B cell receptor signaling pathway involved in benign lymphoepithelial lesions of the lacrimal gland

AIM: To detect the expression of B cell receptor signaling pathway (BCRSP) in lacrimal gland benign lymphoepithelial lesions (LGBLEL). METHODS: Gene microarray was used to compare whole-genome expression in lacrimal gland tissues from LGBLEL patients to tissues from orbital cavernous hemangioma (control tissues). Expression of BCRSP was confirmed by polymerase chain reaction (PCR) and immunohistochemistry. RESULTS: The expression of 22 genes of the BCRSP increased significantly in LGBLEL patients. PCR analysis showed that CD22, CR2, and BTK were all highly expressed in LGBLEL tissues. Immunohistochemical analysis showed that CR2 protein was present in LGBLEL, but CD22 and BTK proteins were negative. CR2, CD22, and BTK were not observed in the orbital cavernous hemangiomas with either PCR or immunohistochemistry. CONCLUSION: BCRSP might be involved in the pathogenesis of LGBLEL.     

补体经典途径在泪腺良性淋巴上皮病变发生中的作用

目的：分析补体系统(CS)及其经典途径在泪腺良性淋巴上皮病变(LGBLEL)发病机制中的作用。

方法：采集LGBLEL患者和眼眶海绵状血管瘤(CH)患者的病变组织标本,使用蛋白质组学方法分析差异蛋白,而后采用逆转录-聚合酶链反应(RT-PCR)、免疫组织化学染色(IHC)和蛋白质印迹法(Western Blotting)验证CS信号通路中差异蛋白表达的变化,明确其在LGBLEL发病机制中的作用。

结果：蛋白质组学分析结果表明,相对于眼眶CH患者,LGBLEL患者病变泪腺组织中CS信号通路重要蛋白C3、C5、C9、C1q等表达均发生改变; RT-PCR检测结果显示,与眼眶CH患者相比,LGBLEL患者病变泪腺组织中C1qA、C5、C9 mRNA表达升高; 免疫组织化学染色结果显示,与眼眶CH患者相比,LGBLEL患者病变泪腺组织中C1qA、C3、C5、C9表达明显增多; Western Blotting检测结果显示,与眼眶CH患者相比,LGBLEL患者病变泪腺组织中C1qA、C3、C9蛋白表达水平明显升高。

结论：CS参与LGBLEL的发病机制,其经典途径可能是其发挥作用的途径之一。     

Association of the macrophage migration inhibitory factor promoter polymorphisms with benign lymphoepithelial lesion of lacrimal gland

AIM: To identify the association of the macrophage migration inhibitory factor (MIF) gene polymorphism with the susceptibility of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. METHODS: A total of 40 BLEL of lacrimal gland cases were matched with 40 healthy subjects (HS). Extraction the plasma and whole blood DNA of patients of lacrimal gland BLEL and HS. Elisa and polymerase chain reaction was used to determine in plasma contents of MIF and MIF gene SNP-173G>C and STR -794 CATT(5-8) polymorphism, respectively. RESULTS: The MIF levels in plasma were significantly higher in patients with lacrimal gland BLEL versus HS (P<0.001). The -173 G>C MIF polymorphism was significantly associated with lacrimal gland BLEL, with a significantly higher frequency of the C allele in lacrimal gland BLEL patients compared with HS (OR=2.38, 95% CI=1.07-5.31, P=0.032), and the -173 C/x is more frequent in patients than in HS, P=0.037. Besides, we found that the carriage rate of the MIF -173C/x is associated with higher plasma levels of MIF in the BLEL of lacrimal gland. CONCLUSION: MIF -173G/C variants play an insidious role in susceptibility of BLEL of lacrimal gland. Otherwise, there is no statistically significant correlation exists between MIF-794 CATT (5-8) and BLEL of lacrimal gland.     

