The tale and molecular trail of a disseminated ocular adnexal malt lymphoma.

PURPOSE: To report a case of a MALT lymphoma of the eyelid, which recurred in several sites over a time period of 14 years, and where the identical B-cell clone could be demonstrated in most samples using polymerase chain reaction (PCR) and GeneScan analysis. METHODS: Clinical, histologic, immunohistochemical, PCR and GeneScan analysis findings are presented. RESULTS: A 58-year-old woman presented with a swelling of the left lower lid. Excisional biopsy of the tumour revealed a low-grade malignant B-cell Non-Hodgkin lymphoma (NHL) of MALT type. Despite localized radiochemotherapy, the patient developed recurrences occurring in the pharynx, in the right orbit, in the skin of the right foot, and in the bone marrow 1, 7, 11 and 14 years, respectively, after establishment of the first diagnosis. PCR for a rearrangement of the immunoglobulin heavy chains (IgH) and GeneScan analysis of the samples produced amplificates identical in size at most sites, indicating derivation from the same B-cell clone. CONCLUSIONS: It is generally assumed that ocular adnexal MALT lymphoma is associated with an indolent clinical course. Using IgH-PCR and GeneScan analysis, we demonstrate that the current case illustrates that these lymphomas do indeed require regular control examinations following treatment, as they often recur and disseminate in some patients in an unpredictable manner.     

The clinical characteristics and treatment results of ocular adnexal lymphoma

PURPOSE: To assess the clinical pattern, the histopathological findings, the response to treatments, the recurrence pattern and the prognosis of malignant lymphoma in the ocular adnexa. METHODS: This study was performed on 22 total eyes from 17 patients who were diagnosed with ocular adnexal malignant lymphoma. We retrospectively analyzed the medical records for patient information including the histological classification based on age, the gender of each patient, the symptoms and signs at the initial diagnosis, the presence of binocular invasion, the findings of the surgical biopsy, the clinical stage of each patient's tumor, and the treatment methods used and their effectiveness. The mean follow-up period was 24.8 months. RESULTS: The mean age of patients studied was 46.8 years old. Six females and 11 males were included in the study. Fifteen cases consisting of 20 total eyes represented extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Five of seven patients (71.4%) whose lymphoma occurred within the conjunctiva relapsed after irradiation or chemotherapy, and four of the relapsed patients were salvaged with further therapy. CONCLUSIONS: Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) constituted 88.2% of all lymphomas involving the ocular adnexa. Lymphoma in the ocular adnexa responded well to conventional treatment, but the recurrence rate of lymphoma in the conjunctiva was significantly high.     

眼附属器黏膜相关淋巴组织淋巴瘤的研究进展

黏膜相关淋巴组织（MALT）淋巴瘤是非霍奇金淋巴瘤中结外边缘带淋巴瘤（MZL）的一种特殊类型。眼附属器MALT淋巴瘤是眼眶恶性肿瘤中较常见的一种，可发生在结膜、泪腺、眼睑和眼眶。近年来，国外许多学者在MALT淋巴瘤的临床特点、病理形态学、免疫表型、分子遗传学及分子生物学方面对它的发生机制在基因水平有了新的认识。就国外对眼附属器MALT淋巴瘤的分子遗传学异常在肿瘤细胞内部信号转导通路中作用的研究做一综述。     

The expressions of metadherin and LEF-1 in mucosa-associated lymphoid tissue lymphoma of ocular adnexal

