Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease

IgG4-related sclerosing disease is a recently recognized inflammatory lesion frequently involving pancreas, submandibular gland, lacrimal gland, and lymph node. We report 3 cases of ocular adnexal lymphoma arising in IgG4-related chronic sclerosing dacryoadenitis, a phenomenon that has not been previously reported. The patients presented with bilateral or unilateral ocular adnexal mass usually present for many years. One patient also had asymptomatic diffuse lymphadenopathy. Two patients had biopsy-proven IgG4-related chronic sclerosing dacryoadenitis before the current presentation, and 1 had systemic involvement by IgG4-related sclerosing disease as evidenced by increased IgG4+ cells in a prior nasopharyngeal biopsy. Two cases showed features of extranodal marginal zone lymphoma of mucosa-associated lymphoid-tissue type (1 with large cell transformation) and 1 follicular lymphoma. Thus, the lymphoid hyperplasia of IgG4-related sclerosing disease can provide a substrate for the emergence of lymphoma. In addition, we report 3 cases of ocular adnexal extranodal marginal zone B-cell lymphoma that show sclerosing inflammation in the background and numerous IgG4+ monotypic plasma cells. In the absence of prior biopsies or information on serum IgG4 titer, it is unclear whether these cases represent lymphoma complicating IgG4-related sclerosing disease or de novo lymphoma. Nonetheless, these cases are distinctive in that the neoplastic cells express IgG4 (light chain restricted), whereas unselected cases of ocular adnexal lymphomas do not show IgG4 expression.     

Not All Küttner Tumors Are IgG4-Related Disease (IgG4-RD)

Küttner tumor is an uncommon cause of salivary gland enlargement that most frequently affects the submandibular gland. More recently it has been considered a manifestation of IgG4-related disease (IgG4-RD) and synonymous with chronic sclerosing sialadenitis (CSS). We present a series of cases to emphasize this clinical entity as a disease pattern and presentation that is separate from IgG4-RD. Retrospective case series of 3 patients with unilateral salivary gland enlargement, or “Küttner tumor,” histologically classified as “chronic sclerosing sialadenitis,” The clinical history, radiology reports, laboratory studies, and pathology slides were reviewed for each case. Radiology showed discrete unilateral mass-like lesions in all three cases. Immunohistochemistry showed reduced tissue IgG4-positive plasma cells in two cases and increased numbers in one case, but insufficient to diagnose IgG4-RD. Storiform fibrosis was not seen in all cases and did not coincide with increased IgG4-positive plasma cells. A systemic workup, including serum IgG4 levels in two cases, was normal. A brief review of the literature on the spectrum of salivary gland involvement by IgG4-RD is presented. Küttner tumor is not necessarily the same as chronic sclerosing sialadenitis and is not always associated with IgG4-related disease. This report includes the second documented case of Küttner tumor of the sublingual gland.     

误诊为胆管肿瘤的两例IgG4相关性胆管炎的诊治分析

目的 通过分析两例术前误诊为胆管肿瘤的IgG4相关性胆管炎的诊治经验和教训,初步探讨IgG4相关性胆管炎疾病的诊断要点和治疗策略.方法 总结2013年3月-2013年4月在南京大学医学院附属鼓楼医院肝胆外科就诊的2例IgG4相关性胆管炎的临床资料,包括病史、体征、实验室检查.重点回顾手术探查、术式选择、术后病理及免疫学指标以及对诊断治疗的意义.结果 2例术前的影像学检查均高度怀疑高位胆管肿瘤.其中1例因病灶位于右肝管而以胆管癌根治的标准行右半肝切除,及高位胆肠吻合术,术后病理诊断为IgG4相关性胆管炎.另1例病灶位于肝总管,行肿块局部切除术,术后病理及免疫学指标均提示为IgG4相关性胆管炎.术后恢复顺利,痊愈出院.结论 IgG4相关性胆管炎是较为罕见的自身免疫性疾病,重点需要与胆管癌鉴别诊断,手术治疗具有临床意义,激素应用在术后恢复治疗中起到一定的作用.     

Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis

Inflammatory abdominal aortic aneurysm (AAA) is a member of a family of disorders referred to as "chronic periaortitis" together with retroperitoneal fibrosis. Retroperitoneal fibrosis is included in IgG4-related disease, which is characterized by numerous infiltrating IgG4-positive plasma cells and high serum IgG4 concentrations. However, the relationship between IgG4-related disease and inflammatory AAA has not been documented. In this study, we examined the clinicopathologic characteristics of inflammatory (10 cases) and atherosclerotic (22 cases) AAAs, based on the hypothesis that inflammatory AAA might be related to IgG4-related disease. Cases of inflammatory AAA could be classified into 2 groups based on immunostaining of IgG4. Four patients showed diffuse infiltration of abundant IgG4-positive plasma cells (IgG4-related cases), whereas the remaining 6 cases of inflammatory AAA and all cases of atherosclerotic AAA had only a few IgG4-positive plasma cells (non-IgG4-related cases). IgG4-related inflammatory AAA was pathologically characterized by the frequent infiltration of eosinophils, lymph follicle formation, perineural inflammatory extension, and inconspicuous infiltration of neutrophils compared with non-IgG4-related inflammatory AAA. Obliterative phlebitis, which is venous occlusion with inflammatory cell infiltration, is observed in all IgG4-related cases. In addition, serum IgG4 concentrations were significantly higher in IgG4-related inflammatory AAA (109 to 559 mg/dL, normal range: 4 to 110 mg/dL) than non-IgG4-related inflammatory AAA (32 to 59 mg/dL) and all atherosclerotic AAA (12 to 83 mg/dL). In conclusion, inflammatory AAAs might be classified into 2 groups: IgG4-related or nonrelated. The former might be one of the IgG4-related diseases, and could be included in IgG4-related periaortitis together with retroperitoneal fibrosis.     

特发性腹膜后纤维化16例临床分析

目的 探讨特发性腹膜后纤维化(iRPF)临床特点、诊疗及转归,以提高临床诊断率,减少漏诊和误诊.方法 回顾分析在青岛大学附属医院住院确诊的16例iRPF患者,其中包括9例IgG4相关腹膜后纤维化患者.结果 iRPF多见于中老年男性,肾功能衰竭合并腰腹疼痛、体重减轻是最常见的临床表现.IgG4-RPF患者与非IgG4-RPF患者Hb、SCr、ESR、CRP组间比较差异无统计学意义.所有患者均存在CT或MRI下腹膜后软组织密度影;IgG4-RPF患者同时还可发现颌下腺、深部淋巴结、胰腺、胆管、胸腺、肾间质、甲状腺等多器官受累.病理学检查发现全部IgG4-RD患者不同受累器官均显示相同特点的改变,且其IgG4阳性的浆细胞计数、IgG4 +/IgG阳性浆细胞计数比例、席纹状纤维化例数较非IgG4-RPF患者有显著的统计学差异.8例行皮质类固醇和免疫抑制剂治疗;6例行药物及手术联合治疗;2例单纯手术治疗.所有接受皮质类固醇治疗的患者病情均缓解,其中2例停药后复发;但单纯外科治疗患者反复发作.结论 特发性腹膜后纤维化与IgG4-RD疾病谱有交集,但临床特点及普通影像学检查无法做出鉴别,需要进一步病理学检查.激素及免疫抑制剂对两者治疗均有效并可减少复发.     

Recurrent Mastoiditis Mimics IgG4 Related Disease: A Potential Diagnostic Pitfall

IgG4-related disease (IgG4-RD) is a recently recognized entity that causes progressive fibrosis and formation of mass lesions. IgG4-RD can be diagnosed histologically by its hallmarks of storiform fibrosis, prominent lymphoplasmacytic infiltrate, and obliterative phlebitis, accompanied by the infiltration of excessive numbers of IgG4-positive plasma cells as well as elevations in serum IgG4 concentrations. A recent publication reported a case of IgG4-RD in the mastoid sinus, representing a new anatomic location for this disease. We report two additional cases of IgG4-RD occurring in the mastoid and causing clinical mastoiditis. The presenting symptoms were varied—tinnitus, hearing loss, and cranial nerve palsies. All three cases showed a dense lymphoplasmacytic infiltrate, storiform type fibrosis as well as elevated numbers of IgG4 positive plasma cells. The three patients responded to immunosuppressive therapy that included steroids and Rituximab. We further investigated 162 consecutive mastoiditis cases at our institution in order to determine the frequency of IgG4-RD as a previously unrecognized cause of mastoiditis. Within this latter cohort we identified nine cases of mastoiditis that had two of the histologic features of IgG4-RD, specifically storiform fibrosis and a dense lymphoplasmacytic infiltrate. Two of these cases showed >50 IgG4-positive plasma cells per high-power field with IgG4–IgG ratio of >40 %, thus fulfilling histological criteria for IgG4-RD. However, both were due to severe acute or chronic infection. In conclusion, we reaffirm IgG4 related mastoiditis as a distinct but uncommon cause of recurrent mastoiditis. The diagnosis of IgG4-related mastoiditis should be rendered with caution, and only after the exclusion of potential mimickers, particularly infection.     