Association analysis of BclI with benign lymphoepithelial lesions of the lacrimal gland and glucocorticoids resistance

AIM: To evaluate the relationship between gene polymorphism (BclI, ER22/23EK, N363S) and the occurrence, progression and sensitivity to glucocorticoid of lacrimal gland benign lymphoepithelial lesion (LGBLEL).METHODS: Clinical peripheral blood samples of 52 LGBLEL patients and 10 normal volunteers were collected for DNA extraction and polymerase chain reaction sequencing to analyze single nucleotide polymorphism (SNP) genotypes. The lacrimal tissues of LGBLEL were surgically removed and made into paraffin sections for subsequent hematoxylin-eosin (HE) and Masson staining analysis. The duration of disease and hormone use of LGBLEL patients from diagnosis to surgery were also analyzed. The Meta-analysis follows PRISMA guidelines to conducted a systematic review of human studies investigating the relationship between the NR3C1 BclI polymorphism and glucocorticoids (GCs) sensitivity.RESULTS: There was no association between ER22/23EK or N363S and the occurrence of LGBLEL or GCs sensitivity (P>0.05); BclI GC genotype was closely related to GCs resistance (P=0.03) as is the minor allele C (P=0.0017). The HE staining and Masson staining showed that the GC genotype of BclI remarkably slowed down the disease progression and reduced fibrosis (P<0.05), especially for GCs-dependent patients (P<0.0001). Meta-analysis showed that BclI was not significantly associated with GCs responsiveness.CONCLUSION: The LGBLEL patients who carry the NR3C1 BclI allele C may be more sensitive to GCs and associated with lower fibrosis and slower disease progression. The results may guide the clinical treatment strategy for the LGBLEL patients.     

泪腺良性淋巴上皮病变免疫组织化学研究

目的 通过研究9种单克隆抗体在泪腺良性淋巴上皮病变中的表达,探讨其免疫病理本质及发病机制,为临床治疗及预后提供理论依据.方法 使用CD4、CD8、CD21、CD34、CD45、CD68、IgG、IgG4和增殖细胞核抗原这9种分子的单克隆抗体,应用免疫组织化学染色SP法对25例泪腺良性淋巴上皮病变的石蜡标本进行免疫组织化学染色.结果 B淋巴细胞表面抗原(CD21)、T淋巴细胞表面抗原(CD4、CD8和CD45)、黏附分子CD34及IgG在25例样本中均呈阳性表达,巨噬细胞表面抗原CD68、增殖细胞核抗原和IgG4这3种分子在25例样本中均有一定比例的阳性表达,表达率分别为12％、8％和80％.结论 泪腺良性淋巴上皮病变是一种主要以B淋巴细胞和T淋巴细胞激活为主要病理免疫基础的疾病,绝大多数属于IgG4相关性疾病的范畴,同时有发生恶变的潜能,临床治疗后的密切随访很有必要.     

Different serum levels of IgG and complements and recurrence rates in IgG4-positive and negative lacrimal gland benign lymphoepithelial lesion

AIM: To analyze the differences in immune indicators and prognosis between IgG4-positive and negative lacrimal gland benign lymphoepithelial lesion (LGBLEL).METHODS: This was a single-center retrospective clinical study including 105 cases of IgG4-positive LGBLEL and 41 cases of IgG4-negative LGBLEL. Basic information, related indicators of peripheral venous blood samples using immunoscattering turbidimetry, treatment (partial surgical excision and glucocorticoid therapy) and prognosis (recurrence and death) were collected. Survival curves for recurrence were created using the Kaplan-Meier analysis. Univariate analysis and multivariate regression analysis were used to analyze prognostic factors.RESULTS: The mean age was 50.10±14.23y and 44.76±11.43y (P=0.033) in IgG4-positive and negative group respectively. The serum C3 and C4 was lower in IgG4-positive group (P=0.005, P=0.002), while the serum IgG and IgG2 was higher in IgG4-positive group (P=0.000 and P=0.008). Twenty-one cases had recurrence in IgG4-positive group and 3 cases recurrence in IgG4-negative group. The 5-year recurrence-free cumulative percentages of IgG4-positive group was 81.85%, and 83.46% in the IgG-negative group (P=0.216). The history of preoperative glucocorticoid therapy, serum C4, IgG1 and IgG2 were the factors affecting recurrence in IgG4-positive group, while serum C4, and IgG1 were the factors affecting recurrence of LGBLEL.CONCLUSION: Serum C4 and IgG1 are the factors affecting recurrence of LGBLEL, while the IgG4 does not affect recurrence of LGBLEL.     

