Clinical observation of orbital IgG4-related diseases.
ABSTRACT: The aim of the present study was to observe the histopathological changes of immunoglobulin G4-related orbital diseases (IgG4-RODs), summarize the clinical manifestations and imaging features of the IgG4-RODs of the eyelids and explore the early diagnosis of IgG4-RODs. Between June 2011 and May 2015, 23 patients with non-specific orbital inflammation in the Department of Ophthalmology at the First Central Hospital of Tianjin were recruited. The serum IgG4 titer in 9 patients ranged from 4.58 to 46.70 g/l (reference value, 0.03-2.01 g/l), with an average value of 21.93±2.18 g/l. Notably, the degree of increase in the 9 patients with IgG4-RODs was different, but all were >1.35 g/l. A total of 6 cases of infraorbital nerve thickening were observed. In addition, there were 3 cases of extraocular muscle thickening and 1 patient with IgG4-ROD had an orbital tissue lesion extending along the inferior temporal septum to the left pterygopalatine fossa, with left sacral fissure widening and involvement of the left maxillary sinus. The study revealed that the thickening of the inferior orbital nerve may be a characteristic of IgG4-ROD. Therefore, on the basis of biopsy and serological examination in the clinic, early diagnosis can be combined with imaging examination, clinical manifestation and laboratory examination, so as to reduce misdiagnosis and missed diagnosis.
Project description:IgG4-related disease (IgG4-RD) is characterized by variable tissue or organ involvements sharing common pathological findings. Orbital or orbital adnexa involvement of the disease has been reported in a few case series. The aim of our study was to characterize and analyze ophthalmic manifestations from a nationwide French case-series.Patients with IgG4-RD and orbital or orbital adnexa involvement included in the French multicentric IgG4-RD case-registry were identified. Only patients fulfilling "modified" comprehensive diagnostic criteria with pathological documentation were retained for the study. Clinical, biological, pathological, radiological findings and data regarding the response to treatment were retrospectively analyzed.According to our data registry, the frequency of IgG4-related ophthalmic disease (IgG4-ROD) was 17%. Mean age at diagnosis was 55.1?±?7.1 years with a male/female ratio of 2.2. The 19 cases of IgG4-ROD consisted of lacrimal gland (68.4%), soft tissue (57.9%), extra-ocular muscles (36.8%), palpebral (21.1%), optical nerve (10.5%), orbital bone (10.5%), and mononeuritis (V1?and/or V2, 10.5%) involvements. IgG4-ROD was bilateral in 57.9% of cases. Extra-ophthalmic manifestations were reported in 78.9% of cases. All patients responded to prednisone but two-thirds of patients relapsed within a mean (SD) of 9.8 (3.5) months and 72.2% required long-term glucocorticoids and/or immunosuppressive agents. Eight patients were treated by rituximab with a favorable response in 87.5% of cases.Lacrimal involvement is the most frequent ophthalmic manifestation of IgG4-RD and is frequently associated with extra-orbital manifestations. Despite initial favorable response to steroids, the long-term management of relapsing patients needs to be improved.
Project description:The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since the work-up and treatment can vary greatly, is often challenging due to the lack of specific biomarkers. Although miRNAs play an important role in the regulation of carcinogenesis and inflammation, the relationship between miRNA and orbital lymphoproliferative diseases remains unknown. We performed a comprehensive analysis of 2565 miRNAs from biopsy and serum specimens of 17 cases with IgG4-ROD, where 21 cases with orbital MALT lymphoma were performed. We identified specific miRNA signatures and their miRNA target pathways, as well as the network analysis for IgG4-ROD and orbital MALT lymphoma. Machine-learning analysis identified miR-202-3p and miR-7112-3p as the best discriminators of IgG4-ROD and orbital MALT lymphoma, respectively. Enrichment analyses of biological pathways showed that the longevity-regulating pathway in IgG4-ROD and the mitogen-activated protein kinase (MAPK) signaling pathway in orbital MALT lymphoma was most enriched by target genes of downregulated miRNAs. This is the first evidence of miRNA profiles of biopsy and serum specimens of patients with IgG4-ROD and orbital MALT lymphoma. These data will be useful for developing diagnostic and therapeutic interventions, as well as elucidating the pathogenesis of these disorders.