AIM: To investigate the expressions of metadherin (astrocyte elevated gene-1, AEG-1) and lymphoid enhancer-binding factor-1 (LEF-1) in ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: The expressions of AEG-1 and LEF-1 were detected on specimens harvested from patients suffering from MALT lymphoma and lymphadenosis of ocular adnexal in Ophthalmology Department, Affiliated Hospital of Qingdao University from 2000 to 2015 by immunohistochemical and polymerase chain reaction (PCR) analysis. RESULTS: AEG-1 and LEF-1 expressions in MALT lymphoma was respectively higher than that in lymphadenosis, both by immunohistochemical and PCR analysis (P<0.05). Diversity of AEG-1 and LEF-1 expressions in different Ann Arbor clinical stages showed a statistically significant result (P<0.05). A positive relevance between AEG-1 and LEF-1 was observed in MALT ocular adnexal lymphoma (r=0.435, P=0.016). CONCLUSION: The over expressions of AEG-1 and LEF-1 at the level of protein and mRNA participates in the tumorigenesis of ocular adnexal MALT lymphoma. They should act as a new biological marker for pathological diagnosis in the future.     

Diagnosis of a primary uveal extranodal marginal zone B-cell lymphoma by chorioretinal biopsy: case report

Purpose To report the clinical, histopathological and molecular biological findings of a primary extranodal marginal zone B-cell lymphoma (EMZL) of the uvea.Methods Conventional histology, immunohistochemistry and polymerase chain reaction for immunoglobulin heavy chain gene rearrangement (IgH-PCR) and GeneScan analysis were performed on a chorioretinal biopsy.Results Histological examination of the chorioretinal biopsy demonstrated a dense infiltrate of small centrocyte-like cells, plasmacytoid tumour cells and occasional blasts. The tumour cells were positive for CD20, showed monotypical expression for Ig-kappa and IgM, and a growth fraction of 10%. Clonality analysis using IgH-PCR disclosed a monoclonal B-cell population. Following localised irradiation of 35 Gy, a complete remission was achieved.Conclusion This report describes a rare uveal EMZL diagnosed following investigation of a chorioretinal biopsy. Despite its rarity, ophthalmic pathologists should consider the diagnosis of a primary uveal EMZL when reviewing chorioretinal biopsies.     

眼附属器MALT淋巴瘤的临床分析

目的 探讨眼附属器包括眼睑、结膜，眼眶和泪腺等部位MALT淋巴瘤的临床诊断要点，影像学检查特征与治疗和预后。方法 回顾性分析1994年至2005年在第二军医大学长征医院眼科确诊的45例眼附属器MALT淋巴瘤的临床表现、影像学检查、手术治疗及病理结果与预后情况。结果 眼附属器MALT淋巴瘤23例发生于眼眶，10例发生于眼睑，8例发生于泪腺，4例发生于结膜。B超、CT、MRI均能进行定位、定性诊断，B超能较好地显示病变内部结构和形态；CT对眶骨结构和肿瘤侵犯范围与周围组织的关系显示良好，具有定性诊断价值；MRI对软组织的分辨力强，成像参数根据不同的信号强度可提示病变的内部结构。45例均行手术治疗；其中22例辅以放疗，10例结合化疗。42例随访4～135个月，1例于手术切除后25个月转移至肺死亡，其余均存活。结论 眼附属器MALT淋巴瘤好发于眼眶上方及眼睑，影像学检查对MALT淋巴瘤的诊断及鉴别诊断有帮助。手术切除肿瘤，结合病理诊断和临床分期判断能提示较准确的病情估计，病变可长期局限，预后较好，一般不会出现全身转移和向弥漫性大细胞高度恶性淋巴瘤转化。     

Primary bilateral small lymphocytic lymphoma of ocular adnexal origin: Imprint cytology suggests the intraoperative diagnosis

Ocular adnexal lymphomas (OAL) involve the peri-global soft tissues like orbit, eyelid, conjunctiva, lacrimal gland. We describe a rare case of primary bilateral OAL, histomorphologically small lymphocytic lymphoma, B cell phenotype of lacrimal gland origin. Rapid intraoperative diagnosis can be suggested on imprint cytology; subsequent histology and immunohistochemistry are helpful for confirmation and further line of management. Since no preformed lymphoid structures are expected within the orbit or lacrimal gland, any lymphoid mass here should be critically evaluated as a lymphoproliferative lesion.     

