocular adnexa. The lesions were categorized using the Revised European American Lymphoma classification of lymphoid tissues and analysed to determine the frequency and prognostic impact of tumour type, location, stage and patient's age and sex. Methods : The clinical, histopathological, immunohistochemical and phenotypic analysis by flow cytometry and follow‐up data were studied. Results : The ocular adnexal lymphoproliferative lesions included 70 lymphomas and six reactive lymphoid hyperplasia. Seventy‐nine per cent had stage IE disease, 4% stage II, 1.5% stage III and 15.5% stage IV. Five patients (7%) had a past history of systemic lymphoma. Major histological types were extranodal marginal zone lymphoma (MZL) in 44 (63%), follicular (FL) in 12 (17%), diffuse large B‐cell (DLBCL) in eight (11%), mantle cell (MCL) in two (3%), B‐cell chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma in two (3%), peripheral T‐cell lymphoma (PTCL) one (1.5%) and natural killer cell lymphoma (NKCL) in one (1.5%). Longest survival was seen in those with low‐grade lymphomas (MZL and FL) and worst in PTCL and NKCL. Lymphoma‐related mortality was 2% for MZL, 33% for FL, 38% for DLBCL, and 100% for MCL, PTCL and NKCL. Systemic lymphoma was present prior to, at presentation or at subsequent follow up in 26/68 (39%) of all lymphoma patients, 17% for MZL, 38% for DLBCL, 83% for FL, and 100% for MCL, CLL, PTCL and NKCL. Conclusion : The majority of ocular adnexal lymphomas were low‐grade B‐cell lymphomas (MZL). Multivariate analysis showed that the only significant independent predictors of all causes of mortality were the histological type of lymphoma and the stage of disease at presentation.     

112例眼附属器淋巴增生性病变临床组织病理学初步分析

目的初步探讨眼附属器淋巴增生性病变的发病情况、临床特征以及组织病理学特点和分型。方法收集112例经组织病理学诊断为眼附属器淋巴增生性病变患者的116份石蜡切片标本,分析归纳临床相关资料,进一步分析组织病理学特点,并根据2001年世界卫生组织淋巴及血液组织肿瘤分类方案进行重新分类诊断。结果患者年龄8～80岁,平均49岁。病程20d至22年,平均22个月。双眼患病者16例（14．3％）。临床常见表现为眼球突出、局限性肿块（69例,占61．6％）。组织病理学检查显示反应性淋巴细胞增生11例（9．8％）,非典型淋巴细胞增生10例（8．9％）,淋巴瘤91例（81．3％）。其中,黏膜相关组织型边缘带B细胞淋巴瘤74例（占淋巴瘤患者81．3％）。结论眼附属器淋巴增生性病变以黏膜相关组织边缘带B细胞淋巴瘤最为多见,好发于中老年人,临床表现为慢性迁延性病程,双眼发病并不少见。（中华眼科杂志,2005,41：871-876）     

Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification. Revised European and American Lymphoma

AIM—To classify ocular adnexal lymphomas according to the Revised European and American Lymphoma (REAL) classification and to determine any correlation between clinical features or histomorphological variables with the patients'' outcome.METHODS—Conventional and immunohistology were performed on representative sections of 53 specimens of 46 patients with ocular adnexal lymphoma. The antibodies used were CD20, BCL-2, CD21, CD23, CD43, CD3, CD5, p53, cyclin D1, pan-cytokeratin, kappa, lambda, IgD, and IgM. The growth fraction of the tumours was determined using the MIB-1 antibody directed against the Ki-67 antigen. Clinical follow up data regarding the outcome were obtained from the treating physicians and/or hospital files. The Student''s t test and log rank test were used for statistical analysis.RESULTS—The patient collective consisted of 29 females and 17 males with an age range of 32-89.7 years (average 63 years). Almost all specimens represented B cell non-Hodgkin''s lymphomas: extranodal marginal zone lymphoma (EMZL) (n=38), diffuse large cell B cell lymphoma (n=8), lymphoplasmocytic lymphoma/immunocytoma (n=2), mantle cell lymphoma (n=2), follicle centre lymphoma (n=1), and plasmacytoma (n=1). One case of a secondary anaplastic large cell lymphoma of T cell type (T-ALCL) was diagnosed. The majority of the patients had stage I disease. A variety of therapeutic regimens was administered, the main form of treatment being radiotherapy. The average follow up time was 85 months. Complete remission was achieved in 24 patients (10 after excision alone, eight after radiotherapy alone, three after combined excision and radiotherapy, one after chemotherapy alone, and two after combined radiotherapy and chemotherapy). 12 patients died of causes related to lymphoma; in one patient the cause of death was unknown. Six patients had persistent tumour at final follow up and two patients were lost to follow up. The stage at presentation, as well as the lymphoma malignancy category, had a significant correlation with the final course of the disease (p=0.0001 and p=0.03, respectively). A significant correlation was also noted between the final outcome (p<0.05) and tumour cell expression for Ki-67 antigen and p53 protein.CONCLUSION—67% of patients with ocular adnexal lymphoma had EMZL. The stage at presentation had a significant influence on the final outcome. MIB-1 and p53 expression by the tumour cells proved to be important immunohistochemical markers concerning the prognosis. It is suggested that, following thorough staging investigations, primary EMZL (stage I) (if accessible) should be treated with excisional biopsy and subsequent low dose radiotherapy. Primary diffuse large cell B cell lymphoma of the ocular adnexa requires at least similar therapeutic measures and regular intensive follow up.     