Project description:<h4>Purpose</h4>To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers.<h4>Methods</h4>We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromatography time-of-flight mass spectrometry. The altered metabolomic profiles were visualized by heat map and principal component analysis. Metabolic pathway analysis was performed by Metabo Analyst 4.0 using differentially expressed metabolites. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. Machine learning algorithms were implemented by random forest using the R environment. Finally, an independent set of 18 IgG4-ROD and 17 orbital MALT lymphoma specimens were used to validate the identified biomarkers.<h4>Results</h4>The principal component analysis showed a significant difference of both IgG4-ROD and orbital MALT lymphoma for biopsy specimens and controls. Interestingly, lesions in IgG4-ROD were uniquely enriched in arachidonic metabolism, whereas those in orbital MALT lymphoma were enriched in tricarboxylic acid cycle metabolism. We identified spermine as the best discriminator between IgG4-ROD and orbital MALT lymphoma, and the area under the receiver operating characteristic curve of the spermine to discriminate between the two diseases was 0.89 (95% confidence interval, 0.803-0.984). A random forest model incorporating a panel of five metabolites showed a high area under the receiver operating characteristic curve value of 0.983 (95% confidence interval, 0.981-0.984). The results of validation revealed that four tissue metabolites: N1,N12-diacetylspermine, spermine, malate, and glycolate, had statistically significant differences between IgG4-ROD and orbital MALT lymphoma with receiver operating characteristic values from 0.708 to 0.863.<h4>Conclusions</h4>These data revealed the characteristic differences in metabolomic profiles between IgG4-ROD and orbital MALT lymphoma, which may be useful for developing new diagnostic biomarkers and elucidating the pathogenic mechanisms of these common orbital lymphoproliferative disorders.
Project description:High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls (n = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ? 2 and p < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs.
Project description:Primary orbital peripheral T-cell lymphoma, not otherwise specified is an exceedingly rare disorder with a very poor outcome, and to the best of our knowledge only a few cases have been reported in the English literature. We present the youngest reported case describing the successful outcome after management with a thorough review of the English literature of all the reported cases of primary peripheral T-cell lymphoma, not otherwise specified.Our patient is a 3-year-old Syrian boy who presented with gradual progressive orbital swelling. A physical examination showed a left orbital dystopia and a superior medial displacement of the globe. Extraocular motility was limited in upward elevation of his left eye. A computed tomography scan and magnetic resonance imaging of his orbit showed a mass involving the lateral and inferior walls of his left orbit and extending intraconally. A diagnosis of peripheral T-cell lymphoma, not otherwise specified was made by careful histopathological examination and Berlin-Frankfurt-Munster protocol was initiated. A 6-month follow up with orbital magnetic resonance imaging showed no sign of orbital or brain involvement.Through this report we emphasize two takeaway lessons: (1) always have a high level of suspicion of this entity regardless of the age of the patient; and (2) careful histopathological examination is very important for prompt confirmation of the diagnosis and early commencement of proper treatment.
