The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a clinical entity characterized by elevated serum IgG4 concentrations and infiltration of IgG4-immunopositive plasmacytes in various organs, including ophthalmic lesions. Diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD) were established in 2014 and describe the most affected ocular adnexal tissues such as lacrimal glands, trigeminal nerves and extraocular muscles, but do not mention optic neuropathy, the most severe indication of ophthalmic lesions. We reviewed published case reports of optic neuropathy in IgG4-related disease (n = 44), and in many cases, decreased visual acuities recovered well following treatment such as systemic corticosteroids, rituximab, and orbital surgery. However, some patients did not recover, especially when pretreatment visual acuities were as low as light perception or less. Herein, we propose a 2023 revised diagnostic criteria for IgG4-ROD, which include a reminder not to overlook optic neuropathy. The 2014 diagnostic criteria specify mucosa-associated lymphoid tissue (MALT) lymphoma as an important differential diagnosis for the relationship between IgG4-ROD and orbital lymphoma. The 2023 revision directs physicians' attention toward lymphomas other than MALT lymphoma, considering that the 2014 criteria might have placed too much emphasis on MALT lymphoma.

Lacrimal Gland and Orbital Lesions in LatY136F Knock-in Mice, a Model for Human IgG4-Related Ophthalmic Disease.

PURPOSE: LatY136F knock-in mice were recently proposed as an animal model for immunoglobulin G4 (IgG4)-related disease. In this study, we investigated whether LatY136F knock-in mice exhibit ophthalmic lesions, specifically in the lacrimal and Harderian glands. METHODS: Lacrimal glands, Harderian glands, and adherent lymphoid follicle lesions were dissected from LatY136F knock-in mice and wild type (WT) C57BL/6 mice between 6 and 24 weeks of age. Tissues were stained with hematoxylin-eosin, immunoglobulin G (IgG), and anti-IgG1, a homologue of human IgG4, for histopathological analysis. RESULTS: In LatY136F knock-in mice, IgG1-positive cells infiltrated the space between the lacrimal gland acinar cells at 6, 9, 12, and 20 weeks or order, and the number of IgG1-positive cells did not differ significantly between these age groups. Infiltration of IgG1-positive inflammatory cell was also observed in the Harderian glands of LatY136F knock-in mice at all ages. The ratio of IgG1/IgG-positive cells averaged 80 and 67% in the lacrimal and Harderian glands, respectively. Dense IgG1-positive lesions were also seen in tissues adjacent to the lacrimal and Harderian glands in some LatY136F knock-in mice. In contrast, there were almost no IgG1-positive cell infiltrates in the lacrimal and Harderian glands of WT mice. CONCLUSION: IgG1-positive cells infiltrate the lacrimal and Harderian glands of LatY136F knock-in mice, indicating that LatY136F knock-in mice could be a representative animal model for IgG4-related ophthalmic disease.

Cases with IgG4-related ophthalmic disease with mass lesions surrounding the optic nerve.

PURPOSE: IgG4-related ophthalmic disease (IgG4-ROD) is a lymphoproliferative disorder with representative symptoms including lacrimal gland enlargement (Mikulicz disease), masses around the trigeminal nerves, and extraocular muscle swelling. Herein, we describe cases of IgG4-ROD with lesions surrounding the optic nerve. METHODS: Of the 56 consecutive patients (35 men and 21 women) with a "definite case" of IgG4-ROD diagnosed from November 2004 through December 2019 at Kanazawa University hospital, seven patients presented with mass lesions around the optic nerve based on magnetic resonance imaging, and four patients showed symptoms of optic neuropathy. The clinical courses of these seven cases were reviewed. RESULTS: Among the 56 cases of IgG4-ROD, seven cases had lesions surrounding the optic nerve and all of these patients were male. The male dominance in the patient group with lesions surrounding the optic nerve was statistically significant based on a Chi-squared test (p < 0.001). Lacrimal gland swelling was also present in all seven cases, extraocular muscle enlargement in six cases, and trigeminal (infraorbital and supraorbital) nerve enlargement in six cases. Four patients showed deteriorated visual acuity compatible with optic neuropathy. These seven patients were treated by systemic steroid administration. Overall, in cases with optic neuropathy, visual function responded well to steroid therapy; however, recovery was limited in the worst case. CONCLUSIONS AND IMPORTANCE: Attention should be paid for mass lesions surrounding the optic nerve in patients with IgG4-related disease, especially in cases with high serum IgG4 levels.

