A case of IgG4-related sclerosing mesenteritis

IgG4-related disease has been recognized as a systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration and sclerosis. This disease has been identified in various sites, including the pancreas, retroperitoneum, lung, head, and neck. Herein we report a case of IgG4-related sclerosing mesenteritis. An 82-year-old woman was admitted to our hospital due to persistent abdominal pain. Abdominal computed tomography demonstrated a solitary mass with a maximal diameter of 11.7 cm in mesentrium of the small intestine. On her laboratory examination, only C-reactive protein level was elevated. Although the pre-operative diagnosis was indefinite, she underwent ileocecectomy. Grossly, an elastic soft mass with foci of hemorrhage was seen in the mesentrium. Microscopically, the lesion was composed of fibroblastic or myofibroblastic spindle cells with abundant stromal fibrosis and inflammatory infiltrate, such as lymphocytes and plasma cells accompanied by lymphoid follicles with a germinal center. Obstructive phlebitis was observed. Immunohistochemically, numerous IgG4-positive plasma cells were observed, and the IgG4/IgG ratio was 75.9%. The serum level of IgG4 examined at post-operation was high. These findings suggested that this lesion was consistent with IgG4-related sclerosing mesenteritis.     

Chronic sclerosing sialadenitis of the submandibular gland: an entity of IgG4-related sclerosing disease

Chronic sclerosing sialadenitis typically involves the submandibular gland. It usually occurs in the middle-aged and elderly adults with a slight male predominance. Recent evidences have suggested that it is an entity of IgG4-related sclerosing disease and has distinct histopathological features, such as a dense lymphoplasmacytic infiltrate, sclerosis and obliterative phlebitis. It is important to discriminate this entity from other diseases, trying to give effective treatment to the patients. In this report, we described a patient having chronic sclerosing sialadenitis in the submandibular gland.     

Inflammatory aortic aneurysm: possible manifestation of IgG4-related sclerosing disease

In this study, we investigate the hypothesis that IgG4-related autoimmune reaction is involved in the formation of inflammatory aortic aneurysms (IAA). We obtained 23 cases of IAA and 11 cases of atherosclerotic aortic aneurysms (AAA) as control group. We evaluated the expression of IgG4 in both IAA study cases and AAA control cases. In addition, immunohistochemical expression of C-Kit, CD21, CD34, S-100 protein, SMA, vimentin, p53, beta-catenin, and ALK-1, and EBV-LMP1 expression by in situ hybridization were performed only in IAA cases. Of the 23 patients, 20 were males and 3 were females (M: F ratio 6.7:1); age ranged from 43 to 81 years (average 64.3 years). Histologically, all 23 cases of IAA formed a mass that displayed inflammatory myofibroblastic tumor-like features. All lesions stained strongly and diffusely for vimentin and SMA (100%); 17 stained strongly and focally for CD34 (74%); and all were negative for C-Kit, CD21, S-100 protein, p53, beta-catenin, EBV-LMP1, and ALK-1. The numbers of infiltrating IgG4-positive plasma cells in IAA cases exceed that of AAA cases. Score 3 (>50 plasma cells/one 40X field) of IgG4-positive plasma cells was only seen in IAA cases (13/23, 57%), whereas none of the 11 cases of AAA showed score 3 IgG4-positive plasma cells (P=0.0018, Fischer‘s exact test). Our findings suggest that IAA may be an aortic manifestation of the IgG4-related sclerosing disease. The high number of positive plasma cells, >50 plasma cells/one 40X field is more specific for the IAA than for AAA; however, lesser number can be seen in both IAA and AAA patients.     

IgG4-related sclerosing disease, an emerging entity: a review of a multi-system disease

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently defined emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. IgG4-RSD usually affects middle aged and elderly patients, with a male predominance. It is associated with an elevated serum titer of IgG4, which acts as a marker for this recently characterized entity. The prototype is IgG4-related sclerosing pancreatitis or autoimmune pancreatitis (AIP). Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, however practically any organ can be involved, including upper aerodigestive tract, lung, aorta, mediastinum, retroperitoneum, soft tissue, skin, central nervous system, breast, kidney, and prostate. Fever or constitutional symptoms usually do not comprise part of the clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). IgG4-RSD may potentially be rarely associated with the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies.     

