What is the meaning of ANCA positivity in IgG4-related disease?

OBJECTIVES: To evaluate the prevalence and meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in a cohort of IgG4-related disease (IgG4-RD). METHODS: We identified patients with ANCA determination from a retrospective cohort of 69 patients with IgG4-RD. ANCA were measured by indirect immunofluorescence microscopy (IIF) and/or proteinase 3 (PR3)-ANCA and MPO-ANCA by ELISA. IIF patterns were classified as perinuclear (P-ANCA), cytoplasmic (C-ANCA) and atypical (X-ANCA). We compared the ANCA-positive vs the ANCA-negative IgG4-RD group. RESULTS: Out of 69 patients, 31 IgG4-RD patients had an ANCA determination. Four patients with concomitant systemic autoimmune diseases were excluded. We found positive ANCA by IIF in 14 (56%) of 25 patients tested. The most common IIF pattern was C-ANCA in eight (57.1%), followed by dual C-ANCA/X-ANCA in four (28.6%) and P-ANCA and dual C-ANCA/P-ANCA in one each (7.1%). Of the 20 patients with ANCA determination by both IIF and ELISA, four have positive ANCA by ELISA (three for MPO-ANCA and one for PR3-ANCA). Of the two patients with only ELISA determination, one was positive for MPO-ANCA. The prevalence of ANCA positivity by ELISA was 22.7% (5 out of 22 patients). ANCA was more frequent in the Mikulizc/systemic phenotype (42.9%) compared with other phenotypes (P = 0.04). ANCA-positive IgG4-RD patients had more frequently lymph node and kidney involvement, high IgG1 levels and erythrocyte sedimentation rate, and positive antinuclear antibodies. CONCLUSION: ANCA are found in a significant number of patients with IgG4-RD and differed from the ANCA-negative group in terms of clinical and serological features.

Isolated Langerhans Cell Histiocytosis of the Lacrimal Gland in Conjunction With Mucosa-Associated Lymphoid Tissue Lymphoma and Elevated IgG4 Plasma Cells.

Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type cells. Orbital LCH is infrequent, typically manifesting as an isolated lytic bony lesion with an adjacent soft tissue mass in a child. Isolated lacrimal gland involvement by LCH is extremely rare, with only 2 previously reported cases. The authors describe a 37-year-old woman with a 6-month history of painless right upper eyelid swelling and diffuse right lacrimal gland enlargement without bony changes on computed tomography scan. Excisional biopsy of the lacrimal gland demonstrated concurrent LCH, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, and increased IgG4-expressing plasma cells. Work-up was negative for systemic hematolymphoid malignancy and IgG4-related disease. This case illustrates the association between LCH, mucosa-associated lymphoid tissue lymphoma, and elevated IgG4 plasma cells in the lacrimal gland, and we review the emerging theories proposed to explain this phenomenon.

Clinical outcomes and pathological characteristics of immunoglobulin G4-related ophthalmic disease versus orbital inflammatory pseudotumor.

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.

Bilateral lacrimal caruncle lesions.

A 65-year-old man was referred to our hospital for the treatment of a lesion on the medial lacrimal canthus of both eyes. He had a history of perinuclear anti-neutrophil cytoplasmic antibodies, i.e., pANCA-positive interstitial pneumonia. Orbital magnetic resonance imaging excluded space occupying lesions, and laboratory testing excluded thyroid-related diseases. The masses were excised, and histopathological examinations showed sebaceous gland hyperplasia and inflammatory changes around the gland. In addition, the specimen from the left eye showed a retention cyst possibly caused by an infection. It was also possible that the use of steroid was involved in the development of the lesions. A relationship between the ANCA and the lesions was not completely eliminated.

Lymphoepithelial Carcinoma of the Nasolacrimal Duct: Clinical, Radiologic, and Immunopathologic Features.

Undifferentiated lymphoepithelial carcinoma (exhibiting both begin lymphoid and malignant epithelial components) most commonly arises in the head and neck, especially in the nasopharynx. It may also be encountered in various ocular adnexal sites, including the nasolacrimal duct. A 63-year-old woman developed a swelling in the region of the right lacrimal sac accompanied by epiphora. CT scanning revealed an enlargement of the nasolacrimal duct from the lacrimal sac to the inferior nasal meatus. A biopsy during dacryocystorhinostomy for symptomatic epiphora revealed hypercellular sheets of small lymphocytes which were interpreted as evidence for a chronic dacryocystitis. Two years later the subtotally excised lesion had substantially grown in size. Repeat CT scans demonstrated an inferonasal anterior orbital mass with further enlargement of the nasolacrimal duct with a solid mass in its lumen, and bone erosion. The biopsy combined a rich background of lymphocytes within which were clusters of undifferentiated carcinoma cells that were cytokeratin and p63 positive. Critical review of the earlier biopsy led to the detection of the same cells, but in smaller numbers, that had been overlooked. An awareness of the possibility of lymphoepithelial carcinoma of the lacrimal sac/duct should improve diagnostic accuracy with the aid of immunohistochemistry. Radiation therapy is often successful in managing this highly sensitive malignant tumor.