Ultrasonography of IgG4-related dacryoadenitis and sialadenitis: Imaging features and clinical usefulness.

OBJECTIVES: To clarify the ultrasonographic features of immunoglobulin G4 (IgG4)-related dacryoadenitis and sialadenitis (IgG4-DS) and their usefulness in clinical diagnostic sessions. METHODS: By re-evaluating 96 consecutive patients with IgG4-related disease, we identified 54 patients (male:female = 37:17; median age, 69.5 years) who underwent lacrimal or submandibular gland (LG or SG, respectively) ultrasonography and computed tomography (CT). Their clinical and ultrasonographic features were retrospectively analysed. Radio-pathological correlations were also examined in LG (23 cases) and SG lesions (20 cases). Additionally, the diagnostic accuracy of CT for LG/SG lesions was evaluated. RESULTS: Abnormal ultrasonographic findings were detected in 33 (LGs) and 38 (SGs) patients, and most of them were observed bilaterally. All lesions were well demarcated and demonstrated diffuse low-echoic areas (rocky pattern) or multiple low-echoic nodules surrounded by high-echoic linear shadows (cobblestone pattern) corresponding to intra-lobular inflammation and inter-lobular fibrosis. Moreover, 42% (LGs; 14/33) and 42% (SGs; 16/38) patients had glandular lesions without clinical symptoms associated with the affected glands. The diagnostic accuracy of CT was ∼80% for LG and 55% for SG. CONCLUSIONS: Ultrasonographic findings in IgG4-DS included diffuse or nodular low-echoic areas with linear high-echoic structures corresponding to inflamed lobules and inter-lobular fibrosis. These findings can help detect IgG4-DS.

Clinical features and symptoms of IgG4-related ophthalmic disease: a multicenter study.

PURPOSE: The aim of this study was to elucidate the clinical features and symptoms of IgG4-related ophthalmic disease (IgG4-ROD). STUDY DESIGN: Retrospective, multicenter study. METHODS: The medical charts of 378 patients with IgG4-ROD diagnosed at 9 hospitals in Japan were reviewed. The demographic profiles, clinical findings, and ocular symptoms of the patients were analyzed. RESULTS: On the basis of the diagnostic criteria for IgG4-ROD, the diagnosis was definite in 261 patients (69%), probable in 45 patients (12%), and possible in 72 patients (19%). The patients' mean age at the time of diagnosis was 60.6 ± 13.9 years; 195 (52%) were male. The mean IgG4 serum level at the time of the initial diagnosis was 578.9 mg/dL. Imaging studies showed pathologic lesions as follows: lesions in the lacrimal glands (86%), extraocular muscles (21%), trigeminal nerve (20%), and eyelids (12%); isolated orbital mass (11%); diffuse orbital lesion (8%); lesion in the perioptic nerve (8%); and lesion in the sclera (1%). The ophthalmic symptoms included dry eye (22%), diplopia (20%), decreased vision (8%), and visual field defects (5%). IgG4-ROD with extraocular lesions was observed in 182 patients (48%). CONCLUSION: Although the lacrimal glands are well known to be the major pathologic site of IgG4-ROD, various ocular tissues can be affected and cause ophthalmic symptoms including visual loss.

Intraorbital Solitary Fibrous Tumor Requiring Preoperative Embolization of Feeding Artery.

Solitary fibrous tumors (SFTs) are derived from mesenchymal cells and commonly develop in thoracoabdominal organs; however, their occurrence in orbit is rare. The first-choice treatment is to surgically remove as much of the SFT as possible; however, if total removal is not achieved, the recurrence rate is high, resulting in poor prognosis. A 42-year-old man presented with painless right-sided proptosis and diplopia 4 years ago. Orbital computed tomography revealed a right extraconal mass medial to the optic nerve, measuring 25 mm. Magnetic resonance imaging demonstrated iso-signal intensity on T1- and T2-weighted imaging, including flow-void signals. During biopsy of the intraorbital mass, which was performed by ophthalmologists 3 years earlier, difficulty with hemostasis occurred due to massive hemorrhage from the mass. The mass grew to reach a maximal diameter of 33 mm, resulting in referral to the authors' department. Diagnostic cerebral angiography revealed a hypervascular orbital tumor with multiple feeding arteries. To control intraoperative bleeding, the patient underwent preoperative endovascular embolization. Subsequently, the tumor was completely removed using a combination of microsurgical craniotomy and endoscopic endonasal approach, without the occurrence of massive intraoperative hemorrhage from the tumor. Postoperatively, his clinical course was uneventful except for the remaining preoperative diplopia. The tumor was diagnosed histologically as SFT and has not recurred for 8 months since surgery. Preoperative intravascular embolization of branches of the ophthalmic artery can be performed safely, resulting in excellent control of intraoperative bleeding and facilitating complete removal of SFT without additional complications.