Immunoglobulin VH gene expression among extranodal marginal zone B-cell lymphomas of the ocular adnexa

PURPOSE: Most lymphomas of the ocular adnexa are primary extranodal non-Hodgkin's lymphomas of the B-cell type, with the most common lymphoma subtype being the extranodal marginal-zone B-cell lymphoma (EMZL). Analysis of somatic mutations in the variable (V) region of the Ig heavy (H)-chain gene segment suggests that EMZL development in other locations is dependent on antigen stimulation. The purpose of this study was to analyze the presence of somatic hypermutations in clonally rearranged Ig H-chain V genes of this lymphoma entity in the ocular adnexa and to estimate whether the mutation pattern is compatible with antigen selection. METHODS: Twenty-six cases of EMZL of the ocular adnexa were diagnosed on the basis of morphology, histology, and immunohistology. A nested polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections. The isolated PCR products were sequenced and compared with published VH germline segments to determine the number of somatic mutations in the complementarity-determining region (CDR) 2 and framework (FW) region 3. RESULTS: The number of somatic mutations in the cases of EMZL varied between 0 and 24: Five cases involved 0 to 3 somatic mutations, and the remaining 21 cases involved 4 to 24 mutations. Based on the ratio of replacement (R) to silent (S) mutations in the CDR2 or FW3 regions, antigen selection seems to have occurred in 60% of ocular adnexal EMZL. The VH3 family was the most commonly expressed germline VH family (54%), followed by VH4 (23%), with biased usage of the latter. Some germline VH1 genes used included DP-8, DP-10, DP-53, DP-63 (VH4.21), and DP-49, which are frequently used by autoantibodies (e.g., rheumatoid factors) and natural autoantibodies. CONCLUSIONS: EMZLs of the ocular adnexa have an Ig H-chain mutation pattern that supports the concept that they represent a clonal expansion of post-germinal-center memory B-cells in most instances. In two thirds of cases, antigen selection may have occurred, and autoantibodies may have a role in their development.     

Ocular adnexal lymphoma-comparison of MALT lymphoma with other histological types.

AIMS: To correlate histological features of ocular adnexal lymphoma using the revised European American lymphoma classification (REAL), with stage of disease at presentation, treatment modalities, and patient outcome. MALT lymphoma defines an extranodal marginal zone B cell lymphoma as outlined in the REAL classification. Comparison groups of patients included those with primary ocular adnexal MALT lymphoma versus primary ocular adnexal lymphomas of other types, MALT lymphoma versus non-MALT lymphomas (primary and secondary), and primary ocular adnexal lymphoma (MALT lymphomas and other types) versus secondary ocular adnexal lymphomas. METHODS: A retrospective review of the National Ophthalmic Pathology Laboratory records identified 20 cases of ocular adnexal lymphoma over a 10 year period which were reclassified using appropriate immunohistochemical stains. Patients' medical records were examined for data including stage of the disease at presentation, mode of treatment, and patient outcome. RESULTS: Among the 20 cases identified 14 had primary ocular adnexal lymphomas. 10 of the primary lymphomas had histological features of MALT lymphoma. One case was a primary ocular adnexal T cell lymphoma, one a follicular centre, follicular B cell lymphoma, and two were large cell B cell lymphomas. Six cases had systemic disease, four large B cell, one follicular centre, follicular B cell, and one mantle cell. A significantly higher proportion of patients with MALT lymphomas had early disease (p = 0.005), initially required local treatment (p = 0.005) and were alive at last follow up (p = 0.001) than those without. Two patients with MALT lymphoma had recurrence of lymphoma which responded to further treatment. CONCLUSIONS: Patients with primary ocular adnexal MALT lymphomas present with localised disease requiring local treatment and have a better outcome compared with patients with other types. As a small percentage of these tumours recur, patients should be followed up indefinitely.     

