IgG4-related Sclerosing Disease Research Articles

Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up

Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.

AB0933 Retroperitoneal Fibrosis, Igg4-Related Diseases and Cardiovascular Fibrosclerosis

BackgroundThe diagnosis of cardiovascular fibrosclerosis (CF), become more feasible parallel to technologic improvements in imaging modalities. CF may manifest as idiopathic retroperitoneal fibrosis (RPF), inflammatory aortic aneurysm (IAA), inflammatory periarteritis,...

Identification of commensal flora-associated antigen as a pathogenetic factor of autoimmune pancreatitis

ObjectivesAutoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disease of the pancreas constituting, in part, a recently defined nosological entity of IgG4-related systemic sclerosing diseases. The pathogenetic factors of AIP have not been fully elucidated. We previously established a mouse model of AIP using chronic exposure to a commensal bacteria, Escherichia coli. MethodsTo determine the pathogenetically relevant antigen of E. coli, the outer membrane fractions of E. coli were subjected to two-dimensional gel electrophoresis followed by immunoblotting against sera from the AIP model. Immunoreactive spots were determined using MALDI TOF/MS and Mascot search. The recombinant protein of the identified antigen was examined for their ability to induce AIP-like disorder in C57BL/6 mice. Furthermore, the antibody titer against that antigen was determined in AIP patients. ResultsOne representative spot reacting with sera from E. coli-inoculated mice was identified as FliC from E. coli, based on the results of TOF/MS. The repeated inoculation of recombinant FliC in C57BL/6 mice induced AIP-like pancreatitis and higher titers of anti-lactoferrin and anti-carbonic anhydrase II. Sera from patients with AIP had the highest antibody titer, while those from patients with pancreatic diseases other than AIP had a higher antibody titer against E. coli and FliC, compared with pancreatic disease-free controls. ConclusionsFliC from E. coli may pathogenetically generate an AIP-like inflammation status. A reconsideration of the importance of commensal bacteria as an environmental factor(s) capable of inducing autoimmunity could provide insight to overcoming AIP.

Isolated IgG4-related Disease of Sphenoid Sinus Manifesting as Blindness

ABSTRACTIntroductionIgG4 related disease is a rare entity which can affect almost all parts of the body. The available literature of this entity related to paranasal sinuses is very limited.Presentation of caseWe present a case of isolated sphenoid sinus affliction by IgG4 related sclerosing disease manifesting as blindness, which recovered fully with pulsed steroid therapy.DiscussionWe present this case in view of developing insights toward diagnosis and management of IgG4 related sclerosing disease in paranasal sinuses, specifically the sphenoid sinus.ConclusionIgG4 disease involving paranasal sinuses (PNS) is rare entity and is managed with pulse methylprednisolone and immunomodulator drugs. Considering the limit of understanding of etiopathogenesis of this disease, surgeon needs to keep this differential diagnosis in mind. It may present atypically like isolated sinus involvement and optic neuritis.

Immunoglobulin G4–related sclerosing disease with orbital inflammation in a 12-year-old girl

Immunoglobulin G4-related sclerosing disease is a rare but potentially debilitating cause of orbital inflammation, with a predilection for older males. We report the case of a 12-year-old African girl with immunoglobulin G4-related sclerosing disease, including possible extraorbital involvement. Because of an escalating severity of illness leading to oculomotor nerve palsy and cavernous sinus thrombosis that was resistant to steroids, systemic immunosuppressive therapy with rituximab was used to achieve disease remission. The diagnosis was histologically confirmed with a tissue biopsy.

Riedel’s Fibrosing Thyroiditis Associated with Elevated Serum IgG4 Levels

Immunoglobulin G4-related sclerosing disease (IgG4-SD), also referred to as IgG4-related disease, is a newly described disease characterized by an infiltration of IgG4+ plasma cells in the early stages of the affection of an organ. Well documented in the pancreas and then detected in other organs, only few cases of thyroid affection have been reported. In addition, no case of IgG4-SD of the thyroid associated with high serum IgG4 levels has ever been described. We report here the first case.