Evaluation of vitrectomy specimens and chorioretinal biopsies in the diagnosis of primary intraocular lymphoma in patients with Masquerade syndrome

Purpose To correlate the histopathological diagnoses established by diagnostic vitrectomy and chorioretinal biopsy in patients with clinically suspected primary intraocular lymphoma (PIOL) or chronic idiopathic uveitis, and the clinical follow-up data.Methods Eighty-four consecutive pars plana vitrectomy (PPV) specimens, three chorioretinal biopsies and two enucleated eyes taken from 80 patients were evaluated. All PPV specimens were unfixed; these were centrifuged, the cytospins being stained conventionally (May-Grünwald-Giemsa) and using immunocytology (CD79a, CD3, CD68, immunoglobulin (Ig) light chains). An extended immunohistochemical panel, as well as polymerase chain reaction (PCR) for rearrangements of the Ig heavy chain gene (IgH-PCR), were used to investigate the chorioretinal biopsies and the enucleated eyes. Diagnoses, made on the basis of morphology and immunophenotype, included reactive cellular infiltrate, malignant lymphoma, suspicious of neoplastic disease, and insufficient for diagnosis. The corresponding clinical data were collected and compared with the diagnosis.Results The 80 patients consisted of 46 women and 34 men. The patients age range varied from 21 to 100 years (mean age 62 years). Sixty-two (74%) of the 84 vitrectomy specimens were diagnosed as reactive cellular infiltrate, 12 (14%) as definite malignant lymphoma, 5 (6%) as suspicious of neoplastic disease and 5 (6%) specimens were considered insufficient for diagnosis. An additional chorioretinal biopsy enabled an unequivocal diagnosis of PIOL to be reached in 3 patients. All PIOL were diffuse large cell B-cell lymphoma (DLBCL), with the immunophenotype CD79+, CD20+, BCL-2+, BCL-6+, MUM1+ and monotypical expression for IgM+. A monoclonal IgH-PCR amplification product was obtained in four vitrectomy specimens, two chorioretinal biopsies and one of the enucleated eyes. Comparison of the diagnoses with long-term follow-up clinical data resulted in concordance in 77 (96%) cases and discrepancies (false-negative diagnoses) in 3 patients (4%). The patients diagnosed with lymphoma were treated with either radiotherapy, chemotherapy or both. At final follow-up (mean 35 months), 5 patients (6%) had developed cerebral lymphomatous manifestation, and 7 (9%) had succumbed to their disease.Conclusion The diagnosis of PIOL is often extremely difficult, requiring sufficient rapidly transported good-quality material, and experienced interpretation. Although cytological examination of vitreal aspirates remains the gold standard in diagnosis, examination of chorioretinal biopsies increase the reliability of diagnosing or excluding a PIOL that involves the retina or choroid. Most PIOL are DLBCL with an immunophenotype suggesting a cellular origin from germinal centre cells.     

Diffuse large B‐cell lymphoma of the ocular adnexal region: A nation‐based study

Purpose: To characterize the clinicopathological features of diffuse large B‐cell lymphoma (DLBCL) of the ocular adnexal region. Methods: The present series of orbital and adnexal DLBCLs were found by searching the Danish Registry of Pathology between 1980 and 2009. Histological specimens were re‐evaluated using a panel of monoclonal antibodies. Clinical files from all patients with confirmed DLBCL were collected. Results: A total of 34 patients with DLBCL of the ocular adnexal region were identified. Eighteen of the patients were men. The patients had a median age of 78 years (range 35–97 years). Ninety‐seven per cent of the patients had unilateral ocular adnexal region involvement, and the orbit (76%) was the most frequently affected site. Nineteen patients (56%) presented with Stage I lymphoma. Of these, 18 were diagnosed with primary lymphoma. Four patients (12%) had Stage II, one patient (3%) had Stage III and ten patients (29%) presented with Stage IV lymphoma. The 5‐year overall survival (OS) rate for the whole study group was 20%. The patients with Stage I lymphoma had a significantly better 5‐year OS rate (28%) than patients in Stage II‐IV (5‐year OS rate, 9%). In Cox regression analysis, concordant bone marrow involvement and the International Prognostic Index (IPI) score were prognostic factors for OS. Conclusions: Diffuse large B‐cell lymphoma of the ocular adnexal region is mainly prevalent in elderly patients. Most patients had unilateral orbital involvement. The overall prognosis is poor. Concordant bone marrow involvement and the IPI score were independent prognostic factors for mortality.     

