cDC2 and plasmacytoid dendritic cells diminish from tissues of patients with non-Hodgkin orbital lymphoma and idiopathic orbital inflammation.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology. To investigate the immune cell composition of these diseases, we performed standardized 29 parameter flow cytometry phenotyping in peripheral blood mononuclear cells of 18 NHOL patients, 21 IOI patients, and 41 unaffected controls. Automatic gating by FlowSOM revealed decreased abundance of meta-clusters containing dendritic cells in patients, which we confirmed by manual gating. A decreased percentage of (HLA-DR+ CD303+ CD123+ ) plasmacytoid dendritic cells (pDC) in the circulation of IOI patients and decreased (HLA-DR+ CD11c+ CD1c+ ) conventional dendritic cells (cDC) type-2 for IOI patients were replicated in an independent cohort of patients and controls. Meta-analysis of both cohorts demonstrated that pDCs are also decreased in blood of NHOL patients and highlighted that the decrease in blood cDC type-2 was specific for IOI patients compared to NHOL or controls. Deconvolution-based estimation of immune cells in transcriptomic data of 48 orbital biopsies revealed a decrease in the abundance of pDC and cDC populations within the orbital microenvironment of IOI patients. Collectively, these data suggest a previously underappreciated role for dendritic cells in orbital disorders.

A pan-inflammatory microRNA-cluster is associated with orbital non-Hodgkin lymphoma and idiopathic orbital inflammation.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.

Intraaxial and Extraaxial Cavernous Malformation with Venous Linkage: Immune Cellular Inflammation Associated with Aggressiveness.

BACKGROUND: Intraorbital and intracerebral cavernous malformation (CM) lesions are considered independent entities. Purely cerebral CMs have variable biology with recent evidence depicting inflammation as an important player and a risk factor for aggressiveness. We describe a case of concomitant left intraaxial and extraaxial CMs, linked by the ipsilateral basal vein, where the extraaxial component has developed an aggressive behavior. CASE DESCRIPTION: A 35-year-old female patient presented with a rapid and progressive exophthalmos and loss of vision on the left eye. Cranial magnetic resonance and angiography examinations demonstrated a left craniofacial CM and large intraorbital component. The lesion was connected through a large basal vein to a cerebral intraventricular CM. Transconjunctival resection showed typical findings of CM. A complete histopathology and immunostaining analysis was performed and revealed a clear acute lymphomononuclear reaction with a predominant immune cellular inflammation. CONCLUSIONS: A case of intraorbital and extracranial cavernomatous mass, connected to a cerebral intraventricular CM through a large basal vein, has presented with an aggressive course. A complete histopathologic and immunohistochemical analysis of the orbital mass has pictured a clear immune-cellular inflammatory reaction adding to the amounting evidence of association between inflammation and site aggressiveness in the setting of CMs.

Programmed Death-1 Pathway in Orbital Invasion of Cutaneous Carcinomas.

PURPOSE: The programmed death-1 pathway negatively regulates the immune system. Previous reports have indicated worse tumor-related outcomes with increased expression of the ligand for this pathway. This study was undertaken to assess the role of the PD pathway in cutaneous malignancies that invade the orbit. METHODS: Immunohistochemical staining for the programmed death-1 receptor and ligand was performed on exenteration specimens of invasive cutaneous orbital malignancies (n = 12) and nodular basal cell carcinoma (n = 10). The numbers of positively-staining cells/40× field were counted across 5 consecutive fields, and statistical analyses were performed to compare the differences between the 2 groups. RESULTS: Programmed death-1 receptor positivity was seen in means of 30.9 cells/40× field and 62.4 cells/40× field for nodular basal cell carcinomas and invasive malignancies, respectively (p = 0.0046). A mean of 4.54 cells/40× field stained positively for the programmed death-1 ligand in nodular basal cell carcinoma, whereas a mean of 46.4 cells/40× field stained positively for programmed cell death ligand-1 in orbital invasive cutaneous carcinomas (p = 0.0015). Both of these differences were statistically significant. CONCLUSIONS: Both the programmed death-1 receptor and its ligand are enriched in invasive cutaneous malignancies. This finding indicates that negative regulation of the immune system likely prohibits tumor surveillance, and facilitates increasing aggressiveness and invasion of cutaneous malignancies.