Thyroid papillary carcinoma with solid sclerosing change in IgG4-related sclerosing disease

IgG4-related sclerosing disease (IgG4-RSD) is an inflammatory and fibrosing disorder characterized by lymphoplasmacytic inflammation with infiltration of various organs, including the pancreas, bile ducts, lung, kidney, and retroperitoneum. As for malignancy in IgG4-RSD, only limited literature is available. We report here a case of thyroid papillary carcinoma showing unique morphology in IgG4-RSD. Solid tumor nests were surrounded by dense IgG4-positive plasma cells and fibrosis at both the primary site and metastatic lymph nodes. In contrast the background thyroid showed focal lymphocytic thyroiditis. IgG4-related sclerosing sialadenitis and autoimmune pancreatitis were also diagnosed, and prednisolone treatment improved symptoms and serum IgG4 abnormality. To the best of our knowledge, this is the first documentation of a malignancy of the thyroid gland occurring in a background of IgG4-RSD. A brief review of the literature on the relationship between IgG4 and malignancy is included.     

IgG4-related systemic sclerosing disease – an emerging and under-diagnosed condition

Autoimmune pancreatitis was first described in 1961, although it was not more widely recognized as an autoimmune condition until 1995. It has now become apparent that this form of pancreatitis is part of a clinical syndrome that is commonly multisystem in nature. One of the most common histopathological features is the presence of IgG4+ plasma cells within involved tissues. Many terms have been proposed to describe the condition, but 'IgG4-related systemic sclerosing disease' appears most appropriate. Commonly affected extrapancreatic tissues include the biliary tract, liver, kidneys and lung, but a wide range of other sites may be involved. Histological examination reveals features that are not entirely disease-specific, but that are often sufficiently characteristic to provide useful support to a clinicopathological diagnosis. The disease often responds well to systemic steroid therapy, unlike some of the conditions that it may simulate clinically. The emergence of this disease as a specific and treatable entity has favourably altered the clinical outlook for patients in whom steroid therapy might not previously have been considered appropriate.     

Acquired reactive perforating collagenosis with the histological features of IgG4-related sclerosing disease in a patient with Mikulicz's disease

Acquired reactive perforating collagenosis has been reported in association with various conditions. To the authors' knowledge there has been no report of a patient with Mikulicz's disease showing acquired reactive perforating collagenosis. A 61-year-old Japanese man presented with non-pruritic multiple umbilicated papules with central keratotic and crusted plagues on the trunk, neck, and scalp. He had been diagnosed with Mikulicz's disease. Histologically, cutaneous biopsy showed a shallow cup-shaped lesion with a central crusted ulceration containing degenerated collagen in vertical strands, parakeratotic horny material, neutrophils, basophilic granular debris and elimination of collagen bundles from the dermis through to the epidermis. These clinical and histological findings suggested reactive perforating collagenosis. In addition, lymphocytes and plasma cells had infiltrated the dermis, with a tendency to be distributed around the sweat glands, accompanied by sclerotic fibrosis. On immunohistochemistry most plasma cells were positive for IgG and IgG4 (IgG4+/IgG+ plasma cells >50%). These histological findings of the skin were similar to findings previously reported for IgG4-related sclerosing diseases in other organs. Herein is described the first case of a patient with Mikulicz's disease showing acquired reactive perforating collagenosis accompanied by the histological features of IgG4-related sclerosing disease.     

Nodular intra-abdominal panniculitis: an accompaniment of colorectal carcinoma and diverticular disease

Intra-abdominal panniculitis is a tumour-like inflammatory condition of adipose tissue. The aetiology and pathogenesis of the disease is unknown, but a number of associated diseases have been recorded. It has been customary to deal with only primary cases in the literature. This study was undertaken in order to describe the entire spectrum of the disease including primary as well as secondary cases. Eleven patients are reported, nine of which had an associated colorectal disease in direct continuity with areas of intra-abdominal panniculitis. It is concluded that intra-abdominal panniculitis should not be regarded as a specific nosological entity but merely a result of injury to the fat cells. Intra-abdominal panniculitis is seen more often as a secondary local phenomenon than as a primary condition, and in both cases it is associated with considerable differential diagnostic problems. Primary diseases involved are, among others, colorectal carcinoma and diverticulosis. The aetiologic agent(s) are still unknown, but substances liberated from a damaged bowel might play a pathogenetic role.     