IgG 亚型与泪腺良性淋巴上皮病变发病关系的研究

目的：检测泪腺良性淋巴上皮病变患者外周血IgG亚型的含量,探讨其与该病发病的关系。方法将2010年8月至2015年12月间来我院眼科就治,手术后病理组织学确诊的58例泪腺良性淋巴上皮病变患者为实验组,26例眼眶海绵状血管瘤患者为对照组,对临床资料及外周静脉血标本进行收集,采用酶联免疫吸附测定方法,分析血液中IgG亚型与泪腺良性淋巴上皮病变之间的关系。结果实验组与对照组外周血中IgG亚型含量的差异主要集中在IgG1、IgG2、IgG4和IgG（ P ＜0．05）,尤以IgG4和IgG差异最为显著。结论在诊断泪腺良性淋巴上皮病变中IgG4和IgG具有一定的参考价值。     

泪腺良性淋巴上皮病变的病理特点及IgG4和C3的表达

目的　探讨IgG4和C3在泪腺良性淋巴上皮病变发生发展中的作用。方法　收集2010年7月至2018年5月就诊于承德医学院附属医院眼科、解放军总医院眼科15例（15眼）泪腺良性淋巴上皮病变患者的泪腺肿物为试验组，10例（10眼）因其他疾病而行眶内容物摘除术的正常泪腺组织标本为对照组。采用HE染色法观察2组泪腺病理形态学变化及其组织病理学特点，采用免疫组织化学染色法检测2组泪腺组织中IgG4、C3的表达，并对二者表达相关性进行分析。结果　HE染色结果显示，对照组泪腺由正常腺泡及导管组成，导管上皮细胞排列整齐，细胞结构清晰，其间有少量的淋巴细胞；试验组泪腺组织中可见大量淋巴细胞、浆细胞浸润，淋巴滤泡形成，其间可见上皮-肌上皮岛结构改变，同时伴有不同程度纤维化。IgG4在试验组阳性表达面积为（30 934.80±16 057.17）像素，对照组阳性表达面积为（325.42±204.43）像素，试验组中明显高于对照组（t=-7.38，P=0.000）；C3在试验组阳性表达面积为（43 169.49±33 206.60）像素，对照组阳性表达面积为（323.24±271.29）像素，试验组中明显高于对照组，差异有统计学意义（t=-5.00，P=0.000）。试验组中IgG4与C3表达无相关性（r=-0.137，P=0.671）。结论　泪腺良性淋巴上皮病变患者的泪腺发生了明确的病理改变，这可能与IgG4和C3在泪腺中的高表达有关。     

泪腺良性淋巴上皮病变与眼眶海绵状血管瘤患者病变标本中差异表达基因的检测

背景 泪腺良性淋巴上皮病变是临床较少见的眼眶病,主要表现为双侧泪腺的对称性、无痛性肿大,其病因和发病机制至今尚未阐明. 目的 筛选泪腺良性淋巴上皮病变组织与眼眶海绵状血管瘤患者病变组织中的差异表达基因,从分子水平探讨泪腺良性淋巴上皮病变的发病机制.方法 收集2010年9月至2013年4月在首都医科大学附属北京同仁医院经病理学检查证实的泪腺良性淋巴上皮病变患者9例的病变标本,并收集同期眼眶海绵状血管瘤患者9例的组织标本作为对照.利用全基因组表达谱芯片技术和limma算法检测2个组患者组织标本中的差异表达基因,并采用实时荧光定量PCR法验证差异基因的表达,采用Fisher法和基因本体(GO)功能富集分析法对差异表达基因进行功能分析和信号通路分析,找到主要差异表达基因的功能群和信号通路. 结果 泪腺良性淋巴上皮病变患者与眼眶海绵状血管瘤患者中共筛选出5 260个差异基因,Fisher差异表达基因的功能显著性分析和信号通路分析显示,109个GO条目中的差异表达基因显著上调,101个GO条目中的差异表达基因显著下调,其中32个功能基因相关的信号通路显著上调,25个信号通路显著下调.GO分析显示,差异表达基因中补体受体介导的信号通路表达丰度最高,其次为T细胞信号通路和B细胞信号通路上调以及丝裂原激活蛋白激酶(MAPK)信号通路和转化生长因子-β(TGF-β)信号通路下调.实时荧光定量PCR结果显示,泪腺良性淋巴上皮病变组患者标本中TIPRL、TLR7和TLR10基因的相对表达量明显高于眼眶海绵状血管病组,差异均有统计学意义(Z=-2.03、-2.32、-2.32,均P＜0.05),与基因芯片检测结果一致.结论 人泪腺良性淋巴上皮病变组织与眼眶海绵状血管瘤病变组织中基因表达谱明显不同,这些差异表达基因除参与T细胞和B细胞信号通路的上调以及MAPK信号通路和TGF-β信号通路的下调外,还涉及补体系统的变化.泪腺良性淋巴上皮病变的发生和发展是多种基因和通路共同作用的结果.     