IgG4-related skin disease may have distinct systemic manifestations: a systematic review.

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

Histopathology and Immunophenotyping of Congenital Lacrimal (Anlage) Fistulae.

PURPOSE: To report the histopathological and immuno histochemical features of congenital lacrimal fistulae. METHODS: Retrospective chart review of all patients who underwent a fistulectomy for congenital lacrimal fistulae, over a 3-year period from a single surgeon's (M.J.A.) database, were included in the study. A detailed lacrimal system evaluation was performed, and intraoperative findings were documented. The excised fistulae were studied using hematoxylin and eosin and periodic acid-Schiff staining. Immunophenotyping was performed using CD3, CD5, CD10, and CD20. RESULTS: Twelve excised fistulae of 12 patients were studied. The mean age at presentations was 5.3 years (range, 3-11 years). The deeper parts of the fistulae were lined with hypertrophied stratified squamous epithelium similar to canalicular tissue in 83.3% (10/12), reflecting its origin from the canalicular tissue, and 16.7% (2/12) originated from the lacrimal sac and were lined with columnar epithelium with areas of squamous metaplasia. The subepithelial areas showed presence of fibrosis and chronic inflammatory infiltrate. The infiltrates were lymphoplasmacytic and were positive for CD3, CD5, and CD20 and negative for CD10 immunostaining. CONCLUSION: Hypertrophied stratified squamous lining was the commonest finding. Immunophenotyping revealed features of chronic inflammatory infiltrate composed of a mixture of both T and B lymphocytes. Histopathological analysis of fistulae may be of adjunctive value in determining the origin of the anlage.

IgG4-related ophthalmic disease. Part I: background and pathology.

PURPOSE: To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). METHODS: A review of the literature and personal experience of the authors. RESULTS: IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several more common recognizable patterns of IgG4-ROD: 1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. CONCLUSIONS: Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

IgG4-Related Ophthalmic Disease. Part II: Clinical Aspects.

PURPOSE: To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). METHODS: A review of the literature and personal experience of the authors. RESULTS: IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several commoner recognizable patterns of IgG4-ROD: (1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. Patients with IgG4-ROD should be investigated and monitored for other organ involvement. Some patients with IgG4-related disease may develop lymphoma, usually marginal zone lymphoma of mucosa-associated lymphoid tissue type. Treatment of IgG4-ROD includes the use of corticosteroids and other immunosuppressants. Rituximab has been shown to be very effective. Longer term studies on the natural course and treatment of IgG4-ROD are needed. CONCLUSIONS: Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

Clinicopathologic features of orbital immunoglobulin G4-related disease (IgG4-RD): a case series and literature review.

BACKGROUND: Involvement of orbital structures by immunoglobulin G4-related disease (IgG4-RD) is not uncommon. We conducted this study to evaluate the clinicopathologic features of orbital IgG4-RD. MATERIAL/METHODS: This was a retrospective, clinicopathologic study. Clinical records, light microscopic features, results of immunostaining with IgG & IgG4 and laboratory findings were reviewed in 16 patients diagnosed with orbital IgG4-RD. RESULTS: Eleven patients had a bilateral disease, and the lacrimal gland was involved in 14. Dense sclerosis, plasma cell aggregates and dense lymphoplasmacytic infiltrate were seen in all patients. Serum IgG4 titre was elevated in 12 patients. Nine patients responded completely to glucocorticoid treatment. Five patients had a relapse on discontinuation of treatment. CONCLUSION: Orbital IgG4-RD is a distinct clinicopathologic entity requiring increased awareness and needs to be differentiated from other orbital lymphoproliferative lesions.

Diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a novel clinical entity characterized by infiltration of IgG4-immunopositive plasmacytes and elevated serum IgG4 concentration accompanied by enlargement of and masses in various organs, including the lacrimal gland, salivary gland, and pancreas. Recent studies have clarified that conditions previously diagnosed as Mikulicz disease as well as various types of lymphoplasmacytic infiltrative disorders of the ocular adnexa are consistent with a diagnosis of IgG4-related disease. Against this background, the diagnostic criteria for IgG4-related ophthalmic disease have recently been established, based on both the clinical and the histopathologic features of the ocular lesions. This article reviews these new criteria with reference to the comprehensive diagnostic criteria for IgG4-related disease for all systemic conditions reported in 2012.

Orbital presentation of a nasal midline destructive lesion in a young boy.

Midline Destructive Lesions (MDL) are well known to cause nasal problems. There is a long differential diagnosis of such lesions. However, in the pediatric population, the 2 main diseases to be aware of are Non-Hodgkin's T-cell lymphoma and granulomatosis with polyangiitis (previously known as Wegener's granulomatosis). The authors present the report of a 15-year-old boy who presented with epiphora, chemosis, and limitation of left abduction. CT scan of his orbits suggested a destructive lesion of the ethmoid sinuses. His laboratory investigations revealed a positive ANCA. The patient underwent endoscopic sinus surgery, and this was characteristic for granulomatosis with polyangiitis. He was treated with systemic steroids and then maintained on cyclophosphamide, which controlled his disease activity. This case highlights the need for ophthalmologists to have a high index of suspicion for MDL and concomitant orbital disease.

The association of lacrimal gland inflammation with alopecia areata.

PURPOSE: To describe the association of lacrimal gland inflammation with alopecia areata. METHODS: We reviewed the medical records of 4 patients diagnosed with lacrimal gland inflammation who had an antecedent or subsequent episode of alopecia. Data was collected on the presentation age, gender, medical history, disease onset, symptoms and signs, imaging, histopathology, systemic evaluation, management and outcome. Pathology and imaging results were correlated with clinical findings. RESULTS: Three patients were Asian and one Caucasian. Two developed alopecia after presentation for lacrimal inflammation. The remaining two had a history of alopecia totalis (2 years and 10 years). Three of the 4 patients presented or developed other systemic disorders, including seizures, thrombocytopenia, optic neuritis, ulcerative colitis, allergic rhinitis, lymphadenopathy, vasculitic rash and positive p-ANCA values. All received oral corticosteroids, with the addition of methotrexate therapy in one for relapsing inflammation. CONCLUSIONS: Lacrimal gland inflammation and alopecia areata are autoimmune processes that can be seen in association with each other.

New therapies in common ocular surface disorders.

Lacrimal dysfunction syndrome (LDS) and meibomian gland dysfunction (MGD) are common pathologies of the ocular surface both characterized by quantitative and/or qualitative tear film changings. They may result in symptoms of eye irritation, clinically apparent inflammation and ocular surface disease. Recent researches about the chronic inflammatory nature of dry eye, revealed the possibility to develop new treatments for LDS like new immunological drugs. MGD, alone or if it occurs contemporary to LDS, can be treated with a thermal pulsation system, a useful tool to alleviate symptoms.

Dacryops: a series of 5 cases and a proposed pathogenesis.

IMPORTANCE: Lacrimal gland ductal cysts (dacryops) are uncommon, occurring anywhere that lacrimal gland tissue is present. While dacryops has long been recognized, its pathogenesis has not been well established. OBSERVATIONS: Five cases of dacryops were identified at the Ottawa Hospital over a 3-year period (2009-2012). Histopathological examination showed immunoreactivity to IgA on the luminal surface of the epithelial ductal cyst and mild chronic inflammation in the underlying stroma or lacrimal gland. CONCLUSIONS AND RELEVANCE: Our results suggest that a multifactorial mechanism leads to dacryops including chronic inflammation, an immune response, and IgA hypersecretion with an osmotic effect, all contributing to the cyst formation. Further research on the pathogenesis is recommended.

Ocular adnexal IgG4-related disease: CT and MRI findings.