Immunology of IgG4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4⁺ plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.     

IgG4相关性疾病临床病理学特征分析

目的：探讨IgG4相关性疾病的病理学形态、免疫表型特征。方法观察12例IgG4相关性疾病的镜下特点,结合免疫组化EnVision两步法染色检测IgG、IgG4、CD138、CD34的表达,分析IgG4相关性疾病的病理学形态特征。结果 IgG4相关性疾病主要表现为组织弥漫性纤维化;伴大量淋巴细胞、浆细胞浸润,围绕血管神经分布;闭塞性静脉炎形成,免疫组化EnVision两步法染色IgG4阳性浆细胞与IgG阳性浆细胞比例>40%。结论 IgG4相关性疾病临床特点和影像学无特异性,易误诊为肿瘤,术前血清IgG4检测可作为疑似病例的首选方法。     

A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis)

There is now increasing evidence that IgG4 is closely involved in idiopathic sclerosing lesions, such as sclerosing pancreatitis and sclerosing sialadenitis. In this report, we describe a case of IgG4-related retroperitoneal and mediastinal fibroses. A 52-year-old man presented with dull back pain and was found to have a continuously surrounding paraaortic mass. A biopsy specimen taken from the retroperitoneum showed a diffuse lymphoplasmacytic infiltration intermixed with fibrosis. Many IgG4-positive plasma cells were demonstrated on immunostaining. His serum IgG4 concentration was 392 mg/dL (reference range, <70). We treated this patient with a corticosteroid, which markedly diminished the paraaortic mass along with lowering of his serum IgG4 concentration. The possible involvement of IgG4 was suggested in the pathogeneses of retroperitoneal and mediastinal fibroses in this patient. IgG4 might be useful in the clinical management of retroperitoneal or mediastinal fibrosis to differentiate them from malignant tumors and predict steroid sensitivity.     

Concomitant occurrence of IgG4-related pleuritis and periaortitis: a case report with review of the literature

IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Some recent reports have demonstrated that this disease can occur in the respiratory system including the pleura. Herein, we describe the first documented case of concomitant occurrence of IgG4-related pleuritis and periaortitis. A 71-year-old Japanese female with a history of essential thrombocythemia presented with persistent cough and difficulty in breathing. Computed tomography demonstrated thickening of the right parietal pleura, pericardium, and periaortic tissue and pleural and cardiac effusions. Histopathological study of the surgical biopsy specimen of the parietal pleura revealed marked fibrous thickening with lymphoplasmacytic infiltration. Phlebitis was noted, however, only a few eosinophils had infiltrated. Immunohistochemical study revealed abundant IgG4-positive plasma cell infiltration and high ratio of IgG4-/IgG-positive plasma cells (84%). Therefore, a diagnosis of IgG4-related pleuritis was made with consideration of the elevated serum IgG4 level (684 mg/dL). Recently, the spectrum of IgG4-related sclerosing disease has expanded, and this disease can occur in the pleura, pericardium, and periaortic tissue. Although histopathological analysis of the pericardium and periaortic tissue was not performed in the present case, it was suspected that thickening of the pericardium and periaortic tissue was clinically due to IgG4-related sclerosing disease. Our clinicopathological analyses of IgG4-related pleuritis and pericarditis reveal that this disease can present as dyspnea and pleural and pericardial effusion as seen in the present case, therefore, it is important to recognize that IgG4-related sclerosing disease can occur in these organs for accurate diagnosis and treatment.     

Ocular adnexal IgG4-related disease: comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions

Go H, Kim J E, Kim Y A, Chung H K, Khwarg S I, Kim C‐W & Jeon Y K
(2012) Histopathology  60, 296–312
Ocular adnexal IgG4‐related disease: comparative analysis with mucosa‐associated lymphoid tissue lymphoma and other chronic inflammatory conditions Aims: Making a differential diagnosis of IgG4‐related disease from mucosa‐associated lymphoid tissue (MALT) lymphoma or any other chronic inflammation is often challenging. Moreover, the association with secondary lymphoma of ocular adnexal IgG4‐related disease needs to be elucidated. Methods and results: We investigated 14 cases of IgG4‐related disease, nine MALT lymphomas and 12 other chronic inflammations involving the lacrimal gland and orbit. Bilateral involvement was frequent in IgG4‐related diseases. The number of IgG4‐positive cells and the ratio of IgG4/IgG‐positive cells were higher in patients with IgG4‐related disease than in those with MALT lymphoma (P = 0.016; P < 0.001) and other types of inflammation (P < 0.001; P < 0.001). Monoclonal B cell proliferation was suspected in two cases (14.3%) of IgG4‐related disease. One of these patients also displayed monomorphous features suggesting secondary MALT lymphoma. In the other case, κ‐chain restriction in IgG4‐positive cells was observed, raising the possibility of IgG4‐producing MALT lymphoma. Trisomy 3, trisomy 18 or MALT1 translocation was observed in none of the IgG4‐related cases. Regulatory T‐cell infiltration was higher in cases of IgG4‐related disease than in MALT lymphomas (P < 0.001) and other types of inflammation (P = 0.006). Conclusions: Some genetically and morphologically complicated cases of ocular adnexal IgG4‐related disease emphasize the need for in‐depth studies to differentiate this disease from MALT lymphoma, and to exclude secondary lymphoma.     

IgG4-related renal disease: clinical and pathological characteristics

IgG4-related disease is a recently established systemic condition. Tubulointerstitial nephritis is the most common renal manifestation. Glomerular lesions, particularly membranous glomerulonephritis, can develop simultaneously. Some patients present with serological renal dysfunction associated with elevated IgG or IgE levels and hypocomplementemia, while others are incidentally found to have abnormalities in kidneys on imaging. A majority of patients with IgG4-related kidney disease have similar lesions at other anatomical sites, which help us to suspect this condition. Serum IgG4 elevation (>135 mg/dL) is the most, although not entirely, specific marker for the diagnosis. Imaging findings varies from small nodules to bilateral diffuse abnormalities. In addition to the renal parenchyma, the renal pelvis and perirenal adipose tissue can be affected. Histological features include dense lymphoplasmacytic infiltration, storiform or “bird’s eye” fibrosis (highlighted by PAM stain), and IgG4-positive plasma cell infiltration (>10 cells/high-power field and IgG4/IgG-positive cell ratio >40%). Immune complex deposition is detectable in the tubular basement membrane by immunofluorescence and/or electron microscopy. Patients usually respond well to corticosteroids, but highly active diseases may require other immunosuppressive therapies. Further investigations will be required to fully understand pathophysiology underlying this emerging condition.     

Lymphadenopathy associated with IgG4-related disease: Diagnosis & differential diagnosis

IgG4-related sclerosing disease, which now encompasses diverse organ-related disorders with various prior eponymic designations, may also present with solitary or multifocal lymph node enlargement. This review considers the histopathologic features of IgG4 lymphadenopathy (IgG4LAD), which has been subdivided by Cheuk & Chan into 5 microscopic subtypes. Those include variants that are typified by multicentric Castleman disease (MCD)-like changes, follicular hyperplasia, interfollicular lymphoplasmacytic proliferation, progressive transformation of germinal centers, and formation of inflammatory pseudotumor (IPT)-like lesions. All of them demonstrate an excess of IgG4-immunoreactive plasma cells in the inflammatory cell population. Differential diagnostic considerations for IgG4LAD include true MCD, true IPT, luetic lymphadenitis, Rosai-Dorfman disease, and inflammatory myofibroblastic tumor, among others. An interpretative distinction between malignant lymphoma and IgG4LAD is also crucial.     

New insights into the pathophysiology of IgG4-related disease and markers of disease activity

Introduction: Recently, IgG4-related disease (IgG4-RD) has become a well-recognized clinical entity, although its causes are still not well understood. The pathophysiology of IgG4-RD has been reported from a variety of aspects.

Areas covered: In this review, we outline a number of recent advances in our understanding of the pathogenesis of IgG4-RD, divided according to acquired immunology and innate immunology and other topics. Furthermore, we also focus on some proposed markers of disease activity of IgG4-RD.

Expert commentary: One striking advance made recently is the identification of novel autoantigens of IgG4-RD. At the onset of IgG4-RD, various T cell side factors such as Tfh, Th2 cells are at work, in addition to B cell side factors like plasmablasts and plasma cells, and innate immunology via TLR and M2 macrophages. The efficacy of B cell depletion therapy using rituximab has been reported, with the establishment of steroid-sparing therapies targeting other molecules also anticipated.