Orbital inflammatory disorders: new knowledge, future challenges.

PURPOSE OF REVIEW: This review aims to bring together recent advances in basic, translational and clinical research on the pathogenesis and treatment of orbital inflammatory conditions. RECENT FINDINGS: Basic science studies provide mechanistic insights into why the orbit is targeted for inflammation by autoimmune inflammatory disorders. Using Graves' disease as a test case reveals that endocrine pathways, such as the TSH and IGF1 receptor pathways play important roles in stimulating orbital inflammation. Furthermore, orbital tissues contain high concentrations of retinoids - byproducts of the visual pathway that diffuse across the sclera and can activate de novo transcription of inflammatory cytokines. Such cytokine expression places the orbit in a hyper-inflammatory 'resting' state, prone to respond to any additional systemic or local pro-inflammatory signals. The HIF2A--LOX pathway appears important for orbital tissue fibrosis. Lastly, bench-to-bedside studies of the IGF1R pathway have led to an FDA-approved drug, teprotumumab that represents a novel treatment approach for Graves' orbitopathy. Unfortunately, high drug costs and misplaced insurance company 'step-therapy' policies may block patients from receiving therapy that can protect vision and improve quality of life. SUMMARY: Improved understanding of orbital inflammatory conditions has led to a new drug and promises additional breakthroughs. Translational research is successful, but requires time, resources, and patience.

Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma.

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

TIMP-1 Mediates Inflammatory and Immune Response to IL-6 in Adult Orbital Xanthogranulomatous Disease.

Purpose: To explore the pathogenesis that TIMP-1 mediated in adult orbital xanthogranulomatous disease (AOXGD), a rare type of non-Langerhans histiocytosis that damages the appearance and quality of life of patientsMethods: We reviewed 22 patients diagnosed with AOXGD based on clinical manifestations and histological analysis, and then investigated the expression of TIMP-1 and IL-6 with q-PCR and IHC in AOXGD tissues and the possible mechanism involved in the induction of TIMP-1 by IL-6.Results: IL-6 and TIMP-1 were significantly increased in AOXGD tissues. IL-6 promoted TIMP-1 production by M1 macrophages by stimulating the phosphorylation of JAK2 and STAT3. Moreover, IL-17 and IFN-γ, the classical markers of Th1 and Th17 cells, were increased in AOXGD.Conclusion: These data implied that the IL6~JAK2/STAT3-TIMP-1 signalling pathway is activated in AOXGD and that adaptive Th1 and Th17 responses are involved in the development of AOXGD.

Paediatric orbital conjunctival epithelial cyst with positive asialotransferrin.

Conjunctival orbital cysts are rare; they are typically either conjunctival dermoid or conjunctival epithelial cysts - congenital or acquired (inclusion). We describe the case of a 15-month-old girl presenting with strabismus and proptosis who had a retrobulbar intraconal cystic lesion displacing the optic nerve, with an adjacent middle cranial fossa anomaly. Aspiration of the orbital cyst tested positive for asialotransferrin, raising the suspicion of a direct communication with cerebrospinal fluid (CSF). Subsequent fine cut CT scanning disproved any connection with the intracranial space, and the cyst was excised complete and intact. Histopathology showed a conjunctival epithelial cyst. To our knowledge, this is the first case report in the literature of an asialotransferrin positive pediatric orbital conjunctival epithelial cyst. It is of clinical relevance as it explores the possibility of either a false positive asialotransferrin or potentially a prior developmental communication with the subarachnoid space. These two diagnostic possibilities are discussed.

Atypical presentation of isolated orbital Langerhans cell histiocytosis.

BACKGROUND: A 9-year old female presented with one month of waxing and waning upper eyelid swelling. An excisional biopsy via anterior orbitotomy was performed. OBJECTIVE: To describe a patient presenting atypically with symptoms concerning for orbital cellulitis who was diagnosed with Langerhans cell histiocytosis (LCH). METHODS: Description of case report. RESULTS: We report a case of a 9-year old female with one month of periorbital edema and erythema suspected to be orbital cellulitis. A complete ophthalmological exam, subsequent imaging, and an excisional biopsy revealed the diagnosis of LCH. With a confirmed diagnosis, the patient started chemotherapy indicated by the Histiocyte Society Evaluation and Treatment Guidelines. CONCLUSION: Langerhans cell histiocytosis (LCH) embodies a spectrum of diseases with the primary pathologic process being the abnormal proliferation of polyclonal Langerhans cells. In children with isolated bony involvement, the most common presenting symptom is pain. Rarely is orbital involvement with associated periorbital edema and erythema the primary presentation.

Ocular Adnexal Amyloidosis: A Mass Spectrometric Analysis.