Imaging and pathological features of gastric lesion of immunoglobulin G4-related disease: A case report and review of the recent literature.

We describe a 67-year-old man with immunoglobulin G4-related disease (IgG4-RD) presenting with optic neuropathy, dacryoadenitis, periaortitis, retroperitoneal fibrosis, and a gastric mass-like lesion. A mass-like lesion measuring 52 × 40 mm in the antrum of the stomach was found incidentally through whole-body screening for other organ involvement of IgG4-RD using contrast-enhanced computed tomography (CT). Histology of the stomach revealed that the lesion was also IgG4-related and was located in the submucosal layer extending to the subserosal region. This case suggests that the stomach can also be a site of involvement of IgG4-RD.

Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease.

OBJECTIVES: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD. METHODS: We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD. RESULTS: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4 + PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138 + cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. CONCLUSIONS: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.

Tenosynovial giant cell tumors in unusual locations detected by positron emission tomography imaging confused with malignant tumors: report of two cases.

BACKGROUND: A tenosynovial giant cell tumor (T-GCT) is a benign synovial tumor arising from the synovium, bursae, or tendon sheath. It can be intra- or extra-articular and localized or diffuse. Diffuse T-GCT is considered as a locally aggressive. Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose with computed tomography (FDG PET/CT) is widely used to differentiate malignant from benign tumors and to detect distant metastasis. However, FDG PET/CT is limited by false-positive findings. In this study, we present two cases of T-GCT that developed in unusual locations and were confused with malignant tumors. The final diagnoses were histologically confirmed as T-GCTs. CASE PRESENTATION: Case 1. A 45-year-old Japanese female presented with a left choroidal melanoma and an abnormal lesion adjacent to the first cervical (C1) lamina confirmed by a PET scan (maximum standardized uptake value [SUVmax] =9.9 g/ml). MRI of the neck also detected a soft tissue mass (14.6 × 7.7 × 7 mm) adjacent to the C1 lamina. The choroidal melanoma was treated by heavy carbon ion radiotherapy. Although the size of the C1 soft tissue tumor remained unchanged, a CT-guided biopsy confirmed the diagnosis of the neck mass as a T-GCT. Case 2. A 15-year-old Japanese male with multiple type 1 neurofibromatosis presented with a soft tissue mass (26.1 × 24.7 × 11.5 mm) of the extra-articular hip joint that was coincidentally detected by FDG PET/CT during examination of a mediastinal soft tissue mass. SUVmax of the mediastinal lesion was 2.6 g/ml and of the hip lesion was 12.8 g/ml. Thus, differentiation from a malignant tumor, such as a malignant peripheral nerve sheath tumor, was necessary. An open biopsy was performed, and the frozen section was diagnosed as T-GCT. The tumor was excised, and the final histological diagnosis confirmed T-GCT. CONCLUSION: T-GCT can show high FDG uptake, which might be confused with malignancy. Although MRI findings and location might help in the diagnosis of a T-GCT, careful assessment is mandatory, especially in unusual locations.

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.

Location and frequency of lesions in patients with IgG4-related ophthalmic diseases.

BACKGROUND: It is well-known that the lacrimal gland (LG) may be affected in IgG4-related ophthalmic disease (IgG4ROD). Recently, IgG4-related ophthalmic lesions other than those of the lacrimal gland have been reported. However, no study to date has revealed the details of these lesions. This study was conducted to evaluate the location and frequency of lesions found in conjunction with IgG4ROD using radiological imaging. METHODS: Radiological images and clinical records of 65 patients collected from seven institutions in Japan were reviewed retrospectively. All patients had been pathologically diagnosed with IgG4ROD. Patients of mucosa-associated lymphoid tissue lymphoma associated with IgG4-related lesions were excluded. Orbital magnetic resonance imaging or computed tomography findings were evaluated. RESULTS: Of the 65 patients, 31 (47.7 %) had lesions involving the LG alone, whereas 34 (52.3 %) had lesions involving the areas other than LG, including eight patients who had lesions without any LG involvement. IgG4-related ophthalmic lesions included LG enlargement in 57 patients (87.7 %), trigeminal nerve branch enlargement in 25 (38.5 %), extraocular muscle enlargement in 16 (24.6 %), diffuse orbital fat lesions in 15 (23.1 %), orbital mass lesions in 11 (16.9 %), eyelid lesions in eight (12.3 %), and nasolacrimal duct lesion in one (1.5 %). Six patients (9.2 %) presented with visual disturbance due to optic nerve disturbance, eight (12.3 %) with a restriction of ocular movement, and 19 (29.2 %) with exophthalmos. CONCLUSIONS: Thirty-four (52.3 %) of the 65 IgG4ROD patients had lesions in areas other than LG. Lesions were found in the trigeminal nerve branch including pterygopalatine fossa, extraocular muscles, orbital fat, eyelid, and nasolacrimal duct.