Clinical features and treatment outcomes of primary ocular adnexal mucosa-associated lymphoid tissue lymphoma: a single center retrospective analysis of 64 patients in China

AIM: To investigate the clinical features, treatment and prognosis of primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML). METHODS: A retrospective analysis was performed on 64 patients with POAML who were admitted to the First Affiliated Hospital of Zhengzhou University from January 2006 to December 2018. RESULTS: With a median follow-up of 61mo (range, 2-156mo), estimated overall survival (OS) rate and progression-free survival (PFS) rate at 10y reached 94.5% and 61.5%, respectively. Median OS time and PFS time were not reached. During this period, only 3 patients died, but none of them died directly due to disease progression. One patient (1.6%) developed transformation to diffuse large B-cell lymphoma (DLBCL). Of the 56 patients achieved complete remission after first-line treatment, 5 (8.9%) developed local and/or systemic relapse eventually. Patients ≥60y had significantly shorter PFS than younger patients (P=0.01). For patients with early stages (Ann Arbor stage I and stage II), univariate analysis confirmed that radiotherapy dose lower than 32 Gy were independently associated with shorter PFS (P=0.04). Other factors including gender, bone marrow involvement, the initial location of the disease, and the laterality were not associated with PFS. CONCLUSION: The data from our center indicate that POAML has a slow clinical progression and has an excellent clinical outcome. Patients with POAML harbor a continual risk of relaps and transformation to aggressive subtype of lymphoma.     

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.     

眼附属器MALT淋巴瘤的临床特征及复发因素分析

目的 通过对眼附属器MALT淋巴瘤的临床特征和复发因素的研究,以期对本病有一个全面的认识和了解,减少临床误诊、漏诊和复发,提高早期诊断率及生存率.方法 回顾性分析1997年1月至2010年6月第二军医大学附属长征医院眼科收治的79例病理确诊为IE期眼附属器MALT淋巴瘤患者的临床表现、影像学结果、治疗方式及预后情况.结果 79例病例中,原发于眼眶49例,结膜14例,泪腺10例,眼睑6例.发生在眼眶内的MALT淋巴瘤多呈包绕眼环的不规则生长,无明显边界,临床表现最为常见的是眼球突出、眼球运动受限.而发生在结膜的MALT淋巴瘤多位于穹窿部结膜,表现为结膜充血、肿块呈“鲑鱼肉”样外观.治疗方法主要包括手术及放射治疗.本组病例全部行手术治疗,全部切除58例,局部切除21例.所有患者均在手术后2～4周行眼局部放射治疗.放疗半年后,有15例出现复发.患者双眼发病(P =0.0143)和对放疗的初始反应(P＜0.0001)与肿瘤的复发有相关性;而性别、年龄、发病部位、肿瘤大小及手术方式等因素对复发均无影响.结论 发生在眼眶内的MALT淋巴瘤多呈包绕眼环的不规则生长,无明显边界.患者双眼发病和对放疗的初始反应与肿瘤的复发有相关性,而手术方式等因素对复发均无影响.选择合适的手术方式可降低术后并发症的发生.     