Project description:BACKGROUND/AIMS:This study investigated the clinical and pathological features of immunoglobulin G4 (IgG4)-related ophthalmic disease. To clarify the features, we compared IgG4-related ophthalmic disease and orbital inflammatory pseudotumor. METHODS:We retrospectively reviewed the medical records of 103 patients who were initially diagnosed with orbital inflammatory pseudotumor, and identified 16 cases in which the diagnosis was based on surgical biopsy and for which data in medical records were sufficient for analysis. Immunohistochemical staining of pathological specimens for IgG and IgG4 was performed. Finally, six of IgG4-related ophthalmic disease patient and 10 of orbital inf lammatory pseudotumor patient were analyzed. RESULTS:The IgG4-related ophthalmic disease group had more IgG4-positive plasma cells and a higher IgG4/IgG plasma cell ratio than the orbital inflammatory pseudotumor group. Collagenous fibrosis and lacrimal gland involvement were significantly more frequent in the IgG4-related ophthalmic disease group. Dense lymphocyte infiltration, obliterative phlebitis, and bilateral lesions were more frequent in IgG4-related ophthalmic disease, but the differences were not significant. The recurrence-free period was shorter in the IgG4-related ophthalmic disease group (p = 0.035). CONCLUSION:The location of the lesion (lacrimal gland), count and ratio of IgG4-positive plasma cells, and collagenous fibrosis aid the diagnosis of IgG4-related ophthalmic disease in patients with idiopathic orbital mass-like lesions. In addition, maintenance therapy should be considered in patients with IgG4-related ophthalmic disease to prevent recurrence.
Project description:PurposeImmunoglobulin G4-related disease is a systemic fibroinflammatory disease of unknown etiology. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) can manifest in multiple ways, but lacrimal sac involvement is rare. We present the first case in Chinese population of lacrimal sac IgG4-ROD.ObservationsLacrimal sac IgG4-ROD is rare, and only 9 cases were reported in literature. Despite reported cases in Asian population, mainly in Japan, there was none from the Chinese population or South Asia. Our index case is a 67-year-old Chinese male, who presented with a left insidious nasolacrimal duct swelling mimicking dacryocystocele. Lacrimal sac IgG4-ROD was diagnosed with radiological, serological, pathological and immunohistochemical evidence. The under-reporting of this disease entity may suggest a benign course of such.Conclusions and importanceThis is the first reported case of biopsy proven lacrimal sac definite IgG4-ROD in Chinese patient on English literature. With the limited cases reported in literature, the pathology of Immunoglobulin G4 immune process in lacrimal sac demands further investigation.
Project description:Orbital sclerosing inflammation is a distinct group of pathologies characterized by indolent growth with minimal or no signs of inflammation. However, contrary to earlier classifications, it should not be considered a chronic stage of acute inflammation. Although rare, orbital IgG4-related disease has been associated with systemic sclerosing pseudotumor-like lesions. Possible mechanisms include autoimmune and IgG4 related defective clonal proliferation. Currently, there is no specific treatment protocol for IgG4-related disease although the response to low dose steroid provides a good response as compared to non-IgG4 sclerosing pseudotumor. Specific sclerosing inflammations (e.g. Wegener's disease, sarcoidosis, Sjogren's syndrome) and neoplasms (lymphoma, metastatic breast carcinoma) should be ruled out before considering idiopathic sclerosing inflammation as a diagnosis.
Project description:A 22-year-old woman presented with progressive swelling of the nasal conjunctiva in the left eye. Anterior segment examination revealed a diffuse cystic appearance to the inferonasal bulbar conjunctiva and plica semilunaris. Anterior segment swept-source optical coherence tomography (OCT) revealed clear hyporeflective spaces demarcated by hyperreflective septae in the affected conjunctiva, consistent with the diagnosis of lymphatic malformation (LM). Magnetic resonance imaging revealed a well circumscribed intraconal mass located inferonasally in the left orbit. Systemic examination revealed a lesion similar to LM on the left hard palate. The left conjunctival mass was excised subtotally. Subsequently, a transconjunctival anterior orbitotomy was performed and the left orbital mass was completely removed intact. Histopathologically, the conjunctival mass was diagnosed as LM and the orbital mass as venous malformation (VM). This case represents a rare coexistence of histopathologically proven conjunctival LM and orbital VM as well as a presumed LM of the hard palate, all 3 lesions occurring in the ipsilateral midface area.