Expression and significance of IgG4 in inflammatory disease of nasal cavity and paranasal sinuses

To study the prevalence of IgG4-positive plasma cells in inflammatory disease of nasal cavity and paranasal sinuses and its association with IgG4-related sclerosing disease (IgG4-SD). The expression of IgG4 and IgG in plasma cells of 103 cases diagnosed as inflammatory disease of nasal cavity and paranasal sinuses with dense lymphoplasmacytic infiltrate was studied by immunohistochemistry (EnVision) and quantitatively analyzed by medical image analysis system. Immunohistochemical study showed marked infiltration by IgG4-positive plasma cells (>50 per high-power field) in 28 cases, moderate infiltration (30 to 50 per high-power field) in 23 cases, mild (10 to 29 per high-power field) in 30 cases and negative (<10 per high-power field) in 22 cases (P < 0.05). Twenty-two cases studied fulfilled the diagnostic criteria of IgG4-SD (>50 IgG4-positive plasma cells per high-power field and IgG4-to-IgG ratio > 40%), including 3 cases of chronic sinusitis (3/20), 3 cases of nasal polyps (3/18), 3 cases of inflammatory pseudotumor (3/17), 4 cases of fungal sinusitis (4/20), 1 case of rhinoscleroma (1/12), 7 cases of Wegener's granulomatosis (7/11) and 1 case of Rosai-Dorfman disease (1/2). Inflammatory disease of nasal cavity and paranasal sinuses fulfilling the diagnostic criteria IgG4-SD is not uncommon. Definitive diagnosis of IgG4-SD requires correlation with other clinical and laboratory findings. Some cases of unexplained inflammatory disease of nasal cavity and paranasal sinus may represent a member of the IgG4-SD spectrum. IgG4 carries diagnostic value in differential diagnosis of inflammatory disease occurring in nasal cavity and paranasal sinuses.

Pulmonary Nodular Lymphoid Hyperplasia (Pulmonary Pseudolymphoma)

On the basis of an initial case, we hypothesized that IgG4-positive plasma cells may be increased in pulmonary nodular lymphoid hyperplasia (PNLH) compared with other lymphoid proliferations of the lung. Six cases of PNLH, 9 cases of low-grade B-cell lymphoma of the bronchus-associated lymphoid tissue (BALT), 8 cases of intraparenchymal lymph nodes, 8 cases of either primary or secondary follicular bronchiolitis, and 4 cases of lymphocytic interstitial pneumonitis were stained by immunohistochemical analysis for IgG4 and IgG. The mean number of IgG4-positive and IgG-positive plasma cells and the IgG4/IgG ratio were determined from a manual count of images from 3 separate high-power fields (hpf) of areas showing the highest numbers of stained cells, respectively. The mean number of IgG4-positive plasma cells and the IgG4/IgG ratio were significantly increased in PNLH (IgG4=78/hpf, IgG4/IgG=0.35) compared to low-grade lymphoma of BALT (IgG4=4/hpf, P=0.02; IgG4/IgG=0.03, P=0.005), intraparenchymal lymph nodes (IgG4=7/hpf, P=0.03; IgG4/IgG=0.06, P=0.007), follicular bronchiolitis (IgG4=0/hpf, P=0.02; IgG4/IgG=0, P=0.004), and lymphocytic interstitial pneumonitis (IgG4=2/hpf, P=0.02; IgG4/IgG=0.06, P=0.007). These findings support our current understanding of PNLH as a distinct form of reactive lymphoid proliferation, potentially aid in its distinction from low-grade B-cell lymphoma of BALT, and raise the possibility that PNLH may belong within the family of IgG4-related sclerosing diseases.

Granuloma Faciale

The pathogenesis of granuloma faciale (GF), framed in the group of cutaneous vasculopathic dermatitis, is poorly understood. The present study investigated whether GF might be part of the spectrum of IgG4-related sclerosing diseases (IgG4-RD). Erythema elevatum diutinum (EED), believed to belong to the same group of disorders as GF, was also studied for comparison. Thirty-one biopsies of GF obtained from 25 patients (18 men, 7 women) and 5 cases of EED (4 women and 1 man) were analyzed morphologically and for the expression of IgG and IgG4 by immunohistochemistry. The distribution of Th1, T regulatory and Th2 T-cell subsets, respectively, identified by anti-T-bet, anti-FoxP3, and anti-GATA-3 antibodies, was also evaluated. The dermal inflammatory infiltrate in GF contained eosinophils and plasma cells in variable proportions. Obliterative venulitis was found in 16 cases, and storiform fibrosis, a typical feature of IgG4-RD, was observed in 8 cases and was prominent in 3 of them. On immunohistochemical analysis 7 of 31 biopsies (22.6%) from 6 GF patients fulfilled the criteria for IgG4-RD (IgG4/IgG ratio >40%, and absolute number of IgG4 per high-power field >50). Interestingly, the 6 patients were male, and 4 showed recurrent and/or multiple lesions. In an additional 5 cases, only the IgG4/IgG ratio was abnormal. None of the 5 EED cases fulfilled the criteria for IgG4-RD. The T-cell subsets in GF were quite variable in number, GATA-3 lymphocytes were generally more abundant, but no relationship with the number of IgG4 plasma cells was found. The study indicates that a significant number of GF cases are associated with an abnormal content of IgG4 plasma cells; this association was particularly obvious in male patients and in cases presenting with multiple or recurrent lesions. As morphologic changes typically found in IgG4-RD, such as obliterative vascular inflammation and storiform sclerosis, are found in GF, we suggest that GF might represent a localized form of IgG4-RD.