脂多糖诱导的肿瘤坏死因子-α基因在眼附属器非霍奇金淋巴瘤的表达及意义

目的 研究脂多糖诱导的肿瘤坏死因子-α(lipopolysaccharide-induced TNF-α factor,LITAF)基因在眼附属器非霍奇金淋巴瘤中的表达,并探讨其与临床病理参数间的关系.方法 采用免疫组织化学法对从青岛大学附属医院收集的50例眼附属器非霍奇金淋巴瘤标本和10例反应性淋巴组织增生病变组织标本中LITAF基因的表达进行检测,并分析其与眼附属器非霍奇金淋巴瘤患者临床病理参数间的关系.结果 眼附属器非霍奇金淋巴瘤中LITAF基因阳性表达率显著低于反应性淋巴组织增生病变(P＜0.05);LITAF基因的阳性表达率与性别、年龄、发病部位、肿瘤大小无关(均为P＞0.05),与非霍奇金淋巴瘤病理分级有关(P＜0.05).结论 LITAF基因可能发挥着抑制眼附属器非霍奇金淋巴瘤的功能.     

眼附属器MALT淋巴瘤的治疗及转化为弥漫性大B细胞淋巴瘤的危险因素

目的 通过对眼附属器MALT淋巴瘤的不同治疗方式及影响其转化为弥漫性大B细胞淋巴瘤（DLBCL）危险因素的研究,以期能选择合适的手术方式,降低术后并发症的发生,提高生存率。设计 回顾性病例系列。研究对象 1997年1月至2010年6月上海第二军医大学附属长征医院眼科收治的79例病理确诊为IE期眼附属器MALT淋巴瘤患者。方法 回顾上述患者的临床表现、治疗方式（包括手术和放射治疗）及预后情况。手术方式包括全部切除和部分切除。预后情况主要观察患者的生存率、有无转化为弥漫性大B细胞淋巴瘤等。主要指标 临床表现、手术治疗、放射治疗、生存率、有无转化为弥漫性大B细胞淋巴瘤等。结果 所有病例均行手术治疗,其中全部切除58例,局部切除21例。所有患者均在手术后2~4周行眼局部放射治疗。5年总生存率86.0%,共有6例转化为DLBCL。放射治疗对眼附属器MALT淋巴瘤有较好的局部控制。患者双眼发病（P=0.0221）和对放射治疗的初始反应（P=0.0033）与肿瘤转化为DLBCL有相关性;而性别、年龄、发病部位、肿瘤大小及手术方式等因素对转化均无影响。结论 双眼发病和对放疗的初始反应与MALT淋巴瘤转化为DLBCL相关,而手术方式对转化无影响;根据不损伤眼部重要结构的原则来选择合适的手术方式,可降低术后并发症的发生。（眼科, 2012, 21: 352-356）     

聚合酶链反应扩增IgH CDR-Ⅲ序列对眼部淋巴样增生病的诊断研究

目的从分子生物学角度探讨眼部淋巴样增生病的诊断、分类及肿瘤细胞的起源。方法应用聚合酶链反应（ｐｏｌｙｍｅｒａｓｅｃｈａｉｎｒｅａｃｔｉｏｎ,ＰＣＲ）对２９例（３１只眼）眼部淋巴样增生病的石蜡切片进行免疫球蛋白重链基因第三互补决定区（ＩｇＨＣＤＲ－Ⅲ）重排检测,并结合形态学及免疫表型进行分析检查。结果１７只眼恶性淋巴瘤、５只眼反应性增生均呈ＩｇＨ基因克隆性重排,电泳产物可见一明显的扩增窄带（１００～１２０ｂｐ）,其中２例双眼恶性淋巴瘤的两侧病变扩增带一致,１只眼恶性淋巴瘤、８只眼反应性增生均呈ＩｇＨ基因多克隆性重排。结论采用ＰＣＲ扩增ＩｇＨＣＤＲ－Ⅲ序列能确定此类疾病的克隆性质,并能发现免疫组化及形态学不能识别的小克隆Ｂ细胞病变,为诊断眼部淋巴样增生病提供了一个较为客观、敏感而又实用的手段。     