PURPOSE: Ocular adnexal amyloidosis (OAA) may represent localized manifestation of an underlying systemic process. Accurate identification of the amyloid fibrils can guide the systemic evaluation and treatment. The aim of this study was to characterize subtypes of OAA using immunohistochemistry and mass spectrometric analysis and to correlate with ocular involvement and systemic association. DESIGN: Retrospective case series. METHODS: Review of patients with OAA subtyped by immunohistochemistry and mass spectrometric analysis at the Cleveland Clinic from June 1995 to June 2017. RESULTS: While immunohistochemistry identified AL amyloid protein in 67% (4/6) of specimens tested, mass spectrometry identified AL amyloid protein in all specimens (10/10). AL lambda was identified in 5 (50%) samples, kappa in 3 (30%), and both kappa and lambda light chains in 2 (20%). The 5 cases of conjunctival amyloidosis were either AL lambda only (3 cases) or both lambda and kappa (2 cases). There were 3 cases that had associated systemic involvement. Two of these had eyelid skin involvement and AL kappa amyloidosis and the other patient had uveal involvement and AL lambda amyloidosis. CONCLUSIONS: Primary amyloidosis-AL is the most common form diagnosed by mass spectrometric analysis in patients with OAA. Immunohistochemistry is ineffective in the characterization of the amyloid deposits in a significant number of cases. Evaluation to exclude systemic involvement or associated underlying lymphoproliferative disorder is warranted.

Ophthalmic Findings of Rosai-Dorfman Disease.

PURPOSE: To describe the ophthalmic, pathologic, and BRAF V600E mutation status of Rosai-Dorfman disease (RDD). DESIGN: Retrospective case series. METHODS: A retrospective review of all cases of RDD seen at Mayo Clinic from 1992 to 2016 identified patients with ophthalmic manifestations (n = 8). Immunostain for BRAF and molecular studies for BRAF V600E mutation were performed on cases with tissue available. RESULTS: Of 76 patients with RDD, 15 had eye examinations; of those, 8 (5 female and 3 male) had ophthalmic manifestations. In RDD patients with ophthalmic manifestations compared to RDD patients without ophthalmic manifestations, the respective median (range) age in years was 42 (15-70) and 56 (32-79) (P = .13) and median (range) logMAR visual acuity was 0.048 (0.000-1.824) and 0.000 (-0.124 to 0.301) (P = .19). Of the 8 patients with ophthalmic manifestations, 4 had ocular involvement and 4 had orbital masses. Patients with ocular involvement had multiorgan disease including tracheal, aortic, renal, skeletal, and soft tissue lesions (n = 4). Patients with orbital masses had no systemic involvement (n = 2), skeletal involvement only (n = 1), or multiorgan disease (n = 1). BRAF immunostaining and molecular studies were negative in all available specimens (n = 6). CONCLUSIONS: In this series of patients with ophthalmic manifestations of RDD, those with ocular involvement had multiorgan disease while those with orbital masses had more limited systemic disease. Patients with ophthalmic manifestations tended to be younger and have worse visual acuity. Additionally, ophthalmic RDD does not seem to be associated with BRAF mutation.

Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa.

BACKGROUND/AIM: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). MATERIALS AND METHODS: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. RESULTS: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. CONCLUSION: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM.

Erdheim-Chester disease with orbital involvement: Case report and ophthalmic literature review.

Erdheim-Chester disease (ECD) is a rare xanthogranulomatous disease in which orbital involvement can have devastating outcomes. Through a case report and review of the ophthalmic literature, we explore orbital findings, disease progression, and treatment options. Cases of orbital involvement in Erdheim-Chester disease were identified in the ophthalmic literature with a PubMed query and review of cited references. A total of 14 publications reporting 19 separate cases that included ophthalmic examination data were identified. Patient ages ranged from 26-77 years with a mean age of 50 years. Seventy-four percent (14/19) were men. Vision progression to no light perception was found in 32% (6/19) of the patients. Reviewed cases reported a variety of medical and surgical treatment approaches, however, only 53% reported cases (10/19) demonstrated disease improvement or stabilization. Erdheim-Chester disease with orbital involvement is a devastating disease with a poor prognosis. Awareness of this entity by the ophthalmologist is important as orbital signs and symptoms may manifest early, and orbital biopsy is often crucial to the definitive diagnosis.

Overexpression of collagen XIII in extraocular fat affected by active thyroid-associated ophthalmopathy: A crucial piece of the puzzle?

Thyroid-associated ophthalmopathy (TAO) causes irreversible increase in extraocular fat volume that contributes to the risk of exophthalmos and compressive optic neuropathy. Collagen XIII is implicated in uncontrolled cell growth in some tumours, but we are not aware of any studies of collagen XIII in TAO-affected solid tissue to date. We conducted immunohistochemical staining for collagen XIII alpha 1 (COL13A1), present in both the transmembrane and cleaved forms of collagen XIII, in consecutive prospectively collected human extraocular tissue specimens from patients with TAO and controls. We identified overexpression of collagen XIII in active TAO-affected fat. We discuss how species and cell-type specific responses of collagen XIII to stressors may help explain the different phenotypes of TAO.

Intraorbital granuloma annulare in an elderly patient.