Clinical Aspects of IgG4-Related Orbital Inflammation in a Case Series of Ocular Adnexal Lymphoproliferative Disorders.

The most frequent ocular adnexal tumors and simulating lesions are lymphoproliferative disorders (LPDs), including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration. IgG4-related orbital inflammation (IgG4-ROI) often involves lacrimal glands and other orbital tissues and is an important differential diagnosis. The present study evaluated clinical aspects of IgG4-ROI in a case series of orbital LPD. Sixty-two consecutive cases of orbital LPD, pathologically diagnosed from November, 2004, through March, 2011, were investigated. Histological types were 22 cases with MALT lymphoma, 11 cases with diffuse large B-cell lymphoma (DLBCL), 3 cases with other malignant lymphomas, 16 cases with IgG4-ROI, and 10 cases with non-IgG4-ROI. Ages of the IgG4-ROI group (56 ± 10 yrs) were significantly lower than the MALT lymphoma (71 ± 12 yrs) and DLBCL (75 ± 14 yrs) groups. Orbital lesions other than lacrimal glands were present in six cases including extraocular muscle swelling, mass lesions surrounding the optic nerve, and supraorbital and infraorbital nerves enlargements. Although none of the malignant lymphomas were related to IgG4, previous evidence suggested that malignant lymphomas can arise from IgG4-ROI. Based on this study (26%) and another report (33%), it is likely that nearly a quarter of orbital LPD are IgG4-ROI.

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Orbital cystic schwannoma originating from the frontal nerve.

Schwannomas of the orbit are very rare benign neoplasms. Intraorbital cystic schwannomas originating from the frontal nerve are even rarer, with only 1 case reported to date. This is most likely due to the fact that, in most cases, the origin of the orbital schwannoma cannot be identified intraoperatively. The nerve origin is usually speculated from histological examination of the specimen and the postoperative neurological deficits of the patient. Here, we present the case of a 65-year-old woman with a one-month history of exophthalmos, whose orbital cystic lesion was completely removed by microsurgical transcranial operation. Intraoperatively, the continuity between the tumor and frontal nerve was seen macroscopically, leading us to confirm the frontal nerve as an origin of the tumor, which was consistent with the postoperative neurological findings. The diagnosis of the tumor was established as schwannoma from the histological examination. As a differential diagnosis of the orbital cystic lesions, the possibility of schwannomas should be kept in mind.

Swelling-activated potassium channel in porcine pigmented ciliary epithelial cells.

PURPOSE: Ion channels in the ciliary epithelium play critical roles in the formation of aqueous humor in the eye. The present study identified a novel, swelling-activated K(+) current in freshly dissociated porcine pigmented ciliary epithelial cells. METHODS: Ciliary epithelial cells were freshly dissociated from porcine eyes. Whole-cell currents were recorded by the patch-clamp technique in pigmented and nonpigmented ciliary epithelial cell (PCE-NPCE) pairs or single PCE cells. RESULTS: The 0-current potential was -49 ± 13 mV in PCE-NPCE cell pairs (n = 97) and -52 ± 12 mV in single PCE cells (n = 30). Whole-cell currents in these cells were dominated by an outwardly rectifying K(+) current activated by potentials more positive than -90 mV, which never inactivated during prolonged depolarization. The K(+) current was significantly augmented by hypotonic cell perfusion. External Ba(2+) was a blocker of this K(+) conductance (IC(50) of 0.38 mM), but the conductance was insensitive to external TEA(+). Linopirdine, a specific inhibitor of KCNQ channels, effectively blocked the K(+) current in these PCE cells. CONCLUSIONS: Porcine PCE cells express a swelling-activated K(+) channel, which may be a member of the KCNQ/Kv7 channel family. This K(+) channel is active near resting potentials and could contribute to the regulation of cell volume and water transport via the ciliary epithelia.