眼附属器MALT淋巴瘤的临床与病理学特征分析

目的:探讨眼附属器包括眼睑、眼眶、泪腺等部位黏膜相关淋巴组织淋巴瘤(lymphphoma of mucosa-associated lymph-oid tissue,MALT)的临床、病理学特征与治疗方法。方法:分析24例眼附属器MALT淋巴瘤的临床、病理学及免疫组化结果,以及手术后治疗与预后情况。结果:24例眼附属器MALT淋巴瘤患者经影像学检查后均行手术治疗,其中16例行放疗,2例行化疗。20例随访3mo～7a后均存活。结论:影像学检查可辅助诊断眼附属器MALT淋巴瘤、术后病理活检及免疫组化分型检查可确诊本病,眼结膜MALT淋巴瘤预后较好,伴全身淋巴瘤转移术后辅以化疗或放疗。     

原发性视网膜色素变性家系的RDS基因Pro216Leu突变及其表型研究

目的　研究原发性视网膜色素变性 (retinitispigmentosa ,RP)家系中缓慢型视网膜变性(retinaldegenerationslow ,RDS)患者的RDS基因突变与临床表型的关联 ,以探讨RP的发病机制。方法对来自同一家系的 2例RP患者及 2例正常人外周血DNA进行分子遗传学分析 ,采用聚合酶链反应(polymerasechainreaction ,PCR)及限制性片段长度多态性 (restrictionfragmentlengthpolymorphism ,RFLP)技术 ,筛查RDS基因突变 ,对有突变的RDS基因片段进行克隆测序及分析 ,同时进行家系分析及眼部临床检查。结果　来自同一家系的 2例RP患者均查出有RDS基因 2 16密码突变 ,而 2例正常人未查出上述突变。经测序证实RDS基因 2 16密码子的第 2个核苷酸出现了C→T的突变 (Pro2 16Leu)。RDS基因Pro2 16Leu突变的眼部临床表型为视力损害严重的弥漫型RP ,伴有黄斑部病变。结论　中国人RP患者存在RDS基因Pro2 16Leu突变 ;其眼部表型为弥漫型RP伴有黄斑部病变。     

Diagnosis of intraocular lymphoma by polymerase chain reaction analysis and cytokine profiling of the vitreous fluid

Purpose  To determine whether a diagnosis of intraocular lymphoma (IOL) can be made using a combination of polymerase chain reaction (PCR) analysis to detect gene rearrangement of immunoglobulin and cytokine concentrations in the vitreous fluid. Methods  Vitreous samples from 22 patients with clinically suspected IOL and ten control patients with acute retinal necrosis or cytomegalovirus retinitis were examined by PCR analysis and cytokine measurements. Genomic DNA was extracted from the cells in the vitreous, and the immunoglobulin heavy chain (IgH) gene was amplified by two PCR procedures: (1) microdissection and PCR to detect IgH gene rearrangement and (2) qualitative PCR to detect IgH VDJ gene rearrangement. The supernatants of the vitreous samples were used for enzyme-linked immunosorbent assay to determine interleukin (IL)-10 and IL-6 levels. Results  PCR examinations detected IgH rearrangement in the vitreous in 21 of the 22 IOL patients (95.5%) and in none of the ten control patients. Elevated IL-10 concentrations (>100 pg/ml) and the IL-10/IL-6 ratio (>1.0) were positive in 18 of the 22 IOL patients (81.8%), but negative in all of the control patients. Sensitivity, specificity, positive predictive value, and negative predictive value of PCR for the diagnosis of IOL were calculated to be 0.955, 1.000, 1.000, and 0.909, respectively, and those of the cytokine concentration assay to be 0.818, 1.000, 1.000, and 0.714, respectively. When both the intravitreal cytokine assay and PCR analysis of the vitreous samples are used, as well as diagnostic criteria of IOL defined as a positive outcome from one of the two assays together with clinical signs, the sensitivity and specificity of the criteria were 1.000. Conclusions  A combination of PCR assay to detect gene rearrangement of IgH and cytokine profiling (IL-10 and IL-6) is extremely useful for the diagnosis of intraocular lymphoma.