IgG4-related tubulointerstitial nephritis

Tubulointerstitial nephritis (TIN) is a disease pattern with heterogeneous causes. Recently a specific subtype of autoimmune TIN, IgG4-related TIN, has been identified that is part of systemic IgG4-related disease/ autoimmune pancreatitis. On biopsy, this TIN shows an IgG4+ plasma cell-rich infiltrate, akin to the pancreatic tissue findings in autoimmune pancreatitis, and may show tubulointerstitial immune complex deposits. Notably, some cases may be mass-forming. Recognition of this specific type of TIN can guide appropriate patient therapy.     

Lymphadenopathy of IgG4-related sclerosing disease

IgG4-related sclerosing disease is a recently recognized syndrome characterized by mass-forming lesions in exocrine glands or extranodal tissues due to lymphoplasmacytic infiltrates and sclerosis, a raised serum IgG4 level and increased IgG4+ plasma cells in the involved tissues. We report the morphologic features of the enlarged regional (n=3) and nonregional lymph nodes (n=3) in patients with this syndrome. The patients presented with autoimmune pancreatitis, lymphoplasmacytic sclerosing cholangitis, chronic sclerosing dacryoadenitis, or chronic sclerosing sialadenitis. The histologic features of the lymph nodes could be categorized into 3 patterns: Castleman diseaselike, follicular hyperplasia, and interfollicular expansion by immunoblasts and plasma cells. The percentage of IgG4+/IgG+ plasma cells was markedly elevated (mean 62% vs. 9.9% in 54 control lymph nodes comprising a wide variety of reactive conditions). We also report 6 cases of primary lymphadenopathy characterized by increased IgG4+/IgG+plasma cells (mean 58%). These cases share many clinical and pathologic similarities with IgG4-related sclerosing disease. In fact, 2 of these patients developed lymphoplasmacytic sclerosing cholangitis or lacrimal and submandibular gland involvement during the clinical course. These cases therefore probably represent primary lymph node manifestation of the disease. The importance of recognition of the lymphadenopathic form of IgG4-related sclerosing disease lies in the remarkable response to steroid therapy, and the potential of mistaking the disease for lymphoma either clinically or histologically.     

Surgical treatment for a patient with immunoglobulin G4-related lung disease

Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune fibroinflammatory disease, and isolated lung disease is a rare phenomenon. IgG4-RD frequently mimics primary pulmonary malignancy. It has been described in association with malignancies, including lung cancer, but it remains unclear if it increases the risk of malignancy. We report the case of a patient who had a left lower lobectomy after relapse while receiving corticotherapy. The pathological findings confirmed the diagnosis of IgG4-RD. After 2 months, the thoracic computerized tomography scan showed an important left pleural effusion that could be a consequence of the recent intervention or a relapse of IgG4-RD.     

Immunoglobulin-G4 related mastitis: A case report

IntroductionIgG4-related mastitis (IgG4-RM) is exceedingly rare with only ten cases reported in the literature to date. Organs that are affected with IgG4-related disease (IgG4-RD) all share the same histopathological hallmarks consisting of dense lymphocytic infiltration, storiform fibrosis and obliterative phlebitis.Presentation of caseThis case report highlights a case of IgG4-RM found incidentally in a 52-year-old woman during a routine breast screen and it explores the current literature about IgG4-RM and IgG4-RD.DiscussionIgG4-RM and IgG4-RD, in general, is a new entity in the field of medicine and its aetiology is not well understood. In the literature, IgG4-RM often presents as a painless palpable breast lump in isolation or with other systemic manifestations. IgG4-RM is considered benign and has excellent prognosis post-conservative treatment with steroid or surgical excision.ConclusionIgG4-RM is diagnosed exclusively on histological analysis. It is hard to distinguish IgG4-RD from malignant breast lesions purely on clinical examination and imaging studies. Increasing awareness of this condition among clinicians will assist them in managing patients better. Extensive whole body imaging is not recommended unless symptomatic.     