Immunophenotypic profiles for distinguishing orbital mucosa-associated lymphoid tissue lymphoma from benign lymphoproliferative tumors.

PURPOSE: To evaluate novel immunophenotypic profiles of patients with orbital lymphoproliferative tumors. METHODS: From 2006 to 2014, surgical biopsies from consecutive patients with newly diagnosed orbital mucosa-associated lymphoid tissue (MALT) lymphoma and IgG4-related ophthalmic disease (IgG4-ROD) were collected from Tokyo Medical University Hospital. A total of 44 tumors from 44 patients were analyzed, including 21 with orbital MALT lymphoma (11 men and 10 women, mean age 67.8 ± 13.4 years) and 23 with definitive IgG4-ROD (9 men and 14 women, mean age 60.5 ± 15.1 years). Patients with secondary orbital MALT lymphoma and MALT lymphoma with IgG4-ROD were excluded. All patients were immunocompetent Asian adults. Samples were analyzed by immunohistochemistry and flow cytometric analysis. Flow cytometry was performed with the following antibodies: CD3, CD4, CD5, CD8, CD10, CD19, CD20, CD23, CD25, CD30, CD34, and CD56 lambda and kappa chains. RESULTS: Expression of CD25 and CD19 was higher in patients with orbital MALT lymphoma compared to patients with IgG4-ROD (p < 0.001). In contrast, expression of CD3, CD4, and CD23 was higher in patients with orbital IgG4-ROD compared to those with MALT lymphoma (all p < 0.01). The presence of CD23 and CD25 in the specimens was confirmed by immunohistochemistry. CONCLUSION: The present study elucidated the novel immunophenotypic features of orbital MALT and benign lymphoproliferative disorders such as IgG4-ROD. Among them, CD23 and CD25 have shown a disease-specific expression pattern.

Immune Checkpoint Inhibitors for Treatment of Metastatic Melanoma of the Orbit and Ocular Adnexa.

Programmed cell death 1 (PD-1) inhibitors are members of a new class of drugs known as immune checkpoint inhibitors and have proven efficacy in the treatment of metastatic melanoma. Herein, the authors report the use of nivolumab and pembrolizumab, 2 recently Food and Drug Administration-approved PD-1 inhibitors, in 3 patients: 1 with metastatic conjunctival melanoma and 2 with metastatic cutaneous melanoma and orbital involvement. The patients' metastatic disease responded well to drug treatment. As of this writing, 2 patients have completed therapy and remain disease free at least 1 year after treatment completion; the other patient is still receiving treatment, and his orbital disease is responding. The authors herein describe the use of PD-1 inhibitors as a new alternative in the treatment of metastatic melanoma to the orbit or metastatic ocular adnexal melanomas in these clinical settings.

Unilateral orbital mass as an unusual presentation of IgG4-related disease.

IgG4-related diseases are a recently recognized systemic syndrome characterized by mass-forming lesions, in mainly exocrine tissue, that consist of lymphoplasmacytic infiltrates and sclerosis, which may mimic malignant neoplasm due to clinical and imaging features. We report an unusual case of a 62-year-old woman who presented with a left orbital mass, which histologically revealed to be an IgG4-sclerosing disease.

[Chronic bilateral orbital tumors in IgG4-related disease]. / Beidseitige, chronisch progrediente Orbitatumoren bei IgG4-assoziierter Erkrankung.

BACKGROUND: The IgG4-related disease describes a new multisystem disorder, which can also be manifested in the orbit. This syndrome is characterized by a multifocal chronic fibroinflammation with high levels of plasma cells expressing IgG4. CASE REPORT: This article reports the case of a patient with advanced bilateral tumors of the upper eyelid and orbit. The diagnosis of IgG4-related disease was only revealed after many years and after many biopsies of the tumors had been carried out. The initiation of a systemic steroid therapy led to a rapid reduction of the tumors and an improvement in the general condition of the patient.