Ocular adnexal lymphoid tumors: progress in need of clarification

PURPOSE: To evaluate recent ophthalmic publications on ocular adnexal lymphomas (OALs) according to histopathologic and immunophenotypic criteria used in the diagnosis of systemic lymphomas (World Health Organization classification). DESIGN: Summary and critical analysis of recent clinical and pathologic studies. METHODS: Literature review and interpretation. RESULTS: In the largest study of 353 cases of OALs published in the pathology literature, extranodal marginal zone lymphoma (EMZL) constituted 52%, follicular lymphoma 23%, mantle cell lymphoma 5%, and small cell lymphocytic and chronic lymphocytic leukemia 4%-plus a residuum of arcane entities. In smaller series of less intensively studied OALs in the ophthalmic literature, EMZLs had a higher preponderance and also were associated with a favorable prognosis. Many EMZLs seemed to arise primarily in the ocular adnexa (mucosa-associated lymphoid tissue [MALT] lymphoma should be restricted for EMZLs involving epithelial tissues). CONCLUSIONS: Rigorous diagnostic criteria and a proposal for a prospective multicenter study may bring further clarification to the emerging order in this set of tumors.     

Ocular adnexal lymphoid tumors

This year, advances in the management of ocular adnexal lymphoid tumors have been based on the distinction between MALT and non-MALT lymphomas. MALT lymphomas have a more indolent course than non-MALT lymphomas, and in the conjunctiva a more conservative approach can be taken than has been recommended previously. In the orbit the likelihood of progression to systemic disease seems high, even with MALT lymphomas, and treatment with radiation is still recommended in all cases. The REAL classification system has replaced the Rappaport and Lukes-Collins system for classifying ocular adnexal lymphomas. Most ocular adnexal lymphomas are composed of neoplastic B-lymphocytes. Additional cases of T-cell lymphoma involving the orbit and conjunctiva were reported in the literature this past year.     

A prevalence study of IgG4-related ophthalmic disease in Japan

Purpose

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.

Methods

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.

Results

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 62 years, which is significantly lower than that of the MALT lymphoma group (median 66 years) and higher than the non-IgG4 orbital inflammation group (median 57 years). The male/female ratio was 105/114 in the IgG4-related orbital inflammation group.

Conclusions

Nearly a quarter of orbital lymphoproliferative disorders in Japan are related to IgG4.     

眼眶及眼附属器淋巴瘤的彩色多普勒超声显像特征分析

目的 探讨眼眶及眼附属器淋巴瘤的彩色多普勒超声显像(CDI)特征.方法 回顾性研究30例经病理证实为眼眶及眼附属器淋巴瘤的CDI,结合临床表现和好发部位分析其特征.结果 淋巴瘤发生部位有眼眶、结膜、泪腺和泪囊;瘤体大多数长径在1cm以上,形态不规则,边界不清,内回声不均匀,以低回声为主,但多可见高回声分隔;14例声衰减中等,16例声衰减不明显;多数肿瘤有轻度可压缩性;可见较明显占位效应.彩色多普勒血流显像(CDFI)显示多数肿瘤内部可见Ⅲ级或Ⅳ级血流信号,均为动脉频谱,峰值流速和阻力指数较高;部分瘤体周围可见血流信号.结论 眼眶及眼附属器淋巴瘤的CDI具有一定特征,结合好发部位及临床表现有助于临床判断.     