An Immunoglobulin G4-Related Sclerosing Disease of the Small Bowel: CT and Small Bowel Series Findings

Immunoglobulin G4 (IgG4)-related sclerosing disease is rare and is known to involve various organs. We present a case of histologically proven IgG4-related sclerosing disease of the small bowel with imaging findings on computed tomography (CT) and small bowel series. CT showed irregular wall thickening, loss of mural stratification and aneurysmal dilatation of the distal ileum. Small bowel series showed aneurysmal dilatations, interloop adhesion with traction and abrupt angulation.

Isolated IgG4-related Disease of Sphenoid Sinus Manifesting as Blindness

ABSTRACTIntroductionIgG4 related disease is a rare entity which can affect almost all parts of the body. The available literature of this entity related to paranasal sinuses is very limited.Presentation of caseWe present a case of isolated sphenoid sinus affliction by IgG4 related sclerosing disease manifesting as blindness, which recovered fully with pulsed steroid therapy.DiscussionWe present this case in view of developing insights toward diagnosis and management of IgG4 related sclerosing disease in paranasal sinuses, specifically the sphenoid sinus.ConclusionIgG4 disease involving paranasal sinuses (PNS) is rare entity and is managed with pulse methylprednisolone and immunomodulator drugs. Considering the limit of understanding of etiopathogenesis of this disease, surgeon needs to keep this differential diagnosis in mind. It may present atypically like isolated sinus involvement and optic neuritis.How to cite this articleChandrasekharan R, Mathew V, Ashish G, Tyagi AK, Job AK. Isolated IgG4-related Disease of Sphenoid Sinus Manifesting as Blindness. Int J Otorhinolaryngol Clin 2013;5(3):178-181.

Immunoglobulin G4–related sclerosing disease of the paranasal sinus

Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic disease characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. We present a case of a 69-year-old man with maxillary sinus IgG4 sclerosing disease, with orbital invasion treated with rituximab and dexamethasone pulse therapy. Surgery was used as well to debulk the disease and to obtain tissue for diagnosis. A PubMed search using the key phrase "IgG4-related Sclerosing Disease" was performed. There were 304 different articles regarding the disease for a multitude of different organ sites. Of the 304 articles, there were 3 articles that reported this disease in the paranasal sinuses. IgG4-related sclerosing disease is a rare entity in the head and neck. There are documented reports of steroid therapy for this disease, but the patient presented here demonstrated clinical progression of disease with steroids alone. The use of combination therapy of surgery, dexamethasone, and rituximab provided clinical improvement and stable disease determined by radiographic means.

Usefulness of Steroid Administration for Diagnosis of IgG4-Related Sclerosing Cholangitis

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is one of the IgG4-related systemic sclerosing diseases and responds well to steroid therapy. A 58-year-old male was admitted with hilar bile duct stenosis revealed by computed tomography. We performed percutaneous transhepatic right portal vein embolization (PTPE) and scheduled a right hepatectomy because a hilar cholangiocarcinoma was first suspected. However, there was no cytologic evidence of malignancy and serum IgG4 was elevated. Steroid therapy was initiated after PTPE. There was no evidence of bile duct stenosis after 4 weeks. Improving diagnostic technique, IgG4-SC was diagnosed and treated with steroid therapy. In some cases, we couldn't deny the malignancy and performed unnecessary resection. We recommend that steroid administration while waiting for the liver volume to increase after PTPE is useful. The therapy aids in the diagnosis of bile duct stenosis, which has value for a hilar bile duct limit type of IgG4-SC, as in the case reported here.

Riedel's Thyroiditis with Increased IgG4 Plasma Cells: Evidence for an Underlying IgG4-Related Sclerosing Disease?