Immunoglobulin G4-related disease (IgG4-RD) in the orbit: mucosa-associated lymphoid tissue (MALT)-type lymphomas.

BACKGROUND: MALT lymphomas were classified for differential diagnostics of IgG4-dependent disease due to their exceptional predilection to intraorbital localization. Therefore, the goal of our studies was large retrospective analysis of patients diagnosed with MALT lymphomas within the orbital tissues, since no such studies have been conducted in Poland. MATERIAL/METHODS: The starting study population consisted of 167 patients with isolated infiltrative tumor diseases within the orbital region treated at the Department of Otolaryngology, Head and Neck Surgery of the Medical College Jagiellonian University in Cracow. The immunohistochemical assays using anti-IgG, anti-IgG4 and anti-CD138 antibodies were used to estimate the IgG4+/CD138+ and IgG4+/IgG+ ratios. RESULTS: Of all the studied and analyzed patients, a final group of 19 patients with orbital MALT lymphomas was selected to undergo diagnostic examinations for IgG4-related disease. Detailed analysis and diagnostic screening for IgG4-related disease was performed and results meeting the criteria of IgG4-dependent disease were obtained in 10 out of 19 patients with the diagnosis of MALT tumor established on the basis of immunohistochemical assays. CONCLUSIONS: MALT lymphomas are the most common of all lymphomas occurring within orbital tissues. In this study, results consistent with the criteria of IgG4-related disease were obtained in approximately 50% patients with immunohistochemical diagnosis of orbital MALT lymphoma.

Extranodal marginal zone B cell lymphoma of the orbit in a patient with sarcoidosis: a case report.

OBJECTIVE: To describe a case of extranodal marginal zone B-cell lymphoma (EMZL) "mucosa associated lymphoid tissue (MALT)" of the orbit that presented with stage IV disease in a patient with sarcoidosis. DESIGN: Clinicopathologic case report. METHODS: Biopsies of the lesion were performed in the operating room and the samples were submitted for pathology processing. Pathology analysis identified the lesion as an extranodal marginal zone B-cell lymphoma "mucosa associated lymphoid tissue (MALT)" via flow cytometry, histopathology, cytogenetics, and immunohistochemical staining and fluorescent in situ hybridization (FISH). The institutional review board of Howard University Hospital waived the need for IRB approval for this intraoperative finding. RESULTS: A 70-year-old Black woman with biopsy-proven sarcoidosis presented complaining of foreign body sensation, redness, swelling of her left upper eyelid and tearing. The patient was found to have an orbital lymphoproliferative malignancy. CONCLUSIONS: It is still unclear if the presence of immunosuppression or an autoimmune disease increases the risk of lymphoproliferative malignancies {6}. Malignancy should always be suspected and investigated.

[Immunoglobulin-G4-related disease: a challenging diagnosis]. / Boala legata de imunglobulinele G4: provocare diagnostica.

INTRODUCTION: Immunglobulin G4 (IgG4)-related disease was recently described and represents a systemic lymphoproliferative disorder. The orbital form of the disease manifests as chronic lid swelling and proptosis. Visual disturbances may occur due to apical orbital lesions. CASE REPORT: A 65-year old pacient presents with the impossibility of maintaining his right eye open due to a progressive swelling of the upper lid. The general clinical examination shows adenopathy at 3 lymph node stations of the head. On ophthalmologic examination, a large tumor of the upper lid is observed in the right eye and proptosis and central retinal vein occlusion are noted in the left eye. The serum levels of the IgG are very high. A lymph node biopsy was performed. DISCUSSION: The differential diagnosis between the IgG4-related orbital disease and non-Hodgkin lymphoma is discussed. CONCLUSION The diagnosis criteria for IgG4-related disease are both the high serum levels of IgG4 and the specific immunohistochemistry stains.