泪腺良性淋巴上皮病变的病因及发病机制

良性淋巴上皮病变以双侧或单侧泪腺、眼睑肿胀和（或）涎腺弥漫性无痛性肿大为主要临床表现.目前该病具体病因及发病机制尚未阐明.从病理学、感染学、免疫学、流行病学、分子生物学等多方面对该病的病因及发病机制进行总结,良性淋巴上皮病变的病因主要包括基底细胞增生浸润、病毒诱导、自身免疫功能障碍、性激素紊乱、蛋白紊乱、IgG4浸润等假说.这些假说都可以从不同侧面对良性淋巴上皮病变的病因及发病机制进行解释,但仍存一定争议,有待更深入研究,以便指导临床诊断及治疗.     

泪腺良性淋巴上皮病变治疗方式的探讨

目的 探讨手术辅以激素治疗泪腺良性淋巴上皮病变（BLEL）的疗效.方法 回顾性系列病例研究.收集2010年8月至2013年2月间经病理组织学证实为泪腺BLEL患者的手术前后资料16例（16只眼）,分析和总结手术前后患者视力、眼压、眼睑肿胀、眼干及并发症.结果 16例患者术后眼睑肿胀明显减轻,眼睑位置及抬举功能正常;16例患者手术前后比较,视力升高1例,无变化15例;16例患者中仅有1例出现眼干症状,与术前比较术后眼干症状未见加重;16例患者仅1例发生手术后短暂的复视,1周后自行恢复.结论 以手术切除辅助激素治疗泪腺BLEL的方式是安全可行的.     

泪腺良性淋巴上皮病变临床表现及诊断思路的研究

目的探讨泪腺良性淋巴上皮病变（BLEL）的临床特点和诊断方法。方法回顾性系列病例研究。收集2010年8月至2011年10月间经病理证实的泪腺BLEL患者资料16例,分析和总结其临床特点、影像学表现及实验室检查结果。结果 16例患者中男：女=1：7;年龄为36～63岁,其中以41～50岁为多;单眼发病：双眼发病=1：7;上眼睑无痛性非充血性持续肿胀为其主要临床表现。眼眶MRI成像扫描显示,16例患者病变均累及眼睑和泪腺组织,受累泪腺明显肿大,T1WI和T2WI均呈等信号,增强扫描可见明显均匀强化,另外,3例患者眼外肌受累,1例颞肌受累,1例额神经受累;实验室检查仅1例患者丙肝抗体阳性,余未见异常。结论眼睑肿胀是BLEL的典型症状,受累泪腺以双侧居多;MRI成像检查在诊断BLEL中具有重要价值,但确诊该病需要有病理组织学检查结果的支持。     

眶内泪腺良性肿瘤的CT诊断临床研究

目的:探讨CT对泪腺良性肿瘤的诊断价值。方法:回顾性分析30例经病理证实良性泪腺肿瘤临床资料和CT影像资料。结果:泪腺良性肿瘤患者30例中26例位于泪腺眶部,泪腺睑部4例。肿瘤椭圆形18例,不规则形4例,边缘不规则呈现分叶状或结节状8例。CT表现大多数为密度均匀,眼眶皮质受压,凹陷18例,骨皮质破坏伴硬化肥厚12例。结论:泪腺良性肿瘤CT有一定特征,诊断准确率高。     