Riedel's thyroiditis (RT) is a very rare chronic fibrosing disorder of unknown etiology that is often associated with multifocal fibrosclerosis (MFS). Immunoglobulin (Ig) G4-related sclerosing disease (IgG4-RSD), a new clinico-pathological entity also associated with MFS, is characterized by IgG4+ plasma cell infiltration and fibrosis in one or more organs. Although the association of RT and IgG4-RSD has been suggested, it has seldom been studied or reported. We report a classical case of RT with serological (IgG4 levels) and immunohistochemical (IgG and IgG4) assessment, in search of an underlying IgG4-RSD. The patient was a 57-year-old woman who underwent a subtotal thyroidectomy for a long-standing goiter with a rapidly enlarging isthmic nodule. Histopathological examination of the surgical specimen revealed all of the morphological features of RT and IgG4-RSD, including partial fibrosis of the thyroid gland with destruction of the thyroid follicular architecture; obliterative phlebitis; and a mixed infiltrate composed of lymphocytes, eosinophils, and plasma cells. The fibro-inflammatory process extended beyond the thyroid capsule into the surrounding tissues. Immunohistochemical examination revealed approximately 70 IgG4+ plasma cells per high power field (HPF) with an IgG4/IgG ratio of 35%. Although serum levels of IgG4 were normal (20 mg/dL), total IgG levels were slightly elevated (1370 mg/dL). There was no evidence of involvement of other organs at the time of RT diagnosis. The morphological similarities between RT and IgG4-RSD suggest that these entities are closely related. Therefore, RT with increased IgG4+ plasma cells, with or without elevated IgG4 serum levels, may represent the first clinical manifestation of an underlying IgG4-RSD. However, due to the rarity of both conditions and the limited specificity and sensitivity of both IgG4 serum levels and IgG/IgG4 immunohistochemistry in the diagnosis of IgG4-RSD, further studies are needed to verify this hypothesis.

Riedel’s thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4 related sclerosing disease?

Riedel’s thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4 related sclerosing disease?

IgG4 expression in chronic sclerosing submaxillaritis

To analyze the clinicopathologic features of chronic sclerosing submaxillaritis (CSS). The clinical and pathological characteristics of 9 CSS were analyzed. In the 9 patients, there were 6 males and 3 females. The age of patients ranged from 51 - 77 years old. All of the tumors were located in the submandibular gland, presenting with painless and firm mass. Histologically, a well-defined mass lesion with extensive lymphocytes and plasma cells infiltration, preservation of lobular architecture, with acinar atrophy. The reactive hyperplasia of lymphoid follicles may be found in CSS. The phlebitis and obliterating phlebitis also formed. Immunohistochemistry showed evidence of diffuse infiltration of plasma cells. The mean number of IgG4-positive plasma cell per high-power field (HPF) was 186, mean value of the IgG4:IgG ratio was 0.71. Three of these 9 cases had manifestations of IgG4-associated systemic disease. CSS is considered as a part of IgG4-related sclerosing diseases, recognition of which is very essential for a successful treatment. When diagnosis is made, it is necessary to ascertain whether lesion occurs within salivary gland only or in combination with outside IgG4-related sclerosing disease. The establishment of follow-up is also necessary. Some patients show good response to steroid therapy.

54-Year-Old Man With Severe Prostatism, Palatal Mass, and History of Pancreatitis

54-year-old man with a history of benign prostatic hypertrophy, hypothyroidism, and well-controlled insulin-dependent diabetes mellitus secondary to idiopathic pancreatitis presented to our internal medicine consultation clinic. He complained of a lump in the hard palate, dry mouth present for 2 years, and bilateral submandibular gland swelling for which he had been evaluated by an otolaryngologist. A previous biopsy of the hard palate mass had demonstrated florid reactive lymphoid hyperplasia with fibrosis, polyclonal plasmacytosis and increased IgG4-positive plasma cells. He also complained of obstructive urinary symptoms and was found to have a very large and nodular prostate on digital rectal examination. The prostate-specific antigen level was 0.13 ng/mL (reference range, 0-3.2 ng/ mL), and results of urinalysis were unremarkable. A computed tomographic scan of the chest from an outside facility showed a mass in the right middle lobe in addition to bilateral renal lesions. Suspicion for a common link among his current symptoms and previous diagnoses was raised. 1. Which of the following is the most likely unifying diagnosis? a. Multiple myeloma b. Amyloidosis c. Metastatic prostate cancer d. IgG4-related sclerosing disease (IgG4RSD)