BACKGROUND/AIMS: To evaluate CT and MRI findings of histopathologically proven ocular adnexa IgG4-related disease. METHODS: Study subjects included 18 patients with histopathologically proven ocular adnexal IgG4-related disease. CT (n=16) and MR (n=3) images were retrospectively evaluated for location, laterality, shape, margin, attenuation on precontrast CT images, T1 and T2 signal intensity on precontrast MRI , internal architecture, ocular adnexal lesion enhancement patterns, sialadenitis of major salivary glands, cervical lymph node enlargement and perilesional bony change. RESULTS: Lacrimal gland enlargement was observed in 16 cases. Extraglandular lesions were observed in the medial canthus (n=2) and extraconal space (n=2). Bilateral supraorbital and infraorbital nerves, pterygopalatine fossa and cavernous sinus involvement were observed in one case. All ocular adnexal lesions showed well defined margins, isoattenuation on precontrast CT images, isointensity on T1- and hypointensity on T2-weighted images, homogenous internal arcithecture and enhancement patterns and bone remodelling without destruction. CONCLUSIONS: Ocular adnexal IgG4-related disease can involve the lacrimal gland, medial canthus, extraconal space, supraorbital and infraorbital nerves, pterygopalatine fossa and cavernous sinus. A diagnosis of ocular adnexal IgG4-related disease should be considered in lesions with the typical imaging features described herein.

Roles of CRTH2+ CD4+ T cells in immunoglobulin G4-related lacrimal gland enlargement.

BACKGROUND: Lacrimal gland enlargement (LGE) is one of the characteristics of Mikulicz's disease (MD). Recently, marked serum immunoglobulin (Ig)G4 elevation and infiltration of IgG4-positive plasma cells in the enlarged exocrine glands have been reported in MD patients. Moreover, we have reported that in patients with LGE and elevated serum IgG4 levels (IgG4-related LGE), T helper type 2 (Th2) cell-mediated immune responses are enhanced. Although prostaglandin D2 (PGD2) and its receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) have been shown to be involved in Th2 cell-related diseases such as bronchial asthma, their roles in IgG4-related diseases remain unknown. AIM: The aim of this study is to address the role of CD4+ T cells expressing CRTH2 (CRTH2+ CD4+ T cells) in IgG4-related LGE. METHODS: We examined the expression of CCR4, CXCR3 and CRTH2 on peripheral blood CD4+ T cells in patients with IgG4-related LGE, in patients with bronchial asthma and in healthy controls. RESULTS: The ratio of CCR4+ to CXCR3+ in CD45RO+ CD4+ T cells was increased in patients with IgG4-related LGE when compared to that in healthy controls, confirming that Th2 cells are predominant in patients with IgG4-related LGE. In addition, the frequency of CRTH2+ cells in CD4+ T cells was significantly increased in these patients, compared to healthy controls. Furthermore, although not statistically significant, the frequency of CRTH2+ cells in CD4+ T cells tended to correlate with the levels of serum IgE and the number of blood eosinophils in patients with IgG4-related LGE. CONCLUSION: CRTH2+ CD4+ T cells may be involved in the pathogenesis of IgG4-related LGE.

Radiological features of IgG4-related disease in the head, neck, and brain.

INTRODUCTION: Immunoglobulin (Ig) G4-related disease is a recently designated benign clinical entity histopathologically characterized by sclerosing inflammation and infiltration of numerous IgG4+ plasma cells that affects multiple organs. The purpose of this study is to characterize the imaging findings of patients with histopathologically proven IgG4-related disease in the head, neck, and brain. METHODS: A total of 17 patients (15 males, 2 females; mean age, 66.1 ± 7.4 years) with histopathologically proven IgG4-related disease in the head, neck, and brain were identified in two hospitals between January 2004 and December 2010. Imaging findings were retrospectively reviewed, with particular attention to the location and number of lesions, internal architecture, enhancement patterns, presence of vascular occlusion or compression, and changes in adjacent bones. RESULTS: The lesions, presented as either enlarged gland(s), or focal, localized nodules/masses, were distributed in the lacrimal gland (n = 7), the parotid gland (n = 14), the submandibular gland (n = 10), the pituitary gland (n = 2), skull base dura mater (n = 2), and the pterygopalatine fossa (n = 3). All lesions were well-defined and iso- to hypointense on T2-weighted magnetic resonance images and showed homogeneous enhancement. No lesion showed vascular occlusion or compression. Bones adjacent to the lesions showed remodeling (erosion or sclerosis) without signs of destruction (n = 6). Four patients had lesions involving multiple areas which extended along the trigeminal nerve, accompanied by expansion of neural foramina along their courses, with no signs of bone destruction. CONCLUSION: Sites of predilection for IgG4-related disease in the head, neck, and brain include the lacrimal, salivary, and pituitary glands. Recognition of the typical radiological features of IgG4-related disease, such as well-defined lesion borders, T2 hypointensity, homogeneous and gradual enhancement pattern, absence of vascular occlusion or compression, and presence of bone remodeling without destruction, may be of help in the diagnosis of this benign clinical entity.

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.