Immunoglobulin heavy chain gene analysis of ocular adnexal extranodal marginal zone B-cell lymphoma

PURPOSE: To clarify the cellular origin of extranodal marginal-zone B-cell lymphoma (EZML) of the mucosa-associated lymphoid tissue (MALT) type in ocular adnexa, the somatic mutation was analyzed in the immunoglobulin heavy-chain variable region (VH) gene. METHODS: Eight cases of EZML in the orbit and four in the conjunctiva were studied. The VH genes were amplified by a seminested PCR and sequenced directly. These were compared with the closest published VH germline segments to determine the somatic mutation frequency. Intraclonal microheterogeneity, which was termed the ongoing mutation frequency in the current study, was estimated by counting the number of single nucleotide substitutions in individual clones and dividing by the total number of nucleotides analyzed. Nine cases of gastrointestinal EMZL were also examined for comparison. RESULTS: The somatic mutation frequency varied between 2.0% and 12.7%, with a mean value of 7.9%. Ten cases with intraclonal microheterogeneity showed between one and six further substitutions. The average of ongoing mutation frequency was 0.11%, with a range of 0% to 0.25%. In the gastrointestinal EMZLs, the average of somatic mutation frequency was 8.5% (1.5%-14.2%) and of ongoing mutation frequency was 0.51% (0.25%-0.75%). CONCLUSIONS: The average of ongoing mutation frequency in ocular adnexal EMZL was lower than that in gastrointestinal EMZL. Both ocular adnexal and gastrointestinal EMZLs are derived from postgerminal center memory B cells, but the low ongoing mutation frequencies of ocular adnexal EMZL may result from less antigen stimulation and follicular colonization in the orbit relative to gastrointestinal EMZL.     

Lymphoproliferative disorders of the ocular adnexa

PURPOSE OF REVIEW: To describe recent advances in clinical features, diagnostic tools, and treatment modalities for lymphoproliferative diseases affecting the ocular adnexa. RECENT FINDINGS: A close relationship of non-Hodgkin lymphoma with long-term use of aspirin and nonaspirin nonsteroidal antiinflammatory drugs has recently been documented. Some infectious agents have also been implicated in the pathogenesis of lymphomas. The advent of immunohistochemistry and polymerase chain reaction have helped to distinguish between benign lymphoproliferation and malignant lymphoma. New techniques for radiation therapy are proposed to decrease complication rates associated to this treatment. SUMMARY: Recent studies demonstrated that ocular adnexal lymphomas may be masked by a number of different diseases and clinical features. Prognosis depends on the stage and histology of lymphoma as well as the location.     

Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival

BACKGROUND: The histological characteristics of ocular adnexal lymphomas have previously provided only a limited guide to clinical outcome for affected patients. This clinicopathological relation was re-examined using the Revised European American Lymphoma (REAL) system to classify the tumours in a large cohort of patients. METHODS: The biopsies and clinical follow up data for 192 patients with ocular adnexal lymphoma were reviewed, the biopsies being regraded in accordance with the REAL classification. For each of five histological groups, logistic regression analysis was used to determine the odds ratios (OR) for the presence of systemic disease at the time of orbital diagnosis and Cox regression analysis was used to assess the hazard ratios (HR) for disseminated disease and lymphoma related death. For 108 patients in whom extraorbital spread occurred, the histological category of lymphoma was compared with the sites of dissemination. RESULTS: At presentation, the frequency of previous or concurrent extraorbital disease increased from marginal zone lymphoma (OR 1.0), diffuse lymphoplasmacytic/lymphoplasmacytoid lymphoma (OR 2.3), follicle centre lymphoma (OR 3.8), diffuse large B cell lymphoma (OR 4.0) to other histological lymphoma variants (OR 26.8). For all histological types, the estimated risk of extraorbital disease and lymphoma related death continued for many years and the proportion of patients with at least one extraorbital recurrence after 5 years was 47% for MZL, 48% for LPL, 64% for FCL, 81% for DLCL, and 95% for other lymphoma variants. The corresponding estimated rates for 5 year lymphoma related mortality were 12%, 19%, 22%, 48%, and 53% respectively. CONCLUSIONS: Patients with ocular adnexal lymphoma can be classified by REAL into five distinct groups, which show a progressive increase in the risks of extraorbital disease at diagnosis, of disease dissemination with time, and of tumour related death.     

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 11–91 years and a median of 36 years. 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 5 months. 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.