Lacrimal gland sparing IgG4-related disease in the orbit.

PURPOSE: We report an unusual case of orbital IgG4-related disease and discuss the distinguishing characteristics of the ophthalmic disease subtype. DESIGN: Case report. METHODS: Literature review and case description. RESULTS: Although lacrimal gland involvement has always been reported and elevated serum IgG4 is commonly observed, our case demonstrated neither in light of biopsy-proven IgG4 orbital involvement. A course of systemic steroids resolved our patient's periorbital abnormalities. CONCLUSIONS: IgG4-related orbital disease mandates a high index of suspicion, and should be confirmed by tissue biopsy. Possible progression to MALT lymphoma necessitates close surveillance and may require repeat biopsy.

IgG4 orbital inflammation in a 5-year-old child presenting as an orbital mass.

IgG4 is a newly known systemic disorder. It can present as orbital inflammation or as an orbital mass. We describe the case of a 5-year-old child with proptosis and globe dystopia who went on to have an orbital biopsy. Initially this was reported to be idiopathic orbital inflammation. After IgG4-RD was considered in the differential, the orbital biopsy was revisited, immunohistochemistry was done and the patient's serum was tested for IgG subclass levels. IgG4-RD was diagnosed and the patient was subsequently treated with prednisone and mycophenolate and made a good recovery. This is the youngest reported case of IgG4-RD in a child.

Local recurrence as immunoglobulin G4 (IgG4)-related disease 10 years after radiotherapy to ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue.

In 2000, a 48-year-old woman developed a left orbital mass with lacrimal gland involvement and then, in 2003, a right orbital mass with lacrimal gland involvement, both of which were diagnosed as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). She underwent 30 Gy external beam radiation to bilateral orbital lesions. The lymphoma cells in both lesions did not share the same clonality, as shown by amplification by polymerase chain reaction of the immunoglobulin heavy chain gene. Immunoglobulin light chain analysis by immunohistochemistry and messenger RNA in situ hybridization showed λ chain monotype in the left orbital lesion but κ chain monotype in the right orbital lesion. She developed recurrent left orbital mass with high uptake on fluorodeoxyglucose positron emission tomography fused with computed tomography in 2010, and excisional biopsy disclosed the formation of follicles and infiltration with immunoglobulin G4 (IgG4)-positive plasma cells mainly in interfollicular areas. The immunoglobulin light chain analysis showed the λ chain and κ chain bitype. With the immunohistopathological diagnosis of IgG4-related disease, the serum IgG4 level was found to show elevation at 376 mg/dL, and the patient chose observation. This is the first reported case of development of IgG4-related disease after bilataral orbital MALT lymphoma with external beam radiotherapy.

Clinical significance of tumor-infiltrating FOXP3+ T cells in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma.

We evaluated the association between tumor-infiltrating FOXP3+ T cells and clinical outcomes in patients with ocular adnexal lymphoma of mucosa-associated lymphoid tissue type (OAML). Pretreatment formalin-fixed paraffin-embedded tissues from 42 patients with OAML were stained with 236A/E7 anti-FOXP3 murine monoclonal antibody as well as CD3, CD4 and CD8 antibodies. The amount of FOXP3+ T cells was numerically quantified using an image analysis program. Front-line treatments were as follows: combination chemotherapy (n = 25); radiotherapy (n = 9); doxycycline (n = 6); and wait and see (n = 2). Complete response (CR) was observed in 20 (50%) of 40 evaluable patients. Median progression-free survival (PFS) was 50 months. A high number of FOXP3+ T cells (n = 21, ≥ 180/0.58 mm(2)) showed a higher CR rate (33%vs 71%, P = 0.013) and tendency towards prolonged PFS (48 vs 67 months, P = 0.110). In the combination chemotherapy group, a high number of FOXP3+ T cells was significantly associated with a higher CR rate (29%vs 82%, P = 0.008) and prolonged PFS (17 vs 79 months, P = 0.003). A high number of tumor-infiltrating FOXP3+ T cells correlates with a favorable clinical outcome in OAML patients.