IgG4相关性甲状腺疾病

目的总结IgG4相关性甲状腺病与IgG4关系的研究进展。方法收集近年来国内外关于IgG4相关性甲状腺病的病理特征及其与IgG4关系的相关文献并作综述。结果IgG4相关性疾病是一类新近被认识的与IgG4淋巴细胞密切相关的慢性、系统性疾病,可单发,也可累及甲状腺及全身多个器官。在桥本甲状腺炎、里德尔甲状腺炎及甲状腺乳头状癌病灶中均发现了IgG4的表达。结论IgG4相关性甲状腺病是对甲状腺炎疾病的一种新的认识,对其的了解有助于对甲状腺炎患者提供合理的治疗手段。     

IgG4-related disease

The term “IgG4-related disease” encompasses several disorders described many years ago under various designations depending on the organ or system involved (e.g., Mikulicz syndrome, Riedel's thyroiditis, and retroperitoneal fibrosis). The clinical presentation varies widely, as one or more organs may be affected, usually in the same region of the body and either synchronously or metachronously. The main targets are the pancreas, bile ducts, salivary glands, lachrymal glands, mediastinal lymph nodes, and retroperitoneum. IgG4-related disease is rare, with an estimated incidence of 0.2 to 1/100 000 in Japan and no available incidence data in occidental countries. Men older than 50 years are predominantly affected. Serum IgG4 levels are often greater than 1.35 g/L. Enlargement of the involved organs, which may be pseudotumoral, is due to a combination of infiltration by T cells and IgG4-expressing plasma cells, storiform fibrosis, and obliterative thrombophlebitis. Glucocorticoid therapy is effective but may be followed by relapses requiring the use of immunomodulating agents such as azathioprine, methotrexate and, more recently, rituximab. IgG4-related disease is not an autoimmune condition related to IgG4 autoantibodies, and neither does it involve immune complexes. Specific joint involvement has been reported in a very small number of patients.     

Therapeutical options in lithiasic biliary fistula

Chronic lythiasic cholecystitis is a disease distinguished by the pathologic changes because of the chronic inflammation of the biliary extrahepatic tree. Sometimes these morphological changes are associated with internal biliary fistulas arising spontaneously in patients with advanced calculus cholecystitis. The vast majority of fistulas result from the adherence of the inflamed gallbladder or common bile duct to an adjacent viscus and erosion of the gallstones into the adherent organ. The authors analyze an amount of 43 patients with bilio-biliary and bilio-digestive lythiasic fistulas, caused by the long evolution of chronic lythiasic atrophic cholecystitis, for 126 cases which were operated in the Surgery Department of the Caritas Clinic Hospital along 20 years. In these 126 cases the surgical strategy was determinated by the method of dealing with the pericolecystitis sclerotic blocks, by the identification methods of the biliary elements and by the approach of the main billiary way and digestive loops injuries occurred after suppressing the fistulae. The surgical solutions adapted for each separate case and the advantages of the axial drainage of prostheting the surgical reconstructions of the main biliary way as well as the results obtained along this project, are in fact the aims of this presentation.     

Xanthogranulomatous cholecystitis: A rare condition with variable presentations

Aim: Patients suffering from xanthogranulomatous cholecystitis have variable clinical presentations. The present study aims to evaluate the clinical presentations of the disease and the various surgical treatment strategies in the management of patients suffering from xanthogranulomatous cholecystitis. Methods: This is a retrospective study in a university teaching hospital and a tertiary referral centre. The histopathological records of 5016 resected gallbladder specimens from January 1991 to June 2007 were reviewed and case notes of patients with a diagnosis of xanthogranulomatous cholecystitis were retrieved. Results: Eighty‐six patients with xanthogranulomatous cholecystitis were identified. The spectrum of presentation was variable and a high proportion of patients had complicated pathology. Patients commonly presented with obstructive jaundice or acute cholecystitis. The proportion of patients with diabetes mellitus who presented with acute cholecystitis was higher than the local prevalence in this study. Conversion rate in laparoscopic cholecystectomy was also higher for patients with xanthogranulomatous cholecystitis. Conclusion: The clinical presentation of xanthogranulomatous cholecystitis is variable. The disease commonly presents as obstructive jaundice or acute cholecystitis but it may mimic carcinoma of the gallbladder. The disease carries a higher rate of conversion if laparoscopic cholecystectomy was attempted.     

Research Progress on IgG4-Related Hashimoto's Thyroiditis

IgG4-related disease is a systemic autoimmune disease with unknown cause and involves multiple organs and tissues. This disease became one of research hotspots in the last ten years. IgG4-related Hashimoto's thyroiditis(HT) exhibits unique clinical pathological characteristics: serum-free thyroxine reduction and increases in thyroid peroxidase antibody and IgG4; massive IgG4-positive plasmocyte infiltration in tissues; significant matrix fibrosis; and severe degeneration of thyroid follicular epithelium. IgG4-related HT is a subtype of HT; it presents relatively good therapeutic effect after thyroxine treatment.Cortical hormones can be used for IgG4 HT patients who may suffer from hypothyroidism with significant thyroid injury during early stage to constrain immune injury. This thesis summarizes clinical and pathological histology of IgG4-related HT based on its characteristics.     

Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor)

Chronic sclerosing sialadenitis (CSS) is a cryptogenic tumor-like condition of the salivary gland(s). While immune-mediated processes are suspected in its pathogenesis, and CSS is occasionally reported to be associated with sclerosing pancreatitis, an IgG4-related disease, the exact immunopathologic processes of CSS remain speculative. In this study, we examined the clinicopathologic findings of CSS (12 cases) in comparison with sialolithiasis (8 cases) and Sjogren's syndrome (13 cases), and tried to clarify whether CSS is an IgG4-related disease or not. Submandibular gland(s) were affected in all cases of CSS. CSS cases could be divided into two types: 5 cases were associated with sclerosing lesions in extrasalivary glandular tissue (systemic type), while only salivary gland(s) were affected in the remaining 7 cases (localized type). In the former type, which showed male predominance, bilateral salivary glands were frequently affected, and eosinophilia and elevations of gamma-globulin and IgG in serum were frequently found. Histologically, all cases of CSS showed marked lymphoplasmacytic infiltration admixed with fibrosis and the destruction of glandular lobules. Obliterative phlebitis was found in the affected salivary glands in all cases of CSS. Immunohistochemically, the proportion of IgG4/IgG-positive plasma cells was more than 45% in CSS, while it was less than 5% in controls. The resemblance of the clinicopathologic features of CSS with those of sclerosing pancreatitis suggests the participation of a similar immunopathologic process with IgG4 disturbance in CSS. The abundance of IgG4-positive plasma cells in the lesions would be useful for distinguishing CSS from other forms of sialadenitis.     

Pancreatic and biliary tract involvement in IgG4-related disease

The diagnosis and treatment of pancreatic and biliary tract involvement in IgG4 disease can be challenging for physicians. A French series shows that the pancreas is the most frequently involved organ in systemic IgG4 disease. Pancreatitis may be found in more than 50% of patients with IgG4 disease and the biliary tract is involved in one third. Pancreatic or biliary involvement may be isolated, metachronous or synchronous of other IgG4-related organ injuries. Pancreatitis related to IgG4 disease is called autoimmune pancreatitis (AIP) type 1. The diagnosis is mainly suspected in the presence of symptoms and morphological features. Changes observed on conventional imaging are not typical and are usually similar to lesions observed in autoimmune pancreatitis type 2. AIP type 1 can also sometimes have a clinical or morphological presentation that mimics pancreatic cancer, especially pseudo-tumoral forms, associated with obstructive jaundice, weight loss and fatigue. Thus, the first challenge is to confirm the diagnosis of autoimmune pancreatitis and to exclude cancer. The AIP type must then be determined to decide on the most appropriate treatment.     

IgG4-related disease of the ileocecal region mimicking malignancy: A case report

INTRODUCTION

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease characterized by chronic fibrosing inflammation with abundant IgG4-positive plasma cells, and responds well to steroids. Previous reports of IgG4-RD have focused on pancreatic and extrapancreatic including the gastrointestinal tract, however, the colonic IgG4-RD is rare.

PRESENTATION OF CASE

We herein report the case of a 74-year-old female with edematous wall thickening of the terminal ileum to the lower ascending colon confirmed by several preoperative imaging studies, who underwent right hemi-colectomy for suspected malignant lymphoma. The resected specimen showed an irregular wall thickness with subserosal sclerosis, and the lesion was 10 cm in length from the terminal ileum to the ascending colon. The patient was diagnosed with IgG4-RD by pathological examinations, which demonstrated an increased number of IgG4-positive plasma cells (150/HPF), and an elevated IgG4/IgG ratio (50%).

DISCUSSION

Gastrointestinal IgG4-RD appears to be difficult to diagnose prior to surgical resection because of its rarity, and the similarity of its features to malignancy.The measurement of the serum IgG4 levels, immunohistochemical examination of biopsy specimens and use of several imaging modalities might help us to diagnose the disease without surgical resection, and this disease can generally be treated with steroid therapy. However, surgical resection for IgG4-RD may still be also necessary for patients with concerns regarding malignancy or with intractable gastrointestinal obstruction caused by this disease.

CONCLUSION

Gastrointestinal IgG4-RD often mimics malignancy, and we should therefore consider this disease in the differential diagnosis of colonic lesions in order to optimize the treatment.