Pediatric Chronic Sclerosing Sialadenitis: Küttner Tumor

Chronic sclerosing sialadenitis is an uncommon cause of salivary gland enlargement mainly occurring in the fifth and seventh decade of life. In the Western population, chronic sclerosing sialadenitis has been characterized as an IgG4-related disease. Although rare, this lesion occurs in children. To increase awareness about this entity in the pediatric age group, we report the case of an 11-year-old boy with a hard, 4.0-cm circumscribed mass in the right submandibular gland. Histologically there was marked distortion of the gland architecture by a dense lymphocytic infiltrate and extensive fibrosis with septa that crossed and distorted the gland, leaving atrophic acini and dilated, irregular ducts. The lymphoid infiltrate formed multiple follicles with active germinal centers, numerous plasma cells, and areas with diffuse arrangement. Immunophenotyping showed abundant CD20- and CD3-positive lymphocytes; cytokeratin AE1/AE3 highlighted the distorted architectural pattern; IgG staining showed large numbers of positive cells infiltrating the interstitium and surrounding the atrophic acini and ducts. IgG4 staining revealed a large proportion of positive infiltrating elements. Küttner tumor belongs to the group of IgG4-related sclerosing diseases. The differential diagnosis includes pleomorphic adenoma and other salivary gland neoplasms. Its recognition in children is important clinically because this entity is amenable to steroid treatment, and additional work up and follow up is warranted to stave off other IgG4-related diseases/complications.

Clinicopathologic features of calcifying fibrous tumor with reappraisal of its histogenesis

To study the clinicopathologic features and histogenesis of calcifying fibrous tumor (CFT). The clinical manifestations, histopathologic characteristics and immunophenotype were analyzed in 11 cases of CFT. The male-to-female ratio was 5:6, with a mean age of 38 years and age range of 25 to 52 years. The sites of involvement included abdominopelvic cavity (n=6), soft tissue (n=4) and scrotum (n=1). Most patients presented with a gradually enlarging and painless mass. Nearly half of the cases were associated with other diseases or history of inflammation, trauma or surgical intervention. One third of the tumors represented incidental findings and showed no recurrence after resection. Imaging revealed a solitary solid soft tissue mass or multiple nodules with clear borders and associated high-density calcifications. Macroscopically, the tumors were well-circumscribed but non-encapsulated. They ranged from 0.5 to 20.0 cm in diameter and were tan-greyish, round to oval, lobulated or irregular and solid with rubbery consistency. The cut surface was whitish to tan-yellowish, gritty and showed scattered spotty yellowish discoloration corresponding to the foci of dystrophic calcifications. Histologically, CFT was composed of hyalinized fibrous tissue and thickened vessel walls with interspersed bland spindly fibroblastic cells, scattered psammomatous calcifications, dystrophic calcification and lymphoplasmacytic infiltration. In addition, focal cloak-like polymorph infiltration at the tumor periphery and entrapment of adipocytes and nerves were demonstrated in some cases. Foci resembling solitary fibrous tumor, fibromatosis, keloid or inflammatory myofibroblastic tumor were observed. Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin and focally positive for CD34, factor VIII-related antigen and beta-catenin. The admixed plasma cells were notably IgG positive, with more than 50% being IgG4 positive. CFT has characteristic histopathologic manifestations and shows morphologic and immunohistochemical overlaps with known IgG4-related sclerosing diseases. It is possible that CFT may represent another example of IgG4-related diseases. It often runs a benign clinical course, with rare recurrence after surgical resection. Previous inflammation and trauma may be the precipitating factors of CFT.

Increased Numbers of IgG4-Positive Plasma Cells May Rarely Be Seen in Lymph Nodes of Patients Without IgG4-Related Sclerosing Disease

IgG4-related sclerosing disease (IRSD) is a steroid-responsive fibroinflammatory disorder characterized by increased IgG4+ cells. Nodal involvement usually lacks the dense sclerosis seen in extranodal sites, with histologic patterns overlapping with other reactive processes. Twenty-six lymph nodes showing IRSD-related histologic patterns were evaluated for IgG and IgG4 positive cells by immunohistochemistry and correlated with the clinical features. Cases included 7 Castleman disease-like cases (type I pattern), 10 follicular hyperplasia (type II), and 9 plasmacytosis (type III). The mean numbers of IgG4+ cells per high-power field (HPF) were 4.8 (I), 8.4 (II), and 26.6(III), and the mean IgG4/IgG ratios were 0.05 (I), 0.04 (II), and 0.08 (III). Using >50 IgG4+cells/HPF and IgG4/IgG ratio of >0.4 for absolute and relative increases, only 1 case fulfilled both criteria for increased IgG4+ cells, a patient with Hashimoto's thyroiditis without clinical evidence of IRSD. The results suggest that increased IgG4+ cells may rarely be seen in non-IRSD lymph nodes.