Classically, granuloma annulare (GA) is a cutaneous disorder localized to the dorsum of the hands and/or feet in children and young adults. Very rarely it can present on the face and rarer still on periorbital structures such as the eyelid and orbital rim. Diagnosis hinges on clinical presentation and histological features, such as palisading granulomas with central destruction of collagen, presence of mucin and lymphohistiocytic infiltration. The etiology of this condition remains unknown, but may involve a delayed-type hypersensitivity reaction, malignancy and/or infection. Herein is the first reported case of an intraorbital GA in an 86-year-old male patient who presented with right eye proptosis.

Langerhans Cell Histiocytosis of the Orbit: Spectrum of Disease and Risk of Central Nervous System Sequelae in Unifocal Cases.

PURPOSE: To describe the spectrum of disease extent and clinical response in Langerhans cell histiocytosis (LCH) presenting with orbital involvement and to determine if unifocal orbital disease increases the risk for central nervous system sequelae (CNS-LCH). METHODS: Retrospective chart review of patients with orbital LCH representing a range of severity treated at the Children's Hospital of Wisconsin from 2003 to 2011; analysis of current international treatment protocols; literature review. RESULTS: Six patients presenting with orbital LCH are described: 1 with unifocal orbital disease completely responsive to local measures; 1 with multifocal bone disease completely responsive to local intervention; 1 with unifocal orbital disease incompletely responsive to surgical intervention, and requiring systemic chemotherapy; and 3 with multisystem disease at presentation. Literature review identified 806 cases of CNS-LCH. Orbital involvement could be determined in 11 cases. Of these, 6 had multisystem disease and 3 had multifocal bone disease; 1 presented with unifocal orbital disease but progressed to multifocal bone involvement; 1 had insufficient clinical information to distinguish unifocal from multisite presentation. No cases of CNS-LCH directly resulted from isolated unifocal orbital disease. CONCLUSIONS: Initial treatment of orbital LCH should depend on disease extent at diagnosis. Unifocal cases that completely respond to biopsy, curettage, and/or corticosteroid instillation may be managed with initial oncologic staging and careful long-term observation, with default to chemotherapy for local recurrence or multisite progression. There is currently little evidence that unifocal orbital disease increases the risk for CNS-LCH and therefore warrants prophylactic systemic chemotherapy in all patients.

Reticulohistiocytoma of the orbit.

Reticulohistiocytoma is a rare, benign histiocytic proliferation of the skin or soft tissue. While ocular involvement has been documented in the past, there have been no previously reported cases of reticulohistiocytoma of the orbit. In this report, the authors describe a reticulohistiocytoma of the orbit in a middle-aged woman.

Primary adnexal angiosarcoma masquerading as periorbital hematoma.

We report an elderly woman who was anticoagulated and presented with a recent history of right-sided orbital contusion and a periorbital hematoma without clinical or radiological evidence of focal mass or orbital involvement. She was initially treated conservatively. Continued progression of adnexal swelling and erythema prompted further investigation, however. There was no improvement with surgical drainage alone; biopsy revealed angiosarcoma. The discovery of this vascular tumor underscores the importance of a reconsideration of the diagnosis in the face of counterintuitive findings. Additionally, we emphasize the need to consider malignancy in the differential diagnosis of prolonged periorbital swelling, regardless of a history of recent trauma.

A clinical, radiologic, and immunopathologic study of five periorbital intraosseous cavernous vascular malformations.

PURPOSE: To correlate the clinical, radiographic, histopathologic, and immunohistochemical features of 5 primary periorbital intraosseous cavernous vascular malformations. DESIGN: Retrospective interventional case series. METHODS: Clinical and operative records and radiographic images were reviewed. Histopathologic slides were evaluated with hematoxylin-eosin, trichrome, and elastin stains. Immunohistochemical studies were performed with a spectrum of monoclonal antibodies directed at antigens of vascular cells. RESULTS: Three men and 2 women ranged in age from 36 to 64 years. Vision was unaffected and there was no proptosis or globe displacement. The slow-growing lesions measured 13-25 mm in greatest diameter (mean 16.4 mm). Computed tomographic studies revealed that 2 lesions were situated in the maxillary bone, 2 in the frontal, and 1 in the zygoma, all anteriorly and with circumscribed, lucent, honeycombed, or sunburst characteristics. Histopathologically the lesions were composed of cavernous or telangiectatic channels; 1 showed advanced fibrotic vascular involution. Immunohistochemistry demonstrated CD31/34 positivity for vascular endothelium and D2-40 negativity for lymphatic endothelium. A typically thin mural myofibroblastic cuff was smooth muscle actin positive, weakly calponin positive, and desmin negative. Glucose transporter-1 and Ki-67 were negative in the endothelium. CONCLUSIONS: Intraosseous vascular lesions resemble orbital cavernous venous malformations (not true hemangiomas), except that their vascular walls are thinner owing to the constraints imposed by neighboring bone spicules, which limit the amount of interstitium from which mural myofibroblasts can be recruited. The bony trabeculae conferred the honeycomb or sunburst appearances observed radiographically. En bloc excision of these lesions was successful and avoided complications (mean follow-up, 46 months).