Orbital solitary fibrous tumor: encompassing terminology for hemangiopericytoma, giant cell angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases.

Hemangiopericytomas and solitary fibrous tumors are uncommon neoplasms found in many locations, including the orbit. Both mesenchymal neoplasms share several clinicopathologic features, thus prompting intense debate as to whether they are variants of the same entity or merit separate designations in the orbit. These 2 entities, with the addition of giant cell angiofibroma of orbit, are of benign- to uncertain-behavior, CD34-positive, collagen-rich, specialized fibroblastic tumors, which may have overlapping or histologically identical features. In addition, so-called fibrous histiocytoma of orbit, a previous designation, has overlapping morphologic features with these tumors. To date, a large series of these collagen-rich fibroblastic tumors of the orbit has not been fully explored. Forty-one fibroblastic orbital tumors, originally diagnosed as hemangiopericytomas (n = 16), fibrous histiocytomas (n = 9), mixed tumors (hemangiopericytomas/fibrous histiocytoma) (n = 14), and giant cell angiofibromas of orbit (n = 2) between 1970 and 2009, were retrieved from our consultation files, the Ophthalmic Registry, at the Armed Forces Institute of Pathology. Slides and clinical records were reviewed, analyzed, and compared. Immunochemistry was performed for CD34, CD99, Bcl-2, Ki-67, and p53. Upon histologic review, all cases were reclassified as solitary fibrous tumor (41/41). The patients included 23 (56%) males, 17 (41%) females, and 1 unknown, with a mean age at presentation of 40.7 years (range, 16-70 years). The sites of involvement were the right orbit in 18 (44%) cases and the left in 16 (39%) cases. Tumors ranged in size from 0.4 to 5.0 cm (mean, 2.2 cm). Seventeen (41%) patients presented with an orbital mass, 8 (20%) with proptosis, 2 (5%) with painful mass, and 2 (5%) with painless mass. Duration of symptoms ranged from 3 to 96 months, with a mean of 23 months (median, 9 months). Microscopically, all lesions showed considerable similarity, varying in degree of cellularity, stromal collagen, and the presence of giant cells. Overlapping features with soft tissue giant cell fibroblastoma were observed. Immunochemistry revealed positivity for CD34 in all cases (100%), p53 in 85%, CD99 in 67.5%, and Bcl-2 in 47.5%. Although Ki-67 labeling was seen in all cases, it ranged from less than 1% in 54.3% of cases to 5% to 10% in 20% of cases. Taken together, the findings of this study suggest that orbital hemangiopericytoma and some cases previously designated as fibrous histiocytoma, giant cell angiofibroma of orbit, and solitary fibrous tumor have overlapping morphologic and immunohistochemical features and should be designated as solitary fibrous tumor. Adipocytes and unusual multivacuolated adipocytic cells may be present in these tumors, as well stromal myxoid change; and even stromal intramembranous ossification can be observed. There are overlapping features of orbital solitary fibrous tumor with another CD34-positive specialized fibroblastic tumor of soft tissue, giant cell fibroblastoma. Morphologic criteria for uncertain behavior to low-grade malignant ocular solitary fibrous tumors can be made by cytologic atypia and increased mitotic activity, but overall outcome for malignant solitary fibrous tumors of the eye should be further explored.

IgA orbital plasmacytoma in multiple myeloma.

The authors report a case of orbital plasmacytoma in a 48-year-old man with known multiple myeloma. He presented with proptosis, diplopia, and decreased vision of the left eye for several weeks. He had been previously treated for IgA lambda multiple myeloma with chemotherapy, radiation, and autologous stem cell transplant. After a left orbitotomy, flow cytometry revealed a tumor rich in plasma cells expressing CD138 with equivocal lambda light chain expression. The patient underwent orbital radiation, with improvement of vision and disc edema OS. The patient is currently undergoing salvage chemotherapy for relapse of multiple myeloma. This is the third reported case of IgA myeloma involving the orbit.