兔泪腺分泌泪液的神经通路的实验研究

目的　探讨新西兰兔泪腺分泌泪液的神经通路。方法　在新西兰兔泪腺分四点注射微量假狂犬病毒（ｐｓｅｕｄｏｒａｂｉｅｓｖｉｒｕｓ,ＰＲＶ）１０μＬ,采用免疫荧光组织化学方法,观察实验兔存活３０ｈ、３８ｈ、４６ｈ后荧光标记神经元在脑中的分布。结果　ＰＲＶ注射到泪腺３０ｈ后,仅在脑桥上泌涎核出现阳性标记神经元;存活３８ｈ后,ＰＲＶ跨突触感染的第二级神经元可见上橄榄核群的上橄榄外侧核和上橄榄内侧核;存活４６ｈ后,在脑桥斜方体核也出现阳性细胞,且上橄榄外侧核和上橄榄内侧核的阳性细胞更为密集,下丘脑的室旁核也出现阳性细胞。结论　中枢神经系统与新西兰兔泪腺分泌泪液可能存在以下通路联系:下丘脑室旁核→脑桥上橄榄核群→脑桥上泌涎核→泪腺。     

Unusual presentations of pleomorphic adenoma and adenoid cystic carcinoma of the lacrimal gland

Purpose: To report two atypical cases of pleomorphic adenoma and adenoid cystic tumours of the lacrimal gland. Methods: Two case reports are presented. The first is of a 65-year-old female with a long history of right hypoglobus with sudden recent worsening. Computed tomography (CT) showed a round, well-defined lesion in the fossa for the lacrimal gland with an anterior hypodense exten- sion suggestive of possible malignancy in a pleomorphic adenoma. The tumour in the second case, a 35-year-old male, was diagnosed after presentation following a relatively minor periorbital injury. The smooth rounded mass on CT scan was suggestive of a benign lacrimal gland tumour. Results: The lesion in case 1 was excised with a diagnosis of haemorrhage within a pleomorphic adenoma. The lesion in case 2 was excised with a diagnosis of adenoid cystic carcinoma of the lacrimal gland with pseudocapsule. Conclusions: Haemorrhagic cyst developing beneath the pseudocapsule of a pleomorphic adenoma should be considered in the differential diagnosis of secondary development of malignancy in a pleomorphic adenoma. Adenoid cystic tumours of the lacrimal gland can present with a pseudocapsule.     

A benign presentation of primary ductal adenocarcinoma of lacrimal gland: A rare malignancy

A 34-year-old patient with a swelling over the upper eyelid for nearly 1 year was seen in our clinic. The history, examination and investigations were suggestive of a benign lacrimal gland tumor. The tumor and lacrimal gland were resected. Subsequent histopathological examination revealed the tumor was a primary ductal adenocarcinoma of the lacrimal gland. This is a very rare tumor with less than half a dozen cases reported so far. This case report is being presented to highlight an unusual presentation of this rare malignancy.     

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis

BACKGROUND: Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS: The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS: The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sj?gren's syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sj?gren's syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sj?gren's syndrome), oligoclonal rearrangement in the other. INTERPRETATION: Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.     

回顾191例泪腺占位性病变临床分析及术后随访观察

目的：探讨191例泪腺占位性病变的临床特点及术后随访情况。

方法：选取2011-01/2015-08我科收治的191例221眼泪腺占位患者,总结其临床特征,并结合病史、影像、病理资料、地域特色进行分析。所有患者行泪腺肿瘤摘除,术后随访1a。

结果：患者191例221眼中,男44例49眼,女147例172眼。炎症性病变171眼,依次是IgG₄硬化性泪腺炎66眼、慢性泪腺炎27眼、泪腺脱垂伴炎性肿大54眼、Grave''s病24眼。淋巴组织增生性病变16眼,依次是恶性淋巴瘤6眼、良性淋巴组织增生10眼。上皮性病变34眼,依次是多形性腺瘤26眼、多形性腺癌2眼、腺样囊性癌3眼、腺癌3眼。泪腺占位性病变以IgG₄硬化性泪腺炎、泪腺脱垂伴炎性肿大多见,其中汉族159眼、维族36眼、哈萨克族16眼、蒙古族10眼。手术后主要表现为眼部干涩,哭时无泪,以双侧泪腺摘除者明显,但局部使用人工泪液可以缓解,无严重不良反应。

结论：病史及影像特点对泪腺占位性病变的诊断和鉴别诊断有很大的帮助,新疆地区泪腺占位,以非上皮性病变最为常见,其次是上皮性病变,多发生于汉族、维族患者,而其它民族少有发生,手术后眼部干涩及哭时无泪为主要症状。对病程短且有干眼倾向的患者需延迟摘除。